JMCP
■ Journal of Managed Care Pharmacy ■ April 2009 ■ Vol. 15, No. 3 ■ Pages 221-296
volume fifteen • number three
April 2009
Peer-Reviewed Journal of the
Academy of Managed Care Pharmacy
Page
244 Meta-Analysis to Assess the Quality of Warfarin Control in
275 Standardizing Quality Assessment of Observational Studies for
253 Analysis of Drug Content and Weight Uniformity for
284 Omalizumab Has a Place in Therapy for Asthma Disease
262 Adherence to International Antimicrobial Prophylaxis
289 Omalizumab and Other New Drug Therapies Occupy a Small
Atrial Fibrillation Patients in the United States
Half-Tablets of 6 Commonly Split Medications
Guidelines in Cardiac Surgery: A Jordanian Study
Demonstrates Need for Quality Improvement
272 Tablet Splitting: Much Ado About Nothing?
Decision Making in Health Care
Management
Space in Asthma Disease Management
294 Selling Real-World Health Care Research to Reluctant Buyers—
Evidence-Based Education or Marketing a Defective Product?
AMCP Headquarters
100 North Pitt St., Suite 400
Alexandria, VA 22314
Tel: 703.683.8416 • Fax: 703.683.8417
Volume 15, No. 3
Board of Directors
C ONTENTS
■ RESEARCH
244 Meta-Analysis to Assess the Quality of Warfarin Control in Atrial
Fibrillation Patients in the United States
William L. Baker, PharmD, BCPS; Deborah A. Cios, PharmD; Stephen D. Sander, PharmD;
and Craig I. Coleman, PharmD
253 Analysis of Drug Content and Weight Uniformity for Half-Tablets of 6
Commonly Split Medications
Shaynan W. Hill, PharmD; Andrew S. Varker, PharmD; Kelly Karlage, BS; and Paul B. Myrdal, PhD
262 Adherence to International Antimicrobial Prophylaxis Guidelines
in Cardiac Surgery: A Jordanian Study Demonstrates Need for
Quality Improvement
Nairooz H. Al-Momany, MSc; Amal G. Al-Bakri, PhD; Zeid M. Makahleh, MD, MRCS;
and Mayyada M.B. Wazaify, PhD
228 Cover Impressions
Baseball Pitcher (1998)
Bill Hall
For advertising information, contact:
Peter Palmer
Professional Media Group, Inc., 52 Berlin Rd.,
Suite 4000, Cherry Hill, NJ 08034
Tel.: 856.795.5777, ext. 13
Fax: 856.795.6777
E-mail: [email protected]
Sheila Macho, Cover Editor
272 Commentary
Tablet Splitting: Much Ado About Nothing?
Robert P. Navarro, PharmD
275 Commentary
editorial
Standardizing Quality Assessment of Observational Studies for Decision Making
in Health Care
Diana I. Brixner, PhD, RPh; Anke-Peggy Holtorf, PhD, MBA; Peter J. Neumann, ScD;
Daniel C. Malone, PhD; and John B. Watkins, RPh, MPH, BCPS
284 Commentary
Omalizumab Has a Place in Therapy for Asthma Disease Management
Lawrence J. Pesko, MS, DSc, RPh
Annual subscription rates: USA, individuals,
institutions–$90; other countries–$110. Single
copies cost $15. Missing issues are replaced free
of charge up to 6 months after date of issue.
Send requests to AMCP headquarters.
Omalizumab and Other New Drug Therapies Occupy a Small Space
in Asthma Disease Management
Frederic R. Curtiss, PhD, RPh, CEBS
294 Editorial
reprints
Selling Real-World Health Care Research to Reluctant Buyers—
Evidence-Based Education or Marketing a Defective Product?
For article reprints and Eprints, contact Tamara
Smith at Sheridan Reprints, 800.352.2210,
ext. 8230; [email protected]. Microfilm and
microfiche editions of Journal of Managed Care
Pharmacy are available from University Microfilms,
300 N. Zeeb Rd., Ann Arbor, MI 48106. Reprint
Guidelines are available at www.amcp.org.
All articles published represent the opinions of the
authors and do not reflect the official policy or views of
the Academy of Managed Care Pharmacy or the authors’
institutions unless so specified. Copyright © 2009,
Academy of Managed Care Pharmacy. All rights
reserved. No part of this publication maybe reproduced or transmitted in any form or by any means,
electronic or mechanical, without written permission
from the Academy of Managed Care Pharmacy.
Kathleen A. Fairman MA, and Frederic R. Curtiss, PhD, RPh, CEBS
222 Journal of Managed Care Pharmacy
Questions related to editorial content should be
directed to JMCP Editor-in-Chief Frederic R. Curtiss:
[email protected].
Manuscripts should be submitted electronically
at jmcp.msubmit.net. For questions about
submission, contact Peer Review Administrator
Jennifer A. Booker: [email protected];
703.317.0725.
subscriptions
289 Editorial
Advertising
Advertising for Journal of Managed Care
Pharmacy is accepted in accordance with the
advertising policy of the Academy of Managed
Care Pharmacy.
■ Departments
President: Cathryn A. Carroll, PhD, MBA, BSPharm,
Comprehensive Pharmacy Services, Smithville,
MO
President-Elect: Shawn Burke, RPh, FAMCP,
Coventry Health Care, Inc., Kansas City, MO
Past President: Richard A. Zabinski, PharmD,
OptumHealth; a division of UnitedHealth Group,
Golden Valley, MN
Treasurer: C.E. (Gene) Reeder, RPh, PhD, FAMCP,
Xcenda-AmerisourceBergen Specialty Group,
Columbia, SC (JMCP liaison)
Secretary: Judith A. Cahill, CEBS,
Academy of Managed Care Pharmacy,
Alexandria, VA (Executive Director, AMCP)
Director: Jean Brown, RPh, PharmD,
Coventry Health Care, Flagstaff, AZ
Director: William K. Fleming, PharmD, RPh,
Humana, Inc., Prospect, KY
Director: Robert S. Gregory, RPh, MS, MBA,
Aetna, Inc., Hartford, CT
Director: Robert McMahan, PharmD, MBA,
Fidelis Care, Rego Park, NY
Director: Pete Penna, PharmD,
Formulary Resources, LLC, Mercer Island, WA
JMCP
April 2009
Vol. 15, No. 3
www.amcp.org
Editorial Mission
JMCP publishes peer-reviewed original research manuscripts, subject reviews, and other content intended to advance the use of the scientific method, including
the interpretation of research findings in managed care pharmacy. JMCP is dedicated to improving the quality of care delivered to patients served by managed
care pharmacy by providing its readers with the results of scientific investigation and evaluation of clinical, health, service, and economic outcomes of pharmacy
services and pharmaceutical interventions, including formulary management. JMCP strives to engage and serve professionals in pharmacy, medicine, nursing, and
related fields to optimize the value of pharmaceutical products and pharmacy services delivered to patients. JMCP employs extensive bias-management procedures
intended to ensure the integrity and reliability of published work.
Editorial staff
Editor-in-Chief
Frederic R. Curtiss, PhD, RPh, CEBS
830.935.4319, [email protected]
Associate Editor, Kathleen A. Fairman, MA
Peer Review Administrator, Jennifer A. Booker
602.867.1343, [email protected]
Cover Editor, Sheila Macho, 952.431.5993, [email protected]
Graphic Designer, Margie Hunter, 703.297.9319, [email protected]
703.317.0725, [email protected]
Publisher
Judith A. Cahill, CEBS, Executive Director, Academy of Managed Care Pharmacy
Editorial advisory board
The JMCP Editorial Advisory Board is chaired by Marvin D. Shepherd, PhD, Center for Pharmacoeconomic Studies,
College of Pharmacy, University of Texas at Austin; Thomas Delate, PhD, Kaiser Permanente of Colorado, Aurora, serves as vice chair.
They and the other advisers review manuscripts and assist in the determination of the value and accuracy of information provided to readers of JMCP.
Carl Victor Asche, PhD, MBA, College of Pharmacy, University of Utah,
Salt Lake City
John P. Barbuto, MD, HealthSouth Rehabilitation Hospital, Sandy, UT
Chris F. Bell, MS, Global Health Outcomes, GlaxoSmithKline Research
& Development, Research Triangle Park, NC
Joshua Benner, PharmD, ScD, Brookings Institution, Washington, DC
Eliot Brinton, MD, School of Medicine, University of Utah, Salt Lake City
Leslee J. Budge, MBA, Kaiser Permanente, Oakland, CA
Scott A. Bull, PharmD, ALZA Corporation, Mt. View, CA
Norman V. Carroll, PhD, School of Pharmacy, Virginia Commonwealth
University, Richmond, VA
Jingdong Chao, PhD, Abbott Laboratories, Abbott Park, IL
Eric J. Culley, PharmD, MBA, Highmark Blue Shield, Pittsburgh, PA
Gregory W. Daniel, RPh, MPH, PhD, HealthCore, Inc., Wilmington, DE
Quan V. Doan, PharmD, MSHS, Outcomes Insights, Inc., Orange, CA
Lida R. Etemad, PharmD, MS, UnitedHealth Pharmaceutical Solutions,
Edina, MN
Patrick R. Finley, PharmD, BCPP, University of California at San Francisco
Feride Frech-Tamas, MPH, Novartis Pharmaceuticals Corp.,
East Hanover, NJ
Patrick P. Gleason, PharmD, BCPS, Prime Therapeutics, LLC, Eagan, MN
Charnelda Gray, PharmD, BCPS, Kaiser Permanente, Atlanta, GA
Ann S. M. Harada, PhD, MPH, Prescription Solutions, Irvine, CA
Noelle Hasson, PharmD, Veterans Affairs Palo Alto Health Care System,
Palo Alto, CA
Lillian Hsieh, MHS, PharmD candidate, School of Pharmacy, University
of California, San Francisco
Mark Jackson, BScPharm, BComm, RPh, Green Shield Canada,
Windsor, Ontario
Richard A. Kipp, MAAA, Milliman USA, Wayne, PA
Stephen J. Kogut, PhD, MBA, College of Pharmacy, University of
Rhode Island, Kingston
Joanne LaFleur, PharmD, MSPH, College of Pharmacy, University of Utah,
Salt Lake City
Daniel C. Malone, PhD, RPh, College of Pharmacy, University of Arizona,
Tucson
Bradley C. Martin, PharmD, PhD, College of Pharmacy, University of
Arkansas, Little Rock
Lynda Nguyen, PharmD candidate, School of Pharmacy, University of
California, San Francisco
Robert L. Ohsfeldt, PhD, School of Rural Public Health, Texas A&M
Health Science Center, College Station
Steven Pepin, PharmD, BCPS, PharmWorks, LLC, Arden Hills, MN
Mary Jo V. Pugh, RN, PhD, South Texas Veterans Healthcare System,
San Antonio, TX
Brian J. Quilliam, PhD, RPh, College of Pharmacy, University of Rhode
Island, Kingston
Gene Reeder, RPh, PhD, Xcenda, Columbia, SC (AMCP Board Liaison)
Elan Rubinstein, PharmD, MPH, EB Rubinstein Associates, Oak Park, CA
Fadia T. Shaya, PhD, MPH, School of Pharmacy, University of Maryland,
Baltimore
Denise Sokos, PharmD, BCPS, School of Pharmacy, University of
Pittsburgh, PA
Brent Solseng, PharmD, BlueCross BlueShield of North Dakota, Fargo
Joshua Spooner, PharmD, MS, Advanced Concepts Institute, Philadelphia, PA
Marilyn Stebbins, PharmD, CHW Medical Foundation, Rancho Cordova,
CA; University of California, San Francisco
Kent H. Summers, RPh, PhD, School of Pharmacy, Purdue University,
West Lafayette, IN
Connie A. Valdez, PharmD, MSEd, Health Sciences Center, University of
Colorado, Denver
Robert J. Valuck, RPh, PhD, School of Pharmacy, University of Colorado
Health Sciences Center, Denver
Peter Whittaker, PhD, School of Medicine, Wayne State University,
Detroit, MI
Journal of Managed Care Pharmacy (ISSN 1083–4087) is published 9 times per year and is the official publication of the Academy of Managed Care Pharmacy (AMCP),
100 North Pitt St., Suite 400, Alexandria, VA 22314; 703.683.8416; 800.TAP.AMCP; 703.683.8417 (fax). The paper used by the Journal of Managed Care Pharmacy meets the
requirements of ANSI/NISO Z39.48-1992 (Permanence of Paper) effective with Volume 7, Issue 5, 2001; prior to that issue, all paper was acid-free. Annual membership dues
for AMCP include $60 allocated for the Journal of Managed Care Pharmacy. Postmaster: Send address changes to JMCP, 100 North Pitt St., Suite 400, Alexandria, VA 22314.
226 Journal of Managed Care Pharmacy
JMCP
April 2009
Vol. 15, No. 3
www.amcp.org
c o v e r
i m p r e s s i o n s
About our cover artist
Baseball Pitcher (1998) ■ Bill Hall
S
ports art occupies a special niche
painting software. And Wacom, the maker
within the fine art market. In an
of the electronic drawing tablet that Hall
article written for the April 2005
uses, features his paintings on their Web
issue of American Artist magazine, Daniel
site. In addition, his digital images have
Grant says that one of the major differences
been published in several industry “howbetween sports art and other fine art is the
to” books, including the Painter IX and
subject of autographs. Not only does the
Painter X Wow! books by Cher Threinendepicted athlete’s autograph increase the
Pendarvis, Digital Collage and Painting:
value of the artwork, but it also creates a
Using Photoshop and Painter to Create Fine
personal link between the fan and the athArt by Susan Ruddic Bloom, and Painter X
lete that most collectors desire.
Creativity by Jeremy Sutton.
Bill Hall got his start as a sports artist
Hall has become a master at capturwhen he created the advertising illustraing movement and action on his cantions for MasterCard at the 1994 World
vases. “Painting action allows me a certain
Cup soccer tournament. His work was
amount of freedom—I don’t have to be
“Painting action allows me a certain
amount of freedom . . .”
very well received, and commissions by
so literal with the subject,” he explains.
other corporations and individuals soon
“I can introduce elements of abstraction
followed. Hall’s numerous corporate clients include Chrysler, into my work that make it fresh and uniquely mine.” Hall’s specCoca-Cola, Dow Chemical, Federal Express, and the Malibu tacular Baseball Pitcher digital painting is a perfect example of
Speed Zone Racing theme parks in Georgia, Texas, and California. his signature style. Some of the broad streaks of color represent
“Businesses like to associate themselves with competition and the true colors of the outdoor scene, such as the brown pitching
success,” he says of the popularity of sports art. Hall has also mound and the green grass—yet other colors, like the red in
created illustrations for many different organizations and events, the foreground, serve a decorative purpose. His compositions
such as the San Antonio Stock Show and Rodeo, the Special are quite distinctive as well. In Baseball Pitcher, the figure’s right
Olympics, and the New York City Marathon. He produces prints foot extends beyond the background, which contributes to the
of his work which are sold through his Web site, billhall.com, image’s 3-dimensional effect. The blurred lines that indicate the
and through sports-memorabilia shops. His original paintings motion of the pitcher’s arm form a half circle, and draw one’s
and prints are available at the Evviva Art Gallery in Beverly Hills, eye toward the baseball that appears to be flying right out of the
California.
painting. In addition, the way that the artist has “colored outside
Hall was born and raised in the town of Bartlesville, Oklahoma, the lines” of the rectangular background lends a delightful, sponlocated about 45 miles north of Tulsa. “When I was very young, taneous feeling to the picture.
I realized that I liked to draw. It gave me a lot of enjoyment, so
Hall believes that his artistic inspiration comes from within.
I kept doing it. Eventually I became good at drawing,” he says. “Creating art is part of who I am. It’s like asking a bird why it
“When you’re good at something, people notice, and you get posi- flies. It flies because it can,” he says. Hall encourages beginning
tive feedback. Positive feedback gives you a feeling of worth, and artists to find their own style by determining what interests them
reinforces the enjoyment of creating. People should enjoy what most. “If you find that the work of another artist appeals to you,
they do for a living—therefore, I decided that I would become incorporate elements of it into the mix,” he advises. “But follow
an artist someday.” As a student, Hall was always the class artist; your own path. Let their influence be a signpost in your personal
teachers asked him to draw decorations on the chalkboard for journey, not a destination.” Hall has certainly followed his own
holidays and special occasions. When he was in his mid teens, his path—one that has led to tremendous success in sports art.
family moved to Dallas, Texas, where he took art classes at South
Sheila Macho
Oak Cliff High School. Several of Hall’s teachers encouraged him
Cover Editor
to continue his art education and get a degree. He did just that,
earning his bachelor of arts in art from the University of Texas at
COVER CREDIT
Arlington in 1970.
Bill Hall, Baseball Pitcher, digital painting. Cedar Hill, Texas, 1998.
Although Hall gained much of his notoriety as a traditional Copyright© Bill Hall/Corbis.
painter, he has become so accomplished at working digitally
that it is difficult to tell his Corel Painter X computer-generated SOURCES
art from his oil paintings once the images are printed. In fact, Interview with the artist.
Corel uses his digital artwork to promote their Painter X digital Grant, Daniel. “The Art of Sports.” American Artist. April 2005:73-75.
228 Journal of Managed Care Pharmacy
JMCP
April 2009
Vol. 15, No. 3
www.amcp.org
Jmcp Editorial Policy
■■ Editorial Content and Peer Review
All articles, editorials, and commentary
in JMCP undergo peer review; articles
undergo blinded peer review. Letters may
be peer reviewed to ensure accuracy. The
funda­mental departments for manuscript
submission are:
• Research
• Subject Reviews
• Formulary Management
• Contemporary Subjects
• Brief Communications
• Commentary/Editorials
• Letters
All submissions other than Editorials,
Commentary, and Letters should include
an abstract and inform the reader at the
end of the manuscript of what is already
known about the subject and what the
article adds to our knowledge of the subject.
For manuscript preparation requirements,
see “JMCP Author Guidelines” in this Journal
or at www.amcp.org.
■■ Research
These are well-referenced articles based
on original research that has not been
published elsewhere and reflect use of
the scientific method. The research is
guided by explicit hypotheses that are
stated clearly by the authors.
■■ Subject Reviews
These are well-referenced, comprehensive
reviews of subjects relevant to managed
care pharmacy. The Methods section in the
abstract and in the body of the manuscript
should make clear to the reader the source
of the material used in the review, including
the criteria used for inclusion and exclusion
of information.
ed i to r i a l M i s si o n a n d p o l i ci e s
JMCP publishes peer-reviewed original research manuscripts, subject reviews, and
other content intended to advance the use of the scientific method, including the
interpretation of research findings in managed care pharmacy. JMCP is dedicated
to improving the quality of care delivered to patients served by managed care
pharmacy by providing its readers with the results of scientific investigation and
evaluation of clinical, health, service, and economic outcomes of pharmacy services
and pharmaceutical interventions, including formulary management. JMCP strives to
engage and serve professionals in pharmacy, medicine, nursing, and related fields
to optimize the value of pharmaceu­tical products and pharmacy services delivered
to patients.
JMCP employs extensive bias-management procedures that include (a) full disclosure of all sources of potential bias and conflicts of interest, nonfinancial as well
as financial; (b) full disclosure of potential conflicts of interest by reviewers as well
as authors; and (c) accurate attribution of each author’s contribution to the article.
Aggressive bias-management methods are necessary to ensure the integrity and
reliability of published work.
Editorial content is determined by the Editor-in-Chief with suggestions from
the Editorial Advisory Board. The views and opinions expressed in JMCP do not
necessarily reflect or represent official policy of the Academy of Managed Care
Pharmacy or the authors’ institutions unless specifically stated.
■■ Brief Communications
The results of a small study or a descriptive
analysis that does not fit in other JMCP
departments may be submitted as a Brief
Communication.
■■ Editorials/Commentary
These submissions should be relevant to
managed care pharmacy and address a
topic of contemporary interest: they do
not require an abstract but should include
references to support statements.
■■ Letters
If the letter addresses a previously published
article, an author response may be appro­
priate. (See “Letter to the Editor” instruc­
tions at www.amcp.org.)
■■ Formulary Management
These are well-referenced, comprehensive
reviews of subjects relevant to formulary
management methods or procedures in the
conduct of pharmacy and therapeutics (P&T) ■■ Advertising/Disclosure Policy
committees and may include description
A copy of the full advertising policy for JMCP
and interpretation of clinical evidence.
is available from AMCP headquarters and the
Advertising Account Manager. All aspects of
■■ Contemporary Subjects
the advertising sales and solicitation process
These are well-referenced submissions that are completely independent of the editorial
are particularly timely or describe research process. Advertising is positioned either at
conducted in pilot projects. Contemporary the front or back of the Journal; it is not
Subjects, like all articles in JMCP, must
accepted for placement opposite or near
describe the hypothesis or hypotheses that subject-related editorial copy.
guided the research, the principal methods, Employees of advertisers may submit
and results.
articles for publication in the editorial
232 Journal of Managed Care Pharmacy
JMCP
April 2009
Vol. 15, No. 3
www.amcp.org
sections of JMCP, subject to the usual
peer-review process. Financial disclosure,
conflict-of-interest statements, and
author attestations are required when
manuscripts are submitted, and these
disclosures generally accompany the
article in abstracted form if the article
is published.
See “Advertising Opportunities” at
www.amcp.org. Contact the Advertising
Representative to receive a Media Kit.
Editorial Office
Academy of Managed Care
Pharmacy
100 North Pitt St., Suite 400
Alexandria, VA 22314
Tel.: 703.683.8416
Fax: 703.683.8417
E-mail: [email protected]
Advertising Sales Office
Professional Media Group, Inc.
52 Berlin Rd., Suite 4000
Cherry Hill, NJ 08034
Tel.: 856.795.5777, ext. 13
Fax: 856.795.6777
E-mail: [email protected]
JMCP Author Guidelines
JMCP accepts for consideration manuscripts prepared
according to the Uniform Requirements for Manu­
scripts Submitted to Biomedical Journals.1
■■ Manuscript Preparation
Manuscripts should include, in this order: title page,
abstract, text, references, tables, and figures (see
Submis­sion Checklist for details).
JMCP abstracts should be carefully written narratives
that contain all of the principal quantitative and
qualita­tive findings, with the outcomes of statistical
tests of comparisons where appropriate. Abstracts are
required for all articles in Research, Subject Reviews,
Formulary Management, Contemporary Subjects, and
Brief Commu­nications. The format for the abstract is
Background, Objective, Methods, Results, Conclusion.
Editorials and Commentary do not require an abstract
but should include references. Letters do not require an
abstract.
For descriptions of editorial content, see “JMCP
Editorial Policy” in this Journal or at www.amcp.org.
Please note:
•The JMCP Peer Review Checklist is the best guide for
authors to improve the likelihood of success in the
JMCP peer-review process. It is available at: www.
amcp.org (Peer Reviewers tab).
•A subsection in the Discussion labeled “Limitations”
is generally appropriate for all articles except
Editorials, Commentaries, and Letters.
•Most articles, particularly Subject Reviews, should
incorporate or at least acknowledge the relevant work
of others published previously in JMCP (see “Article
Index by Subject Category” at www.amcp.org).
• For most articles in JMCP, a flowchart is generally
necessary to make the effects of the inclusion and
exclusion criteria clear to readers – see JMCP examples
in 2007; 13(3):237 (Figure 1), or 2007; 13(1):22
(Figure 1), or 2006; 12(3):234 (Table 3).
• Product trade names may be used only once for the
purpose of providing clarity for readers, generally at
the first citation of the generic name in the article
but not in the abstract.
• Many articles involve research that may pose a threat
to either patient safety or privacy. It is the responsibility of the principal author to ensure that the manuscript is submitted with either the result of review by
the appropriate institutional review board (IRB) or
a statement of why the research is exempt from IRB
review (see JMCP Policy for Protecting Patient Safety
and Privacy at www.amcp.org).
■■ Reference Style
References should be prepared following modified
AMA style. All reference numbers in the manuscript
should be superscript (e.g., 1 ). Each unique reference
should have only one reference number. If that reference is cited more than once in the manuscript, the
same number should be used. Do not use ibid or op cit
for JMCP references. Please provide Web addresses for
references whenever possible. See the following examples of common types of references:
1. Journal articles — (list up to 6 authors; if more, list
only the first 3 and add et al.)—Kastelein JJP, Akdim F,
Stroes ESG, et al., for the ENHANCE Investigators.
Simvastatin with or without ezetimibe in familial hyper­
cholesterolemia. N Engl J Med. 2008;358(14):1431-43.
2. No author given — Anonymous. Top 25 U.S. hospitals, ranked by admissions, 1992. Manag Healthcare.
1994;4(9):64.
3. Journal paginated by issue — Gregory DW,
Malone DC. Characteristics of older adults who meet
the annual prescription drug expenditure threshold for
236 Journal of Managed Care Pharmacy
JMCP
The Journal of Managed Care Pharmacy,
including supplements, is indexed by MEDLINE/
PubMed, the International Pharmaceutical
Abstracts (IPA), Science Citation Index
Expanded (SCIE), Current Contents/Clinical
Medicine (CC/CM), and Scopus.
Medicare medication therapy management programs.
J Manag Care Pharm. 2007;13(2):142-54. Available at:
www.amcp.org/data/jmcp/p142-54.pdf.
4. Book or monograph by authors — Tootelian DH,
Gaedeke RM. Essentials of Pharmacy Management.
St. Louis, MO: C.V. Mosby; 1993.
5. Book or monograph with editor, compiler, or
chairperson as author — Chernow B, ed. Critical Care
Pharma­cotherapy. Baltimore, MD: Williams & Wilkins;
1995.
6. Chapter in a book — Kreter B, Michael KA, DiPiro
JT. Antimicrobial pro­phyl­axis in surgery. In: DiPiro JT,
Talbert RL, Hayes PE, Yee GC, Matzke GR, Posey LM,
eds. Pharmacotherapy: A Pathophysiologic Approach.
Norwalk, CT: Appleton & Lange; 1992:1811-12.
7. Government agency publication — Akutsu T. Total
heart replacement device. Bethesda, MD: National
Institutes of Health, National Heart, Blood, and Lung
Institute; April 1974. Report no.: NIH-NHLI-69-2185 4.
8. Dissertation or thesis — Youssef NM. School adjust­
ment of children with congenital heart disease [disserta­
tion]. Pittsburgh, PA: University of Pittsburgh; 1988.
9. Drug Label — Bristol-Myers Squibb Company.
Gluco­phage (metformin hydrochloride tablets);
Glucophage XR (metformin hydrochloride extendedrelease tablets) [prescribing information]. June 2006.
10. Letter or editorial — Markson, LE, Bukstein, DA,
Luskin AT. Health care utilization determined from
administrative claims analysis for patients who
received inhaled corticosteroids with either
montelukast or salmeterol [letter]. J Manag Care
Pharm. 2006;12(6):486-87. Available at: www.amcp.
org/data/jmcp/letter_486-487.pdf.
11. Paper (or Poster) presented at a meeting — Reagan ME. Workers’ compensation, managed care,
and reform. Poster presented at: 1995 AMCRA Midyear
Managed Care Summit; March 13, 1995; San Diego, CA.
12. Newspaper article — Lee G. Hospitalizations tied
to ozone pollution: study estimates 50,000 admissions
annually. Wash Post. June 21, 1996;A:3.
13. Web site — National Heart, Lung, and Blood Insti­
tute. Expert panel report 3: guidelines for the diagnosis
and management of asthma. Full report 2007 (EPR-3:
full report 2007). Available at: www.nhlbi.nih.gov/
guidelines/asthma/asthgdln.pdf. Accessed August 29,
2007.
14. Supplement — AMCP Task Force on Drug Payment
Methodologies: AMCP guide to pharmaceutical payment methods [suppl]. J Manag Care Pharm. 2007;13(8,
S-c):S1-S40. Available at: www.amcp.org/data/jmcp/
JMCPSUPPC_OCT07.pdf.
■■ Manuscript Submission
Please submit manuscripts electronically at jmcp.
msubmit.net. All text should be submitted in Microsoft
Word, prepared in 12-point type, 1.5 line spacing.
Tables must be prepared in either Microsoft Word or
Excel and may use a smaller text (e.g., 10-point).
Figures should be submitted in their original native format, preferably Adobe Illustrator or Photoshop. Figures
may also be prepared in Microsoft Word, but please
send original native files rather than embedded images
(tables or figures) to permit editing by the JMCP graphic
April 2009
Vol. 15, No. 3
www.amcp.org
designer. The JMCP graphic designer has permission to
re-create any figures. Please identify each file submitted
with the following information: format (PC or MAC),
software application, and file name.
Note: Please do not include author identification in
the electronic manuscript document.
Technical style: P values should be expressed to
no more than 3 decimal points in the format 0.xxx,
to 3 decimal places.
Cover letter: the corresponding (lead) author should
include a cover letter with the manuscript, which
•briefly describes the importance and scope of the
manuscript, and
•certifies that the paper has not been accepted for
publication or published previously and that it is not
under consideration by any other publication.
Disclosures and conflicts of interest: Manuscript
submissions should include a statement that identifies
the nature and extent of any financial interest or affiliation that any author has with any company, product,
or service discussed in the manuscript and clearly indicates the source(s) of funding and financial support and
be accompanied by completed and signed author attestation forms for the principal author and each coauthor.
All manuscripts are reviewed prior to peer review.
Manuscripts may be returned to authors prior to peer
review for clarification or other revisions. Peer review
generally requires 4 weeks but may extend as long as
12 weeks in unusual cases. Solicited manuscripts are
subject to the same peer-review standards and editorial
policy as unsolicited manuscripts.
■■ Submission Checklist
Before submitting the paper copy of your manuscript
to the Journal of Managed Care Pharmacy, please check
to see that your package includes the following:
❑Cover letter
❑Manuscript: prepared in 12-point type, 1.5 line
spacing, including
•abstract: no more than 650 words
•references: cited in numerical order as they
appear in the text (use superscript numbers)
and prepared following modified AMA style;
do not include footnotes in the manuscript
•tables and figures (generally no more than a
total of 6). Submit referenced tables and
figures on separate pages with titles (and
captions, as necessary) at the end of the
manuscript; match symbols in tables and
figures to explanatory notes, if included. May
use 10-point type.
•information indicating what is known about
the subject and what your article adds.
❑Disclosures and conflict-of-interest forms: completed and signed author attestation forms (available
at www.amcp.org); clearly indicate source(s) of funding and financial support.
Note: Please do not include author identification in the
electronic manuscript document.
For “Manuscript Submission Checklist” and “Peer
Review Checklist,” see www.amcp.org.
Reference
1. International Committee of Medical Journal Editors.
Uniform requirements for manuscripts submitted to
biomedical journals: writing and editing for biomedical
publication. Updated October 2008. Available at: http://
www.icmje.org/icmje.pdf. Accessed February 17, 2009.
RESEARCH
Meta-Analysis to Assess the Quality of Warfarin Control
in Atrial Fibrillation Patients in the United States
William L. Baker, PharmD, BCPS; Deborah A. Cios, PharmD;
Stephen D. Sander, PharmD; and Craig I. Coleman, PharmD
ABSTRACT
BACKGROUND: Atrial fibrillation (AF) affects a significant proportion of the
American population and increases ischemic stroke risk by 4- to 5-fold.
Oral vitamin K antagonists, such as warfarin, can significantly reduce this
stroke risk but can be difficult to dose and monitor. Previous research on
the effects of setting (e.g., randomized controlled trials, anticoagulation
management by specialty clinics, usual care by community physicians) on
the proportion of time spent within therapeutic range for the international
normalized ratio (INR) has not specifically examined anticoagulation in AF
patients.
OBJECTIVES: Use traditional meta-analytic and meta-regressive techniques
to evaluate the effect of specialty clinic versus usual care by community
physicians on anticoagulation control, measured as the proportion of time
spent in therapeutic INR range, for AF patients that received warfarin anticoagulation in the United States.
METHODS: Studies included in a previously published meta-analysis (van
Walraven et al., 2006), which systematically searched reports between
1987 and 2005, were also screened for inclusion in our analysis. A subsequent systematic literature search of MEDLINE, EMBASE, and the Cochrane
Central Register of Clinical Trials from January 2005 through February
2008 was conducted. Studies were included if they (a) contained at least
1 warfarin-treated group including more than 25 patients for whom INR
control was monitored for at least 3 weeks; (b) included patients treated
for AF in the United States; (c) used a patient-time approach (patient-year)
to report outcomes; and (d) reported data on the proportion of time spent
in traditional therapeutic INR ranges (i.e., a lower limit INR between 1.8
and 2.0 and an upper limit INR between 3.0 and 3.5. Studies with INR goals
outside this range were excluded). The proportion of time spent within the
therapeutic INR range for each study group was expressed as an incidence
density using a person-time approach (in years). All studies were pooled
using a random effects model and were weighted by the inverse of the
variance of proportion of time spent in the therapeutic range. In order to
determine how study setting influenced the proportion of time spent within
a therapeutic INR range, both subgroup and meta-regression analyses were
conducted.
RESULTS: This analysis included 8 studies and a total of 14 unique warfarin-treated groups; 3 of the 8 studies and 4 of the warfarin groups were not
included in the previous meta-analysis (van Walraven et al., 2006). Overall,
patients spent a mean 55% (95% CI = 51%-58%) of their time in the therapeutic INR range. Meta-regression suggested that AF patients treated in
a community usual care setting compared with an anticoagulation clinic
spent 11% (95% CI = 2%-20%, n = 6 studies with 9 study groups) less time
in range.
CONCLUSIONS: In the United States, AF patients spend only about one-half
the time within therapeutic INR. Anticoagulation clinic services are associated with somewhat better INR control compared with standard community
care.
J Manag Care Pharm. 2009;15(3):244-52
What is already known about this subject
• The 2008 practice guidelines from the American College of Chest
Physicians include a recommendation to use long-term oral anticoagulation in patients with atrial fibrillation (AF) and a recent
stroke or transient ischemic attack, to a target INR of 2.5 (range
2.0 to 3.0; Grade 1A quality of evidence).
• Van Walraven et al. (2006) evaluated 67 studies involving 50,208
patients with 57,155 patient-years of follow-up. Overall, patients
taking vitamin K antagonists for a wide range of indications that
included atrial fibrillation, venous thromboembolism, cardiovascular disease other than atrial fibrillation, peripheral vascular
disease, valvular heart disease, and other indications were within
therapeutic INR range 63.6% of the time (95% CI = 61.6%-65.6%).
For the patients managed in usual care (i.e., by community physicians), time in therapeutic INR was 12.2% lower (95% CI = –19.5
to –4.8%, P < 0.001) compared with patients managed in anticoagulation clinics.
• Study setting is a significant predictor of the time spent in therapeutic INR range, with about 66% of the time in therapeutic range
for anticoagulation therapy in both randomized controlled trials
and anticoagulation clinics versus 57% for community-based care
provided by physicians.
What this study adds
• Our meta-analysis assessed 8 studies including a total of 14
groups involving 22,237 warfarin-treated AF patients with 41,199
years of follow-up. Atrial fibrillation patients in the 14 groups
spent 55% (95% CI = 51%-58%) of their time within the therapeutic INR range.
• Of the 8 studies, 13 groups could be evaluated by setting: warfarin dosing was managed by anticoagulation clinics for 4 (31%)
groups and by community (physician) practice, defined as usual
care, for 9 (69%). Patients in anticoagulation clinics spent on
average 63% (95% CI = 58%-68%) of their time in the therapeutic
range versus 51% (95% CI = 47%-55%) for patients in community practice. Compared with an anticoagulation clinic, patients
treated in the usual care (community) setting spent 11% (95%
CI = 2%-20%, n = 6 studies) less time in therapeutic INR range.
• 5 studies (including 8 groups) reported data on the proportion of
eligible patients receiving warfarin. Overall, 48% (95% CI = 43%54%) of eligible AF patients received warfarin, including 53%
of AF patients managed by anticoagulation clinics, revealing
another gap in protection from ischemic stroke.
Copyright © 2009, Academy of Managed Care Pharmacy. All rights reserved.
244 Journal of Managed Care Pharmacy
JMCP
April 2009
Vol. 15, No. 3
www.amcp.org
Meta-Analysis to Assess the Quality of Warfarin Control in Atrial Fibrillation Patients in the United States
A
trial fibrillation (AF), the most common cardiac rhythm
disorder, increases the risk for ischemic stroke 4- to
5-fold.1,2 Studies have demonstrated that use of oral vitamin K antagonists such as warfarin significantly reduces the risk
of stroke by up to 68% compared with no therapy, from a range
of 4.5% without warfarin to 1.4% with warfarin.3 For patients
receiving therapy with warfarin, the proportion of time spent
in the therapeutic international normalized ratio (INR) range
is strongly associated with reduced risk of both bleeding and
thromboembolism.4-6 However, achieving high-quality anticoagulation control can often be difficult and labor intensive with
warfarin due to its indirect mode of action and a large number
of factors that influence its pharmacokinetics and pharmacodynamics, including patient age, concurrent medications and diet,
comorbidities, and genetics.7
Understanding the overall quality of anticoagulation management in AF patients in the United States can be challenging
because there is variation in the proportion of time spent within
the therapeutic INR range among studies. Study-specific factors,
such as study setting (randomized trial vs. observational anticoagulation clinic-based trial vs. observational community physician office-based trial) may explain at least some of the variance
in reported quality of anticoagulation. A meta-analysis reported
by van Walraven et al. in 2006 included studies from around the
world and included warfarin as well as 4 vitamin K antagonists
that are not available in the United States (acenocoumarol, dicumarol, ethyl biscoumacetate, and phenprocoumon).8 Van Walraven
et al. evaluated 67 studies involving 50,208 patients with 57,155
patient-years of follow-up. Overall, patients taking vitamin K
antagonists for a wide range of indications that included atrial
fibrillation, venous thromboembolism, cardiovascular disease
other than atrial fibrillation, peripheral vascular disease, valvular
heart disease, and other indications were within therapeutic INR
range 63.6% of the time (95% CI = 61.6%-65.6%).
