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Research SubmissionsThe 2012 AHS/AAN Guidelines for Prevention of EpisodicMigraine: A Summary and Comparison With Other Re...
The AHS/AAN guidelines are the result of asystematic search, expert review, and synthesis of rel-evant evidence for preven...
retrieved for potentially relevant clinical practiceguidelines and reviewed against inclusion criteria.The included clinic...
group 5 the lowest. The group assignment, however,was based on a combination of the quality of clinicaltrial evidence but ...
the updated guidelines.Amitriptyline has been down-graded to Level B in the new guidelines.Level B Drugs.—The 2012 AHS/AAN...
for migraine. The Level B group includes amitrip-tyline as well as the herbal treatment feverfew,severalNSAIDs, riboflavin ...
Table4.—CharacteristicsandMethodsUsedForDevelopingthe3MigrainePreventionClinicalPracticeGuidelinesAmericanHeadacheSociety(...
All were sponsored, funded, and carried out byprofessional societies devoted to the study of neurol-ogy or headache. Only ...
in their third category. Some drugs were rated inonly 2 guidelines, and in those cases, there was alsoconcordance for napr...
ment of guideline quality by the 3 reviewers, theAHS/AAN and the Canadian guidelines were recom-mended for use, while the ...
especially in relation to side effects. Some drugsthat have statistically significant evidence of benefit inwell-designed an...
confirm the benefits of many widely used therapies,identify drugs that should be avoided, and remindclinicians of emerging e...
APPENDIX III: RATINGS OF DRUGS EVALUATED IN ONLY 1 GUIDELINEAHS/AAN Guideline Canadian Guideline EFNS GuidelineAcebutolol ...
APPENDIXIV:QUALITYOFTHE3MIGRAINEPREVENTIONGUIDELINESFORTHE6DOMAINSOFTHEAGREE-IIINSTRUMENTGuideline:AHS/AANCanadianEFNSItem...
REFERENCES1. Holland S, Silberstein SD, Freitag F, Dodick DW,Argoff C. Evidence-based guideline update:NSAIDs and other co...
25. McCrory D. Report on gabapentin (Neurontin®)for migraine prophylaxis: Evaluation of efficacy,effectiveness and marketin...
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The 2012 AHS/AAN Guidelines for Prevention of Episodic Migraine: A Summary and Comparison With Other Recent Clinical Practice Guidelines

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The 2012 AHS/AAN Guidelines for Prevention of Episodic Migraine: A Summary and Comparison With Other Recent Clinical Practice Guidelineshead_2185 930..945

Elizabeth Loder, MD, MPH; Rebecca Burch, MD; Paul Rizzoli, MD

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The 2012 AHS/AAN Guidelines for Prevention of Episodic Migraine: A Summary and Comparison With Other Recent Clinical Practice Guidelines

  1. 1. Research SubmissionsThe 2012 AHS/AAN Guidelines for Prevention of EpisodicMigraine: A Summary and Comparison With Other RecentClinical Practice Guidelineshead_2185 930..945Elizabeth Loder, MD, MPH; Rebecca Burch, MD; Paul Rizzoli, MDBackground.—Updated guidelines for the preventive treatment of episodic migraine have been issued by the AmericanHeadache Society (AHS) and the American Academy of Neurology (AAN). We summarize key 2012 guideline recommenda-tions and changes from previous guidelines. We review the characteristics, methods, consistency, and quality of the AHS/AANguidelines in comparison with recently issued guidelines from other specialty societies.Methods.—To accomplish this, we reviewed the AHS/AAN guidelines and identified comparable recent guidelines througha systematic MEDLINE search. We extracted key data, and summarized and compared the key recommendations and assessedquality using the Appraisal of Guidelines Research and Evaluation-II (AGREE-II) tool. We identified 2 additional recentguidelines for migraine prevention from the Canadian Headache Society and the European Federation of NeurologicalSocieties. All of the guidelines used structured methods to locate evidence and linked recommendations with assessment of theevidence, but they varied in the methods used to derive recommendations from that evidence.Results.—Overall, the 3 guidelines were consistent in their recommendations of treatments for first-line use. All ratedtopiramate, divalproex/sodium valproate, propranolol, and metoprolol as having the highest level of evidence. In contrast,recommendations diverged substantially for gabapentin and feverfew. The overall quality of the guidelines ranged from 2 to 6out of 7 on the AGREE-II tool.Conclusion.—The AHS/AAN and Canadian guidelines are recommended for use on the basis of the AGREE-II qualityassessment. Recommendations for the future development of clinical practice guidelines in migraine are provided. In particular,efforts should be made to ensure that guidelines are regularly updated and that guideline developers strive to locate andincorporate unpublished clinical trial evidence.Key words: migraine, guidelines, prevention, prophylaxis, quality, AGREE-II(Headache 2012;52:930-945)INTRODUCTIONThe American Headache Society (AHS) and theAmericanAcademy of Neurology (AAN) have issuedupdated guidelines for pharmacologic preventivetreatment of episodic migraine.1,2Migraine is acommon, disabling, and costly disorder. There isno cure, but preventive treatment to decrease thenumber and severity of headache attacks improveshealth outcomes and quality of life.3It also reducesdisability and costs.4From the Graham Headache Center and the Department ofNeurology, Division of Headache and Pain, Brigham andWomen’s and Faulkner Hospitals, Boston, MA, USA (E.Loder, R. Burch, P. Rizzoli).Address all correspondence to E. Loder, Department of Neu-rology, Brigham and Women’s Hospital, 1153 Centre Street,Boston, MA 02130, USA, email: eloder@partners.orgTo download a podcast featuring further discussion of thisarticle, please visit www.headachejournal.orgAccepted for publication April 23, 2012.Conflict of Interest: PR and RB have no conflicts of interestrelevant to this paper. EL is a member of the disseminationcommittee for the 2012 AHS/AAN Guidelines but was notinvolved in their development. She is the president-elect ofthe American Headache Society, which was a partner in thedevelopment of the guidelines and endorsed the completedguidelines.Financial support for work: None.ISSN 0017-8748doi: 10.1111/j.1526-4610.2012.02185.xPublished by Wiley Periodicals, Inc.Headache© 2012 American Headache Society930
