Cardiovascular and Mortality Risk of Appartent Resistant Hypertension in Women With Suspected Myocardial Ischemia: A Rep...

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Title:
Cardiovascular and Mortality Risk of Appartent Resistant Hypertension in Women With Suspected Myocardial Ischemia: A Report From the NHLBI-Sponsored WISE Study
Physical Description:
Journal Article
Creator:
Smith, Steven M.
Huo, Tianyao
Johnson, B. Delia
Bittner, Vera
Kelsey, Sheryl F.
Thompson, Diane Vido
Merz, C. Noel Bairey
Pepine, Carl J.
Cooper-DeHoff, Rhonda
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American Heart Association (The Journal of the American Heart Association)
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Abstract:
Background-—Women are more likely than men to develop resistant hypertension, which is associated with excess risk of major adverse outcomes; however, the impact of resistant hypertension in women with ischemia has not been explicitly studied. In this Women’s Ischemia Syndrome Evaluation (WISE) analysis, we assessed long-term adverse outcomes associated with apparent treatment-resistant hypertension (aTRH) among women with suspected myocardial ischemia referred for coronary angiography. Methods and Results-—Women (n=927) were grouped according to baseline blood pressure (BP): normotensive (no hypertension history, BP <140/90 mm Hg, no antihypertensive drugs); controlled (BP <140/90 mm Hg and a hypertension diagnosis or on 1 to 3 drugs); uncontrolled (BP ≥140/90 mm Hg on ≤2 drugs); or aTRH (BP ≥140/90 mm Hg on 3 drugs or anyone on ≥4 drugs). Adverse outcomes (first occurrence of death any cause, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure or angina) were collected over 10 years of follow-up. Apparent treatment-resistant hypertension prevalence was 10.4% among those with hypertension. Women with aTRH had a greater incidence of adverse outcomes, compared with normotensive women (adjusted hazard ratio HR, 3.25; 95% confidence interval CI, 1.94 to 5.43), and women with controlled (HR, 1.77; 95% CI, 1.26 to 2.49) and uncontrolled (HR, 1.62; 95% CI, 1.15 to 2.27) hypertension; outcome differences were evident early in follow-up. Risk of all-cause death was greater in the aTRH group, compared to the normotensive women and women with controlled and uncontrolled hypertension. Conclusions-—In this cohort of women with evidence of ischemia, aTRH was associated with a profoundly increased long-term risk of major adverse events, including death, that emerged early during follow-up. ( J Am Heart Assoc. 2014;3:e000660 doi: 10.1161/JAHA.113.000660) Key Words: hypertension • resistant hypertension • WISE • women
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Collected for University of Florida's Institutional Repository by the UFIR Self-Submittal tool. Submitted by Haeden Roberson.
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Thompson, C. Noel Bairey Merz, Carl J. Pepine and Rhonda M. Cooper-DeHoff Steven M. Smith, Tianyao Huo, B. Delia Johnson, Vera Bittner, Sheryl F. Kelsey, Diane Vido Sponsored WISE Study Suspected Myocardial Ischemia: A Report From the NHLBI Cardiovascular and Mortality Risk of Apparent Resistant Hypertension in Women With Online ISSN: 2047-9980 Dallas, TX 75231 is published by the American Heart Association, 7272 Greenville Avenue, Journal of the American Heart Association The doi: 10.1161/JAHA.113.000660 2014;3:e000660; originally published February 28, 2014; J Am Heart Assoc. http://jaha.ahajournals.org/content/3/1/e000660 World Wide Web at: The online version of this article, along with updated information and services, is located on the for more information. http://jaha.ahajournals.org Access publication. Visit the Journal at is an online only Open Journal of the American Heart Association Subscriptions, Permissions, and Reprints: The at Univ Florida on September 4, 2014 http://jaha.ahajournals.org/ Downloaded from at Univ Florida on September 4, 2014 http://jaha.ahajournals.org/ Downloaded from

