023-ACCP 成人肺动脉高压药物治疗指南 2014

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1WordCount:13,680

2PharmacologicalTherapyforPulmonaryArterialHypertensioninAdults:

3CHESTGuideline

4DarrenB.Taichman,MD,PhD,FCCP1(Chair)

5JoeOrnelas,MS,MS)2

6LorindaChung,MD,MS3

7JamesKlinger,MD,FCCP4

8SandraLewis,PhD5

9JessMandel,MD6

10HaroldI.Palevsky,MD,FCCP7

11StuartRich,MD,FCCP8

12NamitaSood,MD,FCCP9

13ErikaB.Rosenzweig,MD10

14

15TerenceK.Trow,MD,FCCP11

16RexYung,MD,FCCP12(GOCLiaison)

17C.GregoryElliott,MD,FCCP*13

18DavidB.Badesch,MD,FCCP*14

19*equalcontribution

201.UniversityofPennsylvania,Philadelphia,PA(

darren.taichman@

)

212.AmericanCollegeofChestPhysicians,Glenview,IL(

jornelas@

)

223.StanfordUniversity,PaloAlto,CA(

shauwei@

)

234.BrownUniversity,Providence,RI(

James_Klinger@B

)

245.AmericanCollegeofChestPhysicians,Glenview,IL(

szlewishcr@

)

256.UniversityofCalifornia,SanDiego,CA(

jmandel@

)

267.UniversityofPennsylvania,Philadelphia,PA(

harold.palevsky@

)

278.UniversityofChicago,Chicago,IL(

srich@

)

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289.OhioStateUniversity,Columbus,OH(

Namita.Sood@

)

2910.ColumbiaUniversityMedicalCenter,NewYork,NY(

esb14@

)

3011.YaleUniversity,NewHaven,CT(

terence.trow@

)

3112.JohnsHopkinsUniversity,Baltimore,MD(

ryung@

)

3213.IntermountainMedicalCenterandtheUniversityofUtah,Murray,UT(

greg.elliott@

)

3314.UniversityofColorado,Denver,CO(

David.Badesch@

)

34

35Correspondenceto:

36JoeOrnelas,MS

37AmericanCollegeofChestPhysicians

382595PatriotBoulevard

39Glenview,Illinois60026

40

41

42GuidelinesDisclaimer:

43CHESTGuidelinesareintendedforgeneralinformationonly,arenotmedicaladvice,anddonotreplace

44professionalmedicalcareandphysicianadvice,whichalwaysshouldbesoughtforanymedical

45condition.Thecompletedisclaimerforthisguidelinecanbeaccessed

46at

/Guidelines-and-Resources/Guidelines-and-Consensus-

47Statements/Methodology.

48JoeOrnelas,StuartRich,andRexYunghavenoconflictsofinterestto

49disclose.

50

51SandraZelmanLewisIamanofficerinaninstitutionthatprobablyhasa

52financialrelationshipwithacommercialentityhavinganinterestinthesubjectof

53thismanuscript.However,thetimeofworkingonthismanuscriptdidnotoverlap

54withthetimeIhavebeenemployedbythiscompany.

55

56Ialsomakepublicstatementsonguidelinemethodology.

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57

58DrKlingerhasservedasasiteinvestigatorfornumerousclinical

59studiesinpulmonaryhypertensionandinnumerouspharmacological,60industrysponsoredstudiesinpulmonaryhypertension.DrKlingerhas

61servedasaconsultantforBayerandUnitedTherapeutics.Hehas

62servedonthesteeringcommitteeandadjudicationcommitteefor

63industrysponsoredclinicaltrials.Hehasreceivedgrantsupportfrom

64NIHforenrollmentofpatientsinclinicalregistries.

65

66

67LorindaChungreceivesgrantfundingfromtheSclerodermaResearchFoundation.

68ShehasreceivedcompensationforclinicaltrialpatientenrollmentfromGilead,69Actelion,UnitedTherapeutics,Pfizer,MedImmune,Genentech/Roche,and

70InterMune.ShehasparticipatedinspeakingactivitiesforActelionandGilead,and

71hasservedontheAdvisoryBoardforGilead.

