CME
Evidence-Based Practice
Answering clinical questions▲
with the best sources
VOLUME 8
NUMBER 2
FEBRUARY 2005
WHAT’S INSIDE
TRANSFORMING PRACTICE
HELP DESK
3
3 What is the best agent for
preventing oral herpes?
■
■
4
■
What is the best agent for
treating oral herpes?
Surgical treatment for morbid obesity
What is the role of herpes virus
serology in sexually transmitted
disease screening?
Evidence points to improved patient-important outcomes
5 What behavioral interventions are safe
and effective in treating obesity?
■
■
■
Is humidified oxygen effective for
treating children with croup?
Are corticosteroids effective for
treating children with mild-tomoderate croup?
6 Is racemic epinephrine effective for
treating children with croup?
■
■
What are the best prevention
strategies for "shin splints" in
athletes? (with Clinical Commentary)
DRUG PROFILE
9
Clinical pharmacology of eplerenone
EVIDENCE IN PERSPECTIVE
11
Effects of Helicobacter pylori eradication
on gastroesophageal reflux disease
EDITORS
BERNARD EWIGMAN, MD, MSPH
University of Chicago
DAVID WHITE, MD
Columbia, MO
Summary of evidence
• Patients undergoing various bariatric surgical procedures lost an average
of 61.2% of their excess weight (varying from 47.5% for gastric banding
to 70.1% for biliopancreatic diversion or duodenal switch procedures)
• Perioperative mortality was relatively low (varying from 0.1% for banding, 0.5% for bypass, to 1.1% for biliopancreatic diversion or duodenal
switch)
• Most patients had resolution of or improvement in comorbid conditions; most notably, resolution of diabetes was 98.9% for biliopancreatic diversion or duodenal switch, 83.7% for gastric bypass, 71.6% for
gastroplasty, and 47.9% for gastric banding
Once an unusual procedure performed only in a few academic centers,
surgical treatment for morbid obesity is now widely available. Its use has
skyrocketed along with the US obesity epidemic and, the best news,
good evidence shows that morbidly obese patients are now achieving
outstanding outcomes from surgery. In a recently published metaanalysis, bariatric surgery led to the loss of more than 60% of body
weight, was associated with resolution of comorbidities (hypertension,
diabetes, hyperlipidemia, obstructive sleep apnea) in more than 75% of
patients, and added an average of 7 years of life.1
Family physicians and general internists need to know the criteria
for referral, provide their patients with information to motivate them to
consider this option, and understand the special needs and potential
complications for long-term care of patients after bariatric surgery.
Herein we review the evidence supporting surgical treatment of morbid
obesity as well as complications.
continued
TRANSFORMING PRACTICE
CONTINUED
TABLE 1
Weight classifications by
body mass index (BMI)
BMI (kg/m2)
18.5–25
25–30
>30
40–50
>50
Classification
Optimal
Overweight
Obese
Morbidly obese
Superobese
Definitions
Current accepted definitions of overweight are
based on the body mass index (BMI). The BMI is
defined as body weight (in kilograms) divided by
height (in meters) squared. Table 1 shows classifications of weight according to BMI. "Excess weight"
refers to the difference between the patient's actual
baseline weight and his or her optimal body weight.
In 1998, the National Heart, Lung, and Blood
Institute Consensus Panel recommended surgery
for weight loss as an option for selected patients
with clinically severe obesity.2 Severe obesity was
defined as BMI of 40 kg/m2 or higher, or BMI
between 35 and 40 kg/m2 with comorbid conditions including poorly controlled hypertension,
type 2 diabetes mellitus, obstructive sleep apnea, or
coronary artery disease. The panel also recommended that patients be required to be free from
substance abuse, major psychosis, and untreated
depression.
Types of surgical procedures
The meta-analysis1 divided the surgical procedures
types into 5 broader categories. Most procedures
restrict the volume capacity of the stomach and
modify the functional anatomy of the stomach (gastroplasty), bypass portions of the gastrointestinal
tract, or divert the contents of the biliopancreatic
segment of the duodenum to the distal small bowel.
The 5 categories of bariatric surgery assessed were
• Gastric banding: Included adjustable and
nonadjustable gastric banding procedures,
without gastroplasty, bypass, or diversion
component
• Gastric bypass: Principally the Roux-en-Y
gastric bypass procedure (includes banding)
or any mixed procedure that included bypass
(bypass plus banding, gastroplasty, or
biliopancreatic diversion)
• Gastroplasty: Principally vertical banding
with gastroplasty
• Biliopancreatic diversion or duodenal
switch: Included a variety of modifications
• Other: Included all other bariatric procedures, as well as nonspecified procedures
Meta-analysis
The primary outcomes of interest for this metaanalysis were rates of resolution or improvement in
4 predefined comorbidities: type 2 diabetes mellitus,
hyperlipidemia, hypertension, and obstructive sleep
apnea.1 Criteria for including an individual study in
the meta-analysis included a minimum of 10
patients who underwent bariatric surgery, publication date between 1990 and 2003, and data on at
least 1 of the predefined comorbidities. Clinical trials and case series were included.
Secondary outcomes of interest were perioperative mortality, defined as death from any cause
within 30 days of surgery, and weight loss.
"Resolution" of the primary outcomes was defined
as the disappearance of the comorbid condition, or
a condition for which therapy was no longer
required.
A total of 136 studies that enrolled 22,094
patients met inclusion criteria. Of these, only 5
studies (621 patients) were randomized controlled
trials (RCTs); 28 (4,613 patients) used nonrandomly assigned control groups and 101 studies (16,860
patients) were case series. The mean age was 39
years (range 16–63), the mean BMI at baseline was
46 (range 32–68), and most patients were female
(72%). The age and baseline BMIs of patients were
similar across surgical procedure types.
FINDINGS
Including all studies, patients lost an average of 61.2%
of their excess weight (95% confidence interval [CI],
58.1%–64.4%). The range of percentage of excess
weight lost was from 47.5% (95% CI, 40.7%–54.2%)
for gastric banding to 70.1% (95% CI, 66.3%–73.9%)
for biliopancreatic diversion or duodenal switch procedures. Perioperative mortality was relatively low, and
varied according to procedure type (banding 0.1%,
bypass 0.5%, biliopancreatic diversion or duodenal
switch 1.1%). Table 2 shows the resolution or
improvement rates for the comorbid conditions of
interest from the combined data.
continued on page 8
2 Evidence-Based Practice
Help Desk
CONCISE ANSWERS TO PHYSICIANS’ CLINICAL QUESTIONS
What is the best agent for
preventing oral herpes?