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CardiovascularandMortalityRiskofApparentResistant HypertensioninWomenWithSuspectedMyocardialIschemia: AReportFromtheNHLBI-SponsoredWISEStudyStevenM.Smith,PharmD,MPH;TianyaoHuo,MS;B.DeliaJohnson,PhD;VeraBittner,MD,MSPH;SherylF.Kelsey,PhD; DianeVidoThompson,MS;C.NoelBaireyMerz,MD;CarlJ.Pepine,MD;RhondaM.Cooper-DeHoff,PharmD,MSBackground- Womenaremorelikelythanmentodevelopresistanthypertension,whichisassociatedwithexcessriskofmajor adverseoutcomes;however,theimpactofresistanthypertensioninwomenwithischemiahasnotbeenexplicitlystudied.Inthis Women sIschemiaSyndromeEvaluation(WISE)analysis,weassessedlong-termadverseoutcomesassociatedwithapparent treatment-resistanthypertension(aTRH)amongwomenwithsuspectedmyocardialischemiareferredforcoronaryangiography. MethodsandResults- Women(n = 927)weregroupedaccordingtobaselinebloodpressure(BP):normotensive(nohypertension history,BP < 140/90mmHg,noantihypertensivedrugs);controlled(BP < 140/90mmHgandahypertensiondiagnosisoron1to 3drugs);uncontrolled(BP 140/90mmHgon 2drugs);oraTRH(BP 140/90mmHgon3drugsoranyoneon 4drugs). Adverseoutcomes( rstoccurrenceofdeath[anycause],nonfatalmyocardialinfarction,nonfatalstroke,orhospitalizationfor heartfailureorangina)werecollectedover10yearsoffollow-up.Apparenttreatment-resistanthypertensionprevalencewas 10.4%amongthosewithhypertension.WomenwithaTRHhadagreaterincidenceofadverseoutcomes,comparedwith normotensivewomen(adjustedhazardratio[HR],3.25;95%con denceinterval[CI],1.94to5.43),andwomenwithcontrolled(HR, 1.77;95%CI,1.26to2.49)anduncontrolled(HR,1.62;95%CI,1.15to2.27)hypertension;outcomedifferenceswereevidentearly infollow-up.Riskofall-causedeathwasgreaterintheaTRHgroup,comparedtothenormotensivewomenandwomenwith controlledanduncontrolledhypertension. Conclusions- Inthiscohortofwomenwithevidenceofischemia,aTRHwasassociatedwithaprofoundlyincreasedlong-termrisk ofmajoradverseevents,includingdeath,thatemergedearlyduringfollow-up. ( JAmHeartAssoc .2014;3:e000660doi: 10.1161/JAHA.113.000660) KeyWords: hypertension resistanthypertension WISE women Hypertension(HTN)affectsanestimated1billionadults globallyandisamajormodi ableriskfactorfor ischemicheartdisease,stroke,heartfailure,diabetes,and death.1,2Anestimated8%to12%ormoreofthosewithHTN arebelievedtohaveresistantHTN,3usuallyde nedas requiring 4antihypertensiveagentstoachieveblood pressure(BP)control,andidenti edasapriorityresearch area.4PreviousstudieshaveshownthatresistantHTN,as comparedwithnonresistantHTN,isassociatedwithan increasedriskofmajoradversecardiovascular(CV)events, all-causemortality,orboth,aswellaslowerhealth-related qualityoflife.5 9Furthermore,inarecentanalysis,resistant HTNportendedanincreasedriskofmajoradverseCV outcomesinpatientswithHTNandestablishedcoronary arterydisease(CAD).10Yet,importantquestionsremain, includingwhethertheincreasedriskforadverseCVoutcomes associatedwithresistantHTNispresentinwomenspeci cally presentingforevaluationofsymptomsandsignsofischemia andwhetherthisriskremainsoverthelongterm. Untilrecently,limitedinformationwasavailableregarding sexdifferencesinHTNcontrolandrelatedoutcomes.Overall prevalenceofHTNappearstobesimilaramongmenand women,consideringtheentireagespectrum;however,more menthanwomenhaveHTNatages < 45years,whereasthe FromtheDepartmentofPharmacotherapy&TranslationalResearch,Collegeof Pharmacy,UniversityofFlorida,Gainesville,FL(S.M.S.,R.M.C-D.);Department ofCommunityHealth&FamilyMedicine,CollegeofMedicine,Universityof Florida,Gainesville,FL(S.M.S.);DivisionofCardiovascularMedicine,DepartmentofMedicine,CollegeofMedicine,UniversityofFlorida,Gainesville,FL (T.H.,C.J.P.,R.M.C.-D.);GraduateSchoolofPublicHealth,Universityof Pittsburgh,Pittsburgh,PA(B.D.J.,S.F.K.);DivisionofCardiovascularDisease, UniversityofAlabamaatBirmingham,Birmingham,AL(V.B.);AlleghenyGeneral Hospital,Pittsburgh,PA(D.V.T.);BarbaraStreisandWomen sHeartCenter, Cedars-SinaiHeartInstitute,LosAngeles,CA(C.N.B.M.). Correspondenceto: StevenM.Smith,PharmD,MPH,UniversityofFlorida, POBox100486,Gainesville,FL32610.E-mail:ssmith@cop.u .edu ReceivedNovember8,2013;acceptedJanuary9,2014. 2014TheAuthors.PublishedonbehalfoftheAmericanHeartAssociation, Inc.,byWileyBlackwell.Thisisanopenaccessarticleunderthetermsofthe CreativeCommonsAttribution-NonCommercialLicense,whichpermitsuse, distributionandreproductioninanymedium,providedtheoriginalworkis properlycitedandisnotusedforcommercialpurposes. DOI:10.1161/JAHA.113.000660 JournaloftheAmericanHeartAssociation1 ORIGINALRESEARCH at Univ Florida on September 4, 2014 http://jaha.ahajournals.org/ Downloaded from