  2. 2. The AHS/AAN guidelines are the result of asystematic search, expert review, and synthesis of rel-evant evidence for preventive treatments of episodicmigraine. The evidence identified in formulating theprevious guidelines in 2000 was supplemented withevidence from a new search that extended throughmid 2009.Despite the availability of such up-to-date,evidence-based recommendations, research suggeststhat a majority of migraine sufferers who wouldbenefit from prevention therapies do not receivethem.5,6Possible barriers to the adequate preventivetreatment of migraine may be lack of physicianawareness of the contents of clinical practice guide-lines or a lack of confidence in the methodology andquality of such guidelines.7-9Variability in guidelinequality and consistency has been demonstrated inother therapeutic areas.10-12One recent study on clini-cal practice guideline quality concluded that thequality of clinical practice guidelines improved onlyslightly over the past 2 decades.13We sought to summarize the key recommenda-tions of the 2012 AHS/AAN guidelines and identifyareas of change from the 2000 guidelines that theyreplace. In addition, we systematically review thequality and consistency of these guidelines in com-parison with 2 other recent migraine preventionclinical practice guidelines.METHODSAll authors read the 2012 AHS/AAN guidelinesfor migraine prevention, and EL summarized keyconcepts and changes from the 2000 guidelines.Thesewere reviewed with PR and RB, and agreement onthe summary was reached by consensus. Althoughthese guidelines were published as 2 separate papers,1 covering traditional pharmacologic agents formigraine prophylaxis and the other coveringnon-steroidal anti-inflammatory drugs (NSAIDs),complementary treatments and other miscellaneoustreatments, for the purposes of this review, weconsider the guidelines as a whole and refer to thecontents of the 2 documents as “the AHS/AANguidelines.”Although the 2012 guidelines incorporatedrugs used for short-term prophylaxis of menstruallytriggered migraine attacks among the other treat-ments, for this review, we consider them separately tofacilitate comparison with other guidelines, whichgenerally do not consider such short-term treatmentsto be comparable with daily, long-duration preventivetreatment.An additional caveat, conspicuous by its absencefrom the guidelines presented here is onabotulinum-toxinA. OnabotulinumtoxinA has been extensivelystudied for treatment of episodic migraine and foundto be ineffective. It was not included in the currentAHS/AAN guidelines for preventive treatment ofepisodic migraine because it is covered in anotherAAN guideline, where it is identified as ineffectivefor episodic migraine. OnabotulinumtoxinA was,however,approved by the Food and DrugAdministra-tion for the treatment of chronic migraine in October2010, and at this writing is the only treatment specifi-cally indicated for that migraine variant. Its exclusionreflects simply that the guidelines we review and sum-marize pertain to the treatment of episodic migraine(ie, migraine with a headache burden of <15 days/month).A discussion of chronic migraine and its treat-ment would be timely (and clinically relevant) but liesbeyond the scope of the present paper.For the systematic review portion of this study,wesearched for clinical practice guidelines for the pre-ventive treatment of migraine in adults 18 or older.We included only guidelines based on a systematicreview and synthesis of evidence, and graded recom-mendations linked to evidence quality. Guidelineshad to be written in English and endorsed by anational or international professional organization.We excluded guidelines that focused solely on thetreatment of specific subgroups of migraineurs,eg, pregnant women or children. To ensure that theclinical practice guidelines included in this review arerelevant to contemporary medical practice, inclusionwas limited to guidelines published from January2008 through April 2012.We searched MEDLINE from January 2008 toApril 2012 using the text words and Medical SubjectHeading terms of “migraine” and “guidelines.” Theelectronic database search was supplemented bysearching websites that list guidelines. The searchstrategy is contained in Appendix II. EL screened thesearch results for inclusion. Full-text papers wereHeadache 931
  3. 3. retrieved for potentially relevant clinical practiceguidelines and reviewed against inclusion criteria.The included clinical practice guidelines were sum-marized descriptively by EL and reviewed by RBaccording to pharmacologic and other preventivetreatment options. For each treatment, we notedwhether the respective guideline recommendedthat treatment, the level of evidence assigned to it,and the appraised quality of studies supporting therecommendation.We compared treatment ratings among theincluded guidelines. Because each guideline used dif-ferent methods to rate and assign treatments to cat-egories, we assumed that the top tier in each ratingsystem was comparable with the top tier in the otherguidelines, and so on.Thus, Level A in the AHS/AANguidelines was considered equivalent to the “High”level of evidence category in the Canadian guidelines(regardless of the strength of the recommendation touse or not use, which was based on judgments aboutthe balance of harms to benefits) and the “drugs offirst choice”category in European Federation of Neu-rological Societies (EFNS). Similarly, Level B wasconsidered equivalent to the “Moderate” level of evi-dence category in the Canadian guidelines and the“drugs of second choice” category in the EFNS guide-lines.Finally,Level C in theAHS/AAN guidelines wasconsidered equivalent to the “Low” level of evidencecategory in the Canadian guidelines and to the “drugsof third choice” category in the EFNS guidelines.All