Outside the United States, self-management of anticoagulation
therapy has been a subject of research designed to find methods
that might be more effective and efficient than usual care or anticoagulation clinics. Gadisseur et al. (2003) in a randomized trial
found that patient self-management using a hand-held prothrombin time monitoring device was at least as effective as specialized
physician management in anticoagulation clinics, as measured
by the proportion of time spent in INR range.9 In the systematic
review and meta-regression reported by van Walraven et al.,
24.4% of the patients were managed in usual care (community
physicians); 68.3% of patients were in anticoagulation clinics;
and 7.3% of the patients were involved in clinical trials.8 Metaregression showed that setting had a significant effect on anticoagulation control, with studies in community practices having
significantly lower control than either anticoagulation clinics or
clinical trials (–12.2%; 95% CI = –19.5 to –4.8; P < 0.001), and
self-management was associated with a significant improvement
of time spent in the therapeutic range (+ 7.0%; 95% CI = 0.7-13.3;
www.amcp.org
P = 0.03). Study setting was a significant predictor of the time
spent in therapeutic INR range, with about 66% of the time in
therapeutic range for anticoagulation therapy in both randomized
controlled trials and anticoagulation clinics as compared with
57% for community-based care provided by physician.8
The findings reported by van Walraven et al.8 are informative
but not specific to AF patients and perhaps not generalizable
to the United States for warfarin therapy. Health system infrastructures and practice patterns vary greatly between nations,
which can lead to differences in degrees of management. Pengo
et al. (2006) highlighted differences in anticoagulation care
between countries in a recently published International Study of
Anticoagulation Management (ISAM) study.10 They found superior INR control in Spain and Italy versus the other countries;
however, hematologists ran all the clinics in Spain and primarily
cardiologists and hematologists ran those in Italy. The studies
conducted in the United States, Canada, and Italy used predominantly warfarin, while studies in Spain and France, respectively,
used acenocoumarol and fluinione.
The purpose of our analysis was to identify and assess (using
traditional meta-analytic and meta-regressive techniques) data
from all published randomized trials or cohort studies evaluating
the quality of management of warfarin use by AF patients in the
United States.
■■ Methods
In order to ensure comparability between our results and those
of the previous meta-analysis by van Walraven et al.,8 we utilized
similar study selection and statistical analytic methodologies.
Study Selection
We first examined the full-text versions of all 67 studies included
in the meta-analysis by van Walraven et al.,8 which searched
reports between 1987 and 2005, for inclusion in our analysis
using the entry criteria described below. A subsequent systematic
literature search was conducted in MEDLINE, EMBASE, and the
Cochrane Central Register of Clinical Trials from January 1, 2005,
through the end of February 2008 to identify additional studies
(either prospective randomized or observational in design) evaluating warfarin as an anticoagulant in patients with AF. The search
used the following Medical Subject Headings (MeSH) and text
keywords: warfarin, vitamin k antagonist, VKA, anticoagulant and
international normalized ratio, INR, prothrombin time, PT, PTR. The
resulting citations were then limited to human subjects, clinical
trials, and English language publications. Furthermore, a manual
search of references from reports of clinical trials or review articles was performed to identify additional relevant trials.
Two investigators (Cios and Coleman) reviewed all potentially
relevant articles independently, with disagreement resolved by a
third investigator (Baker). To be included in this meta-analysis,
studies had to (a) contain at least 1 warfarin-treated group including at least 25 patients for whom INR control was monitored for
Vol. 15, No. 3
April 2009
JMCP
Journal of Managed Care Pharmacy 245
Meta-Analysis to Assess the Quality of Warfarin Control in Atrial Fibrillation Patients in the United States
TABLE 1
Study
Samsa et al.,
200017
McCormick et al.,
200118
Matchar,
200320
Characteristics of U.S. Atrial Fibrillation Warfarin Studies and Groups
Design
RD
RD
PD
Warfarin Indication
AF—identified by new
ECG, chart documentation
of AF, diagnostic code for
AF+warfarin
AF—identified by ECG or physician documentation of AF
AF
Number of
Warfarin-Treated
Patients
43
61
125
174
363
363
317
317
7,445
FollowUp
NR
1 year
9 months
Patient
Interpolation Years of
Study Group
Method
Follow-Upa
AC Clinic
Linear
32.3a
Community
Linear
45.8 a
Community
Linear
93.8 a
Community
Clinic/Comm
Community
Community
Community
2.35 years Community
(1.83-2.81)c
10.5 ± 3.2
AC Clinic
monthsd
3.3 years
Community
(1.0-5.1)b
1 year
AC Clinic
174a
Linear
Other
Other
Other
Other
Linear
272.3a
272.3a
237.8 a
237.8 a
12,958
Proportion
(95% CI)b
0.60 (0.43-0.75)
0.47 (0.33-0.61)
0.36 (0.27-0.46)
0.51 (0.44-0.58)
0.56 (0.50-0.61)
0.49 (0.43-0.55)
0.48 (0.42-0.54)
0.52 (0.46-0.59)
0.63 (0.62-0.63)
RD
Nonvalvular AF
Go et al.,
200321
RD
Nonvalvular AF
600
Linear
525a
0.62 (0.58-0.66)
Menzin et al.,
200526
RD
Hospitalization for AF or
11,016
Linear
24,179
0.55 (0.54-0.55)
Shen et al.,
atrial flutter
200731
PD
AF—verified by ECG
306
Linear
360
0.58 (0.53-0.63)
Hylek et al.,
200735
RD
Nonvalvular AF
756
NR
Community
Halving
1,164.2a 0.42 (0.39-0.45)
Nichol et al.,
351
AC Clinic
Halving
919.6 a 0.68 (0.65-0.71)
200838
a For the indicated studies, patient-years of follow-up were estimated using number of patients in each group and the length of follow-up reported in the study.
bMean (95% confidence interval) proportion of time spent within the therapeutic INR range; none of these patients self-managed their own warfarin regimens.
cData reported as median (interquartile range).
d Data reported as mean ± standard deviation.
AC = anticoagulation; AF = atrial fibrillation; CI = confidence interval; Comm = community; ECG = electrocardiogram; Method = International Normalized Ratio
interpolation method used in the study; NR = not reported; PD = prospective design; RD = retrospective design.
at least 3 weeks; (b) include only patients treated for AF within
the United States; (c) use a patient-time approach that requires
the measurement of serial INRs in each study subject and an
interpolation (any interpolation method was accepted, but linear
was used preferentially when available) of the values between
actual measures so that anticoagulation status could be estimated
for each day of observation; and (d) report data on the proportion of time spent in traditional therapeutic INR ranges (i.e., a
lower limit INR between 1.8 and 2.0 and an upper limit INR
between 3.0 and 3.5. Studies with INR goals outside this range
were excluded).2 Finally, if studies reported INR control on the
same patient group at different time periods, only the time period
of the longest duration was included. Studies were excluded if
serial INRs were measured after the systemic administration of
vitamin K, as these measurements may not be a true marker of
anticoagulation status.
Data Abstraction
Two investigators (Cios, Coleman) used a common data abstraction tool but independently abstracted all data. If a disagreement
arose it was resolved by a third investigator (Baker). The following
information was obtained from each study: author identification,
year of publication, geographic location of the study, type of anticoagulant used, and the study setting (designated as anticoagula246 Journal of Managed Care Pharmacy
JMCP
April 2009
Vol. 15, No. 3
tion clinic, randomized trial, or community practice). The setting
was designated using the following definitions: (a) an anticoagulation clinic if the study took place in an anticoagulation clinic or
if the stated role of the study clinicians in patient care was limited
to managing anticoagulation; (b) a randomized trial if random
allocation was employed to assign subjects to receive warfarin or
another non-warfarin therapy; and (c) all others were classified as
community practice. All of the preceding definitions were similar
to those used by van Walraven et al.8
Statistical Analysis
The proportion of time spent within the therapeutic INR range
for each study group was expressed as an incidence density
using a person-time approach (in years). The numerator was
calculated as the proportion of time that the group spent within
the INR range multiplied by the observation time. The denominator was the total observation time for each study group (or
the total study observation time multiplied by the proportion
of patients in each study group, if the observation time for
the individual study group was not reported in a given study).
Ninety-five percent confidence intervals (CI) were calculated for
each incidence density using the Wilson score method without
continuity correction.11 For the purposes of this meta-analysis,
all studies were pooled using a random effects model and were
www.amcp.org
Meta-Analysis to Assess the Quality of Warfarin Control in Atrial Fibrillation Patients in the United States
weighted by the inverse of the variance of proportion of time
spent in the therapeutic range.8,12
In order to determine how study setting influenced the
proportion of time spent within a therapeutic INR range, both
subgroup and meta-regression analyses were conducted. Metaregression analysis allows evaluating the effect of study setting
independent of other influencing study design aspects (i.e., year,
etc.). A multiple linear mixed method model using both randomand fixed-effects was utilized for meta-regression, which was
weighted by the inverse of the variance of proportion of time
spent in the therapeutic range.13,14 By conducting a mixed linear
model, we accounted for the potential lack of independence of
INR control within studies. Thus, study groups were treated as
dependent within studies, but as independent across studies. The
use of mixed linear models helps to avoid the biased estimation
of variable deviation (i.e., standard error) that can arise due to
the potential lack of independence among multiple groups within
the same study.8 Random effects were assumed for study-level
factors, including the covariates listed below, and fixed effects
for patient-level factors. Study level covariates incorporated into
the model include study design (community vs. anticoagulation clinic), study year (from 1998-2002 and 2003-2008), use
of self-management or not,9 and interpolation method (linear or
other). No hierarchy was used in the model for these covariates.
Statistical analysis was performed using StatsDirect version 2.4.6
(StatsDirect Ltd., Cheshire, England) and SPSS, version 15.0
(SPSS Inc., Chicago, IL).
■■ Results
Our review of studies included in the van Walraven et al. study8
yielded 14 studies meeting our preliminary inclusion criteria
(conducted in the United States, evaluating warfarin, and limited
to patients with AF).15-28 Our updated systematic search from
January 2005 through February 2008 (as depicted in Figure 1)
identified an additional 536 studies for full text review, of which
526 were excluded. Of the studies excluded, most were excluded
because they were not conducted in the United States, or they
were not a primary study. Our preliminary screening process
resulted in a total of 24 studies, including a total of 43 separate
groups.15-38 Of these, 16 studies were excluded because patients
were included for indications other than AF.14,15,19,22-25,27-30,32-34,36,37
Thus, 8 studies, including a total of 14 study groups, met all of the
inclusion criteria and were included in the final analysis (Table
1).17,18,20,21,26,31,35,38
The study groups enrolled a median of 317 patients (interquartile range, 150 to 482 patients; total = 22,237 warfarintreated patients),31 who were followed for a median of 272.3
patient-years (range, 123.9 to 980.8 patient-years; total = 41,471.9
patient-years). Patients spent a median of 146.6 patient-years
(range, 74.9 to 524 patient-years; total = 23,752.1 patient-years)
within the therapeutic INR range. Patient-years data were cal-
www.amcp.org
culated in 5 of the included studies,17,18,20,26,38 whereas the other
3 studies reported the required data.21,31,35 Four groups (31%)
were treated in anticoagulation clinics,17,26,35,38 while 9 (69%)
were treated in community practice.17,18,20,21,31,38 One group in
the study by Matchar (2003)20 could not be classified as either an
anticoagulation clinic or community practice because warfarin
control was reported in this group of patients prior to their use
or nonuse of an anticoagulation clinic. No randomized controlled
trials (RCTs) met our inclusion criteria; thus, no RCTs were available for evaluation in our study.
Overall, patients within the 14 included groups spent 55%
(95% CI = 51%-58%) of their time within the therapeutic INR
range (Figure 2). Differences by study setting were observed,
with patients in an anticoagulation clinic spending a mean 63%
(95% CI = 58%-68%) of their time in the therapeutic range versus
51% (95% CI = 47%-55%) for patients in community practice.
As no RCTs met our inclusion criteria, we could not evaluate
this subgroup. After controlling for covariates, meta-regression
analyses showed similar results to that of the subgroup analyses.
Compared with an anticoagulation clinic, patients treated in a
community setting spent 11% (95% CI = 2%-20%, n = 6 studies,
with 9 study groups) less time in range. Although the differences were not statistically significant, recently reported studies
showed more improved INR control than older ones (difference
of 9% [95% CI = –4% to 21%]); prospective studies showed more
improved control than retrospective ones (2% [95% CI = –10% to
14%]); and studies using linear interpolation methods showed
more improved control than studies using other methods (2%
[95% CI = –10% to 15%]).
We also evaluated the proportion of warfarin-eligible patients
who received warfarin in studies that measured that outcome.
A total of 5 trials (including 8 study groups) reported data on
the proportion of eligible patients receiving warfarin (Figure
3).17,18,20,21,31 Overall, 48% (95% CI = 43%-54%) of eligible AF
patients received warfarin.
■■ Discussion
Warfarin has been shown in clinical trials to significantly reduce
the risk of stroke in AF patients by 64% (absolute risk reduction
2.7% for primary prevention, 8.4% for secondary prevention) versus control (placebo or no treatment).39 Based on these findings,
evidence-based practice guidelines consistently recommend vitamin K antagonists for all patients with AF and at least 1 other risk
factor.2 Rates of efficacy, unfortunately, have not translated into
the real world. A recent analysis of Medicare beneficiaries with
AF showed a disappointing 35% reduction in ischemic strokes
among patients exposed to warfarin versus those that did not
receive warfarin, revealing a discrepancy between effectiveness
in clinical trials and actual clinical practice.40 The results of our
analysis help provide insight into reasons for this discrepancy.
In our meta-analysis of studies evaluating anticoagulation
Vol. 15, No. 3
April 2009
JMCP
Journal of Managed Care Pharmacy 247
Meta-Analysis to Assess the Quality of Warfarin Control in Atrial Fibrillation Patients in the United States
FIGURE 1
Flow Diagram of Study Identification, Inclusion and Exclusion
563 articles initially identified in search
spanning January 2005—February 2008
27 articles excluded:
27 Not English language
536 full-text articles retrieved for
detailed evaluation
10 studies further evaluated
14 U.S. studies from
van Walraven et al.
evaluated
526 articles excluded:
212 Studies not in United States
202 Not primary studies
60 Endpoint not reported
19 < 3 weeks therapy
11 < 25 patients
8 Vitamin K given
7 INR not in pre-specified
range
4 Duplicate studies
2 No dedicated warfarin arm
1 Used IV warfarin
16 studies excluded:
16 Not atrial fibrillation
8 studies with 13 study groups included
(name of first author and year of publication):
AC Clinic – 4 studies/4 study groups
Samsa, 200017 – 1 study group
Matchar, 200320 – 1 study group
Menzin, 200526 – 1 study group
Hylek, 200735 – 1 study group
Community – 6 studies/9 study groups
Samsa, 200017 – 2 study groups
McCormick, 200118 – 1 study group
Matchar, 200320 – 3 study groups
Go, 200321 – 1 study group
Shen, 200731 – 1 study group
Nichol, 200838 – 1 study group
One group in the study by Matchar (2003)20 could not be classified as either an AC clinic or community practice; warfarin control was reported in this group of patients
prior to their use of either an AC clinic or not, and thus their classification could not be determined as either community practice or AC clinic.
AC = anticoagulation; INR = international normalized ratio; IV = intravenous; SM = self management.
control in AF patients in the United States, we found that
patients spent a relatively low percentage of their time within the
therapeutic INR range while on warfarin (55%, 95% CI = 51%58%). In addition, meta-regression showed that studies of usual
care in the community found poorer control as measured by
time within INR therapeutic range than did studies of anticoagulation clinics.
Our meta-analytic methods differed from those of van Walraven
et al.8 and Dolan et al. (2008)41 in notable ways. By including only
studies evaluating anticoagulation control in AF patients in the
248 Journal of Managed Care Pharmacy
JMCP
April 2009
Vol. 15, No. 3
United States and limiting the evaluation exclusively to warfarin,
the information is more readily applicable to the U.S. population
(greater external validity). The 2 prior meta-analyses conducted
by van Walraven et al. and Dolan et al. included studies evaluating a variety of warfarin indications (e.g., atrial fibrillation, venous
thromboembolism, stroke), thus limiting the ability to apply their
results to a particular population. We also included published
U.S. trials to ensure that our observations apply to U.S. practice
patterns. Since we found better INR control with anticoagulation
clinics compared with community-based care, our findings help
www.amcp.org
Meta-Analysis to Assess the Quality of Warfarin Control in Atrial Fibrillation Patients in the United States
FIGURE 2
Cumulative Effect of Warfarin Management on the
Proportion of Time Spent Within Therapeutic INR Rangea
AC Clinic-Based Warfarin Dosing
Samsa, 200017 (n = 43)
0.60 (0.43-0.75)
Menzin, 200526 (n = 600)
0.62 (0.58-0.66)
Hylek, 200735 (n = 306)
0.58 (0.53-0.63)
Nichol, 200838 (n = 351)
0.68 (0.65-0.71)
Subtotal
0.63 (0.58-0.68)
Community-Based Warfarin Dosing
Samsa, 200017 (n = 61)
0.47 (0.33-0.61)
Samsa, 200017 (n = 125)
0.36 (0.27-0.46)
McCormick, 200118 (n = 174)
0.51 (0.44-0.58)
Matchar, 200320 (n = 363)
0.56 (0.50-0.61)
Matchar, 200320 (n = 317)
0.49 (0.43-0.55)
Matchar, 200320 (n = 317)
0.52 (0.46-0.59)
Go, 200321 (n = 7,445)
0.63 (0.62-0.63)
Shen, 200731 (n = 11,016)
0.55 (0.54-0.55)
Nichol, 200838 (n= 756)
0.42 (0.39-0.45)
Subtotal
0.51 (0.47-0.55)
Overall Effect
0.55 (0.51-0.58)
0.2
0.5
1
Time in Therapeutic Range (95% confidence interval)
aThe
squares represent individual studies, and the size of the square represents the weight given to each study in the meta-analysis. Error bars represent 95% confidence
intervals. The diamond represents the combined results. The solid vertical line extending upwards from 1 is the null value. None of these studies were randomized controlled
trials. List of studies shows name of first author and year of publication.
AC = anticoagulation.
to confirm the results seen in other previous evaluations.8,10,41
An additional prior meta-analysis conducted by Reynolds et al.
(2004) reported the overall impact of warfarin anticoagulation
on clinical outcomes in patients with AF.42 They showed that, in
studies with an INR range of 2-3, patients spent 61% of their time
www.amcp.org
within the therapeutic INR range. These results are similar to
ours and demonstrate the lack of adequate anticoagulation control in patients treated with oral vitamin K antagonists for AF.
The low achievement of anticoagulation control seen in
our study is of concern. Unfortunately, a significant portion of
Vol. 15, No. 3
April 2009
JMCP
Journal of Managed Care Pharmacy 249
Meta-Analysis to Assess the Quality of Warfarin Control in Atrial Fibrillation Patients in the United States
FIGURE 3
Proportion of Eligible Atrial Fibrillation Patients Receiving Warfarina
AC Clinic-Based Warfarin Dosing
Samsa, 200017 (n = 43)
0.44 (0.35-0.54)
Matchar, 200320 (n = 363)
0.61 (0.55-0.67)
Subtotal
0.53 (0.38-0.72)
Community-Based Warfarin Dosing
Samsa, 200017 (n = 61)
0.33 (0.29-0.38)
Samsa, 200017 (n = 125)
0.33 (0.27-0.40)
McCormick, 200118 (n = 174)
0.42 (0.37-0.47)
Go, 200321 (n = 7,445)
0.55 (0.54-0.56)
Matchar, 200320 (n = 363)
0.61 (0.57-0.65)
Matchar, 200320 (n = 317)
0.55 (0.51-0.59)
Matchar, 200320 (n = 317)
0.61 (0.56-0.67)
Shen, 200731 (n = 11,016)
0.42 (0.41-0.43)
Subtotal
0.47 (0.41-0.54)
Overall Effect
0.48 (0.43-0.54)
0.2
0.5
1
Proportion of Eligible Patients Receiving Warfarin (95% confidence interval)
aThe squares represent individual studies, and the size of the square represents the weight given to each study in the meta-analysis. Error bars represent 95% confidence
intervals. The diamond represents the combined results. The solid vertical line extending upwards from 1 is the null value. None of these studies were randomized controlled
trials. List of studies shows name of first author and year of publication.
AC = anticoagulation.
the time that patients spend on oral anticoagulants is outside
of the therapeutic range. Economic modeling studies have
projected improved outcomes and cost-savings from increasing the proportion of time spent within range. Chiquette et al.
(1998) estimated that with improvements in time spent within
the therapeutic range (64.0% vs. 51.0%) patients experienced
lower rates of significant bleeding (defined as a decrease in
hematocrit greater than 3% or hemoglobin level greater than
1.2 milligrams per deciliter; 8.1% vs. 35.0%) and thromboembolic events (3.3% vs 11.8%), as well as significant cost savings
($162,058 per 100 patient-years), driven mainly by reduced
250 Journal of Managed Care Pharmacy
JMCP
April 2009
Vol. 15, No. 3
hospitalizations and emergency room visits.15
However, as we saw in the present study of 4 groups managed
by anticoagulation clinics, patients still spend over one-third of
their time out of the therapeutic range.41,43-45 Even within clinics,
newer warfarin dosing strategies—including computer-aided
dosing (time within therapeutic INR range = 56% vs. 32% with
usual care),16 specialty-pharmacy clinics (71% of time spent
within range),23 and genotype-guided dosing32 (30.7% of INRs
were out of range with genotype dosing vs. 33.1% with standard
dosing)—have been investigated, with only modest improvement
in overall time spent within the therapeutic INR range.
www.amcp.org
Meta-Analysis to Assess the Quality of Warfarin Control in Atrial Fibrillation Patients in the United States
Limitations
The results of our study must be taken within the context of
its limitations. As with all meta-analyses, publication bias is a
potential concern. However, given the systematic nature of our
literature search from January 2005 until February 2008, this
risk was minimized. A second limitation of our meta-analysis is
that the INR control in RCTs could not be evaluated, since none
were identified by our search. Since no significant differences
were seen in the results between RCTs and anticoagulation clinics in the previous van Walraven. study (2006), it might be concluded that anticoagulation clinics and RCTs provide similar control, both of which are superior to community practice.8 However,
according to Go et al. (2003),21 clinical trials evaluating warfarin
in patients with nonvalvular AF translated well into their clinical
practice. In addition, Matchar (2003) found no differences in INR
control between patients randomized to either anticoagulation
clinics or usual care.20 An additional limitation to this study is the
differing interpolation methods used to report the time in therapeutic range among the studies. Although our model showed
that the interpolation method used did not significantly impact
the overall study results, caution must be used when interpreting these data. It should also be noted that the included study
samples were clinically and methodologically heterogeneous, as
can be seen in Table 1. For example, studies included various settings (e.g., community, clinic, and hospital) and types of AF (e.g.,
nonvalvular atrial fibrillation and atrial flutter).
■■ Conclusions
In the United States, patients who receive warfarin anticoagulation spend only about one-half the time within therapeutic INR.
The use of anticoagulation clinic services by patients with AF
improves INR control to 63% of the time on warfarin therapy
versus 51% for usual community care.
DISCLOSURES
This study was sponsored by Boehringer Ingelheim Pharmaceuticals, and
Stephen Sander is an employee of Boehringer Ingelheim Pharmaceuticals.
Study concept and design were contributed primarily by Sander and
Coleman. Data collection was performed by Cios with assistance from
Baker and Coleman. Data interpretation was performed primarily by Baker
and Coleman. Baker wrote the manuscript with the assistance of the other
authors. The revision was made primarily by Baker and Coleman. REFERENCES
1. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation: a major contributor to stroke in the elderly: the Framingham Heart Study. Arch Intern Med.
1987;147(9):1561-64.
2. Singer DE, Albers GW, Dalen JE, et al. Antithrombotic therapy in atrial
fibrillation: American College of Chest Physicians Evidence-Based Clinical
Practice Guidelines (8th edition). Chest. 2008;133(6 Suppl):546S-92S.
3. Risk factors for stroke and efficacy of antithrombotic therapy in atrial
fibrillation: analysis of pooled data from five randomized controlled trials.
Arch Intern Med. 1994;154(13):1449-57.
4. Cannegieter SC, Rosendaal FR, Wintzen AR, van der Meer FJ,
Vandenbroucke JP, Briët E. Optimal oral anticoagulant therapy in patients
with mechanical heart valves. N Engl J Med. 1995;333(1):11-17. Available at:
http://content.nejm.org/cgi/reprint/333/1/11.pdf. Accessed March 6, 2009.
5. Odén A, Fahlén M, Hart RG. Optimal INR for prevention of stroke and
death in atrial fibrillation: a critical appraisal. Thromb Res. 2006;117(5):49399.
6. Wysowski DK, Nourjah P, Swartz L. Bleeding complications with warfarin use: a prevalent adverse effect resulting in regulatory action. Arch Intern
Med. 2007;167(13):1414-19. Available at: http://archinte.ama-assn.org/cgi/
reprint/167/13/1414. Accessed March 6, 2009.
7. Ansell J, Hirsh J, Hylek E, Jacobson A, Crowther M, Palareti G; American
College of Chest Physicians. Pharmacology and management of vitamin K
antagonists: American College of Chest Physicians Evidence-Based Clinical
Practice Guidelines (8th edition). Chest. 2008;133(6 Suppl):160S-198S.
8. van Walraven C, Jennings A, Oake N, Fergusson D, Forster AJ. Effect of
study setting on anticoagulation control: a systematic review and metaregression. Chest. 2006;129(5):1155-66. Available at: http://www.chestjournal.
org/content/129/5/1155.full.pdf+html. Accessed February 1, 2009.
Authors
WILLIAM L. BAKER, PharmD, BCPS, is Senior Research Scientist,
University of Connecticut/Hartford Hospital Evidence-Based Practice
Center, Hartford, Connecticut; DEBORAH A. CIOS, PharmD, is
Senior Pharmacist, Department of Pharmacy, Brigham and Women’s
Hospital, Boston, Massachusetts; STEPHEN D. SANDER, PharmD,
is Associate Director of Health Economics & Outcomes Research,
Boehringer Ingelheim Pharmaceuticals, Ridgefield, Connecticut;
CRAIG I. COLEMAN, PharmD, is Assistant Professor of Pharmacy
Practice, School of Pharmacy, and Methods Chief and Program
Director, University of Connecticut/Hartford Hospital EvidenceBased Practice Center, Hartford, Connecticut.
AUTHOR CORRESPONDENCE: Craig I. Coleman, PharmD,
Assistant Professor of Pharmacy Practice, University of Connecticut
School of Pharmacy, Methods Chief and Program Director,
University of Connecticut/Hartford Hospital Evidence-Based Practice
Center, 80 Seymour Street, CB309, Hartford, CT 06102. Tel.:
860.545.2096; Fax: 860.545.2277; E-mail: [email protected]
www.amcp.org
9. Gadisseur AP, Breukink-Engbers WG, von der Meer FJ, van den Besselaar
AM, Sturic A, Rosendaal FR. Comparison of the quality of oral anticoagulant therapy through patient self-management and management by specialized clinics in the Netherlands: a randomized clinical trial. Arch Intern
Med. 2003;163(21):2639-46. Available at: http://archinte.ama-assn.org/cgi/
reprint/163/21/2639. Accessed March 16, 2009.
10. Pengo V, Pegoraro C, Cucchini U, Iliceto S. Worldwide management
of oral anticoagulation therapy: the ISAM study. J Thromb Thrombolysis.
2006;21(1):73-77.
11. Newcombe RG. Two-sided confidence intervals for the single proportion:
comparison of seven methods. Stat Med. 1998;17(8):857-72.
12. Dersimonian R, Laird N. Meta-analysis in clinical trials. Control Clin
Trials. 1986;7(3):177-88.
13. Breslow NE, Clayton DG. Approximate inference in generalized linear
mixed models. J Am Stat Assoc. 1993;88(421):9-25.
14. Tuerlinchx F, Rijmen F, Verbeke G, De Boeck P. Statistical inference in
generalized linear mixed models: a review. Br J Math Stat Psychol. 2006;59(Pt
2):225-55
Vol. 15, No. 3
April 2009
JMCP
Journal of Managed Care Pharmacy 251
Meta-Analysis to Assess the Quality of Warfarin Control in Atrial Fibrillation Patients in the United States
15. Chiquette E, Amato MG, Bussey HI. Comparison of an anticoagulation
clinic with usual medical care: anticoagulation control, patient outcomes,
and health care costs. Arch Intern Med. 1998;158(15):1641-47. Available at:
http://archinte.ama-assn.org/cgi/reprint/158/15/1641. Accessed March 6,
2009.
16. Beyth RJ, Quinn L, Landefeld CS. A multicomponent intervention to
prevent major bleeding complications in older patients receiving warfarin: a
randomized, controlled trial. Ann Intern Med. 2000;133(9):687-95. Available
at: http://www.annals.org/cgi/reprint/133/9/687.pdf. Accessed March 6,
2009.
17. Samsa GP, Matchar DB, Goldstein LB, et al. Quality of anticoagulation
management among patients with atrial fibrillation: results of a review of
medical records from 2 communities. Arch Intern Med. 2000;160(7):967-73.
Available at: http://archinte.ama-assn.org/cgi/reprint/160/7/967. Accessed
February 1, 2009.
18. McCormick D, Gurwitz JH, Goldberg RJ, et al. Prevalence and quality of
warfarin use for patients with atrial fibrillation in the long-term care setting.
Arch Intern Med. 2001;161(20):2458-63. Available at: http://archinte.amaassn.org/cgi/reprint/161/20/2458. Accessed March 6, 2009.
19. Milligan PE, Banet GA, Waterman AD, Gatchel SK, Gage BF. Substitution
of generic warfarin for coumadin in an HMO setting. Ann Pharmacother.
2002;36(5):764-68.
20. Matchar DB. Do anticoagulation management services improve
care? Implications of the Managing Anticoagulation Services Trial. Card
Electrophysiol Rev. 2003;7(4):379-81.
21. Go AS, Hylek EM, Chang Y, et al. Anticoagulation therapy for stroke
prevention in atrial fibrillation: how well do randomized trials translate into
clinical practice? JAMA. 2003;290(20):2685-92. Available at: http://jama.
ama-assn.org/cgi/reprint/290/20/2685. Accessed February 1, 2009.
22. Witt DM, Tillman DJ, Evans CM, Plotkin TV, Sadler MA. Evaluation
of the clinical and economic impact of a brand name-to-generic warfarin
sodium conversion program. Pharmacotherapy. 2003;23(3):360-68.
23. Waterman AD, Milligan PE, Bayer L, Banet GA, Gatchel SK, Gage BF.
Effect of warfarin nonadherence on control of the International Normalized
Ratio. Am J Health Syst Pharm. 2004;61(12):1258-64.
24. Willey VJ, Bullano MF, Hauch O, et al. Management patterns and outcomes of patients with venous thromboembolism in the usual community
practice setting. Clin Ther. 2004;26(7):1149-59.
25. Witt DM, Sadler MA, Shanahan RL, Mazzoli G, Tillman DJ. Effect of a
centralized clinical pharmacy anticoagulation service on the outcomes of
anticoagulation therapy. Chest. 2005;127(5):1515-22. Available at: http://
www.chestjournal.org/content/127/5/1515.full.pdf+html. Accessed March 6,
2009.
26. Menzin J, Boulanger L, Haugh O, et al. Quality of anticoagulation
control and costs of monitoring warfarin therapy among patients with
atrial fibrillation in clinical settings: a multi-site managed-care study. Ann
Pharmacother. 2005;39(3):446-51.
27. Mitra R, Marciello MA, Brain C, Ahangar B, Burke DT. Efficacy of computer-aided dosing of warfarin among patients in a rehabilitation hospital.
Am J Phys Med Rehabil. 2005;84(6):423-27.
28. Johnson SG, Witt DM, Delate T, Sadler MA. An examination of the
association between therapeutic control and glycemic control for patients
with diabetes on oral anticoagulation therapy. J Thromb Thrombolysis.
2005;19(3):209-12.
29. Staresinic AG, Sorkness CA, Goodman BM, Pigarelli DW. Comparison
of outcomes using 2 delivery models of anticoagulation care. Arch Intern
Med. 2006;166(9):997-1002. Available at: http://archinte.ama-assn.org/cgi/
reprint/166/9/997. Accessed March 6, 2009.
252 Journal of Managed Care Pharmacy
JMCP
April 2009
Vol. 15, No. 3
30. Rose AJ, Sharman JP, Ozonoff A, Henault LE, Hylek EM. Effectiveness
of warfarin among patients with cancer. J Gen Intern Med. 2007;22(7):9971002. Available at: http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=2
219727&blobtype=pdf. Accessed March 6, 2009.
31. Shen AY, Yao JF, Brar SS, Jorgensen MB, Chen W. Racial/ethnic differences in the risk of intracranial hemorrhage among patients with atrial
fibrillation. J Am Coll Cardiol. 2007;50(4):309-15.
32. Anderson JL, Horne BD, Stevens SM, et al. Randomized trial of genotype-guided versus standard warfarin dosing in patients initiating oral
anticoagulation. Circulation. 2007;116(22):2563-70. Available at: http://circ.
ahajournals.org/cgi/reprint/116/22/2563. Accessed March 6, 2009.
33. Gurwitz JH, Field TS, Radford MJ, et al. The safety of warfarin therapy
in the nursing home setting. Am J Med. 2007;120(6):539-44.
34. Meier DJ, Seva S, Fay WP. A comparison of anticoagulation results of
patients managed with narrow vs standard international normalized ratio
target ranges. [letter] J Thromb Hemost. 2007 5(6):1332-34. Available at:
http://www3.interscience.wiley.com/cgi-bin/fulltext/117993848/PDFSTART.
Accessed March 6, 2009.
35. Hylek EM, Evans-Molina C, Shea C, Henault LE, Regan S. Major hemorrhage and tolerability of warfarin in the first year of therapy among elderly
patients with atrial fibrillation. Circulation. 2007;115(21):2689-96. Available
at: http://circ.ahajournals.org/cgi/reprint/115/21/2689. Accessed March 9,
2009.
36. Grogan KM, Wong C, Nutescu EA, Shord SS. Examining differences in
weekly warfarin dose in patients with and without cancer. Ther Drug Monit.
2007;29(5):638-43.
37. Ansell J, Hollowell J, Pengo V, Martinez-Brotons F, Caro J, Drouet L.
Descriptive analysis of the process and quality of oral anticoagulation management in real-life practice in patients with chronic non-valvular atrial
fibrillation: the International Study of Anticoagulation Management (ISAM).
J Thromb Thrombolysis. 2007;23(2):83-91.
38. Nichol MB, Knight TK, Dow T, et al. Quality of anticoagulation monitoring in nonvalvular atrial fibrillation patients: comparison of anticoagulation
clinic versus usual care. Ann Pharmacother. 2008;42(1):62-70.
39. Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy
to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann
Intern Med. 2007;146(12):857-67. Available at: http://www.annals.org/cgi/
reprint/146/12/857.pdf. Accessed March 20, 2009.
40. Birman-Deych E, Radford MJ, Nilasena DS, Gage BF. Use and effectiveness of warfarin in Medicare beneficiaries with atrial fibrillation.
Stroke. 2006;37(4):1070-74. Available at: http://stroke.ahajournals.org/cgi/
reprint/37/4/1070. Accessed March 6, 2009.
41. Dolan G, Smith LA, Collins S, Plumb JM. Effect of setting, monitoring, intensity and patient experience on anticoagulation control: a systematic review and meta-analysis of the literature. Curr Med Res Opin.
2008;24(5):1459-72.
42. Reynolds MW, Fahrbach K, Hauch O, et al. Warfarin anticoagulation
and outcomes in patients with atrial fibrillation: a systematic review and
metaanalysis. Chest. 2004;126(6):1938-45. Available at: http://www.chestjournal.org/content/126/6/1938.full.pdf+html. Accessed March 6, 2009.
43. You JH, Chan FW, Wong RS, Cheng G. Cost-effectiveness of two models
of management for patients on chronic warfarin therapy–a Markov model
analysis. Thromb Haemost. 2003;90(6):1106-11.
44. Sullivan PW, Arant TW, Ellis SL, Ulrich H. The cost effectiveness of anticoagulation management services for patients with atrial fibrillation and at
high risk of stroke in the US. Pharmacoeconomics. 2006;24(10):1021-33.
45. Caro JJ. An economic model of stroke in atrial fibrillation: the cost
of suboptimal oral anticoagulation. Am J Manag Care. 2004;10(14 Suppl):
451S-461S.
www.amcp.org
RESEARCH
Analysis of Drug Content and Weight Uniformity for
Half-Tablets of 6 Commonly Split Medications
Shaynan W. Hill, PharmD; Andrew S. Varker, PharmD; Kelly Karlage, BS; and Paul B. Myrdal, PhD
ABSTRACT
BACKGROUND: Cost savings can be achieved with the practice of tablet
splitting. Previous research has shown weight nonuniformity within tablet
halves. However, limited research to date has found that the potential dose
inaccuracy resulting from splitting tablets does not significantly affect clinical outcomes.
OBJECTIVE: To determine the drug content and weight in split half-tablets
of 6 commonly split medications using drug assay analysis.
METHODS: This study was performed by 2 fourth-year pharmacy students
using 30 randomly selected tablets of each of the following 6 medications:
warfarin sodium 5 milligrams (mg), simvastatin 80 mg, metoprolol succinate 200 mg, metoprolol tartrate 25 mg, citalopram 40 mg, and lisinopril
40 mg. A randomly selected half of the tablets were split by a single pharmacy student using a tablet cutter, and the remaining tablets were kept
whole. Drug content was analyzed for 15 whole tablets and 30 half-tablets
for each of the 6 drugs using high performance liquid chromatography, an
analytical tool used to identify and quantify substances in solution. Drug
content uniformity was assessed by comparing drug content within halftablets with one-half of the drug content mean found for all whole tablets
in the sample. Weight uniformity was assessed by comparing half-tablet
weights, as determined by a Mettler analytical balance, with one-half
of the mean weight for whole tablets in the sample. The percentages by
which each whole tablet’s or half-tablet’s drug content and weight differed from sample mean values were compared with proxy United States
Pharmacopeia (USP) specification ranges for drug content (95%-105% for
warfarin sodium and 90%-110% for the other 5 drugs). Additionally, these
outcomes were compared for nonscored versus scored tablets. The percent
relative standard deviation (%RSD, ratio of the standard deviation to the
mean), a commonly used measure of the repeatability and precision of
assays used to analyze drug content, was also calculated in order to determine whether the drugs met proxy USP specification for %RSD (less than
6% for all drugs studied).
