Migraine in Adults: Preventive Pharmacologic Treatments

714 Pages·2013·8.97 MB·English

Comparative Effectiveness Review
Number 103
Migraine in Adults:
Preventive
Pharmacologic
Treatments
Comparative Effectiveness Review
Number 103

Migraine in Adults: Preventive Pharmacologic
Treatments

Prepared for:
Agency for Healthcare Research and Quality
U.S. Department of Health and Human Services
540 Gaither Road
Rockville, MD 20850
www.ahrq.gov

Contract No. 290-2007-10064-I

Prepared by:
Minnesota Evidence-based Practice Center
Minneapolis, MN

Investigators:
Tatyana A. Shamliyan, M.D., M.S.
Robert L. Kane, M.D.
Frederick R. Taylor, M.D.

AHRQ Publication No. 13-EHC068-EF
April 2013
This report is based on research conducted by the Minnesota Evidence-based Practice Center
(EPC) under contract to the Agency for Healthcare Research and Quality (AHRQ), Rockville,
MD (Contract No. 290-2007-10064-I). The findings and conclusions in this document are those
of the authors, who are responsible for its contents; the findings and conclusions do not
necessarily represent the views of AHRQ. Therefore, no statement in this report should be
construed as an official position of AHRQ or of the U.S. Department of Health and Human
Services.

The information in this report is intended to help health care decisionmakers—patients and
clinicians, health system leaders, and policymakers, among others—make well-informed
decisions and thereby improve the quality of health care services. This report is not intended to
be a substitute for the application of clinical judgment. Anyone who makes decisions concerning
the provision of clinical care should consider this report in the same way as any medical
reference and in conjunction with all other pertinent information, i.e., in the context of available
resources and circumstances presented by individual patients.

This report may be used, in whole or in part, as the basis for development of clinical practice
guidelines and other quality enhancement tools, or as a basis for reimbursement and coverage
policies. AHRQ or U.S. Department of Health and Human Services endorsement of such
derivative products may not be stated or implied.

This document is in the public domain and may be used and reprinted without special
permission. Citation of the source is appreciated.

Persons using assistive technology may not be able to fully access information in this report. For
assistance contact [email protected].
None of the investigators have any affiliations or financial involvement that conflicts with the
material presented in this report.

Suggested citation: Shamliyan TA, Kane RL, Taylor FR. Migraine in Adults: Preventive
Pharmacologic Treatments. Comparative Effectiveness Review No. 103. (Prepared by the
University of Minnesota Evidence-based Practice Center under Contract No. 290-2007-10064-I)
AHRQ Publication No. 13-EHC068-EF. Rockville, MD: Agency for Healthcare Research and
Quality; April 2013. www.effectivehealthcare.ahrq.gov/reports/final.cfm.
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Preface
The Agency for Healthcare Research and Quality (AHRQ), through its Evidence-based
Practice Centers (EPCs), sponsors the development of systematic reviews to assist public- and
private-sector organizations in their efforts to improve the quality of health care in the United
States. These reviews provide comprehensive, science-based information on common, costly
medical conditions, and new health care technologies and strategies.
Systematic reviews are the building blocks underlying evidence-based practice; they focus
attention on the strength and limits of evidence from research studies about the effectiveness and
safety of a clinical intervention. In the context of developing recommendations for practice,
systematic reviews can help clarify whether assertions about the value of the intervention are
based on strong evidence from clinical studies. For more information about AHRQ EPC
systematic reviews, see www.effectivehealthcare.ahrq.gov/reference/purpose.cfm
AHRQ expects that these systematic reviews will be helpful to health plans, providers,
purchasers, government programs, and the health care system as a whole. Transparency and
stakeholder input are essential to the Effective Health Care Program. Please visit the Web site
(www.effectivehealthcare.ahrq.gov) to see draft research questions and reports or to join an
email list to learn about new program products and opportunities for input.
We welcome comments on this systematic review. They may be sent by mail to the Task
Order Officer named below at: Agency for Healthcare Research and Quality, 540 Gaither Road,
Rockville, MD 20850, or by email to [email protected].

Carolyn M. Clancy, M.D. Jean Slutsky, P.A., M.S.P.H.
Director Director, Center for Outcomes and Evidence
Agency for Healthcare Research and Quality Agency for Healthcare Research and Quality