Valacyclovir 500 mg once daily reduces recurrence
rate of herpes labialis, but the magnitude of the
benefit is small. Sunscreen applied to the lips
reduced recurrence rates of herpes labialis significantly among college students exposed to ultraviolet (UV) light in a laboratory setting. Although
sunscreen has not been tested in natural conditions it may well be beneficial and is not harmful.
Pooled results from patients with a history of
frequent outbreaks of recurrent herpes labialis (≥4
attacks per year) enrolled in 2 identical randomized
controlled trials (RCTs) showed that the oral valacyclovir group (500 mg once daily for 16 weeks) had
a 38% rate of recurrence during the 4-month study
period, and mean time to first recurrence of 13.1
weeks.1 Corresponding rate and duration for the
placebo group were 60% (NNT=5; P=.041) and
9.6 weeks (P=.016), respectively.
In a study of 147 skiers with a history of suninduced recurrent herpes labialis, participants
were randomly assigned to receive either acyclovir
400 mg orally twice daily beginning 12 hours
before sunlight exposure or placebo.2 The rate of
recurrence in the acyclovir group was lower (5% vs
26% in the placebo group; NNT=5; P<.05).
However a subsequent study of similar design (239
skiers with history of recurrent herpes labialis; 800
mg acyclovir twice daily beginning the day before
sun exposure vs placebo) showed no difference in
recurrence rates (23% with acyclovir vs 21% with
placebo; P=.92).3
Topical sunscreen may also be beneficial, but
the studies done to date for this intervention have
been limited to experimental situations.4,5 In both
of these studies, patients were intentionally
exposed to doses of UV radiation in the lab, and
were found to have significant reduction in the
induction of recurrent herpes labialis when sunscreen was used compared to placebo. The value of
this finding in clinical practice is uncertain.
When patients are planning to be in the sun
for prolonged periods, sunscreen use is prudent
whether or not they have herpes labialis. [Strength
of recommendation (SOR): C, based on laboratory experiment] Valacyclovir is probably not warranted in patients with episodes of herpes labialis
that recur fewer than 4 times per year. For those
with frequent recurrences (>4 times a year), or for
whom the pain or cosmetic concerns are particularly severe, a trial of oral valacyclovir may be warranted. [SOR: A, based on well-done RCT]
Patients need to be informed of the modest effect
size and that the cost of such treatment is high.
The cost of 500 mg oral valacyclovir twice daily for
16 weeks at the local pharmacy is approximately
$1,113.70, although drug prices vary remarkably
these days (University of Missouri, Columbia
Hospital and Clinics outpatient pharmacy;
December 20, 2004).
1.
Baker D, Eisen D. Valacyclovir for prevention of recurrent herpes labialis:
2 double-blind, placebo-controlled studies. Cutis 2003; 71:239–242.
2.
Spruance SL, Hamill ML, Hoge WS, Davis LG, Mills J. Acyclovir prevents
reactivation of herpes simplex labialis in skiers. JAMA 1988;
260:1597–1599.
3.
Raborn GW, Martel AY, Grace MG, McGaw WT. Oral acyclovir in prevention of herpes labialis. A randomized, double-blind, multi-centered clinical trial. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1998;
85:55–59.
4.
Rooney JF, Bryson Y, Mannix ML, et al. Prevention of ultraviolet-lightinduced herpes labialis by sunscreen. Lancet 1991; 338:1419–1422.
5.
Duteil L, Queille-Roussel C, Loesche C, et al. Assessment of the effect of
a sunblock stick in the prevention of solar-simulating ultraviolet lightinduced herpes labialis. Dermatol Treat 1998; 9:11–14.
What is the best agent for
treating oral herpes?
The evidence shows that the best treatment is oral
acyclovir, 400 mg taken 5 times daily, which
reduces duration of symptoms by a mean of 4.4
days.1 [SOR: A, based on well-done RCT]
However, surprisingly few antiviral regimens have
been evaluated for the acute treatment of herpes
labialis.
ORAL ANTIVIRALS
One RCT found that for 174 patients with a history of recurrent herpes labialis, symptoms lasted
for an average of 4.4 days less for those taking 400
Evidence-Based Practice
3
Help Desk
mg acyclovir 5 times daily for 5 days than for
those taking placebo (8.1 vs 12.5 days; P=.002).1
Patients in this study were instructed to start
treatment "at the first sign of symptoms." In a
RCT of similar design, however, no such benefit
was found.2 A total of 149 patients were assigned
to either 200 mg acyclovir 5 times daily for 5 days
or placebo within 12 hours of the onset of symptoms. No significant differences were noted with
respect to the outcomes of pain or lesion duration. This lack of difference may have been due to
the low dose of antiviral medication used.
More recent studies of high-dose, shortduration valacyclovir show modest benefit. The
results of 2 RCTs published in a single article in
20033 demonstrated that for patients who take
either 1- or 2-day courses of high-dose valacyclovir (2 g twice daily for 1 day, or 2 g taken twice
daily for 1 day, followed by 1 g twice daily for the
second day) had reductions in duration of the
episodes by 0.5 (P=.009) to 1.0 (P=.001) days,
respectively.
What is the role of herpes virus serology in
sexually transmitted disease screening?
The use of viral serology has no role as a screening
tool for identification of asymptomatic infected individuals for herpes simplex virus (HSV). The US
Preventive Services Task Force (USPSTF) recommends against the use of surveillance for herpes
infections in asymptomatic individuals. The USPSTF, The American College of Obstetricians and
Gynecologists, the American Academy of Pediatrics,
the Canadian Task Force on the Periodic Health
Examination, and the Infectious Disease Society of
America all recommend against surveillance for herpes infections in asymptomatic pregnant women.