RESULTS: A total of 43 of 180 half-tablets (23.9%) differed from sample
mean values by a percentage that fell outside of proxy USP specification for
drug content; warfarin sodium (11 of 30 half-tablets, 36.7%), simvastatin
(3 of 30 half-tablets, 10.0%) metoprolol succinate (10 of 30 half-tablets,
33.3%), metoprolol tartrate (4 of 30 half-tablets, 13.3%), citalopram (5
of 30 half-tablets, 16.7%), and lisinopril (10 of 30 half-tablets, 33.3%).
Half-tablets outside of proxy USP specification for weight included warfarin sodium (10 of 30 half-tablets, 33.3%), metoprolol succinate (6 of 30
half-tablets, 20%), and lisinopril (7 of 30 half-tablets, 23.3%). The %RSDs
for drug content and weight fell outside of the proxy USP specification for
%RSD for metoprolol succinate (drug content = 8.98%, weight = 7.70%) and
lisinopril (drug content = 10.41%, weight = 8.13%). Mean percent weight
loss after splitting was less than 1% for all drugs except lisinopril, which
had an average weight loss of 1.25%. The total numbers of scored (nonscored) tablet halves that fell outside of proxy USP specification were 20
(23) for drug content and 10 (13) for weight. When measuring drug content,
the numbers of out-of-range half-tablets for scored (nonscored) drugs were
36 (44) at 95%-105%, 9 (23) at 90%-110%, 0 (10) at 85%-115%, and 0 (1)
at 75%-125%. When measuring weight, the numbers of out-of-range halftablets for scored (nonscored) drugs were 28 (38) at 95%-105%, 0 (14) at
90%-110%, 0 (3) at 85%-115%, and 0 (0) at 75%-125%.
Note: This article is the subject of a commentary that appears on pages 272-274 of this issue.
www.amcp.org
CONCLUSION: Dose variation exceeded a proxy USP specification for more
than one-third of sampled half-tablets of warfarin sodium, metoprolol
succinate, and lisinopril and appeared to be greater for nonscored tablets
as compared with scored tablets. Drug content variation in half-tablets
appeared to be attributable primarily to weight variation occurring when
tablets powder or fragment during the splitting process. Therefore, equal
daily doses will be determined by the ability of patients to split tablets perfectly in half.
J Manag Care Pharm. 2009;15(3):253-61
Copyright © 2009, Academy of Managed Care Pharmacy. All rights reserved.
What is already known about this subject
• Manufacturers of FDA-approved medications are required to
adhere to the United States Pharmacopeia (USP) established
ranges for drug content of whole tablets. The USP has created
guidelines to compare drug content for whole tablets; however,
no guidelines have been established to assess the drug content of
half-tablets.
• Teng et al. (2002) found that only 3 of 11 medications passed
an adapted USP uniformity test when half-tablet drug content
uniformity was estimated from half-tablet weight after splitting of
tablets by hand or razor blade.
• To date, 4 published studies have shown that the potential inaccuracy of dose resulting from splitting tablets does not significantly affect clinical and humanistic outcomes.
What this study adds
• This is the first study to determine drug content uniformity
within half-tablets using drug assay; target drug content was
defined as one-half of the per-tablet mean drug content for all
whole tablets in a sample of 15 whole tablets each of 6 commonly
split medications.
• More than 30% of measured half-tablets (n = 30 each drug) of
warfarin sodium, metoprolol succinate, and lisinopril differed
from the target drug content by a percentage that fell outside
of the proxy USP specification (95%-105% for warfarin sodium
and 90%-110% for the other 5 drugs). For all other medications
studied (simvastatin, metoprolol tartrate, and citalopram), 10%17% of half-tablets fell outside of proxy USP specification for drug
content.
• Only 5 of 180 (2.8%) half-tablets in a weight-adjusted analysis, as
compared with 43 of 180 (23.9%) half-tablets in an analysis that
was not weight-adjusted, fell outside of the proxy USP specification for drug content. Thus, drug content variation in half-tablets
appears to be attributable primarily to weight variation occurring
when tablets powder or fragment during the splitting process.
Vol. 15, No. 3
April 2009
JMCP
Journal of Managed Care Pharmacy 253
Analysis of Drug Content and Weight Uniformity for Half-Tablets of 6 Commonly Split Medications
T
ablet splitting has become increasingly common, especially within the geriatric and psychiatric communities,
as a means of reducing medication dose and/or cost.
Physicians frequently write prescriptions for half-tablets in order
to achieve doses less than the smallest available manufactured
strength. Prescribers also write for half- and quarter-tablet doses
of higher-strength tablets in order to reduce costs because parity
pricing (the use of flat rates for medications independent of dose
strength) is common. Cohen and Cohen (2000) showed that an
annual savings of $1.45 billion could be achieved when tablet
splitting was performed for 12 specific psychotropic medications,
while annual savings of $725 million and $325 million could be
achieved from splitting one-half and one-fourth of prescriptions
written, respectively.1 Cohen and Cohen later (2002) estimated
potential cost savings of $1.7 billion nationally if tablet splitting
was performed for 7 antidepressant medications.2 Miller et al.
(2007) found that tablet splitting contributed $342,239 (about
$1.30 per member per month [PMPM]) or 17.3% of total annualized savings of $1,983,153 attributed to 4 managed care interventions that included (a) moving certain brand name drugs in
6 drug classes to nonpreferred status, (b) removing low-sedating
antihistamines from the formulary, (c) limiting the quantity supplied for sedative sleep aids, and (d) tablet splitting for 9 brand
name drugs (6 antidepressants and 3 statins).3 Stafford and
Radley (2002) estimated that tablet splitting for 11 drugs was
infrequent, accounting for annual savings of only $0.03 PMPM
compared with potential savings of $1.14 PMPM.4
Although cost savings may be accomplished, problems may
arise with tablet splitting such as poor cognitive function or
memory, the inability of patients to effectively split tablets, and
the fear of inaccurate dose. The “Uniformity of Dosage Units” section in the U.S. Pharmacopeia (USP) manual states that each unit
within a single lot of a given medication should have drug substance content that is within a narrow range around the labeled
claim.5 Several studies have looked at weight variation of split
tablets as a means of estimating drug content uniformity. Teng
et al. (2002) evaluated the weight uniformity of 11 commonly
split medications through an analysis of half-tablet weights, using
a uniformity test adapted from the USP specifications.6 Eight
medications were split using a single-edged razor blade, and 3
were split by hand (i.e., using only tensile strength of the fingers
or hands). Results revealed that only 3 of 11 medications passed
their adapted USP specifications, and there were no obvious tablet features (e.g., scoring) that determined whether a tablet would
pass or fail the uniformity test. This study also found that tablets
split by hand showed less uniformity than did tablets split using
a razor blade, even though splitting tablets by hand produced
cleaner splits with less tablet crumbling.
A similar study performed by Polli et al. assessed content
uniformity through the analysis of half-tablet weights using the
same adapted USP methods as used by Teng et al.7 In contrast
to the results found by Teng et al., this study, performed at a
254 Journal of Managed Care Pharmacy
JMCP
April 2009
Vol. 15, No. 3
Department of Veterans Affairs (VA) center, found that 8 out of 12
medications split with a tablet-splitting device passed the adapted
uniformity test.7 Another study analyzed the drug weight uniformity of cyclobenzaprine tablets split in half using either a tablet
splitter or a kitchen knife.8 The results showed that both methods
resulted in a wide variation in fragment weight between 49.9% to
149.5% of the theoretical weight (defined as one-half of the mean
weight of the intact tablet) using a kitchen knife and 69.4% to
130.2% using the tablet splitter. Thus, both methods failed the
quality standards for dosage uniformity of manufactured drugs as
outlined by Teng et al.8 Rosenberg et al. (2002) evaluated content
uniformity of discontinued pharmacist-dispensed split-tablet
samples taken from 4 long-term care facilities using a total of 560
fragments.9 These authors found that 2 of 22 medications had
significantly different fragment weights as compared with the
theoretical weight of the half-tablets. The researchers also found
that 30 of the 560 fragments deviated by more than 15% of the
sample mean fragment weight, and 32 of the 560 fragments deviated by more than 15% of the theoretical weight. Lastly, 15 of the
22 medications were found to have relative standard deviations
for weight expressed as a percentage (%RSDs) in excess of 6%, the
upper limit of the USP specification.9
Although studies of weight differences among split tablets
have been performed, the more important analysis of drug content has yet to be explored. Studies to date have assessed drug
content uniformity only as variation in half-tablet weights. These
studies adapted the USP manual section entitled “Uniformity of
Dosage Units”—criteria developed to ensure that actual drug
content is equivalent to manufacturer-labeled drug content—and
indirectly measured half-tablet drug content by measuring halftablet weight.5 Although USP guidelines enforce strict adherence
to drug content per dosage unit for whole tablets, guidelines for
the drug content of split tablets have yet to be established.
In the present study, we defined the target drug content and
weight of a half-tablet as equal to one-half of the mean drug content and weight, respectively, for all whole tablets in a sample of 6
commonly split medications. To assess the acceptability of variation in the half-tablets, defined as the percentage by which each
individual whole tablet and half-tablet differed from the sample
mean values, we adapted USP specifications for drug content and
weight of whole tablets (proxy USP specification). We hypothesized that the drug content and weight of half-tablets would
deviate from these proxy specifications.
■■ Methods
Six drugs were studied: warfarin sodium 5 milligrams (mg), simvastatin 80 mg, metoprolol succinate 200 mg, metoprolol tartrate
25 mg, citalopram 40 mg, and lisinopril 40 mg (Table 1). These
drugs were chosen because they were observed to be commonly
split within a single VA health care network. A total of 30 whole
tablets were randomly selected from each medication lot for each
of the 6 drugs. All 30 whole tablets were weighed using a Mettler
www.amcp.org
Analysis of Drug Content and Weight Uniformity for Half-Tablets of 6 Commonly Split Medications
TABLE 1
Descriptions of Drugs Studied
Lot Number
Expiration (Date) Tablet Description
077079
Peach, non-coated,
(02/2010)
oblong tablet
Scored
Yes
Observationsa
Moderate powdering with tablet splitter,
fractured at score
Mauve, film-coated,
oval tablet
No
Minimal powdering with tablet splitter,
fractured into equal halves
ML0189
(07/2009)
White, film-coated,
oval tablet
No
Moderate powdering with tablet splitter,
fractured into equal halves
7M748
(03/2009)
White, non-coated,
circular tablet
Yes
Minimal powdering with tablet splitter,
fractured at score
Sandoz Inc.,
Princeton, NJ
CT4007008
(02/2009)
White, non-coated,
oblong tablet
Yes
Minimal powdering with tablet splitter,
fractured at score
Sandoz Inc.,
Princeton, NJ
MK070711
(06/2010)
Yellow, non-coated,
oval tablet
No
Significant powdering with tablet splitter,
fractured into equal halves
Drug
Warfarin sodium
5 mg
Manufacturer
Taro Pharmaceuticals
U.S.A. Inc., Hawthorn, NY
Simvastatin
80 mg
Dr. Reddys Laboratories
Limited, Bachepalli, India
C71045
(03/2009)
Metoprolol succinate
200 mg
AstraZeneca LP,
Wilmington, DE
Metoprolol tartrate
25 mg
Mylan Pharmaceuticals
Inc., Morgantown, WV
Citalopram
40 mg
Lisinopril
40 mg
aObservations
of tablet characteristics were made during the tablet splitting process. The first tablet split was used for this observation.
Toledo AG204 (Mettler Toledo, Inc., Columbus, Ohio) analytical
balance that is accurate to 0.1 mg. Fifteen of the 30 randomly
selected tablets were split in half by a single pharmacy student
(SH), using a Locking Tablet Cutter (Apothecary Products, Inc.),
and weighed with the Mettler Toledo analytical balance.
The 15 whole tablets and 30 half-tablets for each of the 6
drugs were then dissolved separately using a combination of
manual agitation and sonication techniques in an appropriate
diluent adapted from respective USP official monographs. All
tablets were assayed in accordance with USP methodology for
determining content uniformity for whole tablets. Assay parameters for each drug were taken directly from USP monographs;5
customary changes were made to allow for column optimization
(Appendix).5 After the tablets were completely dissolved, samples
of each solution were assayed for drug concentration via a Waters
Alliance High Pressure Chromatography system, consisting of a
2695 Separations Module coupled with a 2487 Dual Wavelength
ultraviolet (UV) detector (Waters Corporation, Milford, MA).
A standard curve was created for each drug, using pure drug
powder (obtained from LKT Laboratories, St. Paul, MN, or SigmaAldrich, St. Louis, MO) diluted to 5 known concentrations. These
standard curves were established to verify accurate analysis of the
drug, as opposed to any inactive tablet constituents, and to quantify drug content by calculating concentration from area under
the curve data obtained through high performance liquid chromatography (HPLC) analysis of whole- and half-tablet samples.
The following parameters were assessed for each of the 6
medications (Table 2):
1. Measured drug content:
a. Each whole tablet’s drug content (n = 15) was compared
with the target drug content for whole tablets, defined as
the mean measured drug content for all whole tablets in the
sample.
b. Each half-tablet’s drug content (n = 30) was compared with
www.amcp.org
the target drug content for half-tablets, defined as one-half
of the mean measured drug content for all whole tablets in
the sample.
2. Weight-adjusted target drug content: To account for tablet
powdering/fragmenting and the inability to split tablets into
perfectly equal halves, each half-tablet’s target drug content
(n = 30) was adjusted for the weight of the fragment. The
adjustment formula assumed that within a single half-tablet of
known weight, the half-tablet’s proportion of the whole-tablet
drug content should equal the half-tablet’s proportion of the
whole-tablet weight (e.g., if a half-tablet was 51% of the wholetablet weight, it should equal 51% of the whole-tablet target
drug content).
3. Measured weight:
a. Each whole tablet’s weight (n = 15) was compared with the
target weight for whole tablets, defined as the mean measured weight mean for all whole tablets in the sample.
b. Each half-tablet weight (n = 30) was compared with onehalf of the target weight for whole tablets.
4. For each tablet, the percentage weight loss due to fragmenting and/or powdering was calculated as ([measured weight
of whole tablet – measured weight of both half-tablets] / measured weight of whole tablet) x 100.
5. Nonscored drug tablets (n = 90; simvastatin, metoprolol succinate, and lisinopril) were compared with scored drug tablets
(n = 90; warfarin sodium, citalopram, and metoprolol tartrate)
on 2 outcome measures, half-tablet drug content and halftablet weight
To assess the amount and acceptability of variations in drug
content and weight, several measures were calculated. The measured drug content expressed as a percent of target drug content
was calculated for both whole and half-tablets using the following
equation: ([target drug content – measured drug content] / target
drug content) x 100. Individual values for whole tablets should
Vol. 15, No. 3
April 2009
JMCP
Journal of Managed Care Pharmacy 255
Analysis of Drug Content and Weight Uniformity for Half-Tablets of 6 Commonly Split Medications
TABLE 2
Definitions of Terms
United States Pharmacopeia (USP)
A publication that contains legally recognized standards of identity, strength, quality, purity, packaging, and labeling
for drug substances; dosage forms, and other therapeutic products, including nutritionals and dietary supplements.
Percent (%) RSD
Ratio of the standard deviation to the mean.
standard deviation for measured variable x 100
measured variable mean
A curve consisting of 5 known concentrations of the drug created using pure drug—used to determine that the
drug was isolated by HPLC as opposed to other tablet constituents.
5- point standard curve
High Performance (Pressure) Liquid
Chromatography (HPLC)
A form of liquid chromatography used to separate compounds that are dissolved in solution.
Measured drug content
Measured weight
Target drug content for individual
tablet or half-tablet (measured drug
content mean per tablet for sample)
The amount of drug (mg) determined to be within the whole or half-tablet analyzed using HPLC.
The weight (mg) of the whole or half-tablet as measured using a Mettler analytical balance.
Whole tablets: ∑ drug content for whole tablets
number of whole tablets
Half-tablets: ∑ drug content for half-tablets
number of half-tablets
Whole tablets: ∑ weight for whole tablets
number of whole tablets
Half-tablets: ∑ weight for half-tablets
number of half-tablets
Target weight for individual tablet or
half-tablet (measured weight mean
per tablet for sample)
Weight-adjusted target drug content
Percent of weight-adjusted drug
content
The amount expected to be found within a single half-tablet of known weight, assuming that the half-tablet’s
proportion of whole tablet drug content equals the half-tablet’s proportion of whole tablet weight.
measured half-tablet weight x target drug content for whole tablets
measured whole tablet weight
Measured half-tablet drug content as a percent of weight-adjusted target drug content.
measured drug content for half-tablet x 100
weight-adjusted target drug content
Percent of target drug content
For each tablet or half-tablet, expresses measured drug content as a percentage of target drug content.
Whole tablets: Measured drug content for whole tablet x 100
Target drug content for whole tablets
Half-tablets: Measured drug content for half-tablet x 100
Target drug content for half-tablets
Percent of target weight
For each tablet or half-tablet, expresses measured weight as a percentage of target weight.
Whole tablets: Measured weight for whole tablet x 100
Target weight for whole tablets
Half-tablets: Measured weight for half-tablet x 100
Target weight for half-tablets
The amount of drug loss caused by the splitting process.
weight of whole tablet – weight of half-tablet #1 – weight of half-tablet #2 x 100
weight of whole tablet
Measured drug content of whole or half-tablets within 95%-105% of target drug content for half-tablets for
warfarin sodium and within 90%-110% of target drug content for half-tablets for simvastatin, metoprolol succinate,
metoprolol tartrate, citalopram, and lisinopril.
Measured weight of whole or half-tablets within 95%-105% of target weight for half-tablets for warfarin sodium
and within 90%-110% of target weight for half-tablets for simvastatin, metoprolol succinate, metoprolol tartrate,
citalopram, and lisinopril.
%RSD for whole or half-tablets less than 6%.
Mean percent weight loss
Proxy USP specification for drug
content
Proxy USP specification for weight
Proxy USP specification for %RSD
HPLC = high performance liquid chromatography; mg = milligrams; RSD = relative standard deviation.
fall within 95%-105% for warfarin sodium and 90%-110% for the
other 5 drugs studied (proxy USP specification for drug content)
according to the individual USP drug monographs. Because no
USP criteria for drug content uniformity of half-tablets have yet
been established, this study applied the proxy USP specification
for whole tablets to half-tablets. It should be noted that the proxy
USP specification ranges chosen for this study are the more stringent of ranges described within the individual USP monographs.
256 Journal of Managed Care Pharmacy
JMCP
April 2009
Vol. 15, No. 3
The tighter range is typically applied to samples of 20 or greater.
However, individual tablets are typically subjected to a specification range of 85%-115%.
Relative standard deviation expressed as a percentage (%RSD),
which is a ratio of the standard deviation to the mean of the
variable being analyzed, was calculated for whole tablets (drug
content and weight) and for half-tablets (drug content, weightadjusted drug content, and weight). The %RSD is widely used to
www.amcp.org
Analysis of Drug Content and Weight Uniformity for Half-Tablets of 6 Commonly Split Medications
TABLE 3
Drug
Warfarin sodium
Simvastatin
Metoprolol succinate
Metoprolol tartrate
Citalopram
Lisinopril
Warfarin sodium
Simvastatin
Metoprolol succinate
Metoprolol tartrate
Citalopram
Lisinopril
Warfarin sodium
Simvastatin
Metoprolol succinate
Metoprolol tartrate
Citalopram
Lisinopril
Whole- and Half-Tablet Drug Content
Whole (n = 15)
Whole (n = 15)
Whole (n = 15)
Whole (n = 15)
Whole (n = 15)
Whole (n = 15)
Half (n = 30)
Half (n = 30)
Half (n = 30)
Half (n = 30)
Half (n = 30)
Half (n = 30)
Half wt adj (n = 30)
Half wt adj (n = 30)
Half wt adj (n = 30)
Half wt adj (n = 30)
Half wt adj (n = 30)
Half wt adj (n = 30)
Target Drug
Content (mg)a
------------2.56
38.80
98.04
12.64
19.13
20.46
-------------
Measured Drug
Content
Mean (mg)b
5.12
77.61
196.07
25.29
38.25
40.91
2.57
40.06
98.26
13.14
19.93
21.80
2.55
38.77
97.87
12.57
19.08
22.00
Percent of Target
Drug Content Rangec
97.39 – 102.66
95.74 – 107.15
97.39 – 102.71
94.68 – 106.81
96.14 – 107.80
95.46 – 104.35
90.01 – 109.40
95.21 – 111.35
82.77 – 115.92
94.83 – 112.37
96.50 – 111.93
81.15 – 125.72
95.80 – 107.15
98.95 – 107.79
93.81 – 104.08
101.00 – 108.08
97.89 – 110.75
94.23 – 112.08
%RSD
1.81
3.27
1.63
2.82
3.12
2.05
5.05
4.29
8.98
4.73
4.50
10.41
4.64
3.45
7.67
5.26
3.18
8.07
Outside of
Proxy USP
Specificationd
0
0
0
0
0
0
11 (36.7%)
3 (10.0%)
10 (33.3%)
4 (13.3%)
5 (16.7%)
10 (33.3%)
3 (10.0%)
0
0
0
1 (3.33%)
1 (3.33%)
aTarget drug content for whole tablets is equal to the measured drug content mean per tablet for the sample. Target drug content for half-tablets is one-half of the measured
drug content mean.
bMean drug content values per whole tablet or half-tablet as determined by HPLC.
c A range (smallest to largest) representing measured drug content for whole or half-tablets expressed as a percent of target drug content.
d Number of whole or half-tablets with measured drug content not within 95%-105% of target drug content for warfarin sodium or 90%-110% of target drug content for simvastatin, metoprolol succinate, metoprolol tartrate, citalopram, and lisinopril.
HPLC = high performance liquid chromatography; mg = milligram; %RSD = relative standard deviation expressed as a percentage; USP = United States Pharmacopeia; wt
adj = weight-adjusted.
assess the repeatability and precision of the assays used to analyze
drug content. The %RSD for drug content for all drugs studied
was calculated using the following equation: (standard deviation
for measured drug content / measured drug content mean) x 100.
The %RSD for weight for all drugs studied was calculated using
the following equation: (standard deviation for measured weight
/ measured weight mean) x 100. Individual medication lots for
whole tablets are targeted to have a %RSD less than 6% (proxy
USP specification for %RSD).5
The percentage by which weight-adjusted drug content differed from target drug content was calculated using the following
equation: (measured drug content for half-tablet / weight-adjusted
target drug content for half-tablet) x 100.
■■ Results
Drug Content
For all whole tablets studied, measured drug content expressed as
a percent of target drug content was found to fall within the proxy
USP specification percentage range (Table 3). All whole tablets
also met the proxy USP specification for %RSD. The measured
drug content expressed as a percent of target drug content for
www.amcp.org
half-tablets fell outside of the proxy USP specification for drug
content for at least 3 half-tablets of each drug studied. A total of
43 of 180 half-tablets (23.9%) fell outside of the proxy USP specification for drug content; warfarin sodium (11 of 30 half-tablets,
36.7%), simvastatin (3 of 30 half-tablets, 10.0%) metoprolol succinate (10 of 30 half-tablets, 33.3%), metoprolol tartrate (4 of 30
half-tablets, 13.3%), citalopram (5 of 30 half-tablets, 16.7%), and
lisinopril (10 of 30 half-tablets, 33.3%). The measured drug content variations expressed as a percent of target drug content for
half-tablets were, from smallest to the largest, warfarin sodium
(90.01-109.40%), simvastatin (95.21%-111.35%), metoprolol succinate (82.77%-115.92%), metoprolol tartrate (94.83%-112.37%),
citalopram (96.50-111.93%), and lisinopril (81.15%-125.72%).
Metoprolol succinate and lisinopril were the only agents analyzed
that fell outside of the proxy USP specification for %RSD, with
%RSD values of 8.98% and 10.41%, respectively.
Weight-adjusted drug content expressed as a percent of
target drug content for half-tablets fell outside of the proxy
USP specification for drug content for at least 1 half-tablet of 3
drugs—warfarin sodium, citalopram, and lisinopril (Table 3).
A total of 5 of 180 half-tablets (2.78%) fell outside of the proxy
Vol. 15, No. 3
April 2009
JMCP
Journal of Managed Care Pharmacy 257
Analysis of Drug Content and Weight Uniformity for Half-Tablets of 6 Commonly Split Medications
TABLE 4
Drug
Warfarin sodium
Simvastatin
Metoprolol succinate
Metoprolol tartrate
Citalopram
Lisinopril
Warfarin sodium
Simvastatin
Metoprolol succinate
Metoprolol tartrate
Citalopram
Lisinopril
Whole- and Half-Tablet Weight
Whole (n = 15)
Whole (n = 15)
Whole (n = 15)
Whole (n = 15)
Whole (n = 15)
Whole (n = 15)
Half (n = 30)
Half (n = 30)
Half (n = 30)
Half (n = 30)
Half (n = 30)
Half (n = 30)
Target Weight
(mg)a
------------110.00
407.30
350.35
76.92
134.03
112.17
Measured
Weight Mean
(mg)b
219.99
814.59
700.69
153.85
268.05
224.33
109.36
404.09
349.62
76.91
132.84
110.30
%RSD
1.03
0.45
0.75
0.82
0.89
0.99
4.73
3.51
7.70
5.38
3.37
8.13
Mean Percent
Weight
Loss (SD)c
------------0.50 (0.46)
0.08 (0.04)
0.17 (0.47)
0.57 (0.31)
0.24 (0.16)
1.25 (1.14)
Percent of Target
Weight - Ranged
97.87 – 101.64
99.17 – 100.76
98.82 – 101.34
98.73 – 102.27
98.00 – 101.44
98.65 – 102.21
90.69 – 108.88
93.32 – 105.97
85.71 – 112.97
91.83 – 109.05
92.24 – 107.38
82.16 – 113.27
Outside of
Proxy USP
Specificatione
0
0
0
0
0
0
10 (33.3%)
0
6 (20.0%)
0
0
7 (23.3%)
aTarget
weight for whole tablets is equal to the measured weight mean per tablet for the sample. Target weight for half-tablets is one-half of the measured weight mean.
weight per whole tablet or half-tablet as determined by a Mettler analytical balance.
cThe mean amount of drug loss caused by the splitting process.
d A range (smallest to largest) representing measured weight for whole or half-tablets expressed as a percent of target weight.
eNumber of whole or half-tablets with measured weight not within 95%-105% of target weight for warfarin sodium or 90%-110% of target weight for simvastatin, metoprolol
succinate, metoprolol tartrate, citalopram, and lisinopril.
mg = milligrams; %RSD = relative standard deviation expressed as a percentage; USP = United States Pharmacopeia.
bMean
USP specification for drug content after weight adjustment; these
included warfarin sodium (3 of 30 half-tablets, 10%), citalopram
(1 of 30 half-tablets, 3.33%), and lisinopril (1 of 30 half-tablets,
3.33%). Metoprolol succinate and lisinopril were the only agents
analyzed that fell outside of the proxy USP specification for %RSD
after weight adjustment, with %RSD values of 7.67% and 8.07%,
respectively.
Weight
For all whole tablets studied, measured weight expressed as a
percent of target weight was found to fall within the proxy USP
specification for weight (Table 4). All whole tablets also met the
proxy USP specification for %RSD. Measured weight expressed as
a percent of target weight for half-tablets fell outside of the proxy
USP specification for weight for at least 6 half-tablets of warfarin
sodium, metoprolol succinate, and lisinopril. A total of 23 of 180
half-tablets (12.8%) fell outside of the proxy USP specification for
weight; these included warfarin sodium (10 of 30 half-tablets,
33.3%), metoprolol succinate (6 of 30 half-tablets, 20.0%), and
lisinopril (7 of 30 half-tablets, 23.3%). Metoprolol succinate and
lisinopril were the only agents analyzed that fell outside of the
proxy USP specification for %RSD, with %RSD values of 7.70%
and 8.13%, respectively.
Mean percent weight loss, after splitting, was less than 1%
for all drugs with the exception of lisinopril: warfarin sodium
(0.50%), simvastatin (0.08%), metoprolol succinate (0.17%),
metoprolol tartrate (0.57%), citalopram (0.24%), and lisinopril
(1.25%; Table 4).
258 Journal of Managed Care Pharmacy
JMCP
April 2009
Vol. 15, No. 3
Scored Versus Nonscored Tablets
A total of 20 of 90 (22.2%) half-tablets of scored medications,
and a total of 23 of 90 (25.6%) half-tablets of nonscored medications fell outside of the proxy USP specification for drug content
(Table 5). The numbers of half-tablets for scored (nonscored)
drugs falling outside of range for drug content were 36 (44) for
95%-105%, 9 (23) for 90%-110%, 0 (10) for 85%-115%, and 0 (1)
for 75%-125%.
A total of 10 of 90 (11.1%) half-tablets of scored medications,
and a total of 13 of 90 (14.4%) half-tablets of nonscored medications fell outside of the proxy USP specification for weight (Table
6). The numbers of half-tablets for scored (nonscored) drugs falling outside of range for weight were 28 (38) for 95%-105%, 0 (14)
for 90%-110%, 0 (3) for 85%-115%, and 0 (0) for 75%-125%.
■■ Discussion
When measured half-tablet drug content was compared against
target drug content (one-half of the sample mean drug content)
for each of 6 study medications, 43 of 180 half-tablets (23.9%) fell
outside of a proxy USP specification percentage range. Warfarin
sodium had the highest number of half-tablets falling out of its
proxy specification range, most likely due to its narrower specification window of 95%-105%. Metoprolol succinate and lisinopril
were found to have a relatively large number of half-tablets with
drug content falling outside of the range of 90%-110%. Variation
in half-tablet drug content was greatest with lisinopril, which had
tablet halves ranging from 81.15% to 125.72% of the target drug
www.amcp.org
Analysis of Drug Content and Weight Uniformity for Half-Tablets of 6 Commonly Split Medications
TABLE 5
Tablet type
Scoredd
Nonscorede
Comparison of Scored and Nonscored Half-Tablets: Drug Content
n
90
90
Percent of Target
Drug Content Rangea
89.85 – 112.37
81.15 – 125.72
Outside of
Proxy USP
Specificationb
20 (22.2%)
23 (25.6%)
Out of Range
(95% - 105%)c
36 (40.0%)
44 (48.9%)
Out of Range
(90% - 110%)c
9 (10.0%)
23 (25.9%)
Out of Range
(85% - 115%)c
0
10 (11.1%)
Out of Range
(75% - 125%)c
0
1 (1.1%)
aA
range (smallest to largest) representing measured drug content for whole or half-tablets expressed as a percent of target drug content.
of half-tablets with measured drug content not within 95%-105% of target drug content for half-tablets for warfarin sodium or 90%-110% of target drug content
for half-tablets for simvastatin, metoprolol succinate, metoprolol tartrate, citalopram, and lisinopril.
cDetermined by HPLC. The number (%) of half-tablets that fell outside of the range listed for drug content expressed as a percentage of target half-tablet drug content.
dWarfarin sodium, metoprolol tartrate, and citalopram tablets were scored.
e Simvastatin, metoprolol succinate, and lisinopril tablets were not scored.
HPLC = high performance liquid chromatography; USP = United States Pharmacopeia.
bNumber
TABLE 6
Tablet type
Scoredd
Nonscorede
Comparison of Scored and Nonscored Half-Tablets: Weight
n
90
90
Percent of Mean
Weight - Rangea
90.69 – 109.05
82.16 – 113.27
Outside of proxy
USP Specificationb
10 (11.1%)
13 (14.4%)
Out of Range
(95% - 105%)c
28 (31.1%)
38 (42.2%)
Out of Range
(90% - 110%)c
0
14 (15.6%)
Out of Range
(85% - 115%)c
0
3 (3.3%)
Out of Range
(75% - 125%)c
0
0
aA
range (smallest to largest) representing measured weight for whole or half-tablets expressed as a percent of target weight.
(%) of half-tablets with measured weight not within the 95%-105% specification range for warfarin sodium or 90%-110% for the other 5 drugs.
cDetermined by Mettler analytical balance. The number (%) of half-tablets that fell outside of the range listed for drug weight expressed as a percentage of target half-tablet
drug weight.
dWarfarin sodium, metoprolol tartrate, and citalopram tablets were scored.
e Simvastatin, metoprolol succinate, and lisinopril tablets were not scored.
USP = United States Pharmacopeia.
bNumber
content for half-tablets. Thus, when tablet splitting is performed
for this lot of lisinopril, patients may receive daily doses that vary
by as much as 45%.
Several potential reasons could explain the observed variation in lisinopril half-tablet drug content. Inaccuracy during the
tablet splitting process may have produced variability between
tablet halves due to unequal half-tablet size. This argument is
supported by the weight-adjusted data: Only a single lisinopril
half-tablet fell outside of the range of 90%-110% when half-tablet
drug content was adjusted for weight as compared with 10 halftablets when the data were not adjusted for weight. The results
for lisinopril may also have been affected by weight loss due to
the powdering and fragmenting that occurred during tablet splitting. Although lisinopril half-tablets were shown to have a mean
percent weight loss of 1.25%, the majority of lisinopril half-tablets
did not fall outside the proxy USP specification for drug content
until the weight loss was greater than 1.72%.
Both metoprolol succinate and metoprolol tartrate may also
have been affected by the inability of the tablet splitting device to
accurately split medications into 2 equal halves. Additionally, for
metoprolol succinate, a greater percent of drug content variation
may be attributed to tablet formulation, specifically regarding the
sustained release mechanism. This drug is found within nondis-
www.amcp.org
solving pellets intended to provide a slow release of the drug.
Without the ability to visualize the inside of individual drug pellets, complete dissolution could not be easily determined.
Metoprolol succinate and lisinopril were shown to have %RSD
values greater than 6% with regard to drug content and weight.
This finding indicates that tablets of these medications are not
easily split into equal halves when using a tablet-splitting device.
Lisinopril had the greatest degree of drug content variability, with
a %RSD of greater than 10%, perhaps in part because lisinopril
had the greatest amount of weight loss from splitting. The high
level of variability for metoprolol succinate may be due to the
extended release drug delivery system.
Following the splitting process, half-tablet weight measurements revealed unequal splitting; this finding is likely a result of
tablet powdering and limitations of the tablet splitter, person, and
device. When half-tablet drug content was adjusted for weight, a
large reduction in drug content variation was found. Thus, halftablet weight appears to be directly correlated with drug content.
When compared with the target drug content of a perfectly split
tablet half, 43 of 180 half-tablets (23.9%), but only 5 of 180
weight-adjusted half-tablets (2.8%), fell outside of proxy USP
specification for drug content. Warfarin sodium accounted for the
majority of weight-adjusted half-tablets falling outside of proxy
Vol. 15, No. 3
April 2009
JMCP
Journal of Managed Care Pharmacy 259
Analysis of Drug Content and Weight Uniformity for Half-Tablets of 6 Commonly Split Medications
USP specification for drug content (3 of the 5 half-tablets). It was
also observed that the %RSD for weight-adjusted drug content
for all medications was reduced in comparison with non-weightadjusted drug content. These results would appear to indicate
that the drug is uniformly dispersed within single whole tablets.
The data suggest greater variability in half-tablet drug content
and weight for nonscored medications than for scored medications. Although nonscored and scored tablets produced roughly
an equivalent number of half-tablets falling outside of proxy
USP specification for drug content and weight, it was found that
greater variability existed with the nonscored drug tablets. More
nonscored drug half-tablets were found to have drug content
and weight within the ranges of 85%-115% and 75%-125%. This
finding suggests that when a tablet-splitting device is used, dose
administration may be more accurate and consistent for scored
than nonscored medications; however, a larger sample of scored
and nonscored tablets is needed to determine if there is a significant difference between scored and nonscored tablets.
The pharmacokinetics and the mechanisms by which these
medications act would appear to dictate that half-tablet regimens
may or may not have a clinical impact on long-term patient
outcomes. Metoprolol succinate, lisinopril, and citalopram are
agents with long durations of action, in which minor dose variation should have no significant impact on steady state plasma
concentrations. Additionally, citalopram efficacy is highly subjective; thus, daily efficacy measurements can be variable regardless
of small dose variation. Statins, including simvastatin, are agents
designed to prevent downstream medical problems such as acute
coronary syndromes and stroke; thus, small changes in daily
dose should have no significant impact on long-term clinical end
points. Lastly, antihypertensives, including angiotensin-converting enzyme inhibitors and beta blockers, are used to prevent
medical problems associated with an elevated blood pressure
over an extended period of time, thus, daily fluctuations in dose
would be expected to affect blood pressure measurements and
side effects and have no effect on long-term clinical end points.
In contrast, caution should be taken when splitting warfarin
sodium due to the potential for significant adverse events with
minimal change in daily dose. However, daily variation of international normalized ratio (INR) values, the parameter used to
monitor warfarin sodium efficacy, can result from food interactions, drug interactions, and variations in daily dose. For this
reason, it cannot be stated that the minor differences in warfarin
sodium half-tablet drug content will predict clinical outcomes.
Comparison With Previous Research
and Clinical Significance
In order to determine true clinical significance of tablet splitting, studies looking at clinical outcomes must be examined.
Four studies known to these authors have evaluated the clinical
impact of half-tablet regimens: 3 assessing statins and 1 assessing
lisinopril.10-13 All 4 studies have shown that the dose inaccuracy
260 Journal of Managed Care Pharmacy
JMCP
April 2009
Vol. 15, No. 3
experienced from splitting tablets does not significantly affect
primary outcomes. The study by Duncan et al. (2002) performed
at a VA medical center examined triglycerides, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol
(HDL-C), and total cholesterol values for 109 patients enrolled in
a statin (atorvastatin and simvastatin) tablet splitting program.10
The study concluded that there was a significant decrease in
total cholesterol (187.6 mg per deciliter [dL] to 179.7 mg per
dL; P = 0.005) and LDL-C (111.6 mg per dL to 105.1 mg per dL;
P = 0.004) after at least 6 weeks following the initiation of the split
tablet program. Duncan et al. concluded that there was no clinically significant difference comparing the time periods before and
after the initiation of the tablet-splitting program.