Stephanie Chang, M.D., M.P.H. Suchitra Iyer, Ph.D.
Director Task Order Officer
Evidence-based Practice Program Center for Outcomes and Evidence
Center for Outcomes and Evidence Agency for Healthcare Research and Quality
Agency for Healthcare Research and Quality
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Acknowledgments
The authors gratefully acknowledge the following individuals for their contributions to this
project. We would like to thank the librarians, Judy Stanke, M.A., and Delbert Reed, Ph.D., for
their contributions to the literature search; Jae-Young Choi, M.H.P.A., Ph.D., Rema
Ramakrishnan, M.P.H., Jennifer Biggs Miller, P.T., M.P.H., C.W.S., and Shi-Yi Wang, M.D.,
M.S., Ph.D. for their assistance with the literature search and data abstraction; Jeannine Ouellette
for her help in writing the report; Marilyn Eells for editing and formatting the report; and Christa
Prodzinski, R.N., and Kirsten Johnson B.S., for assistance with data entry, quality control, and
formatting tables. We would like to thank Thomas Trikalinos, M.D., Ph.D., and Gerta Rücker,
Ph.D., for their statistical advice in arcsine transformation of the data and Hwanhee Hong, Ph.D.
candidate, for her help in conducting Bayesian network meta-analyses.
Key Informants
In designing the study questions, the EPC consulted several Key Informants who represent
the end-users of research. The EPC sought the Key Informant input on the priority areas for
research and synthesis. Key Informants are not involved in the analysis of the evidence or the
writing of the report. Therefore, in the end, study questions, design, methodological approaches,
and/or conclusions do not necessarily represent the views of individual Key Informants.
Key Informants must disclose any financial conflicts of interest greater than $10,000 and any
other relevant business or professional conflicts of interest. Because of their role as end-users,
individuals with potential conflicts may be retained. The TOO and the EPC work to balance,
manage, or mitigate any conflicts of interest.
The list of Key Informants who participated in developing this report follows:

Thomas Becker, M.D., M.B.A. Andrew D. Hershey, M.D., Ph.D.
Medica Health Plans University of Cincinnati College of Medicine
Minnetonka, MN Cincinnati, OH
Roger K. Cady, M.D. Brady Patrick-Lake, M.F.S.
Headache Care Center Consumer representative
Springfield, MO Erie, CO
Robert Dalton Alan M. Rapoport, M.D.
National Headache Foundation David Geffen School of Medicine, UCLA
Chicago, IL Los Angeles, CA
Lida Etermad, Pharm.D., M.S. Stephen D. Silberstein, M.D., FACP
United Healthcare Jefferson Headache Center
Edina, MN Philadelphia, PA
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Technical Expert Panel
In designing the study questions and methodology at the outset of this report, the EPC
consulted several technical and content experts. Broad expertise and perspectives were sought.
Divergent and conflicted opinions are common and perceived as healthy scientific discourse that
results in a thoughtful, relevant systematic review. Therefore, in the end, study questions, design,
methodologic approaches, and/or conclusions do not necessarily represent the views of
individual technical and content experts.
Technical Experts must disclose any financial conflicts of interest greater than $10,000 and
any other relevant business or professional conflicts of interest. Because of their unique clinical
or content expertise, individuals with potential conflicts may be retained. The TOO and the EPC
work to balance, manage, or mitigate any potential conflicts of interest identified.
The list of Technical Experts who participated in developing this report follows:

Andrew Blumenfeld, M.D. Alan M. Rapoport, M.D.
Kaiser Permanente David Geffen School of Medicine, UCLA
San Diego, CA Los Angeles, CA
Roger K. Cady, M.D. Stephen D. Silberstein, M.D., FACP
Headache Care Center Jefferson Headache Center
Springfield, MO Philadelphia, PA
Andrew D. Hershey, M.D., Ph.D.
University of Cincinnati College of Medicine
Cincinnati, OH
Peer Reviewers
Prior to publication of the final evidence report, EPCs sought input from independent Peer
Reviewers without financial conflicts of interest. However, the conclusions and synthesis of the
scientific literature presented in this report does not necessarily represent the views of individual
reviewers.
Peer Reviewers must disclose any financial conflicts of interest greater than $10,000 and any
other relevant business or professional conflicts of interest. Because of their unique clinical or
content expertise, individuals with potential nonfinancial conflicts may be retained. The TOO
and the EPC work to balance, manage, or mitigate any potential nonfinancial conflicts of interest
identified.
The list of Peer Reviewers follows:

Andrew Blumenfeld, M.D. Rochelle Fu, Ph.D.
Kaiser Permanente Oregon Evidence-based Practice Center
San Diego, CA Portland, OR
Frederick Freitag, D.O., FAHS Bray Patrick-Lake, M.F.S.
Baylor Research Institute Consumer representative
Dallas, TX Erie, CO
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Structured Abstract
Objectives. To assess comparative effectiveness and safety of preventive pharmacologic
treatments for community-dwelling adults with episodic or chronic migraine.

Data sources. We searched major electronic bibliographic databases and trial registries up to
May 20, 2012.