Approximately 16% of the US adult population is seropositive for HSV 2.1 The vast majority
of these individuals are asymptomatic. Even
though current commercially available serologic
tests for HSV have sensitivities and specificities of
about 95% with a low prevalence population (such
as 16%), 30% to 40% of individuals who test positive would be wrongly diagnosed as being infected.2 Even in high-prevalence populations, the
false-positive rate would be about 10%.
There is no evidence demonstrating effective
means of preventing transmission of HSV 2, so
making false-positive diagnoses cannot be justified. One study of 144 couples with 1 partner having recurrent genital herpes and the other partner
with a seronegative status evaluated the impact of
recommendations for avoiding skin-to-skin contact during times of active lesions. Couples who
used barrier contraception did not have fewer
episodes of the herpes transmission to the previously uninfected individual.3
Until it is demonstrated that some benefit
would be derived from such knowledge, routine
testing for HSV infection in asymptomatic individuals is not recommended.
[SOR: B, based on prevalence studies and 1 nonrandomized trial]
TOPICAL ANTIVIRALS
Clinical Evidence reports on 5 trials that studied
the effect of topical antivirals for the treatment of
recurrent herpes labialis lesions.4 Although some
studies reported shorter duration of pain among
patients using active drug versus placebo, the
effect size was small. The range of decrease in
pain duration in the 5 studies ranged from about
1 to 12 hours. Among the 10 trials that reported
on time to complete healing as an outcome,
again, the effect was variable and small. The
shortened duration to complete healing in the
active treatment groups amounted to a range of 6
hours to 2 days, with most showing reduction
time of less than 1 day.
1.
Spruance SL, Stewart JC, Rowe NH, et al. Treatment of recurrent herpes simplex labialis with oral acyclovir. J Infect Dis 1990;
161:185–190.
2.
Raborn GW, McGaw WT, Grace M, Tyrrell LD, Samuels SM. Oral acyclovir and herpes labialis: a randomized, double-blind, placebo-controlled study. J Am Dent Assoc 1987; 115:38–42.
1.
US Preventive Services Task Force. Guide to Clinical Preventive Services,
3rd ed: Recommendations and Systematic Evidence Reviews,
Guide to Community Preventive Services. Available at:
http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=hstat3.section.10931.
Accessed December 20, 2004.
3.
Spruance SL, Jones TM, Blatter MM, et al. High-dose, short-duration,
early valacyclovir therapy for episodic treatment of cold sores: results
of two randomized, placebo-controlled, multicenter studies. Antimicrob
Agents Chemother 2003; 47:1072–1080.
2.
4.
Worrall G. Herpes labialis. In: Clinical Evidence. London: BMJ Publishing
Group Ltd; 2004:2311–2317.
Krantz I, Lowhagen GB, Ahlberg BM, Nilstun T. Ethics of screening for
asymptomatic herpes virus type 2 infection. BMJ 2004; 329:618–621.
3.
Mertz GJ, Benedetti J, Ashley R, Selke SA, Corey L. Risk factors for the
sexual transmission of genital herpes. Ann Intern Med 1992;
116:197–202.
4 Evidence-Based Practice
Help Desk
What behavioral interventions are safe and
effective in treating obesity?
No behavioral interventions have been shown to
lead to meaningful, sustained weight loss.
A systematic review published in 1998 (search
date 1997) found 3 RCTs that assessed the effect of
adding behavioral interventions to recommendations for low or very low calorie diets.1 All 3 showed
that the patients receiving behavioral counseling
had either more weight loss or less weight gain than
patients who had dietary counseling alone.
However, in the 2 trials that reported 5-year outcomes, these differences did not persist. A second
systematic review from 1999 found no RCTs that
demonstrated sustained benefit with respect to
weight loss for patients receiving behavioral therapy
in addition to dietary counseling.2 A subsequent
RCT, published in 2003, showed some benefit from
the addition of cognitive behavioral therapy (CBT)
to usual care in a primary care setting.3 In this study,
122 obese subjects (body mass index > 30 kg/m2,
mean age 45.2 years) were randomized to receive
either 16 90-minute sessions of group CBT or usual
care. Twelve months after the end of therapy,
patients who received CBT had lost 4 pounds, compared to a 0.5-pound weight loss in the control
group (P<.001).
Behavioral interventions are therefore unlikely
to result in significant, prolonged weight loss.
Particularly for morbidly obese patients (see
Transforming Practice article in this issue), more
aggressive treatment is required.
[SOR: A, based on multiple RCTs]
1.
The National Heart, Lung, and Blood Institute. Clinical Guidelines on the
Identification, Evaluation, and Treatment of Overweight and Obesity in
Adults. Bethesda, Md: National Institutes of Health; 1998. Available at:
http://www.nhlbi.nih.gov/guidelines/obesity/ob_home.htm. Accessed
December 22, 2004.
2.
Douketis JD, Feightner JW, Attia J, et al. Periodic health examination,
1999 update. Detection, prevention and treatment of obesity. Canadian
Task Force on Preventive Health Care. Can Med Assoc J 1999;
160:513–525.
3.
Munsch S, Biedert E, Keller U. Evaluation of a lifestyle change programme for the treatment of obesity in general practice. Swiss Med Wkly
2003; 133:148–154.
Is humidified oxygen effective for
treating children with croup?
Humidified oxygen has not been shown to be effective for treating children with croup, although we
found only 1 trial addressing this question.1
In that trial, 71 children, aged 3 months to 6
years, presenting to the emergency department with
moderate croup were randomly assigned to receive
humidified oxygen mist or no mist. All patients
received a dose of oral dexamethasone (0.6 mg/kg).
Other treatments, such as racemic epinephrine could
be prescribed at the discretion of the treating physician. Baseline croup scores were obtained (initially
2–7), and repeated every 30 minutes for up to 2 hours,
or until the score was less than 2. The 2 treatment
groups had similar characteristics at baseline, and the
initial median croup score was 4 for both groups. The
outcome of interest was change in croup score from
baseline for each of the follow-up time intervals.
No significant differences were noted in the
changes of croup scores for any of the time points
studied (P=.39). Nor were there significant differences in improvement of oxygen saturation, heart
rate, or respiratory rate at any of the assessment
times. [SOR: B, based on 1 RCT]
1.
