CME
Evidence-Based Practice
A Peer-Reviewed Publication of the Family Physicians Inquiries Network
EDITORIAL
3
The news from Roswell
DIVING FOR PURLs
4Patellofemoral osteoarthritis:
To brace or not to brace
Steroids shorten clinical course
of CAP in hospital setting
EBM ON THE WARDS
5Probiotics for hospitalized patients
starting IV antibiotics
HELPDESK ANSWERS
6
Transaminase elevations with use of statin
Amnioinfusion after preterm rupture
7Systemic antibiotics of no benefit
in simple abscess
8
Coronary artery disease screening
in patients with type 2 diabetes mellitus
Nonbenzodiazepine muscle relaxants
for chronic back pain
9
Probiotics in adult GI disorders
10
Physical therapy for fibromyalgia
12
Medications for retrograde ejaculation
Alternative medicines for insomnia
E1
Oral progesterone for miscarriage risk
Antibiotics for acute bacterial sinusitis
E2
Iron deficiency in young children
E3Safety of ARBs in patients with a history
of ACEI-induced angioedema
E4
DMPA risk in the immediate postpartum period
SPOTLIGHT ON PHARMACY
14High-dose gabapentin for neuropathic pain
in diabetes
CME TEST
15
October 2015
V O L U M E 18 N U M B E R 1 0 OCT OBER 2015
IN DEPTH
Is arthroscopic meniscectomy indicated
for nontraumatic degenerative medial
meniscal tears in the setting of no or mild
osteoarthritis?
Evidence-based answer
Probably not. Long-term outcomes (12–24 months) with pain and
function appear to be the same for surgical intervention and for
conservative treatment (SOR: B, systematic review of RCTs).
Evidence summary
A meta-analysis of 7 RCTs (N=805) examined the effectiveness of
arthroscopic surgery for the treatment of degenerative medial meniscus
tears.1 Five trials used exercise as control, 1 used intra-articular steroid
injections, and 1 used sham surgery. All patients were diagnosed with
degenerative meniscal tears with either mild or no osteoarthritis by
MRI or arthroscopy.
No significant difference was noted in pain at 3 months (1–10 scale)
between surgery and conservative treatment (4 trials, n=355; mean
difference [MD] 0.20; 95% CI, –0.67 to 0.26) or in pain at 24 months
(3 trials, n=355; MD –0.06, 95% CI, –0.28 to 0.15). Arthroscopic
surgery did result in a statistically significant but clinically negligible
increase in function at 6 months (6 trials, n=805; standardized mean
difference [SMD] 0.25; 95% CI, 0.02–0.48). This was equivalent to
an improvement of 5.6 on the 100-point Knee Injury Osteoarthritis
Outcome Score (KOOS), in which a difference of 10 is clinically relevant.
At 24 months, no significant difference was noted in function between
surgery and conservative therapy (5 trials, n=794; SMD 0.07; 95% CI,
–0.10 to 0.23).1
A 2013, double-blind RCT of 146 patients, 35 to 65 years old, with
degenerative tears of their medial menisci was included in the analysis
above and is discussed separately here as it examined the effectiveness
of partial arthroscopic meniscectomy compared with sham surgery.2
Meniscal tears were diagnosed on MRI, but ultimate inclusion was
based on findings during arthroscopy. Patients with traumatic onset or
knee osteoarthritis were excluded.
continued
Evidence-Based Practice / Vol. 18, No. 10
1
In Depth
At 12 months, no difference was noted between the
2 groups in knee pain after exercise (0–10 scale; MD 0.1
points; 95% CI, –0.9 to 0.7), in the 100-point qualityof-life Western Ontario Meniscal Evaluation Tool (MD
–2.5 pts; 95% CI, –9.2 to 4.1), or in the 100-point
Lysholm knee score (MD –1.6 points; 95% CI, –7.2 to
4.0).2
A 2014 RCT of 150 patients with knee pain
secondary to meniscal injury persistent after 3 months
of physical therapy compared arthroscopic surgery with
continued physical therapy.3 Patients were diagnosed by
a single orthopedic surgeon and underwent a knee x-ray
to determine there was no osteoarthritis. The nonsurgery
group received a physiotherapy appointment and
instructions on a home exercise program. The surgery
group received the same instructions and underwent
knee surgery within 4 weeks of study entrance.
At 12 months, 130 patients (87%) completed the
12-month survey, 16 patients crossed over from the
nonsurgery group to the surgery group, and 9 patients in
the surgery group did not undergo surgery. Both groups
improved significantly from baseline in the KOOS score
for pain in the intention-to-treat analysis (surgical MD
30; 95% CI, 25–34; nonsurgical MD 19; 95% CI,
13–25), with greater improvement in the surgery group
(MD 11; 95% CI, 3.4–18). Both groups also improved
from baseline to 12 months in symptoms, activities
of daily living, and quality-of-life measures, but there
was no difference between surgery and nonsurgery
EBP
groups.3
Luci Olewinski, MD
Morteza Khodaee, MD
University of Colorado FMR
Denver, CO
REFERENCES
1.Khan M, Evaniew N, Bedi A, Ayeni OR, Bhandari M. Arthroscopic surgery for degenerative
tears of the meniscus: a systematic review and meta-analysis. CMAJ. 2014;186(14):1057–
1064. [STEP 1]
2.
Sihvonen R, Paavola M, Malmivaara A, et al; Finnish Degenerative Meniscal Lesion
Study (FIDELITY) Group. Arthroscopic partial meniscectomy versus sham surgery for a
degenerative meniscal tear. N Engl J Med. 2013;369(26):2515–2524. [STEP 2]
3.Gauffin H, Tagesson S, Meunier A, Magnusson H, Kvist J. Knee arthroscopic surgery is
beneficial to middle-aged patients with meniscal symptoms: a prospective, randomised,
single-blinded study. Osteoarthritis Cartilage. 2014;22(11):1808–1816. [STEP 2]
LETTERS TO THE EDITOR
COUNT FOR SCHOLARLY ACTIVITY!
The ACGME classifies Letters to the Editor as scholarship of integration.
Evidence-Based Practice wants your “op-eds explaining the meaning and
significance of a current public health concern” or “analysis of the results
of a paper published by others.”1
Share your knowledge and submit your letter to the editor
of Evidence-Based Practice via www.fpin.org/letters.
1.Accreditation Council for Graduate Medical Education (ACGME). Scholarly Activity Guidelines. Review Committee for Family
Medicine.https://www.acgme.org/acgmeweb/Portals/0/PFAssets/ProgramResources/120_Family_Medicine_Scholarship_Guidelines.pdf.
Published 2012. Accessed October 4, 2015.
2
Evidence-Based Practice / October 2015
Evidence-Based Practice
Editorial
EDITOR-IN-CHIEF
Jon O. Neher, MD, FAAFP
University of Washington
EXECUTIVE EDITOR/FOUNDING EDITOR-IN-CHIEF
Bernard Ewigman, MD, MSPH, FAAFP
The University of Chicago
The news from Roswell
DEPUTY EDITORS
Clinical Inquiries
Gary Kelsberg, MD, FAAFP
E. Chris Vincent, MD
University of Washington
HelpDesk Answers
Tom Satre, MD
University of Minnesota
Diving for PURLs
Kate Rowland, MD
Rush–Copley Medical Center
Rick Guthmann, MD, MPH
University of Illinois
eMedRef
Robert Marshall, MD, MPH
Valley Medical Center
SECTION EDITORS
Behavioral Health Matters
Vanessa Rollins, PhD
University of Colorado
Geriatrics
Irene Hamrick, MD
University of Wisconsin
Musculoskeletal Health
Andrew W. Gottschalk, MD
Cleveland Clinic
EBM on the Wards
Corey Lyon, DO
University of Colorado
Integrative Medicine
David Rakel, MD, FAAFP
University of Wisconsin
Pharmacy HDAs
Connie Kraus, PharmD, BCACP
University of Wisconsin
EBPediatrics
Jonas A. Lee, MD
A. Ildiko Martonffy, MD
University of Wisconsin
Maternity Care
Lee Dresang, MD
University of Wisconsin
PRODUCTION
Medical Copy Editor
Melissa L. Bogen, ELS
Chester, NY
Managing Editor
Kerri Reynolds, BJ
Columbia, MO
Layout and Design
Robert Thatcher
New York, NY
Statement of Purpose
Evidence-Based Practice (EBP) addresses important patient care questions asked by
practicing family physicians, using the best sources of evidence in a brief, clinically
useful format. Our goal is to instruct our authors on how to write peer-reviewed
scholarly research for the medical and scientific community.
Disclosure
It is the policy of the University of Colorado School of Medicine to require the
disclosure of the existence of any relevant financial interest or any other relationship
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product(s) discussed in an educational presentation. In meeting the requirements
of full disclosure and in compliance with the ACCME Essentials, Standards for
Commercial Support, and Guidelines, the following information has been provided
by the editors regarding potential conflicts of interest: Jon O. Neher, M.D. and John
Saultz, M.D. have disclosed no relationships with commercial supporters.
The PURLs Surveillance System is supported in part by Grant Number UL1RR024999
from the National Center for Research Resources, a Clinical Translational Science
Award to the University of Chicago. The content is solely the responsibility of the
authors and does not necessarily represent the official views of the National Center
for Research Resources or the National Institutes of Health.
EBP CME
Evidence-Based Practice (ISSN 1095-4120) is published monthly to family clinicians
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Credit Designation
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per issue). Physicians should only claim credit commensurate with the extent of their
participation in the activity. Credit must be claimed by March 31, 2016.
2014 Subscription Rates
This is not because I think that Roswell sits on an interstellar
commuter hub, but rather that the regional economy is based
on the UFO mystique. Talk it up and the tourists will come. In
fact, I’d probably not accept the presence of UFOs based on
the testimony of all the people in Roswell combined. When
there’s a sighting in Springfield, maybe I’ll pay more attention.
Some positive research results are like UFO sightings—pretty far
out there. We want to believe, but we’ve been duped before and
must remain skeptical. How then do we become comfortable
with a novel research finding? Duplication of results, of course!
