PNN Pharmacotherapy Line
Jan. 3, 2017 * Vol. 24, No. 1
Providing news and information about medications and their proper use
>>>Internal Medicine Report
Source: Early-release articles from and Jan. 3 issue of the Annals of Internal Medicine
(2017; 166).
Oral Treatment of Type 2 Diabetes: In an update to a 2012 clinical practice guideline,
the American College of Physicians recommends first-line use of metformin for oral
pharmacologic treatment of type 2 diabetes in adults (10.7326/M16-1860). The
guideline, endorsed by the American Academy of Family Physicians, cites the safety
advantages of metformin over other oral agents, particularly its weight loss effect. Based
on a systematic review and meta-analysis of monotherapy and metformin-based
combination therapy (2016;164:740–51; N. M. Maruthur, [email protected]), ACP
makes these recommendations (A. Qaseem, [email protected]):
* ACP recommends that clinicians prescribe metformin to patients with type 2 diabetes
when pharmacologic therapy is needed to improve glycemic control. (Grade: strong
recommendation; moderate-quality evidence)
* ACP recommends that clinicians consider adding either a sulfonylurea, a
thiazolidinedione, an SGLT-2 inhibitor, or a DPP-4 inhibitor to metformin to improve
glycemic control when a second oral therapy is considered. (Grade: weak
recommendation; moderate-quality evidence.) ACP recommends that clinicians and
patients select among medications after discussing benefits, adverse effects, and costs.
Evidence Supporting Increased Metformin Use: Describing evidence that supports
recent changes in recent FDA-approved labeling of metformin-containing products,
authors of a systematic review conclude that “metformin use in patients with moderate
[chronic kidney disease (CKD), congestive heart failure (CHF), or chronic liver disease
(CLD)] with hepatic impairment is associated with improvements in key clinical
outcomes” (10.7326/M16-1901). Studies selected for inclusion in the review assessed
metformin’s effects in adults with type 2 diabetes and CKD, defined as estimated
glomerular filtration rate less than 60 mL/min/1.73 sq m, and reported all-cause mortality,
major adverse cardiovascular events, and other outcomes. The data showed: “On the
basis of quantitative and qualitative syntheses involving 17 observational studies,
metformin use is associated with reduced all-cause mortality in patients with CKD, CHF,
or CLD with hepatic impairment, and with fewer heart failure readmissions in patients
with CKD or CHF.” (M. J. Crowley, [email protected])
Treatment of Gout: One of several articles in this issue on treatment of gout (pp. 26–
36, S. J. Newberry, [email protected]; pp. 37–51, P. G. Shekelle, [email protected];
pp. 73–4, R. M. McLean, [email protected]; pp. 1–16, A. Qaseem), an editorial
concludes that “although some approaches have not yet been formally tested in trials, a
clear understanding of the pathophysiology of gout provides a strong foundation for
rational recommendations while we await clarity on these important clinical issues” (pp.
71–2): “We acknowledge that the existing literature only indirectly addresses what the
optimal serum urate target is. However, it is a disservice to our patients and primary care
colleagues to suggest that treating to avoid symptoms is acceptable with [urate-lowering
therapy (ULT)] in the absence of evidence. At the very least, based on the biochemistry
of urate, a treatment target below the physiologic threshold of urate crystallization (<6.8
mg/dL) would be appropriate, even if a lower target is not yet supported by randomized
trials. A target of less than 6.8 mg/dL (or <357 µmol/L [<6 mg/dL] with assay variation
taken into account) seems reasonable, based on the authors’ own admission that serum
urate levels exceeding this threshold are the cause of gout.” (T. Neogi)
>>>PNN JournalWatch
* 2017 Standards of Medical Care in Diabetes, in Diabetes Care, 2017; 40 (suppl 1).
(American Diabetes Association)
* Hypnotic Medications and Suicide: Risk, Mechanisms, Mitigation, and the FDA, in
American Journal of Psychiatry, 2017; 174: 18–25. (W. V. McCall)
* Risk Stratification for Opioid Misuse in Children, Adolescents, and Young Adults: A
Quality Improvement Project, in Pediatrics, 2017; 139: 10.1542/peds.2016-0258. (R.
Thienprayoon)
* Sweet Solutions to Reduce Procedural Pain in Neonates: A Meta-analysis, in
Pediatrics, 2017; 139: 10.1542/peds.2016-0955. (D. Harrison)
PNN Pharmacotherapy Line is published via e-mail each business day except U.S.
holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201;
571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News
Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail
[email protected] to request missing copies of PNN. Quarterly files archived at
www.PharmacotherapyNewsNetwork.com.
PNN Pharmacotherapy Line
Jan. 4, 2017 * Vol. 24, No. 2
Providing news and information about medications and their proper use
>>>JAMA Report
Source: Jan. 3 issue of JAMA (2017; 317).
Trastuzumab Biosimilar in Metastatic Breast Cancer: In a randomized comparison, a
proposed trastuzumab biosimilar performed similarly to the originator product in women
with ERBB2 (HER2)–positive metastatic breast cancer, researchers report (pp. 37–47).
The phase 3 trial included 500 women treated with a taxane plus either the biosimilar or
trastuzumab, with these results: “Among 500 women randomized, the intention-to-treat
population included 458 women (mean [SD] age, 53.6 [11.11] years) and the safety
population included 493 women. The [overall response rate (ORR)] was 69.6% (95% CI,
63.62%–75.51%) for the proposed biosimilar vs 64.0% (95% CI, 57.81%–70.26%) for
trastuzumab. The ORR ratio (1.09; 90% CI, 0.974–1.211) and ORR difference (5.53;
95% CI, −3.08 to 14.04) were within the equivalence boundaries. At week 48, there was
no statistically significant difference with the proposed biosimilar vs trastuzumab for time
to tumor progression (41.3% vs 43.0%; −1.7%; 95% CI, −11.1% to 6.9%), progression-
free survival (44.3% vs 44.7%; −0.4%; 95% CI, −9.4% to 8.7%), or overall survival
(89.1% vs 85.1%; 4.0%; 95% CI, −2.1% to 10.3%). In the proposed biosimilar and
trastuzumab groups, 239 (98.6%) and 233 (94.7%) had at least 1 adverse event, the
most common including neutropenia (57.5% vs 53.3%), peripheral neuropathy (23.1% vs
24.8%), and diarrhea (20.6% vs 20.7%).” (H. S. Rugo, [email protected])
In addition to exploring the impact of a biosimilar on treatment in developing countries,
editorialists delve into the effect on prices in the U.S. (pp. 30–2): “The trastuzumab
biosimilar will probably reduce prices, although this will not take full effect until the patent
on trastuzumab expires in 2019. Under the prevailing ‘buy and bill’ system of Medicare
Part B, oncology practices are reimbursed for chemotherapy based on a drug’s average
sales price plus a 6% margin intended to cover overhead and inventory management.
To mitigate the financial disincentive to prescribe inexpensive alternatives, the Centers
for Medicare & Medicaid Services has wisely pegged reimbursement for biosimilar
products to the average sales price of the biosimilar plus 6% of the branded version, that
is, the 6% is based on the cost of the more expensive drug.” (D. Schrag,
[email protected])
JAMA editors explain their decision to publish this article in light of trial sponsorship by
the biosimilar developers, including Mylan, which has been under scrutiny for its pricing
of EpiPen (pp. 33–4): “Ultimately, the decision to publish this article was based on the
determination that the scientific merit and potential to contribute meaningful clinical
information for care of patients with breast cancer outweighed other considerations. The
controversy over the pricing of drugs in the United States and around the world is an
ongoing debate, and not unique to 1 company or 1 product. The authors have provided
assurance to the editors that the study was conducted ethically and appropriately. The
lead academic author indicates that she had full access to all data in the study and takes
responsibility for the integrity of the data and the accuracy of the data analysis. The data
from this study will also be subject to additional scrutiny by regulatory agencies in
making determinations about approval of the proposed trastuzumab biosimilar product.”
(H. Bauchner, [email protected])
Longer Dosing Interval for Zoledronic Acid: Administration of zoledronic acid in
patients with cancer every 12 weeks was noninferior to every-4-week dosing in a
randomized open-label trial (pp. 48–58): “Among 1,822 patients who were randomized
(median age, 65 years; 980 [53.8%] women; 855 with breast cancer, 689 with prostate
cancer, and 278 with multiple myeloma), 795 completed the study at 2 years. A total of
260 patients (29.5%) in the zoledronic acid every 4-week dosing group and 253 patients
(28.6%) in the every 12-week dosing group experienced at least 1 skeletal-related event
within 2 years of randomization (risk difference of −0.3% [1-sided 95% CI, −4% to ∞];
P < .001 for noninferiority). The proportions of skeletal-related events did not differ
significantly between the every 4-week dosing group vs the every 12-week dosing group
for patients with breast cancer, prostate cancer, or multiple myeloma.…” (A. L.
Himelstein, [email protected])
PNN Pharmacotherapy Line is published via e-mail each business day except U.S.
holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201;
571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News
Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail
[email protected] to request missing copies of PNN. Quarterly files archived at
www.PharmacotherapyNewsNetwork.com.
PNN Pharmacotherapy Line
Jan. 5, 2017 * Vol. 24, No. 3
Providing news and information about medications and their proper use
>>>NEJM Report
Source: Jan. 5 issue of the New England Journal of Medicine (2017; 376).
Inclisiran for PCSK9–Mediated Cholesterol Lowering: A long-acting RNA
interference therapeutic agent that inhibits the synthesis of proprotein convertase
subtilisin–kexin type 9 (PCSK9), inclisiran significantly reduced levels of PCSK9 and
LDL cholesterol for at least 6 months without serious adverse events, researchers report
(pp. 41–51). Tested in ascending and multiple doses in a phase 1 trial, inclisiran
produced these results in small numbers of healthy volunteers: “The most common
adverse events were cough, musculoskeletal pain, nasopharyngitis, headache, back
pain, and diarrhea. All the adverse events were mild or moderate in severity. There were
no serious adverse events or discontinuations due to adverse events. There was one
grade 3 elevation in the gamma-glutamyltransferase level, which was considered by the
investigator to be related to statin therapy. In the single-dose phase, inclisiran doses of
300 mg or more reduced the PCSK9 level (up to a least-squares mean reduction of
74.5% from baseline to day 84), and doses of 100 mg or more reduced the LDL
cholesterol level (up to a least-squares mean reduction of 50.6% from baseline).
Reductions in the levels of PCSK9 and LDL cholesterol were maintained at day 180 for
doses of 300 mg or more. All multiple-dose regimens reduced the levels of PCSK9 (up
to a least-squares mean reduction of 83.8% from baseline to day 84) and LDL
cholesterol (up to a least-squares mean reduction of 59.7% from baseline to day 84).”
(K. Fitzgerald, [email protected])
Entry of inclisiran into clinical testing brings attention to the new field of oligonucleotide
therapeutics, according to the author of a Perspective article (pp. 4–7): “The [small
interfering RNAs (siRNAs)] consist of two strands, guide and passenger. The guide
strand carries the sequence information necessary for target-gene recognition, while the
passenger strand serves as a prodrug that supports the geometry required for loading
into the RNA-induced silencing complex (RISC). When siRNAs are introduced into the
cells, the guide strand enters the RISC and reprograms the powerful natural mechanism
RNA interference (RNAi), silencing genes on demand. The loaded RISC has a long halflife, and as few as 100 to 200 loaded RISC complexes per cell are sufficient to eliminate
expression of the targeted gene. The importance of this fundamental mechanism is well
recognized — indeed, the two scientists who discovered it, Craig Mello and Andrew Fire,
were awarded the Nobel Prize in 2006.” (A. Khvorova)
Oligonucleotide technology is also being tested with antisense agents, writes the author
of a Clinical Implications of Basic Research article (pp. 86–8). “The advantages of the
targeted delivery strategy are … demonstrated by comparing the results of a pair of
phase 2 studies in which the activity of two antisense oligonucleotides against
apolipoprotein(a), which is expressed in the liver, were compared,” the author explains.
“One of the antisense oligonucleotides was nontargeted, and the second was targeted to
hepatocytes with the use of triantennary [N-acetylgalactosamine]. On the basis of the
reductions in the mean change in circulating levels of apolipoprotein(a) according to
dose, targeted delivery was determined to result in a median effective dose that was one
thirtieth of that associated with nontargeted delivery, which clearly underscored the
potential advantage of the approach.” (A. A. Levin)
Ticagrelor in Symptomatic Peripheral Artery Disease: In 13,885 patients with
symptomatic peripheral artery disease, ticagrelor was not superior to clopidogrel for
reduction of cardiovascular events, and major bleeding rates were similar (pp. 32–40). A
primary efficacy composite end point of adjudicated cardiovascular death, myocardial
infarction, or ischemic stroke occurred in 751 of 6,930 patients (10.8%) receiving
ticagrelor and in 740 of 6,955 (10.6%) receiving clopidogrel (hazard ratio, 1.02; 95%
confidence interval [CI], 0.92 to 1.13; P = 0.65), the investigators report. (M. R. Patel,
[email protected])
>>>PNN NewsWatch
* FDA, now classifying an October recall as Class I, yesterday issued an alert about a
potential link between us of Nurse Assist I.V. Flush Syringes with Burkholderia
cepacia bloodstream infections.
PNN Pharmacotherapy Line is published via e-mail each business day except U.S.
holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201;
571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News
Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail
[email protected] to request missing copies of PNN. Quarterly files archived at
www.PharmacotherapyNewsNetwork.com.
PNN Pharmacotherapy Line
Jan. 6, 2017 * Vol. 24, No. 4
Providing news and information about medications and their proper use
>>>Diabetes Report
Source: Jan. issue and annual standards supplement of Diabetes Care (2017; 40).
2017 Standards of Medical Care in Diabetes: Psychosocial issues have been added
to the ADA’s Standards of Care for 2017, including self-management, mental health,
communication, complications, comorbidities, and life-stage considerations (supplement
1). Several tweaks were made to the pharmacotherapy recommendations, including the
following (Am. Diabetes Assoc.):
* Patients on long-term metformin therapy should have periodic B12 measurements and
supplementation as needed.
* A new section describes newly available biosimilar insulins.
* Empagliflozin or liraglutide are recommended in patients with established
cardiovascular disease to reduce the risk of mortality.
* A figure illustrating antihyperglycemic therapy in type 2 diabetes is updated to
acknowledge the high cost of insulin.
* An algorithm for the use of combination injectable therapy in patients with type 2
diabetes is changed to reflect studies demonstrating the noninferiority of basal insulin
plus glucagon-like peptide 1 receptor agonist versus basal insulin plus rapid-acting
insulin versus two daily injections of premixed insulin, as well as studies demonstrating
the noninferiority of multiple-dose premixed insulin regimens versus basal-bolus therapy.
* New tables show the median costs of noninsulin agents.
Metformin & Gut Microbiome: Clinical data support an emerging hypothesis that use of
metformin “shifts gut microbiota composition through the enrichment of mucin-degrading
Akkermansia muciniphila as well as several [short-chain fatty acid (SCFA)]–producing
microbiota,” researchers report (pp. 54–62). Among 28 patients with type 2 diabetes, half
of whom were taking metformin, and 84 participants without diabetes, these results were
found in clinical tests and gene sequencing of fecal samples: “We found an association
between diabetes and gut microbiota that was modified by metformin use. Compared
with participants without diabetes, participants with diabetes taking metformin had higher
relative abundance of Akkermansia muciniphila, a microbiota known for mucin
degradation, and several gut microbiota known for production of SCFAs, including
Butyrivibrio, Bifidobacterium bifidum, Megasphaera, and an operational taxonomic unit of
Prevotella. In contrast, compared with participants without diabetes, participants with
diabetes not taking metformin had higher relative abundance of Clostridiaceae 02d06
and a distinct operational taxonomic unit of Prevotella and a lower abundance of
Enterococcus casseliflavus.” (J. S. Escobar, [email protected])
Saxagliptin & Renal Outcomes: In the Saxagliptin Assessment of Vascular Outcomes
Recorded in Patients with Diabetes Mellitus–Thrombolysis in Myocardial Infarction 53
(SAVOR-TIMI 53) trial, saxagliptin significantly improved albumin/creatinine ratios
(ACRs) among patients with baseline normoalbuminuria, microalbuminuria, and
macroalbuminuria, an effect that could not be explained by the drug’s glycemic actions
(pp. 69–76). “Treatment with saxagliptin was associated with improvement in and/or less
deterioration in ACR categories from baseline to end of trial (P = 0.021, P < 0.001, and P
= 0.049 for individuals with baseline normoalbuminuria, microalbuminuria, and
macroalbuminuria, respectively),” the authors wrote of the 16,492 study participants. “At
2 years, the difference in mean ACR change between saxagliptin and placebo arms was
−19.3 mg/g (P = 0.033) for estimated glomerular filtration rate (eGFR) >50 mL/min/body
surface area per 1.73 m2 (BSA), −105 mg/g (P = 0.011) for 50 ≥ eGFR ≥ 30
mL/min/BSA, and −245.2 mg/g (P = 0.086) for eGFR <30 mL/min/BSA.…” (I. Raz,
[email protected])
>>>PNN NewsWatch
* After a very quiet beginning of the 2016–17 influenza season, the bug produced its
annual holiday bump in surveillance data during the week before Christmas as
Americans shared a viral gift with other travelers and loved ones. Nationally, 10.4% of
respiratory specimens tested positive for influenza that week, and 9 of the 10 regions in
the U.S. had elevated activity. Remind patients that it’s not too late to get vaccinated and
that peak activity last season was in March.
PNN Pharmacotherapy Line is published via e-mail each business day except U.S.
holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201;
571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News
Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail
[email protected] to request missing copies of PNN. Quarterly files archived at
www.PharmacotherapyNewsNetwork.com.
PNN Pharmacotherapy Line
Jan. 9, 2017 * Vol. 24, No. 5
Providing news and information about medications and their proper use
>>>Lancet Highlights
Source: Jan. 7 issue of Lancet (2017; 389).
Regorafenib in Hepatocellular Carcinoma: In a phase 3 trial of 567 patients with
sorafenib-resistant hepatocellular carcinoma (HCC), regorafenib significantly improved
overall and median survival, researchers report (pp. 56–66). “Regorafenib is the only
systemic treatment shown to provide survival benefit in HCC patients progressing on
sorafenib treatment,” the group concludes based on these study results: “Regorafenib
improved overall survival with a hazard ratio of 0.63 (95% CI 0.50–0.79; one-sided p
<0.0001); median survival was 10.6 months (95% CI 9.1–12.1) for regorafenib versus
7.8 months (6.3–8.8) for placebo. Adverse events were reported in all regorafenib
recipients (374 [100%] of 374) and 179 (93%) of 193 placebo recipients. The most
common clinically relevant grade 3 or 4 treatment-emergent events were hypertension
(57 patients [15%] in the regorafenib group vs nine patients [5%] in the placebo group),
hand–foot skin reaction (47 patients [13%] vs one [1%]), fatigue (34 patients [9%] vs
nine patients [5%]), and diarrhoea (12 patients [3%] vs no patients). Of the 88 deaths
(grade 5 adverse events) reported during the study (50 patients [13%] assigned to
regorafenib and 38 [20%] assigned to placebo), seven (2%) were considered by the
investigator to be related to study drug in the regorafenib group and two (1%) in the
placebo group, including two patients (1%) with hepatic failure in the placebo group.” (J.
Bruix, [email protected])
Atezolizumab in Urothelial Carcinoma: Results of a single-arm, phase 2 trial of the
anti-programmed death-ligand 1 (PD-L1) atezolizumab show improved durable response
rates, survival, and tolerability in 119 previously untreated patients with locally advanced
or metastatic urothelial cancer who were cisplatin ineligible (pp. 67–76): “At 17.2 months’
median follow-up, the objective response rate was 23% (95% CI 16 to 31), the complete
response rate was 9% (n = 11), and 19 of 27 responses were ongoing. Median response
duration was not reached. Responses occurred across all PD-L1 and poor prognostic
factor subgroups. Median progression-free survival was 2.7 months (2.1 to 4.2). Median
overall survival was 15.9 months (10.4 to not estimable). Tumour mutation load was
associated with response. Treatment-related adverse events that occurred in 10% or
more of patients were fatigue (36 [30%] patients), diarrhoea (14 [12%] patients), and
pruritus (13 [11%] patients). One treatment-related death (sepsis) occurred. Nine (8%)
patients had an adverse event leading to treatment discontinuation. Immune-mediated
events occurred in 14 (12%) patients.” (A. V. Balar, [email protected])
>>>BMJ Highlights
Source: Early-release article from BMJ (2017; 354).
“Screen & Treat” in Type 2 Diabetes Prevention: Identification of prediabetes using
the two available screening tests is often inaccurate, a systematic review and metaanalysis shows, indicating “‘screen and treat’ policies alone are unlikely to have
substantial impact on the worsening epidemic of type 2 diabetes” (i6538). Results
indicated that “fasting glucose is specific but not sensitive and HbA1c is neither sensitive
nor specific,” the authors conclude based on these findings: “The final analysis included
49 studies of screening tests (five of which were prevalence studies) and 50 intervention
trials. HbA1c had a mean sensitivity of 0.49 (95% confidence interval 0.40 to 0.58) and
specificity of 0.79 (0.73 to 0.84), for identification of pre-diabetes, though different
studies used different cut-off values. Fasting plasma glucose had a mean sensitivity of
0.25 (0.19 to 0.32) and specificity of 0.94 (0.92 to 0.96). Different measures of glycaemic
abnormality identified different subpopulations (for example, 47%of people with
abnormal HbA1c had no other glycaemic abnormality). Lifestyle interventions were
associated with a 36% (28% to 43%) reduction in relative risk of type 2 diabetes over six
months to six years, attenuating to 20% (8% to 31%) at follow-up in the period after the
trials.” (E. Barry, [email protected])
>>>PNN JournalWatch
* Genetic Polymorphisms and Clopidogrel Efficacy for Acute Ischemic Stroke or
Transient Ischemic Attack, in Circulation, 2017; 135: 21–33. (Y. Wang,
[email protected])
* Treatment of ARDS With Prone Positioning, in Chest, 2017; 151: 215–24. (E. L.
Scholten)
PNN Pharmacotherapy Line is published via e-mail each business day except U.S.
holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201;
571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News
Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail
[email protected] to request missing copies of PNN. Quarterly files archived at
www.PharmacotherapyNewsNetwork.com.
PNN Pharmacotherapy Line
Jan. 10, 2017 * Vol. 24, No. 6
Providing news and information about medications and their proper use
>>>Internal Medicine Report
Source: Jan. issue of JAMA Internal Medicine (2017; 177).
Treating Delirium in Palliative Care: In 247 patients at 11 Australian inpatient hospice
or hospital palliative care units in 2008–14, individualized management and supportive
strategies were significantly better than antipsychotic agents for reducing delirium
symptoms, a study shows (pp. 34–42). Participants, all of whom had life-limiting illness,
received oral risperidone, haloperidol, or placebo solution every 12 hours for 72 hours,
based on symptoms of delirium as measured using the sum of Nursing Delirium
Screening Scale behavioral, communication, and perceptual items, with these results:
“In the primary intention-to-treat analysis, participants in the risperidone arm had delirium
symptom scores that were significantly higher than those among participants in the
placebo arm (on average 0.48 Units higher; 95% CI, 0.09–0.86; P = .02) at study end.
Similarly, for those in the haloperidol arm, delirium symptom scores were on average
0.24 Units higher (95% CI, 0.06–0.42; P = .009) than in the placebo arm. Compared with
placebo, patients in both active arms had more extrapyramidal effects (risperidone, 0.73;
95% CI, 0.09–1.37; P = .03; and haloperidol, 0.79; 95% CI, 0.17–1.41; P = .01).
Participants in the placebo group had better overall survival than those receiving
haloperidol (hazard ratio, 1.73; 95% CI, 1.20–2.50; P = .003), but this was not significant
for placebo vs risperidone (hazard ratio, 1.29; 95% CI, 0.91–1.84; P = .14).” (M. R. Agar)
Experiences with use of antipsychotic agents in patients with dementia may be
instructive for use of the agents in delirium, editorialists write, noting a history of harms
with use of antipsychotic agents for medicating distress (pp. 42–3): “The advertisement
for Thorazine with the white-haired gentleman wielding a cane illustrates that, since their
development, antipsychotic drugs have been seen as useful to treat the distressing
behavioral and psychological symptoms of dementia (BPSD). However, as
manufacturers sought approval to use the newer atypical antipsychotic drugs specifically
for distressing BPSD, it became clear that their use caused an increased risk of death
relative to placebo. In 2005, the US Food and Drug Administration issued a black box
warning regarding the increased risk of mortality associated with the use atypical
antipsychotic drugs to treat BPSD.” (D. T. Maust)
Antihypertensive Medications & Fracture Risk: Compared with other
antihypertensive medications, a thiazide diuretic lowered the risk of hip or pelvic fracture
among 16,622 participants swith mild to moderate hypertension in the Antihypertensive
and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) (pp. 67–76).
Intention-to-treat analysis of data from 1994 through 2006 show these results: “During
the trial, 338 fractures occurred. Participants randomized to receive chlorthalidone vs
amlodipine or lisinopril had a lower risk of fracture on adjusted analyses (hazards ratio
[HR], 0.79; 95% CI, 0.63–0.98; P = .04). Risk of fracture was significantly lower in
participants randomized to receive chlorthalidone vs lisinopril (HR, 0.75; 95% CI, 0.58–
0.98; P = .04) but not significantly different compared with those randomized to receive
amlodipine (HR, 0.82; 95% CI, 0.63–1.08; P = .17). During the entire trial and posttrial
period of follow-up, the cumulative incidence of fractures was nonsignificantly lower in
participants randomized to receive chlorthalidone vs lisinopril or amlodipine (HR, 0.87;
95% CI, 0.74–1.03; P = .10) and vs each medication separately. In sensitivity analyses,
when 1 year after randomization was used as the baseline (to allow for the effects of
medications on bone to take effect), similar results were obtained for in-trial and in-trial
plus posttrial follow-up.” (J. I. Barzilay, [email protected])
These results provide an excellent opportunity for “dodging complexity,” editorialists
write (pp. 77–8). “The large sample size and randomized, masked nature of ALLHAT
greatly mitigate … concerns because … confounders are likely to be balanced between
the groups,” the authors explain. “This is good news for those of us wanting to avoid
complexity because thiazides are also a preferred class for first-line treatment of
hypertension based on lower rates of cardiovascular events observed in ALLHAT and
other trials, as described in American Heart Association/American College of Cardiology
and Joint National Committee 8 guidelines.” (C. S. Colón-Emeric)
PNN Pharmacotherapy Line is published via e-mail each business day except U.S.
holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201;
571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News
Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail
[email protected] to request missing copies of PNN. Quarterly files archived at
www.PharmacotherapyNewsNetwork.com.
PNN Pharmacotherapy Line
Jan. 11, 2017 * Vol. 24, No. 7
Providing news and information about medications and their proper use
>>>JAMA Report
Source: Jan. 10 issue of JAMA (2017; 317).
Etelcalcetide in Secondary Hyperparathyroidism: The intravenous calcimimetic
etelcalcetide was more effective for reducing serum parathyroid hormone (PTH)
concentrations than placebo or orally administered cinacalcet in two trials of patients on
hemodialysis (pp. 146–55, pp. 156–64, G M. Chertow, [email protected]).
Commenting on the trials, editorialists write of “second chances” for improving outcomes
in those with end-stage renal disease (ESRD) (pp. 139–41): “Can nephrologists soon
expect a randomized trial of etelcalcetide with hard clinical end points? Demonstration of
the efficacy of etelcalcetide for improving biochemical end points like PTH and serum
phosphate is the low bar that must be overcome to secure regulatory approval for new
treatments of disordered mineral metabolism in ESRD. This low-cost regulatory pathway
enables more rapid introduction of new agents into ESRD practice but also serves as a
powerful disincentive to conduct costly outcomes trials that are rightfully required in other
therapeutic areas and thereby perpetuates the outcomes trial–deprived culture that
permeates and stifles nephrology. Regulatory authorities should reconsider their
approval processes to incentivize hard end-point trials in ESRD, and the manufacturer of
etelcalcetide should conduct a rigorous second-generation trial to evaluate the effects of
this promising second-generation calcimimetic for reducing mortality and major
cardiovascular events and improving quality of life for patients with ESRD.” (M. Wolf,
[email protected])
Folic Acid for PreventingNeural Tube Defects: Given the mandatory fortification of
foods with folic acid, do women of child-bearing age still need folic acid supplements?
Yes, says the U.S. Preventive Services Task Force (USPSTF) in a recommendation
statement that updates its 2009 conclusion that benefits far outweigh risks (pp. 183–9):
“The USPSTF assessed the balance of the benefits and harms of folic acid
supplementation in women of childbearing age and determined that the net benefit is
substantial. Evidence is adequate that the harms to the mother or infant from folic acid
supplementation taken at the usual doses are no greater than small. Therefore, the
USPSTF reaffirms its 2009 recommendation.” (K. Bibbins-Domingo, [email protected])
Studies conducted before the 1998 initiation of food fortification demonstrate the
effectiveness of the practice, according to authors of USPSTF’s evidence report (pp.
190–203). “Newer postfortification studies have not demonstrated a protective
association but have the potential for misclassification and recall bias, which can
attenuate the measured association of folic acid supplementation with neural tube
defects.” (M. Viswanathan, [email protected])
“While identification of the causal link between folic acid and neural tube defects and the
subsequent reduction in the prevalence of these conditions via folic acid fortification are
remarkable public health successes, the current USPSTF recommendation provides an
important reminder that we have yet to achieve the full benefit of these successes,” a
JAMA Pediatrics writer notes (10.1001/jamapediatrics.2016.4983). “The current
recommendation statement should serve as a catalyst for renewed efforts to develop
and deliver folic acid messages that will translate into further reductions in the population
prevalence of neural tube defects.” (L. E. Mitchell, [email protected])
A JAMA editorialist agrees (pp. 144–5): “The USPSTF recommendation that all women
of childbearing age take folic acid supplements is a prudent one. Ideally, it will educate
all women who are planning or capable of pregnancy to follow this recommendation and
thereby reduce the risk of these severe birth defects in their infants.” (J. L. Mills,
[email protected])
Marijuana Risks in Pregnancy: “Pregnant women and those considering becoming
pregnant should be advised to avoid using marijuana or other cannabinoids either
recreationally or to treat their nausea,” according to Viewpoint authors who note that 29
states and the District of Columbia now allow some form of legal cannabis. (pp. 129–30).
“Physicians and other health care providers in a position to recommend medical
marijuana must be mindful of the possible risks and err on the side of caution by not
recommending this drug for patients who are pregnant.” (E. M. Wargo,
[email protected])
PNN Pharmacotherapy Line is published via e-mail each business day except U.S.
holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201;
571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News
Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail
[email protected] to request missing copies of PNN. Quarterly files archived at
www.PharmacotherapyNewsNetwork.com.
PNN Pharmacotherapy Line
Jan. 13, 2017 * Vol. 24, No. 9
Providing news and information about medications and their proper use
>>>Cardiology Report
Source: Jan. 17 Journal of the Am. College of Cardiology (2017; 69).
Dual Antiplatelet Therapy After CABG: In patients with diabetes after coronary artery
bypass grafting (CABG), routine dual antiplatelet therapy (DAPT) may not be needed,
according to a post-hoc analysis of data from the FREEDOM (Future REvascularization
Evaluation in patients with Diabetes mellitus: Optimal management of Multivessel
disease) trial (pp. 119–27). Comparing patients on aspirin plus thienopyridine or aspirin
monotherapy after CABG, results show: “At 30 days post-CABG, 544 (68.4%) patients
received DAPT and 251 (31.6%) patients received aspirin alone. The median (25th, 75th
percentile) duration of clopidogrel therapy was 0.98 (0.23 to 1.91) years. There was no
significant difference in the 5-year primary composite outcome between DAPT- and
aspirin-treated patients (12.6% vs. 16.0%; adjusted hazard ratio [HR]: 0.83; 95%
confidence interval [CI]: 0.54 to 1.27; p = 0.39). The 5-year primary composite outcomes
were similar for patients receiving DAPT versus aspirin monotherapy respectively, in
subgroups with pre-CABG ACSs (15.2% vs. 16.5%; HR: 1.06; 95% CI: 0.53 to 2.10; p =
0.88) and those with stable angina (11.6% vs. 15.8%; HR: 0.82; 95% CI: 0.50 to 1.343; p
= 0.42).… No treatment-related differences in major bleeding (5.6% vs. 5.7%; HR: 1.00;
95% CI: 0.50 to 1.99; p = 0.99), blood transfusions (4.8% vs. 4.5%; HR: 1.09; 95% CI:
0.51 to 2.34; p = 0.82), or hospitalization for bleeding (2.6% vs. 3.3%; HR: 0.85; 95% CI:
0.34 to 2.17; p = 0.74) were observed between aspirin- and DAPT-treated patients,
respectively.” (S. van Diepen, [email protected])
“Addition, intensification, or prolongation of antiplatelet therapy, although decreasing
ischemic events, increases bleeding complications,” editorialists write (pp. 128–30). “It is
thus not surprising that many surgeons are not prescribing such therapy. Whether
findings from this current study lead to modifications of future guideline
recommendations or impact practice patterns remains to be determined.” (G. N. Levine,
[email protected])
Cangrelor in PCI: For reducing ischemic complications after percutaneous coronary
interventions (PCI), cangrelor is effective with or without concomitant glycoprotein IIb/IIIa
inhibitors, CHAMPION (Cangrelor versus Standard Therapy to Achieve Optimal
Management of Platelet Inhibition) investigators report (pp. 176–85). Patient-level
analysis of 24,902 participants showed the following based on a primary composite
endpoint of all-cause mortality, myocardial infarction, ischemia-driven revascularization,
or stent thrombosis at 48 h after randomization: “Overall, 3,173 patients (12.7%)
received a GPI, most commonly eptifibatide (69.4%).… Rates of the primary composite
endpoint were lower with cangrelor compared with clopidogrel in patients who did (4.9%
vs. 6.5%; odds ratio [OR]: 0.74; 95% confidence interval [CI]: 0.55 to 1.01) or did not
receive a GPI (3.6% vs. 4.4%; OR: 0.82; 95% CI: 0.72 to 0.94; Pint = 0.55). Cangrelor did
not increase the primary safety endpoint, GUSTO-defined severe/life-threatening
bleeding, in patients who did (0.4% vs. 0.5%; OR: 0.71; 95% CI: 0.25 to 1.99) or did not
receive GPIs (0.2% vs. 0.1%; OR: 1.56; 95% CI: 0.80 to 3.04; Pint = 0.21). GPI use was
associated with increased risk of bleeding in both treatment arms.” (D. L. Bhatt,
[email protected])
“Further investigation is needed to better contextualize the role of cangrelor in the setting
of other medications used during PCI,” writes an editorialist (pp. 186–8). “Whether there
is added benefit to using cangrelor with newer antiplatelet agents, such as ticagrelor and
prasugrel, remains unknown. Also, decision making at the point of care may be
challenging without a better accounting of the prognostic significance of the endpoints of
interest.” (S. S. Brar, [email protected])
>>>PNN NewsWatch
* The Biosimilars Forum is critical of an FDA decision to use nonsensical suffixes to
differentiate biosimilars from innovator biologics. In a statement issued yesterday, the
Forum wrote, “Nonmeaningful suffixes will certainly be more difficult for physicians and
patients to recall than meaningful suffixes. Additionally, they will likely lessen the ability
to carefully track the identity of the biologic drug administered to patients, thereby
contrary to the stated purpose of having a suffix to enhance pharmacovigilance.”