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reverseistrueinthose 65.1,11Womenaremorelikelytobe treatedwithantihypertensivedrugsandprescribedagreater numberofantihypertensivedrugs,yetlesslikelytoachieveBP controlthanage-matchedmen,particularlyinagingpopulations.11 18Accordingly,severalstudiesindicatethatresistant HTNpopulationshaveagreaterratiooffemalestomalesthan dononresistantHTNpopulationsandthatfemalesexisan independentpredictorofresistantHTN.7,10,18,19Ontheother hand,womenwithHTNingeneralhavealowerriskfor mortalityandmostadverseCVoutcomes,comparedtoagematchedmenwithHTN.20 22Thisappearstrueeveninolder populations,whereHTNismoreprevalentandpoorly controlledinwomen,23despitesimilarprotectionafforded bothbyantihypertensivetherapies.24Thus,itwouldappear thatwomenarelesslikelythanmentoexperienceadverseCV events,butmorelikelytodevelopresistantHTN.Whether resistantHTNportendsincreasedriskofadverseoutcomesin womenhasnotbeenexplicitlystudiedandrisksassociated withischemiaareunknown. Therefore,theaimofthisstudywastoascertainthelongtermriskofadverseoutcomesassociatedwithapparent treatment-resistantHTN(aTRH)inwomenwithsignsand symptomsofcardiacischemia.WehypothesizedthataTRH wouldbeassociatedwithanincreasedriskforadverseCV outcomes.Totestthishypothesis,weanalyzeddatafromthe Women sIschemiaSyndromeEvaluation(WISE).MethodsStudyDesignTheWISEstudydesignandprotocoldetailshavebeen previouslypublished.25Brie y,WISEisaNationalHeart, LungandBloodInstitute sponsoredobservationalcohort studyaimedatimprovingrecognition,diagnosis,and understandingofpathophysiologicmechanismsunderlying ischemicheartdiseaseinwomen.Womenundergoing clinicallyindicatedcoronaryangiographyforsymptoms and/orsignsofischemiawereenrolledfromSeptember 1996throughMarch2000fromfouracademicinstitutions, includingtheUniversityofAlabama-Birmingham,University ofPittsburgh,UniversityofFlorida,andAlleghenyGeneral Hospital.Majorexclusioncriteriaincludedcomorbiditiesthat compromisedfollow-up,pregnancy,contraindicationsto provocativediagnostictesting,cardiomyopathy,NewYork HeartAssociationclassIIItoIVheartfailure,recent myocardialinfarction(MI),signi cantvalvularorcongenital heartdisease,andlanguagebarriertoquestionnairetesting. Eachwomangaveinformedconsentbeforeenrollment.All clinicalcentershadinstitutionalreviewboardapprovalfor inclusionofwomeninthiscohortstudyaswellasfor collectionoffollow-updata.BaselineandFollow-upProceduresBaselineevaluationsincludedcollectionofdemographics, medicalhistory,symptomdata,physicalexaminationandblood samplingforlipids,reproductivehormones,andin ammatory markers,asdescribedindetailelsewhere.25Bloodpressure wasmeasuredintheclinic/of cesettingatcentersvery experiencedinthetreatmentofHTNcareandfollowingroutine clinicalstandardsinlinewithwhatwasoutlinedbyJNC6,26whichwascurrentduringcollectionoftheBPdatadescribedin thismanuscript.Bloodpressurewasmeasuredwithwomen seatedandafterhavingrestedforatleast5minutes.Blood pressurevaluesrepresentedeitherantihypertensive-na veor on-treatmentBPifabaselineantihypertensiveregimenwas prescribedbyaparticipant sprimaryphysician.Coronary angiographyanalyseswereperformedbyacorelabmasked toallpatientdata,includingsymptomsandresultsofnoninvasivetesting.Anydiameterstenosis 50%wasconsidered obstructiveCAD.27Outcomedatausedherewerecollectedin twoconsecutivephases,asdescribedpreviously.28During phaseI(medianduration,6years),womenwerecontactedat 6weeksandat1-yearintervalsfollowingenrollment.During telephonecontact,ascriptedinterviewwascompletedbyan experiencednurseorphysicianattherespectivecenter:Each patient(orafamilymember,forwomenwhodiedorwerelostto follow-up)wasqueriedforoccurrenceofmajoradversecardiac eventsorhospitalizations.ForcasescaredforataWISEclinical center,patients medicalrecordswerealsoreviewed.Inthe eventofdeath,adeathcerti cateand/orphysiciannarrative wasobtained.Duringthesecondphase,weconducteda NationalDeathIndexsearchto10yearsofmedianfollow-upfor thosewhowerealiveatlastcontactandhadnotwithdrawn consent.AlldeathswereadjudicatedasCVornon-CVbya committeeofseniorWISEinvestigatorsblindedtoangiographic ndings.De nitionofHTNGroupsandAssemblyofStudy CohortForthisanalysis,womenwereassignedtooneoffourgroups accordingtobaselineBPandantihypertensiveuseasfollows: (1)normotensive,de nedasnoself-reportedhistoryofHTN, BP < 140/90mmHg,andtakingnoantihypertensivedrugs; (2)controlledHTN,de nedasBP < 140/90mmHgandeither aself-reportedpreviousHTNdiagnosis(iftakingnoantihypertensivedrugs)oruseof1to3antihypertensivedrugs irrespectiveofHTNdiagnosis;(3)uncontrolledHTN,de ned asBP 140/90mmHgusing 2antihypertensivedrugs;and (4)aTRH,de nedasBP 140/90on 3antihypertensive drugsorBP < 140/90mmHgusing 4antihypertensive drugs.Thenormotensivegroupwasthereferenceinall analyses. DOI:10.1161/JAHA.113.000660 JournaloftheAmericanHeartAssociation2 ApparentResistantHypertensioninWomen SmithetalORIGINALRESEARCH at Univ Florida on September 4, 2014 http://jaha.ahajournals.org/ Downloaded from