authors independently scored retrievedguidelines according to the Appraisal of Guidelinesfor Research and Evaluation (AGREE) II criteria.The AGREE criteria are widely used to assess thequality of clinical practice guidelines. They provide alist of specific information that should be reportedin guideline publications. Specifically, the AGREE-IIassessment instrument contains 23 items distributedamong 6 quality domains, along with 2 global qualityratings.14The 6 domains and the guideline characteristicsassessed within each domain are: (1) Scope andPurpose, which assesses the overall aim of the guide-line and target groups for whom the guideline isintended; (2) Stakeholder Involvement, which evalu-ates the extent to which appropriate stakeholderswere involved in developing the guideline andwhether it represents the views of its intended users;(3) Rigor of Development, which appraises theprocess of gathering and summarizing the evidenceand methods used to develop recommendations; (4)Clarity of Presentation, which evaluates the language,structure, and format of the guideline; (5) Applicabil-ity, which evaluates potential barriers and facilitatorsto implementation and strategies to improve uptakeas well as resources needed to implement the guide-line; and (6) Editorial Independence, which evaluatesbiases because of competing interests. The overallassessment includes rating the overall quality of theguideline and stating whether the guideline is recom-mended for use in practice.Each item within a domain is rated on a 7-pointscale ranging from 1 (strongly disagree) to 7 (stronglyagree). A score of 1 indicates that there is no infor-mation on that item or that it is very poorly reported.A score of 7 indicates that criteria for the item delin-eated in the AGREE-II user manual have been metand that the reporting is complete and clear.A qualityscore for each of the 6 domains is calculated, inaddition to a global assessment of overall guidelinequality and recommendations for clinical use. TheAGREE-II developers recommend that guidelinequality should be assessed by 2-4 reviewers.RESULTSSummary of AHS/AAN Migraine PreventionGuideline Recommendations.—Tables 1–3 summa-rize key recommendations of the AHS/AAN 2012guidelines for preventive treatment of migraine. Thenew guidelines assign treatments to 1 of 5 levels basedon the strength of evidence for their efficacy: Level A,Level B, Level C, Level U, and an “Other” group.Thelast contains drugs that are established as, or probablyor possibly ineffective. This method of categorizingtreatments is based entirely on assessments of thestrength of scientific evidence of drug efficacy anddoes not incorporate evidence about side effects orqualitative clinical impressions.This differs from the method used to classify treat-ments in the 2000 guidelines.15In the 2000 guidelines,treatments were assigned to 1 of 5 groups,with group 1indicating the highest level of recommendation and932 June 2012
  4. 4. group 5 the lowest. The group assignment, however,was based on a combination of the quality of clinicaltrial evidence but also incorporated clinical judgmentsof efficacy and evidence concerning potential adverseeffects.This change in rating method should be bornein mind when the reader compares the ratings of drugsbetween the 2 guidelines.Level A Drugs.—Three beta-blockers (meto-prolol, propranolol, and timolol), several anti-epileptic drugs (topiramate, and divalproex or sodiumvalproate), as well as the herbal drug Butterbur arerated as Level A drugs in the 2012 guidelines. Thisrating is given to treatments for which there are atleast 2 high-quality randomized, controlled trials(RCTs) demonstrating efficacy.The guideline authorssuggest that Level A drugs should be offered topatients who require prophylaxis for migraine. In the2000 guidelines, only 4 drugs were placed in group 1:amitriptyline, divalproex, propranolol, and timolol.Of note, 3 of those 4 drugs retain the highest rating inTable 1.—AHS/AAN Migraine Prevention GuidelinesDrugs Recommended for UseDrug Examples of Studied DosesLevel A: established as effectiveShould be offered to patients requiring migraine prophylaxisDivalproex/sodium valproate 400-1000 mg/dayMetoprolol 47.5-200 mg/dayPetasites (butterbur) 50-75 mg bidPropranolol 120-240 mg/dayTimolol 10-15 mg bidTopiramate 25-200 mg/dayLevel B: probably effectiveShould be considered for patients requiring migraine prophylaxisAmitriptyline 25-150 mg/dayFenoprofen 200-600 mg tidFeverfew 50-300 mg bid; 2.08-18.75 mg tid for MIG-99 preparationHistamine 1-10 ng subcutaneously twice a weekIbuprofen 200 mg bidKetoprofen 50 mg tidMagnesium 600 mg trigmagnesium dicitrate qdNaproxen/naproxen sodium 500-1100 mg/day for naproxen550 mg bid for naproxen sodiumRiboflavin 400 mg/dayVenlafaxine 150 mg extended release/dayAtenolol 100 mg/dayLevel C: possibly effectiveMay be considered for patients requiring migraine prophylaxisCandesartan 16 mg/dayCarbamazepine 600 mg/dayClonidine 0.75-0.15 mg/day; patch formulations also studiedGuanfacine 0.5-1 mg/dayLisinopril 10-20 mg/dayNebivolol 5 mg/dayPindolol 10 mg/dayFlurbiprofen 200 mg/dayMefenamic acid 500 mg tidCoenzyme Q10 100 mg tidCyproheptadine 4 mg/dayBased on Silberstein et al2and Holland et al.1Studied dose information abstracted from these guidelines and Agency for HealthCare Policy and Research technical review (http://www.ncbi.nlm.nih.gov/books/NBK45457/pdf/TOC.pdf). Intended solely to givean idea of tested doses and not as a recommendation for treatment.All drugs given orally unless otherwise noted.AAN = American Academy of Neurology; AHS = American Headache Society; bid = twice a day; qd = daily; tid = 3 times a day.Headache 933