* PNN will not be published on Mon., Jan. 16, King Day.
PNN Pharmacotherapy Line is published via e-mail each business day except U.S.
holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201;
571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News
Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail
[email protected] to request missing copies of PNN. Quarterly files archived at
www.PharmacotherapyNewsNetwork.com.
PNN Pharmacotherapy Line
Jan. 17, 2017 * Vol. 24, No. 10
Providing news and information about medications and their proper use
>>>Internal Medicine Report
Source: Jan. 17 issue of and early-online articles from the Annals of Internal Medicine
(2017; 166).
Medication Adherence in Medical Homes: Adherence to medications for common,
high-cost, chronic diseases is higher among patients receiving care in a patient-centered
medical home than in other primary-care settings, a case–control study shows (pp. 81–
8). Retrospective analysis of Aetna claims show these patterns of prescription refills for
patients initiating therapy in 2011–13 for diabetes, hypertension, or hyperlipidemia: “Of
313,765 patients meeting study criteria, 18,611 (5.9%) received care in patient-centered
medical homes. Mean rates of adherence were 64% among medical home patients and
59% among control patients. Among 4,660 matched control and medical home
practices, medication adherence was significantly higher in medical homes (2.2% [95%
CI, 1.5% to 2.9%]). The association between medical homes and better adherence did
not differ significantly by disease state (diabetes, 3.0% [CI, 1.5% to 4.6%]; hypertension,
3.2% [CI, 2.2% to 4.2%]; hyperlipidemia, 1.5% [CI, 0.6% to 2.5%]).” (N. K. Choudhry,
[email protected])
Figuring out what about medical homes helps people take their long-term medications is
the next step in the research process, an editorialist writes (pp. 146–7): “Success in 4
domains will likely be essential for overall success: 1) fostering sustained, trusting, and
collaborative relationships between providers and patients; 2) systems to systematically
monitor patients’ levels of adherence to medications from all prescribers and to identify
barriers to adherence and appropriate strategies to address them; 3) proactive
identification of patients who require higher levels of adherence support; and 4) provision
of necessary support between face-to-face visits.” (M. Heisler)
Managing Osteoarthritis in Primary Care: Among 537 outpatients with symptomatic
hip or knee osteoarthritis, a combined patient/provider intervention at a VA medical
center did not result in statistically significant improvement in disease markers,
compared with usual care, researchers report (10.7326/M16-1245). The patient
intervention, which used telephone communications to focus on weight management,
physical activity, and cognitive behavioral pain management, was combined with
electronic delivery of patient-specific recommendations to providers. Results showed:
“No difference was observed in [Western Ontario and McMaster Universities
Osteoarthritis Index (WOMAC)] score changes from baseline to 12 months in the patient
(−1.5 [95% CI, −5.1 to 2.0]; P = 0.40), provider (2.5 [CI, −0.9 to 5.9]; P = 0.152), or
patient–provider (−0.7 [CI, −4.2 to 2.8]; P = 0.69) intervention groups compared with
usual care. All groups had improvements in WOMAC scores at 12 months (range, −3.7
to −7.7). In addition, no differences were seen in objective physical function or
depressive symptoms at 12 months in any of the intervention groups compared with
usual care.” (K. D. Allen, [email protected])
>>>Lancet Highlights
Source: Jan. 14 issue of Lancet (2017; 389).
Inhaled Corticosteroids in Mild Asthma: Results of the 3-year inhaled Steroid
Treatment As Regular Therapy (START) study show benefits of once-daily, low-dose
budesonide in patients with mild recent-onset asthma, countering assumptions that
corticosteroids should be restricted to those with symptoms on more than 2 days per
week (pp. 157–66). Findings for the 7,138 pediatric and adult study participants suggest
that “treatment recommendations for mild asthma should consider both risk reduction
and symptoms,” the authors conclude. (H. K. Reddel, [email protected])
>>>PNN JournalWatch
* An Evidence-Based Medicine Approach to Antihyperglycemic Therapy in Diabetes
Mellitus to Overcome Overtreatment, in Circulation, 2017; 135: 180–95. (A. N. Makam,
[email protected])
* Pharmacologic Treatment of Hypertension in Adults Aged 60 Years or Older to Higher
Versus Lower Blood Pressure Targets: A Clinical Practice Guideline From the American
College of Physicians and the American Academy of Family Physicians, in Annals of
Internal Medicine, 2017; 166: 10.7326/M16-1785. (A. Qaseem,
[email protected])
* Migraine and Risk of Perioperative Ischemic Stroke and Hospital Readmission:
Hospital Based Registry Study, in BMJ, 2017; 356: i6635. (M. Eikermann,
[email protected])
PNN Pharmacotherapy Line is published via e-mail each business day except U.S.
holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201;
571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News
Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail
[email protected] to request missing copies of PNN. Quarterly files archived at
www.PharmacotherapyNewsNetwork.com.
PNN Pharmacotherapy Line
Jan. 18, 2017 * Vol. 24, No. 11
Providing news and information about medications and their proper use
>>>JAMA Report
Source: Jan. 17 issue of JAMA (2017; 317).
Fungal Infections After Empiric Antifungals in Critical Care: Among critically ill
patients, use of antifungal agents before a definitive diagnosis of invasive fungal
infection (IFI) is associated with lower rates of IFIs but no significant changes in
mortality, according to a JAMA Clinical Evidence Synopsis (pp. 311–2). Noting the low
quality of the evidence in a Cochrane review, the authors conclude: “Clinical practice
guidelines from Infectious Diseases Society of America and European Society of Clinical
Microbiology and Infectious Diseases support the use of antifungal treatment in critically
ill patients administered before definitive diagnosis of IFI in certain circumstances (eg,
patients at risk of IFI). Evidence from this Cochrane review is only partly consistent with
these guidelines because although no association with reduced mortality was found,
there was an association with lower incidence of [IFIs].” (A. Cortegiani,
[email protected])
Revisiting Asthma Diagnoses in Adults: In a study of adults diagnosed with asthma
within the prior 5 years, one-third of participants had no symptoms after medications
were stopped (pp. 269–79). In Canada in 2012–16, a cohort study found these results
after daily asthma medications were weaned and stopped over 4 study visits: “Of 701
participants (mean [SD] age, 51 [16] years; 467 women [67%]), 613 completed the study
and could be conclusively evaluated for a diagnosis of current asthma. Current asthma
was ruled out in 203 of 613 study participants (33.1%; 95% CI, 29.4%–36.8%). Twelve
participants (2.0%) were found to have serious cardiorespiratory conditions that had
been previously misdiagnosed as asthma in the community. After an additional 12
months of follow-up, 181 participants (29.5%; 95% CI, 25.9%–33.1%) continued to
exhibit no clinical or laboratory evidence of asthma. Participants in whom current asthma
was ruled out, compared with those in whom it was confirmed, were less likely to have
undergone testing for airflow limitation in the community at the time of initial diagnosis
(43.8% vs 55.6%, respectively; absolute difference, 11.8%; 95% CI, 2.1%–21.5%).” (S.
D. Aaron, [email protected])
Urban Diabetes in China: Over a 7-year period, a prospective nationwide study of
512,869 adults in China found a higher prevalence of diabetes in urban areas but a
greater excess mortality rate from the disease in rural sections (pp. 280–9). With
recruitment into the study in 2004–08 and follow-up through Jan. 2014, authors gathered
these results for 30,380 adults with diabetes (4.1% of those in rural areas, 8.1% in urban
areas): “During 3.64 million person–years of follow-up, there were 24,909 deaths,
including 3,384 among individuals with diabetes. Compared with adults without diabetes,
individuals with diabetes had a significantly increased risk of all-cause mortality (1,373
vs 646 deaths per 100,000; adjusted RR, 2.00 [95% CI, 1.93–2.08]), which was higher in
rural areas than in urban areas (rural RR, 2.17 [95% CI, 2.07–2.29]; urban RR, 1.83
[95% CI, 1.73–1.94]). Presence of diabetes was associated with increased mortality from
ischemic heart disease (3,287 deaths; RR, 2.40 [95% CI, 2.19–2.63]), stroke (4,444
deaths; RR, 1.98 [95% CI, 1.81–2.17]), chronic liver disease (481 deaths; RR, 2.32 [95%
CI, 1.76–3.06]), infections (425 deaths; RR, 2.29 [95% CI, 1.76–2.99]), and cancer of the
liver (1,325 deaths; RR, 1.54 [95% CI, 1.28–1.86]), pancreas (357 deaths; RR, 1.84
[95% CI, 1.35–2.51]), female breast (217 deaths; RR, 1.84 [95% CI, 1.24–2.74]), and
female reproductive system (210 deaths; RR, 1.81 [95% CI, 1.20–2.74]). For chronic
kidney disease (365 deaths), the RR was higher in rural areas (18.69 [95% CI, 14.22–
24.57]) than in urban areas (6.83 [95% CI, 4.73–9.88]). Among those with diabetes, 10%
of all deaths (16% rural; 4% urban) were due to definite or probable diabetic
ketoacidosis or coma (408 deaths).” (Z. Chen, [email protected])
“In public health, what gets measured gets done,” writes the WHO director-general (pp.
264–6). “The quality of [these] precise measurement[s] … provides confidence that
Chinese authorities will continue to move the country’s health reforms in the right
direction, with results that also improve the prevention and control of diabetes. The
World Health Organization has identified a number of best-buy interventions for diabetes
and other noncommunicable diseases to help countries do so.” (M. Chan,
[email protected])
PNN Pharmacotherapy Line is published via e-mail each business day except U.S.
holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201;
571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News
Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail
[email protected] to request missing copies of PNN. Quarterly files archived at
www.PharmacotherapyNewsNetwork.com.
PNN Pharmacotherapy Line
Jan. 19, 2017 * Vol. 24, No. 12
Providing news and information about medications and their proper use
>>>NEJM Report
Source: Jan. 19 New England Journal of Medicine (2017; 376).
B-Cell Depletion in Relapsing Multiple Sclerosis: Articles report and discuss results
of phase 3 trials of ocrelizumab, which selectively depletes CD20-expressing B cells.
Among 732 patients with primary progressive multiple sclerosis, ocrelizumab produced
lower rates of clinical and MRI progression than placebo (pp. 209–20). The phase 3 trial
compared I.V. ocrelizumab 600 mg and placebo given every 24 weeks for at least 120
weeks or until progression of disability. Rates of progression were 32.9% and 39.3% in
the two respective groups. Adverse effects were more common with active therapy,
including neoplasms in 2.3% and 0.8% of those receiving ocrelizumab and placebo,
respectively. (X. Montalban, [email protected])
The second article finds lower rates of disease activity and progression with ocrelizumab
in two identical, 96-week, phase 3, head-to-head comparisons with interferon beta-1a
(pp. 221–34): “The annualized relapse rate was lower with ocrelizumab than with
interferon beta-1a in trial 1 (0.16 vs. 0.29; 46% lower rate with ocrelizumab; P <0.001)
and in trial 2 (0.16 vs. 0.29; 47% lower rate; P <0.001). In prespecified pooled analyses,
the percentage of patients with disability progression confirmed at 12 weeks was
significantly lower with ocrelizumab than with interferon beta-1a (9.1% vs. 13.6%; hazard
ratio, 0.60; 95% confidence interval [CI], 0.45 to 0.81; P <0.001), as was the percentage
of patients with disability progression confirmed at 24 weeks (6.9% vs. 10.5%; hazard
ratio, 0.60; 95% CI, 0.43 to 0.84; P = 0.003). The mean number of gadolinium-enhancing
lesions per T1-weighted magnetic resonance scan was 0.02 with ocrelizumab versus
0.29 with interferon beta-1a in trial 1 (94% lower number of lesions with ocrelizumab, P
<0.001) and 0.02 versus 0.42 in trial 2 (95% lower number of lesions, P <0.001). The
change in the Multiple Sclerosis Functional Composite score … significantly favored
ocrelizumab over interferon beta-1a in trial 2 (0.28 vs. 0.17, P = 0.004) but not in trial 1
(0.21 vs. 0.17, P = 0.33). Infusion-related reactions occurred in 34.3% of the patients
treated with ocrelizumab. Serious infection occurred in 1.3% of the patients treated with
ocrelizumab and in 2.9% of those treated with interferon beta-1a. Neoplasms occurred in
0.5% of the patients treated with ocrelizumab and in 0.2% of those treated with
interferon beta-1a.” (S. L. Hauser, [email protected])
While “patients with primary progressive multiple sclerosis … are desperately in need of
a therapy, side effects must also be considered,” an editorialist writes (pp. 280–2).
“Although the dreaded complication of other drugs for multiple sclerosis, infection with
JC virus causing progressive multifocal leukoencephalopathy, has not been seen with Bcell depletion in multiple sclerosis to date, there does appear to be a higher-than-normal
risk of herpes reactivation and of neoplasms, especially breast cancer.” (P. A. Calabresi)
Extensively Drug-Resistant Tuberculosis in South Africa: In a tuberculosis-plagued
region of South Africa, extensively drug-resistant (XDR) organisms are spreading
through transmission rather than acquisition secondary to failed treatment, researchers
report (pp. 243–53). This reinforces the importance of efforts to control the epidemic of
drug-resistant tuberculosis through “an increased focus on interrupting transmission,” the
authors conclude. Differentiating between acquired multidrug-resistant (MDR)
tuberculosis strains and the transmitted XDR ones, the investigators report these results
of data gathered in 2011–14 from interviews, medical records, and genetic analysis of
XDR Mycobacterium tuberculosis isolates: “Of the 404 participants, 311 (77%) had HIV
infection; the median CD4+ count was 340 cells per cubic millimeter (interquartile range,
117 to 431). A total of 280 participants (69%) had never received treatment for MDR
tuberculosis. Genotypic analysis in 386 participants revealed that 323 (84%) belonged to
1 of 31 clusters. Clusters ranged from 2 to 14 participants, except for 1 large cluster of
212 participants (55%) with a LAM4/KZN strain. Person-to-person or hospital-based
epidemiologic links were identified in 123 of 404 participants (30%).” (N. R. Gandhi,
[email protected])
>>>PNN NewsWatch
* FDA has released draft guidances on drug/device manufacturers’ communications
with formulary committees and payers.
PNN Pharmacotherapy Line is published via e-mail each business day except U.S.
holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201;
571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News
Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail
[email protected] to request missing copies of PNN. Quarterly files archived at
www.PharmacotherapyNewsNetwork.com.
PNN Pharmacotherapy Line
Jan. 20, 2017 * Vol. 24, No. 13
Providing news and information about medications and their proper use
>>>Infectious Diseases Report
Source: Feb. 1 issue of Clinical Infectious Diseases (2017; 64).
Vancomycin Taper v. Fecal Transplantation in CDI: In a phase 2/3, open-label trial,
30 patients with single acute episodes of recurrent Clostridium difficile infection (CDI),
fecal transplantation (FT) was not significantly different from oral vancomycin taper,
researchers report (pp. 265–71). In Ontario, 14 days of oral vancomycin therapy
followed by either FT or a 6-week taper of vancomycin produced these results: “The
study was terminated at the interim analysis after randomizing 30 patients. Nine of 16
(56.2%) patients who received FT and 5 of 12 (41.7%) in the vancomycin taper group
experienced recurrence of CDI, corresponding with symptom resolution in 43.8% and
58.3%, respectively. Fecal microbiota analysis of 3 successful FT recipients
demonstrated increased diversity. A futility analysis did not support continuing the study.
Adverse events were similar in both groups and uncommon.” (S. S. Hota,
[email protected])
While more evidence is needed to determine whether a “fecal fixation” is justified in
those who see the intervention as “the holy grail for treatment of recurrent CDI,” this
study adds to the evidence supporting vancomycin taper for this condition, editorialists
write (pp. 272–4): “Refinement of [fecal microbiota transplantation (FMT)] to make it a
more acceptable, safe, and more defined product is an area of active research, with at
least 2 products in phase 2/3 clinical trials.… As we go forward, it is clear that welldesigned [randomized controlled trials] of FMT and related products with appropriate
comparator groups conducted in patients with recently identified episodes of multiply
recurrent CDI are required to assess the efficacy of this potentially highly effective
strategy for prevention of CDI recurrence. In the meantime, we have additional evidence
of the efficacy of vancomycin taper/pulse administration as an effective treatment.” (S.
Johnson, [email protected])
>>>Oncology Highlights
Source: Jan. issue of the Journal of Clinical Oncology (2017; 35).
Basket Trials in Oncology: Testing of targeted therapies that may be present in tumors
of different subtypes or sites — “basket trials” — have “scientific goals [that] are typically
more complex and frequently not specified with the precision conventionally used for
clinical trials,” authors write in a Comments and Controversies article (pp. 271–3): “Most
investigators view a basket trial as a series of independent phase II clinical trials. In fact,
the simplest type of basket trial, the evaluation of a single drug targeting a single
mutation in multiple disease sites, presents a much more complex framework than a
conventional evaluation of a single drug in a single disease. We believe that creative
investigation into design options offers the potential to meet the study goals faster, with
fewer patients. Such investigation must recognize the fact that most basket trials
typically aim to answer multiple questions simultaneously. Most importantly, in this
period of transition to precision medicine, our clinical research tools must maintain the
scientific rigor embedded in the traditional clinical trials paradigm, in which hypotheses
are specified precisely and the clinical trial is designed to address these hypotheses.” (A.
Iasonos, [email protected])
>>>PNN NewsWatch
* Plecanatide (Trulance, Synergy Pharmaceuticals) was approved yesterday for
treatment of chronic idiopathic constipation in adult patients. This is the first drug
designed to replicate the function of uroguanylin, a naturally occurring and endogenous
human gastrointestinal peptide that is thought to stimulate fluid secretion, the company
said in a news release. The result of treatment is a stool consistency associated with
more regular bowel function.
* Just in time for Inauguration Day, FDA Commissioner Robert Califf, MD, has
announced formation of the Oncology Center of Excellence, with Richard Pazdur, MD,
as director. Creation of the center makes oncology the first disease area with a
coordinated clinical review of drugs, biologics, and devices across the agency’s three
medical product centers. Talk of a Trump appointment to head the FDA has centered
around nontraditional picks from Silicon Valley. The president-elect has hinted at relaxed
FDA standards for drug approval but has also attacked the pharmaceutical industry
regarding pricing of drug products.
PNN Pharmacotherapy Line is published via e-mail each business day except U.S.
holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201;
571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News
Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail
[email protected] to request missing copies of PNN. Quarterly files archived at
www.PharmacotherapyNewsNetwork.com.
PNN Pharmacotherapy Line
Jan. 23, 2017 * Vol. 24, No. 14
Providing news and information about medications and their proper use
>>>Lancet Highlights
Source: Jan. 21 issue of Lancet (2017; 389).
Atezolizumab in Previously Treated Non-Small-Cell Lung Cancer: In the first
randomized phase 3 study to report results of a programmed death-1 (PD-1)–targeted
therapy, atezolizumab treatment was significantly more effective than docetaxel for
improving overall survival in previously treated patients with squamous or nonsquamous
non-small-cell lung cancer (pp. 255–65). OAK investigators in 31 countries randomized
patients with squamous or nonsquamous non-small-cell lung cancer to atezolizumab or
docetaxel every 3 weeks, with these intention-to-treat (ITT) results in the first 850 of
1,225 enrolled patients: “Overall survival was significantly longer with atezolizumab in
the ITT and PD-L1-expression populations. In the ITT population, overall survival was
improved with atezolizumab compared with docetaxel (median overall survival was 13.8
months [95% CI 11.8–15.7] vs 9.6 months [8.6–11.2]; hazard ratio [HR] 0.73 [95% CI
0.62–0.87], p = 0.0003). Overall survival in the TC1/2/3 or IC1/2/3 population was
improved with atezolizumab (n = 241) compared with docetaxel (n = 222; median overall
survival was 15.7 months [95% CI 12.6–18.0] with atezolizumab vs 10.3 months [8.8–
12.0] with docetaxel; HR 0.74 [95% CI 0.58–0.93]; p = 0.0102). Patients in the PD-L1
low or undetectable subgroup (TC0 and IC0) also had improved survival with
atezolizumab (median overall survival 12.6 months vs 8.9 months; HR 0.75 [95% CI
0.59–0.96]). Overall survival improvement was similar in patients with squamous (HR
0.73 [95% CI 0.54–0.98]; n = 112 in the atezolizumab group and n = 110 in the
docetaxel group) or non-squamous (0.73 [0.60–0.89]; n = 313 and n = 315) histology.
Fewer patients had treatment-related grade 3 or 4 adverse events with atezolizumab (90
[15%] of 609 patients) versus docetaxel (247 [43%] of 578 patients). One treatmentrelated death from a respiratory tract infection was reported in the docetaxel group.” (D.
R. Gandara, [email protected])
Filgotinib in Crohn Disease: In a phase 2 trial of 174 adults with moderate-to-active
Crohn disease, the Janus kinase 1 (JAK1)-selective inhibitor filgotinib induced remission
significantly more often than placebo, researchers report (pp. 266–75). The safety profile
of the new drug was acceptable as well, the study shows, with these results based on
primary endpoint was clinical remission, defined as Crohn’s Disease Activity Index
(CDAI) less than 150 at week 10: “In the intention-to-treat population, 60 (47%) of 128
patients treated with filgotinib 200 mg achieved clinical remission at week 10 versus ten
(23%) of 44 patients treated with placebo (difference 24 percentage points [95% CI 9–
39], p = 0.0077). In a pooled analysis of all periods of filgotinib and placebo exposure
over 20 weeks, serious treatment-emergent adverse effects were reported in 14 (9%) of
152 patients treated with filgotinib and three (4%) of 67 patients treated with placebo.”
(S. Vermeire, [email protected])
>>>BMJ Highlights
Source: Early-release article from BMJ (2017; 354).
RAS Inhibitors in Stable Coronary Artery Disease: For treating patients with stable
coronary artery disease without heart failure, available evidence does not support a
“preferred status” for agents that inhibit the renin–angiotensin system (RASi), authors of
a meta-analysis of 24 trials of 198,275 patients conclude (j4): “RASi reduced
cardiovascular events and death only when compared with placebo but not when
compared with active controls. Even among placebo controlled trials in this study, the
benefit of RASi was mainly seen in trials with higher control event rates but not in those
with lower control event rates.” (S. Bangalore, [email protected])
>>>PNN JournalWatch
* Early Oral Immunotherapy in Peanut-Allergic Preschool Children Is Safe and Highly
Effective, in Journal of Allergy and Clinical Immunology, 2017; 139: 173–81.e8. (A. W.
Burks, [email protected])
* Increased Antiviral Treatment Among Hospitalized Children and Adults With
Laboratory-Confirmed Influenza, 2010–2015, in Clinical Infectious Diseases, 2017; 64:
364–7. (A. P. Campbell, [email protected])
* Hormone-Related Migraine Headaches and Mood Disorders: Treatment with Estrogen
Stabilization, in Pharmacotherapy, 2017; 37: 120–8. (L. J. Cohen,
[email protected])
PNN Pharmacotherapy Line is published via e-mail each business day except U.S.
holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201;
571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News
Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail
[email protected] to request missing copies of PNN. Quarterly files archived at
www.PharmacotherapyNewsNetwork.com.
PNN Pharmacotherapy Line
Jan. 24, 2017 * Vol. 24, No. 15
Providing news and information about medications and their proper use
>>>Geriatrics Report
Source: Jan. issue of the Journal of the American Geriatrics Society (2017; 65).
Hospitalizations & Pharmacists’ Medication Management: In Hawaii, provision of
medication management services by specially trained community and hospital
pharmacists reduced rehospitalizations of high-risk older adults by 38%, yielding a 2.6:1
return on investment, a study shows (pp. 212–9). Working with high-risk individuals from
hospitalization through transition to home and for up to 1 year after discharge,
Pharm2Pharm pharmacists produced these results at six study and five control Hawaiian
hospitals with more than 50 beds: “The predicted, case mix–adjusted medication-related
hospitalization rate of individuals aged 65 and older was 36.5% lower in the
Pharm2Pharm hospitals after implementation than in the nonintervention hospitals (P =
.01). The estimated annualized cost of avoided admissions was $6.6 million. The annual
cost of the pharmacist services for all Pharm2Pharm participants was $1.8 million.” (K. L.
Pellegrin, [email protected])
Expected Benefit of Warfarin in Atrial Fibrillation: Over time, “competing death
events” diminish the expected benefits of warfarin among patients with atrial fibrillation
(AF), according to community-based cohort results from the Anticoagulation and Risk
Factors in Atrial Fibrillation Study (pp. 35–41). Adults diagnosed with nonvalvular AF in
1996–2003—four-fifths of them aged 65 years or older—had these outcomes based on
longitudinal warfarin exposure and rates of thromboembolism and all-cause deaths: “The
rate of death was much higher in the group not taking warfarin (8.1 deaths/100 person–
years (PY)) than in the group taking warfarin (5.5 deaths/100 PY). The cause-specific
HR indicated a large reduction in thromboembolism with warfarin use (adjusted HR =
0.57, 95% confidence interval (CI) = 0.50–0.65), although this association was
substantially attenuated after accounting for competing death events (adjusted HR =
0.87, 95% CI = 0.77–0.99). In analyses limited to 1 year of follow-up, with fewer
competing death events, the results for models that did and did not account for
competing risks were similar.” (J. M. Ashburner, [email protected])
“These results reinforce the growing understanding that, when treating older adults,
providers can no longer consider any disease or condition in isolation from the
individual’s complete profile of health concerns,” editorialists write (pp. 25–6): “There is
general consensus that use of warfarin is effective in preventing stroke among older
adults with AF. At the same time, there is research suggesting that, even in individuals at
high risk of stroke, oral anticoagulants are widely underused. A plausible explanation for
such underuse appears to be that long-term practitioners prioritize concern about the
risk of bleeding over stroke prevention in some older adults with AF. There is also
agreement that use of anticoagulants such as warfarin is most effective in individuals
with high risk of stroke, whereas treatment with aspirin appears to suffice for persons at
lower risk. The marked attenuation of the protective effect of warfarin reported here
provides a new perspective on the decision-making process that providers and older
adults must navigate. In addition to the older adult’s individual likelihood of stroke, the
decision to prescribe anticoagulants must also consider chronic conditions and the
overall risk of death from nonstroke causes.” (T. E. Murphy)
Medication Use After Dementia Diagnosis: In patients with type 2 diabetes, “use of
cardiometabolic medications fell after a diagnosis of dementia, as recommended in
national guidelines,” researchers report (pp. 77–82). The case–control study population
included Kaiser patients in northern California, who had these outcomes following a new
diagnosis of dementia: “After adjustment, the number of chronic medications and the
subset of cardiovascular medications declined after a dementia diagnosis in the overall
cohort and in age-, sex-, and time-matched reference individuals, but the decline was
significantly greater in the group with dementia (0.71 medications fewer than the
reference group, P = .02). The number of diabetes mellitus medications declined in both
groups, but the declines were not statistically different (0.18 medications fewer than the
reference group, P = .008).” (U. Sarkar, [email protected])
PNN Pharmacotherapy Line is published via e-mail each business day except U.S.
holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201;
571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News
Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail
[email protected] to request missing copies of PNN. Quarterly files archived at
www.PharmacotherapyNewsNetwork.com.
PNN Pharmacotherapy Line
Jan. 25, 2017 * Vol. 24, No. 16
Providing news and information about medications and their proper use
>>>JAMA Report
Source: Jan. 24/31 issue of JAMA (2017; 317).
Continuous Glucose Monitoring in Type 1 Diabetes: Two articles and an editorial
examine utility of continuous glucose monitoring (CGM) in adults with type 1 diabetes.
In the DIAMOND randomized clinical trial, adults using multiple daily insulin injections
had significantly better outcomes when they used continuous glucose monitoring (CGM),
compared with usual care (pp. 371–8). Investigators established a primary endpoint of
decreased glycated hemoglobin levels for the 24-week trial, as noted in these results:
“Among the 158 randomized participants (mean age, 48 years [SD, 13]; 44% women;
mean baseline HbA1c level, 8.6% [SD, 0.6%]; and median diabetes duration, 19 years
[interquartile range, 10–31 years]), 155 (98%) completed the study. In the CGM group,
93% used CGM 6 d/wk or more in month 6. Mean HbA1c reduction from baseline was
1.1% at 12 weeks and 1.0% at 24 weeks in the CGM group and 0.5% and 0.4%,
respectively, in the control group (repeated-measures model P < .001). At 24 weeks, the
adjusted treatment-group difference in mean change in HbA1c level from baseline was –
0.6% (95% CI, –0.8% to –0.3%; P < .001). Median duration of hypoglycemia at less than
<70 mg/dL was 43 min/d (IQR, 27–69) in the CGM group vs 80 min/d (IQR, 36–111) in
the control group (P = .002). Severe hypoglycemia events occurred in 2 participants in
each group.” (R. W. Beck, [email protected])
Similar results come from the GOLD randomized clinical trial, a 26-week comparison of
CGM with usual care (pp. 379–87): “Among 161 randomized participants, mean age was
43.7 years, 45.3% were women, and mean HbA1c was 8.6% (70 mmol/mol). A total of
142 participants had follow-up data in both treatment periods. Mean HbA1c was 7.92%
(63 mmol/mol) during continuous glucose monitoring use and 8.35% (68 mmol/mol)
during conventional treatment (mean difference, −0.43% [95% CI, −0.57% to −0.29%] or
−4.7 [−6.3 to −3.1 mmol/mol]; P < .001). Of 19 secondary end points comprising
psychosocial and various glycemic measures, 6 met the hierarchical testing criteria of
statistical significance, favoring continuous glucose monitoring compared with
conventional treatment. Five patients in the conventional treatment group and 1 patient
in the continuous glucose monitoring group had severe hypoglycemia. During washout
when patients used conventional therapy, 7 patients had severe hypoglycemia.” (M.
Lind, [email protected])
These trials show benefits from CGM and that adult patients with type 1 diabetes like
this approach, editorialists write (pp. 363–4): “CGM limits hyperglycemia and
hypoglycemia, improves diabetes control, and reduces glucose variability. These studies
also show that selected patients favored this method of monitoring. Additional clinical
trials are needed to determine the long-term effect of CGM and whether this approach
translates to improved health outcomes and to determine the potential utility of real-time
CGM for patients with type 1 diabetes encountered in usual clinical practice and in
patients with type 2 diabetes who require insulin injections.” (M. B. Davidson,
[email protected])
Gut Bacteria, Obesity & Diabetes: “It is plausible that the human microbiome may
affect the risk of obesity and type 2 diabetes and other diseases such as atherosclerosis,
and that manipulations of the microbiome might reduce that risk,” writes authors of a
Commentary article (pp. 355–6): “However, biomedical science is a long way from
proving either proposition. Dissecting the possible role of the microbiome in these and
other diseases will be a great challenge, because (1) human genes influence the
composition of the gut microbiota, (2) microbial genes influence the expression of human
genes, (3) the metabolism of some gut microbes influences the metabolism of other gut
microbes, and (4) diet influences both the microbiota and (possibly) the expression of
human genes. In short, human genes, microbial genes, and diet share a complicated set
of interdependencies.” (A. L. Komaroff, [email protected])
>>>PNN NewsWatch
* Hospira is voluntarily recalling one lot of Vancomycin Hydrochloride for Injection,
USP (Lot 591053A, Exp. 11/1/17), to the hospital/retail level due to confirmed presence
of particulate matter, FDA said.
PNN Pharmacotherapy Line is published via e-mail each business day except U.S.
holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201;
571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News
Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail
[email protected] to request missing copies of PNN. Quarterly files archived at
www.PharmacotherapyNewsNetwork.com.
PNN Pharmacotherapy Line
Jan. 26, 2017 * Vol. 24, No. 17
Providing news and information about medications and their proper use
>>>NEJM Report
Source: Jan. 26 issue of the New England Journal of Medicine (2017; 376).
Bezlotoxumab for Recurrent Clostridium difficile Infection: In the phase 3 MODIFY I
and MODIFY II trials, the antitoxin monoclonal antibody bezlotoxumab was associated
with a substantially lower rate of recurrent Clostridium difficile infection than placebo
without producing additional adverse effects, researchers report (pp. 305–17). Addition
of a second monoclonal, actoxumab, had no added effect, as shown in these results: “In
both trials, the rate of recurrent C. difficile infection was significantly lower with
bezlotoxumab alone than with placebo (MODIFY I: 17% [67 of 386] vs. 28% [109 of
395]; adjusted difference, −10.1 percentage points; 95% confidence interval [CI], −15.9
to −4.3; P <0.001; MODIFY II: 16% [62 of 395] vs. 26% [97 of 378]; adjusted difference,
−9.9 percentage points; 95% CI, −15.5 to −4.3; P <0.001) and was significantly lower
with actoxumab plus bezlotoxumab than with placebo (MODIFY I: 16% [61 of 383] vs.