Neto GM, Kentab O, Klassen TP, Osmond MH. A randomized controlled
trial of mist in the acute treatment of moderate croup. Acad Emerg Med
2002; 9:873–879.
Are corticosteroids effective for treating
children with mild-to-moderate croup?
Corticosteroids reduce length of stay in emergency departments, reduce hospital admissions,
reduce rate of return visits to emergency departments and improve clinical measures of croup
severity. One oral dose of dexamethasone (0.6
mg/kg) is effective for mild croup (no stridor, no
intercostals retractions).
One trial randomly assigned children who
presented to the emergency room with croup,
whose illness was not severe enough to warrant
hospitalization, to receive either 0.15 mg/kg of oral
dexamethasone or placebo prior to release.1 A total
of 100 children (age range 4–122 months, 90%
younger than 6) participated in the study, and the
outcome of interest was what percentage would
need subsequent medical contact for croup-related
concerns. Parents of 96 of 100 of these children
were contacted 7 to 10 days after the emergency
room visit, and asked about whether any further
medical attention had been sought for croup.
For patients receiving dexamethasone, none of
the 50 children required further care, but for those
receiving placebo, 8 of 50 (16%) were seen again
Evidence-Based Practice
5
Help Desk
for croup (absolute risk reduction 0.16, NNT to
prevent the need for further croup-related care 7;
P<.01). One of the children in the placebo group
was admitted to the hospital.
In a systematic review (most recent update,
August 2003) the authors identified 31 relevant
studies that included 3,736 patients that compared
the use of corticosteroids to placebo in children
with croup.2 Studies were included regardless of
croup severity. When the data from these studies
were combined, significant benefit was found from
the use of corticosteroids for multiple clinically
important outcomes. A Westley score was used to
measure clinical response. This is a 17-point croup
severity score that includes assessment of air entry
(2 points), stridor (2 points), intercostal retractions
(3 points), cyanosis (5 points), and level of consciousness (5 points). At 6 hours, patients receiving
corticosteroids did better than those receiving
placebo, with a weighted mean difference of –1.2
points (95% confidence interval [CI] –1.6 to –0.8).
At 12 hours the difference was –1.9 (–2.4 to –1.3).
At 24 hours this improvement was no longer significant (–1.3; 95% CI, –2.7 to 0.2). The risk of
having to have a return visit or readmission to the
hospital was also reduced for the patients receiving
corticosteroids (relative risk 0.50; 95% CI, 0.36 to
0.70), as was the length of stay in the emergency
department or the hospital (weighted mean difference 12 hours; 95% CI, 5 to 19). Patients receiving
corticosteroids also were found to require fewer
epinephrine treatments (risk difference 10%;
1%–20%). [SOR: A, based on consistent RCTs]
1.
Geelhoed GC, Turner J, Macdonald WBG. Efficacy of a small single
dose of oral dexamethasone for outpatient croup: a double blind
placebo controlled clinical trial. BMJ 1996; 313:140–142.
2.
Russell K, Wiebe N, Saenz A, et al. Glucocorticoids for croup (Cochrane
Review). In: The Cochrane Library, Issue 4, 2004. Chichester, UK:
John Wiley & Sons, Ltd.
Is racemic epinephrine effective for
treating children with croup?
Multiple RCTs have demonstrated benefit from
nebulized racemic epinephrine in children with
moderately severe croup. This benefit is reflected in
changes in croup scores from baseline.
A trial from 1994 randomized 54 children with
mild-to-moderate croup to receive a nebulized solution containing 2.25% racemic epinephrine, or an
identical solution without active drug.1 Children
6 Evidence-Based Practice
receiving epinephrine had a mean change from a
baseline croup score (on a 15-point scale) of –2.7
compared with –1.1 with placebo (P=.003). Two
other RCTs compared the use of nebulized racemic
epinephrine delivered by intermittent positive-pressure breathing (IPPB) device, and found a similar
benefit.2,3 In the first of these, 20 children with moderate-to-severe croup were treated with either 0.5
mL of nebulized 2.25% racemic epinephrine or
placebo, delivered through IPPB. Croup scores
were significantly improved in children receiving
racemic epinephrine at 10 and 30 minutes, but this
benefit was no longer seen at 120 minutes. In the
second study, 14 children were randomized to
receive either a weight-adjusted dose of 2.25%
racemic epinephrine or placebo through IPPB.
Again, children receiving epinephrine had better
croup scores at 20 minutes than those receiving
placebo, but the researchers also found that within
24 to 36 hours of admission, the clinical status of
patients in the treatment group were not significantly different from those in the control group.
These consistent results from multiple RCTs
show that epinephrine favorably affects the shortterm clinical status of the patient, but that effect wears
off within about 2 hours. This finding is particularly
important with respect to management of moderateto-severe croup in the emergency department.
Significant improvement in a child's respiratory status
following treatment with racemic epinephrine should
not be used as an indication that it is safe to send the
child home. In fact, it is likely that within 2 hours,
unless other interventions are made, that deterioration of respiratory function is likely to ensue.
[SOR: A, based on consistent RCTs]
1.
Kristjansson S, Berg-Kelly K, Winso E. Inhalation of racemic epinephrine in the treatment of mild and moderately severe croup. Clinical
symptom score and oxygen saturation measurements for evaluation of
treatment effects. Acta Paediatr 1994; 83:1156–1160.
2.
Westley CR, Ross EK, Brooks JG. Nebulized racemic epinephrine by
IPPB for the treatment of croup. Am J Dis Child 1978; 132:484–487.
3.
Taussig LM, Castro O, Beaudry PH, et al. Treatment of laryngotracheobronchitis (croup). Use of intermittent positive-pressure breathing and
racemic epinephrine. Am J Dis Child 1975; 129:790–793.
What are the best prevention strategies for
"shin splints" in athletes?
The evidence we found to answer this question
was weak, so we asked an expert to provide guidance (see the following Clinical Commentary).
Help Desk
He recommends a constant level of fitness and
activity, gradual increases in intensity and duration of exercise, good shoes, and training on
softer surfaces.