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OutcomesTheprimaryoutcomeforthisanalysiswasthe rstoccurrence ofdeathfromanycause(includingphaseIIdata),nonfatalMI, nonfatalstroke,orhospitalizationforheartfailureorangina. All-causedeath(includingextendedfollow-upfromphaseII) wasasecondaryoutcome.StatisticalAnalysesDemographicsandmajoreventsweresummarizedusing mean SDforcontinuousvariablesandn(%)forcategorical variables.Comparisonsacrossthefourstudygroupswere madeusingFisher sexacttestforcategoricalvariablesand Kruskal-Wallis testforcontinuousvariables.Thelog-ranktest wasusedtotestoveralldifferencesinoutcomesamong groups.Cox sregressionmodelswere ttoadjustcovariates thatweresigni cantlydifferentbetweengroups.Candidate variablesforthefullmodelsincludedage,race(nonwhite), historyofdiabetes,historyofdyslipidemia,presenceof obesity(de nedasbodymassindex[BMI] > 30kg/m2), historyofsmoking,presenceofobstructiveCAD,andfamily historyofCAD.Modelsweredevelopedusingbackward selectionwithageforcedintothemodel;otherwise,only covariateswitha P value < 0.10remainedinthe nalmodel. Theproportionalhazardassumptionwascheckedbycreating andaddingtime-dependentcovariatesinthemodel;no signi cantviolationoftheassumptionwasdetected.Ahazard ratio(HR)and95%con denceintervals(CIs)wereestimated foreachvariable.UnadjustedKaplan-Meiersurvivalcurves wereplottedforeachoutcome.Overall P values 0.05were consideredsigni cant.Statisticalanalyseswereperformed usingSASversion9.3(SASInstituteInc.,Cary,NC).ResultsAtotalof927womenwithavailableBP,angiographic,and follow-upoutcomesdatawereincludedinthisanalysis.At baseline,only131(14.1%)ofthesewomenwerenormotensive.Amongtheremaining796womenwithHTN,390(48.9%) hadcontrolledHTN(BP < 140/90mmHg),323(40.6%)had uncontrolledHTN,and83(10.4%)hadaTRHaccordingtoour de nitions.Pertinentbaselinecharacteristicsfortheentire studycohortandtheindividualgroupsaresummarizedin Table1.WomenwithHTN,ascomparedwithnormotensive women,wereolder,onaverage,andhadahigherbaseline prevalenceofdiabetes,dyslipidemia,obesity,andobstructive CAD.Notably,womenwithaTRHhadthehighestprevalence ofeachofthesecomorbidities.Additionally,almosthalfofthe womenwithaTRHwerenonwhite,whereasfewerthan1in5 ofwomeninthenormotensive,controlledHTN,anduncontrolledHTNgroupswerenonwhite.BaselineBPandMedicationUseMean SDbaselinesystolicBPwassimilarforthenormotensiveandcontrolledHTNgroups(120 12vs. 123 12mmHg,respectively)andfortheuncontrolledHTN andaTRHgroups(154 15vs.158 21mmHg,respectively).Correspondingmean SDbaselinediastolicBPswere 73 8and72 9mmHgforthenormotensiveandcontrolled HTNgroupsand83 10and81 13mmHgfortheuncontrolledandaTRHgroups. Self-reportedantihypertensivemedicationuseatbaseline issummarizedinTable1.Byde nition,useof 1agentfrom eachantihypertensiveclasswasconsiderablymorecommon inwomenwithaTRHthaninthosewithcontrolledor uncontrolledHTN.InthosewithaTRHatbaseline,diuretics werethemostcommonlyusedagents(89%ofwomen), followedby b-blockers(77%)andangiotensinconverting enzyme(ACE)inhibitors(70%).Inboththecontrolledand uncontrolledHTNgroups, b-blockerswerethemostcommonlyusedagent(50%and33%ofwomenineachgroup, respectively).Diureticswereusedby28%ofthosewith controlledHTNand25%ofthosewithuncontrolledHTN.No womenusedaldosteroneantagonists.AdverseCVandMortalityOutcomesAdverseCVandmortalityoutcomeeventfrequenciesare summarizedinTable2.Unexpectedly,nearlyhalfofthe796 womenwithHTNhadatleastoneofthefollowingevents: deathfromanycause,nonfatalMI,nonfatalstroke,or hospitalizationforheartfailureorangina.IntheaTRHgroup, 69%experiencedanevent,comparedwith46%inthe uncontrolledHTNgroupand44%inthecontrolledHTN group.Considerablyfewerwomeninthenormotensivegroup experiencedanevent(21%),relativetotheHTNgroups (overalllog-rank, P < 0.0001).Thesedifferencesinadverse outcomefrequencybetweengroupswereevidentveryearlyin