28% [109 of 395]; adjusted difference, −11.6 percentage points; 95% CI, −17.4 to −5.9;
P <0.001; MODIFY II: 15% [58 of 390] vs. 26% [97 of 378]; adjusted difference, −10.7
percentage points; 95% CI, −16.4 to −5.1; P <0.001). In prespecified subgroup analyses
(combined data set), rates of recurrent infection were lower in both groups that received
bezlotoxumab than in the placebo group in subpopulations at high risk for recurrent
infection or for an adverse outcome. The rates of initial clinical cure were 80% with
bezlotoxumab alone, 73% with actoxumab plus bezlotoxumab, and 80% with placebo;
the rates of sustained cure (initial clinical cure without recurrent infection in 12 weeks)
were 64%, 58%, and 54%, respectively. The rates of adverse events were similar among
these groups; the most common events were diarrhea and nausea.” (M. H. Wilcox,
[email protected])
“Bezlotoxumab is a new, now-FDA-approved anti–C. difficile agent that has proved
effective in reducing the rate of first post-treatment relapses of C. difficile infection,”
writes an editorialist (pp. 381–2). “However, uptake by clinicians will vary on the basis of
cost and assessments of relapse risk in association with this drug as compared with the
alternative options.” (J. G. Bartlett)
Recombinant Vesicular Stomatitis Virus Ebola Vaccine: Phase 1 trials of an Ebola
vaccine candidate support further evaluation “for preexposure prophylaxis and suggest
that a second dose may boost antibody responses,” rVSV∆G-ZEBOV-GP investigators
conclude (pp. 330–41). The attenuated, replication-competent, recombinant vesicular
stomatitis virus (rVSV)–based vaccine candidate was tested in 39 adults at each of two
sites received one of three doses of the vaccine; volunteers at one site received a
second dose at day 28. Results showed: “The most common adverse events were
injection-site pain, fatigue, myalgia, and headache. Transient rVSV viremia was noted in
all the vaccine recipients after dose 1. The rates of adverse events and viremia were
lower after the second dose than after the first dose. By day 28, all the vaccine recipients
had seroconversion as assessed by an enzyme-linked immunosorbent assay (ELISA)
against the glycoprotein of the ZEBOV-Kikwit strain. At day 28, geometric mean titers of
antibodies against ZEBOV glycoprotein were higher in the groups that received 20
million PFU or 100 million PFU than in the group that received 3 million PFU, as
assessed by ELISA and by pseudovirion neutralization assay. A second dose at 28 days
after dose 1 significantly increased antibody titers at day 56, but the effect was
diminished at 6 months.” (J. A. Regules, [email protected])
Treating Metastatic Renal-Cell Carcinoma: Additional progress against metastatic
renal cell carcinoma will require “new drugs with new targets and mechanisms of action,”
review authors conclude (pp. 354–66). “Although more than 14,000 patients die from
kidney cancer each year, we have seen considerable progress in the systemic treatment
of metastatic renal-cell carcinoma in the past 20 years. Researchers have achieved a
better understanding of the pathogenesis of the most common type of renal-cell
carcinoma, clear-cell renal-cell carcinoma. This understanding has led to new agents,
expanded treatment options, and increased rates of survival.” (T. K. Choueiri,
[email protected])
PNN Pharmacotherapy Line is published via e-mail each business day except U.S.
holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201;
571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News
Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail
[email protected] to request missing copies of PNN. Quarterly files archived at
www.PharmacotherapyNewsNetwork.com.
PNN Pharmacotherapy Line
Jan. 27, 2017 * Vol. 24, No. 18
Providing news and information about medications and their proper use
>>>Diabetes Care Report
Source: Feb. issue of Diabetes Care (2017; 40).
Adverse Pancreatic Reactions to Gliptins: Two studies and a commentary examine
the link between gliptin use and adverse pancreatic outcomes.
In the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS), rates of
pancreatitis and pancreatic cancer were statistically similar between sitagliptin and
placebo groups, researchers report (pp. 164–70). Prospective data on 14,671
participants followed for 3 years showed these patterns: “Baseline differences were
minimal between participants confirmed to have no pancreatic events, acute
pancreatitis, or pancreatic cancer. Among those participants randomized to receive
sitagliptin, 23 (0.3%) (vs. 12 randomized to receive placebo [0.2%]) had pancreatitis
(hazard ratio 1.93 [95% CI 0.96–3.88], P = 0.065; 0.107 vs. 0.056/100 patient–years),
with 25 versus 17 events, respectively. Severe pancreatitis (two fatal) occurred in four
individuals allocated to receive sitagliptin. Cases of pancreatic cancer were numerically
fewer with sitagliptin (9 [0.1%]) versus placebo (14 [0.2%]) (hazard ratio 0.66 [95% CI
0.28–1.51], P = 0.32; 0.042 vs. 0.066 events/100 patient–years). Meta-analysis with two
other DPP-4i cardiovascular outcome studies showed an increased risk for acute
pancreatitis (risk ratio 1.78 [95% CI 1.13–2.81], P = 0.01) and no significant effect for
pancreatic cancer (risk ratio 0.54 [95% CI 0.28–1.04], P = 0.07).” (J. B. Buse,
[email protected])
Combining TECOS data with those from the SAVOR-TIMI 53 (saxagliptin) and
EXAMINE (alogliptin) trials, a significant risk of pancreatitis is evident, a second study
shows (pp. 284–6). A random-effects model meta-analysis of data on 18,238 gliptintreated and 18,157 placebo-treated patients showed these results: “The incidence of
acute pancreatitis was significantly increased in the gliptin-treated patients when
compared with the control groups (odds ratio 1.79 [95% CI 1.13–2.82], P = 0.013). The
difference in the absolute risk was small (0.13%).” (I. Tkác, [email protected])
“DPP-4 inhibitors are well-established agents, and their benefits clearly outweigh the
risks,” Commentary authors conclude (pp. 161–3). “Acute pancreatitis is real, but its
frequency is very low to impede the generalized use of DPP-4 inhibitors unless more
efficacious agents are preferred. Can we identify people at increased risk for developing
DPP-4 inhibitor–related pancreatitis? For those with a history of pancreatitis, avoiding
these drugs is a sensible recommendation. However, avoiding its use in subjects with
risk factors for pancreatitis may sound justified but solid data supporting such a strategy
is lacking. Amylase and lipase levels can be mildly elevated with incretin-based
therapies, but the levels fluctuate to a large extent and therefore the positive predictive
value of an increased level seems so low that this cannot be used to identify people at
risk. Thus, we can conclude that pancreatitis is an established but rare side effect of
DPP-4 inhibitors that occurs at a very low frequency. We should inform patients on this
potential side effect, and in people on DPP-4 inhibitors having even mild gastrointestinal
symptoms suggestive of pancreatitis, it would be justified to measure pancreatic
enzymes and appropriate to perform an abdominal ultrasound to exclude gallstones. On
the basis of the evidence so far, perhaps in some patients when gallstones are present
(even if asymptomatic) and/or when lipase levels are >3 times normal (even if
fluctuating), there may be enough basis to consider replacing an incretin-based agent
used and consider an alternative therapy.” (J. H. DeVries, [email protected])
Oral Diabetic Medications & HIV Infections: While a longitudinal cohort study shows
that effectiveness of oral antidiabetic medications is similar in patients with and without
HIV infection, data indicate a poorer response among the black and Hispanic patients
who make up a large portion of those with the virus (pp. 218–25). The study included
2,454 HIV-infected and 8,892 HIV-uninfected veterans who initiated oral diabetes
medications (metformin in half of patients, sulfonylurea in 49%, thiazolidinediones in 1%)
between 1999 and 2010. Results showed: “Black and Hispanic patients had a poorer
response to therapy compared with white patients, with a relative increase in HbA1c level
of 0.16% (95% CI 0.08, 0.24) [1.7 mmol/mol (0.9, 2.6)] (P <0.001) and 0.25% (0.11,
0.39) [2.7 mmol/mol (1.2, 4.3)] (P = 0.001), respectively.” (J. H. Han,
[email protected])
PNN Pharmacotherapy Line is published via e-mail each business day except U.S.
holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201;
571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News
Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail
[email protected] to request missing copies of PNN. Quarterly files archived at
www.PharmacotherapyNewsNetwork.com.
PNN Pharmacotherapy Line
Jan. 30, 2017 * Vol. 24, No. 19
Providing news and information about medications and their proper use
>>>Lancet Highlights
Source: Jan. 28 issue of Lancet (2017; 389).
Bionic Pancreas in Type 1 Diabetes: Compared with conventional and sensoraugmented insulin pump therapy in 43 patients, a bihormonal bionic pancreas provided
superior glycemic regulation using only the person’s weight, a study shows (pp. 369–80).
At four U.S. sites, adult volunteers with type 1 diabetes were randomized to the bionic
device or pump therapy for 11 days and then crossed over to the alternative therapy.
Participants continued all normal activities, and the bionic pancreas provided both insulin
and glucagon. Results for 39 participants completing the study showed the following:
“The mean [continuous glucose monitoring (CGM)] glucose concentration was 7.8
mmol/L (SD 0.6) in the bionic pancreas period versus 9.0 mmol/L (1.6) in the comparator
period (difference 1.1 mmol/L, 95% CI 0.7–1.6; p <0.0001), and the mean time with
CGM glucose concentration less than 3.3 mmol/L was 0.6% (0.6) in the bionic pancreas
period versus 1.9% (1.7) in the comparator period (difference 1.3%, 95% CI 0.8–1.8; p
<0.0001). The mean nausea score on the Visual Analogue Scale (score 0–10) was
greater during the bionic pancreas period (0.52 [SD 0.83]) than in the comparator period
(0.05 [0.17]; difference 0.47, 95% CI 0.21–0.73; p = 0.0024). Body mass and laboratory
parameters did not differ between periods. There were no serious or unexpected
adverse events in the bionic pancreas period of the study.” (S. J. Russell,
[email protected])
>>>BMJ Highlights
Source: Early-release articles from BMJ (2017; 354).
Thyroid in Subclinical Hypothyroidism of Pregnancy: Among 5,405 pregnant women
with subclinical hypothyroidism whose experiences were recorded in a large U.S.
administrative database, thyroid hormone treatment reduced the risk of pregnancy loss,
a study shows, particularly in those with pretreatment levels of thyroid stimulating
hormone (TSH) in the 4.1–10 mIU/L range (i6865). However, the authors add, other
pregnancy-related adverse outcomes were more common among those receiving
treatment, including preterm delivery, gestational diabetes, and pre-eclampsia. (R. G.
McCoy, [email protected])
Atosiban v. Fenoterol as Uterine Relaxant: In 830 pregnant women undergoing
external cephalic version (ECV) for breech presentation, the beta-mimetic fenoterol was
more effective 30 minutes after the procedure than the oxytocin receptor antagonist
atosiban, but neither agent yielded significant improvements at delivery, researchers
report (i6773): “Cephalic position 30 minutes after ECV occurred significantly less in the
atosiban group than in the fenoterol group (34% v 40%, relative risk 0.73, 95%
confidence interval 0.55 to 0.93). Presentation at birth was cephalic in 35% (n = 139) of
the atosiban group and 40% (n = 166) of the fenoterol group (0.86, 0.72 to 1.03), and
caesarean delivery was performed in 60% (n = 240) of women in the atosiban group and
55% (n = 218) in the fenoterol group (1.09, 0.96 to 1.20). No significant differences were
found in neonatal outcomes or drug related adverse events.” (J. Velzel, [email protected])
>>>PNN NewsWatch
* Homeopathic teething tablets contain inconsistent and sometimes much-higher-thanlabeled amounts of belladonna, FDA said on Friday. The manufacturer of Hyland’s
homeopathic teething products, Standard Homeopathic Company, has not agreed to
conduct a recall, but FDA said it recommends that consumers stop using the products.
“The body’s response to belladonna in children under 2 years of age is unpredictable
and puts them at unnecessary risk,” said Janet Woodcock, MD, director of the FDA’s
Center for Drug Evaluation and Research. ”We recommend that parents and caregivers
not give these homeopathic teething tablets to children and seek advice from their health
care professional for safe alternatives.” The announcement expands on a Sept. FDA
alert and a Nov. recall by another manufacturer.
>>>PNN JournalWatch
* Review: Frontiers of Antifibrotic Therapy in Systemic Sclerosis, in Arthritis &
Rheumatology, 2017; 69: 257–67. (J. H. W. Distler, [email protected])
* Gout and Risk of Fracture in Women: A Prospective Cohort Study, in Arthritis &
Rheumatology, 2017; 69: 422–8. (J. Paik, [email protected])
PNN Pharmacotherapy Line is published via e-mail each business day except U.S.
holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201;
571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News
Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail
[email protected] to request missing copies of PNN. Quarterly files archived at
www.PharmacotherapyNewsNetwork.com.
PNN Pharmacotherapy Line
Jan. 31, 2017 * Vol. 24, No. 20
Providing news and information about medications and their proper use
>>>Health Affairs Report
Source: Jan. issue of Health Affairs, a theme issue on Coverage Expansion,
Accountable Care, and More, and online blogs (2017; 36).
ACA Replacement Bill: An Affordable Care Act (ACA) repeal-and-replace bill
introduced recently by Republican Senators is built around maintaining popular ACA
features, shifting decisions to the states, and pushing use of Roth HSAs as a subsidy
mechanism (Jan. 24 blog). The Patient Freedom Act of 2017 (PFA) would selectively
repeal most of the ACA that dealt with insurance reform and affordability but would give
states the options of maintaining the ACA in their states, adopt a different approach
based on subsidized Roth HSAs, or reject reform altogether. Noting that PFA is even
more complex than ACA, the blog author concludes: “It has become increasingly clear in
recent days that Republicans are trying to find a way to couple ACA repeal with ACA
replacement. The PFA is an attempt to build a replacement plan on Republican
principles of devolution of responsibility to the states and deregulation, but in a way that
might appeal to some Democrats. The bill, however, appears to have been rushed into
legislative language without adequate consideration of how it would actually work and
what it would cost. It may form a basis for discussion, but it is not ready for enactment.”
(T. Jost)
People Newly Insured In 2014: More than one-half of those gaining health insurance in
2014 were long-term uninsured individuals who had been without coverage for 3 years
or more, researchers report (pp. 16–20). Examining the effects of the Affordable Care
Act as reflected in data for 2013–14 from the National Health Interview Survey (NHIS),
the investigators found “that 18.0 percent of nonelderly adults were uninsured in 2013,
with over half of them (9.4 percent) uninsured for more than three years. The
uninsurance rate fell 4.2 percentage points (from 18.0 percent to 13.9 percent) between
2013 and 2014. The percentage of adults uninsured for more than three years fell 2.2
percentage points (from 9.4 percent to 7.1 percent), compared to declines of 0.7
percentage point and 1.1 percentage points among the short- and medium-term
uninsured, respectively.” The authors conclude, “Since those who have been uninsured
for a long time might not be in the habit of using health care, it will be important to
examine the impacts of premium and cost-sharing subsidies on those eligible for
subsidized coverage under the ACA, and the extent to which members of this population
are able to access appropriate health care providers.” (S. L. Decker,
[email protected])
Opioid Withdrawal Without Help: “The medical system is organized in a way that
makes it quite difficult for physicians to live up to their withdrawal care responsibility,”
writes an author who went through a difficult withdrawal after using opioid analgesics
during the aftermath of a major motorcycle accident (pp. 182–5). “The plastic surgeon
who had been managing my prescriptions eventually apologized and admitted that he
simply had not known how to deal with opioid dependence. I hope that he committed to
learning more after this experience.
“My goal is not, however, to change one doctor’s view about what he owes his patients.
Instead, I want to start a broader conversation about physician responsibility for opioidrelated harms, as well as the systemic forces that make it easier or harder for physicians
to recognize and discharge their responsibilities. Opioid withdrawal isn’t minor. It’s not
‘just temporary’ or ‘the price to be paid’ for pain relief. It’s not morally innocuous. The
moments that I was in withdrawal—all of the thousands of moments of genuine
suffering—were the worst of my life. That kind of suffering matters, and its seriousness
needs to be reflected in the way we deal with prescription opioids.” (T. N. Rieder,
[email protected])
ACA Repeal & the Opioid Epidemic: “As our country grapples with an ‘unprecedented
opioid epidemic,’ Congress is taking steps to take away an important tool to fight it — the
Affordable Care Act (ACA),” blog authors write (Jan. 30 blog). “Millions of people will
lose health coverage, including comprehensive behavioral health and [substance use
disorder (SUD)] benefits through Medicaid. People remaining covered in the individual
and small group markets will lose benefits for SUD related services such as behavioral
health services, preventive screenings, and prescription drugs.” (L. Clemans-Cope)
PNN Pharmacotherapy Line is published via e-mail each business day except U.S.
holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201;
571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News
Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail
[email protected] to request missing copies of PNN. Quarterly files archived at
www.PharmacotherapyNewsNetwork.com.
PNN Pharmacotherapy Line
Feb. 1, 2017 * Vol. 24, No. 21
Providing news and information about medications and their proper use
>>>Internal Medicine Report
Source: Online-first articles from JAMA Internal Medicine (2017; 177).
Language Barriers & Antidiabetic Medication Adherence: Among Latinos with
limited–English proficiency (LEP), control of diabetes improved when they changed to
language-concordant primary care providers (PCPs), researchers report
(10.1001/jamainternmed.2016.8648). The Kaiser study tracked 1,605 LEP Latino
patients who preferred language Spanish and compared outcomes among those who
changed PCPs in 2007–13: “There was a significant net improvement in glycemic and
LDL control among patients who switched from language-discordant PCPs to
concordant PCPs relative to those who switched from one discordant PCP to another
discordant PCP. After adjustment and accounting for secular trends, the prevalence of
glycemic control increased by 10% (95% CI, 2% to 17%; P = .01), poor glycemic control
decreased by 4% (95% CI, −10% to 2%; P = .16) and LDL control increased by 9% (95%
CI, 1% to 17%; P = .03). No significant changes were observed in [systolic blood
pressure] control. Prevalence of LDL control increased 15% (95% CI, 7% to 24%;
P <.001) among LEP Latinos who switched from concordant to discordant PCPs. Risk
factor control did not worsen following a PCP switch in any group.” (A. J. Karter,
[email protected])
A second study shows that factors beyond language concordance are reducing
adherence among Latino patients with diabetes (10.1001/jamainternmed.2016.8653).
Observational data from 2006 to 2012 in a large integrated health care delivery system
led investigators to this conclusion: “Nonadherence to newly prescribed diabetes
medications is substantially greater among Latino than white patients, even among
English-speaking Latino patients. Limited English proficiency Latino patients are more
likely to be nonadherent than English-speaking Latino patients independent of the
Spanish-language fluency of their physicians. Interventions beyond access to
interpreters or patient–physician language concordance will be required to improve
medication adherence among Latino patients with diabetes.” (A. Fernández,
[email protected])
“As the US health care system evolves to more accountable care organizations with
integrated health systems, care of the most vulnerable must be prioritized,” editorialists
write (10.1001/jamainternmed.2016.8661). “Latinos with LEP who have diabetes
represent such a population, as evidenced not only by their language status but by their
socioeconomic disadvantage. There is a need to integrate greater granularity on social
determinants into the medical record to provide more precision patient–clinician
interactions. Metrics for our health care system need to include an equity outcome that
sets a high bar for the most vulnerable patients. Healthcare outcomes of LEP Latinos
with diabetes would be an excellent system measure of health equity.” (E. J. PérezStable, [email protected])
High Drug Prices Despite Generic Competition: The case of Duexis — an ibuprofen–
famotidine combination whose monthly wholesale price increased from $158 to $2061 in
2012–16 — provides lessons learned about high prices despite generic competition
(10.1001/jamainternmed.2016.8423): “First, the states and the federal government
should consider banning specialty pharmacies or other third parties from preparing or
submitting prior authorization forms or other medical necessity paperwork; this is the
responsibility of the physician who prescribes the medication. This practice undermines
the intent of utilization controls and raises concerns about patient privacy. Second,
states should consider markedly restricting the use of copay assistance programs,
particularly since the majority of drug coupons are for brand-name medications for which
lower-cost therapeutics are available. Third, better federal regulation and oversight of
charity organizations that provide financial assistance to patients is needed. For
example, contributions to such organizations from manufacturers should not be allowed
for diseases treated by a single drug, because manufacturers can effectively ensure that
donations will be spent only on copay assistance for their products. To preserve the
long-term financial stability of the health care system, the use of medications that
provide high value to patients should be the priority, not high-priced drugs with generic
alternatives.” (J. S. Ross, [email protected])
PNN Pharmacotherapy Line is published via e-mail each business day except U.S.
holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201;
571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News
Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail
[email protected] to request missing copies of PNN. Quarterly files archived at
www.PharmacotherapyNewsNetwork.com.
PNN Pharmacotherapy Line
Feb. 2, 2017 * Vol. 24, No. 22
Providing news and information about medications and their proper use
>>>NEJM Report
Source: Feb. 2 New England Journal of Medicine (2017; 376).
Radiation & Antiandrogen Therapy in Recurrent Prostate Cancer: Patients with
prostate cancer lived longer and had fewer metastases when antiandrogen therapy was
provided for 24 months following salvage radiation therapy, a study shows (pp. 417–28).
Among 760 men with T2- or T3-stage tumors in 1998–2003, radiation plus bicalutamide
150 mg daily or placebo for 24 months yielded these results following prostatectomy with
lymphadenectomy: “The median follow-up among the surviving patients was 13 years.
The actuarial rate of overall survival at 12 years was 76.3% in the bicalutamide group, as
compared with 71.3% in the placebo group (hazard ratio for death, 0.77; 95% confidence
interval, 0.59 to 0.99; P = 0.04). The 12-year incidence of death from prostate cancer, as
assessed by means of central review, was 5.8% in the bicalutamide group, as compared
with 13.4% in the placebo group (P <0.001). The cumulative incidence of metastatic
prostate cancer at 12 years was 14.5% in the bicalutamide group, as compared with
23.0% in the placebo group (P = 0.005). The incidence of late adverse events
associated with radiation therapy was similar in the two groups. Gynecomastia was
recorded in 69.7% of the patients in the bicalutamide group, as compared with 10.9% of
those in the placebo group (P <0.001).” (W. U. Shipley, [email protected])
“This remarkable contribution by the National Clinical Trials Network of the National
Cancer Institute shows the importance of randomized clinical trials with very long followup,” writes an editorialist (pp. 484–5). “Studies that incorporate interventions without
proprietary intellectual property (e.g., surgery or radiation therapy) or pharmaceutical
agents whose patents often expire before the study is completed can be achieved only
with the use of this invaluable national resource.” (I. M. Thompson, Jr.)
Crizanlizumab in Sickle Cell Disease: Pain episodes and adverse events occurred
less frequently in patients with sickle cell disease who received crizanlizumab, compared
with placebo, researchers report (pp. 429–39). The drug, an antibody against the
adhesion molecule P-selectin, was given in low and high doses in a phase 2 trial of 198
patients. Results of 14 intravenous infusions over a 52-week period were as follows:
“The median rate of crises per year was 1.63 with high-dose crizanlizumab versus 2.98
with placebo (indicating a 45.3% lower rate with high-dose crizanlizumab, P = 0.01). The
median time to the first crisis was significantly longer with high-dose crizanlizumab than
with placebo (4.07 vs. 1.38 months, P = 0.001), as was the median time to the second
crisis (10.32 vs. 5.09 months, P = 0.02). The median rate of uncomplicated crises per
year was 1.08 with high-dose crizanlizumab, as compared with 2.91 with placebo
(indicating a 62.9% lower rate with high-dose crizanlizumab, P = 0.02). Adverse events
that occurred in 10% or more of the patients in either active-treatment group and at a
frequency that was at least twice as high as that in the placebo group were arthralgia,
diarrhea, pruritus, vomiting, and chest pain.” (K. I. Ataga, [email protected])
An editorialist supports use of crizanlizumab along with hydroxyurea in management of
sickle cell disease (pp. 485–7): “Lacking a magical ‘silver bullet’ that would increase fetal
hemoglobin in each sickle erythrocyte sufficiently to stop the polymerization of sickle
hemoglobin or one that would completely normalize blood flow and prevent sickle vasoocclusion, a polypharmaceutical approach that is focused on different aspects of the
pathophysiology of sickle cell disease seems to be the most practical near-term
approach. Most experts agree that hydroxyurea should be given to nearly all patients,
starting very early in life. Added to this treatment might be an antiadhesive therapy that
also should be taken for life and ideally started in childhood.” (M. H. Steinberg)
>>>PNN NewsWatch
* Does the pharmaceutical industry want a deregulated FDA as Pres. Trump seems to
be proposing? Not necessarily, according to an article on the STAT News website. “In a
world where the FDA approved medications on scant data, pharma’s wealthiest giants
could litter the market with dubious new drugs — and flood the airwaves with ads touting
them,” reporter Mike Reddy writes. “That would crowd out upstart competitors and kill a
whole industry’s incentive to try new things.”
PNN Pharmacotherapy Line is published via e-mail each business day except U.S.
holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201;
571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News
Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail
[email protected] to request missing copies of PNN. Quarterly files archived at
www.PharmacotherapyNewsNetwork.com.
PNN Pharmacotherapy Line
Feb. 3, 2017 * Vol. 24, No. 23
Providing news and information about medications and their proper use
>>>Pediatrics Report
Source: Feb. issue of Pediatrics (2017; 139).
Protection From Single-Dose Meningococcal Vaccine: Effectiveness of the
meningococcal (groups A, C, W, and Y) polysaccharide diphtheria toxoid conjugate
vaccine (MenACWY-D) wanes 3 to <8 years following a single dose, according to a
study that led the Advisory Committee on Immunization Practices to recommend a
booster dose (10.1542/peds.2016-2193). In a case–control study conducted in 2006–13,
these patterns of vaccine effectiveness (VE) and duration of protection were identified:
“Serogroup C accounted for 88 (49%), serogroup Y 80 (44%), and serogroup W 13 (7%)
of enrolled cases. Thirty-six (20%) cases and 87 (44%) controls received MenACWY-D.
The overall VE estimate 0 to 8 years postvaccination was 69% (51% to 80%); VE was
79% (49% to 91%) at <1 year, 69% (44% to 83%) at 1 to <3 years, and 61% (25% to
79%) at 3 to <8 years. VE was 77% (57% to 88%) against serogroup C and 51% (1% to
76%) against serogroup Y.” (A. C. Cohn)
E-cigarette Use by Adolescents: In the first of two studies of electronic cigarettes and
other electronic vapor products (EVPs), researchers report other risky behaviors by
adolescents who use EVP alone or with cigarette smoking (10.1542/peds.2016-2450).
Among 15,624 students in the 2015 national Youth Risk Behavior Survey, health risk
behaviors based on nonuse, cigarette smoking only, EVP use only, and dual use were
as follows: “In 2015, 73.5% of high school students did not smoke cigarettes or use
EVPs, 3.2% smoked cigarettes only, 15.8% used EVPs only, and 7.5% were dual users.
Frequency of cigarette smoking and EVP use was greater among dual users than
cigarette-only smokers and EVP-only users. Cigarette-only smokers, EVP-only users,
and dual users were more likely than nonusers to engage in several injury, violence, and
substance use behaviors; have ≥4 lifetime sexual partners; be currently sexually active;
and drink soda ≥3 times/day. Only dual users were more likely than nonusers not to use
a condom at last sexual intercourse.” (Z. Demissie)
Adolescents using e-cigarettes would not likely have smoked regular cigarettes, an
analysis of the 2004–2014 National Youth Tobacco Surveys shows (10.1542/peds.2016-
2193): “Youth cigarette smoking decreased linearly between 2004 and 2014 (P = .009
for ever smoking and P = .05 for current smoking), with no significant change in this
trend after 2009 (P = .57 and .23). Based on the psychosocial model of smoking,
including demographic characteristics, willingness to wear clothing with a tobacco logo,
living with a smoker, likelihood of smoking in the next year, likelihood of smoking
cigarettes from a friend, and use of tobacco products other than cigarettes or ecigarettes, the model categorized <25% of current e-cigarette–only users (between
11.0% in 2012 and 23.1% in 2013) as current smokers.” (L. M. Dutra)
Dietary Supplements & Young Teens: Creatine and testosterone products are being
pushed to boy high school athletes by health food store employees, a study shows
(10.1542/peds.2016-1257). Contacted by telephone by research personnel posing as
15-year-olds, staff at 244 U.S. health food stores made these recommendations when
asked about supplements: “A total of 67.2% (164/244) of sales attendants recommended
creatine: 38.5% (94/244) recommended creatine without prompting, and an additional
28.7% (70/244) recommended creatine after being asked specifically about it. A total of
9.8% (24/244) of sales attendants recommended a testosterone booster. Regarding
availability for sale, 74.2% (181/244) of sales attendants stated a 15-year-old was
allowed to purchase creatine, whereas 41.4% (101/244) stated one could purchase a
testosterone booster.” The authors conclude, “In response to these findings,
pediatricians should inform their teenage patients, especially athletes, about safe,
healthy methods to improve athletic performance and discourage them from using
creatine or testosterone boosters. Retailers and state legislatures should also consider
banning the sale of these products to minors.” (R. Milanaik, [email protected])
>>>PNN NewsWatch
* FDA yesterday warned consumers about two dietary supplements containing
undeclared drugs: Lean Extreme Max, which contains sibutramine (pulled from the
market in 2010 for safety reasons), and Goldreallas XXX, a sexual enhancement
product containing sildenafil.
PNN Pharmacotherapy Line is published via e-mail each business day except U.S.
holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201;
571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News
Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail
[email protected] to request missing copies of PNN. Quarterly files archived at
www.PharmacotherapyNewsNetwork.com.
PNN Pharmacotherapy Line
Feb. 6, 2017 * Vol. 24, No. 24
Providing news and information about medications and their proper use
>>>Lancet Highlights
Source: Feb. 4 issue of Lancet (2017; 389).
Treatment of Newly Diagnosed Myeloma Without Intent for Stem-Cell Transplant:
Addition of bortezomib to lenalidomide and dexamethasone significantly improved
progression-free and overall survival of patients with newly diagnosed myeloma and no
intent for immediate autologous stem-cell transplant, researchers report (pp. 519–27). In
the phase 3 SWOG S0777 trial, open-label bortezomib with lenalidomide and
dexamethasone (VRd group) or lenalidomide and dexamethasone alone (Rd group)
produced these outcomes in 473 randomly assigned patients: “Median progression-free
survival was significantly improved in the VRd group (43 months vs 30 months in the Rd
group; stratified hazard ratio [HR] 0.712, 96% CI 0.56–0.906; one-sided p value 0.0018).
The median overall survival was also significantly improved in the VRd group (75 months
vs 64 months in the Rd group, HR 0.709, 95% CI 0.524–0.959; two-sided p value 0.025).
The rates of overall response (partial response or better) were 82% (176/216) in the VRd
group and 72% (153/214) in the Rd group, and 16% (34/216) and 8% (18/214) of
patients who were assessable for response in these respective groups had a complete
response or better. Adverse events of grade 3 or higher were reported in 198 (82%) of
241 patients in the VRd group and 169 (75%) of 226 patients in the Rd group; 55 (23%)
and 22 (10%) patients discontinued induction treatment because of adverse events,
respectively. There were no treatment-related deaths in the Rd group, and two in the
VRd group.” (B. G. M. Durie, [email protected])
Intensified Methotrexate in Plaque-Type Psoriasis: Compared with placebo, an
intensified subcutaneous methotrexate dosing schedule produced a favorable 52-week
risk–benefit profile in 120 patients with moderate-to-severe plaque-type psoriasis, the
METOP trial shows (pp. 528–37). The phase 3 trial included patients who had been
diagnosed at least 6 months and were methotrexate-naive. Starting doses of 17.5
mg/week with escalation to 22.5 mg/week permitted after 8 weeks of therapy produced
these findings: “At week 16, a [Psoriasis Area and Severity Index] 75 response was
achieved in 37 (41%) patients in the methotrexate group compared with three (10%)
patients in the placebo group (relative risk 3.93, 95% CI 1.31–11.81; p = 0.0026).
Subcutaneous methotrexate was generally well tolerated; no patients died or had
serious infections, malignancies, or major adverse cardiovascular events. Serious
adverse events were recorded in three (3%) patients who received methotrexate for the
full 52 week treatment period.” (K. Reich, [email protected])
>>>BMJ Highlights
Source: Early-release article from BMJ (2017; 354).
Treatment of WHO Group II Anovulation: For first-line treatment of women with WHO
group II anovulation who wish to conceive, clomiphene plus metformin are superior to
clomiphene alone in terms of ovulation and pregnancy, according to a systematic review
and meta-analysis of 57 trials of 8,082 women (j138): “All pharmacological treatments
were superior to placebo or no intervention in terms of pregnancy and ovulation.
Compared with clomiphene alone, both letrozole and the combination of clomiphene and
metformin showed higher pregnancy rates (odds ratio 1.58, 95% confidence interval
1.25 to 2.00; 1.81, 1.35 to 2.42; respectively) and ovulation rates (1.99, 1.38 to 2.87;
1.55, 1.02 to 2.36; respectively). Letrozole led to higher live birth rates when compared
with clomiphene alone (1.67, 1.11 to 2.49). Both letrozole and metformin led to lower
multiple pregnancy rates compared with clomiphene alone (0.46, 0.23 to 0.92; 0.22, 0.05
to 0.92; respectively).” (R. Wang, [email protected])
>>>PNN NewsWatch
* FDA warned last week of rare but serious allergic reactions with skin antiseptic
products containing chlorhexidine gluconate. The agency is requesting that
manufacturers add a warning about this risk to products’ Drug Facts labels.
>>>PNN JournalWatch
* Atrial Fibrillation and Ventricular Arrhythmias: Sex Differences in Electrophysiology,
Epidemiology, Clinical Presentation, and Clinical Outcomes, in Circulation, 2017; 135:
593–608. (A. M. Gillis, [email protected])
* Bleeding Disorders in Congenital Syndromes, in Pediatrics, 2017; 139: e20154360. (S.