  5. 5. the updated guidelines.Amitriptyline has been down-graded to Level B in the new guidelines.Level B Drugs.—The 2012 AHS/AAN guidelinesassign 10 drugs to Level B, which is reserved for treat-ments for which there is only 1 high-quality RCT, or 2or more less rigorous studies suggesting efficacy. Theguideline authors suggest that Level B drugs shouldbe considered for patients who require prophylaxisTable 2.—AHS/AAN Migraine Prevention GuidelinesDrugs Recommended for Short-Term Prevention of Migraine Associated With MenstruationDrug Dose or Dose Range CommentLevel A: established as effectiveShould be offered to patients requiring prophylaxisFrovatriptan 2.5 mg bid perimenstrually A loading dose was usedLevel B: probably effectiveShould be considered for patients requiring prophylaxisNaratriptan 1 mg bid for 5 days perimenstrually No loading doseZolmitriptan 2.5 mg bid or tid perimenstrually No loading doseLevel C: possibly effectiveMay be considered for patients requiring prophylaxisEstrogen 1.5 mg estradiol in gel qd ¥ 7 daysperimenstruallyBased on Silberstein et al2and Holland et al.1Studied dose information abstracted from these guidelines and intended solely to givean idea of tested doses and not as a recommendation for treatment.All drugs given orally unless otherwise noted.AAN = American Academy of Neurology; AHS = American Headache Society; bid = twice a day; qd = daily; tid = 3 times a day.Table 3.—AHS/AAN Migraine Prevention GuidelinesDrugs and Treatments With Conflicting or Inadequate Evidence of Efficacy or With Evidence Indicating Lack of EfficacyDrug or TreatmentLevel U: conflicting or inadequate evidenceInsufficient data to support or refute use for migraine prophylaxisAcenocoumarol Hyperbaric oxygenAcetazolamide IndomethacinAspirin NicardipineBisoprolol NifedipineCoumadin NimodipineCyclandelate Omega-3Fluoxetine PicotamideFluvoxamine ProptriptylineGabapentin VerapamilMedications or treatments established as possibly or probably ineffective for migraine prophylaxisShould not be offered or considered for migraine prophylaxis†Acebutolol MontelukastClomipramine NabumetoneClonazepam OxcarbazepineLamotrigine TelmisartanBased on Silberstein et al2and Holland et al.1†The evidence supporting designation of a treatment as ineffective was subcategorized as established, probable, or possible. For thischart, we have collapsed those categories.934 June 2012
  6. 6. for migraine. The Level B group includes amitrip-tyline as well as the herbal treatment feverfew,severalNSAIDs, riboflavin (vitamin B2), venlafaxine, andsubcutaneous histamine.In the 2000 guidelines, 17 drugs were placed inthe second highest group (group 2). These includedatenolol, metoprolol, nadolol, gabapentin, verapamil,fluoxetine, fenoprofen, ketoprofen, naproxen andnaproxen sodium, feverfew, magnesium, and vitaminB2. In contrast with the drugs in the highest ratingcategory in 2000, there has been considerablechange in the ratings assigned to drugs in the formergroup 2. Roughly 50% of them have been upgradedor downgraded. For example, gabapentin, verapamil,and fluoxetine are assigned to Level U in the 2012guidelines, a substantial downgrade from their formerrating that indicates a changed assessment of thequality or the inclusion of new evidence for thesedrugs.At least for gabapentin, this judgment is in linewith recent evidence that has surfaced of seriousproblems with the reporting of clinical trial results.16In contrast, metoprolol has been upgraded to Level Afrom its former position in group 2.Level C Drugs.—The 2012 AHS/AAN guidelinesassign 11 drugs to Level C, which contains drugs forwhich there is a single less rigorous study indicatingefficacy. The guideline authors suggest that Level Ctreatments “may” be considered for patients requir-ing migraine prophylaxis. Level C includes 2 drugsmaking new appearances in the guidelines: lisinopriland candesartan. It also includes clonidine, cyprohep-tadine, coenzyme Q10, and several NSAIDs.In the 2000 guidelines, 16 drugs were placed ingroup 3.These included 10 drugs that are not listed inthe updated 2012 guidelines: buproprion, doxepin,imipramine, mirtazapine, nortriptyline, paroxetine,sertraline,trazodone,diltiazem,and phenelzine.Of theremaining 6 drugs that appeared in group 3 in the 2000guidelines, 2 (fluvoxamine and protriptyline) havebeen downgraded to Level U in the 2012 guidelines,while cyproheptadine remains in the roughly compa-rable Level C group, and ibuprofen and venlafaxinehave been upgraded to Level B. Thus, only 1 drug inthe third tier in 2000 has remained in that tier in 2012.Level U Drugs.—Fourteen drugs are assignedto Level U, a category reserved for treatments thathave “insufficient data to support or refute use formigraine prophylaxis.” This may mean that studieswere judged to have substantial methodologicalshortcomings or that there are conflicting resultsfrom multiple studies. In addition to gabapentin, vera-pamil, and fluoxetine, this group contains the tricyclicantidepressant proptriptyline and the carbonic anhy-drase inhibitor acetazolamide.Ineffective Drugs.—The 2012 AHS/AAN guide-lines also list 8 medications for which evidence isconsidered to show that they are established as, orpossibly or probably ineffective for migraine prophy-laxis. The authors suggest that these should not beoffered or considered for patients requiring migraineprophylaxis. These include the anti-epileptic druglamotrigine, the leukotriene inhibitor montelukast,oxcarbazepine, and telmisartan.In the 2000 guidelines, 8 drugs were placed in thelowest group 5, 3 of which (indomethacin, nicar-dipine, and nifedipine) now are in Level U in the newguidelines. Three drugs included in group 5 in 2000have been upgraded to Level C in the current guide-lines (carbamazepine, pindolol, and clonidine), while2 (clomipramine and clonazepam) are now consid-ered likely to be ineffective.Drugs for Menstrually Triggered Attacks ofMigraine.—For short-term prevention of menstruallytriggered migraine attacks, frovatriptan is assigned toLevel A, and naratriptan and zolmitriptan to Level B,while estrogen is in Level C.Comparison of the 2012 AHS/AAN MigrainePrevention Guidelines With Other ContemporaryMigraine Prevention Clinical Practice Guidelines.—Our search and abstract screen identified 5 additionalcontemporary clinical practice guidelines relevantto migraine prevention in adults and publishedsince 2008. Three were excluded, 2 because theywere not published in English and 1 because it didnot link recommendations to a formal appraisal ofevidence.17-19The 2 guidelines that met criteria forinclusion in this review were guidelines published in2012 by the Canadian Headache Society (referred toherein as the “Canadian guidelines”) and guidelinespublished in 2008 by the EFNS (referred to herein asthe “EFNS guidelines”).20,21Table 4 displays the char-acteristics and methods of the 3 guidelines.Headache 935