However, just duplicating a research protocol and reporting the
outcome is not enough. The duplication has to be independent.
Why? If the research teams are not truly independent, their
results may be biased toward conformity by a number of subtle
and not-so-subtle mechanisms. Said another way, 2 people
claiming to have seen a UFO in Roswell is no better evidence
than 1 sighting.
Is this really much of a problem in research? Apparently, yes—
at least some times. An article in the Journal of Psychosomatic
Research discussed 1 such case, involving data linking type
D personality (negative affect with social inhibition) with
cardiovascular disease.1 Of the 17 most-cited papers on the
topic, 15 were authored by people on the same research team,
and all reported the same association. Two fully independent
research teams with solid research designs failed to find a link.
So be careful. Even a stack of research papers may not get you
closer to the truth. Demand independent verification because,
as they whisper in Roswell, the truth is out there.
Happy Halloween!
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Roswell, New Mexico is known for its high frequency of UFO
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of positive responses than if I randomly asked people in
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just about anywhere else.
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Jon O. Neher, MD
REFERENCE
1.
Carlisle JB. The analysis of 168 randomised controlled trials to test data integrity.
Anesthesia. 2012; 67(5):521–537.
Copyright © 2015 by Family Physicians Inquiries Network, Inc.
Evidence-Based Practice / Vol. 18, No. 10
3
Diving for PURLs
Patellofemoral osteoarthiritis:
To brace or not to brace
Steroids shorten clinical course
of CAP in hospital setting
Callaghan MJ, Parkes MJ, Hutchinson CE, et al. A randomised trial of a brace for
patellofemoral osteoarthritis targeting knee pain and bone marrow lesions. Ann Rheum
Dis. 2015; 74(6):1164–1170.
Blum CA, Nigro N, Briel M, et al. Adjunct prednisone therapy for patients with
community-acquired pneumonia: a multicentre, double-blind, randomised, placebocontrolled trial. Lancet. 2015; 385(9977):1511–1518.
This randomized trial was performed to determine if
braces reduced pain and patellofemoral bone marrow
lesions (PF BML) in patients with patellofemoral
osteoarthritis. The study included 126 patients from
ambulatory care sites between 40 and 70 years old with
patellofemoral osteoarthritis diagnosed by x-ray, clinical
assessment, and physical examination. All patients had
chronic pain for at least 3 months and scored 4 or more
on a 10-cm visual analogue pain scale (VAS).
Patients were randomly assigned to 2 groups
(brace or no brace) for a duration of 6 weeks. During
their evaluation patients identified an activity that
caused them knee pain, and an MRI was performed on
that knee. Each week patients completed the VAS and
Knee Osteoarthritis Outcome Score (KOOS) based on
degree of knee pain experienced doing their nominated
aggravating activity. At the end of 6 weeks, MRIs were
performed again.
Primary outcomes were reduction in knee pain
during the nominated activity using VAS and reduction
of PF BML volume. Secondary outcomes were reduction
of pain, improvement in activities of daily living using
the KOOS, and change in synovial fluid volume.
The brace group had significantly lower knee pain
than the control group at 6 weeks (difference between
groups –1.3 cm; 95% CI, –2.0 to –0.7) and reduced
PF BML volume (difference –491 mm3; 95% CI, –930
to –52). There was no significant association between
reduction in pain and change in PF BML volume.
This double-blind, placebo-controlled RCT compared
prednisone with placebo in adults (aged ≥18 years)
admitted to hospitals in Switzerland with communityacquired pneumonia (CAP). CAP was defined as a new
infiltrate on chest radiograph and at least 1 other clinical
sign of pneumonia. Patients were randomized to receive
either prednisone 50 mg daily for 7 days or placebo in
addition to antibiotic therapy.
The primary outcome was a composite
measurement of clinical stability that included all of the
following factors: temperature, heart and respiratory
rate, blood pressure, mental status, pulse oximetry, and
the ability for oral intake. Secondary endpoints included
time to hospital discharge, recurrent pneumonia, intensive
care unit admission, hospital readmission, duration of
antibiotic treatment, CAP complications, and adverse
effects of corticosteroids.
The median time to clinical stability in patients
treated with prednisone was 3 days (interquartile
range [IQR], 2.5–3.4) compared with 4.4 days (IQR,
4.0–5.0) in patients who received placebo (HR 1.33;
95% CI, 1.1–1.5). Median time to discharge in the
prednisone versus placebo groups was 6 days versus
7 days, respectively (HR 1.2; 95% CI, 1.02–1.4). Overall,
no differences were noted in complications from CAP in
the 2 groups (OR 0.5; 95% CI, 0.2–1.0). The incidence
of hyperglycemia requiring insulin treatment was higher
in patients treated with prednisone: 76 episodes (19%)
versus 43 (11%) episodes (OR 1.96; 95% CI, 1.31–2.93;
NNH=13).
RelevantYes
Medical care setting
Yes
ValidNo
Implementable
Yes
RelevantYes
Medical care setting
Yes
Yes
ValidYes
Implementable
Yes
Change in practiceYes
Clinically meaningful
Yes
Change in practiceYes
Clinically meaningful
Bottom line: While this study showed that using a brace
for treatment of patellofemoral osteoarthritis decreased
knee pain and reduced PF BMLs, we have lingering
concerns with the lack of a placebo in the control group,
only modest reductions in pain, and short-term follow-up.
Review and Summary Author: Kortnee Y. Roberson, MD,
The University of Chicago Department of Family Medicine, Chicago, IL
4
Evidence-Based Practice / October 2015
Bottom line: Prednisone is a reasonable adjunct
therapy for adults with CAP to reduce the time to
EBP
clinical stability and shorten hospitalization.
Review and Summary Authors: Sandy Sauereisen, MD, MPH,
and Jennie Broders Jarrett, PharmD, BCPS,
UPMC St. Margaret FMRP, Pittsburgh, PA
EBM on the Wards
Should probiotics be used when starting IV antibiotics
in the hospitalized patient?
Case
A 66-year-old man with well-controlled hypertension
and hyperlipidemia who presents with dyspnea, fever,
and cough is found to have pneumonia on chest x-ray.
He is admitted to the hospital due to mild hypoxia and
started on IV ceftriaxone and azithromycin. Should
this patient be given probiotics at the same time to
prevent antibiotic-associated diarrhea?
Review of the evidence
A meta-analysis of 82 RCTs (total N not provided) from
1979 to 2012 with a variety of probiotic formulations
examined their effectiveness in the prevention of
antibiotic-associated diarrhea.1 Patients were either
inpatient or outpatient, predominately adults, and
were taking a variety of antibiotics or antibiotic
combinations.
Pooled results demonstrated an overall risk
reduction of antibiotic-associated diarrhea with
probiotics (63 trials, N=11,811; risk ratio [RR] 0.58;
95% CI, 0.50–0.68; NNT=13) compared with a control
group not using probiotics. Of note, there was a high
level of heterogeneity and bias in this analysis (I2=54%)
and the authors were unable to determine which strains
of probiotics produced benefit or in what situations
they were most helpful. The authors concluded there
was an association with probiotic use and decreased
incidence of antibiotic-associated diarrhea.1
A 2013 Cochrane review of 31 RCTs (N=4,492)
examined the effectiveness of probiotics for the
prevention of Clostridium difficile–associated diarrhea
(CDAD) and antibiotic-associated diarrhea in adult
patients receiving antibiotics.2 The probiotic group had
a significant decrease in the risk of CDAD compared
with a placebo group (23 trials, n=4,213; 2.0% vs 5.5%;
RR 0.36; 95% CI, 0.25–0.51). No significant
heterogeneity was noted (I2=0%). There was also a
decreased risk of antibiotic-associated diarrhea with
the use of probiotics compared with placebo or no
treatment controls (25 trials, n=4,097; 13% vs 21%;
RR 0.60; 95% CI, 0.49–0.72), however, significant
heterogeneity was noted (I2=36%).
A recent large, multicenter RCT of 2,941 adults
aged >65 years who received antibiotics within 7 days
of enrollment (IV and oral preparations included)
published after the Cochrane review search date set
out to better control for populations and probiotic
preparation differences.3 All patients were hospitalized
and treated with 1 or more broad-spectrum antibiotics
(oral or IV). Patients were randomized to either a
21-day course of Lactobacillus and Bifidobacteria
(6×1010 organisms) or placebo.
After 12 weeks, no difference was noted in
antibiotic-associated diarrhea (including CDAD)
between groups (RR 1.04; 95% CI, 0.84–1.3).3
Case Wrap-Up
While some data support the association of decreased
antibiotic-associated diarrhea with probiotic use,
no single population or strain has been shown to be
effective, so it is not known which agent or which
EBP
dose would benefit this patient.
Drew Ashby, MD
Corey Lyon, DO
University of Colorado FMR
Denver, CO
REFERENCES
1.Allen SJ, Wareham K, Bradley C, et al. A multicentre randomised controlled trial evaluating
lactobacilli and bifidobacteria in the prevention of antibiotic-associated diarrhoea in older
people admitted to hospital: the PLACIDE study protocol. BMC Infect Dis. 2012; 12:108.
[STEP 1]
2.Goldenberg JZ, Ma SS, Saxton JD, et al. Probiotics for the prevention of Clostridium
difficile-associated diarrhea in adults and children. Cochrane Database Syst Rev. 2013;
(5):CD006095. [STEP 1]
3.Hempel S, Newberry SJ, Maher AR, et al. Probiotics for the prevention and treatment
of antibiotic-associated diarrhea: a systematic review and meta-analysis. JAMA. 2012;
307(18):1959–1969. [STEP 2]
Evidence-Based Practice is actively recruiting authors
for our Feature sections!
Our feature sections cover the full spectrum of family care and are:
• Topics in Maternity Care
• Integrative Medicine
• EBPediatrics
• Spotlight on Pharmacy
• Advances in Geriatrics
• Musculoskeletal Health
• EBM on the Wards
Feature Articles allow residency and fellowship programs
throughout the FPIN Network to showcase their unique area
of excellence.