N. Sarangi)
PNN Pharmacotherapy Line is published via e-mail each business day except U.S.
holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201;
571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News
Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail
[email protected] to request missing copies of PNN. Quarterly files archived at
www.PharmacotherapyNewsNetwork.com.
PNN Pharmacotherapy Line
Feb. 7, 2017 * Vol. 24, No. 25
Providing news and information about medications and their proper use
>>>Internal Medicine Report
Source: Feb. 7 issue of the Annals of Internal Medicine (2017; 166).
High-Risk Prescribing & Dual Health System Use: As reported in PNN when the this
research was first released (Dec. 6), U.S. veterans with dementia who have access to
both VA and outside services are at high risk of potentially unsafe medication (PUM)
prescribing (pp. 157–63). A retrospective cohort study of VA and Medicare Part D data
shows these patterns of prescribing among 75,829 veterans with dementia based on
HEDIS high-risk medication in older adults (PUM-HEDIS), any daily exposure to
prescriptions with a cumulative Anticholinergic Cognitive Burden (ACB) score of 3 or
higher (PUM-ACB), any antipsychotic prescription (PUM-antipsychotic), and any PUM
exposure (any-PUM): “Compared with VA-only users, dual users had more than double
the odds of exposure to any-PUM (odds ratio [OR], 2.2 [95% CI, 2.2 to 2.3]), PUMHEDIS (OR, 2.4 [CI, 2.2 to 2.8]), and PUM-ACB (OR, 2.1 [CI, 2.0 to 2.2]). The odds of
PUM-antipsychotic exposure were also greater in dual users (OR, 1.5 [CI, 1.4 to 1.6]).
Dual users had an adjusted average of 44.1 additional days of any-PUM exposure (CI,
37.2 to 45.0 days).” (J. M. Thorpe, [email protected])
Noting that the VA pharmacy system is “perfectly designed to achieve the outcomes it
gets,” an editorialist writes (pp. 221–2): “Thorpe and colleagues note that the VA system
has a robust integrated pharmacy and medical record system available in all of the VA
health care settings—a system clearly built to achieve better outcomes. Yet when using
3 indicators of unsafe medications among veterans with dementia, the researchers
found that approximately 4 of every 10 VA-only users still received potentially harmful
medications. Anticholinergic medications were the most commonly prescribed drugs but
have long been known to be potentially harmful for elderly persons. The Office of
Inspector General of the U.S. Department of Health and Human Services has shown
that the leading cause of adverse events in hospitals and skilled nursing facilities is
related to medications, many of which induce delirium due to their anticholinergic
properties. Yet we as a profession continue to prescribe these medications for our
elderly patients. Again, the prioritization of choice holds us back from building a better
system.” (D. R. Gifford, [email protected])
Discharge Thresholds in Acute Decompensated Heart Failure: Reacting to a
systematic review of discharge natriuretic peptides (NPs) thresholds in hospitalized
patients with acute decompensated heart failure (HF) (pp. 180–90; C. A. Umscheid,
[email protected]), editorialists describe the difficulty in generating
sufficient evidence to determine the utility of these biomarkers in real-world practice (pp.
223–4): “For one, it is not clear whether patients who do not achieve target NP levels
during hospitalization fail to do so due to inadequate treatment (in either intensity or
duration) or because their underlying HF is too severe to respond adequately to
standard interventions. The former suggests that a strategy focused on intensifying
therapy with a ‘discharge goal’ of achieving a specific NP target would likely be
beneficial. In the latter case, such efforts are unlikely to be fruitful, other than simply
identifying patients at the highest risk. It is unclear whether all admitted patients with HF
would be risk-stratified in a similar manner by NP levels. Inclusion of admitted patients
with de novo HF reduces the overall risk of the cohort. In addition, it is not clear what
‘intensified treatment’ in the face of failure to achieve NP goals should entail—more
diuretics? Higher doses of neurohormonal drugs or vasodilators? Longer length of stay
or intensified postdischarge follow-up? At present, our limited options for treating
hospitalized patients with HF significantly limit our ability to intensify therapy even in
patients identified as being at higher risk.” (D. J. Whellan, [email protected])
Metformin in Chronic Diseases: Metformin use in patients with diabetes plus moderate
to severe chronic kidney disease (CKD), congestive heart failure (CHF), or chronic liver
disease (CLD) with hepatic impairment improves outcomes, a systematic review shows
(pp. 191–200): “Metformin use is associated with reduced all-cause mortality in patients
with CKD, CHF, or CLD with hepatic impairment, and with fewer heart failure
readmissions in patients with CKD or CHF.” (M. J. Crowley,
[email protected])
PNN Pharmacotherapy Line is published via e-mail each business day except U.S.
holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201;
571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News
Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail
[email protected] to request missing copies of PNN. Quarterly files archived at
www.PharmacotherapyNewsNetwork.com.
PNN Pharmacotherapy Line
Feb. 8, 2017 * Vol. 24, No. 26
Providing news and information about medications and their proper use
>>>JAMA Report
Source: Feb. 7 issue of JAMA (2017; 317).
Treatment of Pituitary Adenomas: Dopamine agonists are first-line therapy for
prolactinomas, review authors conclude (pp. 516–24). Other pituitary adenomas initially
require surgery followed by medical therapy only when not cured, they write, adding
these details: “Prolactinomas account for 32% to 66% of adenomas and present with
amenorrhea, loss of libido, galactorrhea, and infertility in women and loss of libido,
erectile dysfunction, and infertility in men; they are generally treated with the dopamine
agonists cabergoline and bromocriptine. Growth hormone–secreting tumors account for
8% to 16% of tumors and usually present with enlargement of the lips, tongue, nose,
hands, and feet and are diagnosed by elevated insulin-like growth factor 1 levels and
growth hormone levels; initial treatment is surgical. Medical therapy with somatostatin
analogues, cabergoline, and pegvisomant is often also needed. Adrenocorticotropic
hormone (ACTH)–secreting tumors account for 2% to 6% of adenomas and are
associated with obesity, hypertension, diabetes, and other morbidity. Measurement of a
late-night salivary cortisol level is the best screening test but petrosal sinus sampling for
ACTH may be necessary to distinguish a pituitary from an ectopic source. The primary
treatment of Cushing disease (hypercortisolism due to ACTH-producing adenomas,
which is the cause in approximately 65% of the cases of hypercortisolism) is adenoma
resection and medical therapies including ketoconazole, mifepristone, and pasireotide.
Hyperthyroidism due to thyroid-stimulating hormone–secreting tumors accounts for 1%
of tumors and is treated with surgery and somatostatin analogues if not surgically cured.
Clinically nonfunctioning adenomas account for 15% to 54% of adenomas and present
with mass effects; surgery is generally required, although incidentally found tumors can
be followed if they are asymptomatic.” (M. E. Molitch, [email protected])
e-Discontinuation: “Prescribers need to be able to e-discontinue prescriptions, just as
easily as they can e-prescribe them,” Viewpoint authors write (pp. 469–70): “ CancelRx
was first defined by the National Council for Prescription Drug Programs and was
published as part of the SCRIPT standard for e-prescribing in the Federal Register by
the Centers for Medicare & Medicaid Services in 2010. However, this approach was not
incorporated into the ‘meaningful use’ program for electronic health record (EHR)
incentive payments, which might have encouraged uptake. Changes to meaningful use
under the Medicare Access and CHIP Reauthorization Act of 2015 (MACRA) included
rules that required EHRs to include the ability to cancel prescriptions and other features
of the SCRIPT 10.6 standard.…
“Adding e-discontinuation functionality has the potential to help reduce medication errors
and take fuller advantage of e-prescribing technology.” (S. Fischer, [email protected])
Global Vaccine Injury Compensation: “Establishing a global compensation system
could build confidence in the processes that lead to the development of vaccines
deployed in low-resource settings, relieve vaccine manufacturers of liability concerns
that impede vaccine investments, and facilitate effective responses to global public
health threats like Ebola and Zika,” according to authors of a Viewpoint article that
reviews three models for addressing vaccine injury (pp. 471–2). After discussing
approaches in which patients or manufacturers bear the costs of injuries, the authors
write: “The third approach, a no-fault compensation system for adverse events attributed
to vaccination, balances these competing principles. Under a no-fault vaccine injury
compensation system, governments compensate individuals who are harmed by
properly manufactured vaccines instead of requiring them to use legal or other
processes against manufacturers. A no-fault system acknowledges that a community
that promotes immunization, knowing individuals will be injured, must share the burden
of the cost of injuries. This approach also acknowledges that manufacturers are a critical
part of vaccine access and that they must have a basic level of economic certainty. It
fulfills the utilitarian and communitarian expectations of a democratic society. Yet nofault compensation systems for vaccine injury prevail in only 19 jurisdictions worldwide
including the United States.” (S. F. Halabi, [email protected])
PNN Pharmacotherapy Line is published via e-mail each business day except U.S.
holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201;
571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News
Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail
[email protected] to request missing copies of PNN. Quarterly files archived at
www.PharmacotherapyNewsNetwork.com.
PNN Pharmacotherapy Line
Feb. 9, 2017 * Vol. 24, No. 27
Providing news and information about medications and their proper use
>>>NEJM Report
Source: Feb. 9 issue of the New England Journal of Medicine (2017; 376).
Thromboprophylaxis After Knee Arthroscopy/Casting: Use of low-molecular-weight
heparins for a few days after knee arthroscopy or for the full duration of lower-leg casting
is not supported by results of the POT-KAST and POT-CAST trials (pp. 515–25).
Compared with no anticoagulation, prophylactic doses of low-molecular-weight heparin
for 8 days after arthroscopy in the POT-KAST trial or during the full period of casting
immobilization in the POT-CAST trial produced these results: “In the POT-KAST trial,
1,543 patients underwent randomization, of whom 1,451 were included in the intentionto-treat population. Venous thromboembolism occurred in 5 of the 731 patients (0.7%) in
the treatment group and in 3 of the 720 patients (0.4%) in the control group (relative risk,
1.6; 95% confidence interval [CI], 0.4 to 6.8; absolute difference in risk, 0.3 percentage
points; 95% CI, −0.6 to 1.2). Major bleeding occurred in 1 patient (0.1%) in the treatment
group and in 1 (0.1%) in the control group (absolute difference in risk, 0 percentage
points; 95% CI, −0.6 to 0.7). In the POT-CAST trial, 1,519 patients underwent
randomization, of whom 1,435 were included in the intention-to-treat population. Venous
thromboembolism occurred in 10 of the 719 patients (1.4%) in the treatment group and
in 13 of the 716 patients (1.8%) in the control group (relative risk, 0.8; 95% CI, 0.3 to 1.7;
absolute difference in risk, −0.4 percentage points; 95% CI, −1.8 to 1.0). No major
bleeding events occurred. In both trials, the most common adverse event was infection.”
(S. C. Cannegieter, [email protected])
Despite these findings, clinicians will likely consider it prudent to anticoagulate some
higher-risk patients during and following knee arthroscopy, an editorialist writes, adding
that the real question could be whether the patient really needs the procedure (pp. 576–
7): “There is no indication to routinely treat all patients undergoing knee arthroscopy or
lower-leg casting with prophylactic anticoagulation. For patients at increased risk for
venous thromboembolism, the use of some prophylactic treatment makes intuitive sense
but is not evidence-based. The appropriate prevention strategy to consider for these
patients — including the type of drug, dose, and duration of treatment — is unknown.
Given the large number of arthroscopic knee surgeries and the reported overall limited
benefit of these procedures in diminishing pain and improving physical function, another
effective strategy to consider in the prevention of venous thromboembolism is a critical
reevaluation as to which patients truly need arthroscopic knee surgery.” (S. Moll)
Red-State Medicaid Expansions & ACA Repeal/Reform: Even in GOP-leaning “red
states,” the benefits of Medicaid expansion of benefits under the Affordable Care Act
(ACA) are associated with overall support for the controversial law, results of a four-state
survey show (e7). Compared with Texas — where Medicaid was not expanded — lowincome individuals residing in Arkansas, Kentucky, and Louisiana felt that overall the law
helped rather than hurt them personally. “Of course, a person’s sense of whether he or
she has been helped by the law is inherently subjective and may be influenced by social
desirability bias, political partisanship, and numerous other factors,” the authors write.
“So what lessons can be drawn from subjective evaluations such as these? In part, the
results are useful evidence that even in the most conservative region in the country,
many people report substantial benefits from the law and are willing to directly credit the
ACA for those changes. These subjective valuations are consistent with the findings of
multiple other studies that used more traditional evaluative approaches and have shown
large gains in access to care and affordability from Medicaid expansion.” (B. D.
Sommers)
>>>PNN NewsWatch
* Citing presence of particulate matter, Exela Pharma Sciences, in association with
marketer X-Gen Pharmaceuticals, is voluntarily recalling lot number PLND1613 of
Ibuprofen Lysine Injection, 20 mg /2 mL (10 mg/mL), vials to the hospital or user level,
FDA said yesterday.
* FDA also notes on its website the recall of Kingsway Trading’s Well Balance
Xanthium & Siler Combo (Bi Yan Pian) batches 130401 and 150201 because they
contain ephedra alkaloids.
PNN Pharmacotherapy Line is published via e-mail each business day except U.S.
holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201;
571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News
Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail
[email protected] to request missing copies of PNN. Quarterly files archived at
www.PharmacotherapyNewsNetwork.com.
PNN Pharmacotherapy Line
Feb. 10, 2017 * Vol. 24, No. 28
Providing news and information about medications and their proper use
>>>Cardiology Report
Source: Feb. issue of the Journal of the American College of Cardiology (2017; 69).
Aspirin Formulation & Resistance in Type 2 Diabetes: Aspirin resistance in patients
with type 2 diabetes is frequently the result of incomplete bioavailability of enteric
formulations, according to a 40-patient, triple-crossover study (doi
10.1016/j.jacc.2016.11.050). Participants received plain aspirin 325 mg, delayedrelease, enteric-coated (EC) aspirin, and a modified-release lipid-based aspirin (PL2200)
in separate phases of the trial. Antiplatelet activity as measured by the rate and extent of
inhibition of serum thromboxane B2 (TXB2) generation showed these patterns: “The rate
of aspirin nonresponsiveness was 15.8%, 8.1%, and 52.8% for plain aspirin, PL2200,
and EC aspirin, respectively (p < 0.001 for both comparisons vs. EC aspirin; p = 0.30 for
comparison between plain aspirin and PL2200). Similarly, 56% of EC aspirin–treated
subjects had serum TXB2 levels >3.1 ng/ml, compared with 18% and 11% of subjects
after administration of plain aspirin and PL2200 (p < 0.0001). Compared with findings for
plain aspirin and PL2200, this high rate of nonresponsiveness with EC aspirin was
associated with lower exposure to acetylsalicylic acid (63% and 70% lower geometric
mean maximum plasma concentration [Cmax] and 77% and 82% lower AUC0–t [area
under the curve from time 0 to the last time measured]) and 66% and 72% lower
maximum decrease of TXB2, with marked interindividual variability.” (D. L. Bhatt,
[email protected])
In patients without diabetes, high patient weight can also contribute to aspirin
nonresponsiveness, an editorialist adds (doi 10.1016/j.jacc.2016.11.049). “Together,
these data suggest that diabetes and obesity are independent and possibly additive
determinants of poor aspirin responsiveness, limiting the duration and/or degree of
platelet COX-1 suppression, and possibly requiring different dosing strategies, well
beyond the uncertain effects of aspirin formulations.” (C. Patrono,
[email protected])
>>>Chest Highlights
Source: Feb. issue of Chest (2017; 151).
Glycopyrrolate/Formoterol Metered Dose Inhaler in COPD: In two phase 3 trials, a
novel glycopyrrolate [GP]/formoterol [FF] 18/9.6-µg (GFF) metered dose inhaler (MDI)
formulated using the Co-Suspension Delivery Technology was superior to placebo and
the components administered separately in a total of 3,718 patients with moderate-tovery severe COPD, PINNACLE-1 and -2 researchers report (pp. 340–57): “At week 24,
differences in change from baseline in the morning predose trough FEV1 for GFF MDI
vs placebo MDI, GP MDI, and FF MDI were 150 mL, 59 mL, and 64 mL in PINNACLE-1
(all P < .0001) and 103 mL, 54 mL, and 56 mL in PINNACLE-2 (all P < .001),
respectively. There were no significant safety findings (incidence of adverse events was
similar between treatment arms).” (F. J. Martinez)
>>>PNN NewsWatch
* FDA yesterday approved the corticosteroid deflazacort (Emflaza, Marathon
Pharmaceuticals) to treat patients age 5 years and older with the rare genetic disorder
Duchenne muscular dystrophy. This is the first FDA approval of any corticosteroid to
treat patients with this condition, which causes progressive muscle deterioration and
weakness, and the first approval of deflazacort for any use in the United States, the
agency said.
* CareFusion is recalling the Alaris Syringe Pump because of a faulty Air-In-Line (AIL)
sensor, which may generate a false alarm and cause the syringe pump to stop supplying
the infusion to the patient, FDA said.
* Tom Price, MD, congressman from Georgia, was approved early this morning as Pres.
Trump’s Secretary of Health and Human Services in a 52–47 party-line vote, STAT news
reports. As a former practicing orthopedic surgeon, Price brings a unique outlook on
Medicare and Medicaid policies to the position. He has been a staunch opponent of the
Affordable Care Act, which the GOP plans to repeal or modify. Price is a member of a
“conservative, fringe medical group,” the Washington Post reports. The article said the
Association of American Physicians and Surgeons is opposed to Medicare and
mandatory vaccinations; the article has a link to a Price video from the group’s 2011
annual meeting in which he said quality is a “buzzword” used by “Washington
bureaucrats and the left … to disrupt [the] patient–family–physician relationship.”
PNN Pharmacotherapy Line is published via e-mail each business day except U.S.
holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201;
571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News
Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail
[email protected] to request missing copies of PNN. Quarterly files archived at
www.PharmacotherapyNewsNetwork.com.
PNN Pharmacotherapy Line
Feb. 13, 2017 * Vol. 24, No. 29
Providing news and information about medications and their proper use
>>>Lancet Highlights
Source: Feb. 11 issue of Lancet (2017; 389).
Thrombolytic Removal of Intraventricular Hemorrhage: In 500 patients with severe
stroke caused by intraventricular hemorrhage and with a routine extraventricular drain,
irrigation with alteplase did not improve functional outcomes but appeared to be safe, a
study shows (pp. 603–11). Based on results obtained in 2009–15, the investigators
conclude, “Protocol-based use of alteplase with extraventricular drain seems safe.
Future investigation is needed to determine whether a greater frequency of complete
intraventricular haemorrhage removal via alteplase produces gains in functional status.”
(D. F. Hanley, [email protected])
Masitinib for Severely Symptomatic Indolent Systemic Mastocytosis: In a phase 3
trial of adults with severely symptomatic indolent or smouldering systemic mastocytosis,
a myeloid neoplasm, masitinib is an effective and well tolerated (pp. 612–20). The KIT
and LYN kinase inhibitor was compared with placebo using a dose-minimization design
based on severe symptoms of the lifelong disorder, with these results: “Between Feb 19,
2009, and July 15, 2015, 135 patients were randomly assigned to masitinib (n = 71) or
placebo (n = 64). By 24 weeks, masitinib was associated with a cumulative response of
18.7% in the primary endpoint (122.6 responses of 656.5 possible responses [weighted
generalised estimating equation]) compared with 7.4% for placebo (48.9 of 656.5;
difference 11.3%; odds ratio 3.6; 95% CI 1.2–10.8; p = 0.0076). Frequent severe
adverse events (>4% difference from placebo) were diarrhoea (eight [11%] of 70 in the
masitinib group vs one [2%] of 63 in the placebo group), rash (four [6%] vs none), and
asthenia (four [6%] vs one [2%]). The most frequent serious adverse events were
diarrhoea (three patients [4%] vs one [2%]) and urticaria (two [3%] vs none), and no lifethreatening toxicities occurred. One patient in the placebo group died (unrelated to study
treatment).” (O. Hermine, [email protected])
>>>BMJ Highlights
Source: Early-release article from BMJ (2017; 354).
Reduced-Dose Anticoagulants in Atrial Fibrillation: In a study of apixaban 2.5 mg,
dabigatran 110 mg, and rivaroxaban 15 mg compared with warfarin, a nonsignificant
statistical trend showed possible poorer efficacy with apixaban and better safety results
with dabigatran, researchers report (j510). Using individual data from three Danish
nationwide registries, the investigators determined: “Among 55,644 patients with atrial
fibrillation who met inclusion criteria, the cohort was distributed according to treatment:
apixaban n = 4,400; dabigatran n = 8,875; rivaroxaban n = 3,476; warfarin n = 38,893.
The overall mean age was 73.9 (SD 12.7), ranging from a mean of 71.0 (warfarin) to
83.9 (apixaban). During one year of follow-up, apixaban was associated with higher
(weighted) event rate of ischaemic stroke/systemic embolism (4.8%), while dabigatran,
rivaroxaban, and warfarin had event rates of 3.3%, 3.5%, and 3.7%, respectively. In the
comparison between a non-vitamin K antagonist oral anticoagulant and warfarin in the
inverse probability of treatment weighted analyses and investigation of the effectiveness
outcome, the hazard ratios were 1.19 (95% confidence interval 0.95 to 1.49) for
apixaban, 0.89 (0.77 to 1.03) for dabigatran, and 0.89 (0.69 to 1.16) for rivaroxaban. For
the principal safety outcome versus warfarin, the hazard ratios were 0.96 (0.73 to 1.27)
for apixaban, 0.80 (0.70 to 0.92) for dabigatran, and 1.06 (0.87 to 1.29) for rivaroxaban.”
(T. B. Larsen, [email protected])
>>>PNN JournalWatch
* Riociguat: Mode of Action and Clinical Development in Pulmonary Hypertension, in
Chest, 2017; 151: 468–80. (H-A Ghofrani)
* Intrathecal Amphotericin B: A 60-Year Experience in Treating Coccidioidal Meningitis,
in Clinical Infectious Diseases, 2017; 64: 519–24. (E. J. C. Goldstein)
* Antineoplastic Treatment of Advanced-Stage Non–Small-Cell Lung Cancer: Treatment,
Survival, and Spending (2000 to 2011), in Journal of Clinical Oncology, 2017; 35: 529–
35. (C. J. Bradley, [email protected])
* Acute Asthma, Prognosis, and Treatment, in Journal of Allergy and Clinical
Immunology, 2017; 139: 438–47. (J. E. Fergeson, [email protected])
* Don’t Pass the Salt: Evidence to Support Avoidance of High Salt Intake in CKD, in
American Journal of Kidney Diseases, 2017; 69: 175–8. (A. K. Leonberg-Yoo,
[email protected])
PNN Pharmacotherapy Line is published via e-mail each business day except U.S.
holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201;
571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News
Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail
[email protected] to request missing copies of PNN. Quarterly files archived at
www.PharmacotherapyNewsNetwork.com.
PNN Pharmacotherapy Line
Feb. 14, 2017 * Vol. 24, No. 30
Providing news and information about medications and their proper use
>>>Internal Medicine Report
Source: Feb. issue of JAMA Internal Medicine (2017; 177).
Beta-Blockers After AMI in Older Nursing Home Residents: Among a cohort of
nursing home residents in 2007–10, use of beta-blockers after acute myocardial
infarction (AMI) was associated with “considerable mortality benefit” but also declines in
functional status, particularly in those with poor cognitive and functional status at
baseline, researchers report (pp. 254–62). Minimum Data Set 2.0 figures and data from
Medicare Parts A and D show these associations based on beta-blocker use in long-stay
residents of nursing homes aged 65 years or older: “The initial cohort of 15,720 patients
(11,140 women [70.9%] and 4,580 men [29.1%]; mean [SD] age, 83 [8] years) included
8,953 new beta-blocker users and 6,767 nonusers. The propensity-matched cohort
included 5,496 new users of beta-blockers and an equal number of nonusers for a total
cohort of 10,992 participants (7,788 women [70.9%]; 3,204 men [29.1%]; mean [SD]
age, 84 [8] years). Users of beta-blockers were more likely than nonusers to experience
functional decline (odds ratio [OR], 1.14; 95% CI, 1.02–1.28), with a number needed to
harm of 52 (95% CI, 32–141). Conversely, beta-blocker users were less likely than
nonusers to die (hazard ratio [HR], 0.74; 95% CI, 0.67–0.83) and had similar rates of
rehospitalization (HR, 1.06; 95% CI, 0.98–1.14). Nursing home residents with moderate
or severe cognitive impairment or severe functional dependency were particularly likely
to experience functional decline from beta-blockers (OR, 1.34; 95% CI, 1.11–1.61 and
OR, 1.32; 95% CI, 1.10–1.59, respectively). In contrast, little evidence of functional
decline due to beta-blockers was found in participants with intact cognition or mild
dementia (OR, 1.03; 95% CI, 0.89–1.20; P = .03 for effect modification) or in those in the
best (OR, 0.99; 95% CI, 0.77–1.26) and intermediate (OR, 1.05; 95% CI, 0.86–1.27)
tertiles of functional independence (P = .06 for effect modification). Mortality benefits of
beta-blockers were similar across all subgroups.” (M. A. Steinman,
[email protected])
After listing limitations of data analyses in an area where higher-quality evidence is
needed, an editorialist writes, “A randomized clinical trial for frail older adults with
cognitive and functional impairment to examine guideline-recommended medications for
AMI is needed to address biases inherent in observational studies” (pp. 262–3).
“Furthermore, a trial for discontinuation of beta-blocker therapy in the population of
elders with life-limiting illness would be prudent given the changing benefits and risks of
treatment across levels of cognitive and functional impairment. The Palliative Care
Research Cooperative Group’s discontinuation trial for statin therapy among adults with
life-limiting illness provides a useful model for such a study. Regardless of the state of
the science, all clinicians should consider improving their approach to communication
regarding initiating (and discontinuing) therapy for those in the last quarter of their life.”
(J. Tjia, [email protected])
Trust but Verify: Commenting on two randomized controlled trials (RCTs) that show no
effects of programs designed to enhance care of high-use veterans through
interdisciplinary efforts (pp. 166–75; D. M. Zulman, [email protected]) and improve
antibiotic prescribing patterns (pp. 176–83; H. C. Bucher, [email protected]), an
editorialist reiterates the need for randomized controlled trials in assessment of quality
improvement efforts (pp. 162–3). “These 2 RCTs demonstrate the importance of
rigorous study design. Common sense doesn’t always prove to be right. Preintervention–
postintervention observational designs can be mistaken, especially when there is no
concurrent control. Just as we would not accept a drug as efficacious without a
randomized clinical design, quality improvement interventions benefit from rigorous
evaluation methodology. As the Russian proverb says: trust but verify.” (M. H. Katz,
[email protected])
Fish Oil or Aspirin in Arteriovenous Fistula Failure: In the randomized Omega-3
Fatty Acids (Fish Oils) and Aspirin in Vascular Access Outcomes in Renal Disease
(FAVOURED) study, neither aspirin nor fish oil supplementation significantly reduced
failure rates of new arteriovenous fistulae within 12 months of surgery in patients
requiring hemodialysis (pp. 184–93; A. B. Irish, [email protected])
PNN Pharmacotherapy Line is published via e-mail each business day except U.S.
holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201;
571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News
Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail
[email protected] to request missing copies of PNN. Quarterly files archived at
www.PharmacotherapyNewsNetwork.com.
PNN Pharmacotherapy Line
Feb. 15, 2017 * Vol. 24, No. 31
Providing news and information about medications and their proper use
>>>JAMA Report
Source: Feb. 14 issue of JAMA (2017; 317).
Scalp Cooling After Breast Cancer Chemotherapy: Women who used a scalp-cooling
device kept more of their hair during chemotherapy for breast cancer, according to two
studies and a related editorial.
During chemotherapy with a taxane and/or anthracycline, 142 women with stage 1 or 2
breast cancer “were significantly more likely to have less than 50% hair loss after the
fourth chemotherapy cycle compared with those who received no scalp cooling,”
researchers conclude (pp. 596–605). Adding that longer-term efficacy and safety data
are needed, the group adds these details regarding results: “Successful hair
preservation was found in 48 of 95 women with cooling (50.5%; 95% CI, 40.7%–60.4%)
compared with 0 of 47 women in the control group (0%; 95% CI, 0%–7.6%) (success
rate difference, 50.5%; 95% CI, 40.5%–60.6%). Because the 1-tailed P value from the
Fisher exact test was <.001, which crossed the superiority boundary (P = .0061), the
data and safety monitoring board recommended study termination on September 26,
2016. There were no statistically significant differences in changes in any of the scales
of quality of life from baseline to chemotherapy cycle 4 among the scalp cooling and
control groups. Only adverse events related to device use were collected; 54 adverse
events were reported in the cooling group, all grades 1 and 2. There were no serious
adverse device events.” (J. Nangia, [email protected])
Scalp cooling during nonanthracycline adjuvant chemotherapy was hair sparing among
122 women with stage 1 or 2 breast cancer, a second study shows (pp. 606–14): “Hair
loss of 50% or less (Dean score of 0–2) was seen in 67 of 101 patients (66.3%; 95% CI,
56.2%–75.4%) evaluable for alopecia in the scalp cooling group vs 0 of 16 patients (0%)
in the control group (P < .001). Three of 5 quality-of-life measures were significantly
better 1 month after the end of chemotherapy in the scalp cooling group. Of patients who
underwent scalp cooling, 27.3% (95% CI, 18.0%–36.6%) reported feeling less physically
attractive compared with 56.3% (95% CI, 31.9%–80.6%) of patients in the control group
(P = .02). Of the 106 patients in the scalp cooling group, 4 (3.8%) experienced the
adverse event of mild headache and 3 (2.8%) discontinued scalp cooling due to feeling
cold.” (H. S. Rugo, [email protected])
With mortality benefits of adjuvant chemotherapy well established in breast cancer, “the
time has come” to address adverse effects of the drugs, writes an editorialist (pp. 587–
8): “Chemotherapy has been a mainstay of adjuvant therapy for breast cancer and has
contributed to a reduction in breast cancer–related mortality. However, with the
introduction of targeted therapies, it is appealing to imagine a future in which
chemotherapy is no longer necessary and some of the distressing adverse effects of
cancer treatments can be avoided. Until that time, identifying interventions, such as
scalp cooling for the prevention of chemotherapy-induced alopecia, that reduce or
eliminate treatment-associated toxic effects will help ease the distress associated with
chemotherapy and may, as a result, improve outcomes for patients with breast cancer.”
(D. L. Hershman, [email protected])
Sublingual Grass Pollen Immunotherapy: Two years of sublingual grass pollen
immunotherapy failed to improve nasal responses to allergen challenge at a 3-year
follow-up, report researchers who studied 92 adult patients with moderate to severe
seasonal allergic rhinitis (pp. 615–25). Comparing the major allergen Phleum p 5 with
placebo controls, participants received daily sublingual tablets and monthly injections,
with these results: “In the intent-to-treat population, mean [total nasal symptom] score for
the sublingual immunotherapy group was 6.36 (95% CI, 5.76 to 6.96) at pretreatment
and 4.73 (95% CI, 3.97 to 5.48) at 3 years, and for the placebo group, the score was
6.06 (95% CI, 5.23 to 6.88) at pretreatment and 4.81 (95% CI, 3.97 to 5.65) at 3 years.
The between-group difference (adjusted for baseline) was −0.18 (95% CI, −1.25 to 0.90;
[P = .75]).” (S. R. Durham, [email protected])
>>>PNN NewsWatch
* Synergy Rx Pharmacy is voluntarily recalling all lots of Human Chorionic
Gonadotropin 5,000 units/vial and 11,000 units/vial to the retail level due to a lack of
sterility assurance, according to an announcement posted on the FDA website.
PNN Pharmacotherapy Line is published via e-mail each business day except U.S.
holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201;
571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News
Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail
[email protected] to request missing copies of PNN. Quarterly files archived at
www.PharmacotherapyNewsNetwork.com.
PNN Pharmacotherapy Line
Feb. 16, 2017 * Vol. 24, No. 32
Providing news and information about medications and their proper use
>>>NEJM Report
Source: Feb. 16 New England Journal of Medicine (2017; 376).
Baricitinib in Rheumatoid Arthritis: An oral reversible inhibitor of Janus kinases JAK1
and JAK2, baricitinib was more effective than placebo or adalimumab in treating 1,307
patients with active rheumatoid arthritis, a phase 3 trial shows (pp. 652–62). In the 52week study, results based on 20% improvement in the criteria of the American College
of Rheumatology (ACR20 response) (the primary end point), Disease Activity Score for
28 joints (DAS28), Health Assessment Questionnaire–Disability Index, and Simplified
Disease Activity Index at week 12 were as follows: “More patients had an ACR20
response at week 12 with baricitinib than with placebo (primary end point, 70% vs. 40%,
P <0.001). All major secondary objectives were met, including inhibition of radiographic
progression of joint damage, according to the [modified Sharp score] at week 24 with
baricitinib versus placebo (mean change from baseline, 0.41 vs. 0.90; P <0.001) and an
increased ACR20 response rate at week 12 with baricitinib versus adalimumab (70% vs.