  7. 7. Table4.—CharacteristicsandMethodsUsedForDevelopingthe3MigrainePreventionClinicalPracticeGuidelinesAmericanHeadacheSociety(AHS)/AmericanAcademyofNeurology(AAN)GuidelineCanadianGuidelineEuropeanFederationofNeurologicalSocieties(EFNS)GuidelineStatus(neworupdated)UpdatedNewNewOrganization(s)participatinginguidelinedevelopmentAAN;AANCanadianHeadacheSocietyEFNSOrganization(s)endorsingguidelineAAN;AAN;AmericanOsteopathicAssociationCanadianHeadacheSocietyEFNSFunding/sponsorshipsource(s)AAN;AANCanadianHeadacheSocietyEFNSDatesofsearchBuiltonMEDLINEsearchdoneforpreviousguidelines,updatedwithinformationfromJune1999throughMay2009MEDLINE,EMBASE,CochraneLibraryinception-April2008;UpdatedinJune2011.Searchlimitedto“thoseagentscommonlyusedinclinicalpractice.”Theyprovidealistoftargetdrugs.“AliteraturesearchwasperformedusingthereferencedatabasesMEDLINE,ScienceCitationIndex,andtheCochraneLibrary...lastsearchinJanuary2009.”Statesthat“allauthorsperformedanindependentliteraturesearch.”Attemptsreportedtolocateunpublishedevidenceorverifyfullstudyreporting?Forexample,searchofthegreyliterature,manufacturerdatabases,regulatorydocuments,ortrialregistries.NoNoNoStudyinclusioncriteria“...randomizedadultpatientswithmigrainetotheagentunderstudyoracomparatordrug(includingplacebo)andutilizedmaskedoutcomeassessment”“...requiredtobeprospective,randomized,double-blind,controlledtrialsofdrugtreatmentsusedtopreventtheoccurrenceofmigraineattacks.”Studieshadtoincludeadultswhometacceptedcriteriaformigraineorprovide“sufficientdetail”tosupportamigrainediagnosis.“AllpaperspublishedinEnglish,GermanorFrenchwereconsideredwhentheydescribedacontrolledtrialoracaseseriesonthetreatmentofatleastfivepatients.InadditionareviewbookandtheGermantreatmentrecommendationsformigrainewereconsidered.”StudyexclusioncriteriaAssessedforheadachesotherthanepisodicmigraine;assessedacutetreatment,auratreatment,nonpharmacologictreatment;usedqualityoflife,disabilityornonstandardizedoutcomes;testeddrugsnotavailableintheUnitedStates.Excludedstudiesofpatientswithheadache15ormoredayspermonth,transformedmigraine,orchronictension-typeheadache.Excludedstudiesofagentsnot“commonlyusedinclinicalpractice.”Notexplicitlystated.MethodsofclassifyingtreatmentsAANtherapeuticclassificationofevidencescheme.EachdrugassignedoneofthefollowingratingsTreatmentclassifiedbasedontheGradingofRecommendationsAssessment,DevelopmentandEvaluation(GRADE)method.Eachdrugwasassigned1of4levelsofevidence:high,moderate,low,orverylow.Therecommendationwasthenfurthergradedasstrongorweakbasedonassessmentofthebalanceofbenefitsandharms.Developersnotethatthiscanresultina“strong”recommendationforatherapythatisonlymodestlyeffectiveorhasalowlevelofevidence,ifitiswelltoleratedandsafe.“ThedefinitionsoftherecommendationlevelsfollowtheEFNScriteria.”EachdrugassignedaratingofA(“drugsoffirstchoice”),B(“drugsofsecondchoice”)...evidenceofefficacybutlesseffectiveormoreside-effectsthanlevelAdrugs),orC(“drugsofthirdchoice”),onlyprobableefficacy.LevelA(medicationswithestablishedefficacy,greaterthanorequalto2ClassItrials);LevelB(medicationsareprobablyeffective[3ClassIor2ClassIIstudies]);LevelC(medicationsarepossiblyeffective[3ClassIIstudies]);LevelU(inadequateorconflictingdatatosupportorrefuteuse);orother(medicationsthatareestablishedaspossiblyorprobablyineffective)Methodsofderivingrecommendations(evidencelinkedwithformalconsensusmethod;evidencelinkedwithinformalconsensusmethod;consensusmethodwithnodetaileddescription;notdescribedEvidencelinkedwithinformalconsensusmethod:“Atleast2panelistsindependentlyreviewedeachstudyandratedit...Differencesinratingswereresolvedbyauthorpaneldiscussion.”EvidencelinkedwithinformalconsensusmethodConsensusmethodwithnodetaileddescriptionAssessedincludedstudiesbasedondisease-specificrecommendationsforoutcomemeasures,trialconduct,andadverseeventreportingrecommendedbyprofessionalsocietyguidelinesInpart:used50%responderratesasmeasureofsuccessInpartNotstatedYearofpublicationofpreviousversion2000NotapplicableNotapplicableYearplannedfornextupdateNotreported“Atleasteverytwoyears.”“Shouldbeupdatedwithinthreeyears”936 June 2012
  8. 8. All were sponsored, funded, and carried out byprofessional societies devoted to the study of neurol-ogy or headache. Only the AHS/AAN guidelines,however, were endorsed by other specialty groups.All of the guidelines reported that a systematic searchfor evidence was conducted, although the dates andbreadth of the searches varied. The search for theAHS/AAN guidelines extended only through May2009, while the search for the Canadian guidelinesextends through June 2011.The inclusion and exclusion criteria differedamong the guidelines, with the result that the AHS/ANS guidelines consider a larger number of drugs,while the Canadian guidelines rate only a previouslyagreed-upon list of medications in common use.All of the guidelines used structured methods toappraise retrieved evidence. None, however, reportedmaking any attempts to identify unpublished orincompletely reported evidence for the treatmentsreviewed. The 3 guidelines also used differentmethods of appraising and classifying the evidencethat was retrieved. Two of the guidelines mentionedthe use of a 50% responder rate as a measure oftreatment efficacy, as recommended by InternationalHeadache Society clinical trial guidelines formigraine-preventive therapies. None, however,reported basing other assessments of study qualityon the disease-specific recommendations for otheroutcome measures, adverse event reporting, or trialmethods that have been developed by professionalsocieties, such as the International Headache Societyrecommendations about the clinical conduct of pre-ventive trials and adverse event reporting.22,23As previously mentioned, the 2012 AHS/AANguidelines assign