A systematic review of prevention of shin splints,
published in 2002, yielded only 4 comparison studies.1
In each of 3 controlled RCTs involving a total of 6,163
military recruits, no change in the rate of shin splints
was noted with the use of heel pads, boot inserts, heelcord stretching exercises, graduated running programs, standard all-leather combat boots, or hotweather canvas top boots for the 8- to 9-week training
period.2–4 In a 4th randomized trial, 250 of 1,511
South African military recruits were randomly selected to receive neoprene-impregnated flat insoles during 9 weeks of basic training.5 Of recruits in the control group, 65 of 1,151 (20.4%) had documented shin
splints compared with 6 of 237 (12.8%) in the insert
group (P<.05).
The quality of the studies cited by this review
was poor.1 None reported adequate methods of
randomization, whether blinding occurred, basic
statistical testing methods or power calculations.
In the second study cited,3 members of the intervention (canvas-top) group who were found to be
noncompliant with the study protocol were
moved to the control group for analysis, compromising random allocation and introducing possible confounding bias. The quality scores for these
4 trials ranged from 29 to 47 points (out of a
possible 100).
Negative findings from poorly designed studies do not prove ineffectiveness. [SOR: B, based on
a systematic review of low-quality studies]
Currently, expert clinical experience is the best
guide available (see Clinical Commentary).
1.
Thacker SB, Gilchrist J, Stroup DF, Kimsey CD. The prevention of shin
splints in sports: a systematic review of literature. Med Sci Sports Exerc
2002; 34:32–40.
2.
Andrish JT, Bergfeld JA, Walheim J. A prospective study on the management of shin splints. J Bone Joint Surg 1974; 56:1697–1700.
3.
Bensel CK, Kish RN. Lower extremity disorders among men and women
in Army basic training and effects of two types of boots. Technical
Report Natick TR-83/026. Natick, Mass: United States Army Natick
Research and Development Laboratories; 1983.
4.
Bensel CK, Kaplan DB. Wear test of boot inserts: memorandum for the
record. Natick, Mass: United States Army Natick Research and
Development Laboratories; 1986:1–8.
5.
Schwellnus MP, Jordaan G, Noakes TD. Prevention of common overuse
injuries by the use of shock absorbing insoles. A prospective study. Am
J Sports Med 1990; 18:636–641.
Clinical Commentary
I recommend a consistent level of fitness and activity or gradual increases in intensity and duration
using an appropriately staged training program to
prevent most shin splints and other overuse
injuries.
Diminishing the force of the impact for the
foot by avoiding training on hard surfaces such as
concrete is also important. Good supportive shoes
are critical to cushion impact, especially for runners with hyperpronation or cavus feet. If shoes are
visibly worn, or have just seen a lot miles, I recommend new shoes.
— Roy Henderson, MD, Director, Sports Medicine Fellowship,
MacNeal Family Practice Residency Program, & Department of
EBP
Family Medicine, The University of Chicago
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This activity has been planned and implemented in accordance with the
Essential Areas and Policies of the Accreditation Council for Continuing
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Medicine, designates this educational activity for a maximum of 3 hours in category 1 credit toward AMA Physician's Recognition Award. Each physician
should claim only those hours of credit that he or she actually spent in the educational activity.
It is estimated that this educational activity will require 3 hours to complete.
The learning objectives of the Evidence-Based Practice newsletter are to
become knowledgeable about evidence-based solutions to commonly encountered
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practice of family medicine, and to become conversant with balanced appraisals of
drugs that are currently being marketed to physicians and/or consumers.
The editors of this educational material may review studies that discuss
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Statements and opinions expressed in abstracts and communications herein are those of the author(s) and not necessarily those of the Publisher nor the
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Evidence-Based Practice
7
TRANSFORMING PRACTICE
CONTINUED FROM PAGE 2
Dumping syndrome (postprandial sweating, weakness, hypoglycemia, general
Improvement or resolution of comorbidities
malaise) is fairly common but is rarely
after bariatric surgery
severe, and usually disappears as patients
Comorbid condition
Resolved (%) Improved* (%) Resolved or improved (%)
adapt to their bypass anatomy. Vitamin
Type 2 diabetes
76.8
—
86.0
deficiency, which can occur as a result of
Hyperlipidemia
—
70
—
any of the bariatric procedures, is found in
Hypertension
61.7
—
78.5
11% of individuals who undergo surgery
Obstructive sleep
85.7
—
83.6
that involves restriction plus bypass.6
apnea
Therefore, daily vitamin and mineral
* Defined as normalization of laboratory values or reduction or
discontinuation of medical therapy.
replacement therapy is essential for all
patients who undergo these procedures.
Gallstones develop in 30% of patients who have
The percent of resolution or improvement for
a bypass procedure. Cholecystitis requiring surgery
these conditions varied according to the surgical procehas been reported by 27% of patients within 3 years.
dure. The most striking change was for resolution of
Prophylactic cholecystectomy is one approach to
diabetes: 98.9% for those undergoing biliopancreatic
prevention. Another is the use of ursodiol, which
diversion or duodenal switch, 83.7% for gastric bypass,
has been shown to reduce gallstone formation at 6
71.6% for gastroplasty, and 47.9% for gastric banding.
months to only 2% in patients who undergo bypass
As noted, only 5 of the studies in this analysis
surgery.7
were RCTs. However, the findings of the RCTs were
Surgical complications, such as stricture formain the range of values for the overall meta-analysis.
tion and the development of fistulas, also are imporAnother concern was that most studies (104 of 136)
tant risks, but have become less common. Excess
reported outcomes with less than 2 years of followskin is noticeable in most patients after extreme
up. Nevertheless, when analyzed separately, studies
weight loss. In addition to being cosmetically diswith follow-up of longer than 2 years had weight
turbing for some, excess skin can also be associated
loss outcomes that did not differ significantly from
with ulcerations, infections, and even disturbance of
those with less than 2 years of follow-up.
ambulation. Surgical revision for these complicaA 20-year study of bariatric surgery is in
EBP
tions is often required.
progress to determine long-term outcomes.3 Started
in 1987, the Swedish Obese Subjects study (SOS)
recruits obese subjects using BMI criteria, and will
REFERENCES
1. Buchwald H, Avidor Y, Braunwald E, et al. Bariatric surgery: a systemateventually enroll 2,000 matched pairs of subjects—
ic review and meta-analysis. JAMA 2004; 292:1724–1737.
one of each pair electing bariatric surgery and the
2. National Institutes of Health. Clinical guidelines on the identification,
other electing aggressive nonsurgical intervention.
evaluation, and treatment of overweight and obesity in adults—the evidence report [published corrections appears in Obes Res 1998; 6:464].