61%, P = 0.014). Adverse events, including infections, were more frequent through week
24 with baricitinib and adalimumab than with placebo. Cancers were reported in five
patients (two who received baricitinib and three who received placebo). Baricitinib was
associated with reductions in neutrophil counts and increases in levels of creatinine and
low-density lipoprotein cholesterol.” (P. C. Taylor, [email protected])
ED Opioid Prescribing & Risk of Long-Term Use: In the nation’s emergency
departments, physicians vary widely in their rates of prescribing of opioid analgesics,
report researchers, who also found increased risks of long-term opioid use among
opioid-naive patients who were seen by high-intensity opioid prescribers (pp. 663–73). A
retrospective analysis of Medicare beneficiaries with index emergency department visits
in 2008–11 showed these rates of prescribing and long-term opioid use: “Our sample
consisted of 215,678 patients who received treatment from low-intensity prescribers and
161,951 patients who received treatment from high-intensity prescribers. Patient
characteristics, including diagnoses in the emergency department, were similar in the
two treatment groups. Within individual hospitals, rates of opioid prescribing varied
widely between low-intensity and high-intensity prescribers (7.3% vs. 24.1%). Long-term
opioid use was significantly higher among patients treated by high-intensity prescribers
than among patients treated by low-intensity prescribers (adjusted odds ratio, 1.30; 95%
confidence interval, 1.23 to 1.37; P <0.001); these findings were consistent across
multiple sensitivity analyses.” (M. L. Barnett, [email protected])
FDA Regulation of Prescription Drugs: FDA officials review the current regulatory
operations of the agency, reaching this conclusion (pp. 674–82): “Many of the FDA’s
benefit–risk assessments and decisions are straightforward, but sometimes the FDA is
confronted with a difficult set of benefits, risks, and uncertainties. Particularly in these
situations, the FDA and the drug company may reach different conclusions based on the
same facts, or there may be differences of opinion among the members of the FDA’s
review team. The FDA encourages transparent, robust scientific discussions among its
staff and has processes for handling differences of opinion. There is also a process for
drug companies to appeal an FDA decision. Such situations can be highly charged and
can elicit strong public reactions, with some people criticizing the FDA for being too
conservative and delaying access to new drugs, and others criticizing the FDA for being
too lenient and approving drugs on the basis of limited data. We believe that the new
structured framework for benefit–risk assessment will facilitate a better understanding of
the data and uncertainties underlying drug approvals and will make this information more
transparent to the public.” (H. V. Joffe, [email protected])
>>>PNN NewsWatch
* FDA yesterday approved the injectable agent brodalumab (Siliq, Valeant
Pharmaceuticals) for treatment of adults with moderate-to-severe plaque psoriasis.
* Bird flu is spreading in China, according to an article in the Sydney Morning Herald.
Some 79 people died of H7N9 influenza last month, Chinese government sources say.
PNN Pharmacotherapy Line is published via e-mail each business day except U.S.
holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201;
571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News
Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail
[email protected] to request missing copies of PNN. Quarterly files archived at
www.PharmacotherapyNewsNetwork.com.
PNN Pharmacotherapy Line
Feb. 17, 2017 * Vol. 24, No. 33
Providing news and information about medications and their proper use
>>>Infectious Diseases Report
Source: Feb. 15 issue of Clinical Infectious Diseases (2017; 64).
Mumps Outbreak in Highly Vaccinated University Community: Illustrating how
outbreaks can occur in a highly vaccinated population, investigators report 56 cases of
mumps from New York City, all linked back to a university community (pp. 408–12). “On
14 January 2014, a vaccinated student presented with parotitis. Mumps immunoglobulin
M (IgM) testing was negative and reverse-transcription polymerase chain reaction (RTPCR) testing was not performed, resulting in a missed diagnosis and the start of an
outbreak at a New York City (NYC) university,” the group writes. “Fifty-six NYC residents
with mumps were identified with onset between 12 January and 30 April 2014. Fiftythree cases (95%) were university students, 1 (2%) was a staff member, and 2 (4%) had
epidemiologic links to the university. The median age was 20 years (range 18–37 years).
All cases had parotitis. Three cases were hospitalized, including 1 of 2 cases with
orchitis. Fifty-four (96%) cases had received ≥1 mumps-containing vaccine, 1 (2%) was
unvaccinated due to religious exemption, and 1 (2%) had unknown vaccination status.
Two of the 44 (5%) cases tested by serology were mumps IgM positive, and 27 of the 40
(68%) tested by RT-PCR were positive.” (L. N. Patel)
Diabetes, Insulin Therapy, Hospitalization for Infection & 28-Day Mortality Risk: In
the REasons for Geographic and Racial Differences in Stroke (REGARDS) study,
community-dwelling adults aged 45 years or older had increased risk of hospitalization
for infection when they had been diagnosed with diabetes, and the odds were increased
further if they were on insulin therapy (pp. 435–42). The prospective cohort study
followed 30,239 participants from 2003 to 2012, identifying these patterns: “Among
29,683 patients from the REGARDS study with complete follow-up, 7,375 had diabetes.
Over a median follow-up period of 6.5 years, we identified 2,593 first and 3,411 total
infection hospitalizations. In adjusted analyses, participants with diabetes had an
increased hazard of infection (hazard ratio, 1.50; 95% confidence interval [CI], 1.37–
1.64) compared with those without diabetes. Participants with diabetes hospitalized for
infection did not have an increased odds of death within 28 days (odds ratio, 0.94; 95%
CI, .67–1.32). Participants receiving insulin therapy had greater hazard of infection
(hazard ratio, 2.18; 95% CI, 1.90–2.51) but no increased odds of mortality (odd ratio,
1.07; 95% CI, .67–1.71).” (J. P. Donnelly)
>>>Oncology Highlights
Source: Feb. 20 issue of the Journal of Clinical Oncology (2017; 35).
Viral Status & Sorafenib Effects in Advanced Hepatocellular Cancer: The overall
survival (OS) benefit of sorafenib varies depending on patients’ hepatitis status,
according to results from the Sorafenib Hepatocellular Carcinoma Assessment
Randomized Protocol (SHARP) trial (pp. 622–8). Among 1,643 patients who received
sorafenib, hazard ratios based on hepatitis C virus (HCV) or hepatitis B virus (HBV)
status were as follows: “Hazard ratios show improved OS for sorafenib in patients who
are both HBV negative and HCV positive (log [hazard ratio], −0.27; 95% CI, −0.46 to
−0.06). Median unadjusted survival is 12.6 (11.15 to 13.8) months for sorafenib and 10.2
(8.88 to 12.2) months for ‘other’ treatments in this subgroup. There was no evidence of
improvement in OS for any other patient subgroups defined by HBV and HCV. Results
were consistent across all trials with heterogeneity assessed using Cochran’s Q
statistic.” (P. Johnson, [email protected])
Personal Genomic Testing for Cancer Risk: When patients learn through genomic
testing that they have elevated cancer risks, they do not change their health-related
behaviors, a study shows (pp. 636–44; S. W. Gray, [email protected]).
>>>PNN NewsWatch
* A reasonably good match between circulating influenza viruses and strains in the
2016–17 vaccine is reported in yesterday’s MMWR. Overall vaccine effectiveness is
preliminarily estimated at 48% against medically attended acute respiratory infection and
43% overall. As of early Nov. 2016, vaccination rates were 37% in pediatric patients,
37% in adults aged 18–64 years, 57% among older adults, and 47% among pregnant
women.
* PNN will not be published on Mon., Feb. 20, Presidents Day.
PNN Pharmacotherapy Line is published via e-mail each business day except U.S.
holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201;
571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News
Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail
[email protected] to request missing copies of PNN. Quarterly files archived at
www.PharmacotherapyNewsNetwork.com.
PNN Pharmacotherapy Line
Feb. 21, 2017 * Vol. 24, No. 34
Providing news and information about medications and their proper use
>>>Internal Medicine Report
Source: Feb. 21 issue of the Annals of Internal Medicine (2017; 166).
Primary Care–Based Opioid Use Disorder Therapy: “Greater integration of
medication-assisted treatment (MAT) for opioid use disorder (OUD) in U.S. primary care
settings would expand access to treatment for this condition,” write authors of a review
article on this topic (pp. 268–78): “Models for integrating MAT into primary care vary in
structure. This article summarizes findings of a technical report for the Agency for
Healthcare Research and Quality describing MAT models of care for OUD, based on a
literature review and interviews with key informants in the field. The report describes 12
representative models of care for integrating MAT into primary care settings that could
be considered for adaptation across diverse health care settings. Common components
of existing care models include pharmacotherapy with buprenorphine or naltrexone,
provider and community education, coordination and integration of OUD treatment with
other medical and psychological needs, and psychosocial services and interventions.
Models vary in how each component is implemented. Decisions about adopting MAT
models of care should be individualized to address the unique milieu of each
implementation setting.” (P. T. Korthuis, [email protected])
Editorialists write that primary care clinicians will need training in three areas to improve
care of patients with OUD: biology of opioid use disorder, rationale for and efficacy of
treatment options, and identification of the spectrum of patients for whom their practice
can provide effective treatment (pp. 307–8). “Federally funded services, such as the
Providers’ Clinical Support System for Medication-Assisted Treatment, can provide
education, mentoring, and support,” the article continues. “Internists have had a
profound effect on developing, researching, disseminating, and implementing the most
effective treatments for opioid use disorder. Primary care practices now have a road
map to follow to help address the pressing health crisis presented by the current
epidemic.” (E. J. Edelman, [email protected])
Oral Treatment of Type 2 Diabetes: As reported earlier in PNN (see Jan. 3), the
American College of Physicians recommends first-line use of metformin for oral
pharmacologic treatment of adults with type 2 diabetes in an update to its 2012 guideline
(pp. 279–90). ACP recommends that clinicians (A. Qaseem, [email protected]):
* Prescribe metformin to patients with type 2 diabetes when pharmacologic therapy is
needed to improve glycemic control. (Grade: strong recommendation; moderate-quality
evidence)
* Consider adding either a sulfonylurea, a thiazolidinedione, an SGLT-2 inhibitor, or a
DPP-4 inhibitor to metformin to improve glycemic control when a second oral therapy is
considered (Grade: weak recommendation; moderate-quality evidence), and select with
patients among medications after discussing benefits, adverse effects, and costs.
>>>BMJ Highlights
Source: Early-release article from BMJ (2017; 356).
Vitamin D Prevention of Respiratory Infections: Supplements of vitamin D protect
against acute respiratory tract infections, according to results of a systematic review and
meta-analysis (i6583). A 12% reduction in risk was found overall, with greater protective
effects in those with lower baseline vitamin D levels (<12 nmol/L) and in those who did
not receive bolus supplements of the nutrient. (A. R. Martineau,
[email protected])
>>>PNN JournalWatch
* Risk of Heart Failure After Community Acquired Pneumonia: Prospective Controlled
Study With 10 Years of Follow-up, in BMJ, 2017; 356: j413. (D. T. Eurich,
[email protected])
* The Scientific Basis of Guideline Recommendations on Sugar Intake: A Systematic
Review, in Annals of Internal Medicine, 2017; 166: 257–67. (B. C. Johnston,
[email protected])
* Systematic Review of the Prevalence of Medication Errors Resulting in Hospitalization
and Death of Nursing Home Residents, in Journal of the American Geriatrics Society,
2017; 65: 433–42. (J. E. Ibrahim, [email protected])
* Pharmacotherapeutic Considerations for Individuals with Down Syndrome, in
Pharmacotherapy, 2017; 37: 214–20. (E. Hefti, [email protected])
* Laboratory and Clinical Monitoring of Direct Acting Oral Anticoagulants: What
Clinicians Need to Know, in Pharmacotherapy, 2017; 37: 236–48. (S. E. Conway, [email protected])
PNN Pharmacotherapy Line is published via e-mail each business day except U.S.
holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201;
571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News
Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail
[email protected] to request missing copies of PNN. Quarterly files archived at
www.PharmacotherapyNewsNetwork.com.
PNN Pharmacotherapy Line
Feb. 22, 2017 * Vol. 24, No. 35
Providing news and information about medications and their proper use
>>>JAMA Report
Source: Feb. 21 issue of JAMA (2017; 317).
Effects of Testosterone Replacement in Older Men: Clinical benefits of testosterone
replacement in older men with low levels of the hormone are examined.
Rather than a decrease in noncalcified coronary artery plaque volume, researchers
found increases in this cardiovascular risk indicator in older men using testosterone gel
for 1 year (pp. 708–16). In the Testosterone Trials (TTrials), conducted in 2010–14,
coronary computed tomographic angiography yielded these results for 138 men with low
serum testosterone levels and symptoms suggestive of hypogonadism: “At baseline, 70
men (50.7%) had a coronary artery calcification score higher than 300 Agatston units,
reflecting severe atherosclerosis.… Testosterone treatment compared with placebo was
associated with a significantly greater increase in noncalcified plaque volume from
baseline to 12 months (from median values of 204 mm3 to 232 mm3 vs 317 mm3 to 325
mm3, respectively; estimated difference, 41 mm3; 95% CI, 14 to 67 mm3; P = .003).” (P.
J. Snyder, [email protected])
In the same study, 492 older men with low testosterone and age-associated memory
impairment (AAMI) had no improvements in memory or cognitive function during 1 year
of testosterone gel, compared with placebo (pp. 717–27). “There was no significant
mean change from baseline to 6 and 12 months in delayed paragraph recall score
among men with AAMI in the testosterone and placebo groups (adjusted estimated
difference, −0.07 [95% CI, −0.92 to 0.79]; P = .88),” the authors write. “Mean scores for
delayed paragraph recall were 14.0 at baseline, 16.0 at 6 months, and 16.2 at 12
months in the testosterone group and 14.4 at baseline, 16.0 at 6 months, and 16.5 at 12
months in the placebo group. Testosterone was also not associated with significant
differences in visual memory (−0.28 [95% CI, −0.76 to 0.19]; P = .24), executive function
(−5.51 [95% CI, −12.91 to 1.88]; P = .14), or spatial ability (−0.12 [95% CI, −1.89 to
1.65]; P = .89).” (P. J. Snyder, [email protected])
“It is unlikely that the limited efficacy shown by the TTrials meets the mandate of the
2004 Institute of Medicine report to warrant public funding for a powerful, long-term,
large randomized clinical trial for evaluating testosterone,” editorialists write (pp. 699–
701). “In September 2015 the FDA mandated that testosterone manufacturers undertake
longer-term safety and efficacy trials for off-label use of testosterone for aging men. If
such a study proceeds, it could provide a valuable extension to the short-term safety of
the TTrials supported by the manufacturers who have reaped large financial benefit from
the boom in testosterone sales. In any case, with the results of [these] studies …, the
hopes for testosterone-led rejuvenation for older men are dimmed and disappointed if
not yet finally dashed.” (D. J. Handelsman, [email protected])
Fibrinogen Concentrate in High-Risk Cardiac Surgery: Intraoperative blood loss was
unchanged in 120 patients receiving fibrinogen concentrate during high-risk cardiac
surgery, a placebo-controlled study shows (pp. 738–47). In the Netherlands, those
undergoing elective, high-risk procedures received fibrinogen concentrate targeted to a
postinfusion plasma fibrinogen level of 2.5 g/L or placebo, with these results: “Median
blood loss in the fibrinogen group was 50 mL (interquartile range [IQR], 29–100 mL)
compared with 70 mL (IQR, 33–145 mL) in the control group (P = .19), the absolute
difference 20 mL (95% CI, −13 to 35 mL). There were 6 cases of stroke or transient
ischemic attack (4 in the fibrinogen group); 4 myocardial infarctions (3 in the fibrinogen
group); 2 deaths (both in the fibrinogen group); 5 cases with renal insufficiency or failure
(3 in the fibrinogen group); and 9 cases with reoperative thoracotomy (4 in the fibrinogen
group).” (S. Bilecen, [email protected])
>>>PNN NewsWatch
* On Friday, a U.S. district court judge entered a consent decree of permanent injunction
against Pick and Pay Inc./Cili Minerals, a manufacturer and distributor of drugs and
dietary supplements, and its owner, Anton S. Botha, requiring the business to
immediately cease operations until it comes into compliance with federal laws, FDA said
yesterday in a news release. Products were sold online, FDA said, and also at a retail
location in Lafayette, LA.
PNN Pharmacotherapy Line is published via e-mail each business day except U.S.
holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201;
571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News
Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail
[email protected] to request missing copies of PNN. Quarterly files archived at
www.PharmacotherapyNewsNetwork.com.
PNN Pharmacotherapy Line
Feb. 23, 2017 * Vol. 24, No. 36
Providing news and information about medications and their proper use
>>>NEJM Report
Source: Feb. 23 issue of the New England Journal of Medicine (2017; 376).
Lanadelumab in Hereditary Angioedema Prophylaxis: In a phase 1b, ascendingdose trial, the kallikrein inhibitor lanadelumab reduced cleavage of high-molecularweight kininogen and attacks of angioedema in 37 patients with hereditary angioedema
with C1 inhibitor deficiency (pp. 717–28). Investigators describe the following
pharmacodynamic profile of the new drug based on two administration periods 14 days
apart: “No discontinuations occurred because of adverse events, serious adverse
events, or deaths in patients who received lanadelumab. The most common adverse
events that emerged during treatment were attacks of angioedema, injection-site pain,
and headache. Dose-proportional increases in serum concentrations of lanadelumab
were observed; the mean elimination half-life was approximately 2 weeks. Lanadelumab
at a dose of 300 mg or 400 mg reduced cleavage of high-molecular-weight kininogen in
plasma from patients with hereditary angioedema with C1 inhibitor deficiency to levels
approaching that from patients without the disorder. From day 8 to day 50, the 300-mg
and 400-mg groups had 100% and 88% fewer attacks, respectively, than the placebo
group. All patients in the 300-mg group and 82% (9 of 11) in the 400-mg group were
attack-free, as compared with 27% (3 of 11) in the placebo group.” (A. Banerji,
[email protected])
“Kallikrein inhibition with lanadelumab given by fortnightly subcutaneous injection would
be convenient and widely accessible,” writes an editorialist (pp. 788–9). “Early safety
indications are encouraging, with no indication of antibody formation or the
anaphylactoid events associated with short-term inhibition of kallikrein; therefore, selfadministration could be feasible. Most exciting, [this] preliminary study … suggests an
unprecedented level of protection against angioedema. If this proves reproducible in
larger studies currently under way, and if the treatment will be affordable, lanadelumab
could herald a transformation in the way that we manage hereditary angioedema and in
the life prospects for families affected by this devastating disorder.” (H. J. Longhurst)
Tight Glycemic Control in Critically Ill Children: Tight glycemic control was not
beneficial in a 35-center trial of 713 patients, researchers report (pp. 729–41).
Comparing target blood glucose ranges of 80–100 versus 150–180 mg/dL, results
showed: “The trial was stopped early, on the recommendation of the data and safety
monitoring board, owing to a low likelihood of benefit and evidence of the possibility of
harm.… In the intention-to-treat analysis, the median number of ICU-free days did not
differ significantly between the lower-target group and the higher-target group (19.4 days
[interquartile range {IQR}, 0 to 24.2] and 19.4 days [IQR, 6.7 to 23.9], respectively; P =
0.58). In per-protocol analyses, the median time-weighted average glucose level was
significantly lower in the lower-target group (109 mg per deciliter [IQR, 102 to 118]; 6.1
mmol per liter [IQR, 5.7 to 6.6]) than in the higher-target group (123 mg per deciliter
[IQR, 108 to 142]; 6.8 mmol per liter [IQR, 6.0 to 7.9]; P <0.001). Patients in the lowertarget group also had higher rates of health care–associated infections than those in the
higher-target group (12 of 349 patients [3.4%] vs. 4 of 349 [1.1%], P = 0.04), as well as
higher rates of severe hypoglycemia, defined as a blood glucose level below 40 mg per
deciliter (2.2 mmol per liter) (18 patients [5.2%] vs. 7 [2.0%], P=0.03). No significant
differences were observed in mortality, severity of organ dysfunction, or the number of
ventilator-free days.” (M. S. D. Agus, [email protected])
Minimizing Health Risks of Recreational Cannabis: “We should be skeptical of
people who claim to know what the net effect of cannabis legalization on public health
will be,” the author of a Perspective article concludes (pp. 705–7). “Much will depend on
implementation decisions, but jurisdictions’ ability to minimize health risks will also
depend on how they respond to new information and other sources of uncertainty.” (B.
Kilmer)
>>>PNN NewsWatch
* Organic Herbal Supply, Inc. has voluntarily recalled of all lots of XtraHRD Natural
Male Enhancement capsules after an FDA analysis showed the product contains
tadalafil, the agency said.
PNN Pharmacotherapy Line is published via e-mail each business day except U.S.
holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201;
571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News
Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail
[email protected] to request missing copies of PNN. Quarterly files archived at
www.PharmacotherapyNewsNetwork.com.
PNN Pharmacotherapy Line
Feb. 24, 2017 * Vol. 24, No. 37
Providing news and information about medications and their proper use
>>>Medical Care Report
Source: Mar. issue of Medical Care (2017; 55).
Readmissions in Safety-Net Hospitals: Safety-net hospitals (SNHs) have more
barriers to reduction of readmissions, according to a national survey, yet are less likely
to use readmission-reduction strategies (pp. 229–35). Responses from a survey of 980
of 1,600 U.S. acute care hospitals in 2013–14 showed these results: “SNHs were more
likely to report patient-related barriers, including lack of transportation, homelessness,
and language barriers compared with non-SNHs (P-values <0.001). Despite reporting
more barriers, SNHs were less likely to use e-tools to share discharge summaries
(70.1% vs. 73.7%, P <0.04) or verbally communicate (31.5% vs. 39.8%, P <0.001) with
outpatient providers, track readmissions by race/ethnicity (23.9% vs. 28.6%, P <0.001),
or enroll patients in postdischarge programs (13.3% vs. 17.2%, P <0.001). SNHs were
also less likely to use discharge coordinators, pharmacists, and postdischarge programs.
When we examined the use of strategies within SNHs, we found trends to suggest that
high-performing SNHs were more likely to use several readmission strategies.” (J. F.
Figueroa, [email protected])
Predictors of Overdose Among Medicaid Beneficiaries: A study demonstrates how
claims data can be used to identify Medicare patients at risk for opioid overdoses (pp.
291–8). Such findings could be used to restrict opioid prescribing or dispensing or make
referrals to treatment, the authors conclude based on these data for adults in the
Pennsylvania Medicaid program in 2007–12: “A total of 372,347 Medicaid enrollees with
583,013 new opioid treatment episodes were included in the cohort. Opioid overdose
was higher among those with abuse (1.5%) compared with those without (0.2%, P
<0.001). Overdose was higher among those with probable (1.8%) and possible (0.9%)
misuse compared with those without (0.2%, P <0.001). Abuse [adjusted rate ratio (ARR),
1.52; 95% confidence interval (CI), 1.10–2.10), probable misuse (ARR, 1.98; 95% CI,
1.46–2.67), and possible misuse (ARR, 1.76; 95% CI, 1.48–2.09) were associated with
significantly more events of opioid medication overdose compared with those without.”
(G. Cochran, [email protected])
Patient Perceptions of Deprescribing: The Patient Perceptions of Deprescribing
questionnaire provides “a novel, multidimensional instrument to measure patients’
attitudes and experiences related to medication discontinuation that can be used to
determine how to best involve patients in deprescribing decisions,” researchers report
(pp. 306–13). The instrument includes dimensions of “Medication Concerns,” “Provider
Knowledge,” “Interest in Stopping Medicines,” “Unimportance of Medicines,” and “Patient
Involvement in Decision-Making.” (A. Linsky, [email protected])
>>>Health Affairs Highlights
Source: Feb. issue of Health Affairs (2017; 36).
End-of-Life Spending & Length of Hospice Service: Seeking to better define the
impact of hospice care on end-of-life spending, investigators assessed costs in Medicare
regions with high expenditures (pp. 328–36). Results for 2004–11 demonstrated both the
potential of cost savings and the limitations of the intervention: “Longer periods of
hospice service were associated with decreased end-of-life expenditures for patients
residing in regions with high average expenditures but not for those in regions with low
average expenditures. Hospice use accounted for 8 percent of the expenditure variation
between the highest and the lowest spending quintiles, which demonstrates the powers
and limitations of hospice use for saving on costs.” (S. Wang, [email protected])
>>>PNN NewsWatch
* Don’t look for Medimmune’s live attenuated influenza virus vaccine to return soon -and maybe never, based on discussions this week at a CDC Advisory Committee on
Immunization Practices meeting. Problems with effectiveness of the H1N1 component of
the vaccine began after the 2009 pandemic, STAT reports based on a company
presentation. While solutions are under study, ACIP won’t likely be willing to reinstate
recommendations to use of the product until data are available from one or more H1N1dominated influenza seasons. Panel members wondered aloud how long the company
will stick with the product given that uncertainty.
PNN Pharmacotherapy Line is published via e-mail each business day except U.S.
holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201;
571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News
Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail
[email protected] to request missing copies of PNN. Quarterly files archived at
www.PharmacotherapyNewsNetwork.com.
PNN Pharmacotherapy Line
Feb. 27, 2017 * Vol. 24, No. 38
Providing news and information about medications and their proper use
>>>Lancet Highlights
Source: Feb. 25 issue of Lancet (2017; 389).
Terminal Room Disinfection & Pathogen Control: Enhanced disinfection of the last
hospital room occupied by discharged patients who had infections or colonizations with
certain pathogens is an effective means of decreasing infection risk in hospitals,
researchers report (pp. 805–14). At nine hospitals in the southeastern U.S., 21,395
patients with methicillin-resistant Staphylococcus aureus, vancomycin-resistant
enterococci, Clostridium difficile, or multidrug-resistant Acinetobacter were studied. The
rooms from which the patients were discharged were disinfected using one of four
strategies, and patients admitted into those rooms were considered infected. Results
showed that the incidence of target organisms was lower when ultraviolet (UV) light was
added to standard cleaning regimens (quaternary ammonium disinfectant except for C.
difficile, for which bleach was used). Addition of bleach or disinfecting UV light to these
cleaning strategies did not significantly lower the incidence of infection or colonization of
exposed patients. (D. J Anderson, [email protected])
Risk Information & Taster Sessions in Smoking Cessation: Delivery of personalized
risk information and an invitation to a no-commitment “come and try it” taster session
increased cessation rates among smokers in the U.K., a study shows (pp. 823–33). The
letter used information from a screening questionnaire and the patient’s medical record
to personalize their risks of smoking; at the taster sessions, information was provided
about the National Health Service Stop Smoking Services (SSSs), address participant
concerns, and encourage signing up for cessation services. Results showed:
“Recruitment, collection of baseline data, delivery of the intervention, and follow up of
participants took place between Jan 31, 2011, and July 12, 2014. We randomly assigned
4,384 smokers to the intervention group (n = 2,636) or the control group (n = 1,748);
4,383 participants comprised the intention-to-treat population. Attendance at the first
session of an SSS course was significantly higher in the intervention group than in the
control group (458 [17.4%] vs 158 [9.0%] participants; unadjusted odds ratio 2.12 [95%
CI 1.75–2.57]; p <0.0001).” (H. Gilbert, [email protected])
>>>BMJ Highlights
Source: Early-release article from BMJ (2017; 356).
Off-Label Antidepressant Use: At primary practices in Quebec, use of prescribed
antidepressants for off-label indications were often not supported by “strong scientific
evidence,” according to analysis of records from 2003 to 2015 (j603). Results showed:
“106,850 antidepressant prescriptions were written by 174 physicians for 20,920 adults.
By class, tricyclic antidepressants had the highest prevalence of off-label indications
(81.4%, 95% confidence interval, 77.3% to 85.5%), largely due to a high off-label
prescribing rate for amitriptyline (93%, 89.6% to 95.7%). Trazodone use for insomnia
was the most common off-label use for antidepressants, accounting for 26.2% (21.9% to
30.4%) of all off-label prescriptions. For only 15.9% (13.0% to 19.3%) of all off-label
prescriptions, the prescribed drug had strong scientific evidence for the respective
indication. For 39.6% (35.7% to 43.2%) of off-label prescriptions, the prescribed drug did
not have strong evidence but another antidepressant in the same class had strong
evidence for the respective indication. For the remaining 44.6% (40.2% to 49.0%) of offlabel prescriptions, neither the prescribed drug nor any other drugs in the class had
strong evidence for the indication.” (J. Wong, [email protected])
>>>PNN NewsWatch
* Advanced Pharma, doing business as Avella of Houston, is conducting a voluntary
recall of all unexpired sterile injectable products labeled “latex free” produced at its
Houston location between Sept. 2016 and mid-February. The recall, extending to the
user level (hospitals and institutions), results from possible synthetic latex and/or natural
latex in the products.
>>>PNN JournalWatch
* Management of Nonalcoholic Fatty Liver Disease in Patients With Type 2 Diabetes: A
Call to Action, in Diabetes Care, 2017; 40: 419–30. (K. Cusi,
[email protected])
* Women in Leadership and the Bewildering Glass Ceiling, in American Journal of
Health-System Pharmacy, 2017; 74: 312–24. (M. A. Chisholm-Burns,
[email protected])
PNN Pharmacotherapy Line is published via e-mail each business day except U.S.
holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201;
571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News
Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail
[email protected] to request missing copies of PNN. Quarterly files archived at
www.PharmacotherapyNewsNetwork.com.
PNN Pharmacotherapy Line
Feb. 28, 2017 * Vol. 24, No. 39
Providing news and information about medications and their proper use
>>>Geriatrics Report
Source: Feb. issue of the Journal of the American Geriatrics Society (2017; 65).
Improving Warfarin Use in Older Adults: Two studies and an editorial show benefits
of using warfarin in older adults, but risks always weight on clinicians’ decisions.
In older adults with atrial fibrillation (AF), more than 40% were not placed on oral
anticoagulants (OACs) at discharge despite a very high stroke risk, researchers report
(pp. 241–8). Based on findings from two large community cohorts of patients with AF,
the group concludes, “Dominant reasons [for not using OACs] included fall risk, poor
prognosis, older age, and dementia. These individuals’ high 1-year mortality rate
confirmed their high level of comorbidity. To improve anticoagulation decisions and
outcomes in this population, future research should focus on strategies to mitigate fall
risk, improve assessment of risks and benefits of anticoagulation in individuals with AF,
and determine whether newer anticoagulants are safer in complex elderly and frail
individuals.” (A. S. Go, [email protected])
Among veterans aged 65 years or older, discontinuance of warfarin after diagnosis of
dementia was followed by a significant increase in stroke and mortality, a study shows
(pp. 249–56). Based on new diagnoses of dementia in 2007 or 2008, patients with at
least a 6-month history of warfarin therapy for nonvalvular atrial fibrillation had these
outcomes: “After a diagnosis of dementia, 405 individuals (16%) persisted on warfarin
therapy. Unadjusted Cox proportional hazards analysis demonstrated a protective effect
of warfarin in prevention of ischemic stroke (hazard ratio (HR) = 0.64, 95% confidence
interval (CI) = 0.46–0.89, P = .008), major bleeding (HR = 0.72, 95% CI = 0.55–0.94, P =
.02), and all-cause mortality (HR = 0.66, 95% CI = 0.55–0.79, P < .001). Using
propensity score matching, the protective effect of continuing warfarin persisted in
prevention of stroke (HR = 0.74, 95% CI = 0.54–0.996, P = .047) and mortality (HR =
0.72, 95% CI = 0.60–0.87, P < .001), with no statistically significant decrease in risk of
major bleeding (HR = 0.78, 95% CI = 0.61–1.01, P = .06).” (A. R. Orkaby,
[email protected])
“Even under the most ideal circumstances of care, there will continue to be large
numbers of older adults with atrial fibrillation who are not treated with warfarin or for
whom therapy will be discontinued once started,” writes an editorialist (pp. 236–7). “The
opportunity to provide safer and highly effective oral anticoagulant therapy is an
extremely attractive prospect for both providers and the complex older patients under
their care. Unfortunately, this will never be the case for warfarin.” (J. H. Gurwitz)
>>>Diabetes Highlights
Source: Mar. issue of the Diabetes Care (2017; 40).
Tackling the Prandial Problem: A review article author “proposes that a greater
proportion of available resources be directed to basic and clinical research on the
prandial problem” (pp. 291–300): “Both basal and postprandial elevations contribute to
the hyperglycemic exposure of diabetes, but current therapies are mainly effective in
controlling the basal component. Inability to control postprandial hyperglycemia limits
success in maintaining overall glycemic control beyond the first 5 to 10 years after
diagnosis, and it is also related to the weight gain that is common during insulin therapy.
The ‘prandial problem’—comprising abnormalities of glucose and other metabolites,
weight gain, and risk of hypoglycemia—deserves more attention. Several approaches to
prandial abnormalities have recently been studied, but the patient populations for which
they are best suited and the best ways of using them remain incompletely defined.
Encouragingly, several proof-of-concept studies suggest that short-acting glucagon-like
peptide 1 agonists or the amylin agonist pramlintide can be very effective in controlling
postprandial hyperglycemia in type 2 diabetes in specific settings.” (M. C. Riddle,
[email protected])
>>>PNN NewsWatch
* Endo Pharmaceuticals is recalling one lot of Edex (alprostadil for injection) 10 mcg to
the consumer level because of a defect in the crimp caps used in the manufacture of the
product lot. This defect has the potential to lead to a loss of container closure integrity
and thereby result in loss of sterility assurance.
PNN Pharmacotherapy Line is published via e-mail each business day except U.S.
holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201;
571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News
Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail
[email protected] to request missing copies of PNN. Quarterly files archived at
www.PharmacotherapyNewsNetwork.com.
PNN Pharmacotherapy Line
Mar. 1, 2017 * Vol. 24, No. 40
Providing news and information about medications and their proper use
>>>JAMA Report
Source: Feb. 28 issue of JAMA (2017; 317).
Antithrombotic Drug Use & Subdural Hematoma: Use of low-dose aspirin, vitamin K
antagonists (VKAs), direct oral anticoagulants, and combined antithrombotic drug
treatment is associated with increased risk of subdural hematoma, according to analysis
of regional and national data from Denmark (pp. 836–46). “The highest odds of subdural
hematoma was associated with combined use of a VKA and an antiplatelet drug,” the
authors conclude. “The increased incidence of subdural hematoma from 2000 to 2015
appears to be associated with the increased use of antithrombotic drugs, particularly use
of a VKA among older patients.” Among 5.2 million people in Denmark, 10,010 patients
with first-ever subdural hematomas had these implicating factors compared with
matched controls: “Current use of low-dose aspirin (cases: 26.7%, controls: 22.4%;
adjusted OR, 1.24 [95% CI, 1.15–1.33]), clopidogrel (cases: 5.0%, controls: 2.2%;
adjusted OR, 1.87 [95% CI, 1.57–2.24]), a direct oral anticoagulant (cases: 1.0%,
controls: 0.6%; adjusted OR, 1.73 [95% CI, 1.31–2.28]), and a VKA (cases: 14.3%,
controls: 4.9%; adjusted OR, 3.69 [95% CI, 3.38–4.03]) were associated with higher risk
of subdural hematoma. The risk of subdural hematoma was highest when a VKA was
used concurrently with an antiplatelet drug (low-dose aspirin and a VKA: 3.6% of cases
and 1.1% of controls; adjusted OR, 4.00 [95% CI, 3.40–4.70]; clopidogrel and a VKA:
0.3% of cases and 0.04% of controls; adjusted OR, 7.93 [95% CI, 4.49–14.02]).… The
largest increase [in incidence] was among older patients (>75 years; n = 4,441) who
experienced an increase from 55.1 per 100,000 person–years to 99.7 per 100,000
person–years (P < .001 for trend).” (D. Gaist, [email protected])
Subsequent Neoplasm Risk in Childhood Cancer Survivors: Lower rates of
subsequent neoplasms among 23,603 childhood cancer survivors from the 1990s are
associated with radiation exposure reduced from 1970s levels, researchers report (pp.