treatments to Levels based on assess-ment of the strength and quality of evidence of effi-cacy. Adverse effects, contraindications to use, andother clinical considerations are reviewed but are notincorporated in the assignment of drugs to a particularlevel. In contrast, both the Canadian and EFNS incor-porate an assessment of the balance of benefits andharms for a drug into their categorization schemes.Areas of apparent agreement among the guide-line ratings are summarized in Table 5. These mustbe interpreted in light of the imperfect correspon-dence among the various categories, as describedearlier. It is notable, however, that there is consider-able consensus among the guidelines about drugsthat are placed in the highest tier, with divalproex,metoprolol, propranolol, and topiramate assigned tothe top category in all 3 of the guidelines. Similarly, allof the guidelines place coenzyme Q10 and linsinoprilTable 5.—Areas of Apparent Agreement on Evidence Quality for Drugs Rated by at Least 2 of 3Migraine Prevention GuidelinesAHS/AANGuidelines Canadian GuidelinesEFNSGuidelinesCoenzyme Q10 C Strong, low-quality evidence CDivalproex A Weak, high-quality evidence AFlunarazine Not rated Weak, high-quality evidence ALisinopril C Weak, low-quality evidence CMetoprolol A Strong, high-quality (but not reviewed for guidelines,instead rating based on Cochrane review)ANadolol B Strong, moderate Not ratedNaproxen B Not rated BPizotifen Not rated Weak, high-quality evidence Not ratedPropranolol A Strong, high-quality evidence ATopiramate A Strong, high-quality evidence AAssuming that Level A = high-quality evidence = first-line (A) drugs; Level B = moderate-quality evidence = second-line (B) drugs;Level C = low-quality evidence = third-line (C) drugs; Level U and established as, or possibly or probably ineffective = do not use(no comparable rating in EFNS guidelines).AAN = American Academy of Neurology; AHS = American Headache Society; EFNS = European Federation of NeurologicalSocieties.Headache 937
  9. 9. in their third category. Some drugs were rated inonly 2 guidelines, and in those cases, there was alsoconcordance for naproxen and nadolol, which wereplaced in the second tier. Drugs rated by only 1 guide-line are listed in Appendix III. The majority of thosewere rated in the AHS/AAN guidelines, which cast awider net for evidence than the Canadian and EFNSguidelines.Table 6 identifies areas of apparent divergenceamong the guidelines. In general, the divergence isnot substantial. For 6 of the 11 treatments (amitrip-tyline, candesartan, magnesium, petasites, riboflavin,and venlafaxine), there is only a difference of a singlecategory up or down for one of the guidelines, whilethe other 2 guidelines place the drug in similar tiers.For 2 drugs, however, the differences in classificationare more substantial. Gabapentin is placed in LevelU (conflicting or insufficient evidence to support orrefute efficacy) whereas in the 2012 AHS/AANguidelines, while the Canadian guidelines rate it ashaving “moderate-quality evidence” and make astrong recommendation for its use based on thecombination of possible efficacy and good tolerability.The EFNS guidelines consider it a “third choice”drug. For feverfew, the Canadian guidelines recom-mend against use based on an interpretation of thetrial evidence as negative overall, while the AHS/AAN guidelines include it in Level B (probably effec-tive, should be considered) and the EFNS guidelinesconsider it a “third choice” treatment.AGREE-II Appraisal Results.—Table 7 shows theresults of the quality rating using the AGREE-II toolfor assessing clinical practice guideline quality. Ingeneral, the Canadian and the AHS/AAN guidelinesreceived higher scores for quality in all domains,with the Canadian guidelines achieving the highestoverall assessment of quality. The AHS/AAN guide-lines received their highest score in Domain 1, whichscores the reporting of the scope and purpose ofthe guidelines, and their lowest score in stakeholderinvolvement, which appraises the extent to whichstakeholders such as patients and nonspecialist clini-cians were involved in guideline development. TheCanadian guidelines also received their highest scorein Domain 1 and their lowest in Domain 6, whichrates the reporting of factors associated with editorialindependence.The EFNS guidelines had consistently low scoresin all domains with the exception of Domain 6, edi-torial independence, where they achieved theirhighest score. They were rated lowest in Domain 4,Clarity of Presentation. Based on an overall assess-Table 6.—Areas of Apparent Divergence About Evidence Quality for Drugs Rated by at Least 2Guidelines for Migraine PreventionAHS/AANGuidelines Canadian GuidelinesEFNSGuidelinesAmitriptyline B Strong, high-quality evidence BAspirin U Not rated CBisoprolol U Not rated BCandesartan C Strong, moderate-quality evidence CFeverfew B Do not use CGabapentin U Strong, moderate-quality evidence CMagnesium B Strong, low-quality evidence CPetasites A Strong, moderate-quality evidence BRiboflavin B Strong, low-quality evidence CVenlafaxine B Weak, low-quality evidence BVerapamil U Weak, low-quality evidence N/AAssuming that Level A = high-quality evidence = first-line (A) drugs; Level B = moderate-quality evidence = second-line (B) drugs;Level C = low-quality evidence = third-line (C) drugs; Level U and established as, or possibly or probably ineffective = do not use(no comparable rating in EFNS guidelines).AAN = American Academy of Neurology; AHS = American Headache Society; EFNS = European Federation of NeurologicalSocieties.938 June 2012