Each pair will be followed for 10 years and reObes Res 1998; 6(suppl 2):51S–209S.
examined at 15 and 20 years.
3. Flegal KM, Carroll MD, Ogden CL, Johnson CL. Prevalence and trends in
obesity among US adults, 1999-2000. JAMA 2002; 288:1723–1727.
By February 2000, 1,879 patient-pairs had been
4.
Torgerson JS, Sjostrom L. The Swedish Obese Subjects (SOS) study—
enrolled, and preliminary data have suggested that
rationale and results. Int J Obes Relat Metab Disord 2001;
the benefits of weight loss and the resolution of dia25(suppl 1):S2–S4.
betes persist at 8 years, but that the rates of hyper5. Sjostrom CD, Lissner L, Wedel H, Sjostrom L. Reduction in incidence of
diabetes, hypertension and lipid disturbances after intentional weight
tension may begin to converge.4 Nine-year followloss induced by bariatric surgery: the SOS Intervention Study. Obes Res
up in SOS revealed that the surgical group had a
1999; 7:477–484.
mortality rate of 9%, compared with 28% of those in
6. Balsiger BM, Kennedy FP, Abu-Lebdeh HS, et al. Prospective evaluation
of Roux-en-Y gastric bypass as primary operation for medically complithe nonsurgical group. Most of the deaths were from
cated obesity. Mayo Clin Proc 2000; 75:673–680.
5
cardiovascular causes.
7. Sugerman HJ, Brewer WH, Shiffman ML, et al. A multicenter, placebo-
TABLE 2
LONG-TERM COMPLICATIONS
Multiple complications, some potentially serious,
are associated with bariatric surgical procedures.
8 Evidence-Based Practice
controlled, randomized, double-blind, prospective trial of prophylactic
ursodiol for the prevention of gallstone formation following gastricbypass-induced rapid weight loss. Am J Surg 1995; 169:91–96.
DRUG PROFILE
Objective reviews of drugs in family medicine
Clinical pharmacology of eplerenone
A new selective aldosterone antagonist shows efficacy without
the side effects associated with nonselective agents
RAMINDER KUMAR, MD, Clinical Associate Professor,
Department of Family Medicine, University of Chicago
Eplerenone (Inspra) is a new aldosterone antagonist. Compared with spironolactone, it has
markedly increased selectivity for the aldosterone
receptor and low binding for progesterone (<1%)
and androgen receptors (0.1%).1 Therefore,
eplerenone does not cause the gynecomastia or
breast pain seen with spironolactone. Eplerenone
is indicated in treatment of hypertension and in
patients who have left ventricular dysfunction
(LVD) plus congestive heart failure (CHF) or diabetes mellitus (DM) after a recent (3–14 days)
myocardial infarction (MI).2
LVD plus CHF or DM after recent MI
Aldosterone blockade prevents ventricular remodeling and collagen formation in patients with LVD
after acute MI. In a large, multicenter, international, randomized, double-blind, placebo-controlled
trial 6,632 patients were randomized to receive
eplerenone 25 to 50 mg/day (3,319 patients) or
placebo (3,313 patients). Inclusion criteria were MI
within 3 to 14 days; left ventricular ejection fraction
of 40% or less or LVD by other tests plus CHF or
DM; and optimal therapy including angiotensinconverting enzyme inhibitors (ACEI), angiotensinreceptor inhibitors (ARBs), diuretics, beta-blockers
(BB), or coronary reperfusion therapy. Exclusion
criteria were use of potassium-sparing diuretics,
serum creatinine greater than 2.5 mg/dL, and
serum potassium greater than 5 mEq/L. Potassium
levels were checked frequently and within 1 week of
dose changes. Concurrent therapy with other agents
known to be beneficial in treating CHF or MI was
as follows: ACEI/ARB, 87%; BB, 75%; aspirin, 88%;
and diuretics, 60%. The estimated benefits of
eplerenone therapy at 1 year are given in the Table.
Despite exclusion of patients with renal dysfunction and high potassium levels at baseline, serious
hyperkalemia (>6 mEq/L) occurred in 5.5% of the
eplerenone group and 3.9% of the placebo group
(P=.002). Hyperkalemia correlated with a lower
creatinine clearance (Clcr). Serious hypokalemia
(<3.5 mEq/L) occurred in 8.4% of the eplerenone
group and 13.1% of the placebo group. No significant increase was noted in gynecomastia, breast
pain, or impotence.3
Hypertension
For mild-to-moderate hypertension, eplerenone produces significant decreases in systolic blood pressure
(SBP) and diastolic blood pressure (DBP) when
comapred with placebo, whether measured in the clinic or by ambulatory monitoring.4,5 Reduction is greater
in SBP than DBP. Although the antihypertensive
effect is dose dependent, most of the benefit is achieved
with 100 mg/day. Eplerenone is 50% to 75% as effective as spironolactone, but has an effect equal to
enalapril.5,6 As monotherapy for 12 months,
eplerenone and enalapril controlled blood pressure
(BP) in 55% and 53% of patients, respectively.6
Eplerenone is effective regardless of renin levels; it
is superior to losartan in black patients and as effective
as losartan in white patients.7 In patients with systolic
hypertension, eplerenone is equivalent to amlodipine
in reducing SBP and pulse pressure, but not DBP. 8 In
patients with inadequate BP control with ACEI,
ARBs, calcium-channel blockers, or BB monotherapy,
addition of eplerenone lowers SBP in all groups but
decreases DBP only in patients taking ARBs and
BB.9,10 Eplerenone produces greater reductions in
microalbuminuria than enalapril or amlodipine.6,8 It is
as effective as enalapril in reversing left ventricular
Evidence-Based Practice
9
DRUG PROFILE
CONTINUED
TABLE
Endpoints with eplerenone therapy compared with placebo
Eplerenone group
(n= 3,319)
Placebo group
(n= 3,313)
Relative risk
(95% CI)
Death from any cause
14.4%
16.7%
Death from CV causes
or hospitalization
from CV events
26.7%
Death from any cause
or any hospitalization
Endpoint
Death from CV
causes
P value
Absolute risk
reduction
Numbers needed to
treat (95%CI)
0.85
(0.75–0.96)
0.008
2.3%
44
(25–174)
30%
0.87
(0.79–0.95)
0.002
3.3%
31
(19–88)
52%
55%
0.92
(0.86–0.98)
0.020
3%
33
(19–147)
12.3%
14.6%
0.83
(0.72–0.94)
0.005
2.3%
44
(26–148)
CI, confidence interval; CV, cardiovascular.