A similar study performed at a different VA medical center
assessed clinical endpoints before and after the initiation of a tablet-splitting program for 2,019 patients.11 This study by Gee et al.
(2002) also found no clinically significant changes in serum lipid
levels before and after implementation of the tablet-splitting program. A more recent retrospective chart review was performed
across 6 VA medical centers, comparing 3,196 patients assigned
to a split-tablet regimen with a whole-tablet regimen of varying
simvastatin doses.12 Similar to the other previously mentioned
studies, no statistically significant difference in LDL-C was found
between patients in the split-tablet group and in the whole-tablet
comparison group (P = 0.304). A randomized crossover study
performed at another VA medical center found no statistically
significant differences in systolic or diastolic blood pressure for
patients treated with whole- and half-tablet regimens for lisinopril.13 No studies to date have been performed that assess the
clinical impact of half-tablet regimens for citalopram, metoprolol
tartrate, metoprolol succinate, or warfarin sodium; thus, no conclusions about the clinical impact of half-tablet regimens for these
agents can be made.
Limitations
First, the USP has not created a method for assessing half-tablet
drug content uniformity; thus, previous studies assessing halftablet drug content uniformity have used adapted USP methods
for assessing weight variability as a means of estimating drug
content uniformity. Second, all of the medications in this study
are now available generically, and there is little financial value
in splitting these particular drugs today. Third, the medications
chosen for analysis were determined by prevalence of tablet
splitting within a single health care network. The medications
studied may not be representative of the most commonly split
medications, and the purpose of the present research is not to
suggest which drug classes may or may not be split. For these
reasons, health care practitioners may not extrapolate the findings of this study to medications not studied. Fourth, the only
tablet-splitting technique studied was the use of a tablet-splitting
device. Splitting by hand or with sharp instruments including
knives and razor blades are also commonly used techniques
www.amcp.org
Analysis of Drug Content and Weight Uniformity for Half-Tablets of 6 Commonly Split Medications
in the outpatient setting. With greater precision and accuracy,
tablet-splitting devices generally provide greater consistency in
half-tablet doses. Thus, tablets split using other techniques may
lead to greater variability than that observed in this study. Fifth, a
single pharmacy student performed all tablet splitting and weight
measurements in an intentional effort to eliminate variability that
might be introduced by multiple testers. However, this tester’s
technique may not be representative of tablet-splitting when
performed by patients in the general population. In particular,
certain patient populations may have increased difficulty splitting tablets, such as the elderly and patients with arthritis, movement disorders, or poor cognitive function. Lastly, this research
does not permit clinical conclusions since no clinical end points
were assessed.
■■ Conclusion
Dose variation, measured as the difference between actual halftablet drug content and sample mean drug content, exceeded
a proxy USP specification for more than one-third of sampled
half-tablets of warfarin sodium, metoprolol succinate, and lisinopril. The percentages of half-tablets exceeding a proxy USP
specification for drug content were roughly equal for scored and
nonscored tablets; however, dose variation appeared to be greater
with nonscored tablets. Fewer half-tablets in a weight-adjusted
analysis than in an analysis that was not weight-adjusted fell
outside of the proxy USP specification for drug content. Thus,
drug content variation in half-tablets appears to be attributable
primarily to weight variation occurring when tablets powder
or fragment during the splitting process. Therefore, equal daily
doses will be determined by the ability of patients to split tablets
perfectly in half.
DISCLOSURES
The authors reported no external funding for this research and no financial or
other conflicts of interest related to the subject of this manuscript.
Hill was primarily responsible for the study concept and design, with
assistance from Karlage and Myrdal. The data were collected primarily by
Hill and Varker, with assistance from Karlage. Hill and Myrdal interpreted the
data, with assistance of the other 2 authors. Hill and Varker wrote the manuscript, and Varker was primarily responsible for revision of the manuscript,
with assistance from the other 3 authors.
REFERENCES
1. Cohen CI, Cohen SI. Potential cost savings from pill splitting of newer
psychotropic medications. Psychiatr Serv. 2000;51(4):527-29.
2. Cohen CI, Cohen SI. Potential savings from splitting newer antidepressant
medications. CNS Drugs. 2002;16(5):359-60.
3. Miller DP, Furberg CD, Small RH, et al. Controlling prescription drug
expenditures: a report of success. Am J Manag Care. 2007;13(8):47380. Available at: http://www.ajmc.com/files/articlefiles/AJMC_07auf_
Miller473to480.pdf. Accessed February 5, 2009.
www.amcp.org
Authors
SHAYNAN W. HILL, PharmD, is Pharmacy Practice Resident,
Department of Pharmacy, Long Beach Veterans Affairs Health
Care System, Long Beach, California. (At the time this study was
performed, Hill was a fourth-year pharmacy student, University
of Arizona College of Pharmacy, Tucson, Arizona.) ANDREW S.
VARKER, PharmD, is Pharmacy Practice Resident, Department
of Pharmacy, Phoenix Veterans Affairs Health Care System,
Phoenix, Arizona. (At the time this study was performed, Varker
was a fourth-year pharmacy student at the University of Arizona
College of Pharmacy, Tucson, Arizona.) KELLY KARLAGE, BS, is
Chemist, and PAUL B. MYRDAL, PhD, is Associate Professor of
Pharmaceutics, University of Arizona College of Pharmacy,
Tucson, Arizona.
CORRESPONDENCE: Shaynan Hill, PharmD, Pharmacy Practice
Resident, Department of Pharmacy, Long Beach Veterans Affairs
Hospital, 5901 E. 7th St. (119), Long Beach, CA 90822. Tel.:
520.990.0847; E-mail: [email protected]
4. Stafford RS, Radley DC. The potential of pill splitting to achieve cost savings. Am J Manag Care. 2002;8:706-12. Available at: http://www.ajmc.com/
files/articlefiles/AJMC2002augStafford706_712.pdf. Accessed February 5,
2009.
5. The Official Compendia of Standards, USP28/NF23. Rockville, MD:
United States Pharmacopeia Convention, Inc. 2005 Official Monographs and
Uniformity of Dosage Units.
6. Teng J, Song CK, Williams RL, Polli JE. Lack of medication dose uniformity in commonly split tablets. J Am Pharm Assoc (Wash). 2002;42(2):195-99.
7. Polli JE, Kim S, Martin BR. Weight uniformity of split tablets required by
a Veterans Affairs policy. J Manag Care Pharm. 2003;9(5):401-07. Available at:
http://www.amcp.org/data/jmcp/Research-401-407.pdf.
8. Cook TJ, Edwards S, Gyemah C, Shah M, Shah I, Fox T. Variability in
tablet fragment weights when splitting unscored cyclobenzaprine 10 mg tablets. J Am Pharm Assoc (2003). 2004;44(5):583-86.
9. Rosenberg JM, Nathan JP, Plakogiannis F. Weight variability of pharmacist-dispensed split tablets. J Am Pharm Assoc (Wash). 2002;42(2):200-05.
10. Duncan MC, Castle SS, Streetman DS. Effect of tablet splitting on serum
cholesterol concentrations. Ann Pharmacother. 2002;36(2):205-09.
11. Gee M, Hasson NK, Hahn T, Ryono R. Effects of a tablet-splitting program in patients taking HMG-CoA reductase inhibitors: analysis of clinical
effects, patient satisfaction, compliance, and cost avoidance. J Manag Care
Pharm. 2002;8(6):453-58. Available at: http://www.amcp.org/data/jmcp/
Research-453-458.pdf.
12. Parra D, Beckey NP, Raval HS, et al., for the Veterans Integrated Service
Network 8 Pharmacy Benefits Management Utilization Committee. Effect
of splitting simvastatin tablets for control of low-density lipoprotein cholesterol. Am J Cardiol. 2005;95(12):1481-83.
13. Rindone JP. Evaluation of tablet-splitting in patients taking lisinopril for
hypertension. J Clin Outcomes Manage. 2000;7(4):22-24.
Vol. 15, No. 3
April 2009
JMCP
Journal of Managed Care Pharmacy 261
RESEARCH
Adherence to International Antimicrobial Prophylaxis
Guidelines in Cardiac Surgery: A Jordanian Study
Demonstrates Need for Quality Improvement
Nairooz H. Al-Momany, MSc; Amal G. Al-Bakri, PhD; Zeid M. Makahleh, MD, MRCS;
and Mayyada M.B. Wazaify, PhD
ABSTRACT
midnight dose of intravenous antibiotic the night before surgery.
BACKGROUND: Antimicrobial prophylaxis in cardiac surgery has been
demonstrated to lower the incidence of surgical site infection (SSI).
Inappropriate antimicrobial prophylaxis, such as inappropriate selection
of the antimicrobial agent or inappropriate dosing regimen, can increase
the prevalence of antibiotic resistant strains, prolong hospital stay, cause
adverse reactions, and negatively affect an institution’s pharmacy budget
for antibiotics. In developing countries such as Jordan, where the role of
clinical pharmacists is still in its primary stages, the first step in establishing an organized clinical pharmacy service is the evaluation of current
practice to determine the need for improvement.
CONCLUSION: Study findings indicate that adherence to international
guidelines for antimicrobial prophylaxis is far from optimal in QAHI, leading
to the inappropriate administration of many antibiotics. Developing local
hospital guidelines, as well as giving the clinical pharmacist a central role
in the administration, monitoring, and intervention of antimicrobial prophylaxis may improve the current practice.
OBJECTIVE: To assess the degree of adherence to international guidelines
for antimicrobial prophylaxis practice in cardiac surgery performed at
Queen Alia Heart Institute (QAHI) in Amman, Jordan, as part of an attempt
to determine opportunities for clinical pharmacist intervention.
METHODS: For a total of 236 patients who were admitted for cardiac
surgery to QAHI—the only official referral hospital for cardiac patients in
Jordan—between November 19, 2006, and January 22, 2007, the antimicrobial prophylaxis indication, choice, duration, dose, dosing interval,
and timing appropriateness were assessed against 3 international guidelines using a pre-tested, structured clinical data collection form that was
completed by 2 of the authors who work at QAHI. The study design was
prospective. All patients who were scheduled for surgery were monitored
daily during their inpatient stay until discharge and then were tracked in
the outpatient clinic for 2 months following surgery. Data regarding antimicrobial prophylaxis indication, choice, duration, dose, dosing interval,
and timing appropriateness were collected during the patient’s inpatient
stay; data collection was performed periodically thereafter as data became
available until the end of the 2-month follow-up. The 3 guidelines agreed
that (a) antimicrobial prophylaxis should be given to all patients undergoing cardiac surgeries; (b) the first- or second-generation cephalosporins
(cefazolin or cefuroxime) are the antibiotics of choice, and vancomycin use
is reserved for cases of allergy to beta-lactams or if presumed or known
methicillin-resistant Staphylococcus aureus (MRSA) colonization is present;
(c) the timing of the first dose should be within 60 minutes prior to the skin
incision; and (d) the duration of antimicrobial prophylaxis should not be
longer than 48 hours.
RESULTS: Adherence to all antimicrobial prophylaxis guidelines was not
achieved for any study patients. For the 6 evaluated criteria, (1) indication:
in 100% of patients the appropriate decision was made to use antimicrobial prophylaxis in concordance with guidelines; (2) choice: only 1.7% of
patients received the antibiotic of choice; (3) duration: 39.4% of patents
received antimicrobial prophylaxis for a total duration of 48 hours or less in
concordance with guidelines, and for 58.9% of patients, duration was longer
than recommended; (4) dose: 27.9% of patients received an appropriate
dose; (5) dosing interval: only 13.0% of patients received an appropriate
dosing interval, and none of the doses of antimicrobial prophylaxis used at
induction of anesthesia was repeated in operations that lasted longer than
the half-life of the antibiotic used; and (6) timing: 99.1% of patients received
antimicrobial prophylaxis dose within 60 minutes prior to skin incision as
recommended by guidelines, but 97.0% of patients received an unnecessary
262 Journal of Managed Care Pharmacy
JMCP
April 2009
Vol. 15, No. 3
J Manag Care Pharm. 2009;15(3):262-71
Copyright © 2009, Academy of Managed Care Pharmacy. All rights reserved.
What is already known about this subject
• Several studies worldwide have described adherence to international guidelines in antimicrobial prophylaxis in different
countries. Gorecki et al. (1999) found that in 74% of 211 patients
undergoing elective or emergency surgery in a New York private
teaching hospital, the antimicrobial prophylaxis administration
was inappropriate according to Surgical Infection Society guidelines. Problems included excessive duration (66%), switch to
inappropriate antibiotics (32%), spectrum (31%), and timing (i.e.,
no pre-operative dose, 22%).
• In a study of the application of guidelines on pre-operative antibiotic prophylaxis in León, Nicaragua, van Disseldorp et al. (2006)
estimated that antibiotic choice was discordant with the hospital
guidelines in 69% of the cases, dose in 20% of the cases, and both
the timing of administration and duration in 78% of the cases.
Overall adherence was achieved in 7% of patients.
What this study adds
• This study represents the first attempt to assess the degree of
adherence to antimicrobial prophylaxis practice standards in
cardiac surgery performed in the only official referral hospital
for cardiac patients in Jordan. This is an important step in
developing strategies in Jordan and in other hospitals with
similar conditions.
• Complete adherence to international antimicrobial prophylaxis
guidelines was not achieved for any study patients. The lowest
measured adherence rate (1.7%) was for antibiotic choice, and the
highest (100%) was for appropriate decision making regarding
use or nonuse of antimicrobial prophylaxis (indication), followed
by timing of the first dose at a fixed time before incision (99.1%).
Adherence rates in the other studied parameters were 39.4% for
total duration of antimicrobial prophylaxis use, 27.9% for dose,
and 13.0% for dosing interval.
• The study indicates the need for interventions to improve the
rational use of antibiotic prophylaxis to prevent the complications
of inappropriate administration of antimicrobials.
www.amcp.org
Adherence to International Antimicrobial Prophylaxis Guidelines in Cardiac Surgery:
A Jordanian Study Demonstrates Need for Quality Improvement
A
lthough cardiac surgery is generally considered a clean
procedure, antibiotic prophylaxis has been demonstrated
to lower the incidence of surgical site infection (SSI).
SSIs of the sternal wound and underlying mediastinum occur
in 0.4%-4% of cardiac surgical procedures, with over 50% due
to the coagulase-positive Staphylococcus aureus or the coagulasenegative Staphylococcus epidermidis.1 Patients who develop SSIs
after coronary artery bypass graft (CABG) surgery have a mortality rate of 22% at 1 year compared with 0.6% for those who do
not develop an SSI.2
Practice guidelines are intended to assist physicians and other
health care providers in clinical decision making by describing
a range of generally acceptable approaches for the diagnosis,
management, or prevention of specific diseases or conditions.3
The last decade has seen a proliferation of evidence-based clinical
practice guidelines.4 Antibiotic guidelines and associated interventions have been demonstrated to be effective in improving
antibiotic use.5 Organizations that have promulgated guidelines
for antimicrobial prophylaxis in cardiac surgery include the
National Surgical Infection Prevention Project (NSIPP),6 the
Society of Thoracic Surgeons (STS),1,3 and the American College
of Cardiology/American Heart Association (ACC/AHA).7
The main recommendations of the 3 guidelines are as follows: (a) antimicrobial prophylaxis should be given to all patients
undergoing cardiac surgeries; (b) the first- or second-generation
cephalosporins (cefazolin or cefuroxime) are the antibiotics of
choice, and vancomycin use is reserved for cases of allergy to
beta-lactams or if presumed or known methicillin-resistant
Staphylococcus aureus (MRSA) colonization is present; (c) the duration of antimicrobial prophylaxis use should not be longer than
48 hours; and (d) the timing of the first dose should be within
60 minutes prior to the skin incision (Table 1).6,7 The practice of
giving a midnight (on call) dose of intravenous (IV) antibiotic
the night prior to surgery as part of antimicrobial prophylaxis is
inconsistent with guidelines; moreover, it has been frankly discouraged by the Centers for Disease Control (CDC).8
Some countries have incorporated these guidelines into a
national drug policy and provided government funding for a
range of activities aimed at improving rational drug use.9 Health
organizations have become interested in such policies because of
concerns about inappropriate antibiotic prescribing and reported
increase in the prevalence of antibiotic-resistant organisms.10,11
Antibiotic resistance has been described as a major threat to
global public health by the World Health Organization (WHO)
because there are now few and, in some cases, no antibiotics
available to treat certain life threatening infections.12
Despite the availability of these guidelines, recent studies
assessing the current practice of prophylaxis throughout the
world have shown that inappropriate antibiotic choice, excessive duration of use, and inappropriate timing of antimicrobial
drugs remains a problem in surgical prophylaxis.13-20 In an Italian
teaching hospital, Motola et al. (1998) found that third-generation
www.amcp.org
cephalosporins were the most frequently used antibiotics both
in patients undergoing clean (74.1%) and clean-contaminated
(73.0%) surgical procedures.15 The resulting costs were about
10-fold higher than estimated costs of antibiotic prophylaxis
carried out according to international guidelines.15 In Belgium,
Kurz et al. (1993) found that antimicrobial prophylaxis was given
in 57% of the procedures for which prophylaxis is generally not
recommended, was not used in 14% of procedures for which it is
generally recommended and in 14% of contaminated procedures,
and was prolonged by more than 2 days postoperatively after 23%
of the procedures and by more than 4 days in 8%.13 In a Canadian
survey of antimicrobial prophylaxis use among patients who
underwent surgical repair of a fractured hip with insertion of
prosthetic material, Zoutman et al. (1999) reported that 70% of
cases did not receive a dose of antimicrobial prophylaxis within
2 hours pre-operatively; instead, antimicrobial prophylaxis was
administered either too early or during the procedure. In 39%
of cases receiving antibiotic prophylaxis, the first dose was not
administered until the end of the procedure. Antimicrobial prophylaxis consisted of a parenteral first-generation cephalosporin
for 94% of cases.18
Monitoring and intervention can be effective in increasing the
adherence to guidelines. In descriptive studies lacking a control
group, stricter implementation of the existing antimicrobial prophylaxis protocols was associated with an increase in the appropriateness of antibiotic prophylaxis from approximately 50% to
95%-100%.21,22
In Jordan in general and, specifically, in the Queen Alia Heart
Institute (QAHI), in which the present study was conducted, antimicrobial prophylaxis in cardiac surgery is not governed either by
national or by local guidelines. This problem is typical of other
developing countries.23,24 Studies that assess the current clinical
practice of antimicrobial prophylaxis in Jordan were lacking until
the present study. Previous research in this topic area focused on
the presence of a clear evidence of antibiotic misuse among the
Jordanian population.25-27 In light of this absence of local or institutional antimicrobial prophylaxis guidelines, the present study
used the aforementioned 3 international guidelines—NSIPP,
STS, and ACC/AHA—to assess the appropriateness and compliance of antibiotic prophylaxis practices in cardiac surgery within
QAHI.1,3,6,7
■■ Methods
Setting and Study Design
Patients enrolled in the present study were admitted to QAHI for
cardiology services and cardiac surgery. QAHI is the only official
referral hospital for cardiac patients in Jordan, performing an
average of 30 cardiac surgeries per week. Eligible patients were
enrolled in the study between November 19, 2006, and January
22, 2007. Generally, the study evaluated practitioner adherence to
antibiotic prophylaxis guidelines using a clinical data collection
form. The study was approved by the Career Ethics Committee,
Vol. 15, No. 3
April 2009
JMCP
Journal of Managed Care Pharmacy 263
Adherence to International Antimicrobial Prophylaxis Guidelines in Cardiac Surgery:
A Jordanian Study Demonstrates Need for Quality Improvement
TABLE 1
Guideline
Antimicrobial
Prophylaxis
for Surgery:
An Advisory
Statement from
the National
Surgical Infection
Prevention
Project (NSIPP),
2005a
Summary of 3 International Guideline Recommendations
for Antimicrobial Prophylaxis in Cardiothoracic Surgery
Antibiotic Choice
Cefazolin, cefuroxime,
or cefamandole
Dose and Route of Administration
Cefazolin IV: 1-2 gm (20-30) mg per kg
standard dose. If < 80 kg, use 1 gm; if > 80 kg,
use 2 gm. End stage renal disease t½ = 40-70
hours.
If the patient has a
beta-lactam allergy,
vancomycin or
clindamycin
Total Duration
of AMP Use
24 hours or less
Timing of First Dose at Fixed Time
Before Incision; Dosing Interval
Within 60 minutes before incision.
For vancomycin the infusion should
begin within 120 minutes before
incision.
Cefuroxime IV: 1.5 gm standard dose,
50 mg/kg adjusted dose. End stage renal disease t½ = 15-22 hours.
Doses should be repeated intraoperatively if the operation is still in
progress 2 half-lives after the first
dose.
Cefamandole IV: 1 gm standard dose.
End stage renal disease t½ = 12.3-18 hours.
Vancomycin IV infusion: 1 gm over 60 minute
standard dose, 10-15 mg per kg (adult)
adjusted. End stage renal disease t½ = 44.1406.4 hours.
The Society
of Thoracic
Surgeons
(STS) Practice
Guideline Series:
Antibiotic
Prophylaxis In
Cardiac Surgery,
2006-2007b
American College
of Cardiology/
American Heart
Association
(ACC/AHA)
Guideline Update
for Coronary
Artery Bypass
Surgery, 2004c
Clindamycin IV: 600-900 mg standard dose.
If < 10 kg, use at least 37.5 mg; if > 10 kg, use
3-6 mg/kg. End stage renal disease t½ = 3.5-5.0
hours.
Cefazolin IV: 1 gm pre-operative
prophylactic dose; for a patient > 60 kg,
2 gm is recommended.
Cefazolin
If presumed or known
MRSA colonization,
vancomycin (1-2 doses)
+ cefazolin
In patients with
beta-lactam allergy,
vancomycin (up to 48
hours) + aminoglycoside
(1 pre-operative and 1
post-operative dose).
Cephalosporin class:
cefuroxime (superior
efficacy compared with
the other cephalosporins),
cefazolin or cefamandol.
48 hours or less
Vancomycin IV infusion over 1 hour:
dose of 1-1.5 gm or a weight-adjusted
dose of 15 mg per kg.
For vancomycin: administration
slowly over 1 hour, with completion
within 1 hour of the skin incision.
Aminoglycoside IV; (usually gentamicin,
4 mg per kg) in addition to vancomycin prior
to cardiac surgery.
Cefuroxime: 1.5 gm pre-operatively,
1.5 gm after cardiopulmonary bypass,
1.5 gm every 12 hours.
Cefamandole, cefazolin: 1 gm pre-operatively,
1 gm at sternotomy, 1 gm after
cardiopulmonary bypass, 1 gm every 6 hours.
For cefazolin: administration
within 60 minutes prior to the skin
incision; second dose of 1 gram
should be administered every 3-4
hours, if long procedure.
48 hours or less
For aminoglycosides: the initial dose
should be administered within 1
hour of the skin incision.
Initial dose to be given 30-60 minutes before skin incision.
Vancomycin: 30- to 60-minute
infusion timed to end before skin
incision.
Vancomycin: reserved for
penicillin-allergic and
Vancomycin: 1 gm every 12 hours until lines/
justified in periods of
tubes are out. At least 2 doses.
MRSA outbreaks.
a Bratzler DW, Houck PM. Am J Surg. 2005;189(4):395-404.6
bEngleman et al. Ann Thoracic Surg. 2007;83(4):1569-76;1 Edwards et al. Ann Thoracic Surg. 2006;81(1):397-404.3
cEagle et al. J Am Coll Cardiol. 2004;44(5):e213-310.7
AMP = antimicrobial prophylaxis; gm = gram; IV = intravenous; kg = kilogram; mg = milligram; MRSA = methicillin-resistant Staphylococcus aureus; t½ = elimination half-life.
the equivalent of an institutional review board in Jordan, in the
Royal Medical Services.
Patients
Patients scheduled for any type of cardiac surgery were eligible for
the study with a few exceptions. Patients diagnosed with human
immunodeficiency virus (HIV) infection, tuberculosis, or cystic
fibrosis were excluded from the study. To avoid difficulties in discriminating prolonged prophylaxis from post-operative therapy,
patients with suspected or established infection during surgery
were also excluded. Patients who died due to a cause other than
264 Journal of Managed Care Pharmacy
JMCP
April 2009
Vol. 15, No. 3
SSI before the end of the follow up period were not included in
the data analysis. Patients were enrolled in the study if informed
consent was obtained from the patient or his/her representative.
Data Collection
Data were collected from patients’ verbal self-reports, files, medication sheets, and prescriptions using a clinical data collection
form (summarized in Table 2). The form had been pre-tested on a
small pilot scale (n = 10) and subsequently modified to ensure that
the data would provide valid information. The entire clinical data
collection form is available from the authors upon request.
www.amcp.org
Adherence to International Antimicrobial Prophylaxis Guidelines in Cardiac Surgery:
A Jordanian Study Demonstrates Need for Quality Improvement
FIGURE 1
Patient Selection Flow Chart
Patients scheduled for all types of cardiac surgery (n = 264)
Surgery was not performed or postponed (n = 12):
• Patients with rise in white blood cell count and suspected infection (n = 9)
• Patients who did not come to the hospital (n = 3)
Patients underwent cardiac surgery (n = 252)
•
•
•
•
Total number of patients included in the study (n = 241)
Excluded (n = 11):
Tuberculosis (n = 1)
Cystic fibrosis (n = 2)
Pneumonia (n = 4)
Suspected infection (not surgical site infection)
that required the use of antibiotics (n = 4)
Lost to follow up:
Died within or after surgery due to a cause other
than surgical site infection (n = 5)
Data available for analysis for (n = 236) patients
All parts of the form were completed by 2 of the authors (NM,
a clinical pharmacist and ZM, a cardiac surgeon) who work at
QAHI. All patients who were scheduled for surgery were monitored daily during their inpatient stay until discharge and then
tracked in the outpatient clinic for 2 months following surgery.
Data regarding antimicrobial use in the hospital were collected
during the patient’s inpatient stay; additional data collection was
performed periodically thereafter as data became available, until
the end of the 2-month follow-up period.
Analysis of Prophylactic Antibiotic Use
The compliance of current prophylactic antibiotic practices in
cardiac surgery at QAHI with 3 published international guidelines was assessed. These guidelines were from the NSIPP
(Antimicrobial prophylaxis for surgery: an advisory statement),6
the STS (Antibiotic prophylaxis in cardiac surgery, part I: duration, and part II: antibiotic choice),1,3 and the ACC/AHA (2004
guideline update for coronary artery bypass graft surgery).7 The
following 6 aspects of antimicrobial prophylaxis were assessed:
(1) indication—appropriate decision making regarding use or
nonuse of antimicrobial prophylaxis; (2) choice—antibiotic choice
for patients with and without allergy; (3) total duration of use; (4)
dose; (5) dosing interval—includes both repeating of doses in procedures with durations longer than the half-life of the antibiotic
used, and interval between doses; and 6) timing of dose given at a
fixed time before incision (within 60 minutes prior to skin incision). The criteria for evaluation of adherence are summarized in
Table 3.
If more than 1 drug was prescribed for a single procedure, all
parameters were evaluated separately for each drug. Final assessment of the antibiotic course was composed by combining these
www.amcp.org
TABLE 2
Summary of Clinical
Data Collection Form
Part A Demographic data: patient’s name, identification number, gender,
age, weight, date of admission, date of discharge.
Part B
Medical data: diagnosis and type of surgery, past medical history,
drug history, drug allergy, antibiotic use in the last 2 weeks,
previous hospitalization in the last 2 years.
Prophylactic antibiotic(s) used: trade and scientific name, dose,
frequency, timing of doses, route of administration, duration of use,
and number of doses of all antibiotics used (pre-, intra-, and postoperatively) as surgical prophylactic antibiotics.
Duration of the surgery in minutes
separate drug evaluations. Any divergence from the guidelines in
the prescription of 1 of the drugs led to a final assessment of the
prophylactic course as discordant with the guidelines. If no antibiotic orders or prescriptions had been recorded, it was assumed
that antibiotics were not given. If data on a certain parameter of
the antibiotic prescription were lacking, the case was classified
as missing data on this parameter only. We defined an antibiotic
administered the day before surgery (e.g., in a midnight dose the
night before surgery) as not indicated, and for these events, the
parameters of antibiotic choice, duration, dose, dosing interval,
and timing were not evaluated for that nonindicated drug; however, if the same patient received an antibiotic on the day of the
surgery, all parameters were evaluated for that drug because it
was indicated.
All data were coded, entered, and analyzed using SPSS for
Windows, version 14.0 (SPSS Inc., Chicago, IL). Frequency and
percentages were calculated and presented.
Vol. 15, No. 3
April 2009
JMCP
Journal of Managed Care Pharmacy 265
Adherence to International Antimicrobial Prophylaxis Guidelines in Cardiac Surgery:
A Jordanian Study Demonstrates Need for Quality Improvement
TABLE 3
Criteria to Assess Adherence and Compliance With Current Antimicrobial
Prophylaxis Practices Within QAHI Compared With International Guidelinesa
Parameter
1. Antibiotic indication
2.Antibiotic choice
Concordant if
•Decision was made to use antimicrobial prophylaxis.
•Agent recommended by guidelines.
•Combination used only when indicated.
3.Total duration of prophylactic antimicrobial use
4. Dose
•No switch to another antibiotic in the absence of microbiologic or clinical indication.
Duration as recommended by guidelines (48 hours or less).
Dose as recommended by guidelines. For pediatric patients, doses calculated according to body
weight using Drug Information Handbook.b
5. Dosing interval
(a) during surgery
Additional dose was given in surgical procedure longer than the half-life of the prophylactic
antibiotic used, and dosing interval did not exceed the guideline by more than 30 minutes.
(b) on the ward
Dosing interval did not deviate from the guideline by more than 60 minutes.
Timing of dose did not deviate by more than 15 minutes from the recommended time
6.Timing
Timing of dose given at fixed time before incision. (within 30-60 minutes prior to skin incision).
a Guidelines used: National Surgical Infection Prevention Project;6 The Society of Thoracic Surgeons;1,3 and American College of Cardiology/American Heart Association.7
bLacy et al. Drug Information Handbook, 2006.41
QAHI = Queen Alia Heart Institute.
■■ Results
Between November 19, 2006, and January 22, 2007, 252 cardiac surgeries were conducted in QAHI. After the application of
inclusion and exclusion criteria, 236 patients were enrolled in
the study (Figure 1). Patients’ characteristics and types of cardiac
surgeries are presented in Table 4.
the midnight antibiotic might have differed from the antibiotic
that was given later at induction of anesthesia, the parameters
of antibiotic choice, dose, dosing interval and timing were not
evaluated for the drug given at midnight; however, these parameters were evaluated for any antibiotics given to the patient on the
surgery date.
Overall Assessment of All Parameters
Adherence to guidelines in antimicrobial prophylaxis for all
parameters was not fulfilled in any of the 236 cardiac surgeries assessed in this study. Two common deviations from the
guidelines were observed: (a) the unexplained switch from an
appropriate or inappropriate agent(s) to an inappropriate agent(s)
in the same patient in 230 (97.5%) patients; and (b) the practice of
giving a midnight dose of IV antibiotic the night prior to surgery
as part of antimicrobial prophylaxis in 229 (97.0%) patients.
Antibiotic Choice: Overall, antibiotic choice was concordant
with guidelines for only 4 (1.7%) patients (Table 5), almost
entirely because of post-operative treatment decisions. In the
operating room and during induction of anesthesia, the antibiotic choice (cefuroxime) was concordant with guidelines in 226
(95.8%) patients and discordant in 10 patients. The reasons for
discordance were the following:
• Suspicion of beta-lactam allergy in 5 patients where cefuroxime was given.
• Use of a vancomycin and cefuroxime combination in 3
patients who did not have either beta-lactam allergy or presumed colonization with MRSA.
• Missing induction-antimicrobial prophylaxis dose in 2 patients
to whom a third-generation cephalosporin was given 8 hours
after the end of the operation.
After surgery, for nearly all patients, there was an unexplained
switch from an appropriate or inappropriate agent(s) to an inappropriate agent(s). Switches were made from a second-generation cephalosporin cefuroxime (or combination of cefuroxime
with vancomycin) to (a) a combination of a third-generation
cephalosporin with 1 of these antibiotics: vancomycin, amikacin, flucloxacillin, or imipenem in 145 (61.4%) patients; (b)
a combination of vancomycin with amikacin or flucloxacillin or imipenem in 34 (14.4%) patients; (c) a third-generation
Assessment of Individual Parameters
Parameters were also evaluated separately, so that nonadherence
to 1 parameter did not preclude assessment of the others. Rates
of adherence to international guidelines for indication, choice,
total duration, dose, dosing interval, and timing are presented
in Table 5.
Indication: In concordance with the guidelines, antimicrobial
prophylaxis was given for all of the 236 (100%) patients who
underwent cardiac surgeries (Table 5). However, a midnight dose
of IV antibiotic on the night before surgery was given to 229
(97.0%) of patients (third-generation cephalosporin in 85% of
patients, second-generation in 10%, other antibiotics in 2%). As
this antibiotic dose was given while not indicated, and because
266 Journal of Managed Care Pharmacy
JMCP
April 2009
Vol. 15, No. 3
www.amcp.org
Adherence to International Antimicrobial Prophylaxis Guidelines in Cardiac Surgery:
A Jordanian Study Demonstrates Need for Quality Improvement
cephalosporin alone in 32 (13.6%) patients; or (d) vancomycin
alone in 19 (8.1%) patients. Cefuroxime was maintained as a
single prophylactic antibiotic in only 4 (1.7%) patients, and the
third-generation cephalosporin ceftriaxone was maintained as a
single prophylactic antibiotic in only 2 (0.8%) patients.
Total Duration of Antimicrobial Prophylaxis Use: In 93 of
236 patients (39.4%), total duration of all agents used as antimicrobial prophylaxis was concordant with the guidelines (48
hours or less). In 139 (58.9%) patients, duration was longer than
recommended. In 4 cases (1.7%), duration could not be evaluated
because medication charts were incomplete.
Dose: Only doses of antibiotics used in concordance with the
guidelines were evaluated. The dose was concordant with the
guidelines in only 63 (27.9%) of 226 evaluated doses. In all of
the 163 (72.1%) discordant doses, the dose was lower than what
is recommended, either because (a) a lower dose (e.g., 750 milligrams instead of 1.5 grams) was given to an adult patient; (b)
no dose adjustment was made for an obese patient; or (c) the
dose per kilogram calculated for a child was lower than recommended.
Dosing Interval: Only dosing intervals of agents used in concordance with the guidelines were evaluated (n = 230, Table 5).
Of these, only the dosing interval of antibiotics repeated during
surgery or in the ward could be calculated. Of the 226 doses of
antimicrobial prophylaxis used at induction of anesthesia, none
was repeated, even though antimicrobial prophylaxis should
have been repeated in 196 surgeries because the duration of the
surgery was longer than the half-life of the antibiotic used. In
the 4 patients for whom cefuroxime was maintained as a single
prophylactic antibiotic in the ward after surgery (in compliance
with the guidelines), the dosing interval was discordant with the
guidelines (every 8 hours instead of every 12 hours). Thus, only
30 (13.0%) out of 230 evaluated agent dosing intervals were concordant with the guidelines.
Timing of Doses Given on the Surgery Date: For doses given
on the day of the surgery, timing was concordant with the
guidelines (at induction of anesthesia within 30 minutes before
incision) in 224 of 226 (99.1%) of the evaluated cardiac surgeries.
For the 2 surgeries in which antimicrobial prophylaxis timing
was discordant with the guidelines, no antimicrobial prophylaxis
was given in the hours prior to or during the surgery; instead, a
third-generation cephalosporin was given 8 hours after the end
of the operation.
■■ Discussion
Adherence in Current Practice
The present study demonstrates that adherence to the international guidelines for antimicrobial prophylaxis is disappointingly
www.amcp.org
TABLE 4
Characteristics and Types of
Cardiac Surgeries for Patients
Enrolled in the Study
Characteristic
Mean [SD] (range) age in years
Male % (n)
Patient Weight a
N = 236
43 [25.7] (0.1-73)
78.0%(184)
Underweight (BMI ≤ 18.5)
Normal weight (BMI = 18.5-24.9)
Overweight (BMI = 25-29.9)
Obese (BMI ≥ 30)
Mean [SD] (range) length of hospital stay before surgery
in days
Mean [SD] (range) total length of hospital stay before and
after surgery in days
Hospitalization in the past 2 years % (n)
Diabetes mellitus % (n)
Current smoking % (n)
3 medical diagnoses or moreb % (n)
Steroids intake before and within hospitalization % (n)
Type of Cardiac Surgery
Congenital heart surgery % (n)
Valve replacement surgery % (n)
Coronary artery bypass surgery % (n)
Other surgeriesc % (n)
Mean duration of surgery [SD] (range) in hours
Antibiotic Use
30.1% (71)
11.4% (27)
55.1% (130)
3.4% (8)
3.2 [1.4] (2.2-6.5)
3.4% (8)
44.9%(106)
33.9% (80)
17.8% (42)
3.4 [4.0] (1-13)
22.6 [2.3] (9-41)
15.6%
35.2%
25.0%
33.5%
40.2%
(37)
(83)
(59)
(79)
(95)
Within hospitalization % (n)
100%(236)
Within 2 weeks before hospitalization % (n)
11.4% (27)
a BMI (Body Mass Index) = weight in kilograms divided by height in squared meters
(Lacy et al. Drug Information Handbook, 2006).41
b Only chronic diseases that are present in patient’s history or diagnosed in the current admission were counted (e.g,. diabetes mellitus, hypertension, ischemic heart
diseases).
cThe other surgeries were correction of aortic coarctation, excision of left atrial
myxoma, carotid endarterectomy, and repair of aortic dissection.
far from optimal. One of the most striking findings of this study
was that no patient’s care adhered to all guideline parameters.