72

73Dr.MandelreceivesroyaltiesasanauthorandeditorfromElsevierandWolters-74Kluwer.

75

76Withinthepastthreeyears,Dr.PalevskyhasservedasaconsultantforActelion,77Bayer,GileadandUnitedTherapeutics,andhasservedonDSMBsforAIRESand

78Pfizer.HehasalsoservedasagrantreviewerfortheEntelligencePAHYoung

79InvestigatorsAwardProgram,andhasgivenCMEandotherPAHlectures;heison

80nopharmaceuticalcompanySpeaker'sBureaus.

81

82Dr.Badeschhasreceivedhonorariaforserviceonsteeringcommitteesoradvisory

83boards(orasaconsultant)tothefollowingcompaniesworkingintheareaof

84pulmonaryhypertension:Actelion/CoTherix,Gilead,Pfizer,United

85Therapeutics/LungRx,Bayer,Ikaria,andArena.Hehasreceivedgrantsupportfor

,

86clinicalstudiesfromActelion/CoTHerix,Gilead,Pfizer,UnitedTherapeutics/LungRx

87Bayer,Novartis,Ikaria,andReatta.Heprovidedinformationpertinenttoalegal

88matterforActelion.

89

90Dr.TrowhasinthedistantpastservedasaconsultantforBayer,Actelion,and

91Gilead,UntitedTherapeutticspharmaceuticals.HealsousedtoserveonSpeaker's

92BureausforActelion,Gilead,andUnitedTherapeutics.Nosuchtalkshavebeen

93giveninthe2.5yearspriortothispublication.Inaddition,Dr.Trowhasservedas

94thePIontheCOMPASS2trialandRESPIRERegistrywhichhavenow

95finished.

s

96

97DrSoodhasreceivedpharmaceuticalgrantmoneyforresearchproductsandserve

98asaconsultantforadvisoryboardmeetingsforActelion,Bayer,Gilead,andUnited

99Therapeutics.

100

101Until2009,DrTaichmanwasanemployeeoftheUniversityofPennsylvaniawhich

102receivedresearchgrantsupportfromActelionforparticipationinREVEAL.He

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103receivedhonoriaforCMEtalkssponsoredbythePulmonaryHypertension

104Association.Since2009,hehasbeenanemployeeoftheAmericanCollegeofPhysicians."

105Dr.RosenzweighasreceivedhonorariafromActelion,GileadScience,andUnitedTherapeuticsasanadvisor

106onScientificAdvisoryBoardPanelsandIkariaforastudyoversightcommitteeinthepastthreeyears.

107

108DrElliottisemployedbyIntermountainHealthcare(IHCHealthService,Inc.)and

109IHCHealthServices,Inchasreceivedcompensationtrials(onwhichheisthe

110principalinvestigator)fromActelion,Bayer,GeNo,Gilead,andUnitedTherapeutics.

111DrElliottservesontheEnd-PointAdjudicationCommitteeforastudysponsoredby

112LungLLC.BothheandIHCHealthServicesreceivedcompensationforhisservice

113ontheEnd-PointAdjudicationCommittee.Hehasreceivedtraveland

114reimbursementformeetingsheattendedsponsoredbyBayer,LungLLC,Ikaria.He

115servesasaconsultanttoBayerPharmaceuticals.Hereceivedhonoriaforservingon

116theREVEALSteeringCommittee,whichwassupportedbyCoTherix/Actelion.He

117servesontheboardofdirectorsforthePulmonaryHypertensionAssociation,

118servedontheAmericanCollegeofChestPhysiciansConsensusGuidelines

119CommitteeforPulmonaryArterialHypertensionandisanadvisorfortheScientific

120LeadershipCouncilofthePulmonaryHypertensionAssociations.