follow-up(Figure1). Inmultivariable-adjustedanalysescontrollingforage,race, andavailableclinicalcharacteristics,HTNofanytypewas associatedwithahigherriskofadverseoutcome,relativeto normotensivewomen.Speci cally,weobservedagraded associationwherebyexcessrisk(relativetonormotensive women)wasintermediateinthosewithcontrolledHTN(HR, 1.84;95%CI,1.19to2.84)anduncontrolledHTN(HR,2.01; 95%CI,1.29to3.13)andhighestintheaTRHgroup(HR, 3.25;95%CI,1.94to5.43).WomenwithaTRHalsohad greaterrisk,comparedwiththoseinthecontrolled(HR,1.77; 95%CI,1.26to2.49; P = 0.001)anduncontrolledHTN(HR, 1.62;95%CI,1.15to2.27; P = 0.006)groups.Nodifference wasobservedinriskbetweencontrolledanduncontrolled HTNgroups(HR,0.91;95%CI,0.72to1.16; P = 0.45). DOI:10.1161/JAHA.113.000660 JournaloftheAmericanHeartAssociation3 ApparentResistantHypertensioninWomen SmithetalORIGINALRESEARCH at Univ Florida on September 4, 2014 http://jaha.ahajournals.org/ Downloaded from

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Table1. BaselineCharacteristicsAccordingtoStudyGroupandfortheCohortVariable Overall (n = 927) Normotensive (n = 131) ControlledHTN (n = 390) UncontrolledHTN (n = 323) ApparentResistantHTN (n = 83) P Value*Age,mean SD58 1252 11 57 12 61 11 63 11 <0.0001 Nonwhite,% 19 12 15 19 46 <0.0001 HTN,% 59 0 61 72 97 <0.0001 Diabetes,% 25 4 25 26 54 <0.0001 Dyslipidemia,%51 30 60 53 77 <0.0001 Obese,% 40 31 39 44 48 0.019 ObstructiveCAD,%38 18 43 36 53 <0.0001 FamilyHxofCAD,%64 63 70 64 63 0.17 Hxofsmoking,%53 51 58 50 45 0.044 SBP(mmHg), mean SD 137 21120 12 123 12 154 15 158 21 <0.0001 DBP(mmHg), mean SD 77 1173 87 2 98 3 10 81 13 <0.0001 Antihypertensivedrugs ACEinhibitor,%26 0 29 22 70 ARB,% 3 0 2 3 13 b -blocker,%39 0 50 33 77 Diuretic,% 29 0 28 25 89 Vasodilator,%9 0 7 9 28 CCB,% 28 0 33 25 61 Numberofantihypertensivedrugs 0drugs,% 23 100 4 21 0 1drug,% 39 0 56 43 0 2drugs,% 25 0 28 37 0 3drugs,%14 0 12 0 100 ACEindicatesangiotensin-convertingenzyme;ARB,angiotensinreceptorblocker;CAD,coronaryarterydisease;CCB,calciumchannelblocker;DBP,diastolicbloodpressure; HTN,hypertension;Hx,history;SBP,systolicbloodpressure. P valuesrepresentcomparisonacrossthefourstudygroupsusingFisher sexacttestforcategoricalvariablesandKruskal-Wallis testforcontinuousvariables.Nogroupcomparisons weremadeforantihypertensivedrugsandnumberofantihypertensivedrugsbecausethesevariableswereeither0%or100%fornormotensivepatientsb yde nition.Self-reporteddiagnosisofhypertensionatbaseline. Table2. OutcomeFrequencybyStudyGroupOutcome Normotensive(n = 131)ControlledHTN(n = 390)UncontrolledHTN(n = 323)ApparentResistantHTN(n = 83)Total(n = 927)Primaryoutcome*,n(%)28(21) 170(44) 149(46) 57(69) 404(44) Individualcomponentsofprimaryoutcome NonfatalMI,n(%) 1(1) 15(4) 12(4) 5(6) 33(4) NonfatalStroke,n(%)4(3) 17(4) 15(5) 6(7) 42(5) HFhospitalization,n(%)1(1) 16(4) 28(9) 17(20) 62(7) Anginahospitalization,n(%)21(16) 106(27) 91(28) 38(46) 256(28) All-causedeath,n(%)5(4) 81(21) 63(20) 34(41) 183(20)HFindicatesheartfailure;HTN,hypertension;MI,myocardialinfarction. *Firstoccurrenceofdeathfromanycause(includingextendedfollow-up),nonfatalMI,nonfatalstroke,orhospitalizationforheartfailureorangina. DOI:10.1161/JAHA.113.000660 JournaloftheAmericanHeartAssociation4 ApparentResistantHypertensioninWomen SmithetalORIGINALRESEARCH at Univ Florida on September 4, 2014 http://jaha.ahajournals.org/ Downloaded from

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InadditiontoHTNtype,thepresenceofobstructiveCAD, nonwhiterace,andhistoryofdyslipidemiaalsocontributed signi cantlytohigherriskofadverseoutcome(Table3). AmongthosewithHTN,nearly1in4womendiedduring the10-yearmortalityfollow-upperiod(Table2).TheproportionofwomendyingfromanycausewashighestintheaTRH group(41%),whereasdeathoccurredlessfrequentlyinthe uncontrolledHTN(20%)andcontrolledHTN(21%)groups. Only4%ofwomeninthenormotensivegroupdied.The Kaplan-Meiercurvefortheunadjustedanalysisofall-cause deathisdisplayedinFigure2.Afteradjustment,HTNofany typewasassociatedwithanincreasedriskofall-causedeath. Thegreatestexcessrisk,relativetonormotensivewomen, wasobservedinthosewithaTRHatbaseline(HR,7.36;95% CI,2.16to25.1),followedbythosewithcontrolledHTN(HR, 4.24;95%CI,1.31to13.7)anduncontrolledHTN(HR,3.83; 95%CI,1.17to12.5).Riskofall-causedeathwasalsogreater inwomenwithaTRH,comparedwithcontrolledHTN(HR, 1.74;95%CI,1.07to2.81; P = 0.03)anduncontrolledHTN (HR,1.92;95%CI,1.17to3.15; P = 0.01),whereasno differenceinriskwasobservedbetweenwomenwith controlledversusuncontrolledHTN(HR,1.11;95%CI,0.75 to1.64; P = 0.62).HazardratiosfromthefullCoxregression modelforall-causedeatharesummarizedinTable4.DiscussionDespiteincreasingawarenessofCVDastheleadingcauseof mortalityforwomen,relativelyfewstudieshavefocusedon womeninrelationtoCVDandassociatedoutcomes.29We testedthehypothesisthataTRH,de nedinthisstudyas baselineBP 140/90mmHgusing 3antihypertensivedrugs oruseof 4antihypertensivedrugsregardlessofBP,portends anincreasedriskofadverseoutcomesamongadultwomen withsignsorsymptomsofmyocardialischemia.Weshow,for the rsttime,thatwomen,referredtocoronaryangiographyto evaluatesymptoms/signsofischemia,withaTRHhavea profoundlyincreasedriskofCVeventsandall-causemortality, comparedwithnormotensivewomenandthosewithoutaTRH. Moreover,weobservedanassociationwithboth rstoccurrenceofnonfatalstroke,nonfatalMI,hospitalizationforangina orheartfailure,orall-causedeath,andall-causedeathalone, wherebywomenwithaTRHconsistentlyhadthegreatest excessrisk,followedbythosewithnonresistantHTN(regardlessofBPcontrol),whereasnormotensiveindividualshadthe lowestrisk.Importantly,thispronouncedincreaseinrisk occurredearlyinfollow-up,particularlyfortheprimary outcome,andpersistedoverthelongtermforboththe primaryoutcomeandall-causemortality. Thesubstantialandearlyexcessriskofadverseoutcomes amongwomenwithaTRHenrolledinWISEisnoteworthyfor severalreasons.First,thisistheonlystudy,toourknowledge, thathasquanti edriskassociatedwithaTRHinafemale-only population.Comparedtomen,womenareknowntohave moredif cultyachievingBPcontrol,thusrequiringmore aggressivetherapy,and,consequently,aremorelikelyto developresistantHTN.Recentdataalsoindicatethatwomen withHTNhaveasigni cantlylowerriskofmostmajoradverse CVevents,CVmortality,andall-causemortality,when comparedtoage-matchedmenwithHTN.20 23However, resistantHTNinwomenhasnotbeenexplicitlystudied previouslyandwhetherornotaTRHportendsincreasedriskin womenhasnotbeenclearlyestablished.Thus,our ndings highlighttwokeypointsregardingaTRHinwomen:(1) RegardlessofanysexdifferenceinCVormortalityriskinthe Figure1.Kaplan-Meiercurveforprimaryoutcomeevent-free survivalaccordingtohypertensiongroup.HTNindicates hypertension. Table3. IndependentPredictorsFromMultivariateCox RegressionModelforFirstOccurrenceofDeathFromAny Cause(IncludingPhaseIIData),NonfatalMI,NonfatalStroke, orHospitalizationforHeartFailureorAnginaParameter HR(95%CI) P ValueAge(peryear) 1.00(0.99to1.01)0.45 Non-white 1.50(1.15to1.95)0.003 Historyofdyslipidemia(yesvsno)1.30(1.04to1.63)0.021 ObstructiveCAD(yesvsno)1.93(1.54to2.42) <0.0001 Historyofsmoking(yesvsno)1.23(0.99to1.52)0.06 Normotensive(reference) ControlledHTN 1.84(1.19to2.84)0.006 UncontrolledHTN 2.01(1.29to3.13)0.002 ApparentresistantHTN3.25(1.94to5.43) <0.0001CADindicatescoronaryarterydisease;CI,con denceinterval;HR,hazardratio;HTN, hypertension;MI,myocardialinfarction. DOI:10.1161/JAHA.113.000660 JournaloftheAmericanHeartAssociation5 ApparentResistantHypertensioninWomen SmithetalORIGINALRESEARCH at Univ Florida on September 4, 2014 http://jaha.ahajournals.org/ Downloaded from

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overallhypertensivepopulation,aTRHisassociatedwitha profoundincreaseinriskofadverseCVoutcomesanddeath inwomenwithsymptoms/signsofischemia,and(2)the associationbetweenaTRHandincreasedriskisindependent ofseveraltraditionalriskfactorsforadverseoutcomes, includingobstructiveCAD,diabetes,dyslipidemia,andobesity.Second,theexcessmortalityriskassociatedwithaTRHin thepresentstudyappearstopersistforatleast10years.To ourknowledge,thisisamongthelongestfollow-upperiod reportedinstudiesofresistantHTN.Mostpreviousstudies haveincludedoutcomeassessmentonlyupto5years.6 8,10Third,thissubstantialandlong-termdivergenceinriskamong thestudygroupswasobservedusingonlybaselineclinicBP data.Almostassuredly,someofthewomenenrolledinWISE hadpseudoresistantHTN,wherebybaselineclinicBP(usedin ourde nitionofaTRH)waselevated,but24-hourambulatory BPwouldhavebeennormal,haditbeenmeasured.Datafrom theSpanishAmbulatoryBloodPressureMonitoring(ABPM) registrysuggestthatasmanyas 40%ofwomenwithaTRH basedonclinicBPwouldnotbeclassi edashavingresistant HTNonthebasisof24-hourABPM(ie,pseudoresistant HTN).30Unfortunately,preciseestimatesofpseudoresistant