814–24). Analysis of data from pediatric tertiary hospitals in the U.S. and Canada
showed these patterns for 1970 through 1999, with follow-up through the end of 2015:
“Proportions of individuals receiving radiation decreased (77% for 1970s vs 33% for
1990s), as did median dose (30 Gy [interquartile range, 24–44] for 1970s vs 26 Gy
[interquartile range, 18–45] for 1990s). Fifteen-year cumulative incidence of subsequent
malignancies decreased by decade of diagnosis (2.1% [95% CI, 1.7%–2.4%] for 1970s,
1.7% [95% CI, 1.5%–2.0%] for 1980s, 1.3% [95% CI, 1.1%–1.5%] for 1990s). Reference
absolute rates per 1,000 person–years were 1.12 (95% CI, 0.84–1.57) for subsequent
malignancies, 0.16 (95% CI, 0.06–0.41) for meningiomas, and 1.71 (95% CI, 0.88–3.33)
for nonmelanoma skin cancers for survivors with reference characteristics (no
chemotherapy, splenectomy, or radiation therapy; male; attained age 28 years).” (L. M.
Turcotte, [email protected])
Early Complications of Type 1 vs. Type 2 Diabetes: In patients diagnosed with
diabetes before age 20, those with type 1 conditions have fewer early complications and
comorbidities than those with type 2 diabetes, but such problems are common in both
patient types, a study shows (pp. 825–35). In 2,018 participants followed from diagnosis
in 2002 to 2015, these outcomes were observed in 2011–15: “After adjustment for
established risk factors measured over time, participants with type 2 diabetes vs those
with type 1 had significantly higher odds of diabetic kidney disease (odds ratio [OR],
2.58; 95% CI, 1.39–4.81; P=.003), retinopathy (OR, 2.24; 95% CI, 1.11–4.50; P = .02),
and peripheral neuropathy (OR, 2.52; 95% CI, 1.43–4.43; P = .001), but no significant
difference in the odds of arterial stiffness (OR, 1.07; 95% CI, 0.63–1.84; P = .80) and
hypertension (OR, 0.85; 95% CI, 0.50–1.45; P = .55).” (D. Dabelea,
[email protected])
>>>PNN NewsWatch
* FDA on Tuesday approved elotristat ethyl (Xermelo, Lexicon Pharmaceuticals) as the
first and only orally administered therapy for treatment of carcinoid syndrome diarrhea in
combination with somatostatin analog (SSA) therapy in adults inadequately controlled by
SSA therapy. The new drug targets overproduction of serotonin by metastatic
neuroendocrine tumors. It will be distributed by specialty pharmacies beginning Mar. 6.
PNN Pharmacotherapy Line is published via e-mail each business day except U.S.
holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201;
571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News
Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail
[email protected] to request missing copies of PNN. Quarterly files archived at
www.PharmacotherapyNewsNetwork.com.
PNN Pharmacotherapy Line
Mar. 2, 2017 * Vol. 24, No. 41
Providing news and information about medications and their proper use
>>>NEJM Report
Source: Mar. 2 issue of the New England Journal of Medicine (2017; 376).
Treatment of Thyroid Deficiency in Pregnancy: Levothyroxine therapy was ineffective
for improving offspring cognitive function when administered during pregnancy to
mothers with subclinical hypothyroidism or hypothyroxinemia, researchers report (pp.
815–25). Compared with placebo, levothyroxine administered at 8–20 weeks’ gestation
produced these outcomes based on children’s IQ at 3–5 years of age or at death in
those younger than 3 years: “A total of 677 women with subclinical hypothyroidism
underwent randomization at a mean of 16.7 weeks of gestation, and 526 with
hypothyroxinemia at a mean of 17.8 weeks of gestation. In the subclinical
hypothyroidism trial, the median IQ score of the children was 97 (95% confidence
interval [CI], 94 to 99) in the levothyroxine group and 94 (95% CI, 92 to 96) in the
placebo group (P = 0.71). In the hypothyroxinemia trial, the median IQ score was 94
(95% CI, 91 to 95) in the levothyroxine group and 91 (95% CI, 89 to 93) in the placebo
group (P = 0.30). In each trial, IQ scores were missing for 4% of the children. There were
no significant between-group differences in either trial in any other neurocognitive or
pregnancy outcomes or in the incidence of adverse events, which was low in both
groups.” (B. M. Casey, [email protected])
While these findings “indicate that screening and treatment for subclinical
hypothyroidism, if performed well into the second trimester of pregnancy, are unlikely to
be beneficial,” drug administration at an earlier point in pregnancy remains a reasonable
option, editorialists write (pp. 876–7): “Because more than 75% of women in the United
States have their first prenatal visit before 12 weeks of gestation, earlier treatment
appears to be feasible. We continue to endorse the recent guidelines of the American
Thyroid Association, since the early initiation of low-dose levothyroxine therapy for
subclinical hypothyroidism may be of benefit, is inexpensive, and is unlikely to be
harmful.” (D. S. Cooper)
Anti–Interleukin-31 Receptor A Antibody for Atopic Dermatitis: Targeting of the
interleukin-31 receptor A was effective for reducing pruritus symptoms in 264 patients
with moderate-to-severe atopic dermatitis, a phase 2 study shows (pp. 826–35). Based
on a primary end point of percentage improved (lowered) scores on the pruritus visualanalogue scale at week 12, subcutaneous nemolizumab every 4–8 weeks showed these
results: “At week 12, among the patients who received nemolizumab every 4 weeks,
changes on the pruritus visual-analogue scale were −43.7% in the 0.1-mg group,
−59.8% in the 0.5-mg group, and −63.1% in the 2.0-mg group, versus −20.9% in the
placebo group (P <0.01 for all comparisons). Changes on the [Eczema Area and
Severity Index] were −23.0%, −42.3%, and −40.9%, respectively, in the nemolizumab
groups, versus −26.6% in the placebo group. Respective changes in body-surface area
affected by atopic dermatitis were −7.5%, −20.0%, and −19.4% with nemolizumab,
versus −15.7% with placebo. Among the patients receiving nemolizumab every 4 weeks,
treatment discontinuations occurred in 9 of 53 patients (17%) in the 0.1-mg group, in 9 of
54 (17%) in the 0.5-mg group, and in 7 of 52 (13%) in the 2.0-mg group, versus in 9 of
53 (17%) in the placebo group.” (T. Ruzicka, [email protected])
“New therapies [such as nemolizumab] should be included as part of a comprehensive
approach that includes education on skin care and trigger avoidance, psychological
support to enhance adherence and reduce itching, and treatment of the already
established mental health and sleep disorders,” writes an editorialist (pp. 878–9). “Data
from larger long-term studies and pediatric trials are needed to fully understand how
these new agents will fit into the management of atopic dermatitis. It will be important to
evaluate how quickly patients have disease flares after stopping the agents and whether
the addition of topical agents may provide more effective or longer remission.” (L. C.
Schneider)
>>>PNN NewsWatch
* FDA yesterday approved Odactra (Merck, Sharp & Dohme; Catalent Pharma), the first
sublingually administered allergen extract for treatment of house dust mite–induced
allergic rhinitis, with or without conjunctivitis, in people 18 through 65 years of age.
PNN Pharmacotherapy Line is published via e-mail each business day except U.S.
holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201;
571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News
Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail
[email protected] to request missing copies of PNN. Quarterly files archived at
www.PharmacotherapyNewsNetwork.com.
PNN Pharmacotherapy Line
Mar. 3, 2017 * Vol. 24, No. 42
Providing news and information about medications and their proper use
>>>Pediatrics Report
Source: Mar. issue of Pediatrics (2017; 139).
Improving Adolescent Immunization Rates: Practical approaches for optimizing
adolescent immunizations are offered in a clinical report from the American Academy of
Pediatrics (AAP; 10.1542/peds.2016-4187): “With the expansion of the adolescent
immunization schedule during the past decade, immunization rates notably vary by
vaccine and by state. Addressing barriers to improving adolescent vaccination rates is a
priority. Every visit can be viewed as an opportunity to update and complete an
adolescent’s immunizations. It is essential to continue to focus and refine the appropriate
techniques in approaching the adolescent patient and parent in the office setting. Health
care providers must continuously strive to educate their patients and develop skills that
can help parents and adolescents overcome vaccine hesitancy. Research on strategies
to achieve higher vaccination rates is ongoing, and it is important to increase the
knowledge and implementation of these strategies. This clinical report focuses on
increasing adherence to the universally recommended vaccines in the annual
adolescent immunization schedule of the American Academy of Pediatrics, the American
Academy of Family Physicians, the Centers for Disease Control and Prevention, and the
American Congress of Obstetricians and Gynecologists. This will be accomplished by (1)
examining strategies that heighten confidence in immunizations and address patient and
parental concerns to promote adolescent immunization and (2) exploring how best to
approach the adolescent and family to improve immunization rates.” (H. H. Bernstein)
In an accompanying clinical report, AAP reviews vaccines recommended for
administration during the adolescent years and discusses evidence supporting the need
for immunization (10.1542/peds.2016-4186): “The adolescent period heralds the
pediatric patient’s transition into adulthood. It is a time of dynamic development during
which effective preventive care measures can promote safe behaviors and the
development of lifelong health habits. One of the foundations of preventive adolescent
health care is timely vaccination, and every visit can be viewed as an opportunity to
update and complete an adolescent’s immunizations.” (H. H. Bernstein)
Overdoses Among Children of Mothers Prescribed Opioids: Based on a study
showing a “markedly increased risk of overdose” among young children whose mothers
are prescribed opioids, researchers conclude, “Physicians, pharmacists, and parents
should take measures to mitigate the risk of opioid-related harm to children, such as
prescribing smaller quantities, emphasizing the importance of secure medication
storage, and the prompt disposal of unused opioids” (10.1542/peds.2016-2887). The
study compared 103 children with opioid overdose with 412 matched controls. Results
showed: “Children with an opioid overdose were far more likely to have a mother who
received a prescription opioid (unadjusted odds ratio, 2.41; 95% confidence interval,
1.68–3.45) and who was prescribed antidepressants. The most commonly implicated
overdose opioids were codeine (53.4%), oxycodone (32.0%), and methadone (15.5%).”
(Y. Finkelstein)
>>>Psychiatry Highlights
Source: Mar. issue of the American Journal of Psychiatry (2017; 174).
Mood Switch Rates During Acute Bipolar Treatment: Mood switches among patients
with bipolar II depression were similar for two commonly used medications in a 16-week
study of 142 participants, and combination therapy produced higher discontinuance
rates without improvement in responses (pp. 266–76). Random assignment to lithium,
sertraline, or both produced these changes in mood at patient visits: “Twenty participants
(14%) experienced a switch during the study period (hypomania, N = 17; severe
hypomania, N = 3). Switch rates did not differ among the three treatment groups, even
after accounting for dropout. No patient had a manic switch or was hospitalized for a
switch. Most switches occurred within the first 5 weeks of treatment. The treatment
response rate for the overall sample was 62.7% (N = 89), without significant differences
between groups after accounting for dropout. The lithium/sertraline combination group
had a significantly higher overall dropout rate than the monotherapy groups but did not
have an accelerated time to response.” (L. L. Altshuler)
PNN Pharmacotherapy Line is published via e-mail each business day except U.S.
holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201;
571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News
Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail
[email protected] to request missing copies of PNN. Quarterly files archived at
www.PharmacotherapyNewsNetwork.com.
PNN Pharmacotherapy Line
Mar. 6, 2017 * Vol. 24, No. 43
Providing news and information about medications and their proper use
>>>BMJ Highlights
Source: Early-release articles from BMJ (2017; 356).
Congenital Heart Defects With SSRI Use During Pregnancy: Use of SSRIs by
pregnant women during the cardiogenesis phase of fetal development can lead to
congenital heart defects when the mother or child has certain variants in folate,
homocysteine, or transsulfuration pathways, a study shows (j832). Using data from the
U.S. National Birth Defects Prevention Study on 1,180 liveborn infants with congenital
heart defects and 1,644 controls born in 1997–2008, investigators found these
correlations of outcomes with single nucleotide polymorphism panels: “For women who
reported taking SSRIs periconceptionally, maternal SHMT1 (rs9909104) GG and AG
genotypes were associated with a 5.9 and 2.4 increased risk of select congenital heart
defects in offspring, respectively, versus the AA genotype ([Bayesian false discovery
probabilities (BFDP)] = 0.69). Compared with the AA genotype, BHMT (rs492842 and
rs542852) GG and AG genotypes were associated with twice the risk of congenital heart
defects (BFDP = 0.74 and 0.79, respectively). MGST1 (rs2075237) CC and AC
genotypes were associated with an increased risk compared with the GG genotype (8.0
and 2.8, respectively; BFDP = 0.79). Single nucleotide polymorphism in infant genes in
the folate (MTHFS rs12438477), homocysteine (TRDMT1 rs6602178 and GNMT
rs11752813) and transsulfuration (GSTP1 rs7941395 and MGST1 rs7294985) pathways
were also associated with an increased risk of congenital heart defects.” (W. Nembhard,
[email protected])
Immunosuppression & Serious Infections During Pregnancy: Among 4,961
pregnant women with systemic inflammatory conditions, use of high-dose steroids is
associated with an increased risk of serious infections, while risks are similar among
those on steroids, nonbiologic agents, or TNF inhibitors, researchers report (j895). In an
observational cohort study based on public and private insurance program data, the
authors found: “The crude incidence rates of serious infections per 100 person years
among 2,598 steroid users, 1,587 non-biologic users, and 776 TNF inhibitors users
included in this study were 3.4 (95% confidence interval 2.5 to 4.7), 2.3 (1.5 to 3.5), and
1.5 (0.7 to 3.0), respectively. No statistically significant differences in the risk of serious
infections during pregnancy were observed among users of the three
immunosuppressive drug classes: non-biologics v steroids, hazard ratio 0.81 (95%
confidence interval 0.48 to 1.37), TNF inhibitors v steroids 0.91 (0.36 to 2.26), and TNF
inhibitors v non-biologics 1.36 (0.47 to 3.93). In the dose–response analysis, higher
steroid dose was associated with an increased risk of serious infections during
pregnancy (coefficient for each unit increase in average prednisone equivalent mg daily
dose = 0.019, P = 0.02).” (R. J. Desai, [email protected])
>>>PNN NewsWatch
* In the first FDA approval of a product for nocturnal polyuria, the agency has OK’d
desmopressin acetate (Noctiva; Renaissance Lakewood, Serenity Pharmaceuticals)
nasal spray for adults who awaken at least two times per night to urinate. The product
carries a boxed warning about severe hyponatremia risk, and a Medication Guide must
be dispensed with prescriptions.
>>>PNN JournalWatch
* Neuraminidase Inhibitors During Pregnancy and Risk of Adverse Neonatal Outcomes
and Congenital Malformations: Population Based European Register Study, in BMJ,
2017; 356: j629. (S. Graner, [email protected])
* Intra-articular Corticosteroids Versus Intra-articular Corticosteroids Plus Methotrexate
in Oligoarticular Juvenile Idiopathic Arthritis: A Multicentre, Prospective, Randomised,
Open-Label Trial, in Lancet, 2017; 389: 909–16. (A. Ravelli, [email protected])
* Treatment-Resistant Schizophrenia: Treatment Response and Resistance in Psychosis
(TRRIP) Working Group Consensus Guidelines on Diagnosis and Terminology, in
American Journal of Psychiatry, 2017; 174: 216–29. (O. D. Howes)
* Treatment of Prescription Opioid Use Disorder in Pregnant Women, in American
Journal of Psychiatry, 2017; 174: 208–14. (C. Guille)
* Inhaled Corticosteroids and Respiratory Infections in Children With Asthma: A Metaanalysis, in Pediatrics, 2017; 139: 10.1542/peds.2016-3271. (C. Cazeiro)
* Pulmonary Hypertension Therapy and a Systematic Review of Efficacy and Safety of
PDE-5 Inhibitors, in Pediatrics, 2017; 139: 10.1542/peds.2016-1450. (C. Unegbu)
PNN Pharmacotherapy Line is published via e-mail each business day except U.S.
holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201;
571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News
Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail
[email protected] to request missing copies of PNN. Quarterly files archived at
www.PharmacotherapyNewsNetwork.com.
PNN Pharmacotherapy Line
Mar. 7, 2017 * Vol. 24, No. 44
Providing news and information about medications and their proper use
>>>Internal Medicine Report
Source: Early-release articles from and Mar. 7 issue of the Annals of Internal Medicine
(2017; 166).
Anakinra in Chronic Fatigue Syndrome: Symptoms of chronic fatigue syndrome
(CFS) were not improved by 4 weeks of subcutaneous anakinra therapy, researchers
report (10.7326/M16-2391). Cytokine inhibition was tested in 50 women aged 18–59
years of age with CFS and severe fatigue, with these results during 4 weeks of treatment
and 20 weeks of follow-up: “At 4 weeks, 8% (2 of 25) of anakinra recipients and 20% (5
of 25) of placebo recipients reached a fatigue level within the range reported by healthy
persons. There were no clinically important or statistically significant differences between
groups in … fatigue score at 4 weeks (mean difference, 1.5 points [95% CI, −4.1 to 7.2
points]) or the end of follow-up. No statistically significant between-group differences
were seen for any secondary outcome at 4 weeks or the end of follow-up. One patient in
the anakinra group discontinued treatment because of an adverse event. Patients in the
anakinra group had more injection site reactions (68% [17 of 25] vs. 4% [1 of 25]).” (M.
E. Roerink, [email protected])
Moving Health Care to a Single-Payer System: With the process of repealing and
replacing Obamacare under way, authors of an opinion article advocate moving toward a
single-payer system as a solution to the high overhead associated with billing and
payment under current processes (10.7326/M17-0302): “The president has promised
universal coverage and reduced deductibles and copayments, all within tight budgetary
constraints. That is a tall order and unlikely to be filled by proposals that Republicans
have offered thus far.…
“The economic case for single-payer reform is compelling. Private insurers’ overhead
currently averages 12.4% versus 2.2% in traditional Medicare. Reducing overhead to
Medicare’s level would save approximately $220 billion this year. Single-payer reform
could also sharply reduce billing and paperwork costs for physicians, hospitals, and
other providers. For example, by paying hospitals lump-sum operating budgets rather
than forcing them to bill per patient, Scotland and Canada have held hospital
administrative costs to approximately 12% of their revenue versus 25.3% in the United
States. Simplified, uniform billing procedures could reduce the money and time that
physicians spend on billing-related documentation.” (S. Woolhandler,
[email protected])
Pay-for-Performance Programs: Paying for performance in health care leads to
improved processes but not to better health outcomes, authors of a systematic review
conclude (pp. 341–53). Data from 69 studies of pay-for-performance (P4P) programs
show the following: “Low-strength evidence suggested that P4P programs in ambulatory
settings may improve process-of-care outcomes over the short term (2 to 3 years),
whereas data on longer-term effects were limited. Many of the positive studies were
conducted in the United Kingdom, where incentives were larger than in the United
States. The largest improvements were seen in areas where baseline performance was
poor. There was no consistent effect of P4P on intermediate health outcomes (lowstrength evidence) and insufficient evidence to characterize any effect on patient health
outcomes. In the hospital setting, there was low-strength evidence that P4P had little or
no effect on patient health outcomes and a positive effect on reducing hospital
readmissions.” (D. Kansagara, [email protected])
>>>Health Affairs Highlights
Source: Mar. issue of Health Affairs, a theme issue on Delivery System Innovation
(2017; 36).
Value-Based Insurance Design & Med Adherence: Patients with high-deductible
health plans require value-based insurance designs to avoid reduced medication
adherence, an analysis indicates (pp. 516–23): “We found that the value-based plan
offset reductions in medication adherence associated with switching to a deductible plan.
The value-based plan appeared particularly beneficial for patients who started with low
levels of medication adherence. Patients with additional clinical complexity or vulnerable
populations living in neighborhoods with lower socioeconomic status, however, did not
show adherence improvements and might not be taking advantage of value-based
insurance design provisions.…” (M. E. Reed, [email protected])
PNN Pharmacotherapy Line is published via e-mail each business day except U.S.
holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201;
571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News
Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail
[email protected] to request missing copies of PNN. Quarterly files archived at
www.PharmacotherapyNewsNetwork.com.
PNN Pharmacotherapy Line
Mar. 8, 2017 * Vol. 24, No. 45
Providing news and information about medications and their proper use
>>>JAMA Report
Source: Mar. 7 issue of JAMA (2017; 317).
Opioid Agonist for Dependence Treatment: Long-term maintenance therapy with
methadone or buprenorphine is more effective in patients with dependence than opioid
taper or psychological treatments alone, according to a summary of a Cochrane review
(pp. 967–8): “For patients who are dependent on prescription opioids, long-term
maintenance of opioid agonists is associated with less prescription opioid use and better
adherence to medication and psychological therapies for opioid dependence compared
with opioid taper or psychological treatments alone. Methadone maintenance was not
associated with differences in therapeutic efficacy compared with buprenorphine
maintenance treatment. Evidence quality was low to moderate.” (S. Nielsen,
[email protected])
Diet & Mortality: Many U.S. deaths attributed to heart disease, stroke, or type 2
diabetes are associated with poor diet, according to data from the National Health and
Nutrition Examination Surveys for 1999–2002 and 2009–12 (pp. 912–24). Overall,
48.6% of deaths of men from cardiometabolic disease and 41.8% of deaths of women
from these causes were associated with suboptimal dietary factors. The pattern held in
various age, race/ethnicity, and education subgroups. These patterns were noted for
consumption of 10 foods or nutrients that have been associated with cardiometabolic
diseases: “The largest numbers of estimated diet-related cardiometabolic deaths were
related to high sodium (66,508 deaths in 2012; 9.5% of all cardiometabolic deaths), low
nuts/seeds (59,374; 8.5%), high processed meats (57,766; 8.2%), low seafood omega-3
fats (54,626; 7.8%), low vegetables (53,410; 7.6%), low fruits (52,547; 7.5%), and high
[sugar-sweetened beverages (SSBs)] (51,694; 7.4%). Between 2002 and 2012,
population-adjusted US cardiometabolic deaths per year decreased by 26.5%. The
greatest decline was associated with insufficient polyunsaturated fats (−20.8% relative
change [95% UI, −18.5% to −22.8%]), nuts/seeds (−18.0% [95% UI, −14.6% to
−21.0%]), and excess SSBs (−14.5% [95% UI, −12.0% to −16.9%]). The greatest
increase was associated with unprocessed red meats (+14.4% [95% UI, 9.1%-19.5%]).”
(R. Micha, [email protected])
“The findings reported by Micha et al appear correct—a substantial proportion of
[cardiometabolic disease (CMD)] deaths are associated with suboptimal diet, and
improving diet quality could help prevent a large fraction of CMD deaths and reduce
health disparities,” conclude editorialists (pp. 908–9). “There is some precedence, such
as from trials of the Mediterranean diet plus supplemental foods, that modification of diet
can reduce cardiovascular disease risk by 30% to 70%. Yet estimation of downstream
benefits is complex and imprecise. Whether the authors overestimated or
underestimated the potential effects of improved diet, the likely benefits are substantial
and justify policies designed to improve diet quality.” (N. T. Mueller,
[email protected])
Lipoprotein Lipase Gene Variants & Coronary Artery Disease: People with rare,
damaging mutations in the gene for lipoprotein lipase (LPL) have an increased risk of
higher triglyceride levels and early-onset coronary artery disease (CAD), a study shows
(pp. 937–46). Case–control genomic and clinical cohorts showed these associations:
“Among 46,891 individuals with LPL gene sequencing data available, the mean (SD) age
was 50 (12.6) years and 51% were female. A total of 188 participants (0.40%; 95% CI,
0.35%–0.46%) carried a damaging mutation in LPL, including 105 of 32,646 control
participants (0.32%) and 83 of 14,245 participants with early-onset CAD (0.58%).
Compared with 46,703 noncarriers, the 188 heterozygous carriers of an LPL damaging
mutation displayed higher plasma triglyceride levels (19.6 mg/dL; 95% CI, 4.6–34.6
mg/dL) and higher odds of CAD (odds ratio = 1.84; 95% CI, 1.35–2.51; P < .001). An
analysis of 6 common LPL variants resulted in an odds ratio for CAD of 1.51 (95% CI,
1.39–1.64; P = 1.1 × 10−22) per 1-SD increase in triglycerides.” (S. Kathiresan,
[email protected])
>>>PNN NewsWatch
* A&H Focal Inc. is voluntarily recalling all lots marketed as dietary supplements for
male sexual enhancement since January 2014 because FDA tests show they contain
phosphodiesterase-5 inhibitors.
PNN Pharmacotherapy Line is published via e-mail each business day except U.S.
holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201;
571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News
Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail
[email protected] to request missing copies of PNN. Quarterly files archived at
www.PharmacotherapyNewsNetwork.com.
PNN Pharmacotherapy Line
Mar. 9, 2017 * Vol. 24, No. 46
Providing news and information about medications and their proper use
>>>NEJM Report
Source: Mar. 9 issue of the New England Journal of Medicine (2017; 376).
Long-Term Imatinib Outcomes in CML: Among patients with newly diagnosed chronic
myeloid leukemia (CML), the selective BCR-ABL1 kinase inhibitor imatinib was effective
and had no unacceptable cumulative or late toxic effects over 11 years of follow-up, a
Novartis-funded study shows (pp. 917–27). The trial, an open-label multicenter
crossover study, compared imatinib and interferon alfa plus cytarabine, with these
outcomes based on overall survival, response to treatment, and serious adverse events:
“The median follow-up was 10.9 years. Given the high rate of crossover among patients
who had been randomly assigned to receive interferon alfa plus cytarabine (65.6%) and
the short duration of therapy before crossover in these patients (median, 0.8 years), the
current analyses focused on patients who had been randomly assigned to receive
imatinib. Among the patients in the imatinib group, the estimated overall survival rate at
10 years was 83.3%. Approximately half the patients (48.3%) who had been randomly
assigned to imatinib completed study treatment with imatinib, and 82.8% had a complete
cytogenetic response. Serious adverse events that were considered by the investigators
to be related to imatinib were uncommon and most frequently occurred during the first
year of treatment.” (A. Hochhaus, [email protected])
“Although the journey to cancer cure has just begun, the use of imatinib to treat CML has
pointed oncology in a new direction,” concludes an editorialist (pp. 982–3). “The
development of imatinib fundamentally altered the field of oncology. Priorities shifted
from agents that were active on dividing cells to understanding the biology of individual
types of cancer. Once genetic analysis of tumors began, nearly all the cancer types had
more complex genetic abnormalities than did CML, but the complexity gave rise to a
revolution in cancer nosology. We now recognize that the grouping of tumors on the
basis of the appearance of a hematoxylin and eosin–stained tissue fragment examined
under a light microscope lumps together entities that are distinct both genetically and
clinically. Lung cancer is now considered to be at least eight or nine entities, and the
number of variants is continuing to expand. That is the good news. The bad news is that
the inherent genetic instability of many cancers also facilitates the development of
resistance to these interventions. In some instances, new genetic abnormalities create
vulnerabilities that can be attacked by new agents.” (D. L. Longo)
Access Problems With Medicaid Expansion: While increased insurance coverage
was evident in the second year after 29 states and the District of Columbia expanded
Medicaid programs under the Affordable Care Act, wait times for appointments also
climbed, researchers report, suggesting persistence of access problems (pp. 947–56).
Among 60,766 U.S. adults ages 18–64 years with low incomes, uninsurance rates fell by
8.2 percentage points in expansion states in the second year of increased coverage,
compared with nonexpansion states. Rates of Medicaid coverage increased by 15.6
percentage points. Expansion states showed fewer reports of inability to afford needed
follow-up care (3.4 percentage points less than nonexpansion states), and reports of
worrying about how to pay medical bills dropped by 7.9 percentage points. However,
reports of longer wait times climbed by 2.6 percentage points in expansion states,
compared with nonexpansion jurisdictions. (S. Miller, [email protected])
>>>PNN NewsWatch
* Only about one-third of smokers hospitalized for myocardial infarction and other
serious heart conditions received proven smoking-cessation therapy while they were in
the hospital, according to research scheduled for presentation at next week’s American
College of Cardiology’s 66th Annual Scientific Session. The findings come from a study
of 282 U.S. hospitals and 36,675 patients in 2004–14. Of patients who received
smoking-cessation therapy, about 20% were given the nicotine patch, which was the
most commonly given treatment, and about 10% received professionally delivered
smoking-cessation counseling. Few patients received medication or other forms of
nicotine replacement therapy such as nicotine gum or lozenges.
PNN Pharmacotherapy Line is published via e-mail each business day except U.S.
holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201;
571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News
Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail
[email protected] to request missing copies of PNN. Quarterly files archived at
www.PharmacotherapyNewsNetwork.com.
PNN Pharmacotherapy Line
Mar. 10, 2017 * Vol. 24, No. 47
Providing news and information about medications and their proper use
>>>Chest Highlights
Source: Mar. issue of Chest (2017; 151).
Asthma—Catching Up With the Evidence? In a retrospective cohort study of
adolescents and adults with asthma in British Columbia, inappropriate use of shortacting beta-agonists (SABAs) declined over time but increased over the course of the
disease, researchers report (pp. 612–8). Examination of the administrative health
database for the province showed these trends between 2002 and 2013 for those
between ages 15 and 67 years: “Three hundred fifty-six thousand, one hundred twelve
patients (56.5% female sex; mean age, 30.5 years) contributed 2.6 million patient-years.
In 7.3% of the patient-years, SABAs were prescribed inappropriately. This proportion
dropped by a relative rate of 5.3% per year (P <.001). In the first year of asthma, 6.3% of
patients had indicators of inappropriate SABA use, which dropped within the first 3 years
but increased thereafter. Excessive prescription of SABAs increased rapidly during the
time course of asthma (change of 23.3% per year; P <.001) and by age (change of 5.1%
per year; P <.001).” (M. Sadatsafavi)
Management of Chronic Hypersensitivity Pneumonitis: Assessed retrospectively for
effectiveness in patients with chronic hypersensitivity pneumonitis (cHP), use of either
mycophenolate mofetil (MMF) or azathioprine (AZA) was associated with improvements
in lung function, a study shows (pp. 619–25). Experiences at four interstitial lung disease
centers showed these patterns: “Seventy patients were included: 51 were treated with
MMF and 19 with AZA. Median follow-up after treatment initiation was 11 months. Prior
to treatment initiation, FVC and diffusion capacity of the lung for carbon monoxide (Dlco)
% predicted were declining at a mean rate of 0.12% (P <.001) and 0.10% (P <.001) per
month, respectively. Treatment with either MMF or AZA was not associated with
improved FVC (0.5% at 1 year; P = .46) but was associated with a statistically significant
improvement in Dlco of 4.2% (P <.001) after 1 year of treatment. Results were similar in
the subgroup of patients treated with MMF for 1 year; the FVC increased nonsignificantly
by 1.3% (P = .103) and Dlco increased by 3.9% (P < .001).” (J. Morisset)
>>>Cardiology Report
Source: Mar. 14 issue of the Journal of the American College of Cardiology (2017; 69).
Rheumatoid Arthritis & Heart Failure: Patients diagnosed with rheumatoid arthritis
(RA) are at increased risk of developing heart failure (HF), a Swedish study shows, with
symptoms developing quickly that were not explainable by increased risk of ischemic
heart disease (pp. 1275–85). Implicating inflammatory factors associated with RA,
investigators found a 25% increased risk of HF that was evident quickly after RA onset.
(Ä. Mantel, [email protected])
“Although effective treatments for heart failure targeting inflammation are at least years
away, an immediate clinical implication of the association of rheumatoid arthritis and
heart failure is the potential for improved diagnosis of left ventricular dysfunction,” writes
an editorialist (pp. 1286–7; P. Heidenreich).
>>>PNN NewsWatch
* A study of 43,145 men followed for a mean of 3.3 years shows beneficial effects of
phosphodiesterase-5 inhibitors following myocardial infarction (MI). In research
scheduled for next week’s American College of Cardiology’s 66th Annual Scientific
Session, Andersson et al. found that Swedish men who had prescriptions filled for the
erectile dysfunction drugs had a 30% lower all-cause mortality rate and a 36% reduced
risk of hospitalization for heart failure after an incident MI.
* Another ACC presentation reports increased risk of stroke and heart failure among
U.S. marijuana users. Kalla et al. studied adults aged 18–55 years with records in the
Nationwide Inpatient Sample 2009–10, finding a 10% increased risk of heart failure and
24% increased risk of cerebrovascular accident among cannabis users after correcting
for potentially confounding factors.
* Regeneca Worldwide, division of VivaCeuticals, is conducting a nationwide recall of
all of its herbal and dietary supplement products pursuant to a consent decree entered
by the federal court for the Central District of California, FDA announced yesterday. This
recall applies to all lot numbers produced from June 1, 2011, to Feb. 8, 2017.
PNN Pharmacotherapy Line is published via e-mail each business day except U.S.
holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201;
571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News
Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail
[email protected] to request missing copies of PNN. Quarterly files archived at
www.PharmacotherapyNewsNetwork.com.
PNN Pharmacotherapy Line
Mar. 13, 2017 * Vol. 24, No. 48
Providing news and information about medications and their proper use
>>>Lancet Highlights
Source: Mar. 11 issue of Lancet (2017; 389).