hypertrophy (LVH).11 Microalbuminuria and LVH
are associated with increased risk of cardiovascular
events. Microalbuminuria is also associated with renal
failure. However, whether reversal of LVH or microalbuminuria with eplerenone will improve clinical outcomes is unclear.
Adverse events
In most studies adverse events were similar to placebo.
Hyperkalemia is the most serious potential adverse
event with eplerenone, although no significant
increase was reported in most of the studies. However,
patients with risk factors for hyperkalemia (renal disease/insufficiency, DM, mild hyperkalemia, or use of
potassium-sparing diuretics, nonsteroidal antiinflammatory drugs, and BB) were excluded from
many of these studies, potassium levels were checked
frequently, and patients in whom hyperkalemia developed were withdrawn. In hypertensive patients with
DM and proteinuria, hyperkalemia was common,
with potassium levels greater than 5.5 mEq/L seen in
33% of patients and 6.0 mEq/L or higher in 11% of
patients.12,13 Gynecomastia or breast pain was reported
in no more than 1% of patients. However, most studies were of short duration.
Contraindications
Eplerenone is contraindicated in patients with
serum potassium greater than 5.5 mEq/L, Clcr of
30 mL/min or less, and concomitant use of strong
CYP3A4 inhibitors. For hypertensive patients,
eplerenone is contraindicated if they also have
noninsulin-dependent DM with microalbuminuria, serum creatinine of greater than 2.0 mg/dL in
10 Evidence-Based Practice
males and greater than 1.8 mg/dL in females, Clcr
less than 50 mL/min, or concomitant use of potassium supplements or potassium-sparing diuretics.13
REFERENCES
1.
Delyani JA. Mineralocorticoid receptor antagonist: the evolution of utility and
pharmacology. Kidney Int 2000; 57:1408–1411.
2.
Brown NJ. Eplerenone: cardiovascular protection. Circulation 2003;
107:2512–2518.
3.
Pitt B, Remme W, Zannad F, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N
Engl J Med 2003; 348:1309–1321.
4.
White WB, Carr AA, Krause S, et al. Assessment of the novel selective aldosterone blocker eplerenone using ambulatory and clinical blood pressure in
patients with systemic hypertension. Am J Cardiol 2003; 92:38–42.
5.
Weinberger MH, Roniker B, Krause SL, et al. Eplerenone, a selective aldosterone blocker, in mild-to-moderate hypertension. Am J Hypertens 2002;
15:709–716.
6.
Williams GH, Burgess E, Kolloch RE, et al. Efficacy of eplerenone versus
enalapril as monotherapy in systemic hypertension. Am J Cardiol 2004;
93:990–996.
7.
Flack JM, Oparil S, Pratt JH, et al. Efficacy and tolerability of eplerenone and
losartan in hypertensive black and white patients. J Am Coll Cardiol 2003;
41:1148–1155.
8.
White WB, Duprez D, St Hillaire R, et al. Effect of the selective aldosterone
blocker eplerenone versus the calcium antagonist amlodipine in systolic
hypertension. Hypertension 2003; 41:1021–1026.
9.
Krum H, Nolly H, Workman D, et al. Efficacy of eplerenone added to reninangiotensin blockade in hypertensive patients. Hypertension 2002;
40:117–123.
10. Van Mieghem W, von Behren V, Balazovjech I, et al. Eplerenone is safe and
effective as add-on therapy in hypertensive patients uncontrolled with calcium channel blockers or beta-blockers [abstract]. Eur Heart J 2002;
23(suppl):211.
11. Pitt B, Reichek N, Willenbrook R, et al. Effects of eplerenone, enalapril and
eplerenone/enalapril in patients with essential hypertension and left ventricular hypertrophy: the 4E-left ventricular hypertrophy study. Circulation 2003;
108:1831–1838.
12. Epstein M, Buckalew V Jr, Martinez F, et al. Antiproteinuric efficacy of
eplerenone, enalapril, and eplerenone/enalapril combination therapy in diabetic hypertensives with microalbuminuria. Am J Hypertens 2002; 15(suppl
I):24A.
13. Inspra [package insert]. Chicago, Ill: Pharmacia; 2003. Available at:
http://www.inspra.com. Accessed October 28, 2004.
EVIDENCE IN PERSPECTIVE
Primary care guidance on reports from other sources
Effects of Helicobacter pylori eradication on
gastroesophageal reflux disease
H pylori eradication has no effect on symptoms or healing rates of gastroesophageal
reflux disease, nor does it prevent this condition in asymptomatic patients
RAMINDER KUMAR, MD, Clinical Associate Professor,
Department of Family Medicine, University of Chicago
We found 4 randomized controlled trials addressing
this question, 3 of them published in 2004. Three
trials evaluated patients with history of gastroesophageal reflux disease (GERD) symptoms of at
least 1-year duration.1–3 Of these, 2 studies found no
benefit of Helicobacter pylori eradication and the
third found higher rates of treatment failure with H
pylori eradication. The fourth trial evaluated the
impact of H pylori eradication on the development
of new heartburn or reflux in a large population
screened for H pylori.4
In the first trial patients with history of recurrent heartburn of at least 1-year duration with grade
A esophagitis (patients with higher grades of
esophagitis, peptic ulcer disease [PUD], or use of
proton-pump inhibitors [PPIs] or H2 receptor
blockers within the previous month were excluded)
or normal endoscopy were randomized to receive H
pylori eradication treatment or placebo.1 Both
groups were given omeprazole for 8 weeks. Patients
were given antacids to use as rescue medication.