Review methods. We performed a systematic review of published, English-language original
studies of pharmacologic treatments for prevention of episodic or chronic migraine. Studies that
compared drugs with inactive controls, nonpharmacologic interventions, or other drugs were
eligible. Outcomes evaluated included rates of complete migraine cessation, ≥50 percent
reduction in monthly migraine frequency, reduction in migraine-related disability, and
improvement in quality of life. We calculated absolute risk differences, pooled them with
random-effects models and with Bayesian network meta-analysis, and calculated numbers of
outcome events attributable to treatments per 1,000 participants treated.

Results. Of 5,244 retrieved references, 245 publications of randomized controlled clinical trials
(RCTs) and 76 publications of nonrandomized therapeutic studies met eligibility criteria. Most
enrollees were middle-aged Caucasian women, with an average of five monthly migraine attacks.
Few trials reported the proportion of obese subjects, but many subjects were overweight. More
than half of the RCTs defined migraine according to the International Headache Society criteria.
Studies excluded adults with severe medical or psychiatric illnesses or contraindications to
examined drugs. Strength of evidence was mostly low due to risk of bias and imprecision in
individual RCTs and pooled estimates.

For chronic migraine, botulinum toxin formulations were examined in 20 RCTs of 4,237 adults.
Onabotulinumtoxin A was more effective than placebo in reducing monthly chronic migraine
attacks by ≥50 percent (low-strength evidence from 3 RCTs of 459 adults) with inconsistent
improvement in quality of life. Pooled analyses demonstrated that per 1,000 treated adults, 170
(95% confidence interval [CI], 82 to 258) would experience ≥50 percent reduction in migraine
frequency, 155 (95% CI, 90 to 220) would experience adverse effects, and 26 (95% CI, 10 to 43)
would discontinue treatments due to bothersome adverse effects. Topiramate reduced disability
in patients with chronic migraine but failed to decrease monthly migraine frequency by ≥50
percent (low-strength evidence from one RCT of 328 adults). Individual RCTs examined the
comparative effectiveness of onabotulinumtoxin A with topiramate or divalproex and found no
differences in chronic migraine prevention. Propranolol combined with topiramate treatment
demonstrated no benefits in nonresponders to topiramate monotherapy (low-strength evidence
from one RCT of 191 adults).

For episodic migraine, RCTs examined 59 drugs from 14 drug classes. All approved drugs
(topiramate, divalproex, timolol, and propranolol), some off-label beta blockers, ACE inhibitors,
and the angiotensin II receptor antagonist candesartan were better than placebo in reducing
episodic monthly migraine frequency by ≥50 percent. Drugs would result in clinical
improvement in 200 to 400 patients per 1,000 treated. Adverse effects leading to treatment
discontinuation were examined in 68 RCTs. Topiramate, off-label antiepileptics, and
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antidepressants resulted in bothersome adverse effects leading to treatment discontinuation more
often than placebo.

Limited direct evidence of comparative effectiveness from head-to-head RCTs demonstrated no
consistent significant differences in outcomes with examined drugs in patients with episodic
migraine. Exploratory indirect adjusted frequentist analysis offered low-strength evidence that
the angiotensin II receptor blocker candesartan was more effective than approved drugs
including topiramate, propranolol, timolol, and divalproex. Exploratory network Bayesian meta-
analysis offered low-strength evidence that angiotensin inhibiting drugs (captopril, lisinopril,
candesartan) were the most effective and tolerable for episodic migraine prevention in adults
who have no contraindications to examined drugs.

Individual RCTs of drug-management interventions for episodic migraine offered low-strength
evidence that compared with usual care, multidisciplinary team care improved quality of life and
reduced migraine-related disability; a headache management program resulted in complete
cessation of migraine; a minimal-contact cognitive-behavioral program improved patient
satisfaction with treatments; headache school decreased overuse of drugs for acute headache
attacks and reduced migraine disability; pharmaceutical care improved self-efficacy; and an
intensive pharmaceutical care campaign had no statistically significant impact on use of acute
drugs.