While this result is consistent with those of similar studies in Iran
and Nicaragua, where rates of complete adherence to practice
guidelines were 0.3%24 and 7%,28 respectively, higher percentages
of adherence to antimicrobial prophylaxis guidelines have been
reported in other studies. Gorecki et al. (1999, United States), van
Kasteren et al. (2003, the Netherlands), Lallemand et al. (2002,
France), and Voit et al. (2005, United States) found in their studies that overall adherence was achieved in 26%, 28%, 41.1%, and
approximately 50% of surgical patients, respectively.17,29-31
Interestingly, although the present study reported lower
adherence to all parameters than did earlier studies, the rate
of adherence to timing of antimicrobial prophylaxis at a fixed
time before incision (99.1%) is higher than that reported in
most other studies. Paradiso-Hardy et al. (2002), Lallemand
Vol. 15, No. 3
April 2009
JMCP
Journal of Managed Care Pharmacy 267
Adherence to International Antimicrobial Prophylaxis Guidelines in Cardiac Surgery:
A Jordanian Study Demonstrates Need for Quality Improvement
TABLE 5
Adherence to International Guidelines in Antimicrobial Prophylaxis in Cardiac Surgery
International Guidelinea
A = NSIPP 2005
B = STS 2006-2007
C = ACC/AHA 2004
Any antimicrobial prophylaxis recommended by A,B,C
Any recommended duration by A,B,C
Any recommended dose by A,B,C. For pediatric doses
calculated according to body weightc
Any recommended dosing interval by A,B,C
Any recommended appropriate timing of first dose by A,B,C
Any of the guidelines A,B,C
a NSIPP = National
Recommendation Criteria
1. Appropriate decision making regarding use of
antimicrobial prophylaxis (indication)
Number (%) Meeting
Criteria (Concordant With
any of A,B,C) (n = 236)
236 (100.0)
2.Appropriate antibiotic choice
3.Appropriate total duration of antimicrobial prophylaxis use 4. Appropriate dose
4 (1.7)
93 (39.4)
63 (27.9)b
5. Appropriate dosing interval
6.Appropriate timing of first dose at fixed time (within 30-60 minutes before incision)
Appropriate compliance with all recommendations
30 (13.0)d
224 (99.1)e
0
(0.0)
Surgical Infection Prevention
STS = The Society of Thoracic
Association.7
bNumber evaluated = 226.
cWeight calculated according to Lacy et al. Drug Information Handbook, 2006.41
d Number evaluated = 230.
eNumber evaluated = 226.
Surgeons;1,3
et al. (2002), van Kasteren et al. (2003), and van Disseldorp et
al. (2006) reported in their studies that timing of the first dose
was concordant with guidelines in 72%, 61.4%, 50%, and 22%
of cases, respectively.28-30,32
It is noteworthy that adherence in all of the previously mentioned studies, except ours and that of Askarian et al. (2006,
Iran), was compared with local, rather than international, guidelines. The higher adherence rates in studies that used local guidelines (7%-50%) as opposed to studies that used international
guidelines because of lack of national or local guidelines (0%0.3%), suggest that adherence to local guidelines may be easier to
achieve than adherence to international guidelines.17,24,28-31
One potential strategy to improve antimicrobial practice
in hospitals is standardization, either by adopting an international guideline or by developing a local hospital guideline.
Standardization efforts should be overseen by a committee that
includes surgeons, anesthesiologists, microbiologists, pharmacists, and members of hospital epidemiology and infection control departments. Guidelines should be based on hospital-specific
bacterial epidemiology patterns, the best literature evidence,
and surgeon preference. Standardized protocols should then be
provided to surgeons, in an effort to achieve consensus, before
implementation.
The present study revealed several areas for improvement at
the study hospital. At QAHI, the on-call surgeon (usually a junior
surgeon) routinely prescribes a midnight antimicrobial prophylaxis dose the night before surgery and records it on the follow-up
sheet in the patient’s file. The anesthesiologist gives the intraoperative antibiotic dose and records it only on the anesthesia
chart. After surgery, the consultant, or senior surgeon, prescribes
post-operative antimicrobial doses and records them on the
follow-up sheet in the patient’s file. The absence of a standardized
antimicrobial practice guideline creates a lack of communication
between anesthesiologists, surgeons, and even among the members of the surgical team. This lack of communication produced
poor monitoring, resulting in 2 main deviations that led to 100%
nonadherence in this study. These deviations from the guidelines
are as follows:
(a)Unexplained switch to inappropriate antibiotic(s) without microbiological or clinical indication. The most common antimicrobial
prophylaxis agents used in this study were a combination of a
third-generation cephalosporin with another antibiotic (vancomycin, amikacin, flucloxacillin, or imipenem); a combination
of vancomycin with amikacin. flucloxacillin, or imipenem;
or a third-generation cephalosporin alone. Third-generation
cephalosporins and broad spectrum combinations should not
be used for SSI prophylaxis because they have less activity
against Staphylococci than does cefazolin. Such use induces the
emergence of resistant organisms and is more costly.14,33
(b)Giving a midnight dose of IV antibiotic the night prior to surgery.
This practice should be strongly discouraged in group education and consensus meetings. One method of preventing
this practice is to assign the prescription of antimicrobials to
the anesthesiologist in charge only. Prevention could also be
achieved by providing better staff training as to the benefits
of adherence to standard international antimicrobial prophylaxis guidelines and the risks of unnecessarily dispensing
antibiotics.
268 Journal of Managed Care Pharmacy
Project;6
JMCP
April 2009
Vol. 15, No. 3
ACC/AHA = American College of Cardiology/American Heart
www.amcp.org
Adherence to International Antimicrobial Prophylaxis Guidelines in Cardiac Surgery:
A Jordanian Study Demonstrates Need for Quality Improvement
Potential solutions to avoid both of these mistakes include
better organization of work and specification of tasks among
individuals on the surgical team, introduction of special forms
for ordering antimicrobial prophylaxis, and use of an antibiotic
prophylaxis chart in the operating theaters. Another suggestion
is to give a central role to the clinical pharmacists in antimicrobial prophylaxis administration. In a descriptive study without a
control group, Prado et al. (2002) showed that when pharmacists
were given a central role in the administration of prophylaxis, the
appropriateness of the indication increased from 56% to 100%,
while the costs decreased by 40%.21 Moreover, in a study of an
intervention to reduce the prescribing of antibiotics for upper
respiratory infections by general practitioners in Australia, Zwar
et al. (2002) found that giving feedback on prescription behavior
increased the appropriateness of the prescriptions.34
The present study also demonstrated that, although adherence
to all guidelines was not achieved for any study patients, adherence was better for some specific guidelines than for others. For
example, the decision to use antimicrobial prophylaxis (indication) and the timing of antimicrobial prophylaxis before incision
showed high rates of adherence (100.0% and 99.1%, respectively),
indicating that the surgical teams were aware of the importance
of giving antimicrobial prophylaxis within 30-60 minutes prior
to skin incision to prevent SSI in cardiac surgeries. The importance of the timely administration of pre-operative antibiotics is
well established and is broadly applicable to all procedures for
which prophylactic antibiotics are administered.1 It has been
suggested that antimicrobial selection is a moot point if the agent
is not delivered during the optimal 30-60 minute window just
before incision and that the beneficial effect is negated if the drug
is given after incision.7 Investigation of the reasons for adherence
to timing guidelines revealed that anesthesiologists were responsible for giving the intra-operative antimicrobial prophylaxis
doses, providing further support for the suggestion to improve
adherence by specifying tasks and distributing responsibilities
among members of the surgical team.
Use of antibiotics for longer than the recommended period,
especially in the absence of any evidence of secondary infection or SSI until the day of discharge in an attempt to prevent
infection while patients were hospitalized, was observed in
58% of our study patients and has also been reported by some
other researchers.24,35-36 Prolonged antibiotic prophylaxis is, at
best, of no benefit and, at worst, potentially harmful to patients
because of drug toxicity, the risk of super-infection, and the
risk of inducing more bacterial resistance, both in surgical
www.amcp.org
patients and throughout the hospital.37-39
Doses and dosing intervals were discordant in 72% and 88%
of patients, respectively. That is, no dose adjustment was done
when it was needed and doses were not repeated intra-operatively
in long-duration procedures. These findings are consistent with
the work of Gupta et al. (2003), who found that prophylactic
antibiotic administration in procedures lasting more than 4 hours
was repeated in only 9 patients (3%) in 300 cases at the correct
time for the entire duration of the surgery in complete compliance
with the published guidelines.40
Limitations
First, the exact timing of the intra-operative antimicrobial prophylaxis dose was assessed based on the anesthesiologists’ notes
on the anesthesia chart, and it was recorded always at induction.
However, we cannot guarantee the accuracy of recorded notes.
In the future, one could consider a method to record the time of
dose administration more precisely. Second, although anecdotal
information suggests that most hospitals in Jordan share similar
standards, our results may not be entirely applicable to other
countries. However, our results can be generalized to hospitals in
other developing countries, where not much attention is paid to
international practice guidelines. Additionally, previous research
has documented widespread nonadherence to antimicrobial
practice guidelines in many countries, including the United
States and Canada.17,18,31
■■ Conclusion
We found that adherence to international antimicrobial prophylaxis guidelines for cardiac surgery is far from optimal in the
QAHI, which led to the inappropriate administration of many
antibiotics. This pattern unnecessarily increases expenditures and
likely plays a major role in the growing prevalence of antibioticresistant microbial strains. Strategies such as the development
of local hospital guidelines may improve current antimicrobial
prophylaxis practice in QAHI specifically and in other hospitals
in general. There is a need to increase adherence to clinical guidelines for antimicrobial prophylaxis in cardiac surgery patients in
QAHI, and other research has shown quality improvement using
clinical pharmacists in a central role in the administration, monitoring, and intervention of antimicrobial prophylaxis. Additional
effort should also be directed towards increasing the awareness
of practitioners about the dangers of inappropriate use of antimicrobials before, during, and after surgeries.
Vol. 15, No. 3
April 2009
JMCP
Journal of Managed Care Pharmacy 269
Adherence to International Antimicrobial Prophylaxis Guidelines in Cardiac Surgery:
A Jordanian Study Demonstrates Need for Quality Improvement
Authors
NAIROOZ H. AL-MOMANY, MSc, is Clinical Pharmacist in charge
of the inpatient pharmacy, King Hussein Medical Center, Amman,
Jordan; AMAL G. AL-BAKRI, PhD, is Associate Professor of
Pharmaceutical Microbiology, Faculty of Pharmacy, The University
of Jordan, Amman, Jordan; ZEID M. MAKAHLEH, MD, MRCS,
is Specialist Cardiac Surgeon, Queen Alia Heart Institute, Amman,
Jordan; and MAYYADA M.B. WAZAIFY, PhD, is Assistant Professor
of Pharmacy Practice, Faculty of Pharmacy, The University of
Jordan, Amman, Jordan.
AUTHOR CORRESPONDENCE: Mayyada M.B. Wazaify, PhD,
Faculty of Pharmacy, University of Jordan, Amman, Amman 11942,
Jordan. Tel.: 009626-5355000, ext. 23354; E-mail:
[email protected]
9. Commonwealth of Australia, The Department of Communications,
Information Technology and the Arts. The National Strategy for Quality Use of
Medicines. Canberra, Australia: Commonwealth of Australia; 2002, pp. 1-36.
10. Yang Y-H, Fu S-G, Peng H, et al. Abuse of antibiotics in China and its
potential interference in determining the etiology of pediatric bacterial diseases. Pediatr Infect Dis J. 1993;12(12):986-88.
11. Li H, Li X, Zeng X. A study on antibiotic abuse in 750 children with
acute respiratory infection in Tongxian County of Beijing. Zhonghua Yu Fang
Yi Xue Za Zhi [Chinese Journal of Preventive Medicine]. 1995;29(6):331-34.
12. World Health Organization (WHO). Antimicrobial resistance: the facts.
Essential Drugs Monitor. 2000; 28 and 29:8-9. Available at: http://mednet2.
who.int/edmonitor/edition/EDM2829en.pdf. Accessed February 24, 2009.
13. Kurz X, Mertens R, Ronveaux O. Antimicrobial prophylaxis in surgery in
Belgian hospitals: room for improvement. Eur J Surg. 1996;162(1):15-21.
14. Silver A, Eichorn A, Kral J, et al. Timeliness and use of antibiotic prophylaxis in selected inpatient surgical procedures. The Antibiotic Prophylaxis
Study Group. Am J Surg. 1996;171(6):548-52.
DISCLOSURE AND ACKNOWLEDGEMENTS
This study was funded by the Deanship of Academic Research at The
University of Jordan.
All authors contributed equally to concept and design, data collection and
interpretation, and writing and revision of the manuscript.
The authors would like to thank all the physicians and nurses working at
Queen Alia Heart Institute (QAHI) who helped us in patient recruitment and
data collection.
15. Motola G, Russo F, Mangrella M, Vacca C, Mazzeo F, Rossi F. Antibiotic
prophylaxis for surgical procedures: a survey from an Italian university hospital. J Chemother. 1998;10(5):375-80.
16. Sasse A, Mertens R, Sion JP, et al. Surgical prophylaxis in Belgian
hospitals: estimate of costs and potential savings. J Antimicrob Chemother.
1998;41(2):267-72.
17. Gorecki P, Schein M, Rucinski JC, Wise L. Antibiotic administration in
patients undergoing common surgical procedures in a community teaching
hospital: the chaos continues. World J Surg. 1999;23(5):429-32.
REFERENCES
1. Engelman R, Shahian D, Shemin R, et al.; Workforce on EvidenceBased Medicine, Society of Thoracic Surgeons. The Society of Thoracic
Surgeons practice guideline series: antibiotic prophylaxis in cardiac
surgery, part II: antibiotic choice. Ann Thorac Surg. 2007;83(4):156976. Available at: http://www.sts.org/documents/pdf/guidelines/
AntibioticProphylaxisCardiacSurgeryPart_IIAntibiotic_Choice.pdf.
Accessed February 24, 2009.
2. Hollenbeak CS, Murphy DM, Koenig S, Woodward RS, Dunagan WC,
Fraser VJ. The clinical and economic impact of deep chest surgical infections
following coronary artery bypass graft surgery. Chest. 2000;118(2):397-402.
3. Edwards FH, Engelman RM, Houck P, Shahian DM, Bridges CR; The
Society of Thoracic Surgeons. The Society of Thoracic Surgeons practice
guideline series: antibiotic prophylaxis in cardiac surgery, part I: duration.
Ann Thorac Surg. 2006;81(1):397-404. Available at: http://www.sts.org/documents/pdf/guidelines/AntibioticProphylaxisinCardiacSurgeryPartIDuration.
pdf. Accessed December 20, 2008.
4. Silagy CA, Weller DP, Lapsley H, Middleton P, Shelby-James T, Fazekas B.
The effectiveness of local adaptation of nationally produced clinical practice
guidelines. Fam Pract. 2002;19(3):223-30.
5. Harvey K, Dartnell J, Hemming M. Improving antibiotic use: 25 years of
antibiotic guidelines and related initiatives. Commun Dis Intell. 2003;(Suppl
27):S9–S12.
6. Bratzler DW, Houck PM; Surgical Infection Prevention Guideline Writers
Workgroup. Antimicrobial prophylaxis for surgery: an advisory statement from the National Surgical Infection Prevention Project. Am J Surg.
2005;189(4):395-404.
7. Eagle KA, Guyton RA, Davidoff R, et al. ACC/AHA 2004 guideline update
for coronary artery bypass graft surgery: a report of the American College of
Cardiology/American Heart Association Task Force on Practice Guidelines
(Committee to Update the 1999 Guidelines for Coronary Artery Bypass
Graft Surgery). J Am Coll Cardiol. 2004;44(5):e213-310.
270 Journal of Managed Care Pharmacy
8. Mangram AJ, Horan TC, Pearson ML, Silver LC, Jarvis WR. Guideline for
prevention of surgical site infection, 1999. Centers for Disease Control and
Prevention (CDC) Hospital Infection Control Practices Advisory Committee.
Am J Infect Control. 1999;27(2):97-132.
JMCP
April 2009
Vol. 15, No. 3
18. Zoutman D, Chau L, Watterson J, Mackenzie T, Djurfeldt M. A Canadian
survey of prophylactic antibiotic use among hip-fracture patients. Infect
Control Hosp Epidemiol. 1999;20(11):752-55.
19. Burke JP. Maximizing appropriate antibiotic prophylaxis for surgical patients: an update from LDS Hospital, Salt Lake City. Clin Infect Dis.
2001;33(Suppl 2):S78-S83.
20. Talon D, Mourey F, Touratier S, et al. Evaluation of current practices in
surgical antimicrobial prophylaxis before and after implementation of local
guidelines. J Hosp Infect. 2001;49(3):193–98.
21. Prado MA, Lima MP, Gomes IR, Bergsten-Mendes G. The implementation of a surgical antibiotic prophylaxis program: the pivotal contribution of
the hospital pharmacy. Am J Infect Control. 2002;30(1):49-56.
22. Alerany C, Campany D, Monterde J, Semeraro C. Impact of local guidelines and an integrated dispensing system on antibiotic prophylaxis quality
in a surgical centre. J Hosp Infect. 2005;60(2):111-17.
23. al-Harbi M. Antimicrobial prophylactic practice in surgical patients. East
Afr Med J. 1998;75(12):703-07.
24. Askarian M, Moravveji AR, Mirkhani H, Namazi S, Weed H. Adherence
to American Society of Health-System Pharmacists surgical antibiotic prophylaxis guidelines in Iran. Infect Control Hosp Epidemiol. 2006;27(8):876-78.
25. Otoom S, Batieha A, Hadidi H, Hasan M, Al-Saudi K. Evaluation of drug
use in Jordan using WHO prescribing indicators. East Mediterr Health J.
2002;8(4-5):537-43.
26. Al-Bakri AG, Bustanji Y, Yousef AM. Community consumption of antibacterial drugs within the Jordanian population: sources, patterns and
appropriateness. Int J Antimicrob Agents. 2005;26(5):389-95.
27. Otoom SA, Sequeira RP. Health care providers’ perceptions of the problems and causes of irrational use of drugs in two Middle East countries. Int J
Clin Pract. 2006;60(5):565-70.
www.amcp.org
Adherence to International Antimicrobial Prophylaxis Guidelines in Cardiac Surgery:
A Jordanian Study Demonstrates Need for Quality Improvement
28 van Disseldorp J, Slingenberg EJ, Matute A, Delgado E, Hak E,
Hoepelman IM. Application of guidelines on preoperative antibiotic prophylaxis in Leon, Nicaragua. Neth J Med. 2006;64(11):411-16.
29. Lallemand S, Thouverez M, Bailly P, Bertrand X, Talon D. Nonobservance of guidelines for surgical antimicrobial prophylaxis and surgicalsite infections. Pharm World Sci. 2002;24(3):95-99.
30. van Kasteren ME, Kullberg BJ, de Boer AS, Mintjes-de Groot J, Gyssens
IC. Adherence to local hospital guidelines for surgical antimicrobial prophylaxis: a multicentre audit in Dutch hospitals. J Antimicrob Chemother.
2003;51(6):1389-96.
31. Voit SB, Todd JK, Nelson B, Nyquist AC. Electronic surveillance
system for monitoring surgical antimicrobial prophylaxis. Pediatrics.
2005;116(6):1317-22.
32. Paradiso-Hardy FL, Cornish P, Pharand C, Fremes SE. A national survey
of antimicrobial prophylaxis in adult cardiac surgery across Canada. Can J
Infect Dis. 2002;13(1):21-27.
35. Thomas M, Govil S, Moses BV, Joseph A. Monitoring of antibiotic use in
a primary and tertiary care hospital. J Clin Epidemiol. 1996;49(2):251-54.
36. Hu S, Liu X, Peng Y. Assessment of antibiotic prescription in hospitalised patients at a Chinese university hospital. J Infect. 2003;46(3):161-63.
37. Heineck I, Ferreira MB, Schenkel EP. Prescribing practice for antibiotic
prophylaxis for 3 commonly performed surgeries in a teaching hospital in
Brazil. Am J Infect Control. 1999;27(3):296-300.
38. Martelli A, Mattioli F. A retrospective study showing the misuse of prophylactic antibiotics in patients undergoing appendectomy and cholecystectomy. Curr Ther Res Clin Exp. 2000;61:534-39.
39. Harbarth S, Samore MH, Lichtenberg D, Carmeli Y. Prolonged antibiotic
prophylaxis after cardiovascular surgery and its effect on surgical site infections and antimicrobial resistance. Circulation. 2000;101(25):2916-21.
33. Martin C, Pourriat JL. Quality of perioperative antibiotic administration
by French anaesthetists. J Hosp Infect. 1998;40(1):47-53.
40. Gupta N, Kaul-Gupta R, Carstens MM, Franga D, Martindale RG.
Analyzing prophylactic antibiotic administration in procedures lasting
more than four hours: are published guidelines being followed? Am Surg.
2003;69(8):669-73 (discussion 673-74).
34. Zwar N, Henderson J, Britt H, McGeechan K, Yeo G. Influencing antibiotic prescribing by prescriber feedback and management guidelines: a
5-year follow-up. Fam Pract. 2002;19(1):12-17.
41. Lacy CF, Armstrong LL, Goldman MP, Lance LL. Drug Information
Handbook 2006-2007. 15th ed. Washington, D.C.: The American
Pharmaceutical Association; 2006.
www.amcp.org
Vol. 15, No. 3
April 2009
JMCP
Journal of Managed Care Pharmacy 271
C O M M E N TA R Y
Tablet Splitting: Much Ado About Nothing?
Robert P. Navarro, PharmD
P
harmacists have been splitting scored tablets to individualize and titrate dosages since the end of the pill-rolling era.
We have generally accepted that scored tablets may be
evenly divided, resulting in 2 half-tablets containing one-half
of the whole tablet strength. Slight powdering is unavoidable,
but it is generally accepted that loss of a few molecules of active
drug is not likely to be clinically significant. However, even when
tablets are split by pharmacists, 1 study found significant weight
deviations in almost 10% of half-tablets.1 We do not know if this
weight variation correlates with active drug in each tablet half,
or more importantly, if this variation will jeopardize clinical
outcomes or safety.
In some instances, there may be no other way to satisfy the prescribed dose other than tablet splitting. In any case, we rationalize that the patient receives the necessary dose during the course
of chronic therapy because the patient eventually consumes all
tablet halves as prescribed—1 half-tablet at a time. Assuming a
10% weight deviation, if one half-tablet provides 90%, and the
next contributes 110%, on average, the patient receives 100% of
the dose over 2 doses. Presumably pharmacists rely on pharmacokinetics and pharmacodynamics when selecting opportunities
for tablet splitting and pass on those drugs for which fluctuations
may be a concern; one wonders if physicians share such concerns
when nonstandard doses are prescribed. Pharmacists must be
involved and vigilant when advising individual patients and participating in population-based tablet-splitting programs.
We have made assumptions and selected appropriate drugs to
be halved based on our understanding of pathophysiology, pharmacology, and pharmacodynamics. We assume homogenous
distribution of active drug in whole tablets, and thus, an equal
distribution of active drug in the half-tablets. Some variation is
expected, and the U.S. Food and Drug Administration (FDA)
bioequivalence standards permit variance of plus or minus 20%.2
So, even with whole tablets, the actual dose ingested may fluctuate from whole tablet to whole tablet.
Past tablet-splitting research has assessed the half-tablet
weight, uniformity, and even the clinical outcome of split tablets,3
including the work of Gee et al. (2002), which assessed clinical,
service, and cost outcomes associated with tablet splitting.4 In
this issue of JMCP, Hill et al. offer an unprecedented analysis of
the accuracy and precision of tablet splitting by measuring the
active drug component in tablet halves.5 This use of assay is an
important step in assessing half-tablet weight variations.
Half-Tablet Variations—Do They
Have Clinical or Practical Meaning?
As pharmacists, we presume that if the dose of an angiotensinconverting enzyme (ACE) inhibitor, statin, analgesic, or anti272 Journal of Managed Care Pharmacy
JMCP
April 2009
Vol. 15, No. 3
depressant fluctuates by a few molecules more or less than the
prescribed dose, surely this fluctuation would not jeopardize
effectiveness or safety, as these drugs are titrated in approximate milligram increments even with whole tablets. However,
warfarin is typically not included in half-tablet programs.6-8
Controversy surrounding the narrow therapeutic index of this
drug, its relatively low cost, and the often short-term nature of
dosing associated with acute events such as orthopedic surgery
for hip or knee replacement probably contribute to the absence
of warfarin from formal tablet-splitting programs. For example,
UnitedHealthcare’s Half Tablet Program in June 2007 listed only
15 drugs in 4 categories: 3 ACE inhibitors, 5 angiotensin receptor
blockers (ARBs), 4 antidepressants, and 4 statins.6
While most health plans do not promote splitting of warfarin
tablets, Hill et al. included warfarin in their research because
it was among the drugs “commonly split” in 1 Department of
Veterans Affairs (VA) health care system.5 It is important to note
that Hill et al. used an arbitrary standard for warfarin individual
tablet variation (95%-105%), which is more narrow than the
variation standard that they used for other drugs (90%-110%)
and more narrow than the standard used by the United States
Pharmacopeia (USP; 85%-115%) for weight and content uniformity of individual tablets. The standards used by Hill et al. are
“typically applied to samples of 20 [tablets] or greater.”5
Also curious are inconsistencies in Hill et al.’s recommendations regarding splitting warfarin tablets. The authors include a
warning that “caution should be taken when splitting warfarin
sodium due to the potential for significant adverse events with
minimal change in daily dose.”5 However, the authors seem to
negate their concerns by stating that “daily variation of international normalized ratio (INR) values…can result from food interactions, drug interactions, and variations in daily dose. For this
reason, it cannot be stated that the minor differences in warfarin
sodium half-tablet drug content will predict clinical outcomes.”5
While splitting of warfarin tablets presents a theoretically realistic
concern in a population-based program, apparently the VA, the
setting for the Hill et al. study, splits warfarin, presumably without problems.
Another point of confusion surrounds lisinopril half-tablet
fluctuations. Hill et al. report that drug content variation for
half-tablets “was greatest with lisinopril, which had tablet
halves ranging from 81.15% to 125.72% of the target drug content for half-tablets. Thus, when tablet splitting is performed
for this lot of lisinopril, patients may receive daily doses that
vary by as much as 45%.” This admonition is somewhat inconsistent with Hill et al.’s later statement that “daily fluctuations
in dose [of antihypertensives] would be expected to affect
www.amcp.org
Tablet Splitting: Much Ado About Nothing?
blood pressure measurements and side effects and have no
effect on long-term clinical end points.”5
This confusion over the clinical significance of variation in
warfarin and lisinopril half-tablets creates negative sound bites
that may cast an unjustified pall over tablet splitting in general
for the hasty or uninformed reader who researches the topic
no further.
Tablet Splitting as a Managed Care Issue
We acknowledge and accept that dispensing pharmacists split
tablets—with fingers, a counting knife, device, or a blade—to
accommodate prescribed doses not available in whole tablets. But
why did tablet splitting migrate from solely a professional practice
issue to a sometimes controversial managed care concern?
The reason is that tablet splitting both satisfies and challenges
the raison d’être of managed care pharmacy: to deliver a valuebased pharmacy benefit. The value equation puts the drug benefit
in the numerator and cost in the denominator. In this equation,
value increases with a greater benefit and/or a lower cost, and
decreases with a lower benefit and/or higher cost. Tablet splitting
delivers the same clinical outcomes at a lower cost. From this
perspective, managed care can embrace tablet splitting.
For example, the generic lisinopril 40 mg cash price is about
$18.00 for 30 tablets, and lisinopril 20 mg is about $14.00 for 30
tablets.9 If a patient is prescribed 20 mg daily, and the pharmacist
splits fifteen 40 mg tablets to dispense 30 half-tablets (20 mg per
half-tablet), the cost would be $9.00 for a 30-day supply, rather
than $13.99, a savings of 36% without jeopardizing patient care.
This is a tantalizing opportunity for pharmacy benefit plans and
for patients, who typically experience a copayment savings of
about 50% when participating in a half-tablet program.
In their study, Hill et al. cite other sources, including the VA,
claiming success and forecasting significant cost savings from
dividing certain drugs when a half-tablet of a larger strength is
less expensive than a whole tablet of the half-strength.10 One
source identified annual savings of approximately $342,000
through tablet-splitting in a plan with $10 million in annual
pharmacy benefit expenditures.11 In 2004, the VA announced
that splitting simvastatin tablets saved $46.5 million systemwide
in fiscal year 2003.12 In another VA study, Gee et al. (2002) found
that splitting statins produced savings of approximately $68 per
patient per year without compromising lipid reduction.4
Concerns About Unintended Consequences Overstated?
Detractors and concerned patient advocates have voiced concern
about tablet splitting, challenging that tablet halves may not provide exactly one-half of the dose of the whole tablet; patients may
be confused by one-half tablets and take an erroneous (double)
dose, or splitting an extended-release tablet may jeopardize the
rate of absorption; and any 1 of these occurrences may jeopardize
clinical outcomes including patient safety. For example:
• The Institute for Safe Medication Practices advises patients
www.amcp.org
to split tablets “only if you ‘half’ to” although the practice
may be necessary for dosage titration or to reduce drug
costs; the institute also acknowledges potential risks and
admonishes prescribers to select the proper patient candidate for tablet splitting.13
• In 2004, the American Pharmacists Association stated that
tablet splitting can be effective for certain drugs and certain
patients but should not be automatic or mandatory.14
• A 2006 article in the Journal of Family Practice acknowledged
the potential cost savings from tablet splitting but provided
guidelines on what dosage forms or patients may or may not
be appropriate candidates for tablet splitting. Also, the article
pointed out that certain tablet-splitting devices may be more
effective than others in creating mirror halves.15
• Is there room for misinterpretation and a pharmaceutical
misadventure if a patient is dispensed one-half tablets (split
by the pharmacist) and the instructions read “take one-half
tablet”? Might the patient further split the half-tablet and take
one quarter-tablet?
• Might a busy pharmacy dispense a whole tablet with the
instructions reading “take one-half tablet” and expect the
patient to split the tablet? Can patients be expected to accurately and precisely split tablets themselves? Should they be
given a tablet splitter by their managed care organization
(MCO)? (Some MCOs have provided splitters to patients.)
Perhaps it is not tablet splitting per se that is objectionable, but
the regimented splitting that may appear forced upon patients
by managed care. As a sound bite headline, a “mandatory tabletsplitting program” sounds Orwellian; without more specific
definition, it may erroneously be perceived to apply to all drugs
and all patients.
In reality, the pharmacy directors at the MCOs and VA centers
that recommend tablet splitting for some drugs are well aware of
these and other concerns and, as a result, carefully select drugs to
be split without potential for hazard. They generally avoid drugs
for which slightly fluctuating blood levels may compromise outcomes or safety (so-called narrow therapeutic index drugs); drugs
that are frequently titrated or monitored with lab assays; and,
in general, drugs requiring accurate and precise dosage adjustments on a chronic basis to maintain desired effectiveness and
safety outcomes, particularly in frail or otherwise fragile patients.
Similarly, patients physically unable to split tablets are excused
from this requirement.
Is Current Splitting Practice a Non-Issue?
In preparing this commentary I spoke with pharmacy directors of several large MCOs—open-panel as well as closed-panel
plans with clinic pharmacies—who had instituted mandatory
tablet splitting confined to a limited number of specific brand
name drugs. Most acknowledged that the tablet-splitting programs reduced drug costs. However, many have abandoned their
tablet-splitting programs because the target drugs have become
Vol. 15, No. 3
April 2009
JMCP
Journal of Managed Care Pharmacy 273
Tablet Splitting: Much Ado About Nothing?
available as generics—instituting a maximum allowable cost program is an easier way to achieve cost savings.
Some MCOs and VA centers, however, continue to achieve cost
savings with tablet splitting for select drugs. Others may once
again embrace tablet splitting as new brand tablets are launched
that satisfy desired criteria, particularly flat pricing among
strengths of the same drugs. For all plans that do, Hill et al. have
advanced our scientific understanding by showing that drug
content was uniformly distributed for all medications analyzed,
and half-tablet weight seems to be directly correlated with halftablet drug content. However, they also cautioned that a potential
for half-tablet dose variation may occur with warfarin sodium,
metoprolol succinate, and lisinopril. Warfarin may be a concern;
lisinopril perhaps not so much, despite the varied opinions presented in Hill et al.’s paper. Pharmacy directors will use these new
data to help design and execute tablet-splitting programs with
value for patients and health plans.
In their penultimate paragraph, Hill et al. state that unless
performed by a device, tablet splitting, even by pharmacists and
especially by patients, will likely result in significant tablet weight
variations, and they further opine that “therefore, equal daily
doses will be determined by the ability of patients to split tablets
perfectly in half.”5 While we all agree that certain patients with
challenges in cognition or dexterity are not appropriate candidates, the authors confirm by their research that most split tablets
are within accepted ranges, and even those that are not may not
result in negative clinical outcomes due to the gross dosages used.
Hill et al. did not measure clinical outcomes, and the takeaway
message is that there is reasonable content and weight uniformity
among most tablet halves that result from tablet splitting. An
opportunity to improve efficiency without jeopardizing patient
safety, tablet splitting has been endorsed in a professional practice advisory from the Academy of Managed Care Pharmacy.16
Likewise, tablet splitting may be increasingly important from
the consumer’s perspective; in a February 2009 Kaiser Health
Tracking Poll, 15% of respondents reported that they had either
split tablets or skipped medication doses to save on prescription
drug costs in the previous year.17 Tablet splitting may be an effective method to individualize dosages and/or reduce costs when
performed under the guidance of pharmacists, for informed and
competent patients, and for appropriate drugs.
Author
ROBERT P. NAVARRO, PharmD, is President, Navarro Pharma,
LLC, Green Cove Springs, Florida.
AUTHOR CORRESPONDENCE: Robert P. Navarro, PharmD,
Navarro Pharma, LLC, 411 Walnut Street, Suite 4641, Green Cove
Springs, FL 32043. E-mail: [email protected]
274 Journal of Managed Care Pharmacy
JMCP
April 2009
Vol. 15, No. 3
DISCLOSURES
The author reports no conflicts of interest related to the subjects or products
discussed in this article.
REFERENCES
1. Rosenberg JM, Nathan JP, Plakogiannis F. Weight variability of pharmacist-dispensed split tablets. J Am Pharm Assoc (Wash). 2002;42(2):200-05.
2. U.S. Food and Drug Administration. Food and Drug Administration Center
for Drug Evaluation and Research Approved Drug Products with Therapeutic
Equivalence Evaluations. 29th edition. Available at: http://www.fda.gov/Cder/ob/
docs/preface/ecpreface.htm. Accessed March 3, 2009.
3. Duncan MC, Castle SS, Streetman DS. Effect of tablet splitting on serum
cholesterol concentrations. Ann Pharmacother. 2002;36(2):205-09.
4. Gee M, Hasson NK, Hahn T, Ryono R. Effects of a tablet-splitting program in patients taking HMG-CoA reductase inhibitors: analysis of clinical
effects, patient satisfaction, compliance, and cost avoidance. J Manag Care
Pharm. 2002;8(6):453-58. Available at: http://www.amcp.org/data/jmcp/
Research-453-458.pdf.
5. Hill S, Varker A, Karlage K, Myrdal P. Analysis of drug content and weight
uniformity for half-tablets of 6 commonly split medications. J Manag Care
Pharm. 2009;15(3):253-61.
6. The UnitedHealthcare Half Tablet Program. June 2007. Available
at: https://www.uhctools.com/document/3836.pdf;jsessionid=
BDGKIEGLHNFD. Accessed March 2, 2009.
7. RegenceRx Half-Tablet Program. November 2008. Available at:
http://www.regencerx.com/programs/halfTablet/index.html.
Accessed March 2, 2009.
8. STRS Ohio/Express Scripts 2009 Voluntary Tablet-Splitting Program.
Available at: http://www.strsoh.org/pdfs/12-549-2009.pdf. Accessed
March 2, 2009.
9. Drugstore.com. Available at http://www.drugstore.com/pharmacy/drugindex/rxsearch.asp?search=lisinopril&expand=Lisinopril&trx=1Z5007.
Accessed February 13, 2009.
10. Polli JE, Kim S, Martin BR. Weight uniformity of split tablets required by
a Veterans Affairs policy. J Manag Care Pharm. 2003;9(5):401-07. Available at:
http://www.amcp.org/data/jmcp/Research-401-407.pdf.
11. Miller DP, Furberg CD, Small RH, et al. Controlling prescription drug
expenditures: a report of success. Am J Manag Care. 2007;13(8):473-80.
12. U.S. Department of Veterans Affairs. Tablet-splitting saves VA
$46.5 million on popular statin. November 10, 2004. Available at:
http://www.research.va.gov/news/press_releases/tablet-splitting-111004.cfm.
Accessed March 2, 2009.
13. Institute for Safe Medication Practices. Tablet splitting: do it only if
you “half” to, and then do it safely. Available at: http://www.ismp.org/
Newsletters/acutecare/articles/20060518.asp. Accessed February 2, 2009.
14. American Pharmacists Association. Press release. Tablet splitting can
be ok, but shouldn’t be automatic. May 19, 2004. Available at http://www.
pharmacist.com/AM/Template.cfm?Section=Current_News&template=/CM/
ContentDisplay.cfm&ContentID=10448. Accessed February 3, 2009.
15. Noviasky J, Lo V, Luft D: Clinical inquiries. Which medications can be
split without compromising efficacy and safety? J Fam Pract. 2006;55(8):
707-08. Available at: http://www.jfponline.com/pdf%2F5508%2F5508JFP_
ClinicalInquiries1.pdf. Accessed February 3, 2009.
16. Academy of Managed Care Pharmacy. Professional practice advisory on
tablet splitting. Available at: http://www.amcp.org/amcp.ark?p=AA8CD7EC.
Accessed March 15, 2009.
17. The Henry J. Kaiser Family Foundation. Kaiser Health Tracking Poll.
February 2009. Available at: www.kff.org/kaiserpolls/upload/7866.pdf.