HTNprevalenceinthispopulationareunavailableand24-hour ABPMwasnotperformedintheWISE.Nevertheless,persons withisolatedclinicBPelevations(akaa whitecoat effect) havealowerriskthanthosewithelevatedclinicand24-hour ambulatoryBPinunselectedHTNpopulations31,32and, possibly,resistantHTNpopulations.8Thus,theexcessrisk attributabletoaTRHinthepresentstudyisallthemore impressivebecause,presumably,asigni cantproportionof thesewomenlikelyhadonlyisolatedclinicBPelevationsat baseline. FewstudieshaveexaminedpredictorsofadverseoutcomesinpatientswithaTRH.Age,smoking,low-density lipoproteincholesterol,leftventricularhypertrophy,and diabeteshavebeensuggestedaspredictorsforadverse outcomes(eg,MI,stroke,renalfailurerequiringdialysis, coronaryorperipheralrevascularization,orheartfailure hospitalization).5Amongpatientswithchronickidneydisease, predictorsofadverseoutcome(ie,CVdeathornonfatalCV eventrequiringhospitalization)includedonlyincreasingage, malesex,decreasingglomerular ltrationrate,historyofCV events,and true resistantHTN(ie,asassessedby24-hour ambulatoryBP);BMIanddiabeteswerenotsigni cantly associatedwiththeadverseoutcomeandracewasnot consideredinthemodelbecauseonlywhiteswereenrolled.8AlthoughnotdirectlycomparableintermsofCVoutcomesor patientpopulationsassessed,wefoundthat,inadditionto aTRH,independentpredictorsofadverseoutcomesinwomen inourstudyincludednonwhiterace,historyofdyslipidemia, andobstructiveCAD.Wefoundnoevidenceofobesityor diabetesbeingindependentlyassociatedwiththeadverse outcome.However,diabeteswasindependentlyassociated withall-causedeath,aswereage,obstructiveCAD,and smoking.Theapparentdifferences,betweenpredictorsof adverseeventsinthesestudies,likelyre ectdifferencesin patientpopulations,aswellasde nitionsofoutcomesand resistantHTN.Nevertheless,thesedata,takentogether, clearlydemonstratethattheassociationbetweenadverse outcomesandaTRHisnotsimplyare ectionoftheknown riskofcomorbidities(eg,obstructiveCAD)foundmoreoften inthosewithresistantHTN.Rather,resistantHTNlikely re ectsasickerpatientpopulationwithunderlyingpathophysiologicchanges,forexample,increasedarterialstiffness33 35and/orsympatheticnervoussystemactivation resultinginalteredvascularrepairinteractingtoaggravate myocardialischemia.36 38A nalpointisthatalthoughwomenenrolledinWISEhada higherprevalenceofHTNthanthegeneralfemaleadult Figure2.Kaplan-Meiercurveforsurvivalfromall-causedeath accordingtohypertensiongroup.HTNindicateshypertension. Table4. IndependentPredictorsFromMultivariateCox RegressionModelforAll-CauseDeathParameter HR(95%CI) P ValueAge(peryear) 1.03(1.02to1.05)0.0003 Historyofdiabetes(yesvsno)1.88(1.31to2.72)0.0007 Historyofsmoking(yesvsno)1.85(1.29to2.65)0.0009 ObstructiveCAD(yesvsno)1.83(1.25to2.68)0.002 Normotensive(reference) ControlledHTN 4.24(1.31to13.7)0.017 UncontrolledHTN 3.83(1.17to12.5)0.026 ApparentresistantHTN7.36(2.16to25.1)0.001CADindicatescoronaryarterydisease;HTN,hypertension. DOI:10.1161/JAHA.113.000660 JournaloftheAmericanHeartAssociation6 ApparentResistantHypertensioninWomen SmithetalORIGINALRESEARCH at Univ Florida on September 4, 2014 http://jaha.ahajournals.org/ Downloaded from

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population,the10.4%prevalenceofaTRHamongonlythose withHTNisgenerallyconsistentwithpreviousanalysesof resistantHTNprevalenceinunselectedpatientswithHTN.3Furthermore,thisprevalenceissimilartothatobservedinthe ReductionofAtherothrombosisforContinuedHealthregistry, where12.7%ofadults 45yearsofagewith 3atheroscleroticriskfactorsorestablisheddiseasehadresistantHTN basedonbaselineBPdataandantihypertensivedruguse.7However,notsurprisingly,weobservedaconsiderablylower prevalenceinthepresentstudy,comparedwithINternational VErapamilSR-TrandolaprilSTudy(INVEST)participants,who allhadHTNandestablishedCADatbaseline,where approximatelyonethirdhadresistantHTN.10Ourstudyhassomenoteworthylimitations.First,BPand antihypertensiveusedatawerecollectedonlyatbaselineand thusourstudygroupswerede nedaccordingly.Wecannot excludethepossibilitythatsomewomenwouldhavebeen classi eddifferentlybasedondatafromlatertimepoints(eg, justbeforeanevent).However,inanalysesofINVESTdata, outcomesdidnotdifferamongthosewithcontrolledresistant HTNversusuncontrolledresistantHTN.10Thus,itisunclear whetherachievementofBPcontrol,orlackthereof,would substantiallyalteroutcomesintheaTRHgroup.Unfortunately, thegroupsizesandoutcomefrequencyweretoosmallto