Interested? For more information, please contact ebp@fpin.org.
We look forward to hearing from you!
Evidence-Based Practice / Vol. 18, No. 10
5
What are the risks of transaminase and creatine
kinase elevations with the use of a statin?
Evidence-Based Answer
Higher dose statins increase the risk of hepatic
transaminase elevations, especially the hydrophilic
statins (atorvastatin or pravastatin). Lipophilic
statins (simvastatin or lovastatin) may increase the
risk of creatine kinase elevation at higher doses
(SOR: C, systematic review of RCTs using diseaseoriented outcomes).
A meta-analysis of 9 RCTs (N=30,653) compared
different doses and types of statin therapy for
adverse effects of hepatic toxicity, muscle toxicity,
and elevation of transaminase and creatine kinase
(CK) levels.1 Follow-up ranged from 1 to 5 years. The
trials compared different doses (higher/lower) of the
same drug: atorvastatin 80 vs 10 mg/d, simvastatin
40–80 mg/d vs 20–40 mg/d, lovastatin 76 vs 4 mg/d,
and pravastatin 40 mg/d.
In all 9 RCTs, the higher dose statin group had
significantly higher transaminase levels (defined as
>2 or 3 times the upper limit of normal [ULN])
compared with the lower dose group (1.5% vs 0.4%;
risk ratio [RR] 3.1; 95% CI, 1.7–5.6). The analysis also
showed greater increase in transaminase levels with
higher dose hydrophilic statins (pravastatin and
atorvastatin) compared to the lower dose hydrophilic
group (5 RCTs, n=15,592; RR 3.5; 95% CI,
1.8–6.9). There was no increase in CK elevation in
either hydrophilic group. The high-dose lipophilic
statins (lovastatin and simvastatin) were more likely to
cause increase in CK levels (defined as 3–10 times ULN)
compared with the low-dose lipophilic group (2 RCTs,
n=5,848; RR 6.1; 95% CI, 1.4–27).1
A subsequent network meta-analysis of 135
RCTs involving 246,955 patients with and without
cardiovascular disease compared several individual
statin therapies.2 Patients randomized to all statins had
a clinically significant increased risk of transaminase
elevation (defined as 3 times ULN) compared with
controls (OR 1.5; 95% CI, 1.2–1.8). Atorvastatin
(OR 2.5; 95% CI, 1.7–3.7) and fluvastatin (OR 5.2;
95% CI, 1.9–15) had higher odds of transaminase
elevations compared with controls. When compared
head to head, pravastatin (OR 0.4; 95% CI, 0.2–
0.7), rosuvastatin (OR 0.6; 95% CI, 0.4–0.9), and
6
Evidence-Based Practice / October 2015
simvastatin (OR 0.5; 95% CI, 0.3–0.7) had lower odds
of transaminase elevations compared with atorvastatin.
When CK elevations were compared, statins as a class
did not demonstrate a significant increase compared
with controls (OR 1.13; 95% CI, 0.8–1.5). However
there was a dose–response relationship with certain
statins like simvastatin; doses >40 mg/d had significantly
higher odds of elevated CK levels compared with
controls (OR 4.1; 95% CI, 1.1–16).
Kumuda Ranjan, MD
Adity Bhattacharyya, MD, FAFP
Rutgers–Robert Wood Johnson Medical School FMR at Capital Health
New Brunswick, NJ
1. Dale KM, et al. Am J Med. 2007; 120(8):706–712. [STEP 1]
2. Naci H, et al. Circ Cardiovasc Qual Outcomes. 2013; 6(4):390–399. [STEP 1]
Is amnioinfusion beneficial for neonates
after preterm premature rupture
of membranes (PPROM)?
Evidence-Based Answer
Transcervical amnioinfusion (TCA) does not appear
to improve clinical outcomes in PPROM (SOR: A,
systematic review). Transabdominal amnioinfusion
(TA) may reduce the risk of neonatal sepsis, pulmonary
hypoplasia, and neonatal death, but the evidence is
conflicting (no SOR given).
A systematic review evaluated neonatal morbidity and
perinatal mortality in newborns born after PPROM
(gestational age 24–35 weeks).1 Outcomes of newborns
whose mothers received TCA (2 RCTs, N=147) or TA
(2 RCTs, N=94) were examined. Control groups
received no amnioinfusion. Saline fluid or Ringer’s
lactate was infused transcervically through a catheter
into the uterine cavity or transabdominally through a
narrow gauge needle. Studies utilized varying fluids,
infusion rates, and durations of therapy.
Rates of neonatal sepsis, pulmonary hypoplasia,
and neonatal death were similar for TCA compared
with controls. Neonates in the TA intervention group
had reduced rates of neonatal sepsis (1 trial, n=60;
RR 0.26; 95% CI, 0.11–0.61), pulmonary hypoplasia
(1 trial, n=34; RR 0.22; 95% CI, 0.06–0.88), neonatal
death (2 trials, n=94; RR 0.30; 95% CI, 0.14–0.66),
and likelihood of delivery within 7 days (1 trial, n=34;
RR 0.18; 95% CI, 0.05–0.70). Adverse effects of the
interventions were not discussed.1
Another systematic review and meta-analysis of
4 observational trials (n=147) and 3 RCTs (n=165)
evaluated fetal outcomes after TA in pregnancies
complicated by PPROM and oligohydramnios at a
gestational age of 16 to 33 weeks.2 In the observational
trials, there was an increased latency (time from
membrane rupture until delivery) period (mean
difference [MD] 14 days; 95% CI, 8.2–21 days). The
group receiving TA had decreases in perinatal death
(OR 0.12; 95% CI, 0.02–0.61) and pulmonary
hypoplasia (OR 0.17; 95% CI, 0.04–0.78) compared
with those not receiving TA. Neonatal death was
reduced (OR 0.09; 95% CI, 0.01–0.84) in the 1 study
(n=18) reporting this outcome. In the RCT group
(2 of the 3 RCTs were included in the review referenced
above), no statistically significant difference was noted
in latency period (MD +11 days; 95% CI, –3.4 to 26),
perinatal mortality (OR 0.33; 95% CI, 0.10–1.1), or
pulmonary hypoplasia (OR 0.3; 95% CI, 0.05–1.7).
Adverse effects of interventions were not addressed.
A case series (N=7) described continuous
amnioinfusion via subcutaneous port system and a
variety of different solutions (isotonic and 1 hypotonic
solution) in pregnancies complicated with PPROM
and anhydramnion.3 The average gestational age was
20 weeks (range 14–26 weeks) with an average duration
of amnioinfusion of 21 days (range 4–49 days). Patients
also received standard treatment with antibiotics and
antenatal corticosteroids. Neonatal outcomes were
described in the 6 live births (1 fetal death was unrelated
to amnioinfusion).
Gestational age at delivery was 29 weeks with an
average latency period of 49 days (range 9–77 days).
There was no incidence of pulmonary hypoplasia.
No differences were seen among fluid types, but this
conclusion was limited by small sample size. Prospective
international randomized studies are ongoing.3
Christian Orji, MD
Ron Brimberry, MD
Lois Coulter, PharmD
Jonell Hudson, PharmD
UAMS Northwest FMRP
Fayetteville, AR
1. Hofmeyr G, et al. Cochrane Database Syst Rev. 2011; (12):CD000942. [STEP 1]
2. Porat S, et al. Am J Obstet Gynecol. 2012; 207(5):393.e1–e11. [STEP 1]
3. Tchirikov M, et al. J Perinat Med. 2013; 41(6):657–663. [STEP 4]
In addition to incision and drainage,
are antibiotics indicated for treatment
of uncomplicated abscesses?
Evidence-Based Answer
Systemic antibiotics are not indicated for treatment
of simple abscesses after incision and drainage as
there is no improvement in cure rates even in the
setting of wounds containing methicillin-resistant
Staphylococcus aureus (MRSA) (SOR: A, meta-analysis
of RCTs). Antibiotics should be considered if systemic
inflammatory response syndrome is present (SOR: C,
expert opinion).
A 2014 systematic review and meta-analysis of
4 RCTs evaluated the effect of adding antibiotics after
incision and drainage (I&D) on cure rates in emergency
department patients (428 adults, 161 children) with
a simple abscess.1 A simple abscess was defined as
having erythema, induration, and fluctuance with
or without purulent drainage. Symptoms must have
started within the previous 7 days and signs of systemic
infection, including fever, were absent. One of 3 oral
antibiotics or matching placebos were given for 7 to
10 days after I&D: cephradine (250 mg every 6 hours),
cephalexin (500 mg every 6 hours), or trimethoprimsulfamethoxazole (TMP-SMX) dosed at 160/800 mg
BID for adults or 5–6 mg TMP/kg BID for pediatric
patients.
Antibiotics after I&D did not change the cure rate
at 7 to 10 days’ follow-up compared with I&D alone
(88% vs 86%, risk difference [RD]=2%; 95% CI, –4
to 7). Long-term outcomes were assessed 30 days after
I&D in 1 trial and 90 days after I&D in another, both
of which used TMP-SMX. The pooled rate of clinical
improvement without recurrent abscess was higher
with antibiotics after I&D, but the difference was not
statistically significant (82% vs 72%; 2 trials, n=148;
RD=10%; 95% CI, –2 to 22). The MRSA prevalence
in these 2 trials ranged from 53% to 80% and all
MRSA isolates were sensitive to TMP-SMX. No
significant heterogeneity or evidence of publication
bias was found; however, even the pooled results may
be underpowered to detect a small clinically relevant
effect.1
The 2014 Infectious Diseases Society of America
evidence-based guideline for the diagnosis and
management of skin and soft-tissue infections
Evidence-Based Practice / Vol. 18, No. 10
7
recommended I&D as the primary treatment for
cutaneous abscesses (strong recommendation, highquality evidence).2 The guideline states that cure rates
are not improved by the addition of systemic antibiotics
after I&D (strong recommendation, low-quality
evidence). In their expert opinion, antibiotics should
be considered in the presence of systemic inflammatory
response syndrome, with antibiotics directed against
S aureus in an immunocompetent patient and MRSA in
an immunocompromised patient.