  10. 10. ment of guideline quality by the 3 reviewers, theAHS/AAN and the Canadian guidelines were recom-mended for use, while the EFNS guidelines were not.Appendix IV provides the ratings for each compo-nent of the 6 domains.DISCUSSIONThe 2012 AHS/AAN guidelines for episodicmigraine prevention provide a welcome summary ofthe evidence that underpins commonly used treat-ments for migraine.Most of the drugs deemed to havethe highest level of evidence in the 2000 guidelinesremain in that category in 2012. Although themethods used to locate and appraise evidence andlink it to recommendations varied among the 3 guide-lines we reviewed, there was remarkable consistencyin the ratings of drugs for first-line use.In contrast, recommendations diverged substan-tially for gabapentin and feverfew. This divergenceis potentially confusing for clinicians and patients.7It may be related to differences in search strategiesor methods for selecting the evidence. In our view,however, it is most likely due to the way in whichrecommendations were formulated. The AHS/AANratings were assigned solely on the basis of an assess-ment of efficacy,while the Canadian and EFNS catego-rizations sought to balance efficacy and side effects. Inthe case of gabapentin, which is widely believed to bewell tolerated, it is therefore not surprising that theCanadian and EFNS guidelines place the drug in theirsecond and third tiers, respectively, while the AHS/AAN guidelines downgrade the drug because of con-flicting and poor-quality evidence of efficacy.We believe this example points out a seriousshortcoming in rating methods that seek to incorpo-rate both benefits and harms. First, although willing-ness to use treatments is influenced by both benefitsand harms, ratings assigned by others can never hopeto correctly capture the views of different patients.Second, it is well known that potential harm andadverse events are not systematically sought orreported in clinical trials, so that published evidenceof harms is likely to be an underestimate.24Andfinally, it is questionable whether a drug with low oruncertain efficacy should be recommended for wide-spread use on the basis of tolerability when moreeffective drugs are available.The quality and credibil-ity of clinical trial evidence for gabapentin hasrecently been called into considerable question.16,25This evidence quality problem is better addressed bymethods that use a purer approach in generating rec-ommendations, one that is based principally onassessments of efficacy.On the other hand, a pure efficacy-based systemof recommendations raises the question of whatconstitutes a clinically meaningful treatment effect,Table 7.—Overall Assessment and Domain Scores for the 3 Migraine Prevention Clinical Practice Guidelines Using theAGREE-II InstrumentAHS/AAN RawScore (percentageof possible score†)Canadian RawScore (percentageof possible score†)EFNS RawScore (percentageof possible score†)Best PossibleScoreDomain 1: Scope and Purpose 17.6 (84%) 20.7 (99%) 7 (33%) 21Domain 2: Stakeholder Involvement 6 (29%) 18.3 (87%) 5.3 (25%) 21Domain 3: Rigor of Development 32 (57%) 52 (93%) 19.6 (35%) 56Domain 4: Clarity of Presentation 15.6 (74%) 19.3 (92%) 1.3 (6%) 21Domain 5: Applicability 10 (36%) 24.7 (88%) 5.6 (20%) 28Domain 6: Editorial Independence 8.3 (59%) 11.3 (81%) 9.6 (69%) 14Overall Assessment (scale of 1-7) 4.3 (61%) 6 (86%) 2 (29%) 7Recommended for use? Yes Yes No Yes†Raw score is the average of the scores of 3 independent reviewers, rounded to 1 decimal place. Percentages are rounded to thenearest whole number.AAN = American Academy of Neurology; AGREE-II = Appraisal of Guidelines Research and Evaluation-II; AHS = AmericanHeadache Society; EFNS = European Federation of Neurological Societies.Headache 939
  11. 11. especially in relation to side effects. Some drugsthat have statistically significant evidence of benefit inwell-designed and conducted trials may nonethelessprovide very marginal benefits when applied toroutine clinical practice.An example of this situation isfrovatriptan,where the magnitude of clinical benefit isquite small in comparison with treatment burden andcost.26One compromise might be to present informa-tion about both efficacy and side effects but to refrainfrom incorporating them in a composite measure.Thisallows clinicians using the guidelines to individualizetreatment decisions based on both efficacy and patientpreferences regarding specific risks.The quality of the AHS/AAN and Canadianguidelines, as assessed with the AGREE-II tool,was better than that of guidelines in other specialties,which is heartening.13Both are recommended for useon the basis of the AGREE-II quality assessment. Itis likely that the Canadian guidelines scored particu-larly high on the AGREE measure because they weredeveloped in accordance with AGREE recommenda-tions. In contrast, the EFNS guidelines do not appearto meet widely accepted standards for guidelinequality and are not recommended for use.Future efforts are needed to ensure that guide-lines are regularly updated and that guideline devel-opers make use of methods to locate and incorporateunpublished clinical trial evidence.27There are manyreasons that it can be difficult to locate clinical trialevidence. Some have to do with problems in taggingstudies as RCTs in MEDLINE or the need to con-dense information to meet word limits imposed bymedical journals.28,29It is clear, however, that muchclinical trial evidence has never been published or hasbeen incompletely reported.30Unfortunately, thereis substantial reason to believe that this problem ofmissing or manipulated evidence affects the clinicalevidence when one evaluates migraine therapy.22,31-33The incorporation of unpublished evidence into meta-analyses has been shown to alter conclusions abouttreatment efficacy.To ensure the integrity,validity,andcredibility of migraine clinical practice guidelines,developers should make strenuous efforts to locate allrelevant evidence.34This and other recommendationsfor the development of future migraine clinical prac-tice guidelines are listed in Box 1.In summary, the 2012 updated AHS/AAN guide-lines for preventive treatment of episodic migraineprovide a welcome and comprehensive overview ofthe breadth and quality of existing evidence. TheyBox 1.—Seven recommendations for thedevelopment of clinical practice guidelines formigraine treatment.