Accessed March 23, 2009.
www.amcp.org
C O M M E N TA R Y
Standardizing Quality Assessment of Observational
Studies for Decision Making in Health Care
Diana I. Brixner, PhD, RPh; Anke-Peggy Holtorf, PhD, MBA; Peter J. Neumann, ScD;
Daniel C. Malone, PhD; and John B. Watkins, RPh, MPH, BCPS
T
his report summarizes a roundtable discussion of managed
care experts and academic pharmacoeconomists, held in
March 2008 with the objective of defining action steps to
overcome barriers to the incorporation of real-world data into
health care decision making. The roundtable meeting was the
result of an initial program in July 2007 where managed care
decision makers and pharmacoeconomic experts defined these
barriers.1 Real-world data in this context were characterized as
data not routinely collected in Phase III drug registration studies, including administrative claims data, patient registries, large
simple trials, resource use collection alongside clinical trials, and
electronic medical records.1,2 These data are considered along
with standard safety, efficacy, and pricing information. However,
one conclusion from the first roundtable discussion was that concerns around the quality assessment of such data have hindered
widespread use in decision making.
The Foundation of Managed Care Pharmacy (FMCP) recognized the value of real-world data in its AMCP Format for
Formulary Submissions, version 2.1, a structured outline for the
presentation of information by pharmaceutical companies on
their products to managed care decision makers.3 As a sponsor
and developer of this standard, FMCP has invested in the adoption of the AMCP Format by manufacturers and health plans.
Following a broad communication strategy, over 50 training seminars to managed care pharmacists on using the AMCP Format
have been held.4 The acceptance of the AMCP Format approach
has improved since its inception in the year 2000; however, its
impact on formulary decisions is still in its infancy. A recent survey found that approximately one-third of all pharmacy directors
request information from drug manufacturers in a form that is
consistent with the AMCP Format.5 While information delivered
in the dossier concerning the safety and efficacy for labeled use
was perceived by the health plans to be mostly satisfactory, the
information related to off-label use, costs, and benefits was perceived as incomplete, lacking in clarity, and potentially biased.
These data indicate that despite extensive efforts, the implementation process has not yet been fully effective in promoting the
utilization of real-world data.
The struggle for adoption of new processes in health care
delivery is not new. In the United Kingdom (UK), an initiative
called PARiHS (Promoting Action on Research Implementation
Note: This article is the subject of an editorial that appears on pages 294-296 of this issue.
www.amcp.org
in Health Services) has addressed the importance of process
implementation, and in the United States a framework called REP
(Replicating Effective Programs) has been established.6,7 Both
present conceptual frameworks and their application for transfer
of health care knowledge from research into practice or from one
organization to another from the perspective of implementation
sciences. Within the circles of implementation science, a theory of
“sticky knowledge” has been propagated, referring to the inherent
resistance of the old process against the new. This leads to inefficient knowledge transfer as a significant barrier to implementation of new processes into the health care environment.6-9
These publications highlight that a structured process must
support the effective introduction of an innovation. This process
consists of actions before the actual change (learning before
doing) and actions after the first day of usage (learning by doing).
The process involves the source of the knowledge, the recipient of
the knowledge and the environment for the change, and it should
be guided by personal facilitation. As related to the incorporation
of real-world data into formulary decision making, the creation of
a process or technique for using real-world data is only a starting
point. Implementation requires a multistep process, to be carefully planned and executed.
Thus, while the 2007 meeting of managed care experts and
academic pharmacoeconomists recognized the importance of
real-world data, identified the potential barriers, and recommended methodological approaches to overcome those barriers,
the issue of process implementation was not fully addressed.
The methods and the planning of process implementation were
targeted in 2008, where the participants focused on (a) integration of currently available tools for quality assessment of realworld data studies into 1 standard instrument; (b) creation of an
implementation process for the dissemination of the instrument,
including its validation by peer groups; and (c) establishment of a
training certificate program to educate the potential users of such
a tool. Here, we report the progress of the work and the resulting
integrated action plan to support the developing body of research
on this topic.
Methods
Prior to the roundtable event, participants were assigned to the
following 4 workgroups: (1) Next steps for the International
Society for Pharmacoeconomics and Outcomes Research (ISPOR)
Task Force on Real-World Data; (2) Real-world data assessment
instruments for researchers and users of research; (3) Acceptance
Vol. 15, No. 3
April 2009
JMCP
Journal of Managed Care Pharmacy 275
Standardizing Quality Assessment of Observational Studies for Decision Making in Health Care
process for an assessment instrument; and (4) Training and
education on the use of an instrument. The roundtable program was structured in sequential steps, including preparatory
workgroup activities, discussion and assessment at the roundtable, and work-up in the workgroups. Finally, all recommendations were collected, refined at the roundtable, and prioritized to
yield an integrated action plan.
Results
The discussions are presented in the sequence of the 4 workgroups including the findings of the preparatory phase and the
recommendations formed during the course of the workshop.
Workgroup 1: Continuation of the Work of the ISPOR Task
Force on the Use of Real-World Data. In response to the
increasing request by decision makers for real-world outcomes
information,2 ISPOR created a Task Force on Real-World Data
to develop a framework to assist health care decision makers in
understanding real-world data in the context of application to
reimbursement decisions.2 The open comment period yielded
over 70 comments from ISPOR members and these comments
were summarized by the workgroup. The following core needs
were identified:2,10 (a) more guidance on defining a “Hierarchy
of Evidence” that incorporates real-world data; and (b) guidance
on how real-world data should be applied to reimbursement
decisions, perhaps through guidelines or case studies. These key
requests validated the overall premise of the roundtable discussion by expressing a strong need for specific guidance on interpreting real-world data.
Various systems have been suggested to grade the quality of
evidence for clinical decision making.2,11-19 In a nutshell, the criteria for grading use either technical criteria to evaluate strength
of research design and internal validity or the “net benefit”
criterion (e.g., the magnitude of benefit compared to trade-offs).
Discussion is ongoing about whether it is possible, or useful, to
determine a ”fixed” system for defining a hierarchy of evidence
that can accommodate both criteria.14 Critics fear that hierarchies
of evidence are over-simplistic, pseudo-quantitative approaches
to replace informed judgment.20 Proponents state that such
instruments will help producers and users of these data to orient
themselves in a standard framework. The recommendation of
the workgroup was that organizations vested in the creation and
utilization of such evidence, such as ISPOR and AMCP, should
evaluate the state of the art in developing and using “evidence
hierarchies” and the feasibility of adopting a standard, more
inclusive, hierarchy system.
In order to substantiate the potential for using real-world data
for reimbursement decisions, the group analyzed 4 case studies
where real-world data based evidence was used to make a decision involving conditional reimbursement. The first example was
the conditional reimbursement for a targeted multiple sclerosis
therapy of interferon and glatiramer acetate. The agreement
276 Journal of Managed Care Pharmacy
JMCP
April 2009
Vol. 15, No. 3
between the UK authorities and the manufacturer was that
drug costs would be reduced if a cost-effectiveness threshold of
£36,000 per quality-adjusted life year over 20 years was exceeded
based on an ongoing collection of real-world data.21 The second
example was the reimbursement scheme for bortezomib (Velcade)
in the UK. The manufacturer agreed to rebate the full cost of the
drug if the patient did not achieve at least a partial response to the
treatment after a maximum of 4 treatment cycles as measured by
a marker protein.22 In the third case study, the reimbursement of
the Oncotype Dx, a test for the identification of recurrence risk
for women with early stage breast cancer, was deemed acceptable
by the health insurer United Healthcare for 18 months if the test
led to reduced volume of chemotherapy in those women who
had been identified as low risk.23 The final example of “Coverage
with Evidence Development” has been suggested by the Centers
for Medicare & Medicaid Services (CMS), whereby reimbursement is given for a limited time on the condition that evidence of
effectiveness and/or safety of treatment is collected, often as part
of real-world trials.24,25
Agreements like the ones outlined above may allow additional
data collection for new therapeutic interventions while limiting
the risk for the payer. Conditions for reimbursement become
linked to real-world effectiveness, as determined by the evaluation of real-world data. For such agreements it is important to
use clear definitions of the type of data used, the quality of data
requested, and the cut-off points for the reimbursement, and to
agree on a manageable volume or length for data collection. In a
subsequent step, further decisions can then be made based on
improved real-world evidence on the treatment effectiveness.
To avoid biased reporting of the results of observational studies and to make sure that all existing evidence is accessible to
decision makers, Workgroup 1 suggested a voluntary registry of
observational studies, which should lead to increased credibility
of these studies and the organizations conducting these studies.
Transparency is important for models and real-world evidence.
However, the degree of transparency depends, among other factors, on the level of expertise of the user of this information. To
allow more standardized qualifications of models or real-world
data studies, Workgroup 1 proposed the establishment of an
independent body or review process, which could be formed as a
consortium of experts giving access to a broad range of resources
and expertise for an audit, review or quality certification process.
Such a body could, for example, be associated with an organization like FMCP as a service to the AMCP membership.
Workgroup 2: Assessment Tool for Researchers and Users
of Research. The 4 managed care organization participants
reviewed how instruments for assessing the quality of realworld data studies have been used in their organizations.
Among them, none used a published instrument for assessment
of the quality of real-world data studies currently, or had done
so in the past. In order to consider such a tool, the instrument
www.amcp.org
Standardizing Quality Assessment of Observational Studies for Decision Making in Health Care
TABLE 1
Year
2004
Authors
and Source
Philips,
Ginnelly,
Sculpher,
et al.33
Summary of Checklists Evaluated as Basis for the Roundtable Discussions
Country
UK
Title
Review of guidelines for
good practice in decisionanalytic modeling in health
technology assessment
1996
Drummond,
Jefferson 26
UK
Guidelines for authors and
peer reviewers of economic
submissions to the BMJ
2007
von Elm,
Altman,
Egger, et al.34
International
The Strengthening the
Reporting of Observational
Studies in Epidemiology
(STROBE) Statement: guidelines for reporting observational studies
2007
Peterson,
Nau, Cramer,
et al.32
International
2003
Motheral,
Brooks,
Clark, et al.31
US
1998
Halpern,
Luce, Brown,
Geneste29
Mauskopf,
Sullivan,
Annemans,
et al.30
International
2003
Collège des
Économistes
de la Santé38
France
A checklist for medication
compliance and persistence
studies using retrospective
databases
A checklist for retrospective
database studies—report
of the ISPOR Task Force on
Retrospective Databases
Health and economic outcomes modeling practices: a
suggested framework
Principles of good practice
for budget impact analysis:
report of the ISPOR Task
Force on Good Research
Practices--Budget Impact
Analysis
Guide méthodologique pour
l’évaluation économique des
stratégies de santé
2000
Hannover
Consensus
Group37
Germany
2003
Weinstein,
O’Brien,
Hornberger,
et al.35
Des Jarlais,
Lyles, Crepaz,
et al.28
International
Ofman,
Sullivan,
Neumann,
et al.36
International
2007
2004
2003
International
International
Deutsche Empfehlungen zur
gesundheitsökonomischen
Evaluation (German recommendations for health care
economic evaluation studies)
Principles of good practice
for decision analytic modeling in health-care evaluation
(ISPOR).
Improving the Reporting
Quality of Nonrandomized
Evaluations of Behavioral
and Public Health
Interventions: The TREND
Statement
Examining the value and
quality of health economic
analyses: implications of utilizing the QHES
Objectives
• To summarize published guidelines for assessing the quality of
decision-analytic models in HTA.
• To develop a synthesized guideline and accompanying checklist using
available good practice guidelines.
• To provide guidance on key issues not yet covered in published
guidelines.
• To consider expectations of future decision-analytic models for NICE
technology appraisal process and HTA.
To improve the quality of submitted and published economic evaluations by agreeing on acceptable methods and their systematic application
before, during, and after peer review. Includes:
• Easy guidelines for economic evaluation
• A checklist for use by referees and authors
• A checklist for use by editors
To develop recommendations on what should be included in an
accurate and complete report of an observational study. The scope of
the recommendations was to cover 3 main study designs:
• cohort
• case–control
• cross-sectional studies
To develop a checklist of items that should be either included, or at least
considered, when a retrospective database analysis of medication compliance or persistence is undertaken.
Number
of Criteria
69
35
22
20
To develop a checklist supporting decision makers in evaluating the
quality of published studies that use health-related retrospective
databases.
27
To improve the development and review of models by defining
recommendations and a quality control checklist
26
To present guidance on methodologies for budget impact analysis for
producers and reviewers and users
29
To develop a format for presenting the results
To improve the quality of health-economic studies in France
To define the minimum requirements for methodology and transparence
10
To provide modelers with guidelines for conducting and reporting modeling studies
40
The main goals of the meeting were to:
(1) communicate the usefulness and importance of adequate reporting
standards,
(2) reach consensus on reporting standards for behavioral interventions,
(3) develop a checklist of reporting standards to guide authors and journal reviewers, and
(4) Develop strategies to disseminate the resulting reporting standards.
To create a quantitative approach to the appraisal of health economic
studies
46
www.amcp.org
Vol. 15, No. 3
April 2009
JMCP
16
Journal of Managed Care Pharmacy 277
Standardizing Quality Assessment of Observational Studies for Decision Making in Health Care
TABLE 1
1998
Downs,
Black 27
Summary of Checklists Evaluated as Basis for the Roundtable Discussions
(continued from previous page)
UK
The feasibility of creating a
To test the feasibility of creating a valid and reliable checklist with the
26
checklist for the assessment
following features: appropriate for assessing both randomized and nonof the methodological qualrandomized studies; providing both an overall score for study quality and
ity both of randomized and
a profile of scores not only for the quality of reporting, internal validity
non-randomized studies of
(bias and confounding) and power, but also for external validity.
health care interventions
HTA = health technology assessment; ISPOR = International Society for Pharmacoeconomic and Outcomes Research; NICE = National Institute for Clinical Excellence;
QHES = Quality of Health Economic Studies; TREND = Transparent Reporting of Evaluations with Non-randomized Designs; UK = United Kingdom; US = United States.
would need to be short, simple to use, concise, and validated.
In addition, recommendation by a national organization would
be seen as a positive factor.
With these objectives in mind, Workgroup 2 evaluated
existing instruments for application towards the assessment of
real-world data studies. The goal would be to consolidate these
instruments into a useful tool for decision makers to evaluate
real-world data.
Individual members of the workgroup nominated various
instruments for inclusion in the evaluation. The resulting 13
published assessment tools were reviewed for suitability to
critique real-world data studies.26-36,38 Table 1 summarizes the
evaluation tools included in this work. Prior to the meeting,
members of the workgroup assessed the tools according to (a)
target user (researcher, journal reviewer, systematic reviewer,
decision maker); (b) study type (prospective, retrospective, modeling); (c) phase of research (planning, publishing, using); (d)
type and number of domains used in the assessment tool; (e)
grading system used; (f) strengths and weaknesses; and (g) geographic transferability. The perspectives of evaluation tools can be
either from the viewpoint of the researcher (assurance of research
quality), of the reviewer (assurance of research and publication
quality), or of the decision maker (assurance of evidence quality
and relevance). The instruments evaluated had been developed
for a variety of study types, including modeling,26,29-31,33,35 nonrandomized studies,27 budget impact analysis,30 retrospective
studies,26,27,31,32,34 or studies of compliance and persistence.32
The number of questions or criteria assessed varied considerably across the instruments. The mean number of criteria was
30.5 with a range of 10 to 69 questions. The structure of the questions was either by publication outline (objectives, background,
methods, results, discussion, and limitations) or by methods
(comparators, bias, and sensitivity analysis). Only 2 of the instruments indicated that they had been validated,27,36 whereby a
validation process involves determination of the congruency of
independent assessments of the same research report by several
evaluators using the instrument to be validated. For the majority
of instruments, no updates were available. In general, yes-or-no
questions were used in the evaluation as opposed to a scale.
Although our review was not intended to be comprehensive of
every real-world data assessment tool available, this evaluation
278 Journal of Managed Care Pharmacy
JMCP
April 2009
Vol. 15, No. 3
of a selection of 13 assessment tools confirms the findings of a
previous study performed by the Agency for Healthcare Research
and Quality (AHRQ) in 2002. There are a variety of checklists,
which may lead to different assessment results, and it is up to the
user to select the most suitable tool.39
This workgroup recommended the collection of all instruments available and classification according to their usefulness
and impact on decisions from the viewpoint of a decision maker.
The overriding objective of this work would be the development
of 1 consolidated instrument in the form of a modular assessment tool with different axes by (a) study objective: economic
impact or cost-effectiveness, heath outcomes, patient reported
outcomes; and (b) study type: model, clinical prospective study,
or retrospective data analysis. Workgroup 2 also acknowledged
the importance of validating a consolidated instrument for quality assessment of real-world data by a broader group of users.
Consolidation does not necessarily mean the creation of a new
additional instrument. Instead, it involves a thorough comparison of the existing instruments and selection of those criteria that
are recognized as key indicators of the required quality assessment. In the September 2008 issue of JMCP, Fairman and Curtiss
reported a comparison of a range of research and publication
guidelines.40 A similar comparison, with a focus on real-world
database research, would form the foundation of a consolidated
tool to quickly link assessment to the quality evaluation at hand.
Consequently, the first step for a consolidated tool would be the
development of a comprehensive list of criteria, which define the
quality standard expectations by type of quality assessment need.
However, such a comprehensive list must be balanced against a
key request from the user perspective, which was to keep it short
and simple. There are 2 different approaches to deal with this tension. To create a “user-friendly” tool, the items could be ranked to
identify the 10 most important factors from the decision maker’s
perspective. Alternatively, an independent body or review process could decrease the skepticism of decision makers towards
real-world data studies, without increasing the complexity in the
individual decision-making process.
Workgroup 3: Process to Achieve Dissemination and
Acceptance of an Assessment Tool. One conclusion reached in
the Fairman and Curtiss review of guidelines was that there is
www.amcp.org
Standardizing Quality Assessment of Observational Studies for Decision Making in Health Care
ample guidance existing, but that the use of it is limited.40 Thus,
guidelines are not widely adopted, and their existence does not
guarantee a minimum quality standard of published research.
Due to the demonstrated challenges regarding the uptake of
tools such as the AMCP Format for Formulary Submissions5 and
implementation of evidence-based decisions in health care,6-8,41
Workgroup 3 was assigned to outline a process for high-level
agreement on the acceptance of an instrument for quality assessment to ensure widespread adoption of the instrument.
The initial recommendation was to establish an expanded,
multidisciplinary advisory board composed of key decision makers and academic pharmacoeconomic researchers. The primary
goal of this group would be to advance the content from the 3
workgroups to present to a larger, public “user forum” including professional bodies of decision makers and researchers,
clinicians, employers, patient or quality assurance organizations. Potential stakeholders represented in such a forum could
be the National Committee for Quality Assurance (NCQA) or
the AHRQ, CMS, Congressional Budget Office, Wellpoint, Blue
Cross Blue Shield, Kaiser, state Medicaid agencies, Department
of Veterans Affairs, University HealthSystem Consortium [UHC],
Institute of Medicine, World Association of Medical Editors, and
the recently formed Pharmacy Quality Alliance. The objective
would be to increase public awareness of the need for quality
assessment of observational evidence and subsequently, the
acceptance of observational studies meeting defined quality standards to be used in the decision-making process.
An alternative recommendation to a grass-roots initiative
was the involvement of an independent body or review process
for the “Quality Assessment of Real-World Information.” Such
an independent body could evaluate existing real-world data
information, based on the assessment tool, and provide recommendations concerning the use of such information back to the
users, such as decision makers. Such an institution could also be
involved in the maintenance of the tools and in long-term studies
on the accuracy of the predictions drawn from real-world data
when executed within a health plan system, similar to case studies presented by Workgroup 1.
For either recommendation an important part of the process
would be input into the dissemination and adoption of a consolidated instrument and a training platform for all stakeholders who
may use the instrument.
Workgroup 4: Training and Education. The objective of
Workgroup 4 was to outline an education process to communicate the efficient and competent use of the assessment tool to
all stakeholders. The goal of this initiative was to make training
available to all potential users, including researchers, evaluators,
journal editors, managed care representatives, physicians, and
patient organizations. The workgroup determined that any training program would have to assume that participants start from a
broad range of pre-existing knowledge.
www.amcp.org
An inventory was taken of existing educational resources
of related professional societies. There are several sources for
education on the use of pharmacoeconomic evidence in formulary decision making provided by ISPOR and AMCP/FMCP
including workshops, short courses, live seminars and program
content from annual meetings, which can be retrieved through
the respective internet sites (www.amcp.org and www.ispor.
org). The American College of Clinical Pharmacy (ACCP) has
a training module on the use of pharmacoeconomics and outcomes research in patient care,42 as well as guidelines for pharmacoeconomic fellowship training.43 Other organizations such as
Health Technology Assessment international, Society for Medical
Decision Making, and AcademyHealth, offer links to existing
training programs, but have no internal programs of their own.
Workgroup 4 recommended the creation of a training certificate program on evaluating real-world data studies. The inventoried coursework could be provided through the Web as introductory courses, and advanced courses tying this work together to
the application of real-world data in formulary decision making
could be conducted face-to-face. The certificate program could
then be supplemented by an ongoing mentoring option. The
program was envisioned as a set of sequential modules. Once all
the Web-based modules have been successfully completed, the
participant qualifies for an interactive live program, or advanced
course, on quality assurance for real-world studies. For the faceto-face advanced programs, a “speaker’s bureau” was recommended with qualified trainers for these courses. Training could
be offered from the associations to their members, or organizations or companies to train their employees could hire trainers.
After the live advanced course, the participants could then enroll
into an ongoing mentoring program to facilitate the uptake of the
methodology in the participant’s work routines. This mentoring
program was envisioned as a “mentor’s bureau” formed by the
active users of the tool in their decision-making process. The
reason for suggesting such a mentoring system is the experience
that it is often difficult to transfer a newly acquired process or
methodology into daily practice. While the newly learned process
and method may seem to be clear in the classroom situation,
obstacles often appear only in the practical application. A mentoring system may be a faster way of overcoming the obstacles and
avoiding frustrations in the application. Conversely, a mentoring
system could also help to bring the typical problems in the application back to the development team.
The development of the program should be financed by
sources independent from manufacturers of products to be
decided on. The recently passed economic stimulus package may
provide government-based funding options through the AHRQ.
The ongoing delivery of the training should be self-sustaining and
financed by fees for participation and certification. A mandatory
certificate for decision makers of leading organizations would
fundamentally increase the utilization and adoption of the instrument and the standardization of the process.
Vol. 15, No. 3
April 2009
JMCP
Journal of Managed Care Pharmacy 279
Standardizing Quality Assessment of Observational Studies for Decision Making in Health Care
FIGURE 1
Phase
Instrument
Training
Summary of Results From the Second Roundtable Discussion
on Using Real-World Data for Formulary Decision Making
Driver & Guidance
Procurement of Funding
Sounding Board
Health Policy Interaction
Interdisciplinary Board for the Quality
Assurance of Real-World Data:
Pre-Implementation
Analyze existing:
Prioritization,
Consolidate
Categorization
Version 0
Workshops (AMCP, ISPOR)
Implementation
Validate
Pilot
Expand
Pilot
Roll-Out
Version 0.1
Version 0.2
Version 0.5
Version 1.0
Web based
training modules
Board for the Quality Assurance
of Real-World Data
Mentoring
Integrated Results of the 4 Workgroups. Workgroup 1 defined
the current status around the need for real-world evidence
through examples of its use in drug reimbursement decisions.
Figure 1 depicts the overall process, which was elaborated by
the 4 workgroups with the goal to improve the utilization of realworld data by decision makers. The core of this approach was to
create a standardized instrument for quality assessment, which
was led by Workgroup 2; then to develop a process for uptake
and dissemination as outlined by Workgroup 3; and finally to
support the establishment of this approach with a certified training series defined by Workgroup 4. The roundtable participants
could serve as a steering committee for these activities and pursue
funding procurement. A larger body, to include interaction with
concerned stakeholders could be considered an “Interdisciplinary
Board for the Quality Assurance of Real-World Data.”
Discussion
The goal of the current roundtable discussions was to suggest
processes through which to improve the quality and acceptance of
studies based on real-world data to be used for decision making.
The preceding event in 2007 had identified hurdles for the integration of such studies into the decision-making process and led
to the need to begin formulation of a joint action plan developed
by formulary decision makers from managed care and pharmacoeconomic research experts on how to overcome these obstacles.1
The process recommended by the second roundtable includes:
(a) the establishment of a standard quality assessment tool by
consolidating previously suggested tools; (b) pilot testing and subsequent validation of the robustness of the instrument in a larger
user forum; and (c) the communication of the tool through publications and workshops. In addition the creation of an oversight
board for safeguarding credibility and dissemination was recommended along with a multistage training program with access to
a growing pool of users of the instrument. Quality assessment
280 Journal of Managed Care Pharmacy
Complete training
series
JMCP
April 2009
Vol. 15, No. 3
Complete series with
certification
Growing mentoring pool
through users
using an assessment tool or process is expected to help diminish
the research-to-practice gap44 with respect to real-world data.
The process suggested in this roundtable has been formally
described as “knowledge transfer,”45 defined as the implementation of knowledge by key stakeholders with the intention of
improving health outcomes and efficiencies of the health care
system. Change in health care does not happen easily, even if
there is hard evidence for the advantages of the new direction or
intervention.6,7,44 The existence of quality processes such as the
AMCP Format or quality assessment instruments as they were
discussed during the roundtable event does not lead to their
automatic adoption.5,40 Hurdles along the way can be located
on the individual, intra-organizational, or inter-organizational
level. Insufficient financial, intellectual, or structural resources
can limit acceptance of the new intervention. Those who should
change often fall back on the familiar way of doing things despite
evidence in support of the new ways.5 Change has to be carefully
planned and facilitated throughout both pre- and post implementation phases. How the intervention is packaged, training,
technical assistance, and fidelity assessment are reported to be
crucial to the successful implementation of effective interventions
in health care.6
However, the suggested process and tool are only first steps
to improve the utilization and outcomes of decision making with
real-world data. An iterative improvement process is mandatory.
For example, the AMCP Format, which was originally published
in the year 2000, was revised in 2002 (version 2.0) and 2005
(version 2.1), and further revisions will follow.3 In addition to the
expert groups helping to keep the AMCP Format up-to-date, surveys and studies have been conducted among the target audience
on the utilization and usefulness of the document.5,46-48
This report only considers the validation of the instrument
for consistencies of the results when used by different users.
The important question, whether the inclusion of high quality
www.amcp.org
Standardizing Quality Assessment of Observational Studies for Decision Making in Health Care
real-world data and a standardization of the process of including
these data in decision making will improve the decisions and
their impact on health outcomes, is not addressed.
In May 2006, an international collaborative initiative called
the Enhancing the QUAlity and Transparency Of health Research
(EQUATOR) network was launched in London. The goal of this
initiative is “to enhance reliability of medical research literature
by promoting transparent and accurate reporting of health
research.”49 Assuring the quality of medical research literature
will be in high synergy with the goals of the ideas discussed
in the roundtable reported here. If such standards will be used
more consistently, they may facilitate the task of decision makers to assess the impact of research results on the health of their
membership.
Alternatives to the process suggested here were discussed
throughout the roundtable session, such as the creation of a quality certification body or review process, which would as an intermediary certify the quality of real-world data and evidence and
interpret the potential impact on health outcomes and budgets.
The disadvantage of such an institution, in addition to the organizational and operational issues, would be that it would introduce an additional interpretation level into the process instead of
increasing the general level of knowledge and experience within
the organizations.
One key limitation of this discussion is the presumption that
in most organizations a structured decision-making process exists
and the issue is only how to incorporate assessment of real-world
data into this process. This may not be the case for all health
plans, pharmaceutical benefit management companies, or other
organizations making decisions on drug formularies. However,
following the suggested pathway will not only increase standardization of quality assessment of real-world data, but at the same
time it will also direct some attention to the decision-making
process in general and allow for a growing exchange among those
involved in the drug formulary decision-making process.
Conclusions and Recommendations
The roundtable discussion between formulary decision makers
of managed care and pharmacoeconomic academic experts led
to a multistep action plan to increase the utilization of real-world
data in decision making (Table 2). The proposed process should
involve all relevant stakeholders in the development, testing,
validation, and dissemination of a consolidated quality assessment instrument. To increase the general level of qualification
for users of real-world data among decision makers, a multilevel
certificate-training program has been recommended. To facilitate
the integration of the instrument into the user’s organizational
procedures, a mentoring program for all graduates of the training
was proposed.
www.amcp.org
TABLE 2
Key Recommendations for
Improving the Use of
Real-World Data in Drug
Formulary Decision Making
Summary of recommendations:
•Formation of “Interdisciplinary Board for the Quality Assurance of RealWorld Data”
•Analysis of existing instruments for quality assessment of real-world data
•Prioritization of assessment criteria depending on decision context
•Consolidation of assessment tool
•Validation of tool in small user group, improvement where needed
•Pilot of tool in larger user group
•Development of certificate training series (Web based training modules and
face-to-face training)
•Roll out of instrument and training program
•Formation of mentoring group and system
•Ongoing support and guidance through “Interdisciplinary Board for the
Quality Assurance of Real-World Data”
Roundtable Participants
Managed Care: John B. Watkins, RPh, MPH, BCPS, Premera
Blue Cross; Lawrence J. Pesko, MS, DSc, RPh, Lovelace Sandia
Health System; Leslie Fish, PharmD, RPh, Fallon Community
Health Plan; H. Eric Cannon, PharmD, IHC Health Plans; Lynn
M. Nishida, BS, The Regence Group (in preparatory phase only);
Linda Sturm, MHA, RPh, BCPS, Formulary Resources, LLC.
Health Economics/Academic: Lou P. Garrison, PhD, University
of Washington; Peter J. Neumann, ScD, Tufts University School of
Medicine; C. Daniel Mullins, PhD, University of Maryland School
of Pharmacy; Daniel C. Malone, PhD, College of Pharmacy,
University of Arizona; Karl A. Matuszewski, MS, PharmD, Clinical
Knowledge Service, University HealthSystem Consortium.
Organizations: Richard Fry, RPh, Foundation for Managed Care
Pharmacy; Marilyn Dix-Smith, PhD, RPh, International Society
of Pharmacoeconomics and Outcomes Research.
Authors
DIANA I. BRIXNER, PhD, RPh, is Professor and Chair and
Executive Director, Pharmacotherapy Outcomes Research Center;
and ANKE-PEGGY HOLTORF, PhD, MBA, is Adjunct Assistant
Professor, Pharmacotherapy Outcomes Research Center, Department
of Pharmacotherapy, University of Utah, Salt Lake City, Utah. PETER
J. NEUMANN, ScD, is Director of the Center for the Evaluation
of Value and Risk in Health, Tufts University School of Medicine,
Boston, Massachusetts. DANIEL C. MALONE, PhD, is Professor,
College of Pharmacy, University of Arizona, Tucson, Arizona. JOHN
B. WATKINS, RPh, MPH, BCPS, is Pharmacy Manager, Formulary
Development, Premera Blue Cross, and Clinical Associate Professor of
Pharmacy, University of Washington, Seattle, Washington.
AUTHOR CORRESPONDENCE: Diana I. Brixner, PhD, RPh,
Professor and Chair, Department of Pharmacotherapy, University
of Utah, Pharmacotherapy Outcomes Research Center, Wakara Way
421, Salt Lake City, UT 84108. Tel.: 801.581.3182; E-mail:
[email protected]
Vol. 15, No. 3
April 2009
JMCP
Journal of Managed Care Pharmacy 281
Standardizing Quality Assessment of Observational Studies for Decision Making in Health Care
DISCLOSURES
The roundtable meeting and this report were supported by an unrestricted
educational grant from Procter and Gamble Pharmaceuticals to the Millcreek
Outcomes Group, LLC. None of Procter and Gamble’s representatives or
employees was involved in the outline or conduct of the expert discussions or
in writing the manuscript.
Brixner and Holtorf planned, presented and moderated this roundtable
discussion, with assistance from Joseph Biskupiak, PhD, MBA. The 5 authors
contributed equally to data collection and interpretation. Brixner and Holtorf
wrote and revised the manuscript, with assistance from Malone, Neumann,
and Watkins.
REFERENCES
1. Holtorf A, Watkins JB, Mullins CD, Brixner D. Incorporating observational data into the formulary decision-making process—summary of a
roundtable discussion. J Manag Care Pharm. 2008;14(3):302-08. Available at:
www.amcp.org/data/jmcp/JMCPMaga_April08_302-308.pdf.
2. Garrison LP, Neumann PJ, Erickson P, Marshall D, Mullins CD. Using
real-world data for coverage and payment decisions: the ISPOR Real-World
Data Task Force report. Value Health. 2007;10(5):326-35.
3. Anonymous. The AMCP Format for Formulary Submissions version 2.1. J
Manag Care Pharm. 2005;11(5 Suppl B): vi-xvi, 1-29, 1-4. Available at: http://
www.amcp.org/data/jmcp/formatsupp.pdf. Accessed February 15, 2009.
4. Anonymous. Business Wire: Research examines formulary decision process among health Plans. Business Wire. April 16, 2008. Available at: http://
findarticles.com/p/articles/mi_m0EIN/is_2008_April_16/ai_n25156554/
print. Accessed May 27, 2008.
5. Anonymous. Insights Into Formulary Decision Processes: Findings
From A National Survey Of Health Plans. Presented to: The Foundation for
Managed Care Pharmacy. Silver Spring, MD: Social & Scientific Systems,
Inc.; March 2008. Available at: http://www.fmcpnet.org/cfr/waSys/f.cfc?meth
od=getListFile&id=3EE4422A. Accessed February 15, 2009.
6. Kilbourne AM, Neumann MS, Pincus HA, Bauer MS, Stall R.
Implementing evidence-based interventions in health care: application of
the replicating effective programs framework. Implement Sci. 2007;2(1):42.
Available at: http://www.implementationscience.com/content/2/1/42.
Accessed March 19, 2008.
7. Kitson AL, Rycroft-Malone J, Harvey G, McCormack B, Seers K, Titchen
A. Evaluating the successful implementation of evidence into practice using
the PARiHS framework: theoretical and practical challenges. Implement
Sci. 2008;3(1):1. Available at: http://www.implementationscience.com/content/3/1/1. Accessed March 19, 2008.
8. Elwyn G, Taubert M, Kowalczuk J. Sticky knowledge: A possible model
for investigating implementation in healthcare contexts. Implement Sci.
2007;2(1):44. Available at: http://www.implementationscience.com/content/2/1/44. Accessed March 19, 2008.
9. Stetler CB, McQueen L, Demakis J, Mittman BS. An organizational
framework and strategic implementation for system-level change to enhance
research-based practice: QUERI Series. Implement Sci. 2008;3(1):30.
Available at: http://www.implementationscience.com/content/pdf/17485908-3-30.pdf. Accessed February 15, 2009.
10. ISPOR Using ‘Real World’ Data in Coverage and Reimbursement
Decisions Task Force. Members’ comments on draft report. Available at:
http://www.ispor.org/workpaper/RWD_TF/MemberComments.pdf. Accessed
June 6, 2008.
11. Atkins D, Best D, Briss PA, et al. Grading quality of evidence and
strength of recommendations. BMJ. 2004;328(7454):1490. Available at:
http://www.bmj.com/cgi/reprint_abr/328/7454/1490.pdf. Accessed February
15, 2009.
282 Journal of Managed Care Pharmacy
JMCP
April 2009
Vol. 15, No. 3
12. Atkins D, Briss PA, Eccles M, et al. Systems for grading the quality of
evidence and the strength of recommendations II: pilot study of a new system. BMC Health Serv Res. 2005;5(1):25. Available at: http://www.biomedcentral.com/content/pdf/1472-6963-5-25.pdf. Accessed February 15, 2009.
13. Schünemann HJ, Oxman AD, Brozek J, et al. Grading quality of evidence and strength of recommendations for diagnostic tests and strategies. BMJ. 2008;336(7653):1106-10. Available at: http://www.bmj.com/cgi/
reprint/336/7653/1106. Accessed February 15, 2009.
14. Tevaarwerk GJ. Grading evidence. CMAJ. 2004;170(6):928-29; author
reply 929-30.
15. Upshur RE. Are all evidence-based practices alike? problems in the ranking of evidence. CMAJ. 2003;169(7):672-73.
16. Guyatt G, Gutterman D, Baumann MH, et al. Grading strength of recommendations and quality of evidence in clinical guidelines: report from an
American College of Chest Physicians task force. Chest. 2006;129(1):174-81.
17. Levels of Evidence. From the Centre for Evidence-based Medicine,
Oxford. May, 2001. Available at: http://www.essentialevidenceplus.com/concept/ebm_loe.cfm?show=oxford. Accessed March 2, 2009.
18. Agency for Healthcare Research and Quality. U.S. Preventive Services
Task Force (USPSTF). Available at: http://www.ahrq.gov/clinic/USpstfix.htm.
Accessed February 8, 2009.
19. ACC/AHA Task Force on Practice Guidelines. Manual for ACC/AHA
Guideline Writing Committees. 2004. Available at: http://www.acc.org/qualityandscience/clinical/manual/manual%5Fiistep6.htm. Accessed February
8, 2009.
20. Rawlins M. De Testimonio: on the evidence for decisions about the use
of therapeutic interventions. Lancet. 2008;372(9656):2152-61.
21. Department of Health. Drug treatment for multiple sclerosis (beta-interferons and glatiramer acetate) - risk-sharing scheme (HSC 2002/004 briefing
note). January 12, 2004. Available at: http://www.dh.gov.uk/en/Healthcare/
Primarycare/Primarycaretrusts/DH_4000556. Accessed August 26, 2008.
22. Anonymous. Bortezomib Monotherapy for Relapsed Multiple Myeloma.
Care Guideline. London, UK: National Institute for Health and Clinical
Excellence; October 2007. Available at: http://www.nice.org.uk/nicemedia/
pdf/TA129Guidance.pdf. Accessed February 27, 2009.
23. Watkins J, Bresnahan B, Veenstra D, Garrison L, Sullivan S.
Determining the value of diagnostic/genetic testing to inform health plan
decision making: oncotype dx as a case study. Poster abstract. Value Health.
2007;10(3):A206.
24. Centers for Medicare & Medicaid Services. National coverage determinations with data collection as a condition of coverage: coverage with evidence
development. July 12, 2006. Available at: https://www.cms.hhs.gov/mcd/
ncpc_view_document.asp?id=8. Accessed August 18, 2008.
25. Tunis SR, Pearson SD. Coverage options for promising technologies:
Medicare’s ‘coverage with evidence development’. Health Aff (Millwood).