Garth Brand, MD
Emily Colson, MD
Montana FMR
Billings, MT
noted in mortality rate in the combined treatment
group compared with the medical treatment only group
(16% vs 17%; P=.90). In the 645 patients with either
metabolic syndrome or diabetes, there was also no
difference between groups (25% vs 25%; P=.84).
Another RCT looked at mortality outcomes in
2,368 patients with type 2 diabetes and stable CAD
undergoing either optimal medical therapy alone or
medical therapy and revascularization.3 After a 5-year
follow-up, no difference was noted in survival rates
between the groups (88% vs 88%; mean difference
[MD] 0.5%; 95% CI, –2 to 3.1; P=.97). Also, there was
no difference in freedom from major cardiovascular
events at 5 years (77% vs 76%; MD 0.3%; 95% CI,
–2.2 to 4.9; P=.70).
1. Singer AJ, et al. Emerg Med J. 2014; 31(7):576–578. [STEP 1]
2. Stevens DL, et al. Clin Infect Dis. 2014; 59(2):147–159. [STEP 5]
Should we screen for coronary artery disease
in patients with type 2 diabetes mellitus?
Evidence-Based Answer
Probably not. Screening for coronary artery disease
(CAD) in patients with type 2 diabetes using myocardial
perfusion imaging does not improve outcomes. In
patients with type 2 diabetes and asymptomatic stable
CAD, percutaneous interventions and medical therapy
do not decrease long-term mortality rates compared
with medical management alone (SOR: B, RCTs).
An RCT followed 1,123 asymptomatic patients with
type 2 diabetes for an average of 4.8 years to determine
the event rate of cardiac death or nonfatal myocardial
infarction (MI) in patients who received CAD screening
with myocardial perfusion imaging.1 All patients were
medically managed for diabetes based on established
American Diabetes Association guidelines. Primary
events measured were cardiac death or nonfatal MI.
No difference was noted in primary events
(HR 0.88; 95% CI, 0.44–1.8) or revascularizations
(HR 0.71; 95% CI, 0.45–1.1) in patients undergoing
screening compared with patients who had no screening.1
A post hoc analysis of data from a multicenter
RCT examined the rate of death in 121 patients with
CAD and diabetes after an average of 4.6 years who
were treated with percutaneous coronary intervention
and optimal medical therapy versus medical therapy
alone.2 In patients with diabetes, no difference was
8
Evidence-Based Practice / October 2015
William A. Stevens, MD
Sterling Brodniak, DO
Madigan Army Medical Center FMR
Tacoma, WA
The opinions and assertions contained herein are the private views
of the authors and are not to be construed as official or as reflecting the views
of the Medical Department of the US Army or the US Army Service at large.
1. Young LH, et al. JAMA. 2009; 301(15):1547–1555. [STEP 2]
2. Maron DJ, et al. J Am Coll Cardiol. 2011; 58(2):131–137. [STEP 2]
3. The BARI 2D Study Group. N Engl J Med. 2009; 360(24):2503–2515. [STEP 2]
What is the efficacy of nonbenzodiazepine
centrally acting muscle relaxants for the
treatment of chronic nonspecific back pain
in adults?
Evidence-Based Answer
Oral cyclobenzaprine may be beneficial for up to
2 weeks in the treatment of chronic nonspecific
back pain (SOR: B, systematic review). Two other
nonbenzodiazepine muscle relaxants, flupirtine and
tolperisone (not available in the United States), may be
also be beneficial for 1 to 3 weeks (SOR: B, based on
2 RCTs within the systematic review).
A 2003 Cochrane review (30 RCTs) examined the
effectiveness of centrally acting skeletal muscle relaxants
for relief of nonspecific back pain.1 Within this review,
6 trials focused on chronic low back pain (>12 weeks)
and only 3 RCTs (n=295) used nonbenzodiazepine
skeletal muscle relaxants. Authors were unable to
pool the data into a meta-analysis because of design
heterogeneity.
One RCT (n=76) found no difference between
cyclobenzaprine (10 mg TID) and placebo for
reduction of muscle spasm after 13 to 18 days. Another
RCT (n=112), examining the use of tolperisone (not
available in the United States) at a dose of 100 mg TID
versus placebo, found no difference in Clinical Global
Impression of efficacy on day 10 and day 21. However,
subjective ratings of overall efficacy were higher at
day 21: very good (15 vs 6 patients), good (17 vs 21
patients), moderate (19 vs 15 patients), or ineffective
(5 vs 14 patients) (no P values provided). The third RCT
(n=107) showed no difference in pain intensity or muscle
spasm (both using a 5-point rating scale) at day 7 with
use of flupirtine (also not available in the United States)
at a dose of 100 mg QID for 7 days versus placebo.
However, for the outcome of overall assessment by the
physician (as to categories labeled as very good, good,
or satisfactory taken as a combined score), there was a
positive effect with the use of flupirtine (85% vs 54%
for placebo; no P value provided).1
One specific limited pooled analysis of these last
2 RCTs (n=246) demonstrated no statistical difference
in adverse events (events not specified) between the
tolperisone or flupirtine and placebo groups with
7 to 21 days of treatment (RR 1.0; 95% CI, 0.67–1.6).
Efficacy and adverse effects with long-term use of
tolperisone or flupirtine were not reported. Adverse
effects of cyclobenzaprine were also not reported in this
review.1
A 2004 systematic review, which included 101
RCTs, 4 systematic reviews, and 3 meta-analyses,
examined comparative efficacy and safety of skeletal
muscle relaxants for spasticity and musculoskeletal
conditions.2 A total of 14 RCTs (n=3,315) included
in this systematic review evaluated the use of
cyclobenzaprine for back pain (not spasticity). Various
outcome measures were reported, but 13 of the 14 trials
included a global measure of symptom improvement as
scored by patients on visual analogue or categorical
pain scales.
Cyclobenzaprine 10 mg TID was associated with
greater global improvement score (pooled self- and
physician-rated symptom scores) at day 14 (10 trials,
n=1,446; OR 4.7; 95% CI, 2.7–8.1; NNT=2.7)
compared with placebo. The magnitude of global
improvement was modest, however, with an effect
size of 0.38 to 0.58 (0.2 is considered small; 0.6 is
considered moderate) for the 5 outcomes measured
(local pain, muscle spasm, tenderness to palpation,
range of motion, and activities of daily living). These
RCTs were also clinically heterogeneous and included
subacute back and neck pain in addition to chronic low
back pain. Use of cyclobenzaprine longer than 14 days
was not assessed for safety or efficacy in this review.2
A joint clinical practice guideline published in
2007 from the American College of Physicians and
American Pain Society, “Diagnosis and Treatment of
Low Back Pain,” using systematic methodology and
evidence-based practices, found insufficient evidence
to recommend for or against use of nonbenzodiazepine
skeletal muscle relaxants for the treatment of chronic
back pain.3
Igor Bedarev, MD
Natalie Nunes, MD
Tacoma FMR
Tacoma, WA
1. Van Tulder MW, et al. Cochrane Database Syst Rev. 2003; (2):CD004252. [STEP 1]
2. Chou R, et al. J Pain Symptom Manage. 2004; 28(2):140–175. [STEP 1]
3. Chou R, et al. Ann Intern Med. 2007; 147(7):478–491. [STEP 1]
For what gastrointestinal disorders in adults
are probiotics effective?
Evidence-Based Answer
Probiotics are better than placebo at inducing
remission in patients with ulcerative colitis (SOR: A,
based on meta-analysis of RCTs). VSL#3®, a proprietary
combination probiotic, is more effective than placebo
for the maintenance of remission of chronic pouchitis
(inflammation of ileal pouch-anal anastomosis) (SOR: A,
based on systematic review). Saccharomyces boulardii
added to triple therapy for Helicobacter pylori increases
eradication rates (SOR: A, based on meta-analysis
of 5 RCTs). Probiotics reduce the risk of antibioticassociated diarrhea (SOR: A, based on meta-analysis
of RCTs).
A meta-analysis of 7 RCTs compared the remission
rate of ulcerative colitis between 180 patients receiving
a standard therapy versus placebo and 219 patients
receiving probiotics in addition to standard therapy or
placebo.1 Study duration varied from 1 to 12 months.
The remission rate for patients with ulcerative
colitis who received probiotics versus the nonprobiotics
group who received either standard therapy or placebo
Evidence-Based Practice / Vol. 18, No. 10
9
was 1.35 (95% CI, 0.98–1.85). Compared with the
subgroup that received placebo only, the remission rate
of the probiotic group was 2.00 (95% CI, 1.35–2.96).1
A Cochrane review of 2 RCTs, with a total of 76
adult patients after ileal pouch-anal anastomosis for
chronic ulcerative colitis, compared the effect of the
probiotic VSL#3 and placebo for the maintenance
of remission of chronic pouchitis.2 The duration of
treatment was 1 year for 1 trial, and 3 years for the
second.
The pooled results revealed remission was
maintained at greater rates with VSL#3 than with
placebo (97% vs 3%; OR 25; 95% CI, 10–62). The
number needed to treat (NNT) with oral VSL#3 to
prevent 1 additional relapse was 2. The quality of both
studies was rated very high.2
A meta-analysis (5 RCTs, N=1,307 adults and
children) evaluated the effect of S boulardii (daily doses
of 500–1,000 mg) as a supplement to standard triple
therapy on H pylori eradication and adverse effects
of treatment.3 In pooled analysis, the S boulardiisupplemented group had a significantly higher H pylori
eradication rate than the placebo group (3 trials, n=825;
RR 1.1; 95% CI, 1.0–1.2) and a significantly lower
risk of therapy-related diarrhea than the control group
(4 RCTs, n=1,215, 5.6% vs 12%, respectively; RR 0.47;
95% CI, 0.32–0.69; NNT=16).