• Ensure that guideline processes conform toauthoritative recommendations about idealguideline development and reporting, suchas the Appraisal of Guidelines Research andEvaluation (AGREE) measures• Provide explicit definitions for terms suchas “acute” or “preventive/prophylactic” treat-ment• Avoid limiting the initial evidence search tofamiliar or widely used treatments in order tominimize the chance of missing importantnew research and developments• Make and document attempts to locateunpublished and missing clinical trial evi-dence, for example by searching the grey lit-erature, manufacturer web sites, and clinicaltrial registration and reporting sites such asclinicaltrials.gov• Assess trial quality against headache-specificrecommendations for outcome measures,quality of adverse event collection andreporting, and trial conduct. See in particularthe International Headache Society guide-lines for the conduct of controlled trials ofmigraine prophylaxis and adverse eventreporting in migraine trials• Present separate assessments and recommen-dations regarding the efficacy and side effectsof treatments. Avoid the use of compositerecommendations that seek to balance effi-cacy and tolerability because the quality andcompleteness of evidence for side effects isknown to be poor• Present and adhere to a timeline for regularupdates and modifications to guidelines940 June 2012
  12. 12. confirm the benefits of many widely used therapies,identify drugs that should be avoided, and remindclinicians of emerging evidence for a wide array ofnewer treatment choices.APPENDIX I: SEARCH STRATEGYMEDLINE Search Strategy:Database: Ovid MEDLINE(R) <1950 to AprilWeek 3 2012>1. guideline.pt.2. practice guideline.pt.3. Health Planning Guidelines/4. Consensus Development Conference/5. (guideline or guidelines).m_titl.6. *Clinical Protocols/7. or/1-68. exp migraine/9. “migraine”.tw.10. or/8-1011. 7 and 1012. limit 11 to yr=“2008-Current”Guideline website search strategy:We searched the website of the National GuidelineClearinghouse maintained by the United States Agencyfor Health Care Quality. The search was conductedat http://www.guideline.gov/search/search.aspx?term=migraine using the keyword “migraine” on April 17,2012.APPENDIX II: FLOW OF GUIDELINES THROUGH THE REVIEW5 guidelines, in addition to theAHS/AAN guidelines, met criteria forretrieval17-212 additional guidelines retrieved andincluded in the review20,213 excluded* 2 not in English17,18* 1 not based onsystematic review orevidence grading19Headache 941
  13. 13. APPENDIX III: RATINGS OF DRUGS EVALUATED IN ONLY 1 GUIDELINEAHS/AAN Guideline Canadian Guideline EFNS GuidelineAcebutolol Possibly not effective Not rated Not ratedAcenocoumadin U Not rated Not ratedAcetazolamide U Not rated Not ratedAtenolol B Not rated Not ratedCarbamazepine C Not rated Not ratedClomipramine Probably not effective Not rated Not ratedClonazepam Possibly not effective Not rated Not ratedClonidine C Not rated Not ratedCoumadin C Not rated Not ratedCyclandelate U Not rated Not ratedCyproheptadine C Not rated Not ratedEstrogen C Not rated Not ratedFenoprofen B Not rated Not ratedFluoxetine U Not rated Not ratedFlurbiprofen C Not rated Not ratedFluvoxamine U Not rated Not ratedFrovatriptan A Not rated Not ratedGuanfacine C Not rated Not ratedHistamine SC B Not rated Not ratedHyperbaric oxygen U Not rated Not ratedIbuprofen B Not rated Not ratedIndomethacin U Not rated Not ratedKetoprofen B Not rated Not ratedLamotrigine Established as ineffective Not rated Not ratedMefenamic acid C Not rated Not ratedMontelukast Probably not effective Not rated Not ratedNabumetone Possibly not effective Not rated Not ratedNaproxen sodium B Not rated Not ratedNaratriptan B Not rated Not ratedNebivolol C Not rated Not ratedNicardipine U Not rated Not ratedNimodipine U Not rated Not ratedOmega 3 U Not rated Not ratedOxcarbazepine Possibly not effective Not rated Not ratedPicotamide U Not rated Not ratedPindolol C Not rated Not ratedPitzotifen Not rated Weak, high-quality evidence Not ratedProtriptyline U Not rated Not ratedTelmisartan Possibly not effective Not rated Not ratedTimolol A Not rated Not ratedZolmitriptan B Not rated Not rated942 June 2012
  14. 14. APPENDIXIV:QUALITYOFTHE3MIGRAINEPREVENTIONGUIDELINESFORTHE6DOMAINSOFTHEAGREE-IIINSTRUMENTGuideline:AHS/AANCanadianEFNSItemnumberAverageof3reviewerratings;possiblescoreof7Domain1:ScopeandPurpose1.Theoverallobjective(s)oftheguidelineis(are)specificallydescribed.6.76.73.62.Thehealthquestion(s)coveredbytheguidelineis(are)specificallydescribed.671.73.Thepopulation(patients,public,etc)towhomtheguidelineismeanttoapplyisspecificallydescribed.571.7Domain2:StakeholderInvolvement4.Theguidelinedevelopmentgroupincludesindividualsfromallrelevantprofessionalgroups.2.76.32.75.Theviewsandpreferencesofthetargetpopulation(patients,public,etc)havebeensought.1516.Thetargetusersoftheguidelineareclearlydefined.3.772.3Domain3:RigorofDevelopment7.Systematicmethodswereusedtosearchforevidence.4.66.72.68.Thecriteriaforselectingtheevidenceareclearlydescribed.4.16.72.79.Thestrengthsandlimitationsofthebodyofevidenceareclearlydescribed.4.66.31.710.Themethodsforformulatingtherecommendationsareclearlydescribed.4.36.32.611.Thehealthbenefits,sideeffects,andriskshavebeenconsideredinformulatingtherecommendations.3.36.7212.Thereisanexplicitlinkbetweentherecommendationsandthesupportingevidence.6.77213.Theguidelinehasbeenexternallyreviewedbyexpertspriortoitspublication.5.36.31.714.Aprocedureforupdatingtheguidelineisprovided.26.35.7Domain4:ClarityofPresentation15.Therecommendationsarespecificandunambiguous.4.76.33.316.Thedifferentoptionsformanagementoftheconditionorhealthissueareclearlypresented.56317.Keyrecommendationsareeasilyidentifiable.671.7Domain5:Applicability18.Theguidelinedescribesfacilitatorsandbarrierstoitsapplication.26.7119.Theguidelineprovidesadviceand/ortoolsonhowtherecommendationscanbeputintopractice.4.36.7120.Thepotentialresourceimplicationsofapplyingtherecommendationshavebeenconsidered.2.76121.Theguidelinepresentsmonitoringand/orauditingcriteria.1.75.62.3Domain6:EditorialIndependence22.Theviewsofthefundingbodyhavenotinfluencedtheguideline(explicitstatement).57723.Competinginterestsofguidelinedevelopmentgroupmembershavebeenrecordedandaddressed.3.74.32.7Headache 943
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