2006;25(5):1218-30.
26. Drummond MF, Jefferson TO. Guidelines for authors and peer reviewers
of economic submissions to the BMJ: the BMJ Economic Evaluation Working
Party. BMJ. 1996;313(7052):275-83.
27. Downs SH, Black N. The feasibility of creating a checklist for the
assessment of the methodological quality both of randomised and non-randomised studies of health care interventions. J Epidemiol Community Health.
1998;52(6):377-84.
28. Des Jarlais DC, Lyles C, Crepaz N. Improving the reporting quality of
nonrandomized evaluations of behavioral and public health interventions:
the TREND statement. Am J Public Health. 2004;94(3):361-66.
29. Halpern MT, Luce BR, Brown RE, Geneste B. Health and economic
outcomes modeling practices: a suggested framework. Value Health.
1998;1(2):131-47.
www.amcp.org
Standardizing Quality Assessment of Observational Studies for Decision Making in Health Care
30. Mauskopf JA, Sullivan SD, Annemans L, et al. Principles of good practice
for budget impact analysis: report of the ISPOR Task Force on good research
practices--budget impact analysis. Value Health. 2007;10(5):336-47.
31. Motheral B, Brooks J, Clark MA, et al. A checklist for retrospective database studies—report of the ISPOR Task Force on Retrospective Databases.
Value Health. 2003;6(2):90-97.
32. Peterson AM, Nau DP, Cramer JA, Benner J, Gwadry-Sridhar F, Nichol
M. A checklist for medication compliance and persistence studies using retrospective databases. Value Health. 2007;10(1):3-12.
33. Philips Z, Ginnelly L, Sculpher M, et al. Review of guidelines for good
practice in decision-analytic modelling in health technology assessment.
Health Technol Assess. 2004;8(36):iii-iv, ix-xi, 1-158. Available at: http://www.
hta.ac.uk/execsumm/summ836.htm. Accessed March 2, 2009.
34. von Elm E, Altman D, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke
JP. The Strengthening the Reporting of Observational Studies in
Epidemiology (STROBE) Statement: guidelines for reporting observational
studies. Prev Med. 2007;45(4):247-51.
35. Weinstein MC, O’Brien B, Hornberger J, et al. Principles of good practice
for decision analytic modeling in health-care evaluation: report of the ISPOR
Task Force on Good Research Practices-Modeling Studies. Value Health.
2003;6(1):9-17.
36. Ofman JJ, Sullivan SD, Neumann PJ, et al. Examining the value and
quality of health economic analyses: implications of utilizing the QHES. J
Manag Care Pharm. 2003;9(1):53-61. Available at: http://www.amcp.org/data/
jmcp/Formulary%20Management-53-61.pdf.
37. Hannover Consensus Group. [German recommendations for health care
economic evaluation studies. revised version of the Hannover consensus.
Hannover Consensus Group]. Med. Klin. (Munich). 2000;95(1):52-55.
38. Travail réalisé par les Membres du Collège des Économistes de la
Santé. Guide méthodologique pour l’évaluation économique des stratégies
de santé. July 2003. Available at: http://www.ces-asso.org/docs/Guide_
Methodologique_CES_2003.pdf. Accessed February 15, 2009.
39. Agency for Healthcare Research and Quality. Systems to Rate the
Strength of Scientific Evidence. Summary, Evidence Report/Technology
Assessment: Number 47. AHRQ Publication No. 02-E015, March 2002.
Available at: http://www.ahrq.gov/clinic/epcsums/strengthsum.htm.
Accessed February 2, 2009.
www.amcp.org
40. Fairman KA, Curtiss FR. Rethinking the “whodunnit” approach to
assessing the quality of health care research—a call to focus on the evidence in evidence-based practice. J Manag Care Pharm. 2008;14(7):661-74.
Available at: http://www.amcp.org/data/jmcp/661-674_FairmanCurtissFinal.pdf.
41. McAlister FA, Fradette M, Graham M, et al. A randomized trial to assess
the impact of opinion leader endorsed evidence summaries on the use of
secondary prevention strategies in patients with coronary artery disease:
the ESP-CAD trial protocol [NCT00175240]. Implement Sci. 2006;1(1):11.
Available at: http://www.implementationscience.com/content/1/1/11.
Accessed March 19, 2008.
42. Grauer DW, Lee J, Odom TD, et al., eds. Pharmacoeconomics and
Outcomes: Applications for Patient Care, Second Edition. Kansas City:
American College of Clinical Pharmacy; 2003. Available for purchase at:
http://www.accp.com/bookstore/peoc.aspx. Accessed February 27, 2009.
43. Kane-Gill S, Reddy P, Gupta SR, Bakst AW. Guidelines for pharmacoeconomic and outcomes research fellowship training programs: joint
guidelines from the American College of Clinical Pharmacy and the
International Society of [sic] Pharmacoeconomics and Outcomes Research.
Pharmacotherapy. 2008;28(10):269e-76e. Available at: http://www.accp.
com/docs/positions/guidelines/PEORFellowshipGuidelines.pdf. Accessed
February 27, 2009.
44. Graham ID, Tetroe J. Some theoretical underpinnings of knowledge
translation. Acad Emerg Med. 2007;14(11):936-41.
45. Graham ID, Logan J, Harrison MB, et al. Lost in knowledge translation:
time for a map? J Contin Educ Health Prof. 2006;26(1):13-24.
46. Lyles A. Standards and certification to recognize pharmacoeconomics as
a profession. Clin Ther. 2003;25(3):1004-06.
47. Nichol MB, Knight TK, Epstein J, Honda DH, Tretiak R. Opinions
regarding the Academy of Managed Care Pharmacy dossier submission
guidelines: results of a small survey of managed care organizations and
pharmaceutical manufacturers. J Manag Care Pharm. 2007;13(4):360-71.
Available at: http://www.amcp.org/data/jmcp/360-71.pdf.
48. Spooner JJ, Gandhi PK, Connelly SB. AMCP Format dossier requests:
manufacturer response and formulary implications for one large health plan.
J Manag Care Pharm. 2007;13(1):37-43. Available at: http://amcp.org/data/
jmcp/37-43.pdf.
49. About EQUATOR. Enhancing the QUAlity and Transparency Of health
Research Network Website. Available at: http://www.equator-network.org/
index.aspx?o=1017. Accessed February 27, 2009.
Vol. 15, No. 3
April 2009
JMCP
Journal of Managed Care Pharmacy 283
C O M M E N TA R Y
Omalizumab Has a Place in Therapy for
Asthma Disease Management
Lawrence J. Pesko, MS, DSc, RPh
A
sthma is a complex disease because its presentation can
vary considerably from patient to patient. The nature of
asthma often requires physicians to use a multifaceted
approach to ensure optimal outcomes (i.e., control of symptoms)
and to prevent asthma exacerbations and increased health care
utilization. Evidence-based disease management guidelines have
been developed and published to aid in the diagnosis of asthma
and to help guide treatment decisions. In 2007, the National
Asthma Education and Prevention Program (NAEPP) released
its updated guidelines for the management and treatment of
asthma.1 National guidelines such as these generally present the
evidence currently available to support best practices for managing chronic diseases.
In the January 2008 issue of JMCP, Urbano reviewed 7 changes
to the NAEPP guidelines that were considered by a small expert
panel to be the most important and clinically relevant messages
in the updated document.2 The bulk of these changes address
diagnosis, successful comprehensive management, assessing disease severity, monitoring disease control, and managing asthma
exacerbations. Some of the changes deal directly with medication
use and choice. Because there is often a lag between the release of
a new guideline and implementation in clinical practice, there is
an opportunity to provide education and develop strategies that
incorporate new recommendations into current programs.
The management and treatment of asthma remain challenging for all health care stakeholders—patients, providers, and
payers. Unlike other chronic diseases such as heart disease,
which become increasingly prevalent with age, asthma affects
patients across the age spectrum. Over the past 25 to 30 years,
the prevalence of asthma has continued to grow at an alarming
rate, with the greatest increase seen among children.3,4 Current
estimates cite the overall prevalence of asthma in the United
States at approximately 22 million people, or about 7.7% of the
population.5
Despite growing recognition of asthma as a chronic disease
and strides toward improving its treatment, the financial burden of this disease is enormous. The total direct and indirect
costs associated with asthma are approximately $20 billion
annually,6 the greatest proportion of which is attributable to
poorly controlled asthma.7 According to The Epidemiology and
Natural History of Asthma: Outcomes and Treatment Regimens
Note: This article is the subject of an editorial that appears on pages 289-293 of this issue.
284 Journal of Managed Care Pharmacy
JMCP
April 2009
Vol. 15, No. 3
(TENOR) study, a prospective, observational, multicenter,
3-year U.S. study of 4,756 patients with severe or difficult-totreat asthma, the highest percentage of health care utilization in
the prior 3 months was linked to patients with severe asthma.8
The mandate for improving the care of asthma is clear.
However, the existence of guidelines does not always ensure
improved patient care. In a 2-year retrospective study of claims
data from more than 4 million United Healthcare enrollees
nationwide, overall adherence to evidence-based practice guidelines was 59% for select chronic conditions, including coronary
artery disease, congestive heart failure, hyperlipidemia, asthma,
and diabetes.9 For adults with persistent asthma, 79% of the
commercially insured population filled a prescription for inhaled
corticosteroid (ICS) therapy, whereas only 58% of Medicare
enrollees filled an ICS prescription.9 Adherence to national
asthma guidelines among inner-city physicians is even poorer. In
a survey of 202 primary care providers in East Harlem, New York,
62% reported adhering to the National Heart, Lung and Blood
Institute (NHLBI) asthma guidelines for ICS use.10 However, 34%
reported adherence to the NHLBI guidelines recommendations
for peak flow monitoring, 10% for referrals to allergy testing,
and 9% for using an asthma action plan. It was also noted that
greater provider self-efficacy was associated with greater adherence to peak flow monitoring, ICS use, and use of an asthma
action plan.10
Even with various expert-derived guidelines that provide
asthma treatment strategies, many patients remain symptomatic and their asthma symptoms suboptimally controlled.4,11,12
In the retrospective study by Thier et al., patient adherence
to ICS therapy was poor, even though 78% of all adults with
persistent asthma filled an ICS prescription. Among this
population, 37% were nonadherent to ICS therapy. In children
with persistent asthma, nonadherence to ICS medications was
42%.9 A retrospective cross-sectional study of nearly 12 million elderly adults showed that physicians were not adherent
to asthma therapy recommendations from the NAEPP Expert
Panel Report (EPR)-2 guidelines. This analysis, based on data
from the National Ambulatory Medical Care Survey, found that
individuals aged 65 years or older were 54% as likely to be prescribed controller medications compared with those aged 35 to
64 years. Those aged 65 years or older were also 48% less likely
to be prescribed long-acting beta-2 agonists (LABAs), 49% less
likely to be prescribed short-acting beta agonists (SABAs), and
49% less likely to be prescribed combination ICS and LABA
www.amcp.org
Omalizumab Has a Place in Therapy for Asthma Disease Management
therapy.13 These data point to the fact that physician and patient
adherence to clinical practice guidelines and recommended
therapies are often suboptimal and may be contributing to poor
outcomes and increased health care utilization.
Medication management—balancing efficacy, safety, and
pharmacoeconomic data—is a central component of managed
care. As disease state information evolves, managed care medical
and pharmacy directors must keep abreast of new information
and monitor formulary management options to determine if the
currently employed strategies for medication management reflect
current practice guidelines. This task may be especially important for diseases that affect large numbers of individuals and are
associated with significant negative economic consequences if
not managed effectively.
The release of updated clinical guidelines provides an opportunity for managed care organizations (MCOs) to reassess their disease management programs. Continuous monitoring is needed to
evaluate the outcomes achieved by these programs so they can be
adjusted, as necessary, to optimize the overall quality of care. The
inclusion of omalizumab (Xolair) in the NAEPP guidelines offers
another treatment option for patients who have immunoglobulin
E (IgE)-mediated asthma. Health plans, however, need to identify,
through pharmacy and medical data claims, the prevalence of
uncontrolled asthma in their populations and then reassess their
formulary management strategies to target the appropriate use of
omalizumab in select populations.
Identification of “At-Risk” Populations
Implementing strategies to identify high risk patients—those with
difficult-to-treat or uncontrolled moderate-to-severe asthma—is
in the best interest of MCOs. From a disease standpoint, it appears
that the costs associated with moderate-to-severe asthma and the
resulting morbidity and mortality are substantial. These data
imply that identifying patients with poorly controlled asthma
and employing implementation strategies that provide ongoing
education, as well as therapeutic alternatives, to improve control
are important cost-management strategies for MCOs.
Measures have been evaluated to identify at-risk patients
in large patient populations. Pharmacy-driven measures that
include the frequency of dispensing events for SABAs or oral
corticosteroids can predict future emergency care.14 In a retrospective review of patients with persistent asthma in a managed
care population, use of 5 to 13 canisters of a SABA in the first
year was associated with an increased risk of emergency hospital
utilization in the second year compared with use of only 0 to 4
canisters in the first year (odds ratio [OR] = 2.2, 95% CI = 1.2-3.8).
Similarly, use of more than 2 courses of oral corticosteroids in
the first year was associated with an increased risk of emergency
hospital utilization in the second year compared with use of 0 to
2 courses of oral corticosteroids (OR = 2.6, 95% CI = 1.5-4.5).14
In addition to clinical measures to determine asthma severity and control, the NAEPP guidelines suggest specific quality-
www.amcp.org
of-life (QOL) measures, such as the Asthma Quality of Life
Questionnaire (AQLQ) and the Asthma Control Test (ACT), to
assess the impact of asthma on patient QOL and daily functioning.1 AQLQ scores were an adequate measure of control, as
determined by Bateman et al.15 This study showed that, across a
range of asthma disease severity, well-controlled asthma patients
had consistently higher AQLQ scores at end point and larger
AQLQ improvements from baseline than patients who were not
well controlled. This correlation suggests a relationship between
guideline-based asthma control and improvement in QOL.15
Similarly, the ACT has been shown to be a practical and simple
tool that can effectively assess the level of asthma control, with or
without lung function testing.16 This brief 5-item questionnaire
measures several different areas of asthma control, including
symptoms, rescue inhaler usage, and the impact of asthma on
everyday functioning. It is important to note, however, that the
2007 NAEPP guidelines state that lack of experience with QOL
surveys and the time needed to administer these instruments
preclude their general adoption for routine encounters.1 As more
information becomes available, the use of QOL measures may
become more commonplace. Questionnaires have been used, in
some cases in addition to administrative data, to identify patients
at highest risk for emergency care and may offer MCOs another
means to identify at-risk patients.17-19
The NAEPP 2007 update also addresses the role of spirometry
in the evaluation of asthma control. It is recommended that the
forced expiratory volume in 6 seconds (FEV6), forced vital capacity (FVC) and the FEV1/FVC ratio be done before and following
the use of a short-acting bronchodilator for the initial diagnosis
of asthma and should be subsequently used to assess the risk for
future adverse events.1 While these measures are useful in the
physician office, they are generally not available in administrative
databases to help MCOs identify members who are at risk for
future adverse events secondary to asthma so that interventions
to reduce risk can be initiated. Moreover, assessments of lung
function alone may not provide a clear picture of asthma control
without additional information about symptoms and their effect
on a patient’s QOL.11,20 Even with these additional measures for
assessing control, accurate assessment can be difficult.
The Case for Omalizumab in Medication Management
The updated NAEPP guidelines (2007) include an expansion
of the stepwise approach for treating asthma. Unlike previous
NAEPP guidelines, which had 4 steps based on asthma severity, the current edition now uses 6 steps to better address those
whose asthma remains uncontrolled with traditional therapies.1
According to the stepwise approach as outlined in the current update and previous (2002) NAEPP guidelines, allergen
immunotherapy should be considered in Steps 2-4, regardless
of age. The guidelines recommend that immunotherapy should
be considered in patients whose symptoms occur year round
or during a significant portion of the year and are difficult to
Vol. 15, No. 3
April 2009
JMCP
Journal of Managed Care Pharmacy 285
Omalizumab Has a Place in Therapy for Asthma Disease Management
control pharmacologically.1
As noted by Urbano et al.,2 one significant change in
the NAEPP guidelines is the inclusion of omalizumab as
adjunctive therapy for youths aged 12 years or older and adults
with perennial allergies and severe persistent asthma that is not
adequately controlled with the combination of ICS and a LABA.
Omalizumab, a recombinant deoxyribonucleic acid (DNA)derived human monoclonal antibody, is approved by the U.S.
Food and Drug Administration (FDA) for use in patients with
moderate-to-severe persistent asthma.21,22 Omalizumab binds to
IgE, forming complexes that inhibit the response to allergens.21,22
Sources of relevant perennial allergens include dust mites, cockroaches, cats, and dogs.
The NAEPP 2007 update reserves the use of omalizumab for
Steps 5 and 6 which, by definition, are adjunctive therapy for
patients aged 12 years or older who have allergies with severe persistent asthma. In such cases—patients who remain uncontrolled
despite traditional therapies, especially those with IgE-mediated
allergic asthma—adjunctive therapy with agents that target the
underlying allergic component may be beneficial. Identification
of the patient populations that could most benefit from omalizumab therapy remains a challenge, however. According to package labeling, omalizumab is “indicated for adults and adolescents
(12 years of age and above) with moderate to severe persistent
asthma who have a positive skin test or in vitro reactivity to a
perennial aeroallergen and whose symptoms are inadequately
controlled with inhaled corticosteroids.”22
The clinical benefits of omalizumab as adjunctive therapy
have been detailed in the literature. Clinical studies have
found that combining omalizumab with ICS reduces asthma
exacerbations,23,24 improves lung function,23,24 and results in
greater reductions in steroid dosing compared with placebo.23-25
Improvements in QOL have also been reported in patients
receiving omalizumab compared with placebo.25,26 Unlike other
adjunctive therapies that also improve outcomes and reduce steroid dosing, omalizumab has demonstrated added benefit when
combined with high-dose ICS and LABA in the management of
severe persistent allergic asthma.26
The National Institute for Health and Clinical Excellence
(NICE) noted in its appraisal (2007) that omalizumab may
be considered as add-on therapy only to optimized, standard
therapy in adults and adolescents aged 12 years or older who
have severe, unstable disease.27 Use of and compliance with
the standard treatments, including high-dose ICS therapy and
LABAs in addition to leukotriene receptor agonists, theophylline,
oral corticosteroids, and oral beta-2 agonists, are recommended
before considering omalizumab as add-on therapy. In order to be
considered for omalizumab therapy, the NICE guidelines define
the criteria that patients must meet to establish the existence of
severe, unstable allergic asthma: (a) confirmation of IgE-mediated
allergic asthma by clinical history and allergy skin test; and (b)
at least 2 severe exacerbations requiring hospitalization within
286 Journal of Managed Care Pharmacy
JMCP
April 2009
Vol. 15, No. 3
the previous year, or at least 3 severe exacerbations within the
previous year, with 1 requiring hospitalization or 2 requiring
treatment or monitoring beyond the patient’s usual regimen.27
The NICE guidelines also recommend discontinuation of omalizumab after 16 weeks if there is no adequate response to therapy
based on a full clinical assessment that includes degree of asthma
control, QOL, control of exacerbations, avoidance of unscheduled
health care utilization, spirometry and peak expiratory flow measures, and physician global assessment of treatment efficacy.27
The NICE appraisal of omalizumab included evaluation of the
results from the Investigation of Omalizumab in Severe Asthma
Treatment (INNOVATE), a randomized, double-blind, multicenter study in patients with poorly controlled severe persistent
asthma that measured clinically significant exacerbations and
clinically significant severe exacerbations in patients receiving
omalizumab as add-on therapy. The NICE committee noted
that the rate of clinically significant exacerbations (the primary
efficacy outcome) in the primary intention-to-treat population
in INNOVATE was 0.74 for the omalizumab group versus 0.92
for the placebo group (rate ratio = 0.806, 95% CI = 0.600-1.083,
P = 0.153), which was not statistically significant until after posthoc adjustments were made. Other INNOVATE results included
statistically significant reductions in clinically significant severe
asthma exacerbations and greater improvement in AQLQ scores
for omalizumab compared with placebo.27
In addition to the post hoc adjustments, NICE criticized the
INNOVATE study on several points such as the exclusion of
13% of randomized patients prior to the implementation of the
protocol amendments. The NICE committee wrote, “There were
aspects of the INNOVATE RCT [randomized controlled trial]
that led to uncertainty, including lack of detail on concealment of
treatment allocation, the possibility of inadequate double blinding, selection bias, and exclusion of randomised patients for the
intention-to-treat population.”27 These uncertainties led NICE
to question “the improvement observed for the primary efficacy
outcome.”27 Following testimony from both clinical specialists
and patient experts, NICE concluded that “omalizumab as an
add-on to optimised standard therapy is more clinically effective
in particular groups of patients than optimised standard therapy
alone.”27
In clinical studies, omalizumab has been shown to reduce
asthma-related hospitalizations and emergency room visits.26,28
Ayres et al. compared the safety and efficacy of omalizumab
versus best standard care in patients with moderate-to-severe
asthma in a randomized, open-label, multicenter study.28 The primary efficacy measure (annualized asthma deterioration-related
incidents defined as asthma-related need for systemic antibiotics
or corticosteroids, missed school or work, unscheduled physician
office visits or hospitalization or emergency room visits) was 9.76
with best standard care alone (n = 106) versus 4.92 (n = 206) per
patient-year with omalizumab (P < 0.001).28 In the INNOVATE
study, the addition of omalizumab to high-dose ICS and LABA
www.amcp.org
Omalizumab Has a Place in Therapy for Asthma Disease Management
during the 28-week study period resulted in fewer total emergency visits compared with placebo added to high-dose ICS and
LABA (50 vs. 93, P = 0.038). The omalizumab group also had
nonsignificantly lower rates of hospital admissions (13 vs. 25 for
placebo, P = 0.117) and unscheduled doctor visits (28 vs. 54 for
placebo, P = 0.090).26
Administration of omalizumab is not without risks.1 Pain and
bruising can occur in 5%-20% of patients following administration and malignant neoplasms were reported in 0.5% of patients
compared with 0.2% in those treated with placebo. Anaphylaxis
has also been reported in 0.2% of patients. Because of the risk
of anaphylaxis, clinicians that decide to administer omalizumab
must be prepared and equipped to identify and treat anaphylaxis
should it occur.1 Additionally, the manufacturers of omalizumab
added a black-box warning in 2007 to highlight the possibility of
anaphylaxis, which includes bronchospasm, hypotension, syncope, urticaria, and/or angioedema of the throat or tongue.22 The
warning also notes that anaphylaxis has been reported from the
time of the first dose and beyond 1 year of treatment.22 Physicians
are also advised to be prepared to manage life-threatening anaphylaxis if it occurs, inform patients of the signs/symptoms of
anaphylaxis, and instruct patients to seek medical care if any
symptoms occur.22 The NAEPP guidelines suggest referral to an
asthma specialist for consultation or comanagement if the patient
is not well controlled, if the patient requires Step 4 therapy or
higher, if immunotherapy or omalizumab are considered, or if the
patient has had an exacerbation requiring a hospitalization.1
As with the identification of the at-risk patient with asthma,
the optimal method of identifying the patient who is a candidate
for omalizumab is complicated. Belliveau et al. noted in their
review in JMCP (2005) that appropriate screening is needed
to determine which patients would respond most favorably to
omalizumab treatment, and that when this subset of patients is
targeted, the reduction of medical resources could potentially
offset the drug’s high acquisition cost.29 In an accompanying editorial, Curtiss commented that based on the evidence to date, the
efficacy of omalizumab beyond 7 months is unknown and the
key to cost-effective use lies in selective and specific use.30
Currently, most health plans have placed prior authorization
(PA) restrictions on omalizumab due to its high cost, the availability of other agents, and concerns regarding its safety, including the potential for anaphylaxis and lack of safety data beyond
1 year of treatment.
Since its approval by the FDA in 2003, the safety and efficacy
of omalizumab and its appropriate use in asthma patients have
been debated in the clinical literature. The release of the 2007
NAEPP update provides an opportunity to re-evaluate the place
in therapy of omalizumab. At this point, the definition of the
ideal candidate most likely to respond favorably to omalizumab
therapy is not clear. Continued monitoring of outcomes for
patients who receive omalizumab, however, will be essential and
perhaps, with continued use, a pattern will evolve that better
defines those who best respond to this therapy.
www.amcp.org
Conclusion
As noted previously by Urbano,2 currently available clinical
guidelines serve as an ideal starting point for improving the
quality of care for the asthma disease state. The NAEPP guideline
update in August 2007 should help clinicians in assessing and
monitoring asthma. With a shift in focus to measuring control
with a combination of outcomes tools, the identification and
treatment of patients with poorly controlled asthma may be
improved. The integration of various outcomes measures will
be required and should include clinical assessments, physician and patient-reported measures of productivity/avoidance
of activity, and burden to society and the workplace. In certain
high-risk patients with severe persistent asthma, omalizumab
may be considered as a treatment option. The ideal candidate for
omalizumab therapy is as of yet unknown. Therefore, continued
evaluation of this treatment is needed to refine the parameters for
targeting patients who may benefit most from omalizumab.
Author
LAWRENCE J. PESKO, MS, DSc, RPh, is Director of Pharmacy,
Presbyterian Medical Services, Santa Fe, New Mexico.
AUTHOR CORRESPONDENCE: Lawrence J. Pesko, MS, DSc,
RPh, Director of Pharmacy, Presbyterian Medical Services, 1422
Paseo de Peralta, P.O. Box 2267, Santa Fe, NM 87504-2267. Tel.:
505.820.3490; E-mail: [email protected].
DISCLOSURES
This commentary was sponsored by Genentech, Inc., manufacturer of omalizumab. The author reports no financial interest or other potential conflict of
interest.
The author acknowledges Linda Wagner, Charlotte Kenreigh, and Dennis
Bloshuk, editor, Strategic Healthcare Alliance, for their assistance in the
preparation and revision of this manuscript.
REFERENCES
1. National Heart, Lung, and Blood Institute, National Asthma Education
and Prevention Program. Expert Panel Report 3. Guidelines for the Diagnosis
and Management of Asthma. Bethesda, MD: National Institutes of Health;
August 2007. NIH Publication No. 07-4051. Available at: http://www.nhlbi.
nih.gov/guidelines/asthma/asthgdln.pdf. Accessed November 6, 2008.
2. Urbano F, for a panel of 9 asthma disease specialists. Review of the
NAEPP 2007 expert panel report-3 (EPR-3) on asthma diagnosis and treatment guidelines. J Manag Care Pharm. 2008;14:41-49. Available at: http://
www.amcp.org/data/jmcp/JMCPMaga_ JanFeb%2008_041-049.pdf.
3. Fireman P. Understanding asthma pathophysiology. Allergy Asthma Proc.
2003;24:79-83.
4. Fuhlbrigge AL, Adams RJ, Guilbert TW, et al. The burden of asthma in
the United States: level and distribution are dependent on interpretation
of the national asthma education and prevention program guidelines. Am J
Respir Crit Care Med. 2002;166:1044-49.
Vol. 15, No. 3
April 2009
JMCP
Journal of Managed Care Pharmacy 287
Omalizumab Has a Place in Therapy for Asthma Disease Management
5. Akinbami L. Asthma prevalence, health care use, and mortality: United
States 2003-05. November, 2006. National Center for Health Statistics,
Centers for Disease Control and Prevention. Available at: http://www.cdc.
gov/nchs/products/pubs/pubd/hestats/ashtma03-05/asthma03-05.htm.
Accessed January 28, 2009.
6. American Lung Association, Epidemiology & Statistics Unit, Research
and Program Services. Trends in asthma morbidity and mortality. January
2009. Available at: http://www.lungusa.org/atf/cf/%7B7a8d42c2-fcca-46048ade-7f5d5e762256%7D/ASTHMA%20JAN%202009.PDF. Accessed January
28, 2009.
7. Sullivan SD, Rasouliyan L, Russo PA, Kamath T, Chipps BE; TENOR
Study Group. Extent, patterns, and burden of uncontrolled asthma in severe
and difficult-to-treat asthma. Allergy. 2007;62:126-33.
8. Dolan CM, Fraher KE, Bleecker ER, et al. Design and baseline characteristics of The Epidemiology and Natural History of Asthma: Outcomes and
Treatment Regimens (TENOR) study: a large cohort of patients with severe
or difficult-to-treat asthma. Ann Allergy Asthma Immunol. 2004;92:32-39.
9. Thier SL, Yu-Isenberg KS, Leas BF, et al. In chronic disease, nationwide
data show poor adherence by patients to medication and by physicians to
guidelines. Manag Care. 2008;17:48-52,55-57.
10. Wisnivesky JP, Lorenzo J, Lyn-Cook R, et al. Barriers to adherence to
asthma management guidelines among inner-city primary care providers.
Ann Allergy Asthma Immunol. 2008;101(3):264-70.
11. Bateman ED, Boushey HA, Bousquet J, et al.; GOAL investigators group.
Can guideline-defined asthma control be achieved? The Gaining Optimal
Asthma ControL study. Am J Respir Crit Care Med. 2004;170:836-44.
Available at: http://ajrccm.atsjournals.org/cgi/reprint/170/8/836. Accessed
March 18, 2009.
12. Miller MK, Johnson C, Miller DP, Deniz Y, Bleeker ER, Wenzel SE;
TENOR study group. Severity assessment in asthma: an evolving concept. J
Allergy Clin Immunol. 2005;116:990-95.
13. Navaratnam P, Jayawant SS, Pedersen CA, Balkrishnan R. Asthma pharmacotherapy prescribing in the ambulatory population of the United States:
evidence of nonadherence to national guidelines and implications for elderly
people. J Am Geriatr Soc. 2008;56:1312-17.
14. Schatz, M, Zeiger RS, Vollmer WM, et al. Development and validation of
a medication intensity scale derived from computerized pharmacy data that
predicts emergency hospital utilization for persistent asthma. Am J Manag
Care. 2006;12:478-84.
17. Vollmer WM, Markson LE, O’Connor E, Frazier EA, Berger M, Buist AS.
Association of asthma control with health care utilization. A prospective
evaluation. Am J Respir Crit Care Med. 2002;165:195-99.
18. Peters D, Chen C, Markson LE, Allen-Ramey FC, Vollmer WM. Using an
asthma control questionnaire and administrative data to predict health-care
utilization. Chest. 2006;129:918-24.
19. Yurk RA, Diette GB, Skinner EA, et al. Predicting patient-reported asthma outcomes for adults in managed care. Am J Manag Care. 2004;10:321-28.
20. Luskin AT. Achieving asthma control: the need for risk assessment.
Manag Care. 2005;14(Suppl 8):12-15.
21. Ruffin CG, Busch BE. Omalizumab: a recombinant humanized anti-IgE
antibody for allergic asthma. Am J Health Syst Pharm. 2004;61:1449-59.
22. Genentech, Inc. Xolair (omalizumab) for subcutaneous use [prescribing
information]. July, 2007.
23. Busse W, Corren J, Lanier BQ, et al. Omalizumab, anti-IgE recombinant
humanized monoclonal antibody, for the treatment of severe allergic asthma.
J Allergy Clin Immunol. 2001;108:184-90.
24. Solèr M, Matz J, Townley R, et al. The anti-IgE antibody omalizumab
reduces exacerbations and steroid requirement in allergic asthmatics. Eur
Respir J. 2001;18:254-61.
25. Holgate ST, Chuchalin AG, Hébert J, et al.; Omalizumab 011
International Study Group. Efficacy and safety of a recombinant anti-immunoglobulin E antibody (omalizumab) in severe allergic asthma. Clin Exp
Allergy. 2004;34:632-38.
26. Humbert M, Beasley R, Ayres J, et al. Benefits of omalizumab as addon therapy in patients with severe persistent asthma who are inadequately
controlled despite best available therapy (GINA 2002 step 4 treatment):
INNOVATE. Allergy. 2005;60:309-16.
27. National Institute for Health and Clinical Excellence. Omalizumab
for severe persistent allergic asthma. NICE technology appraisal guidance
TA133, November 2007. Available at: www.nice.org.uk/nicemedia/pdf/
TA133Guidance.pdf. Accessed September 10, 2008.
28. Ayres JG, Higgins B, Chilvers ER, Ayre G, Blogg M, Fox H. Efficacy
and tolerability of anti-immunoglobulin E therapy with omalizumab in
patients with poorly controlled (moderate-to-severe) allergic asthma. Allergy.
2004;59:701-08.
15. Bateman ED, Frith LF, Braunstein GL. Achieving guideline-based asthma
control: does the patient benefit? Eur Respir J. 2002;20:588-95.
29. Belliveau PP, Lahoz MR. Evaluation of omalizumab from a health plan
perspective. J Manag Care Pharm. 2005;11(9):735-45. Available at: http://
www.amcp.org/data/jmcp/formular_735-745.pdf.
16. Nathan RA, Sorkness CA, Kosinski M, et al. Development of the asthma
control test: a survey for assessing asthma control. J Allergy Clin Immunol.
2004;113:59-65.
30. Curtiss FR. Selectivity and specificity are the keys to cost-effective use
of omalizumab for allergic asthma. J Manag Care Pharm. 2005;11(9):774-76.
Available at: http://www.amcp.org/data/jmcp/editorial_774-776.pdf.
288 Journal of Managed Care Pharmacy
JMCP
April 2009
Vol. 15, No. 3
www.amcp.org
EDITORIAL
Omalizumab and Other New Drug Therapies Occupy a
Small Space in Asthma Disease Management
Frederic R. Curtiss, PhD, RPh, CEBS
A
sthma disease management can be a frustrating experience for clinician and patient, and it seems what we don’t
know about the subject is about as much as what we do
know. Asthma is a stubborn disease to manage due to variability
in patient response to treatment and difficulty in identifying (targeting) the patients at risk of exacerbation sufficient to precipitate
urgent care in the form of hospitalization or emergency room visits. Nonetheless, despite the increasing prevalence of asthma in
the United States, hospital discharge rates for asthma decreased
16.2% between 2003 and 2005.1
The patient variability in response to pharmacotherapy suggests that there may be a strong pharmacogenetic influence. For
example, the long-acting beta-2 agonists (LABAs) have a black-box
warning of increased risk of exacerbation of asthma and death,2,3
but the results of the Salmeterol Multicenter Asthma Research
Trial (SMART) suggest that the risk associated with LABAs seems
significant primarily in certain subgroups of patients.4 For example, retrospective analysis of data from 6 randomized controlled
trials (RCTs) showed that persons homozygous or heterozygous
for the arginine (Arg)-16 Gly polpmorphism may have worse
outcomes on LABAs, regardless of use of inhaled corticosteroids.5
Hall noted that 15% of the white population has this genetic
characteristic, but there are not yet sufficient data to ascertain
the role of Arg-16 in the variable response to the bronchodilator
effects of LABAs.6
We have also recently learned more about how the effectiveness of asthma disease management is influenced by psychological factors. Negative child affect, measured by the Children’s
Depression Inventory and the Revised Children’s Manifest
Anxiety Scale, and negative parent affect, measured by the
Center for Epidemiologic Studies Depression Scale, have been
found to predict higher asthma symptom scores (a composite of
self-reported wheezing, tightness of chest, shortness of breath,
coughing from exercise, coughing from other causes, and nighttime symptoms).7 This new research has implications for both
clinical trials and clinical practice; i.e., clinicians need to consider
the emotional state of the asthma patient and of the parent of an
adolescent or child patient.
Aside from the role of psychological and genetic factors in
asthma disease management, from a population perspective there
are 3 risk factors that appear to help explain the rising prevalence
of asthma and disease severity: (a) control of infectious diseases
www.amcp.org
and reduced exposure to endotoxins in the food and water supply
that interfere with development of childhood antibody responses
to allergens; (b) prolonged indoor exposure to allergens, particularly house mites and cockroaches; and (c) a sedentary lifestyle
since there appears to be a direct relationship between physical activity and anti-inflammatory response.8 The relationship
between upper airway disease and allergies has intrigued clinicians and researchers for decades, and recent research points to
possible localized sensitization to immunoglobulin E (IgE).9 This
evolution in research in the etiology of airway disease is logical
because allergic rhinitis can occur without systemic evidence of
IgE sensitization (i.e., negative skin allergy test and no specific
serum IgE).
What About Omalizumab?
In this issue of JMCP, Pesko suggests that injectable omalizumab
(Xolair), approved by the U.S. Food and Drug Administration
(FDA) 6 years ago in June 2003, represents a promising therapeutic option for asthma disease management, citing the product
labeling that includes the following indication, “For adults and
adolescents 12 years of age and older with moderate to severe
persistent asthma who have a positive skin test or in vitro reactivity to a perennial aeroallergen and whose symptoms are inadequately controlled with inhaled corticosteroids. Omalizumab has
been shown to decrease the incidence of asthma exacerbations
in these patients. Safety and efficacy have not been established
in other allergic conditions.”10 Notably, the primary off-label use
of omalizumab appears to be seasonal allergic rhinitis,11 despite
the absence of evidence of safety or efficacy in allergic conditions
other than asthma.
An underlying theme in Pesko’s suggestions that the market
space for omalizumab might be larger than previously thought
has to do with the number of patients who are inadequately
controlled with other first-line and second-line drugs. For
example, some of the results of the Gaining Optimal Asthma
control (GOAL) trial might be cited as evidence that even with
intervention in a clinical trial to control asthma with escalation
of the dose of inhaled corticosteroid (ICS), a large proportion of
patients remain uncontrolled.12 In fact, it is impressive that 59%
of patients in the GOAL study with previously uncontrolled
asthma were well controlled at 1 year with higher doses of fluticasone alone, and 71% of patients were well-controlled with higher
doses of fluticasone plus LABA.13 However, the persistence of
Vol. 15, No. 3
April 2009
JMCP
Journal of Managed Care Pharmacy 289
Omalizumab and Other New Drug Therapies Occupy a Small Space in Asthma Disease Management
symptoms in some patients with severe asthma despite treatment
invites continued research on the pathophysiology of asthma.