121

122

123

124

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125Abstract

126

127Background:Choicesofpharmacologicaltherapiesforpulmonaryarterialhypertension(PAH)are

128ideallyguidedbyhigh-levelevidence.

129Objective:ProvidecliniciansadviceregardingpharmacologictherapyforadultpatientswithPAHas

130informedbyavailableevidence.

131Design/Methodology:ThisguidelinewasbasedonsystematicreviewsofEnglishlanguageevidence

132publishedbetween1990andNovember2013,identifiedusingtheMEDLINEandCochraneLibrary

133databases.ThestrengthofavailableevidencewasgradedusingtheGRADEmethodology.Guideline

134recommendations,orconsensusstatementswhenavailableevidencewasinsufficienttosupport

135recommendations,weredevelopedusingamodifiedDelphitechniquetoachieveconsensus.

136Results:Availableevidenceislimitedinitsabilitytosupporthigh-levelrecommendations.Thereforewe

137draftedconsensusstatementstoaddressmanyclinicalquestionsregardingpharmacotherapyforpatients

138withPAH.Atotalof79recommendationsorconsensusstatementswereadoptedandgraded.

139Conclusions:ClinicaldecisionsregardingpharmacotherapyforPAHshouldbeguidedbyhigh-level

140recommendationswhensufficientevidenceisavailable.Absenthigher-levelevidence,consensus

141statementsbaseduponavailableinformationmustbeused.Furtherstudiesareneededtoaddressthegaps

142inavailableknowledgeregardingoptimalpharmacotherapyforPAH.

143

144

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145Abbreviations

146

1476MWDSix-MinuteWalkDistance

148ACCPAmericanCollegeofChestPhysicians

149AHRQAgencyforHealthcareResearchandQuality

150BORBoardofRegents

151CBConsensus-based

152CCBsCalciumChannelBlockers

153CICardiacIndex

154COCardiacOutput

155COIConflictofInterest

156CTEPHChronicThromboembolicPulmonaryHypertension

157EPCEvidence-BasedPracticeCenter

158ETRAEndothelinReceptorAntagonist

159FDAFoodandDrugAdministration

160GOCGuidelinesOversightCommittee

161IOMInstituteofMedicine

162IPAHIdiopathicPulmonaryArterialHypertension

163KQKeyQuestion

164mMeters

165MeSHMedicalSubjectHeadings

166mPAPMeanPulmonaryArteryPressure

167NT-proBNPN-TerminalPro–BrainNatriureticPeptide

168PAHPulmonaryArterialHypertension

169PDE5IPhosphodiesterase-5Inhibitor

170PHPulmonaryHypertension

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171PICOTSPopulation,Intervention,Comparator,Outcome,Timing,andSetting

172PVRPulmonaryVascularResistance

173QOLQualityofLife

174RAPRightAtrialPressure

175RCTsRandomizedControlledTrials

176TPRTotalPulmonaryResistance

177USFDAUSFoodandDrugAdministration

178WHOWorldHealthOrganization

179

180

181

182

183

184

185

186

187

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188SummaryofRecommendations

189

190PharmacologicalTherapyofPAHinAdults

191

1921.)WesuggestthattheseverityofaPAHpatient’sdiseasebeevaluatedinasystematicand

193consistentmanner,usingacombinationofWorldHealthOrganizationfunctionalclass,exercise

194capacity,echocardiographic,laboratoryandhemodynamicvariablesinordertoinformtherapeutic

195decisions.(GradeCB)

196

1972.)Wesuggestthat,wheneverpossible,allPAHpatientsbeevaluatedpromptlyatacenterwith

198expertiseinthediagnosisofPAH,ideallypriortotheinitiationoftherapy.(GradeCB)

199

2003.)WesuggestcollaborativeandcloselycoordinatedcareofPAHpatientsinvolvingtheexpertiseof

201bothlocalphysiciansandthosewithexpertiseinPAHcare.(GradeCB)

202Remarks:Appropriatecaremayrequirethecoordinatedeffortsofcardiologists,pulmonologists,

203rheumatologists,primarycare,orotherspecialties.