Quarter-Dose Quadpills for Hypertension: In a small trial, quarter-doses of four
antihypertensive agents combined in one tablet showed promise for additive effects in
the control of high blood pressure, researchers report (pp. 1035–42). Testing irbesartan
37.5 mg, amlodipine 1.25 mg, hydrochlorothiazide 6.25 mg, and atenolol 12.5 mg, the
group found these effects among 21 patients with hypertension: “The placebo-corrected
reduction in systolic 24-h blood pressure with the quadpill was 19 mm Hg (95% CI 14–
23), and office blood pressure was reduced by 22/13 mm Hg (p <0.0001). During
quadpill treatment, 18 (100%) of 18 participants achieved office blood pressure less than
140/90 mm Hg, compared with six (33%) of 18 during placebo treatment (p = 0.0013).
There were no serious adverse events and all patients reported that the quadpill was
easy to swallow. Our systematic review identified 36 trials (n = 4,721 participants) of one
drug at quarter-dose and six trials (n = 312) of two drugs at quarter-dose, against
placebo. The pooled placebo-corrected blood pressure-lowering effects were 5/2 mm Hg
and 7/5 mm Hg, respectively (both p <0.0001), and there were no side-effects from
either regimen.” (C. K. Chow, [email protected])
“Obtaining the full public health benefit of polypills will require education, advocacy,
endorsement, and implementation by key global agencies such as WHO and national
clinical bodies, as well as endorsement from governments,” authors of a related article
write (pp. 1066–74). “The evidence clearly shows polypills improve adherence and
cardiovascular disease risk factors for patients with indications for use of polypill
components—ie, those with established cardiovascular disease or at high risk. However,
the implementation of polypills into clinical practice has many challenges. The clinical
trials literature provides insights into the clinical impact of a polypill strategy, including
cost-effectiveness, safety of use, substantial improvement in adherence, and better risk
factor control than usual care. Despite the clear need for such a strategy and the
available clinical data backing up the use of the polypill in different patient populations,
challenges to widespread implementation, such as an absence of government
reimbursement and poor physician uptake (identified from on the ground experience in
countries following commercial rollout), have greatly obstructed real-world
implementation.” (R. Webster, [email protected])
>>>BMJ Highlights
Source: Early-release article from BMJ (2017; 356).
Insulin Initiation in Primary Care: A novel, nurse-centered model of care improved
insulin initiation rates among patients with type 2 diabetes in a cluster-randomized trial in
Australia (j783). The Stepping Up model involved a practice nurse leading insulin
initiation and mentoring by registered nurses with diabetes educator credentials, with
these results in 266 patients at 74 practices: “HbA1c improved in both arms, with a
clinically significant between arm difference (mean difference −0.6%, 95% confidence
interval −0.9% to −0.3%), favouring the intervention. At 12 months, in intervention
practices, 105/151 (70%) of participants had started insulin, compared with 25/115
(22%) in control practices (odds ratio 8.3, 95% confidence interval 4.5 to 15.4, P
<0.001). Target HbA1c (≤7% (53 mmol/mol)) was achieved by 54 (36%) intervention
participants and 22 (19%) control participants (odds ratio 2.2, 1.2 to 4.3, P = 0.02).
Depressive symptoms did not worsen at 12 months (PHQ-9: −1.1 (3.5) v −0.1 (2.9), P =
0.05).” (J. Furler, [email protected])
>>>PNN JournalWatch
* 2017 Infectious Diseases Society of America’s Clinical Practice Guidelines for
Healthcare-Associated Ventriculitis and Meningitis, in Clinical Infectious Diseases, 2017;
64: 701–6. (A. R. Tunkel)
* The Role of Stewardship in Addressing Antibacterial Resistance: Stewardship and
Infection Control Committee of the Antibacterial Resistance Leadership Group, in a
special supplement to Clinical Infectious Diseases, 2017; 64(suppl 1): S36–40. (D. J.
Anderson)
* Improving the Management of COPD in Women, in Chest, 2017; 151: 686–96. (C. R.
Jenkins)
* Management of Patients on Non–Vitamin K Antagonist Oral Anticoagulants in the
Acute Care and Periprocedural Setting: A Scientific Statement From the American Heart
Association, in Circulation, 2017; 135: e604–33. (A. N. Raval)
PNN Pharmacotherapy Line is published via e-mail each business day except U.S.
holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201;
571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News
Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail
[email protected] to request missing copies of PNN. Quarterly files archived at
www.PharmacotherapyNewsNetwork.com.
PNN Pharmacotherapy Line
Mar. 14, 2017 * Vol. 24, No. 49
Providing news and information about medications and their proper use
>>>Internal Medicine Report
Source: Mar. issue of JAMA Internal Medicine (2017; 177).
Language & Diabetes Care: Researchers and editorialists examine antidiabetic
medication adherence and glycemic control based on language discordance between
patients and providers.
Limited English proficiency (LEP) Latino patients with diabetes were significantly less
likely to adhere to newly prescribed antidiabetic agents than other groups, a study
shows, including English-speaking Latinos (pp. 371–9). Observational data from 2006
through 2012 at a large integrated health care delivery system showed that Spanish
fluency of the physician and availability of interpreters were insufficient to improve LEP’s
primary medication adherence (never dispensed), early-stage persistence (dispensed
only once), late-stage persistence (two or more cycles dispensed, but discontinued
within 24 months), or inadequate overall medication supply (more than 20% of time with
insufficient medication supply during first 24 months). (A. Fernández,
[email protected])
A second study, using a pre–post, difference-in-differences design, found that switching
LEP Latino patients from language-discordant primary-care providers (PCPs) to
language-concordant care improved clinical outcomes (pp. 380–7). In 2007–13, Kaiser
Northern California adult patients with diabetes who identified as Latino had these
clinical outcomes based on patient–PCP language concordance: “Overall, 1,605 LEP
Latino adults with diabetes (mean [SD] age, 60.5 [13.1] years) were included in this
study, and there was a significant net improvement in glycemic and LDL control among
patients who switched from language-discordant PCPs to concordant PCPs relative to
those who switched from one discordant PCP to another discordant PCP. After
adjustment and accounting for secular trends, the prevalence of glycemic control
increased by 10% (95% CI, 2% to 17%; P = .01), poor glycemic control decreased by 4%
(95% CI, −10% to 2%; P = .16) and LDL control increased by 9% (95% CI, 1% to 17%;
P = .03). No significant changes were observed in SBP control. Prevalence of LDL
control increased 15% (95% CI, 7% to 24%; P < .001) among LEP Latinos who switched
from concordant to discordant PCPs. Risk factor control did not worsen following a PCP
switch in any group.” (A. J. Karter, [email protected])
“As the US health care system evolves to more accountable care organizations with
integrated health systems, care of the most vulnerable must be prioritized,” editorialists
write (pp. 313–5). “Latinos with LEP who have diabetes represent such a population, as
evidenced not only by their language status but by their socioeconomic disadvantage.
There is a need to integrate greater granularity on social determinants into the medical
record to provide more precision patient–clinician interactions. Metrics for our health
care system need to include an equity outcome that sets a high bar for the most
vulnerable patients. Healthcare outcomes of LEP Latinos with diabetes would be an
excellent system measure of health equity.” (E. J. Pérez-Stable, [email protected])
Outcomes Data Imbalance Among Antidiabetic Drugs: FDA requirements for
randomized controlled trial data on adverse cardiovascular events for new antidiabetic
drugs have created an imbalance in available information, a Viewpoint author writes,
such that “there is no longer more evidence for the cardiovascular benefit of metformin
than there is for some of the newer second-line drugs” (pp. 301–2): “At what point can
newer drugs be used instead of metformin as first-line agents? Although direct
comparisons between metformin and newer agents in randomized clinical trials with
primary cardiovascular outcomes are the best way to address this question, no such
studies are under way, as evidenced by studies that have been registered at
clinicaltrials.gov as of November 2016.” (J. Flory, [email protected])
Better Adult Pneumococcal Vaccine Needed: “A new [pneumococcal] vaccine
exclusively for older adults and those who are immunocompromised is needed,”
Viewpoint authors suggest (pp. 303–4). “Simply creating a new vaccine with additional
serotypes and administering it to both children and adults is unlikely to solve this
problem. A compelling solution is to develop a conjugate vaccine for exclusive use in
adults while continuing to use PCV13 and PPV23 in children.” (D. M. Weinberger,
[email protected])
PNN Pharmacotherapy Line is published via e-mail each business day except U.S.
holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201;
571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News
Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail
[email protected] to request missing copies of PNN. Quarterly files archived at
www.PharmacotherapyNewsNetwork.com.
PNN Pharmacotherapy Line
Mar. 15, 2017 * Vol. 24, No. 50
Providing news and information about medications and their proper use
>>>JAMA Report
Source: Mar. 14 issue of JAMA (2017; 317).
Adequacy of Anticoagulation & Stroke: When ischemic stroke occurs, patients with
atrial fibrillation who are adequately anticoagulated have lower odds of developing
moderate or severe symptoms and of dying during hospitalization for the event, a study
shows (pp. 1057–67). In the Patient-Centered Research Into Outcomes Stroke Patients
Prefer and Effectiveness Research (PROSPER) study, retrospective analysis of data
from 1,622 hospitals in 2012–15 showed these patterns based on participation in the Get
With the Guidelines–Stroke program: “Of 94,474 patients (mean [SD] age, 79.9 [11.0]
years; 57.0% women), 7,176 (7.6%) were receiving therapeutic warfarin (international
normalized ratio [INR] ≥2) and 8,290 (8.8%) were receiving non–vitamin K antagonist
oral anticoagulants (NOACs) preceding the stroke. A total of 79,008 patients (83.6%)
were not receiving therapeutic anticoagulation; 12,751 (13.5%) had subtherapeutic
warfarin anticoagulation (INR <2) at the time of stroke, 37,674 (39.9%) were receiving
antiplatelet therapy only, and 28,583 (30.3%) were not receiving any antithrombotic
treatment. Among 91,155 high-risk patients (prestroke CHA2DS2-VASc score ≥2),
76,071 (83.5%) were not receiving therapeutic warfarin or NOACs before stroke. The
unadjusted rates of moderate or severe stroke were lower among patients receiving
therapeutic warfarin (15.8% [95% CI, 14.8%–16.7%]) and NOACs (17.5% [95% CI,
16.6%–18.4%]) than among those receiving no antithrombotic therapy (27.1% [95% CI,
26.6%–27.7%]), antiplatelet therapy only (24.8% [95% CI, 24.3%–25.3%]), or
subtherapeutic warfarin (25.8% [95% CI, 25.0%–26.6%]); unadjusted rates of in-hospital
mortality also were lower for those receiving therapeutic warfarin (6.4% [95% CI, 5.8%–
7.0%]) and NOACs (6.3% [95% CI, 5.7%–6.8%]) compared with those receiving no
antithrombotic therapy (9.3% [95% CI, 8.9%–9.6%]), antiplatelet therapy only (8.1%
[95% CI, 7.8%–8.3%]), or subtherapeutic warfarin (8.8% [95% CI, 8.3%–9.3%]). After
adjusting for potential confounders, compared with no antithrombotic treatment,
preceding use of therapeutic warfarin, NOACs, or antiplatelet therapy was associated
with lower odds of moderate or severe stroke (adjusted odds ratio [95% CI], 0.56 [0.51–
0.60], 0.65 [0.61–0.71], and 0.88 [0.84–0.92], respectively) and in-hospital mortality
(adjusted odds ratio [95% CI], 0.75 [0.67–0.85], 0.79 [0.72–0.88], and 0.83 [0.78–0.88],
respectively).” (Y. Xian, [email protected])
Getting to Goal in Type 2 Diabetes: “Patient-centered diabetes management can be
accomplished with lifestyle modification and combination therapy,” write the authors of a
Viewpoint on managing type 2 diabetes in 2017 (pp. 1015–6). “Metformin is an optimal
first-line agent; newer GLP1 and SGLT2 agents have efficacy for glucose lowering
coupled with weight loss and potential cardiovascular risk reduction; and insulin therapy
is generally safe and effective for patients not controlled with noninsulin agents. In
younger, healthy, newly diagnosed patients, a hemoglobin A1c level less than 7% should
be the goal; in older individuals with comorbidities, less stringent goals with a focus on
safety and avoidance of hypoglycemia are critical. Antihyperglycemic therapy should be
combined with evidence-based treatment of cholesterol and blood pressure for
cardiovascular risk reduction. Although the cardiovascular benefits of SGLT2 and GLP1
agents merit consideration, these medications are not replacements for statin therapy or
blood pressure management for reducing the risk of cardiovascular disease.” (J. E.
Manson, [email protected])
Efficacy Endpoints in Diabetes Studies: Achieving glycemic control in patients with
type 2 diabetes is not a valid predictor of reduced risk of complications of the disease,
according to Viewpoint authors who argue for use of heart disease and mortality
outcomes in studies of the disease (pp. 1017–8; H. M. Krumholz,
[email protected]).
>>>PNN NewsWatch
* A U.S. district judge yesterday entered a consent decree of permanent injunction
against EonNutra LLC, CDSM LLC and HABW LLC, manufacturers and distributors of
unapproved drugs and dietary supplements, and their owner, Michael Floren, requiring
Floren’s businesses to immediately cease operations until they come into compliance
with federal laws, FDA said.
PNN Pharmacotherapy Line is published via e-mail each business day except U.S.
holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201;
571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News
Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail
[email protected] to request missing copies of PNN. Quarterly files archived at
www.PharmacotherapyNewsNetwork.com.
PNN Pharmacotherapy Line
Mar. 16, 2017 * Vol. 24, No. 51
Providing news and information about medications and their proper use
>>>NEJM Report
Source: Mar. 16 issue of the New England Journal of Medicine (2017; 376).
Pembrolizumab in Advanced Urothelial Carcinoma: Used as second-line therapy in
542 patients with platinum-refractory advanced urothelial carcinoma, pembrolizumab
extended overall survival by approximately 3 months with a lower rate of treatmentrelated adverse events, compared with chemotherapy, the KEYNOTE-045 trial shows
(pp. 1015–26). The drug, a highly selective, humanized monoclonal IgG4-kappa isotype
antibody against programmed death 1 (PD-1), produced these results in an open-label,
phase 3 comparison with paclitaxel, docetaxel, or vinflunine: “The median overall
survival in the total population was 10.3 months (95% confidence interval [CI], 8.0 to
11.8) in the pembrolizumab group, as compared with 7.4 months (95% CI, 6.1 to 8.3) in
the chemotherapy group (hazard ratio for death, 0.73; 95% CI, 0.59 to 0.91; P = 0.002).
The median overall survival among patients who had a tumor [PD-1 ligand] combined
positive score of 10% or more was 8.0 months (95% CI, 5.0 to 12.3) in the
pembrolizumab group, as compared with 5.2 months (95% CI, 4.0 to 7.4) in the
chemotherapy group (hazard ratio, 0.57; 95% CI, 0.37 to 0.88; P = 0.005). There was no
significant between-group difference in the duration of progression-free survival in the
total population (hazard ratio for death or disease progression, 0.98; 95% CI, 0.81 to
1.19; P = 0.42) or among patients who had a tumor PD-L1 combined positive score of
10% or more (hazard ratio, 0.89; 95% CI, 0.61 to 1.28; P = 0.24). Fewer treatmentrelated adverse events of any grade were reported in the pembrolizumab group than in
the chemotherapy group (60.9% vs. 90.2%); there were also fewer events of grade 3, 4,
or 5 severity reported in the pembrolizumab group than in the chemotherapy group
(15.0% vs. 49.4%).” (J. Bellmunt, [email protected])
This trial “will have a practice-changing effect,” an editorialist writes, adding that PD-1
and PD-L1 inhibitors are active as first-line therapy (pp. 1073–4). “Indeed, they are being
investigated in randomized phase 3 trials assessing their use as first-line therapy in
combination with platinum-based chemotherapy (NCT02853305 and NCT02807636)
and cytotoxic T-lymphocyte–associated 4 (CTLA-4)–inhibiting immune modulators
(NCT02516241 and NCT03036098) and as adjuvant therapy after surgery for high-risk
disease (NCT02450331 and NCT02632409).” (G. Sonpavde)
Radiation + Temozolomide in Older Patients with Glioblastoma: Compared with
short-course radiotherapy alone, the combination of radiotherapy with temozolomide
nearly doubled survival time in some patients 65 years or older with newly diagnosed
glioblastoma, researchers report (pp. 1027–37): “A total of 562 patients underwent
randomization, 281 to each group. The median age was 73 years (range, 65 to 90). The
median overall survival was longer with radiotherapy plus temozolomide than with
radiotherapy alone (9.3 months vs. 7.6 months; hazard ratio for death, 0.67; 95%
confidence interval [CI], 0.56 to 0.80; P <0.001), as was the median progression-free
survival (5.3 months vs. 3.9 months; hazard ratio for disease progression or death, 0.50;
95% CI, 0.41 to 0.60; P <0.001). Among 165 patients with methylated O6methylguanine–DNA methyltransferase (MGMT) status, the median overall survival was
13.5 months with radiotherapy plus temozolomide and 7.7 months with radiotherapy
alone (hazard ratio for death, 0.53; 95% CI, 0.38 to 0.73; P <0.001). Among 189 patients
with unmethylated MGMT status, the median overall survival was 10.0 months with
radiotherapy plus temozolomide and 7.9 months with radiotherapy alone (hazard ratio
for death, 0.75; 95% CI, 0.56 to 1.01; P = 0.055; P = 0.08 for interaction). Quality of life
was similar in the two trial groups.” (J. R. Perry, [email protected])
>>>PNN NewsWatch
* FDA is warning that eluxadoline (Viberzi, Allergan), used to treat irritable bowel
syndrome with diarrhea, should not be used in patients who do not have a gallbladder.
An FDA review found these patients have an increased risk of developing serious
pancreatitis that could result in hospitalization or death. Among 120 reports received by
FDA of serious cases of pancreatitis or death, some patients also had sphincter of Oddi
spasm (n = 6) or abdominal pain (n = 16).
PNN Pharmacotherapy Line is published via e-mail each business day except U.S.
holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201;
571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News
Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail
[email protected] to request missing copies of PNN. Quarterly files archived at
www.PharmacotherapyNewsNetwork.com.
PNN Pharmacotherapy Line
Mar. 17, 2017 * Vol. 24, No. 52
Providing news and information about medications and their proper use
>>>Infectious Diseases Report
Source: Apr. 1 issue of Clinical Infectious Diseases (2017; 64).
Influenza Vaccine Booster Doses in Transplant Recipients: Solid organ transplant
recipients (SOTR) have an increased antibody response when a booster influenza
vaccine dose is administered 5 weeks after the initial standard-dose injection, according
to findings from the TRANSGRIPE 1–2 trial (pp. 829–38). The phase 3, open-label study
randomly assigned 499 SOTR to 1 or 2 influenza vaccine doses, with these results:
“Although seroconversion at 10 weeks did not meet significance in the modified
intention-to-treat population, seroconversion rates were significantly higher in the
booster arm for the per-protocol population (53.8% vs 37.6% for influenza A(H1N1)pdm;
48.1% vs 32.3% for influenza A(H3N2); and 90.7% vs 75% for influenza B; P < .05).
Furthermore, seroprotection at 10 weeks was higher in the booster group: 54% vs 43.2%
for A(H1N1)pdm; 56.9% vs 45.5% for A(H3N2); and 83.4% vs 71.8% for influenza B (P <
.05). The number needed to treat to seroprotect 1 patient was <10. The clinical efficacy
(99.2% vs 98.8%) and serious adverse events (6.4% vs 7.5%) were similar for both
groups.” (E. Cordero)
HPV Vaccine Responses 6 Years After 1, 2, or 3 Doses: A study from Fiji shows
effectiveness of human papillomavirus (HPV) vaccine after only 2 doses and suggests
that a single dose might be sufficient (pp. 852–9). Testing a single dose of a bivalent
HPV vaccine in 200 girls from two main ethnic groups in Fiji, investigators found these
levels of neutralizing antibodies (NAb) against HPV-6, -11, -16, and -18 at 28 days
based on the current and previously administered vaccines: “After 6 years (before a
dose of 2vHPV was given), the geometric mean NAb titers for all 4 HPV types were not
statistically different between 2-dose (2D) and 3-dose (3D) recipients: HPV-6 (3D: 2216
[95% confidence interval {CI},1695–2896]; 2D: 1476 [95% CI, 1019–2137]; P = .07),
HPV-11 (3D: 4431 [95% CI, 3396–5783]; 2D: 2951 [95% CI, 1984–4390]; P = .09), HPV16 (3D: 3373 [95% CI, 2511–4530]; 2D: 3275 [95% CI, 2452–4373]; P = .89); HPV-18
(3D: 628 [95% CI: 445–888]; 2D: 606 [95% CI, 462–862]; P = .89), and were higher in
FID than iTaukei girls. Although 1-dose recipients had significantly lower NAb titers than
2-/3-dose recipients, their NAb titers were 5- to 30-fold higher than unvaccinated girls.
Post-2vHPV NAb titers against HPV-16 and -18 were not statistically different between
girls who received 1, 2, or 3 doses of 4vHPV previously.” (Z. Q. Toh)
PPIs & Listeriosis: Prescribed proton pump inhibitors (PPIs) place patients at increased
risk of listeriosis, report researchers who looked at 721 cases and matched controls in
the Danish national registry (pp. 845–51): “The adjusted OR for current use of PPIs and
development of listeriosis was 2.81 (95% confidence interval [CI], 2.14–3.69). PPI usage
up to 90 days before the index date remained statistically significant. Subgroup analyses
revealed increasing ORs with decreasing age and level of comorbidity and an increased
OR for concurrent glucocorticoid treatment (OR, 4.61; 95% CI, 3.01–7.06). No significant
association was found for current use of histamine-2-receptor antagonists (adjusted OR,
1.82; 95% CI, 0.89–3.71).” (A. K. Jensen)
>>>Oncology Highlights
Source: Mar. 20 issue of the Journal of Clinical Oncology, a theme issue on genomics in
hematologic malignancies (2017; 35).
Genomics in Defining the Biology of Hematologic Malignancies: “Each hematologic
malignancy discussed [in this issue] has complex genetics caused by the combinatorial
diversity of somatic genetic mutations,” authors of an overview article write of the special
issue (pp. 927–8). “However, many malignancies are associated with frequent disruption
of a single biologic process, such as Janus kinase 2 signaling in myeloproliferative
neoplasms, the mRNA spliceosome in myelodysplastic syndrome, and mitogenactivated protein kinase signaling in multiple myeloma. Clinical genetics offers the
potential for improved disease classification, prognostication, identification of predictors
of therapeutic response, and evaluation of the depth of disease remission. The articles in
this issue, written by international authorities in the field, emphasize the translation of
this increased genomic understanding to the clinic, with the practicing hematologist and
oncologist in mind.” (B. L. Ebert)
PNN Pharmacotherapy Line is published via e-mail each business day except U.S.
holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201;
571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News
Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail
[email protected] to request missing copies of PNN. Quarterly files archived at
www.PharmacotherapyNewsNetwork.com.
PNN Pharmacotherapy Line
Mar. 20, 2017 * Vol. 24, No. 53
Providing news and information about medications and their proper use
>>>NEJM Report
Source: Early-release articles from the New England Journal of Medicine (2017; 376).
Targeting PCSK9 in Cholesterol Management: In articles released in conjunction with
the American College of Cardiology’s 66th Annual Scientific Session, researchers and
an editorialist examine the effects of medications that target the gene for proprotein
convertase subtilisin–kexin type 9 (PCSK9).
Evolocumab reduced risks of cardiovascular events among 27,564 participants in the
FOURIER clinical trial, reported investigators at the ACC meeting (doi:
10.1056/NEJMoa1615664). A primary composite efficacy end point of cardiovascular
death, myocardial infarction (MI), stroke, hospitalization for unstable angina, or coronary
revascularization, evolocumab produced these outcomes in comparison with placebo in
patients with atherosclerotic cardiovascular disease whose LDL cholesterol remained
above 70 mg/dL during statin therapy: “At 48 weeks, the least-squares mean percentage
reduction in LDL cholesterol levels with evolocumab, as compared with placebo, was
59%, from a median baseline value of 92 mg per deciliter (2.4 mmol per liter) to 30 mg
per deciliter (0.78 mmol per liter) (P <0.001). Relative to placebo, evolocumab treatment
significantly reduced the risk of the primary end point (1,344 patients [9.8%] vs. 1,563
patients [11.3%]; hazard ratio, 0.85; 95% confidence interval [CI], 0.79 to 0.92; P
<0.001) and the key secondary end point [of cardiovascular death, MI, or stroke] (816
[5.9%] vs. 1,013 [7.4%]; hazard ratio, 0.80; 95% CI, 0.73 to 0.88; P <0.001). The results
were consistent across key subgroups, including the subgroup of patients in the lowest
quartile for baseline LDL cholesterol levels (median, 74 mg per deciliter [1.9 mmol per
liter]). There was no significant difference between the study groups with regard to
adverse events (including new-onset diabetes and neurocognitive events), with the
exception of injection-site reactions, which were more common with evolocumab (2.1%
vs. 1.6%).” (M. S. Sabatine, [email protected])
“The FOURIER trial is a landmark trial providing formal evidence that treatment targeted
at PCSK9 inhibition confers additional cardiovascular benefit beyond that achieved by
lipid-lowering treatment alone,” an editorialist writes (doi: 10.1056/NEJMe1703138).
“However, in this trial, the duration of evolocumab treatment was rather short [median,
2.2 years]. The efficacy, with regard to atherosclerotic cardiovascular disease, of PCSK9
inhibition treatment that is started shortly after an acute event still needs to be
determined, as does the efficacy of the treatment in other categories of high-risk
patients. End-point studies of alirocumab and other monoclonal antibodies against
PCSK9 (bococizumab and LY3015014) are under way, and an RNA interference
therapeutic agent that inhibits PCSK9 synthesis and lowers plasma LDL cholesterol
levels has been tested in a phase 1 study.” (R. P. F. Dullaart)
In the phase 2 ORION-1 trial, inclisiran lowered PCSK9 and LDL cholesterol in 501
patients with high cardiovascular risk and elevated LDL cholesterol levels (doi:
10.1056/NEJMoa1615758). The RNA interference therapeutic agent produced these
results: “Patients who received inclisiran had dose-dependent reductions in PCSK9 and
LDL cholesterol levels. At day 180, the least-squares mean reductions in LDL
cholesterol levels were 27.9 to 41.9% after a single dose of inclisiran and 35.5 to 52.6%
after two doses (P <0.001 for all comparisons vs. placebo). The two-dose 300-mg
inclisiran regimen produced the greatest reduction in LDL cholesterol levels: 48% of the
patients who received the regimen had an LDL cholesterol level below 50 mg per
deciliter (1.3 mmol per liter) at day 180. At day 240, PCSK9 and LDL cholesterol levels
remained significantly lower than at baseline in association with all inclisiran regimens.
Serious adverse events occurred in 11% of the patients who received inclisiran and in
8% of the patients who received placebo. Injection-site reactions occurred in 5% of the
patients who received injections of inclisiran.” (K. K. Ray, [email protected])
>>>PNN JournalWatch
* Targeted Strategies Directed at the Molecular Defect: Toward Precision Medicine for
Select Primary Immunodeficiency Disorders, in Journal of Allergy and Clinical
Immunology, 2017; 139: 715–25. (T. A. Fleisher, [email protected])
* Geriatric Infectious Diseases: Current Concepts on Diagnosis and Management, in
Journal of the American Geriatrics Society, 2017; 65: 631–41. (T. T. Yoshikawa,
[email protected])
PNN Pharmacotherapy Line is published via e-mail each business day except U.S.
holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201;
571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News
Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail
[email protected] to request missing copies of PNN. Quarterly files archived at
www.PharmacotherapyNewsNetwork.com.
PNN Pharmacotherapy Line
Mar. 21, 2017 * Vol. 24, No. 54
Providing news and information about medications and their proper use
>>>Internal Medicine Report
Source: Mar. 21 issue of the Annals of Internal Medicine (2017; 166).
Intensive Blood Pressure Treatment in Older Adults: Treating older adults
aggressively to blood pressures below a target of 150/90 mm Hg has advantages that
outweigh problems such as hypotension, syncope, and greater medication burden,
according to a systematic review and clinical guidelines released by the American
College of Physicians (ACP) and the American Academy of Family Physicians (AAFP).
Improved health outcomes were evident among participants of 21 randomized controlled
trials and 3 observational studies, review authors note (pp. 419–29): “Nine trials provided
high-strength evidence that BP control to less than 150/90 mm Hg reduces mortality
(relative risk [RR], 0.90 [95% CI, 0.83 to 0.98]), cardiac events (RR, 0.77 [CI, 0.68 to
0.89]), and stroke (RR, 0.74 [CI, 0.65 to 0.84]). Six trials yielded low- to moderatestrength evidence that lower targets (≤140/85 mm Hg) are associated with marginally
significant decreases in cardiac events (RR, 0.82 [CI, 0.64 to 1.00]) and stroke (RR, 0.79
[CI, 0.59 to 0.99]) and nonsignificantly fewer deaths (RR, 0.86 [CI, 0.69 to 1.06]). Low- to
moderate-strength evidence showed that lower BP targets do not increase falls or
cognitive impairment.” (D. Kansagara, [email protected])
ACP and AAFP make these recommendations based on the available evidence (pp.
430–7; A. Qaseem, [email protected]):
* ACP and AAFP recommend that clinicians initiate treatment in adults aged 60 years or
older with systolic blood pressure persistently at or above 150 mm Hg to achieve a
target systolic blood pressure of less than 150 mm Hg to reduce the risk for mortality,
stroke, and cardiac events. (Grade: strong recommendation, high-quality evidence).
ACP and AAFP recommend that clinicians select the treatment goals for adults aged 60
years or older based on a periodic discussion of the benefits and harms of specific blood
pressure targets with the patient.
* ACP and AAFP recommend that clinicians consider initiating or intensifying
pharmacologic treatment in adults aged 60 years or older with a history of stroke or
transient ischemic attack to achieve a target systolic blood pressure of less than 140 mm
Hg to reduce the risk for recurrent stroke. (Grade: weak recommendation, moderatequality evidence). ACP and AAFP recommend that clinicians select the treatment goals
for adults aged 60 years or older based on a periodic discussion of the benefits and
harms of specific blood pressure targets with the patient.
* ACP and AAFP recommend that clinicians consider initiating or intensifying
pharmacologic treatment in some adults aged 60 years or older at high cardiovascular
risk, based on individualized assessment, to achieve a target systolic blood pressure of
less than 140 mm Hg to reduce the risk for stroke or cardiac events. (Grade: weak
recommendation, low-quality evidence). ACP and AAFP recommend that clinicians
select the treatment goals for adults aged 60 years or older based on a periodic
discussion of the benefits and harms of specific blood pressure targets with the patient.
Editorialists outline characteristics of programs that have produced large improvements
in blood pressure (BP) and have the potential to lower hypertension-related morbidity
and mortality in older adults (pp. 445–6): “On the basis of these recommendations,
providers who wish to prevent hypertension-related morbidity and mortality by
implementing high-value, population-based practices should develop an office-based
program with the following features: high-fidelity BP measurement support, including
office BP measurement conducted by well-trained staff, resources for training patients in
home monitoring or the availability of ambulatory BP monitoring, and ongoing quality
assurance efforts; routine assessment of global [cardiovascular disease (CVD)] risk in all
patients aged 40 years or older and in younger individuals with multiple risk factors or
extreme elevations of a single risk factor; provider training in shared decision making for
hypertension treatment and CVD risk reduction in general; creation of a registry to track
patients receiving hypertension treatment (and other forms of CVD risk reduction); and
use of non–visit-based follow-up for patients with moderate to severe hypertension who
have had treatment initiation or changes (to monitor effectiveness and potential adverse
effects).” (M. Pignone, [email protected])
PNN Pharmacotherapy Line is published via e-mail each business day except U.S.
holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201;
571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News
Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail
[email protected] to request missing copies of PNN. Quarterly files archived at
www.PharmacotherapyNewsNetwork.com.
PNN Pharmacotherapy Line
Mar. 22, 2017 * Vol. 24, No. 55
Providing news and information about medications and their proper use
>>>JAMA Report
Source: Mar. 21 issue of JAMA (2017; 317).
Consumer Advertising & Testosterone Use: Increased levels of direct-to-consumer
advertising (DTCA) were associated with increased testosterone testing, new initiations
of therapy with the hormone, and initiation without recent testing, according to a study of
75 designated market areas (DMAs) in the U.S. (pp. 1159–66). Insurance claims from
2009–13 showed these patterns in relation to Nielsen-measured DTCA for the 75 largest
DMAs: “Of 17,228,599 commercially insured men in the 75 DMAs, 1,007,990 (mean
age, 49.6 [SD, 11.5] years) had new serum testosterone tests and 283,317 (mean age,
51.8 [SD, 11.3] years) initiated testosterone treatment. Advertising intensity varied by
geographic region and time, with the highest intensity seen in the southeastern United
States and with months ranging from no ad exposures to a mean of 13.6 exposures per
household. Nonbranded advertisements were common prior to 2012, with branded
advertisements becoming more common during and after 2012. Each household
advertisement exposure was associated with a monthly increase in rates of new
testosterone testing (rate ratio [RR], 1.006; 95% CI, 1.004–1.008), initiation (RR, 1.007;
95% CI, 1.004–1.010), and initiation without a recent test (RR, 1.008; 95% CI, 1.002–
1.013). Mean absolute rate increases were 0.14 tests (95% CI, 0.09–0.19), 0.05 new
initiations (95% CI, 0.03–0.08), and 0.02 initiations without a recent test (95% CI, 0.01–
0.03) per 10,000 men for each monthly ad exposure over the entire period.” (J. B.
Layton, [email protected])
“As learned intermediaries, physicians are supposed to protect consumers from the
potential adverse effects of drug advertisements,” writes an editorialist (pp. 1124–5).