Conclusions. For chronic migraine, onabotulinumtoxin A reduced migraine attacks but increased
the risk of adverse effects and treatment discontinuation due to adverse effects. For episodic
migraine, approved drugs are effective but increase risk of adverse effects and treatment
discontinuation due to adverse effects. Some off-label beta blockers and angiotensin inhibiting
drugs are effective without bothersome harms and therefore offer the best benefits-to-harms
ratio. We could not determine the long-term (i.e., trials of more than 3 months’ duration),
preventive benefits and adherence with drugs. Evidence on improving quality of life was
inconsistent across individual drugs. Evidence for individualized treatment decisions is very
limited. Future research should examine the role of patient characteristics on drug benefits and
safety.
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Contents
Executive Summary .................................................................................................................ES-1
Introduction ....................................................................................................................................1
Topic Refinement and Review Prototocol .................................................................................2
Key Questions ......................................................................................................................2
Methods ...........................................................................................................................................4
Literature Search Strategy..........................................................................................................4
Search Strategy ....................................................................................................................4
Inclusion Criteria .................................................................................................................4
Exclusion Criteria ................................................................................................................5
Study Selection ..........................................................................................................................6
Data Extraction ..........................................................................................................................6
Risk of Bias Assessment ............................................................................................................6
Data Synthesis ............................................................................................................................7
Grading the Evidence for Each Key Question ...........................................................................9
Assessing Applicability ...........................................................................................................10
Peer Review and Public Commentary ...............................................................................10
Results ...........................................................................................................................................11
Publication Bias .......................................................................................................................12
Applicability ......................................................................................................................16
Risk of Bias ........................................................................................................................16
KQ 1. What are the efficacy and comparative effectiveness of pharmacologic
treatments for preventing migraine attacks in adults? .................................................21
KQ 1a. How do preventative pharmacologic treatments affect patient-centered and
intermediate outcomes when compared with placebo or no active treatment? ...........21
Prevention of Chronic Migraine ........................................................................................28
Prevention of Episodic Migraine .......................................................................................29
KQ 1b. How do preventive pharmacologic treatments affect patient-centered and
intermediate outcomes when compared with active pharmacologic treatments? ........35
Indirect Evidence of Comparative Effectiveness of Preventive Drugs
for Episodic Migraine ..................................................................................................38
KQ 1c. How do preventive pharmacologic treatments affect patient-centered and
intermediate outcomes when compared with active nonpharmacologic
treatments? ...................................................................................................................47
KQ 1d. How do preventive pharmacologic treatments combined with nondrug
treatments afect patient-centered and intermdiate outcomes when compared with
pharmacologic treatments alone? .................................................................................47
KQ 1e1. How might dosing regimens or duration of treatments influence the effects
of the treatments on patient-centered outcomes? .........................................................51
KQ 1e2. How might approaches to drug management (such as patient-care teams,
integrated care, coordinated care, patient education, drug surveillance, or
interactive drug monitoring) influence results? ...........................................................54
KQ 2. What are the comparative harms from pharmacologic treatments for
preventing migraine attacks in adults? .........................................................................57
KQ 2a. What are the harms from preventive pharmacologic treatments when
compared with placebo or no active treatment? ..........................................................57
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KQ 2b. What are the harms from preventive pharmacologic treatments when
compared with active pharmacologic treatments? .......................................................62
Indirect Evidence of Comparative Safety of Drugs for Episodic Migraine
Prevention in Adults ....................................................................................................65
KQ 2c. How might approaches to drug management (such as patient-care teams,
integrated care, coordinated care, patient education, drug surveillance, or
interactive drug monitoring) influence results? ...........................................................65
KQ 3. Which patient characteristics predict the effectiveness and safety of
pharmacologic treatments for preventing migraine attacks in adults?.........................77
Discussion......................................................................................................................................81
Future Research Needs ............................................................................................................83
Key Messages ..........................................................................................................................84
Efficacy and Comparative Effectiveness of Pharmacologic Treatments
for Preventing Migraine Attacks in Adults ..................................................................84
References .....................................................................................................................................91

Tables
Table A. Efficacy of migraine preventive pharmacological treatments, evidence
from meta-analyzed randomized controlled clinical trials that compared
active drugs with placebo...................................................................................................ES-10
Table B. Comparative effectiveness with migraine preventive drugs in adults,
direct evidence from head-to-head randomized controlled clinical trials ..........................ES-13
Table C. Treatment discontinuation due to adverse effects with migraine preventive
drugs in adults, evidence from meta-analyzed randomized controlled clinical trials ........ES-17
Table 1. Strength of evidence ranks and definitions ......................................................................10
Table 2. Registration, publication, and cost of the NIH-funded grants aimed
at migraine prevention (as of May 2012) .................................................................................13
Table 3. Years between the NIH-funded project end dates and the publication
dates of the results ....................................................................................................................13
Table 4. Publication and posting of the results of migraine prevention studies
registered in ClinicaltTrials.gov...............................................................................................14
Table 5. Odds of publication and posting of results in ClinicalTrials.gov among
all studies registered in ClinicalTrials.gov...............................................................................15
Table 6. Total number randomized, weeks of followup, and loss of followup
in randomized controlled clinical trials of migraine prevention in adults ...............................17
Table 7. Reporting of patient baseline characteristics in randomized controlled
clinical trials of migraine prevention drugs in adults...............................................................18
Table 8. Number of randomized controlled clinical trials of migraine prevention
in adults that met risk of bias criteria .......................................................................................20
Table 9. 100 percent reduction in monthly migraine frequency with pharmacologic
preventive treatments versus placebo in adults with episodic migraine, results
from randomized controlled clinical trials ...............................................................................22
Table 10. Migraine prevention with approved pharmacologic preventive treatments
versus placebo in adults, results from randomized controlled clinical
trials (pooled with random effects models) .............................................................................23
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