The raison d’être for Pesko’s commentary is that the National
Asthma Education and Prevention Program (NAEPP) guideline
update (2007)14 should precipitate some action by health plans to
reassess prior authorization (PA) criteria and utilization management of omalizumab. Two points are important with respect to
this assertion. First, omalizumab was not available for consideration when the 2002 NAEPP update was written because omalizumab did not receive FDA approval until June 2003.15 Second,
there was no sudden realization in the 2007 NAEPP update that
omalizumab had an important place in therapy.
In fact, the NAEPP update in 2007 recommended use of
omalizumab in a more narrow corridor than stated in the
omalizumab product label approved 4 years earlier by the FDA
(i.e., appropriate for use only in patients with “severe persistent
asthma” versus the FDA-approved labeling that includes patients
with “moderate-to-severe persistent asthma”). In the justification
for this recommendation and in Figure 3-22 (long-term control
medications), the NAEPP Full Report includes the warning that
“Adverse effects reported from omalizumab in the trials have also
included injection-site pain and bruising in up to 20 percent of
patients (Holgate et al. 2004). In the trials reported to the FDA,
twice as many patients receiving omalizumab had malignancies
(20 of 48,127, or 0.5%) as did those receiving placebo (5 of 2,236,
or 0.2%), but there were no trends for a specific tumor type.”14
In essence, Pesko suggests in his commentary that we should
ignore the wisdom of the experts, as reflected in the NAEPP 2007
update and the guidance (TA133) from the National Institute for
Health and Clinical Evidence (NICE) released in November 2007
(Appendix),16 and instead rely on a product label that was developed based on data evaluated by the FDA prior to approval of the
omalizumab. Pesko also fails to inform readers adequately about
some important points raised by the authors of the NICE guidance. Ignored completely in this commentary are the 25 malignancies cited in the NICE guidance among 5,015 patients treated
with omalizumab (0.50%) in 35 clinical trials, compared with
5 of 2,854 patients (0.18%) treated with standard therapy. Also
skirted is the thrust of the summary of the NICE guidance: “The
Committee concluded that it would only be clinically appropriate
to consider the use of omalizumab add-on therapy once standard
therapy has been optimized and that for the purposed of this
guidance, optimized standard therapy is defined as a full trial of,
and documented compliance with, inhaled high-dose corticosteroids and LABAs in addition to leukotriene receptor antagonists,
theophyllines, oral corticosteroids and beta-2 agonist tablets and
smoking cessation where clinically appropriate.”16
Unfortunately, omalizumab falls short of being a “magic bullet” for allergic asthma. Among the outcomes that under-perform
the expectations for this drug, the NAEPP 2007 update referred
290 Journal of Managed Care Pharmacy
JMCP
April 2009
Vol. 15, No. 3
to the steroid-sparing effect of omalizumab as “modest” (median
25% reduction),14 and the NICE guidance noted the evidence that
“asthmatic patients who are known to be refractory to high-dose
oral corticosteroids may be less likely to respond to omalizumab
treatment, whereas omalizumab may provide steroid-sparing
benefits on lower doses of oral steroids.”16
Omalizumab is administered by subcutaneous injection, and
it is expensive. It should be dosed by body weight and baseline
serum IgE level, and the drug cost alone is $4,000 to $30,000
per year of therapy, with an average drug cost of about $1,000
per month.17,18 Actual claims analysis for calendar year 2008 in
1 employer health plan showed that omalizumab had an average
cost of about $20 per day of therapy at its lowest dose (150 mg
every 4 weeks).19 The key to cost-effective use of omalizumab
depends on selectivity and specificity in the asthma population,20
but the clinical characteristics that predict individual patient
response to therapy are unreliable.21
There is also a sizable safety risk associated with the use of
omalizumab beyond the aforementioned increased risk of malignancies. Four years after approval of omalizumab by the FDA on
June 20, 2003, a black-box warning was added in July 2007.22,23
The black-box warning followed an FDA alert released 5 months
earlier, in February 2007, regarding possible anaphylaxis after
any dose of omalizumab, up to 24 hours after the dose is administered, and even if there was no reaction to the first dose.24
Narrowing the Target Space for Omalizumab
The size of the space that omalizumab might occupy in asthma
management is small, but the precise size is unknown. We know
that severe persistent asthma accounts for less than 20% of the
asthma population. For example, of the adults in Michigan who
took asthma medication in the past 30 days, 16.1% were categorized as severe persistent, and about 1 in 5 of all adult asthma
patients report daily symptoms.25
In an attempt to precisely identify the target population of
asthma patients most likely to benefit from omalizumab, it is
helpful to recall that the clinical trials of omalizumab enrolled
patients who had demonstrated sensitivity by positive skin
test to specific perennial aeroallergens (specifically, dust mites,
cockroaches, dog or cat dander) and baseline serum IgE levels in
the range of 30 to 700 international units (IU) per milliliter for
patients 12 to 75 years of age.17 Bousquet et al. (2004) found that
3 factors predicted response to omalizumab, although the absolute differences compared with placebo are small and statistically
insignificant for forced expiratory volume: high dose of the ICS
beclomethasone (800 mcg or more per day; 65% for omalizumab
vs. 40% for placebo, P = 0.037), a history of emergency treatment
for asthma in the past year (67% for omalizumab vs. 40% for
placebo, P = 0.015), and poor lung function (forced expiratory
volume in 1 second [FEV1] ≤ 65% predicted; 67% for omalizumab
www.amcp.org
Omalizumab and Other New Drug Therapies Occupy a Small Space in Asthma Disease Management
vs. 53% for placeo, P = 0.072).26 These results were derived from
pooled analysis of 2 placebo-controlled clinical trials involving
1,070 allergic asthma patients (n = 542 assigned to omalizumab)
who remained symptomatic despite moderate-to-high doses
(mean 725 mcg per day) of inhaled beclomethasone.
Some health plans in the United States have adopted PA
criteria for coverage of omalizumab that incorporate a high level
of detail derived from these clinical trials including restriction
of coverage to nonsmokers and patients with severe persistent
asthma defined as: symptoms throughout the day, nighttime
awakenings often (7 times per week), use of short-acting beta agonists (SABAs) for symptom control several times per day, extreme
interference with normal activity, and compromised lung function measured as FEV1 less than 60% of predicted and a ratio of
FEV1 to forced vital capacity (FVC) reduced by more than 5%.27
Strunk and Bloomberg also propose that the clinical trial data
predict poor response to omalizumab in patients who require
daily oral corticosteroids to control their asthma.17
New Therapies Fall Short for the
Difficult-to-Treat Asthma Patient
Currie et al. (2009) reviewed the characteristics of the difficultto-treat adult asthma patient.28 This category of patient represents about 5%-10% of adults with asthma but accounts for
disproportionately high morbidity, medical costs, and fatal and
near-fatal exacerbations. There are few new approaches to better manage this difficult population, and the clinical results are
not encouraging. The tumor necrosis factor (TNF) antagonist
etanercept showed initial promise, but a double-blind RCT over
12 weeks found no significant improvement in patients with
steroid-dependent asthma. And, a 24-week trial with the human
anti-TNF monoclonal antibody golimumab showed not only
no improvement in efficacy but significantly increased risk of
infections and malignancies. A number of older drugs such as
cyclosporine, methotrexate, gold, and subcutaneous terbutaline
have been tried with apparent efficacy in difficult-to-treat adult
asthma, but these drugs have been used by specialists rather than
mainstream primary care practitioners.28
The outlook for possible biologic interventions seemed to
brighten, at least for small subsets of asthma patients, with the
publication of 2 studies in March 2009 of the interleukin-5
monoclonal antibody mepolizumab in a total of 38 patients with
eosinophilic asthma. In 1 of the 2 studies, Halder et al. found that
monthly injections of mepolizumab 750 mg for 12 months in
29 patients with refractory eosinophilic asthma and a history of
recurrent severe exacerbations was associated with improvement
in the primary end point (exacerbations per subject at 50 weeks)
and improvement in the Asthma Quality of Life Questionnaire
(AQLQ) score but no improvement in other outcomes including asthma symptoms, FEV1 after bronchodilator use, or airway
www.amcp.org
hyperresponsiveness; there were 3 cases (10%) of hospitalization
for asthma in the mepolizumab group versus 11 (34%) in the
placebo group, and 1 of the 29 patients was withdrawn from
the study due to an adverse drug reaction (a transient maculopapular rash that developed 24 hours after the first infusion of
mepolizumab).29 Mepolizumab was associated with mean exacerbations of 2.0 per patient versus 3.4 for placebo over 50 weeks
of treatment (relative risk = 0.57, 95% CI = 0.32-0.92, P = 0.02). In
an accompanying editorial, Wenzel observed that the observed
improvement in AQLQ was not clinically meaningful.30
In the second study, Nair et al. found 1 asthma exacerbation
in 9 prednisone-dependent patients with persistent sputum
eosinophilia treated with 5 monthly injections of mepolizumab
750 mg compared with 12 asthma exacerbations in 10 patients
who received placebo (P = 0.002).31 The dose of prednisone was
reduced by a mean 83.8% (SD = 33.4%) of the maximum dose
in the mepolizumab patients versus 47.7% (SD = 40.5%) in the
placebo group (P = 0.04). The collective data from these 2 studies
of mepolizumab and what was already known about eosinophilic
asthma tell us that (a) eosinophils may not be the major cell
involved in the genesis of asthma, even in patients with severe
asthma; (b) except for the measure of exacerbations, mepolizumab had no effect on other physiological and clinical factors;
(c) the subjects recruited in the 2 recent studies were extraordinary asthma patients (e.g., Nair et al. screened hundreds of severe
asthma patients to obtain the 20 patients in their study); and (d)
the eosinophilic form of asthma accounts for about 5% of the
total number of cases of adult-onset asthma, the more likely target
group compared with childhood-onset asthma.30 Therefore, the
newest light on biologic factors in asthma appears to illuminate
better the path to further research rather than provide solutions
to the challenge of improving outcomes in patients with difficultto-treat asthma.
Confining the Space for Omalizumab
In the category of drugs to suppress IgE, the biological omalizumab should be effective, but (a) Currie et al. remind us that
the Scottish Medicines Consortium advises the use of omalizumab only in patients who require maintenance oral steroids
when all other treatments have failed, and (b) NICE advises
its use only in patients with severe unstable allergic asthma
who have had at least 2 severe exacerbations requiring hospital
admission within the previous year.16 The important takeaway
message from the collective evidence is that the therapeutic
space for omalizumab is a small. NAEPP 2007 makes this very
clear: omalizumab is considered add-on treatment at the end
steps of management of persistent asthma in patients who have
allergies and continue to have symptoms uncontrolled with
high-dose ICS and LABA (step 5) and with oral corticosteroid
(step 6), and administered by clinicians who are “prepared and
Vol. 15, No. 3
April 2009
JMCP
Journal of Managed Care Pharmacy 291
Omalizumab and Other New Drug Therapies Occupy a Small Space in Asthma Disease Management
equipped to identify and treat anaphylaxis that may occur.”14
NICE is somewhat less nice to omalizumab, restricting its
recommended use to add-on therapy in patients with:
• confirmation by clinical history and skin test of IgE-mediated
allergy to a perennial allergen;
• evidence of severe exacerbations of asthma in the last year,
defined as (a) at least 2 exacerbations that required hospital
admission, or (b) 3 or more exacerbations that included at
least 1 hospital admission and 2 emergency room visits;
• discontinuation of omalizumab at 16 weeks in the absence of
response to therapy (Appendix).
Despite ostensible promise in patients with allergic asthma,
omalizumab is appropriate in only a small proportion of asthma
patients.
Appendix
Author
FREDERIC R. CURTISS, PhD, RPh, CEBS, is Editor-in-Chief of the
Journal of Managed Care Pharmacy.
AUTHOR CORRESPONDENCE: Frederic R. Curtiss, PhD, RPh,
CEBS, Academy of Managed Care Pharmacy, 100 North Pitt St.,
Suite 400, Alexandria, VA 22314. Tel.: 830.935.4319; E-mail:
[email protected]
DISCLOSURES
The author reports no conflicts of interest related to the subjects or products
discussed in this article.
NAEPP 2007 and NICE Recommendations (2007) for Appropriate Use of Omalizumab
NAEPP 2007 Guidelinesa
•“The Expert Panel recommends that omalizumab may be considered as adjunctive therapy in step 5 or 6 care for patients who have allergies
and severe persistent asthma that is inadequately controlled with the combination of high-dose ICS and LABA (Evidence B).”
NICE Technology Appraisal Guidance 133 – Omalizumab for Severe Persistent Allergic Asthma b
1.1 Omalizumab is recommended, within its licensed indication, as an option for the treatment of severe persistent allergic (IgE mediated)
asthma as add-on therapy to optimized standard therapy, only in adults and adolescents (12 years and older) who have been identified as
having severe unstable disease.
1.2 For the purposes of this guidance, optimized standard therapy is defined as a full trial of, and documented compliance with, inhaled highdose corticosteroids and long-acting beta-2 agonists in addition to leukotriene receptor antagonists, theophyllines, oral corticosteroids and
beta-2 agonist tablets and smoking cessation where clinically appropriate.
1.3 Omalizumab add-on therapy should only be initiated if the patient fulfills the following criteria of severe unstable allergic asthma: (a) confirmation of IgE mediated allergy to a perennial allergen by clinical history and allergy skin testing, and (b) either 2 or more severe exacerbations of asthma requiring hospital admission within the previous year, or 3 or more severe exacerbations of asthma within the previous year,
at least one of which required admission to hospital, and a further two which required treatment or monitoring in excess of the patient’s
usual regimen, in an accident and emergency unit.
1.4 Omalizumab add-on therapy should be initiated and monitored by a physician experienced in both allergy and respiratory medicine in a
specialist centre.
1.5 Omalizumab add-on therapy should be discontinued at 16 weeks in patients who have not shown an adequate response to therapy.
Response to treatment should be defined on the basis of a full clinical assessment comprising: degree of asthma control, quality of life,
control of exacerbations, avoidance of unscheduled healthcare utilization; spirometry and peak expiratory flow measures and a global evaluation of treatment effectiveness, as assessed by the physician.”
The NICE TA133 Guidance includes some particularly succinct points regarding cost-effectiveness: “Overall, therefore, the Committee concluded that there were a number of considerations which meant the ICER was higher than acceptable for
patients with severe persistent allergic asthma. However, the Committee was persuaded that for a narrowly defined severely affected group of
asthma patients, at an elevated risk of asthma-related mortality, cost-effective treatment with omalizumab was possible, if therapy was discontinued in non-responders at 16 weeks and if vial wastage could be minimized to reduce costs. The Committee concluded that omalizumab add-on
therapy is recommended as an option for the treatment of asthma in patients with severe unstable disease (that is, those who have had either
two or more severe exacerbations of asthma requiring hospital admission within the previous year, or three or more severe exacerbations of
asthma within the previous year, at least one of which required admission to hospital, and a further two which required treatment or monitoring
in excess of the patient’s usual regimen, in an accident and emergency unit), who have clinical confirmation of IgE mediation of asthma exacerbations and have had a full trial of, and documented compliance with all standard asthma medication (see 4.4). It also concluded that omalizumab treatment should only be initiated and monitored by physicians experienced in both allergy and chest medicine in a specialist centre.”
a Page
225 of the National Asthma Education and Prevention Program 2007 Full Report.14
Institute for Health and Clinical Excellence. Omalizumab for severe persistent allergic asthma. NICE technology appraisal guidance TA133, November 2007.16
bNational
292 Journal of Managed Care Pharmacy
JMCP
April 2009
Vol. 15, No. 3
www.amcp.org
Omalizumab and Other New Drug Therapies Occupy a Small Space in Asthma Disease Management
REFERENCES
1. American Lung Association. Asthma. 2008. Available at: http://www.
lungusa.org/atf/cf/{7a8d42c2-fcca-4604-8ade-7f5d5e762256}/ALA_LDD08_
ASTHMA_FINAL.PDF. Accessed March 5, 2009.
16. National Institute for Health and Clinical Excellence. Omalizumab
for severe persistent allergic asthma. NICE technology appraisal guidance
133. November, 2007. Available at: http://www.nice.org.uk/nicemedia/pdf/
TA133Guidance.pdf. Accessed March 14, 2009.
2. U.S. Food and Drug Administration. FDA Talk Paper. Labeling changes
for drug products that contain salmeterol. August 14, 2003. Available at:
http://www.fda.gov/bbs/topics/ANSWERS/2003/ANS01248.html. Accessed
March 5, 2009.
17. Strunk RC, Bloomberg GR. Omalizumab for asthma. N Engl J
Med. 2006;354(25):2689-95. Available at: http://content.nejm.org/cgi/
reprint/354/25/2689.pdf. Accessed March 14, 2009.
3. U.S. Food and Drug Administration. Advair Diskus, Advair HFA,
Brovana, Foradil, Perforomist, Servent Diskus, and Symbicort information (long acting beta agonists). November 18, 2005; updated April 2008.
Available at: http://www.fda.gov/cder/drug/infopage/LABA/default.htm.
Accessed March 5, 2009.
19. Analysis of pharmacy claims data for a self-insured employer for dates of
service from January 1, 2008 through December 31, 2008.
4. Nelson HS, Weiss ST, Bleecker ER, Yancey SW, Dorinsky PM, SMART
study group. The salmeterol multicenter asthma research trial. Chest.
2006;129:15-26. Available at: http://www.chestjournal.org/content/129/1/15.
full.pdf+html. Accessed March 5, 2009.
5. Lee DK, Currie GP, Hall IP, et al. The arginine-16 beta2-adrenoceptor
polymorphism predisposes to bronchoprotective subsensitivity in patients
treated with formoterol and salmeterol. Br J Clin Pharmacol. 2004;57:68-75.
Available at: www.pubmedcentral.nih.gov/picrender.fcgi?artid=1884417&blo
btype=pdf. Accessed November 6, 2008.
6. Hall IP. Pharmacogenetics of asthma. Chest. 2006;13):1873-78.
7. Bender B, Zhang L. Negative affect, medication adherence, and asthma
control in children. J Allergy Clin Immunol. 2008;122:490-95.
8. Platts-Mills TAE. Asthma severity and prevalence: an ongoing interaction between exposure, hygiene, and lifestyle. PLoS Med. 2005;2(2):012226. Available at: http://medicine.plosjournals.org/archive/1549-1676/2/2/
pdf/10.1371_journal.pmed.0020034-S.pdf. Accessed March 5, 2009.
9. Saltoun C, Avila PC. Advances in upper airway diseases and allergen
immunotherapy in 2007. J Allergy Clin Immunol. 2008;122:481-87.
10. Pesko, LJ. Omalizumab has a place in therapy for asthma disease management. J Manag Care Pharm. 2009;15(3):284-88.
11. Facts and Comparisons 4.0, online. Wolters Kluwer Health. Accessed
November 6, 2008.
12. Bateman ED, Boushey HA, Bousquet J, et al. for the GOAL Investigators
Group. Can guideline-defined asthma control be achieved? The Gaining
Optimal Asthma Control Study. Am J Respir Crit Care Med. 2004;170:
836-44. Available at: http://ajrccm.atsjournals.org/cgi/reprint/170/8/836.
Accessed January 11, 2009.
13. Curtiss FR. More evolution of the evidence in asthma disease management–SMART versus GOAL clinical trials debate the cost-benefit of LABA
while the value of leukotriene modifiers, particularly montelukast, is uncertain. J Manag Care Pharm. 2006;12(40:343-46. Available at: http://amcp.org/
data/jmcp/editorial_in_this_343-346.pdf.
18. Fanta CH. Asthma. N Engl J Med. 2009;360(10):1002-14.
20. Curtiss FR. Selectivity and specificity are the keys to cost-effective use
of omalizumab for allergic asthma. J Manag Care Pharm. 2005;11(9):774-76.
Available at: www.amcp.org/data/jmcp/editorial_774-776.pdf.
21. Bousquet J, Rabe K, Humbert M, et al. Predicting and evaluating
response to omalizumab in patients with severe allergic asthma. Respir Med.
2007;101:1483-92.
22. U.S. Food and Drug Administration. Omalizumab (marketed as Xolair)
information. July 5, 2007. Available at: www.fda.gov/cder/drug/infopage/
omalizumab/default.htm. Accessed September 21, 2008.
23. Giezen TJ, Mantel –Teeuwisse AK, Straus SMJM, Schellekens H,
Leufkens HGM, Egberts ACG. Safety-related regulatory actions for
biologicals approved in the United States and the European Union.
JAMA. 300(16):1887-96. Available at: http://jama.ama-assn.org/cgi/
reprint/300/16/1887. Accessed March 4, 2009.
24. U.S. Food and Drug Administration. FDA News – FDA proposes to
strengthen label warning for Xolair. February 21, 2007. Available at: www.
fda.gov/bbs/topics/NEWS/2007/NEW01567.html. Accessed September 21,
2008.
25. Michigan Department of Community Health. Asthma prevalence, severity, and management for Michigan adults. Available at: http://www.michigan.
gov/documents/AsthmaPrevSevMgmnt_127071_7.pdf. Accessed March 23,
2009.
26. Bousquet J, Wenzel S, Holgate S, et al. Predicting response to omalizumab, an anti-IgE antibody, in patients with allergic asthma. Chest. 2004;
125:1378-86. Available at: http://www.chestjournal.org/content/125/4/1378.
full.pdf+html. Accessed March 5, 2009.
27. Prior authorization criteria/guidelines: Xolair (omalizumab). Coventry
Health Care. Issue date: September 25, 2003; updated in January
2008. Available at: http://www.vistahealthplan.com/VistaParSecure/
ParApplications/ContactUsProvider/PDF/Rx%20Prior%20Auths/PRIOR%20
AUTHORIZATION%20CRITERIA/Xolair.pdf. Accessed March 4, 2009.
28. Currie G, Douglas JG, Heaney LG. Difficult to treat asthma in adults.
BMJ. 2009;338:b494. Accessed February 24, 2009.
14. National Asthma Education and Prevention Program. Expert Panel
Report 3. Guidelines for the Diagnosis and Management of Asthma.
Bethesda, MD: National Institutes of Health; August 28, 2007. NIH
Publication No. 07-4051. Available at: www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf Accessed January 12, 2009.
29. Halder P, Brightling CE, Hargadon B, et al. Mepolizumab and exacerbations of refractory eosinophlic asthma. N Engl J Med. 2009;360(10):973-84.
15. U.S. Food and Drug Administration. Label and approval history: Xolair.
Available at: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.
cfm. Accessed January 12, 2009.
31. Nair P, Pizzichini MMM, Kjarsgaard M, et al. Mepolizumab for
prednisone-dependent asthma with sputum eosinophilia. N Engl J Med.
2009;360(10):985-93.
www.amcp.org
30. Wenzel SE. Eosinophils in asthma – closing the loop or opening the
door? N Engl J Med. 2009;360(10):1026-28.
Vol. 15, No. 3
April 2009
JMCP
Journal of Managed Care Pharmacy 293
EDITORIAL
Selling Real-World Health Care Research to Reluctant Buyers—
Evidence-Based Education or Marketing a Defective Product?
Kathleen A. Fairman MA, and Frederic R. Curtiss, PhD, RPh, CEBS
I
n December 2004, the editors of BMJ announced a new policy
requiring submission of a priori research protocols with manuscripts reporting the results of randomized controlled trials
(RCTs). Under the new policy, RCTs would have to be registered
at their outset with “a suitable trial registry,” and manuscripts
lacking a registered protocol would no longer be sent to peer
review. The editors explained that this decision had been made
because their “experience of chasing authors for trial protocols,
when we have suspected deviation in the protocol or found it
hard to fathom what the authors set out to do,” had been “miserable.”1
As occasionally miserable editors, we too are familiar with
the experience of seeking information from an author who is
unable or unwilling to provide it; and evidence is mounting that
we are not alone. As we and others have observed previously,
the practices of selective reporting of study findings, publication
planning, and other forms of misconduct are, sadly, reportedly
endemic in health care research.2,3 Studies that use observational
or “real-world” data, particularly pharmacoeconomic modeling and retrospective analyses of administrative databases, are
particularly vulnerable to manipulation; it is especially easy to
make post hoc changes to a planned protocol behind closed doors
when only claims data and hypothetical patient populations, not
prospectively studied human subjects, are involved.4
Thus, to the extant problem presented by Brixner et al. in their
commentary on use of real-world data in this issue of JMCP 5 —
that decision makers are sometimes reluctant to rely on analyses
of real-world data—one reasonable response is that the most
reluctant “buyers” of research may well be the best informed.
After all, public denunciations of the “scandal of poor epidemiological research” by von Elm and Egger in 2004,6 and the “scandal of poor medical research” by Altman in 1994 and again in
20027,8 are well-known to anyone who has been following health
care research even peripherally, and have spawned dozens of
publications on how to improve a demonstrably inadequate pool
of knowledge about the economic and clinical outcomes of health
care interventions.2 Yet, we also know that many—perhaps even
most—researchers are “playing by the rules,” endeavoring to
provide accurate information, and producing high-quality work.
So for a typical decision maker, the question becomes how to
distinguish between accurate and inaccurate information.
This is essentially the question raised by Brixner et al., and it
is an important one. The proposals offered by the March 2008
participants in a roundtable discussion of real-world data, whose
views are reported in the Brixner et al. commentary, merit consideration. Nonetheless, currently these ideas appear to generate
294 Journal of Managed Care Pharmacy
JMCP
April 2009
Vol. 15, No. 3
more new questions than specific guidance. More troubling is
the possibility that the effort to promote use of real-world data by
decision makers may detract from ongoing efforts to improve the
quality of information provided to them.
“Independent Body or Review Process”—
Different From Journal Peer Review?
Among the proposals advanced by Brixner et al.’s first workgroup,
which examined the “continuation of the work of the ISPOR
[International Society for Pharmacoeconomics and Outcomes
Research] Task Force on the Use of Real-World Data,” was the
formation of an “independent body or review process.” The body
would “be formed as a consortium of experts giving access to
a broad range of resources and expertise for an audit, review,
or quality certification process.”5 We wonder how such a group
would differ from the available pool of journal peer reviewers
who, as experts in particular topic areas, are already tasked with
screening the quality of research articles. Certainly, any consortium of experts would be faced with, and challenged by, the
same lack of transparency in research reporting that has by now
become infamous among journal peer reviewers, editors, and
methodologists. A key task of peer review—to ensure that limitations of published work are transparently disclosed in terms that
are relevant to journal readers—depends in part on the cooperation of authors, and most journal editors would acknowledge that
some authors are more cooperative than others.
Brixner et al. mention the efforts of the Enhancing the QUAlity
and Transparency Of health Research (EQUATOR) network,
formed in May 2006 to “improve the quality of scientific publications by promoting transparent and accurate reporting of health
research.”9 They opine that the EQUATOR network’s endeavors
would be synergistic with the efforts proposed by the roundtable.
However, at this early stage of development, Brixner et al. offer little specific information about how the process that they propose
would incorporate the EQUATOR guidelines, or how an expert
consortium might be more successful in encouraging transparency than are organizations and journals that are already measuring research reports against the EQUATOR standards. Brixner
et al. do raise the possibility of a voluntary registry of observational studies, similar to the registries now required by most
journals for the submission of manuscripts that describe clinical
trials. This idea has merit, but either voluntary or mandatory
registration would pose unique challenges; voluntary registration
would lack “teeth,” while journals that impose mandatory registration of observational studies would at least temporarily experience a reduction in the flow of manuscript submissions.
www.amcp.org
Selling Real-World Health Care Research to Reluctant Buyers—Evidence-Based Education or Marketing a Defective Product?
Public Information Campaign—How Great Is The Need?
A second key proposal advanced by the roundtable participants
was a “process to achieve dissemination and acceptance of an
assessment tool,” essentially a public information campaign that
would “increase public awareness of the need for quality assessment of observational evidence and subsequently, the acceptance
of observational studies meeting defined quality standards to be
used in the decision-making process.”5 The window of opportunity for public dissemination of this information appears to
be open—but only by the slightest crack. Deficiencies in the
research literature have been publicly acknowledged for about
15 years, and EQUATOR standards have been adopted by a wide
variety of journals, including Annals of Internal Medicine, BMJ,
JAMA, PLoS Medicine, the Journal of Clinical Epidemiology, and others.10 EQUATOR standards have been endorsed by the Council
of Science Editors, and guideline documents promulgated by
EQUATOR are referenced by the International Committee of
Medical Journal Editors in their uniform guidelines for manuscript submission.11,12 Certainly these efforts must be known
among those who routinely read health care journals.
However, it is possible that many decision makers will not
fall into that category. The roundtable’s work, which is in its
early stages, has to date included only informal assessments
of informational needs that were expressed by small numbers
of meeting participants and by a convenience sample (N = 70,
including an unknown number of decision makers) responding to a draft ISPOR report during an open comment period.
Before launching a widespread informational campaign, Brixner
et al. should be encouraged to conduct a more quantitative and
systematic evaluation of the informational needs of decision makers. It might even be wise to “quiz” decision makers to assess
gaps in their knowledge of observational research methods and
pharmacoeconomic modeling. For example, in advance of the
first EQUATOR meeting, network organizers “searched literature
to identify published reporting guidelines and surveyed authors
to examine how the guidelines were developed and to identify
problems encountered during the development” and used “the
survey results and meeting discussions [to help us prioritize]
main activities that were necessary for a successful start of the
EQUATOR Network’s efforts to improve the quality of reporting
of health research.”13 This kind of systematic, evidence-based
approach is most likely to result in a process that will address the
needs of decision makers.
An educational effort should also reflect a realistic acknowledgement of the time and resources available to a typical health
care decision-maker. Although the key elements of high-quality
research—such as transparency, minimization of bias, and a
presentation that is sufficiently detailed to facilitate replication of
study methods—are promulgated universally by guideline documents,2 putting these ideas into practice sometimes requires time
and expertise. The expertise required for use of research guideline documents—at about the level of upperclass undergraduate
or beginning graduate school research methods and statistics
classes—should not exceed the ability of any researchers seeking
www.amcp.org
journal publication, but could potentially be too far outside the
time or expertise available to a decision maker, even after a brief
educational intervention. For example, a common error seen in
research reporting is the use of an underpowered sample size
to compare 2 treatment approaches, followed by the assertion
of a researcher that the treatments are equivalent. An author
or journal peer reviewer can easily obtain the necessary power
calculation tables and determine if the sample size was adequate
for the task, but asking for this level of effort from a health plan
executive/decision maker is probably unrealistic. However, it is
realistic to train decision makers to recognize an even more common error, the description of a clinically meaningless result as
important based solely on statistical significance. For example, a
difference of 1 percentage point in medication possession ratio,
representing only about 4 days of additional pharmacotherapy
per year, is clearly unimportant whether it is statistically significant or not.
Standardized Quality Instrument—A Worthwhile Endeavor?
An additional key element in the strategy proposed by the roundtable participants in the report by Brixner et al. is a “standardized instrument for quality assessment,” which would represent
“criteria that are recognized as key indicators” of quality. For the
instrument to be “user-friendly,” Brixner et al. posit, it would
“identify the 10 most important factors from the decision maker’s
perspective.” However, they also indicate that the instrument
would take “the form of a modular assessment tool with different
axes by (a) study objective: economic impact or cost-effectiveness,
health outcomes, patient reported outcomes; and (b) study type:
model, clinical prospective study, or retrospective data analysis.”
This proposal is the weakest and least evidence-based of those
advanced by Brixner et al.
First, it appears that Brixner et al. may be proposing too much
for just 1 document. When the Agency for Healthcare Research
and Quality (AHRQ) undertook a systematic review of checklists
used to rate the strength of scientific evidence in 2002, it wisely
opted not to attempt a single checklist for all study types. “In the
worst case,” the AHRQ observed, “combining all such systems
into a single evaluation framework risked nontrivial confusion
and misleading conclusions, and [we] were not willing to take
the chance that users of this report would conclude that ‘a single
system’ would suit all purposes. That is clearly not the case.”14
Second, the most important potential need, education, does
not require a new checklist. In an era of scarce resources, Brixner
et al. should be mindful of the degree to which their work
duplicates that already being undertaken, or already completed,
by EQUATOR. For example, among the EQUATOR network’s
primary objectives are the development of “a comprehensive webbased ‘Resource Centre’ providing up-to-date information, tools
and other materials relating to reporting health research” and
“training courses for editors, peer reviewers and researchers, and
other educational activities raising awareness and importance
of reporting guidelines.”15 A library of standards for numerous
types of study reports—including RCTs, observational research,
Vol. 15, No. 3
April 2009
JMCP
Journal of Managed Care Pharmacy 295
Selling Real-World Health Care Research to Reluctant Buyers—Evidence-Based Education or Marketing a Defective Product?
analyses of health care interventions, meta-analyses, and more—
is already available on-line,16 and training courses have begun.9
Since sensible and high-quality guideline documents already
exist for nearly every conceivable major type of study,2 expending
effort to create yet another tool seems unproductive at best, and
at worst has the clear potential to become a pyrrhic attempt at an
ineffective and possibly misleading “one size fits all” approach.
Our Continued Plea for Transparency
We continue to believe that the best hope for improving the
quality of research evidence available to decision makers lies in
a strengthened journal peer review system. Although far from
perfect, the system of editorial and peer review has already been
bolstered by the efforts of the EQUATOR network and others
to add transparency to research reporting and by the increased
“disinfectant/sunshine” that has resulted from public attention to
incidents of research misconduct. Creating a new review body or
expert consortium, composed of the same people who make up
the current peer reviewer pool, is unlikely to be productive and
at worst may divert attention from current quality improvement
efforts.
The proposal from the roundtable session reported by Brixner
et al. that has the most potential is the education of decision makers in the critical review of studies employing real-world data.
However, such education should (a) be based on a systematic
and quantitative assessment of the informational needs of decision makers; (b) openly acknowledge the scope of the problem
of poor-quality research; (c) train decision makers in review
methods that can be used to refute rather than accept poor quality; and (d) acknowledge the limitations of time and resources
available to a typical decision maker.
Finally, the process proposed by Brixner et al. should be
designed so as to minimize duplication of effort. In that regard,
the clearest area for improvement in Brixner’s et al.’s proposals
involves the standardized checklist, which is almost entirely
duplicative of work already completed by others.
Brixner et al. address an issue that has become increasingly
important in managed care—how to encourage decision making that is based on high-quality evidence. However, the process
currently advocated by the roundtable meeting participants poses
the risk of inadvertently encouraging decision makers to accept
poor-quality work—providing a false sense of security about
published real-world research evidence instead of facilitating a
critical assessment of its strengths and weaknesses. To reduce
this risk, measurement of the unmet informational needs of
managed care decision makers is essential to establish a base of
evidence before “promoting the utilization of real-world data.”5
Authors
KATHLEEN A. FAIRMAN, MA, is Associate Editor and Senior
Methodology Reviewer, and FREDERIC R. CURTISS, PhD, RPh,
CEBS, is Editor-in-Chief, Journal of Managed Care Pharmacy.
AUTHOR CORRESPONDENCE: Kathleen A. Fairman, MA,
Kathleen Fairman LTD, P.O. Box 31278, Phoenix, AZ 85046. Tel.:
602.867.1343; E-mail: [email protected]
REFERENCES
1. Jones G, Abbasi K. Trial protocols at the BMJ: authors must submit the
protocol with the trial. BMJ. 2004 Dec 11;329(7479):1360.
2. Fairman KA, Curtiss FR. Rethinking the ‘whodunnit’ approach to assessing the quality of health care research—a call to focus on the evidence in
evidence-based practice. J Manag Care Pharm. 2008;14(7):661-74. Available
at: http://www.amcp.org/data/jmcp/661-674_FairmanCurtiss-Final.pdf.
3. Fairman KA, Curtiss FR. What should be done about bias and misconduct in clinical trials? J Manag Care Pharm. 2009;15(2):154-60. Available at:
http://www.amcp.org/data/jmcp/154-60.pdf.
4. Fairman KA. Differentiating effective data mining from fishing, trapping,
and cruelty to numbers. J Manag Care Pharm. 2007;13(6):517-27. Available at:
http://www.amcp.org/data/jmcp/pages%20517-27.pdf.
5. Brixner DI, Holtorf A-P, Neumann PJ, Malone CD, Watkins JB.
Standardizing quality assessment of observational studies for decision making in health care. J Manag Care Pharm. 2009;15(3):275-83.
6. von Elm E, Egger M. The scandal of poor epidemiological research:
reporting guidelines are needed for observational epidemiology. BMJ.
2004;329:868-69.
7. Altman DG. The scandal of poor medical research. BMJ. 1994;308:283-84.
8. Altman DG. Poor-quality medical research: what can journals do? JAMA.
2002;287(11):2765-67.
9. EQUATOR network website home page. Available at: http://www.equatornetwork.org/. Accessed March 19, 2009.
10. EQUATOR network. Examples of editorials introducing reporting guidelines. Available at: http://www.equator-network.org/index.aspx?o=1036.
Accessed March 19, 2009.
11. EQUATOR network. CSE supports EQUATOR. Available at: http://www.
equator-network.org/?o=1060. Accessed March 19, 2009.
12. International Committee of Medical Journal Editors. Uniform requirements for manuscripts submitted to biomedical journals: writing and editing
for biomedical publication. October 2008. Available at: http://www.icmje.
org/. Accessed March 19, 2009.
13. EQUATOR network. History of EQUATOR. Available at: http://www.
equator-network.org/index.aspx?o=1019. Accessed March 19, 2009.
14. Agency for Healthcare Research and Quality. Systems to Rate the
Strength of Scientific Evidence. Summary, Evidence Report/Technology
Assessment: Number 47. AHRQ Publication No. 02-E015, March 2002.
Agency for Healthcare Research and Quality, U.S. Department of Health and
Human Services. Rockville, MD. Available at: http://www.ahrq.gov/clinic/
epcsums/strengthsum.htm. Accessed March 23, 2009.
DISCLOSURES
15. EQUATOR network. EQUATOR core programme. Available at: http://
www.equator-network.org/index.aspx?o=1021. Accessed March 19, 2009.
The authors report no conflicts of interest related to the subjects or products
discussed in this article.
16. EQUATOR network. Introduction to reporting guidelines. Available at:
http://www.equator-network.org/index.aspx?o=1032. Accessed March 19, 2009.
296 Journal of Managed Care Pharmacy
JMCP
April 2009
Vol. 15, No. 3
www.amcp.org