Using life-table methods the probability of relapse
defined as moderate-to-severe GERD symptoms
was 83% at 12 months in both groups. No significant difference was noted in rates of esophagitis by
follow-up endoscopy at 12 months in the 2 groups.
In the second trial 231 patients with GERD
diagnosed either by endoscopy or 24-hour
esophageal pH-metry, who had been on maintenance therapy with omeprazole for 12 months or
longer, were randomized to H pylori eradication
versus no eradication for 1 week and then continued
on maintenance omeprazole therapy at previous
doses.2 Patients with complicated PUD were
excluded. After a 2-year follow-up the prevalence of
reflux symptoms was similar in the eradication
(25%) and noneradication groups (34%).
In the third trial 104 consecutive patients with
weekly attacks of heartburn or acid regurgitation in
the previous 12 months were enrolled.3 Patients
with PUD, complications of reflux such as strictures
or Barrett’s esophagus, and patients using nonsteroidal anti-inflammatory drugs or PPIs within 4
weeks were excluded. Patients were randomized to
either H pylori eradication treatment or omeprazole
20 mg bid with placebo antibiotics for 1 week followed by omeprazole 20 mg daily for 8 weeks.
Patients with complete resolution of symptoms and
esophagitis were maintained on omeprazole 10 mg
daily for 52 weeks. A composite endpoint of treatment failure included incomplete resolution of
symptoms or esophagitis at initial treatment (8week period), or relapse of symptoms or esophagitis
during maintenance phase. The 12-month probability of treatment failure was significantly higher in
the eradication group (43.2%; 95% confidence interval [CI], 29.9%–56.5%) than in the placebo group
(21.1%; 95% CI, 9.9%–32.3%). Most of this difference arose from initial treatment failure (5 of 53 in
eradication group and 0 of 51 in the noneradication
group), with relapse rates being similar (10 of 53 in
eradication group and 8 of 51 in the placebo group).
The placebo group also had lower reflux symptom
scores (median score 0, range 0–1) than the eradication group (median score 1, range 0–2).
In a large community-based trial, 1,634 patients
tested positive for H pylori (out of 10,537 screened).4
Of these, 1,558 were randomized to receive H pylori
Evidence-Based Practice
11
EVIDENCE IN PERSPECTIVE
CONTINUED
eradication therapy or placebo. The principal outcome was the consultation rate for dyspepsia during a
2-year follow-up. Symptom frequency, symptom type,
quality of life, and costs due to dyspepsia were secondary endpoints. H pylori eradication had no significant effect on the prevalence of heartburn (23.9%
with treatment and 24.2% with placebo; odds ratio
[OR] 0.99; 95% CI, 0.88–1.12) or reflux (18.9% with
treatment and 17.6% with placebo; OR 1.04; 95% CI,
0.91–1.19). Treatment also had no impact on development of new heartburn (OR 0.90; 95% CI,
0.78–1.04) or reflux (OR 1.05; 95% CI, 0.90–1.21). In
patients with these symptoms at baseline no significant improvement was seen for either heartburn (OR
0.90; 95% CI, 0.71–1.14) or reflux (OR 0.89; 95% CI,
0.62–1.29). Although the baseline characteristics of
the total group of patients in the 2 arms were similar,
the baseline characteristics of the subgroup of patients
with reflux or heartburn were not given.
This relatively recent evidence indicates that H
pylori eradication does not lead to improved outcomes in patients with GERD symptoms and does
not prevent development of GERD symptoms in a
screened population that tests positive for H pylori.
REFERENCES
Evidence-Based Practice
1.
Moayyedi P, Chandu B, Lynne Y, et al. Helicobacter pylori eradication
does not exacerbate reflux symptoms in gastroesophageal reflux disease.
Gastroenterology 2001; 121:1120–1126.
Family Physicians Inquiries Network, Inc.
409 West Vandiver Drive
Building 4, Suite 202
Columbia, MO 65202
2.
Kuipers EJ, Nelis GF, Klinkenberg-Knol EC, et al. Cure of Helicobacter
pylori infection in patients with reflux oesophagitis treated with long term
omeprazole reversed gastritis without exacerbation of reflux disease:
results of a randomized controlled trial. Gut 2004; 53:12–20.
3.
Wu JCY, Chan FKL, Ching JYL, et al. Effect of Helicobacter pylori eradication on treatment of gastro-esophageal reflux disease: a double blind,
placebo controlled , randomized trial. Gut 2004; 53:174–179.
4.
Harvey RF, Lane JA, Murray LJ, et al. Randomized controlled trial of
effects of Helicobacter pylori infection and its eradication on heartburn
and gastro-oesophageal reflux: Bristol helicobacter project. BMJ 2004;
328:1417–1419.
STATEMENT OF PURPOSE
Evidence-Based Practice (EBP) addresses the most important patient care questions
asked by practicing family physicians, using the best sources of evidence in a brief, clinically useful format.
NEWSLETTER TOPICS
Transforming Practice: Research evidence on diagnostic testing or treatment periodically
accumulates to a “tipping point” that warrants a change in practice. Each month the editors select one topic for which a substantial change in clinical practice seems justified.
Help Desk: Practicing family physicians submit questions about specific patient problems
to the Family Practice Inquiries Network (FPIN; www.fpin.org). Practicing physicians within the FPIN organization then single out the questions of greatest interest through a webbased voting system. The EBP editors search the highest quality sources for best evidence
(Cochrane, Clinical Evidence, US Preventive Services Task Force, AHRQ Evidence Based
Guidelines). If definitive answers are not available from these sources, the editors turn to
high-quality, well-referenced sources (UpToDate, DynaMed, National Guideline
Clearinghouse, University Pathologists Consortium Medical Databases). Other resources are
used at the editors’ discretion.
Drug Profile: Pharmaceutical information is promoted directly to consumers as well as physicians,
and is readily available on the Internet and in other mass media. In each issue of EBP, the editors objectively review the advantages and disadvantages of a featured medication based on scientific evidence.
Evidence in Perspective: The editors select topics covered in the highest quality evidencebased sources (eg, Cochrane, Clinical Evidence) and provide a clinical perspective and
guidance for applying the evidence specifically in primary care practice.
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