A systematic review and meta-analysis of the use
of probiotics for the prevention and treatment of
antibiotic-associated diarrhea included 63 RCTs with
11,811 patients.4 The use of single antibiotics such as
amoxicillin, azithromycin, and clarithromycin were
reported in 16 trials, while others included multiple
antibiotics or were otherwise unspecified. The probiotic
used most frequently was Lactobacillus based, either
alone or combined with other probiotics. Combined
Evidence-Based Practice learning objectives
1To become knowledgeable about evidence-based
solutions to commonly encountered clinical problems.
2To understand how ground-breaking research is
changing the practice of family medicine.
3To become conversant with balanced appraisals of
drugs that are marketed to physicians and consumers.
10
Evidence-Based Practice / October 2015
data from all 63 trials found probiotic use compared
with placebo or no probiotics was associated with a
decreased risk of diarrhea (RR 0.58; 95% CI, 0.50–
0.68; NNT=13).
Maleeha Faisal, MD
Diane Madlon–Kay, MD, MS
University of Minnesota Medical School
Minneapolis, MN
1. Sang LX, et al. World J Gastroenterol. 2010; 16(15):1908–1915. [STEP 1]
2. Holubar S, et al. Cochrane Database Syst Rev. 2010; (6):CD001176. [STEP 1]
3. Szajewska H, et al. Aliment Pharmacol Ther. 2010; 32(9):1069–1079. [STEP 1]
4. Hempel S, et al. JAMA. 2012; 307(18):1959–1969. [STEP 1]
Does physical therapy improve symptoms
of fibromyalgia?
Evidence-Based Answer
Aerobic exercise and strength training 2 to 3 times
per week as well as water-based physical therapy for
at least 20 weeks can modestly improve the symptoms
of fibromyalgia (SOR: B, meta-analyses of lower quality
RCTs).
A 2007 Cochrane review of 34 RCTs (N=2,276)
assessed how exercise interventions affect pain,
global well-being, physical function, tender points,
and depression in patients with fibromyalgia when
compared with usual care.1 The mean age of patients
in each trial ranged from 28 to 60 years and 96% were
female. Exercise was performed 2 to 3 times per week
for 2.5 to 24 weeks and regimens were subclassified as
aerobic-only, strength-only, flexibility-only, and mixed.
Aerobic exercise lasted at least 20 minutes per day
while strength training consisted of 8 to 12 repetitions
per exercise.
Short-term (6–23 weeks) aerobic-only and strengthonly exercise regimens improved multiple symptoms of
fibromyalgia (TABLE 1 ). Only 4 trials were classified
as high quality and more than half of the studies
were deficient on 6 or more internal validity criteria.
The clinical effect of strength training could not be
determined due to small sample sizes.1
A 2010 meta-analysis of 35 RCTs (N=2,494),
including 20 RCTs from the 2007 Cochrane review,
studied the effect of type and duration of aerobic
exercise on fibromyalgia.2 The median age of patients
was 45 years (range 13–59 years). The studies involved
TABLE 1
Effect of exercise on fibromyalgia symptoms by exercise type1
Aerobic exercise only
Outcome
Trials
Pain
4
N
SMD
223
Strength training only
95% CI
Trials
0.810.15–1.5 1
N
SMD
21
3.0 1.7–4.3
95% CI
Global well-being
4
269
0.49
0.23–0.75
2
47
1.4
0.76–2.1
Physical functioning
4
253
0.66
0.41–0.92
2
47
0.52
–0.07 to 1.1a
Depression
5
273
0.540.14–0.94 1
21
1.1 0.20–2.1
Reduction in tender points
6
349
0.76
–0.01 to 1.5 1
26
1.5 0.63–2.4
a
Not statistically significant.
CI=confidence interval; SMD=standard mean difference.
a
TABLE 2
Effect of aerobic exercise on fibromyalgia symptoms2
Posttreatment
Outcome
Latest follow-up (median=26 weeks)
Trials
N
SMD
95% CI
Trials
N
SMD
95% CI
Pain
22
1,038
0.31
0.16–0.46
9
374
0.18
–0.02 to 0.39a
Health-related QOL
25
1,266
0.40
0.20–0.60
8
424
0.27
0.05–0.48
Physical fitness
16 7910.52
0.37–0.66
16 7910.52
0.37–0.66
Depression
19
870
0.32
0.12–0.53
8
374
0.44
–0.01 to 0.88a
Fatigue
15
670
0.22
0.05–0.38
4
179
0.23
–0.17 to 0.62a
Not statistically significant.
CI=confidence interval; QOL=quality of life; SMD=standard mean difference.
a
TABLE 3
Effect of aquatic physical therapy (PT) on
fibromyalgia symptoms at the end of treatment3
Aquatic PT >20 weeks’ duration
Outcome
Trials
N
SMD
95% CI
Quality of life
3
118
1.4
0.67–2.0
Stiffness
2
87
1.60.58–2.6
6-minute walk
2
88
44
3.8–83
CI=confidence interval; SMD=standard mean difference.
primarily women. Exercise was performed from
1 to more than 3 times per week for 7 to more than
12 weeks in most studies. Aerobic exercise at least
2 times per week was necessary for a reduction of
symptoms.
Multiple outcome measures improved at the end of
treatment; however, at the latest follow-up appointment
(median of 26 weeks), only the improvements in
health-related quality of life (QOL) and physical
fitness remained statistically significant (TABLE 2 ). No
significant differences were noted in outcomes between
land-based and water-based aerobic therapy, or between
low- and moderate-intensity aerobic exercise. Other
than heterogeneity in the outcomes of posttreatment
health-related QOL and latest follow-up depression, no
significant biases were observed.2
A 2013 meta-analysis of 15 RCTs (N=1,265)
compared the effectiveness of aquatic physical therapy
(PT) with land-based exercise and no treatment in adult
patients with fibromyalgia.3 No pooled demographic
data were reported. Trials were prospectively placed
into 3 groups based on treatment duration (4–8 weeks,
9–20 weeks, and >20 weeks).
Only aquatic PT of longer than 20 weeks
was associated with improvement at the end of
treatment versus no treatment (TABLE 3 ). No significant
differences were noted at the 6-month follow-up. Most
studies were at high risk of bias in the domains of
allocation concealment, blinding of assessment, and
intention-to-treat.3
Jean Gustafson, MD
Jeff Hostetter, MD
University of North Dakota Center for Family Medicine
Bismarck, ND
1. Busch AJ, et al. Cochrane Database Syst Rev. 2007; (4):CD003786. [STEP 1]
2. Hauser W, et al. Arthritis Res Ther. 2010; 12(3):R79. [STEP 1]
3. Lima TB, et al. Clin Rehabil. 2013; 27(10):892–908. [STEP 1]
Evidence-Based Practice / Vol. 18, No. 10
11
Are any medications effective
for retrograde ejaculation?
Evidence-Based Answer
There are no placebo-controlled trials to guide the
treatment of retrograde ejaculation. Sympathomimetic
and
anticholinergic
medications
have
been
recommended as possible treatments (SOR: C, based
on case series and international guideline).
A 2012 systematic review of 9 case series of
137 men with retrograde ejaculation evaluated the
effect of medical management on reversal of the
condition.1 Each case series included 1 to 5 different
treatment arms. Monotherapy with sympathomimetic
drugs (synephrine, pseudoephedrine, ephedrine,
phenylpropanolamine, and midodrine) was used in
6 series while monotherapy with anticholinergic drugs
(brompheniramine, imipramine, and chlorpheniramine)
was used in 4 series. Two series used a combination
of sympathomimetic and anticholinergic medications.
One series used acupuncture and a combination of
traditional Chinese medicines. Successful antegrade
ejaculation was diagnosed by comparing pre- and
posttreatment ejaculate volumes and sperm counts.
Antegrade ejaculation was achieved in 11/40
(28%) treated with sympathomimetics, 11/50 (22%)
treated with anticholinergics, 5/13 (39%) treated
with combination therapy, and 17/25 (68%) treated
with acupuncture and a combination of traditional
Chinese medicines. Three case series included 1 to 7
nontreatment control patients, and antegrade
ejaculation was achieved in 2/9 (22%). The authors
were unable to make any statistical comparison due
to the small patient numbers. Only 3 of the studies
measured fertility outcomes such as pregnancy rate
or live birth rate; however, none of the series reported
pregnancy rate per cycle. No significant adverse effects
were reported. Some of the medications used in these
series are not available in the United States and others
must be given as an intramuscular injection.1
The 2014 European Association of Urology
guideline on male infertility stated that in the absence
of spinal cord injury, anatomic urethral anomalies, or
drug-related retrograde ejaculation, drug treatment
to induce antegrade ejaculation is recommended.2
Regimens included the following: ephedrine 10 to
15 mg 4 times a day, midodrine 5 mg 3 times a day,
12
Evidence-Based Practice / October 2015
brompheniramine 8 mg twice a day, imipramine
25 to 75 mg 3 times a day, or desipramine 50 mg every
other day. Alternatively, patients can be encouraged to
ejaculate when the bladder is full since this increases
bladder neck closure. The strength of these specific
recommendations was not graded.
Rade N. Pejic, MD
Kiernan A. Smith, MD
Tulane University School of Medicine
New Orleans, LA
1. Jefferys A, et al. Fertil Steril. 2012; 97(2):306–312. [STEP 4]
2.Jungwirth A, et al. Euroweb 2015. http://uroweb.org/guideline/male-infertility/# Accessed
September 25, 2015. [STEP 5]
Are complementary and alternative medicines
effective in treating insomnia?
Evidence-Based Answer
In children with delayed sleep phase disorder, total
sleep time increased by 28 minutes and sleep onset
latency decreased by 16 minutes with melatonin
(SOR: C, disease-oriented outcome). Yoga and tai chi
may reduce insomnia. Acupuncture and L-tryptophan
studies have had mixed results. Kava and valerian root
are not likely effective (SOR: C, systematic reviews of
poor-quality RCTs).