204

205TreatmentNaïvePAHpatientswithoutsymptoms(WHOfunctionalclassI)andpatientsat

206increasedriskforthedevelopmentofPAH

207

2084.)FortreatmentnaïvePAHpatientswithWHOfunctionalclassIsymptoms,wesuggestcontinued

209monitoringforthedevelopmentofsymptomsthatwouldsignaldiseaseprogressionandwarrantthe

210initiationofpharmacotherapy.(GradeCB)

211

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2125.)WesuggestthatpatientsatriskforthedevelopmentofPAH(e.g.,patientswithsystemic

213sclerosisorthepresenceofaknownmutationplacingthepatientatriskforPAH)bemonitoredfor

214thedevelopmentofsymptomsofPAH.(GradeCB)

215

216(6.)WesuggestalsothatcontributingcausesofPH(e.g.,sleepapneaandsystemichypertension)in

217patientswithPAHbetreatedaggressively.(GradeCB)

218

219

220SymptomaticPatientswithPAH

221

222VasoreactivityTestingandUseofCCBs

223

2247.)WesuggestthatpatientswithPAH,intheabsenceofcontraindications,shouldundergoacute

225vasoreactivitytestingusingashort-actingagentatacenterwithexperienceintheperformanceand

226interpretationofvasoreactivitytesting.(GradeCB)

227Remarks:Contraindicationstoacutevasoreactivitytestingincludealowsystemicbloodpressure,low

228cardiacoutputorthepresenceoffunctionalclassIVsymptoms.Acutevasoreactivitytestingmaybe

229complicatedbyhypotensionandthemisinterpretationofresultsmayresultintheinappropriateexposure

230ofpatientstotherisksofatreatmenttrialwithCCBswithoutthepossibilityofclinicalbenefit.

231Vasoreactivitytestingshouldbeperformedbyindividualswithappropriatetrainingintestperformance

232andinterpretation.

233

234

2358.)WesuggestthatpatientswithPAHwho,intheabsenceofright-heartfailureor

236contraindicationstocalcium-channelblockertherapy,demonstrateacutevasoreactivityaccording

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237toconsensusdefinition,shouldbeconsideredcandidatesforatrialoftherapywithanoralcalcium-

238channelblocker.(GradeCB)

239

2409.)WesuggestthatCCBsshouldnotbeusedempiricallytotreatPAHintheabsenceof

241demonstratedacutevasoreactivity.(GradeCB)

242

243

244PAH-specificpharmacotherapies

245

246PatientswithWHOFunctionalClassIISymptoms

247

248FortreatmentnaïvePAHpatientswithWHOfunctionalclassIIsymptomswhoarenotcandidates

249for,orwhohavefailedCCBtherapy,weadvisemonotherapybeinitiatedwithacurrently

250approvedETRA,PDE5inhibitor,orthesolubleguanylatecyclasestimulatorriociguat.More

251specificallyinthesepatients:

252•10.)Werecommendambrisentantoimprove6MWD.(Grade1C)

253•11–12.)Wesuggestbosentantodelaytimetoclinicalworsening(GradeCB)andimprove

254cardiopulmonaryhemodynamics.

255•13.)Wesuggestmacitentantodelaythetimetoclinicalworsening.(GradeCB)

256•14.)Werecommendsildenafiltoimprove6MWD.(Grade1C)

257•15.)Wesuggesttadalafiltoimprove6MWD.(GradeCB)

258•16–19.)Wesuggestriociguattoimprove6MWD(GradeCB),improveWHOFC(Grade259CB),delaythetimetoclinicalworsening(GradeCB)andimprovecardiopulmonary

260hemodynamics.

261

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26220.)Wesuggestalsothatparenteralorinhaledprostanoidsnotbechosenasinitialtherapyfor

263treatmentnaïvePAHpatientswithWHOfunctionalclassIIsymptomsorassecondlineagentsfor

264PAHpatientswithWHOfunctionalclassIIsymptomswhohavenotmettheirtreatmentgoals.