“However, when clinical indications are weak or uncertain, signals of harm are
suggestive but unproven, and patient demand is strong, physicians may not be able to
provide that protection. In a recent observational study, DTCA was associated with an
increase in statin prescribing that was largest among patients with the lowest
cardiovascular risk—precisely the opposite of what would be desired from the
perspective of cardiovascular risk reduction. Findings like these suggest that DTCA of
prescription drugs as currently regulated in the United States is unlikely to yield
consistent public health gains.” (R. L. Kravitz, [email protected])
Dabigatran, Warfarin & Risk of Osteoporotic Fractures: In a retrospective cohort
study, use of dabigatran rather than warfarin was associated with a lower risk of
osteoporotic fractures among patients in Hong Kong with nonvalvular atrial fibrillation
(NVAF), researchers report (pp. 1151–8). Results from 2010–14 showed the following
associations: “Among 51,496 patients newly diagnosed with NVAF, 8,152 new users of
dabigatran (n = 3,268) and warfarin (n = 4,884) were matched by propensity score (50%
women; mean [SD] age, 74 [11] years). Osteoporotic fracture developed in 104 (1.3%)
patients during follow-up (32 dabigatran users [1.0%]; 72 warfarin users [1.5%]). Results
of Poisson regression analysis showed that dabigatran use was associated with a
significantly lower risk of osteoporotic fracture compared with warfarin (0.7 vs 1.1 per
100 person–years; ARD per 100 person–years, −0.68 [95% CI, −0.38 to −0.86]; IRR,
0.38 [95% CI, 0.22 to 0.66]). The association with lower risk was statistically significant
in patients with a history of falls, fractures, or both (dabigatran vs warfarin, 1.6 vs 3.6 per
100 person–years; ARD per 100 person–years, −3.15 [95% CI, −2.40 to −3.45]; IRR,
0.12 [95% CI, 0.04 to 0.33]), but not in those without a history (0.6 vs 0.7 per 100
person–years; ARD per 100 person–years, −0.04 [95% CI, 0.67 to −0.39]; IRR, 0.95
[95% CI, 0.45 to 1.96]) (P value for interaction, <.001).” (I. C. K. Wong,
[email protected])
>>>PNN NewsWatch
* Safinamide (Xadago, Newron Pharmaceuticals) tablets have been approved by FDA
as an add-on treatment for patients with Parkinson disease who are currently taking
levodopa/carbidopa and experiencing “off” episodes. The drug is an MAO-B inhibitor;
because of the risk of serotonin syndrome and other serious interactions, safinamide is
contraindicated in patients taking other MAO inhibitors, opioids, dextromethorphan,
amphetamine, methylphenidate, cyclobenazprine, some antidpressants, or St. John’s
wort.
PNN Pharmacotherapy Line is published via e-mail each business day except U.S.
holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201;
571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News
Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail
[email protected] to request missing copies of PNN. Quarterly files archived at
www.PharmacotherapyNewsNetwork.com.
PNN Pharmacotherapy Line
Mar. 23, 2017 * Vol. 24, No. 56
Providing news and information about medications and their proper use
>>>NEJM Report
Source: Mar. 23 issue of the New England Journal of Medicine (2017; 376).
Pregabalin in Acute and Chronic Sciatica: After 8 weeks of pregabalin therapy,
intensity of leg pain associated with sciatica was not altered, researchers report, and
adverse effects were higher in comparison with placebo (pp. 1111–20). With doses of
pregabalin of up to 600 mg/d for up to 8 weeks and evaluation through week 52, results
showed: “A total of 209 patients underwent randomization, of whom 108 received
pregabalin and 101 received placebo; after randomization, 2 patients in the pregabalin
group were determined to be ineligible and were excluded from the analyses. At week 8,
the mean unadjusted leg-pain intensity score was 3.7 in the pregabalin group and 3.1 in
the placebo group (adjusted mean difference, 0.5; 95% confidence interval [CI], −0.2 to
1.2; P = 0.19). At week 52, the mean unadjusted leg-pain intensity score was 3.4 in the
pregabalin group and 3.0 in the placebo group (adjusted mean difference, 0.3; 95% CI,
−0.5 to 1.0; P = 0.46). No significant between-group differences were observed with
respect to any secondary outcome at either week 8 or week 52. A total of 227 adverse
events were reported in the pregabalin group and 124 in the placebo group. Dizziness
was more common in the pregabalin group than in the placebo group.” (C. Lin,
[email protected])
“These results indicate failure of the drug to improve this condition; however, the design
of the trial does not exclude a possible benefit in chronic sciatica,” editorialists write (pp.
1169–70). “This trial highlights a need in the field of pain treatment — namely, to identify
biomarkers that could link the efficacy of a drug with the biologic causes of diverse types
of pain.” (N. Attal)
Efficacy of Low-Cost, Heat-Stable Oral Rotavirus Vaccine: In a study of infants in
Niger, an oral rotavirus vaccine had an efficacy of 66.7% against severe rotavirus
gastroenteritis (pp. 1121–30). The live, oral bovine rotavirus pentavalent vaccine was
administered in three doses at 6, 10, and 14 weeks of age in a placebo-controlled trial,
with these results: “Among the 3,508 infants who were included in the per-protocol
efficacy analysis, there were 31 cases of severe rotavirus gastroenteritis in the vaccine
group and 87 cases in the placebo group (2.14 and 6.44 cases per 100 person–years,
respectively), for a vaccine efficacy of 66.7% (95% confidence interval [CI], 49.9 to 77.9).
Similar efficacy was seen in the intention-to-treat analyses, which showed a vaccine
efficacy of 69.1% (95% CI, 55.0 to 78.7). There was no significant between-group
difference in the risk of adverse events, which were reported in 68.7% of the infants in
the vaccine group and in 67.2% of those in the placebo group, or in the risk of serious
adverse events (in 8.3% in the vaccine group and in 9.1% in the placebo group); there
were 27 deaths in the vaccine group and 22 in the placebo group. None of the infants
had confirmed intussusception.” (R. F. Grais, [email protected])
“Rotavirus gastroenteritis is the leading cause of diarrhea-associated hospitalization and
death in children younger than 5 years of age,” editorialists write, “with more than 85% of
the approximately 200,000 annual rotavirus deaths occurring in Africa and Asia” (pp.
1170–2). “During the past three decades, remarkable progress has been made in
reducing mortality from diarrheal disease, but the goal of ending such deaths cannot be
achieved without aggressive implementation of a comprehensive approach to diarrhea
prevention and treatment, including providing access of rotavirus vaccines to every child
regardless of economic status. Increased availability of low-cost, programmatically
suitable vaccines in abundant supply will be key to achieving this goal.” (M. Santosham)
C1 Inhibition in Hereditary Angioedema Attacks: Self-administered subcutaneous
CSL830, a C1 inhibitor, reduced the frequency of acute angioedema attacks among 90
patients with type I or II hereditary angioedema in a phase 3 trial (pp. 1131–40).
Compared with placebo, two doses of the drug “reduced the rate of attacks of hereditary
angioedema (mean difference with 40 IU, –2.42 attacks per month; 95% confidence
interval [CI], –3.38 to –1.46; and mean difference with 60 IU, –3.51 attacks per month;
95% CI, –4.21 to –2.81; P <0.001 for both comparisons),” the authors write. (H.
Longhurst, [email protected])
PNN Pharmacotherapy Line is published via e-mail each business day except U.S.
holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201;
571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News
Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail
[email protected] to request missing copies of PNN. Quarterly files archived at
www.PharmacotherapyNewsNetwork.com.
PNN Pharmacotherapy Line
Mar. 24, 2017 * Vol. 24, No. 57
Providing news and information about medications and their proper use
>>>Allergy/Immunology Report
Source: Mar. issue of the Journal of Allergy and Clinical Immunology (2017; 139).
Aspirin-Exacerbated Respiratory Disease: “Aspirin-exacerbated respiratory disease
(AERD) is characterized by adult-onset asthma and severe chronic eosinophilic
rhinosinusitis with nasal polyposis,” write authors of a review article (pp. 764–6). “AERD
is not consistently associated with atopy, although serum total IgE levels can be
increased. Steady-state levels of urinary or nasal lavage fluid mast cell activation
products (histamine and tryptase) and leukotriene (LT) E4, the stable metabolite of the
cysteinyl leukotrienes (cysLTs), exceed those found in patients with aspirin-tolerant
asthma and sinonasal disease.” (J. A. Boyce, [email protected])
Automated Identification of New Patients With AERD: Patients with previously
undiagnosed aspirin-exacerbated respiratory disease (AERD) can be identified using an
informatics algorithm, a study shows (pp. 819–25.e6). All three clinical features of AERD
— asthma, nasal polyposis, and respiratory reactions to cyclooxygenase-1
inhibitors/NSAIDs — are noted in electronic health records (EHRs), the authors explain.
Using an informatics algorithm to search EHRs of adults in the Partners Healthcare
system over a 10-year period, they found: these patterns among those with asthma,
nasal polyps, and record of respiratory (cohort A) or unspecified (cohort B) reactions to
NSAIDs: “Our algorithm identified 731 ‘possible AERD’ cases, of which 638 were not in
our AERD patient registry. Chart review of cohorts A (n = 511) and B (n = 127)
demonstrated a positive predictive value of 78.4% for ‘clinical AERD,’ which rose to
88.7% when unspecified reactions were excluded. Of those with clinical AERD, 12.4%
had no mention of AERD by any treating caregiver and were classified as ‘undiagnosed
AERD.’ ‘Undiagnosed AERD’ cases were less likely than ‘diagnosed AERD’ cases to
have been seen by an allergist/immunologist (38.7% vs 93.2%; P <.0001).” (K. N. Cahill,
[email protected])
Capsaicin-Evoked Cough Responses in Asthma: Neuronal dysfunction is the likely
mechanism of exaggerated capsaicin-evoked cough responses in patients with mild-tomoderate asthma, researchers report, and nonatopic asthmatic patients had the highest
cough responses (pp. 771–9.e10). Compared with healthy volunteers, patients with
stable asthma had these reactions to capsaicin inhalational challenge: “Ninety-seven
patients with stable asthma (median age, 23 years [interquartile range, 21–27 years];
60% female) and 47 healthy volunteers (median age, 38 years [interquartile range, 29–
47 years]; 64% female) were recruited. Asthmatic patients had higher Emax and lower
ED50 values than healthy volunteers. Emax values were 27% higher in female subjects (P
= .006) and 46% higher in patients with nonatopic asthma (P = .003) compared with
healthy volunteers. Also, patients with atopic asthma had a 21% lower Emax value than
nonatopic asthmatic patients (P = .04). The ED50 value was 65% lower in female patients
(P = .0001) and 71% lower in all asthmatic patients (P = .0008). ED50 values were also
influenced by asthma control and serum IgE levels, whereas Emax values were related to
24-hour cough frequency. Age, body mass index, FEV1, PC20, fraction of exhaled nitric
oxide, blood eosinophil counts, and inhaled steroid treatment did not influence cough
parameters.” (J. A. Smith, [email protected])
>>>PNN NewsWatch
* The APhA House of Delegates convenes this weekend at the Association’s Annual
Meeting & Exposition in San Francisco. Pharmacy’s only professionwide policy-setting
body is considering three topics: Patient Access to Pharmacist-Prescribed Medications,
Pharmacists’ Role Within Value-Based Payment Models, and Pharmacy Performance
Networks. Delegates to the House have submitted several items of new business to be
considered, including expansion of the statement on equal employment opportunity for
pharmacists to include all pharmacy personnel, drug disposal, on-label indication and
medication safety, work schedules (to include meal and rest breaks, on-site dependent
care, and flexible spending accounts), support for clinically validated blood pressure
measurement devices, and pharmacy technician education, training, and development
(to include completion of an educational/training program and certification by 2027).
PNN Pharmacotherapy Line is published via e-mail each business day except U.S.
holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201;
571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News
Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail
[email protected] to request missing copies of PNN. Quarterly files archived at
www.PharmacotherapyNewsNetwork.com.
PNN Pharmacotherapy Line
Mar. 27, 2017 * Vol. 24, No. 58
Providing news and information about medications and their proper use
>>>Lancet Highlights
Source: Mar. 25 issue of Lancet (2017; 389).
Sirukumab in Refractory Rheumatoid Arthritis: In the phase 3 SIRROUND-T study,
the interleukin-6 inhibitor sirukumab relieved disease symptoms with minimal adverse
effects among 878 patients with active rheumatoid arthritis refractory or intolerant to
previous treatment with at least one anti-TNF drug (pp. 1206–17). Participants received
subcutaneous sirukumab or placebo every 2 or 4 weeks, with these results: “The
proportions of patients who achieved [20% improvement in American College of
Rheumatology criteria (ACR20) scores] at week 16 were 117 (40%) of 292 with 50 mg
sirukumab every 4 weeks, and 132 (45%) of 292 with 100 mg sirukumab every 2 weeks
versus 71 (24%) of 294 with placebo; differences compared with placebo were 0.16
(95% CI 0.09–0.23) for 50 mg sirukumab every 4 weeks and 0.21 (0.14–0.29) for 100
mg sirukumab every 2 weeks (both p <0.0001). Adverse event incidences in the 24week placebo-controlled period were similar across groups (at least one event occurred
for 182 patients assigned to placebo [62%, including early escape patients switched to
sirukumab at week 18] of 294; 194 [66%] of 292 with 50 mg sirukumab every 4 weeks;
and 207 [71%] of 292 with 100 mg sirukumab every 2 weeks). The most common
adverse events in this period were injection-site erythema (four [1%] with placebo, 22
[8%] with 50 mg sirukumab every 4 weeks, and 41 [14%] with 100 mg sirukumab every 2
weeks). At week 52, of all patients receiving sirukumab including those reassigned from
placebo, the most common adverse events were again injection-site erythema (33 [8%]
of 416 with 50 mg sirukumab every 4 weeks and 66 [16%] of 418 with 100 mg sirukumab
every 2 weeks).” (P. P. Tak, [email protected])
>>>BMJ Highlights
Source: Early-release article from BMJ (2017; 356).
Alcohol & Cardiovascular Diseases: “Heterogeneous associations … between level of
alcohol consumption and the initial presentation of cardiovascular diseases” suggest the
need for “a more nuanced approach to the role of alcohol in prevention of cardiovascular
disease is necessary,” according to authors of a population-based cohort study (j909).
Using medical records of 1.9 million adults without cardiovascular disease at baseline,
the authors found: “114,859 individuals received an incident cardiovascular diagnosis
during follow-up. Non-drinking was associated with an increased risk of unstable angina
(hazard ratio 1.33, 95% confidence interval 1.21 to 1.45), myocardial infarction (1.32,
1.24 to1.41), unheralded coronary death (1.56, 1.38 to 1.76), heart failure (1.24, 1.11 to
1.38), ischaemic stroke (1.12, 1.01 to 1.24), peripheral arterial disease (1.22, 1.13 to
1.32), and abdominal aortic aneurysm (1.32, 1.17 to 1.49) compared with moderate
drinking (consumption within contemporaneous UK weekly/daily guidelines of 21/3 and
14/2 units for men and women, respectively). Heavy drinking (exceeding guidelines)
conferred an increased risk of presenting with unheralded coronary death (1.21, 1.08 to
1.35), heart failure (1.22, 1.08 to 1.37), cardiac arrest (1.50, 1.26 to 1.77), transient
ischaemic attack (1.11, 1.02 to 1.37), ischaemic stroke (1.33, 1.09 to 1.63), intracerebral
haemorrhage (1.37, 1.16 to 1.62), and peripheral arterial disease (1.35; 1.23 to 1.48),
but a lower risk of myocardial infarction (0.88, 0.79 to 1.00) or stable angina (0.93, 0.86
to 1.00).” (S. Bell, [email protected])
>>>PNN NewsWatch
* FDA on Thursday granted accelerated approval to avelumab (Bavencio, EMD Serono)
for first-line treatment of adults and pediatric patients 12 years and older with metastatic
Merkel cell carcinoma. This is the first FDA-approved treatment for this rare, aggressive
form of skin cancer.?
* At the APhA Annual Meeting & Exhibition in San Francisco, Daniel A. Hussar,
BSPharm, MS, PhD, received the Remington Honor Medal.The long-time professor at
the Philadelphia College of Pharmacy is well-known for his advocacy in pharmacy and
his articles and presentation on new drugs.
>>>PNN JournalWatch
* Osteoporosis Treatment Efficacy for Men: A Systematic Review and Meta-Analysis, in
Journal of the American Geriatrics Society, 2017; 65: 490–5. (S. Nayak,
[email protected])
* Review: Breaking From Bisphosphonates, in Arthritis & Rheumatology, 2017; 69: 494–
8. (M. Seton)
PNN Pharmacotherapy Line is published via e-mail each business day except U.S.
holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201;
571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News
Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail
[email protected] to request missing copies of PNN. Quarterly files archived at
www.PharmacotherapyNewsNetwork.com.
PNN Pharmacotherapy Line
Mar. 28, 2017 * Vol. 24, No. 59
Providing news and information about medications and their proper use
>>>Geriatrics Report
Source: Mar. Journal of the American Geriatrics Society (2017; 65).
High-Dose Vitamin D for Preventing Respiratory Infections: Administered to older
adults residing in long-term care facilities, high-dose vitamin D supplements given once
monthly reduced the frequency of acute respiratory infection (ARI) but also increased
falls without an increase in fractures, researchers report (pp. 496–503). Participants
assigned to the high-dose group received monthly supplements of vitamin D3 100,000
IU. Outcomes were compared with participants who received placebo if they were
receiving vitamin D3 400–1000 IU/d as part of usual care or vitamin D3 12,000 IU monthly
if they were on lower doses as part of usual care. Results showed: “Participants (55 high
dose, 52 standard dose) were randomized and included in the final analysis. The highdose group had 0.67 ARIs per person–year and the standard-dose group had 1.11
(incidence rate ratio (IRR) = 0.60, 95% confidence interval (CI) = 0.38–0.94, P = .02).
Falls were more common in the high-dose group (1.47 per person–year vs 0.63 in
standard-dose group; IRR = 2.33, 95% CI = 1.49–3.63, P < .001). Fractures were
uncommon and similar in both groups (high dose 0.10 vs standard dose 0.19 per
person–year; P = .31). Mean trough 25-hydroxyvitamin D levels during the trial were 32.
ng/mL in the high-dose group and 25.1 ng/mL in the standard-dose group. There was no
hypercalcemia or kidney stones in either group.” (A. A. Ginde,
[email protected])
Vitamin D Deficiency, Incident Frailty & Cardiometabolic Diseases: In a prospective
longitudinal cohort study conducted from 1994 through 2008, low vitamin D levels were
associated with development of incident frailty, but the relationship was no longer
significant after accounting for the presence of cardiometabolic diseases (pp. 619–24).
Concluding that “future studies should explore mechanisms to explain this relationship,”
the authors report these findings based on serum circulating 25-hydroxyvitamin D
(25[OH]D) concentrations: “Incidence rate of frailty was 32.2 per 1,000 person–years in
participants with 25(OH)D < 10 ng/mL, compared to 12.9 per 1,000 person–years in
those with 25(OH)D ≥ 30 ng/mL (mean follow-up = 8.5 ± 3.7 years). In cumulative
incidence analyses, those with lower 25(OH)D exhibited higher frailty incidence, though
differences were non-significant (P = .057). In regression models adjusted for
demographics, smoking, and season, 25(OH)D < 10 ng/mL (vs ≥30 ng/mL) was
associated with nearly three-times greater frailty incidence (hazard ratio (HR) = 2.77,
95% CI = 1.14, 6.71, P = .02). After adjusting for BMI, the relationship of 25(OH)D < 10
ng/mL (vs ≥30 ng/mL) with incident frailty persisted, but was attenuated after further
accounting for cardiometabolic diseases (HR = 2.29, 95% CI = 0.92, 5.69, P = .07).” (R.
R. Kalyani, [email protected])
Delirium Prevention Strategies in Older Adults: Delirium-friendly preprinted
postoperative orders (PPOs) for individuals with hip fracture, used by regular nursing
staff in a tertiary-care hospital, significantly lowered the occurrence of postoperative
delirium but made no difference with respect to length of stay, discharge site, or inhospital mortality, a study shows (pp. 567–73). The PPOs provided doses of
medications for nighttime sedation, analgesia, and nausea and called for attention to
catheter removal and bowel movements, producing these results: “Orthopedic nurses
adhered reasonably well with delirium-friendly PPOs. Of 283 participants, 42%
developed postoperative delirium, with significantly less delirium in the intervention
group (intervention 33%, control 51%, P = .001). The effect of the intervention was
stronger in individuals with preexisting dementia (intervention 60%, control 97%, P <
.001). Participants with postoperative delirium had longer hospital stays and were more
likely to die or be discharged to a nursing home, but there was no significant betweengroup difference in these outcomes.” (S. Freter, [email protected])
>>>PNN NewsWatch
* Niraparib (Zejula, Tesaro) has been approved by FDA for maintenance treatment of
adults with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who
have had a complete or partial response to platinum-based chemotherapy. The drug is a
poly ADP-ribose polymerase (PARP) inhibitor that blocks an enzyme involved in
repairing damaged DNA.
PNN Pharmacotherapy Line is published via e-mail each business day except U.S.
holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201;
571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News
Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail
[email protected] to request missing copies of PNN. Quarterly files archived at
www.PharmacotherapyNewsNetwork.com.
PNN Pharmacotherapy Line
Mar. 29, 2017 * Vol. 24, No. 60
Providing news and information about medications and their proper use
>>>JAMA Report
Source: Mar. 28 issue of JAMA (2017; 317).
Vitamin D, Calcium Supplementation & Cancer Incidence in Older Women:
Administered to older women in a 4-year trial, dietary supplementation with vitamin D3
and calcium produced no significant difference in all-type cancer incidence, researchers
report (pp. 1234–43). Nonmelanoma skin cancers were excluded from the analysis,
which showed these results for 2,000 IU/d of vitamin D3 and 1,500 mg/d of calcium:
“Among 2,303 randomized women (mean age, 65.2 years [SD, 7.0]; mean baseline
serum 25-hydroxyvitamin D level, 32.8 ng/mL [SD, 10.5]), 2,064 (90%) completed the
study. At year 1, serum 25-hydroxyvitamin D levels were 43.9 ng/mL in the vitamin
D3 + calcium group and 31.6 ng/mL in the placebo group. A new diagnosis of cancer was
confirmed in 109 participants, 45 (3.89%) in the vitamin D3 + calcium group and 64
(5.58%) in the placebo group (difference, 1.69% [95% CI, −0.06% to 3.46%]; P = .06).
Kaplan–Meier incidence over 4 years was 0.042 (95% CI, 0.032 to 0.056) in the vitamin
D3 + calcium group and 0.060 (95% CI, 0.048 to 0.076) in the placebo group; P = .06. In
unadjusted Cox proportional hazards regression, the hazard ratio was 0.70 (95% CI,
0.47 to 1.02). Adverse events potentially related to the study included renal calculi (16
participants in the vitamin D3 + calcium group and 10 in the placebo group), and elevated
serum calcium levels (6 in the vitamin D3 + calcium group and 2 in the placebo group).”
(J. Lappe, [email protected])
“Fortunately, large-scale, general-population, high-dose vitamin D supplementation trials
designed to overcome many of the limitations of previous trials are ongoing,” editorialists
write (pp. 1217–8). “The largest of these trials, the Vitamin D and Omega-3 Trial (VITAL;
NCT01169259), a 5-year trial of supplemental vitamin D (2,000 IU/d) for the primary
prevention of cancer and cardiovascular disease in a racially/ethnically diverse cohort of
nearly 26,000 men and women across the United States, is expected to provide results
soon regarding the role of supplementation for nonskeletal outcomes and the overall
balance of benefits and risks. As ongoing large-scale trials report their findings, an
improved understanding of these important relationships should come to light.” (J. E.
Manson, [email protected])
For-Profit Medical Schools: A Viewpoint author reviews the “sea change” in medical
education resulting from the recent openings of schools such as the one at California
Northstate U., where a pharmacy school had earlier begun enrolling pharmacy students
(pp. 1209–12): “Characterized by a tuition-dependent business model, the new for-profit
medical schools will probably continue to evolve. Indeed, for-profit medical schools are
unlikely to maintain their investment allure absent growth of the tuition-paying base.
Gradual expansion of the total active enrollment to levels maintained by some of the
largest not-for-profit medical schools is therefore to be expected. Potential loss of quality
in the face of quantity would have to be guarded against by way of the reaccreditation
process. The new for-profit medical schools may also give consideration to a growing
presence in the online distance learning space. Enticing as digital education might be as
a means of expanding the tuition-paying base, the hands-on requirements of the
discipline may prove constraining. Whatever business model emerges, it is all but certain
that the old adage ‘there’s no profit like not-for-profit’ is no more.” (E. Y. Adashi,
[email protected])
>>>PNN NewsWatch
* FDA yesterday approved dupilumab injection (Dupixent, Regeneron
Pharmaceuticals) for treatment of adults with moderate-to-severe atopic dermatitis. The
drug is intended for patients whose eczema is not controlled adequately by topical
therapies, or those for whom topical therapies are not advisable; it can be used with or
without topical corticosteroids.
* The APhA House of Delegates on Monday approved policies or business items on
patient access to pharmacist-prescribed medications, pharmacists’ role within valuebased payment models, pharmacy performance networks, and drug disposal,
pharmacist.com reports. Installed as APhA president was Nancy Alvarez, PharmD,
BCPS, FAPhA, of Chapman U. Michael Hogue, PharmD, FAPhA, FNAP, of Samford U.
is the new speaker of the APhA House.
PNN Pharmacotherapy Line is published via e-mail each business day except U.S.
holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201;
571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News
Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail
[email protected] to request missing copies of PNN. Quarterly files archived at
www.PharmacotherapyNewsNetwork.com.
PNN Pharmacotherapy Line
Mar. 30, 2017 * Vol. 24, No. 61
Providing news and information about medications and their proper use
>>>NEJM Report
Source: Mar. 30 New England Journal of Medicine (2017; 376).
Extended Treatment of Venous Thromboembolism: In the phase 3 EINSTEIN
CHOICE trial, patients with venous thromboembolism who had completed 6–12 months
of anticoagulation had lower risks of a recurrent event when they received prophylactic
or treatment doses of rivaroxaban than with low-dose aspirin, researchers report (pp.
1211–22). All participants “were in equipoise regarding the need for continued
anticoagulation,” the group writes. A primary efficacy outcome of symptomatic recurrent
fatal or nonfatal venous thromboembolism and a principal safety outcome of major
bleeding showed: “A total of 3,365 patients were included in the intention-to-treat
analyses (median treatment duration, 351 days). The primary efficacy outcome occurred
in 17 of 1,107 patients (1.5%) receiving 20 mg of rivaroxaban and in 13 of 1,127 patients
(1.2%) receiving 10 mg of rivaroxaban, as compared with 50 of 1,131 patients (4.4%)
receiving aspirin (hazard ratio for 20 mg of rivaroxaban vs. aspirin, 0.34; 95% confidence
interval [CI], 0.20 to 0.59; hazard ratio for 10 mg of rivaroxaban vs. aspirin, 0.26; 95% CI,
0.14 to 0.47; P <0.001 for both comparisons). Rates of major bleeding were 0.5% in the
group receiving 20 mg of rivaroxaban, 0.4% in the group receiving 10 mg of rivaroxaban,
and 0.3% in the aspirin group; the rates of clinically relevant nonmajor bleeding were
2.7%, 2.0%, and 1.8%, respectively. The incidence of adverse events was similar in all
three groups.” (J. I. Weitz, [email protected])
“The emergence of rivaroxaban and other direct oral anticoagulant agents has altered
the standard of care among patients with venous thromboembolism,” editorialists write
(pp. 1279–80). “For patients without cancer, the use of direct oral anticoagulant agents
might be considered as first-line treatment for those with acute venous
thromboembolism. Full-dose treatment could be continued for a minimum of 3 to 6
months. In patients in whom there is equipoise with respect to continuing anticoagulant
therapy beyond this period, the use of a reduced-intensity direct oral anticoagulant agent
might be considered. Clinicians who choose this strategy can be confident of excellent
efficacy and low bleeding risk similar to that observed with aspirin or placebo.” (M. A.
Crowther)
HPV Vaccination During Pregnancy: Quadrivalent human papillomavirus (HPV)
vaccination of women during pregnancy showed no adverse outcomes in an analysis of
Danish registries (pp. 1223–33). Data from 2006 to 2013 showed the following: “In
matched analyses, exposure to the quadrivalent HPV vaccine was not associated with
significantly higher risks than no exposure for major birth defect (65 cases among 1,665
exposed pregnancies and 220 cases among 6,660 unexposed pregnancies; prevalence
odds ratio, 1.19; 95% confidence interval [CI], 0.90 to 1.58), spontaneous abortion (20
cases among 463 exposed pregnancies and 131 cases among 1,852 unexposed
pregnancies; hazard ratio, 0.71; 95% CI, 0.45 to 1.14), preterm birth (116 cases among
1,774 exposed pregnancies and 407 cases among 7,096 unexposed pregnancies;
prevalence odds ratio, 1.15; 95% CI, 0.93 to 1.42), low birth weight (76 cases among
1768 exposed pregnancies and 277 cases among 7,072 unexposed pregnancies;
prevalence odds ratio, 1.10; 95% CI, 0.85 to 1.43), small size for gestational age (171
cases among 1,768 exposed pregnancies and 783 cases among 7,072 unexposed
pregnancies; prevalence odds ratio, 0.86; 95% CI, 0.72 to 1.02), or stillbirth (2 cases
among 501 exposed pregnancies and 4 cases among 2,004 unexposed pregnancies;
hazard ratio, 2.43; 95% CI, 0.45 to 13.21).” (N. M. Scheller, [email protected])
This “carefully conducted postlicensure safety study of HPV vaccine … is a model for
others to emulate,” an editorialist adds (pp. 1280–2). “In the case of HPV vaccine or
other vaccines that are not intended for pregnant women but are inadvertently
administered to them, postmarketing safety evaluations assume great importance.” (K.
M. Edwards)
>>>PNN NewsWatch
* The first drug for primary progressive multiple sclerosis (PPMS), ocrelizumab
(Ocrevus, Genentech) was approved yesterday by FDA for treatment of adults with
relapsing forms of multiple sclerosis and PPMS.
* Envy Me is recalling all lots of LaBri’s Body Health Atomic, a weight-loss dietary
supplement, because of undeclared sibutramine.
PNN Pharmacotherapy Line is published via e-mail each business day except U.S.
holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201;
571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News
Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail
[email protected] to request missing copies of PNN. Quarterly files archived at
www.PharmacotherapyNewsNetwork.com.
PNN Pharmacotherapy Line
Mar. 31, 2017 * Vol. 24, No. 62
Providing news and information about medications and their proper use
>>>Diabetes Report
Source: Apr. issue of Diabetes Care, with a special section on Emerging Science and
Concepts for Management of Diabetes and Aging (2017; 40).
Diabetes & Aging: Discussing the challenges of treating diabetes in older adults,
authors introducing the special section write, “The difficulty results from having continued
gaps in research that investigates diabetes in older adults, the age-group with the
highest prevalence rates of diabetes and the fastest growing segment of the population,”
(pp. 440–3). “We also recognize that given the exclusion of older participants from most
traditional randomized controlled trials of diabetes interventions, treatment decisions are
often made with much uncertainty and need to be individualized. Therefore, future
research should allow and account for the complexity of older adults. Beyond
broadening the inclusion criteria for randomized controlled trials, we will increasingly
need comparative effectiveness studies to assess safety and efficacy of therapies in
older adults with diabetes who are particularly vulnerable to adverse effects from
overtreatment. Older adults with diabetes are a heterogeneous population ranging from
the robust to the frail and represent unique challenges and considerations for both the
clinician and researcher that will need to be urgently addressed in the future.” (R. R.
Kalyani, [email protected])
Atherosclerotic Disease in Older Adults With Diabetes: Authors present a pragmatic
approach to management of atherosclerotic cardiovascular disease (ASCVD) in older
adults with diabetes (pp. 476–84): “Older adults with diabetes are at higher risk for
[ASCVD] than younger adults with diabetes and older adults without diabetes. The
rationale to implement ASCVD risk–lowering therapies in older adults with diabetes is
compelling. Recommendations for lifestyle modification, lipid-lowering therapy, blood
pressure management, blood glucose control, and aspirin therapy are often based on
studies that show their efficacy in younger populations. However, the risks associated
with each of these interventions increase with age, and favorable risk-to-benefit ratios
demonstrated in younger adults with diabetes are less certain in older populations. The
variability in health status among older adults is pertinent. Those with robust health are
more likely to tolerate and derive benefit from many therapies when compared with
those who have more complex health including frailty. Age- and/or frailty-stratified data
to help clarify these relationships are sparse. In this Perspective, current
recommendations for modifying ASCVD risk are described with a review of the pertinent
literature that guides their application in older adults.” (M. T. Korytkowski,
[email protected])
Lixisenatide in Older Adults With Type 2 Diabetes: In the GetGoal-O Trial, the
addition of lixisenatide to current regimens (including insulin) in nonfrail older adults
whose type 2 diabetes was not adequately controlled was significantly more effective
than placebo (pp. 485–93). A total of 350 patients without risk of malnutrition and without
moderate-to-severe cognitive impairment were randomized in the 24-week trial, with
these results: “HbA1c decreased substantially with lixisenatide (−0.57% [6.2 mmol/mol])
compared with placebo (+0.06% [0.7 mmol/mol]) from baseline to week 24 (P <0.0001).
Mean reduction in 2-h [postprandial plasma glucose] was significantly greater with
lixisenatide (−5.12 mmol/L) than with placebo (−0.07 mmol/L; P <0.0001). A greater
decrease in body weight was observed with lixisenatide (−1.47 kg) versus placebo
(−0.16 kg; P <0.0001). The safety profile of lixisenatide in this older population, including
rates of nausea and vomiting, was consistent with that observed in other lixisenatide
studies. Hypoglycemia was reported in 17.6% of patients with lixisenatide versus 10.3%
with placebo.” (G. S. Meneilly, [email protected])
>>>PNN NewsWatch
* Medicaid enrollees might benefit from policies that require review and justification for
use of methadone for pain, according to investigators who analyzed the effects of
methadone’s preferred status in North Carolina and Florida. Compared with South
Carolina, where methadone is not a preferred drug, North Carolina and Florida had
significantly higher rates of fatal and nonfatal methadone overdose among Medicaid
beneficiaries in 2012–13. The report of this research is in this week’s MMWR.
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