adequatelycomparewomenwithcontrolledaTRHversus uncontrolledaTRHinthepresentstudy.Second,medication adherenceandsecondarycausesofHTNwerenotexamined inWISEparticipants.Someofthesewomenlikelywere nonadherenttoantihypertensivetherapyandwecannot excludethepossibilitythatnonadherencemayhaveimpacted adverseeventratesinthehypertensivegroups,especially thosewithaTRH.Third,our ndingsareapplicabletowomen withsignsorsymptomsofmyocardialischemiaofsuf cient severitytopromptreferralforangiographyandshouldnotbe extrapolatedtoalladultwomen.Speci cally,patientsreferred totheWISEstudyhadsignsandsymptomsofischemiabased onavarietyofdifferentpositivediagnostictests;whetherour ndingswouldapplytoacohortofwomenwithoutischemia referralbiasisnotclear.Fourth,withoutacomparativemale cohort,itisunknownwhetherour ndingswouldapplyto men.Unlikeourwomen,moremenundergoingangiography areidenti edwithobstructiveCAD39,40andthereforemore intenselytargetedfortherapytopreventatherosclerosis progression.Futureinvestigationshouldbedirectedattesting theseconceptsinmen.WISEcentersmayalsohaveobserved ahigherpercentageofwomenreferredforcoronaryangiographywithoutobstructiveCADasaresultoftertiarycare referralbiasandpublicizedinterestinheartdiseaseamong women.Fifth,althoughwecontrolledforbaselinepresenceof severalknownriskfactorsformajoradverseCVevents,we cannotexcludethepossibilitythatunmeasuredconfounders impactedourresults.Moreover,our ndingsshouldnotbe construedasde nitiveproofofacausalrelationshipbetween aTRHandmajoradverseevents.Sixth,nonfatalandfatal outcomeswereveri edbyreviewofthemedicalrecordsinall caseswhererecordswereavailable;however,wecannot excludethepossibilitythatsomeuncorroborated,patientreportednonfataloutcomesmayhavebeensubjectto misclassi cation.Finally,theWISEcohorthadmoderaterates ofaspirinandstatinmedicationuse,bothofwhichareknown toreduceadverseoutcomesintheabsenceofHTN.Useof theseagentswouldhavethepotentialtoreducerisksand minimizerelationshipsbetweentheHTNgroupsandadverse outcomesandthereforeleadtoanunderestimationofthe observedrelationships.Likewise, b-blockerandACEinhibitor usewerebothgreaterintheaTRHgroupversusthe nonresistantHTNgroups,whichwouldhavethepotentialto resultinunderestimationoftherelationshipbetweenaTRH andadverseoutcomesinthesewomenwithevidenceof myocardialischemia. Inconclusion,thisanalysiscon rmsthataTRHis associatedwithaprofound,earlyincreaseinriskofadverse outcomesamongwomenwithsignsandsymptomsof myocardialischemiaregardlessofthepresenceofobstructiveCAD.Furthermore,theriskofall-causemortality associatedwithaTRHpersistsforatleast10yearsfrom initialdeterminationofresistantstatus.These ndings lla gapintheliteratureandhaveimportantimplicationsfor clinicalpracticeandfutureresearch.Ourobservations reinforcetheimportanceofrecognizingwomenwith,orat riskofdeveloping,resistantHTN.Additionally,our ndings highlighttheneedforfuturestudiestoclarifythepathophysiologiccausesunderlyingincreasedCVriskinpatients withaTRHandtodetermineappropriateriskreduction strategies,includingpharmacologicandnonpharmacologic therapies.SourcesofFundingThisworkwassupportedbycontractsfromtheNational Heart,LungandBloodInstitutes(nos.N01-HV-68161,N01HV-68162,N01-HV-68163,andN01-HV-68164);grants U0164829,U01HL649141,U01HL649241,T32HL69751, R01HL090957,and1R03AG032631fromtheNational InstituteonAging;GCRCgrantMO1-RR00425fromthe NationalCenterforResearchResources;theNationalCenter forAdvancingTranslationalSciences(grantUL1TR000124); andgrantsfromtheGustavusandLouisPfeifferResearch Foundation,Danville,NJ;TheWomen sGuildofCedars-Sinai MedicalCenter,LosAngeles,CA;TheLadiesHospitalAid SocietyofWesternPennsylvania,Pittsburgh,PA;andQMED, Inc.,LaurenceHarbor,NJ;theEdytheL.BroadWomen sHeart ResearchFellowship;Cedars-SinaiMedicalCenter,LosAngeles,CA;theBarbraStreisandWomen sCardiovascular DOI:10.1161/JAHA.113.000660 JournaloftheAmericanHeartAssociation7 ApparentResistantHypertensioninWomen SmithetalORIGINALRESEARCH at Univ Florida on September 4, 2014 http://jaha.ahajournals.org/ Downloaded from

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ResearchandEducationProgram;andTheSocietyfor Women sHealthResearch(SWHR),Washington,DC.DisclosuresNone.References1.KearneyPM,WheltonM,ReynoldsK,MuntnerP,WheltonPK,HeJ.Global burdenofhypertension:analysisofworldwidedata. 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