265(GradeCB)

266

267

268PatientswithWHOFunctionalClassIIISymptoms

269

270Fortreatment-naïvePAHpatientswithWHOfunctionalclassIIIsymptomswhoarenotcandidates

271for,orwhohavefailedCCBtherapy,weadvisemonotherapybeinitiatedwithacurrently

272approvedendothelinreceptorantagonist,aphosphodiesterase-5inhibitor,orthesolubleguanylate

273cyclasestimulatorriociguat.Morespecificallyinthesepatients:

274

275•21.)Werecommendtheuseofbosentantoimprove6MWD.(Grade1B)

276•22-23.)WesuggesttheuseofbosentantodecreasehospitalizationsrelatedtoPAHinthe

277short-term(Grade2C),andtoimprovecardiopulmonaryhemodynamics.

278•24.)Werecommendtheuseofambrisentantoimprove6MWD.(Grade1C)

279•25-26.)WesuggestmacitentantoimproveWHOFC(GradeCB)anddelaythetimeto

280clinicalworsening.(GradeCB)

281•27-29.)Werecommendtheuseofsildenafiltoimprove6MWD(Grade1C)andtoimprove

282WHOfunctionalclass.(GradeCB)Wesuggesttheuseofsildenafiltoimprove

283cardiopulmonaryhemodynamics.

284•30-33.)Wesuggesttheuseoftadalafiltoimprove6MWD(GradeCB),toimproveWHO

285functionalclass(GradeCB),todelaytimetoclinicalworsening(GradeCB)andtoimprove

286cardiopulmonaryhemodynamics.

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287•34-37.)Wesuggestriociguattoimprove6MWD(GradeCB),improveWHOFC(GradeCB),288delaythetimetoclinicalworsening(GradeCB)andimprovecardiopulmonary

289hemodynamics.

290

291FortreatmentnaïvePAHpatientswithWHOfunctionalclassIIIsymptomswhohaveevidenceof

292rapidprogressionoftheirdisease,orothermarkersofapoorclinicalprognosis,weadvise

293considerationofinitialtreatmentwithaparenteralprostanoid.Morespecificallyinthesepatients:

294•38-40.)Wesuggestcontinuousintravenousepoprostenoltoimprovefunctionalclass(Grade295CB),improve6MWD(GradeCB),andimprovecardiopulmonaryhemodynamics.

296•41.)Wesuggestcontinuousintravenoustreprostiniltoimprove6MWD.(GradeCB)

297•42-43.)Wesuggestcontinuoussubcutaneoustreprostiniltoimprove6MWD(GradeCB)and

298improvecardiopulmonaryhemodynamics.

299

300ForPAHpatientsinWHOfunctionalclassIIIwhohaveevidenceofprogressionoftheirdisease,301and/ormarkersofpoorclinicalprognosisdespitetreatmentwithoneortwoclassesoforalagents,302weadviseconsiderationoftheadditionofaparenteralorinhaledprostanoid.Morespecificallyin

303thesepatients:

304•44-46.)WesuggestintravenousepoprostenoltoimproveWHOFC(GradeCB),improve6

305MWD(GradeCB),andimprovecardiopulmonaryhemodynamics.

306•47-48.)Wesuggestintravenoustreprostiniltoimprove6MWD(GradeCB)andimprove

307cardiopulmonaryhemodynamics.

308

30949.)InpatientswithPAHwhoremainsymptomaticonstableandappropriatedosesofan

310endothelinreceptorantagonist(ETRA)oraPDE5inhibitor,wesuggesttheadditionofinhaled

311treprostiniltoimprove6MWD.(Grade2C)

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312Remarks:Theusualinitialdoseofinhaledtreprostinilis3inhalations(18µg)every6hours.However,313optimaleffectofinhaledtreprostinilmayrequiretitratingtreprostinildosesupto9inhalations(54µg)

314every6hours.