A 2010 meta-analysis (9 RCTs, N=317) examined
the effect of supplemental melatonin compared with
placebo in children and adults with delayed sleep
phase disorder, defined when the sleep-wake timing
is late with regard to societal norms.1 In children,
melatonin increased total sleep time by 28 minutes
(95% CI, 13–44) and decreased sleep onset latency by
16 minutes (95% CI, 8.3–24) compared with placebo.
No significant changes in total sleep time or sleep onset
latency occurred in adults. Neither children nor adults
experienced a change in wake-up time.
Adverse effects included headache, feeling cold,
dizziness, mood dip, and decreased appetite. Limitations
of this meta-analysis included a low number of studies
(most of which were crossover trials), nonexclusion
of comorbid ADHD, possible sampling bias (3 out
of 4 studies in children were performed by the same
research group), inconsistent outcome measures, and
no reporting of changes in daily functioning.1
A 2011 systematic review (20 RCTs, N=2,248)
examined the effectiveness of complementary medicine
in adults with insomnia.2 In this review, results
were quantified using effect size (ES, in which 0.2 is
considered small, 0.6 medium, and >1.2 large). Six
RCTs evaluated acupressure and acupuncture (n=442).
Two trials reported sleep parameter results equal to
sham acupuncture (n=60; no data provided and ES
unable to be calculated) or basic sleep hygiene (n=30;
no data provided and ES unable to be calculated).
One trial (n=180) reported improvement of the
Pittsburg Sleep Quality Index (PSQI) on sleep quality
outcome compared with clonazepam (ES 1.3; P<.05)
and another (n=44) reported acupuncture was more
effective than sham acupuncture or estazolam (n=44;
no data provided). For acupressure, an improvement of
PSQI was seen in 2 trials (n=128) compared with sham
therapy (ES 1.4–2.1; P<.05 for all ES).
Ten RCTs examined natural pharmacotherapies in
the 2011 systemic review.2 In 3 trials of L-tryptophan
(n=192), 2 showed benefit to sleep, with 1 study
demonstrating improved sleep quality (ES 0.3; P<.05)
and sleep duration (ES 1.2; P<.05). Valerian root trials
(6 trials, n=649) demonstrated mixed results with
3 studies showing positive results (no data provided)
and 3 trials showing results equal to placebo. No
effect sizes could be calculated. Two trials of valerian
with hops (n=214) showed a large effect size (ES 0.81;
P=.06) compared with placebo. Finally, 2 RCTs of kava
(n=390) had results equal to those of placebo.
Three RCTs studying mind-body therapies were
evaluated in the 2011 systemic review.2 One yoga
trial (n=69) demonstrated positive outcomes on sleep
duration (ES 0.6; P<.05), latency (ES 1.2; P<.05), and
quality (ES 0.8; P<.05). Two Tai Chi RCTs (n=230)
showed improvement in sleep quality (ES 0.4 and 1.1;
P<.05 for each ES) and duration (ES 0.2 and 2.2; P<.05
for each ES). Limitations of the review included small
sample sizes, short study duration, limited statistical
analysis, insufficient data, and “active” control groups.
A 2007 systematic review of 37 trials, including
24 RCTs, 2 placebo-controlled studies, and 5 placebocontrolled, double-blind studies (N=1,900), evaluated
the effectiveness and safety of valerian.3 Studies were
not standardized in the results they presented, so not all
parameters were measured in all studies.
Five studies (n=328) found improved sleep quality
and 4 studies (n=116) found decreased sleep latency
while 8 studies (n=841) reported results equal to
placebo. Five studies (n=184) used valerian with hops
and only 1 of them showed decreased sleep latency,
decreased awakenings, and increased sleep efficiency.
Four studies (n=194) evaluated valerian and lemon
balm. Two of them demonstrated increased sleep
quality and 1 demonstrated decreased sleep latency. The
systematic review reported rare, mild adverse effects.
Results were not pooled due to the high variety in study
design, particularly concerning preparations, dosages,
EBP
study length, and controls.3
Sarah Kay Welch, DO
Erin Vaughan, MD
Daniel Hunter-Smith, MD
Adventist La Grange Memorial Hospital
La Grange, IL
1. van Geijlswijk IM, et al. Sleep. 2010; 33(12):1605–1614. [STEP 1]
2. Sarris J, et al. Sleep Med Rev. 2011; 15(2):99–106. [STEP 1]
3. Taibi DM, et al. Sleep Med Rev. 2007; 11(3):209–230. [STEP 2]
GLOSSARY
ARR=absolute risk reduction
HR=hazard ratio
OR=odds ratio
CDC=Centers for Disease Control
and Prevention
LOE=level of evidence
RCT=randomized controlled trial
MRI=magnetic resonance imaging
RR=relative risk
NNH=number needed to harm
SOR=strength of recommendation
NNT=number needed to treat
SSRI=selective serotonin reuptake
inhibitor
CI=confidence interval
CT=computed tomography
FDA=US Food and Drug
Administration
NSAID=nonsteroidal
anti-inflammatory drug
WHO=World Health Organization
Evidence-Based Practice / Vol. 18, No. 10
13
Spotlight on Pharmacy
How effective is high-dose gabapentin for the treatment
of adults with diabetes who have neuropathic pain?
Bottom line
Gabapentin dosed at 900–3,600 mg/d yields decreased
pain scores in adults with diabetes and neuropathic
pain relative to placebo, but at the risk of more
adverse effects (SOR: A, Cochrane review with a clear
recommendation).
Evidence summary
A 2011 Cochrane review of 29 RCTs with 3,571 patients
studied gabapentin at daily doses of 1,200 mg or more
in 12 chronic pain conditions.1 Of these studies, 4 RCTs
with 829 patients who had chronic neuropathy or
fibromyalgia examined the effectiveness of gabapentin
for neuropathic pain.
Compared with placebo, 1,200 to 3,600 mg
gabapentin daily for 4 to 12 weeks was more effective
in achieving at least 50% pain reduction in patients
with diabetes mellitus (type 1 or type 2) and painful
peripheral diabetic neuropathy (4 trials, n=829; risk
ratio [RR] 1.8; 95% CI,1.4–2.2; NNT=6). Moderate
benefit (equivalent to ≥30% pain relief) occurred in
43% and a substantial benefit (equivalent to ≥50%
pain relief) occurred in 31%.1
More patients had at least 1 adverse event such
as dizziness or somnolence with daily doses of 1,200
mg gabapentin or more, compared with placebo
(11 trials, n=2,356; 66% vs 51%; RR 1.3; 95% CI,
1.2–1.4; NNH=7). Serious adverse events (such as
hypersensitivity reactions, Stevens–Johnson syndrome,
and death) were no more common with gabapentin
than placebo (14 trials, n=2,702; RR 1.3; 95% CI, 0.9–
2.0).1
An 8-week, double-blind RCT included in the
Cochrane review above, and discussed separately as
it included a lower dose of gabapentin, compared the
efficacy of gabapentin monotherapy with placebo in
165 patients with type 1 or type 2 diabetes who had
had peripheral diabetic neuropathy for more than
3 months.2 The gabapentin dose was titrated from 900
to 3,600 mg/d or maximum tolerated dosage. Patients
reported pain daily using an 11-point Likert scale (0, no
pain; 10, worst possible pain).
Of the patients who were assessed at the termination
visit, those receiving gabapentin had a decreased mean
14
Evidence-Based Practice / October 2015
daily pain score from 6.4 to 3.9 compared with placebotreated patients who had a decreased score from 6.5
to only 5.1 (P<.001.) Approximately 60% of patients
receiving gabapentin reported at least a moderate
improvement on the Patient Global Impression of
Change scale compared with 33% patients on placebo
EBP
(P=.01).2
Ashley Higbea, PharmD, BCPS
Stephen A. Wilson, MD, MPH
UPMC St. Margaret
Pittsburgh, PA
Tomoko Sairenji, MD, MS
UPMC Shadyside
Pittsburgh, PA
REFERENCES
1.Moore RA, Wiffen PJ, Derry S, McQuay HJ. Gabapentin for chronic neuropathic pain and
fibromyalgia in adults. Cochrane Database Syst Rev. 2011; (3):CD007938. [STEP 1]
2.Backonja M, Beydoun A, Edwards KR, et al. Gabapentin for the symptomatic treatment
of painful neuropathy in patients with diabetes mellitus: a randomized controlled trial.
JAMA. 1998; 280(21):1831–1836. [STEP 2]
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CONTINUING MEDICAL EDUCATION TEST
OCTOBER 2015
EBP CME Tests are online at www.fpin.org/cme
Each month CME subscribers may earn up to 4 AMA PRA Category 1 credits™ per test!
For each question, please mark the single best answer by checking the appropriate box.
To receive CME credit, a minimum score of 75% (6 out of 8 correct) is required.
1.A 67-year-old woman with right knee pain is found to have a degenerative
medial meniscal tear and only mild osteoarthritis. She inquires about surgery.
Which response is correct?
o a.Surgery will improve function but not pain at 1 year compared
with prolonged physical therapy
o b.Surgery will reduce both pain and function at 2 months, 1 year,
and 2 years compared with exercise
o c.Surgery will have no effect on pain at 1 year compared
with sham surgery
o d.Surgery will improve quality of life at 1 year compared
with usual therapy
5.A 34-year-old man with a known history of methicillin-resistant Staphylococcus
aureus (MRSA) infection presents with an abscess over his left buttocks without any
systemic symptoms. On physical examination it is warm and tender with induration
and fluctuance 3 cm in diameter and a small amount of purulent drainage. In
the absence of systemic inflammatory response syndrome, which of the following
antibiotic regimens after incision and drainage (I&D) is recommended?
o a.7-day course of trimethoprim-sulfamethoxazole (TMP-SMX, 160/800 mg by
mouth twice daily)
o b. 10-day course of TMP-SMX (160/800 mg by mouth twice daily)
o c. 10-day course of cephalexin (500 mg by mouth every 6 hours)
o d. None of the above
2.