315

31650-51.)InpatientswithPAHwhoremainsymptomaticonstableandappropriatedosesofanERA

317oraPDE5inhibitor,wesuggesttheadditionofinhalediloprosttoimproveWHOFC(GradeCB)

318anddelaythetimetoclinicalworsening.(GradeCB)

319

320PatientswithWHOFunctionalClassIVSymptoms

321

322FortreatmentnaïvePAHpatientsinWHOfunctionalclassIV,weadviseinitiationofmonotherapy

323withaparenteralprostanoidagent.Morespecificallyinthesepatients:

324•52-54.)WesuggestcontinuousintravenousepoprostenoltoimproveWHOFC(GradeCB),325improve6MWD(GradeCB),andimprovecardiopulmonaryhemodynamics.

326•55.)Wesuggestcontinuousintravenoustreprostiniltoimprove6MWD(GradeCB).

327•56-57.)Wesuggestcontinuoussubcutaneoustreprostiniltoimprove6MWD(GradeCB)and

328improvecardiopulmonaryhemodynamics.

329

330FortreatmentnaïvePAHpatientsinWHOfunctionalclassIVwhoareunableordonotdesireto

331manageparenteralprostanoidtherapy,weadvisetreatmentwithaninhaledprostanoidin

332combinationwithanendothelinreceptorantagonist.Morespecificallyinthesepatients:

333•58-59.)Wesuggestbosentantoimprove6MWD(Grade2B)andcardiopulmonary

334hemodynamics.

335•60-61.)Wesuggestinhalediloprosttoimprove6MWD(GradeCB),andimproveWHOFC.

336(GradeCB)

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337•62.)Wesuggestinhaledtreprostinil(incombinationonly)toimprove6MWD.(GradeCB)

338

339

340PAHpatientsonestablishedPAH-specifictherapy

341

34263.)InPAHpatientsinitiatingtherapywithIVepoprostenol,wesuggestagainsttheroutine

343simultaneousinitiationofbosentan.(GradeCB)

344

345ForWHOfunctionalclassIIIorIVPAHpatientswithunacceptableclinicalstatusdespite

346establishedPAH-specificmonotherapy,weadviseadditionofasecondclassofPAHtherapyto

347improveexercisecapacity.Suchpatientsareideallyevaluatedatcenterswithexpertiseinthe

348evaluationandtreatmentofcomplexpatientswithPAH.Morespecifically:

349•64.)InpatientswithPAHwhoremainsymptomaticonstabledosesofanERAoraPDE5

350inhibitor,wesuggesttheadditionofinhalediloprosttoimprove6MWD.(GradeCB)

351•65.)InpatientswithPAHwhoremainsymptomaticonstabledosesofanERAoraPDE5

352inhibitor,werecommendtheadditionofinhaledtreprostiniltoimprove6MWD.(Grade1C)

353Remarks:Theusualinitialdoseofinhaledtreprostinilis3inhalations(18µg)every6hours.

354However,optimaleffectofinhaledtreprostinilmayrequiretitratingtreprostinildosesupto9

355inhalations(54µg)every6hours.

356•66.)InPAHpatientswhoremainsymptomaticonstabledosesofestablishedintravenous

357epoprostenol,wesuggesttheadditionofsildenafiloruptitrationofepoprostenoltoimprove

3586MWD.(GradeCB)

359•67-70.)InpatientswithPAHwhoremainsymptomaticonstabledosesofbosentan,

360ambrisentanoraninhaledprostanoid,wesuggesttheadditionofthesolubleguanylate

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361cyclasestimulatorriociguattoimprove6MWD(GradeCB)WHOFC(GradeCB)and

362cardiopulmonaryhemodynamicsandtodelaythetimetoclinicalworsening.(GradeCB)

363•71-73.)InpatientswithPAHwhoremainsymptomaticonstabledosesofaPDE5inhibitor

364oraninhaledprostenoidwesuggestmacitentantoimprove6MWD(GradeCB),WHOFC

365(GradeCB)andtodelaythetimetoclinicalworsening.(GradeCB)

366

36774.)ForWHOfunctionalclas