6.Which of the following statements is true regarding the use of probiotics in adults?
o a. Saccharomyces boulardii is effective as an adjunct H pylori treatment
o b. Probiotics have no effect on remission in patients with ulcerative colitis
o c. Probiotics increase the risk of antibiotic-associated diarrhea
o d.VSL#3 is no more effective than placebo in maintaining remission in
pouchitis
All
o
o
o
o
of the following are reasonable therapies for retrograde ejaculation except
a. Timing ejaculation with an empty bladder
b. Anticholinergic medications
c. Sympathomimetic medications
d. Combination anticholinergic/sympathomimetic therapy
3.Which of the following statements is true regarding elevation of transaminase levels
with the use of statins?
o a.Lipophilic and hydrophilic statins have the same adverse effect profile
o b.Lipophilic statins (such as lovastatin) are more likely to cause elevated
transaminases
o c.Hydrophilic statins (such as atorvastatin) are more likely to cause elevated
transaminases
o d.Lipophilic statins elevate creatine kinase at consistent rates across
all doses
4.Which of the following statements is true regarding the treatment of fibromyalgia
with physical therapy?
o a.Aerobic-only exercise has been shown to have no effect on fibromyalgia
symptoms
o b. Exercise improves global well-being and physical functioning
o c. Aquatic physical therapy is superior to land-based exercise
o d. Strength training increases trigger point pain and worsens global well-being
7.Which of the following statements is true regarding administration of oral
progesterone to reduce the risk of miscarriage?
o a.Progesterone by oral route reduces the risk of miscarriage in women who have
had only 1 or 2 previous miscarriages
o b.Progesterone does not decrease miscarriages for any women
o c.Progesterone by oral or other routes reduces the risk of miscarriage in women
with ≥3 consecutive miscarriages
o d.The number of previous miscarriages has no bearing on the efficacy of
progesterone in reducing risk of subsequent miscarriages
8.In cases of preterm premature rupture of membranes, transcervical amnioinfusion is
associated with
o a. Decreased risk of neonatal sepsis
o b. Decreased risk of pulmonary hypoplasia
o c. Decreased risk of neonatal death
o d. Fewer clinical benefits than transabdominal infusion
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Answer key: 1. c; 2. a; 3. c; 4. b; 5. d; 6. a; 7. c; 8. d
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Evidence-Based Practice
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Evidence-Based Practice
E L E C T R O N I C V E R S I O N •
In women who have experienced one or
more miscarriages, does the addition of oral
progesterone improve pregnancy outcomes?
Evidence-Based Answer
Oral progesterone does not reduce the risk of miscarriage
in women who have had only 1 or 2 previous miscarriages
(SOR: A, meta-analysis). Progesterone by oral or other
routes may reduce the risk of miscarriage in women with
3 or more consecutive miscarriages (SOR: B, subgroup
meta-analysis of low-quality RCTs).
A 2013 Cochrane meta-analysis of 14 randomized
or quasirandomized controlled studies (N=2,158)
investigated the effects of progesterone administered
via various routes to prevent miscarriage.1 Five
studies (n=517) evaluated various doses of oral
medroxyprogesterone, cyclopentyl enol ester of
progesterone, or dydrogesterone 1 to 3 times daily
in pregnant women at less than 20 weeks’ gestation.
Duration of treatment was only reported in 2 studies—14
to 17 days or until the 12th week of gestation. Most
women had a history of 2 or more miscarriages, but
1 study (n=40) included women with or without a prior
miscarriage. Results were reported as Peto odds ratios,
a statistical method for pooling odds ratios.
Compared with placebo, oral progesterone showed
no statistical difference in the risk of miscarriage (Peto
OR 0.96; 95% CI, 0.65–1.4). A subgroup analysis of
4 trials (n=225) of women with 3 or more consecutive
miscarriages compared progesterone therapy by any
route with either placebo or no treatment. Two trials
(n=234) used oral administration, 1 trial (n=30) used
intramuscular administration, and 1 trial (n=113)
used gluteal pellets. Although progesterone resulted in
a reduction in miscarriages (Peto OR 0.39; 95% CI,
0.21–0.72), these trials were of poorer methodological
quality due to poor randomization and lack of
consistent placebo-control. There was no analysis by
route of administration.1
A peer-reviewed, evidence-based Royal College of
Obstetricians and Gynecologists guideline published in
2011 stated “there is insufficient evidence to evaluate
the effect of progesterone supplementation in pregnancy
to prevent a miscarriage in women with recurrent
miscarriage.”2 This recommendation was assigned
V O L U M E 18
NUMBER 10
O C TOBER 2015
level of evidence 1+ (based on “well-conducted metaanalyses, systematic reviews of randomised controlled
trials or randomised controlled trials with a low risk of
bias”).
Lauren Oshman, MD, MPH
University of Chicago (Northshore) FMRP
Glenview, IL
1. Haas DM, et al. Cochrane Database Syst Rev. 2013; (10):CD003511. [STEP 1]
2.
Royal College of Obstetricians and Gynaecologists. The investigation and treatment
of couples with recurrent first-trimester and second-trimester miscarriage. Recurrent
Miscarriage, Investigation and Treatment of Couples (Green-top Guideline No. 17).
https://www.rcog.org.uk/globalassets/documents/guidelines/gtg_17.pdf. Published April
2011. Accessed September 25, 2015. [STEP 1]
Which antibiotic therapy, if any, is effective
in reducing symptom severity and duration
of acute bacterial sinusitis?
Evidence-Based Answer
The use of antibiotics for acute bacterial sinusitis
appears to reduce clinical failure rate at 7 to
15 days, although the clinical benefit over placebo is
small (NNT=21). No antimicrobial therapy is superior
to another and antibiotics are associated with more
adverse effects (SOR: A, meta-analyses). Antibiotic
use does not significantly reduce symptom severity
(SOR: B, RCT).
A 2014 Cochrane review of 63 RCTs (N=19,238)
evaluated the effectiveness of antibiotics for adults with
acute maxillary sinusitis, defined as an upper respiratory
infection (URI) lasting 7 to 30 days with 2 or more
clinical signs, including sinus pain at palpation,
postnasal drip, purulent nasal discharge, nasal
obstruction, unilateral facial pain, maxillary toothache,
or impaired smell.1 Of the 63 trials, 9 (n=1,915) were
placebo-controlled. Patients were recruited from
community-based general practices in 7 of the 9 trials.
The average patient was 36 years old and 65% were
women.
Compared with placebo, penicillin or amoxicillin
demonstrated a statistically significant decrease in
clinical failure rate, defined as lack of full recovery or
improvement at 7 to 15 days (5 trials, n=1,058; RR 0.66;
95% CI, 0.47–0.94; NNT=21). The clinical benefit was
small, however, as cure or improvement rates were 86%
Evidence-Based Practice / Vol. 18, No. 10
E-1
in the placebo group and 91% in the antibiotic group.
The remaining 54 trials compared antibiotics from
different classes head-to-head and showed no antibiotic (penicillin, amoxicillin, amoxicillin-clavulanate,
macrolides, tetracyclines, fluoroquinolones, and
cephalosporins) was superior to another.1
A 2012 Cochrane review of 10 RCTs (N=2,450)
compared the effect of antibiotics versus placebo in
adults with clinically diagnosed acute rhinosinusitis, a
less stringent diagnosis than the 2014 Cochrane review.2
Out of the 10 trials, 3 trials included in this review were
also included in the 2014 Cochrane review.
Cure rates were high for both the antibiotic and
placebo groups, but slightly favored the antibiotic
group, with 60% in the antibiotic group and 55%
in the placebo group experiencing patient-evaluated
resolution or improvement of major symptoms at
7 days (OR 1.3; 95% CI, 1.0–1.5). Antibiotics shortened
the time to cure compared with placebo, with 5 more
patients per 100 experiencing cure faster between 7 and
14 days if they received antibiotics instead of placebo
(NNT=18). However, the antibiotic group demonstrated
an increase in adverse events versus the placebo group
(NNH=8), most commonly gastrointestinal distress.2
A
2012
placebo-controlled,
double-blind
RCT (N=166) examined symptom reduction with
antibiotic treatment.3 This study was also included
in the Cochrane review for antibiotic cure rates,2
but specifically addressed symptom reduction. Adult
patients with clinically diagnosed acute rhinosinusitis
were given a 10-day course of either amoxicillin
(1,500 mg/d) or placebo, along with a 5- to 7-day
supply of medication for symptomatic treatment.
There was no difference in patient-reported
symptom improvement for amoxicillin versus placebo
on day 3 (37% vs 34%; P=.67) or on day 10 (78%
vs 80%; P=.71). However, on day 7 there was a
statistically significant reduction in symptoms with
amoxicillin versus placebo (74% vs 56%; P=.02). The
authors noted that the benefit at day 7 was too small to
represent any clinically important change.3
Chase Ellingsworth, MD
Sarah Swofford, MD, MSPH
University of Missouri–Columbia FMR
Columbia, MO
1. Ahovuo-Saloranta A, et al. Cochrane Database Syst Rev. 2014; (2):CD000243. [STEP 1]
2. Lemiengre MB, et al. Cochrane Database Syst Rev. 2012; (10):CD006089. [STEP 1]
3. Garbutt JM, et al. JAMA. 2012; 307(7):685–692. [STEP 2]
E-2
Evidence-Based Practice / October 2015
What is the appropriate management
of iron deficiency in young children?
Evidence-Based Answer
Iron supplementation improves hemoglobin and
ferritin levels in anemic and nonanemic iron deficiency
(SOR: C, disease-oriented outcomes). There appears
to be an increase in cognitive scores, height, and weight
in anemic children, but not in nonanemic children
with iron deficiency (SOR: B, systematic reviews with
inconsistent results). Giving oral ferrous sulfate once a
day is as effective as splitting the dose and giving TID
(SOR: B, RCT).
A 2013 systematic review and meta-analysis of 32
RCTs (N=7,089) evaluated the effect of oral iron
supplementation of various dosages and durations in
anemic children 5 to 12 years old.1 Cognitive, growth,
and hematologic measurements were followed.
Children receiving iron supplementation had
higher global cognitive scores than controls (9 trials,
n=2,355; standard mean difference [SMD] 0.50;
95% CI, 0.11–0.90) as measured by IQ tests, authoradapted scales of global cognitive performance,
and overall school performance. (An SMD of 0.2 is
considered small, 0.6 moderate and 1.2 large.) Ageadjusted IQ scores improved among anemic children
compared with controls (mean difference [MD] 4.6;
95% CI, 0.16–9.0). Iron supplementation improved
age-adjusted height (z score) in children (2 trials, n=922;
MD 0.12; 95% CI, 0–0.23) and age-adjusted weight
(z score) among anemic children (1 trial, n=78;
MD 0.13; 95% CI, 0.04–0.22). Changes in global
cognitive scores and weight were not seen in nonanemic
children. Iron supplementation reduced the prevalence
of anemia (2 trials, n=334; risk ratio [RR] 0.12; 95% CI,
0.02–0.66).1
A 2011 systematic review of 2 RCTs (N=69)
evaluated the efficacy of iron therapy for improving
developmental and hematologic status of children
(1–5 years old) with nonanemic iron deficiency.2
Inclusion criteria were a serum ferritin ≤12 µg/L and
Hb >11.9 g/dL. Patients were randomized to oral iron
therapy (3–4 mg Fe/kg body wt per day or twice a day)
or no treatment for 3 to 4 months.
The Mental Developmental Index (similar to IQ, a
standardized test with a population mean of 100 and
SD of 15) posttreatment scores were higher in children
in the treatment group compared with the control group
in 1 trial but not the other (1 trial, n=40; MD 6.3; 95%
CI, 1.5–11; and 1 trial, n=29; MD –1.6; 95% CI, –9.4
to 6.2). A significant improvement was noted in serum
ferritin level in the treatment groups of both trials (MD
51 µg/L; 95% CI, 34–69; and MD 17 µg/L; 95% CI,
7.5–27).2
A 2001 RCT (n=557) compared the efficacy of
iron supplementation once daily with 3 times daily in
anemic children (ages 6–24 months; hemoglobin values
7–9.9 g/dL).3 Patients were randomized to ferrous
sulfate drops 40 mg once daily or 40 mg divided in
3 equal doses daily for 2 months.
Mean hemoglobin levels significantly increased
from baseline to final visit for both groups (8.8 to
10.2 g/dL and 8.7 to 10 g/dL, respectively, P<.001)
as did mean ferritin levels (35 to 101 µg/L and 40 to
107 µg/L, respectively, P<.001). The percentage of
patients advancing from an anemic to a nonanemic
state was similar for both the once daily and 3 times
daily groups (61% and 56%, respectively, P=.51).3
Thomas W. Allen, DO, MPH
Douglas Ivins, MD
Kristina Petsas, MD
Jason Chung, MD
University of Oklahoma School of Community Medicine
Tulsa, OK
1. Low M, et al. CMAJ. 2013; 185(17):E791–E802. [STEP 1]
2. Abdulla K, et al. Public Health Nutr. 2013; 16(8):1497–1506. [STEP 1]
3. Zlotkin S, et al. Pediatrics. 2001; 108(3):613–616. [STEP 2]
Are angiotensin receptor blockers (ARBs) safe
to use in patients with a history of angiotensinconverting enzyme inhibitor (ACEI)–induced
angioedema?
Evidence-Based Answer
The use of an ARB is not contraindicated in patients
with a history of ACEI-induced angioedema. A cautious
trial of ARBs by these patients appears to be safe
(SOR: B, RCTs).
A 2008 RCT of patients intolerant to ACEIs randomized
5,926 patients to telmisartan 80 mg/d (n=2,954) or
placebo (n=2,972) to assess the primary outcome of
cardiovascular (CV) death, myocardial infarction (MI),
stroke, or hospitalization for congestive heart failure
(CHF); it also measured angioedema recurrence.1 The
mean follow-up duration was 56 months.
Of the 75 patients with angioedema as the reason
for initial intolerance (1.3% of the study population),
there was 1 recurrence in the placebo group and none in
the ARB group. There were 2 new cases of angioedema
in the ARB group (0.07%) and 2 new cases in the
placebo group (0.07%).1
A 2003 RCT of patients intolerant to ACEIs
randomized 2,028 patients to candesartan 32 mg/d
(n=1,013) or placebo (n=1,015) to assess the primary
outcome of CV death or hospitalization for CHF; it also
measured angioedema recurrence.2 The mean follow-up
was 33.7 months.
Of the 83 patients with angioedema as the reason
for initial intolerance (4.1% of the study population),
there were 3 recurrences in the candesartan group, with
1 patient discontinued from treatment, and none in the
placebo group. There were no new cases of angioedema
in either group.2
In a 2011 retrospective cohort study of 111 patients
with a history of ACEI-induced angioedema, 59 were
switched to an ARB, 31 to a calcium channel blocker
(CCB), 11 to a beta-blocker (BB), and 7 to another
antihypertensive agent.3 Patients were followed for a
minimum of 12 months after ACEI discontinuation.
Of the 59 patients who were switched to an ARB,
31 (53%) had a recurrence of angioedema. However, 16
of the 31 (52%) patients prescribed CCBs and 5 of the
11 (45%) patients prescribed BBs also had a recurrence,
suggesting that the episodes may have been independent
of the antihypertensive agent. No statistical analysis
was performed on the data.3
Amanda Wojtusik, PharmD, BCPS
Providence Medical Group
Portland, OR
Soo Jung Lee, MD
Heritage Valley Health System
Beaver Falls, PA
Stephen A. Wilson, MD, MPH, FAAFP
UPMC St. Margaret
Pittsburgh, PA
1. Yusuf S, et al. Lancet. 2008; 372(9644):1174–1183. [STEP 2]
2. Granger CB, et al. Lancet. 2003; 362(9386):772–776. [STEP 2]
3. Beltrami L, et al. J Hypertens. 2011; 29(11):2273–2277. [STEP 3]
Evidence-Based Practice / Vol. 18, No. 10
E-3
What lactation issues occur from using DMPA
for contraception in the immediate postpartum
period?
Evidence-Based Answer
Immediate depomedroxyprogesterone (DMPA) does not
appear to decrease the rate of breastfeeding continuation
or the amount of breastmilk produced (SOR: B, cohort
trials). Immediate DMPA is recommended to prevent
close interval pregnancy in at-risk populations (SOR: C,
expert opinion).
A 2010 Cochrane review of 5 RCTs compared
combined estrogen and progesterone, nonhormonal,
and progestin-only contraception methods and their
effects on lactation in 541 women in the postpartum
period.1 Data were unable to be pooled due to different
interventions, lack of quantifiable outcomes, and poor
quality. The review found existing evidence insufficient
to establish any effect of hormonal contraception
on milk quality and quantity. It called for a least
1 sufficiently powered RCT to guide practice.
A 2002, nonrandomized, prospective, cohort trial
of 319 postpartum women examined the effects of
breastfeeding with various contraception methods,
both hormonal and nonhormonal.2 One arm included
102 patients who received an immediate postpartum
unspecified dose of intramuscular DMPA. In the data
analysis, the immediate DMPA group was combined
with other hormonal birth control methods and
compared to the nonhormonal group of 138 patients.
There was no statistically significant difference in rates
of breastfeeding continuation at 2 weeks (89% vs
90%; P=.9) or 6 weeks (74% vs 78%; P=.3). However,
there was a significant difference at 4 weeks (79% vs
83%; P=.02). Rates of supplementation or perception
of insufficient milk production did not differ between
the groups.
A 1971 Egyptian prospective cohort study examined
the effects of progesterone contraception on lactation
in 331 postpartum women.3 Average 3-hour milk
production was measured for all patients according
to the following groups: 100 controls, 119 patients
given norethindrone ethanate 200 mg or DMPA
150 mg intramuscular injections 7 days after delivery,
and 112 patients given norethindrone ethanate 200 mg
or DMPA 150 mg intramuscular injections 40 days
after delivery.
E-4
Evidence-Based Practice / October 2015
At 3 months, there was increased objective 3-hour
milk supply in both early and late injection groups
compared to control (133 mL for 40 days; 138 mL
for 7 days vs 120 mL for control; P<.05 for both
comparisons).3
A 2001 Iranian prospective cohort study examined
breast milk components (triglycerides, protein, essential
salts, or minerals) at 26 weeks and infant growth
throughout the first 26 weeks in 140 postpartum women
given either a progesterone-only pill (unspecified dose)
or DMPA (unspecified dose) intramuscular injection
injection for birth control versus nonhormonal
methods.4 There was no statistically significant difference
in breast milk components at 26 weeks. There was also
no statistically significant difference in infant weight
gain from 2 weeks through 26 weeks postpartum.
An expert consensus statement from the University
of California-San Francisco on the safety of immediate
use of DMPA 150 mg injection attempted to weigh
the risk of close interval pregnancies with any
lactation issues. The authors recommended immediate
administration of DMPA in transient or unreliable
patients, regardless of lactation status, to prevent close
EBP
interval pregnancy.5
Sophia Hermann, MD
Baumholder Army Health Clinic Baumholder
Germany
Scott Grogan, DO, MBA, FAAFP
Eisenhower Army Medical Center
Fort Gordon, GA
The opinions and assertions contained herein are those of the authors and
are not to be construed as official or as reflecting the views of the US Army
Medical Department, the US Army at large, or the Department of Defense.
1. Truitt ST, et al. Cochrane Database Syst Rev. 2003; (2):CD003988. [STEP 1]
2. Halderman L, et al. Am J Obstet Gynecol. 2002; 186(6):1250–1256. [STEP 3]
3.Karim M, et al. Br Med J. 1971; 1(5742):200–203. [STEP 3]
4. Baheiraei A, et al. Int J Gynecol Obstet. 2001; 74(2):203–205. [STEP 3]
5. Rodriguez M, et al. Contraception. 2009; 80(1):4–6. [STEP 5]
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