Race and Sex Differences in Response to Endothelin Receptor Antagonists for Pulmonary Arterial Hypertension

Transcription

1 CHEST Originl Reserch Rce nd Sex Differences in Response to Endothelin Receptor Antgonists for Pulmonry Arteril Hypertension PULMONARY VASCULAR DISEASE Nicole B. Gler, PhD, MHA ; Benjmin French, PhD ; Brin L. Strom, MD, MPH ; Ziyue Liu, PhD ; Hrold I. Plevsky, MD, FCCP ; Drren B. Tichmn, MD, PhD, FCCP ; Steven M. Kwut, MD, FCCP ; nd Scott D. Hlpern, MD, PhD Bckground: Recently studied therpies for pulmonry rteril hypertension (PAH) hve improved outcomes mong popultions of ptients, ut little is known out which ptients re most likely to respond to specific tretments. Differences in endothelin-1 iology etween sexes nd etween whites nd lcks my led to differences in ptients responses to tretment with endothelin receptor ntgonists (ERAs). Methods: We conducted pooled nlyses of deidentified, ptient-level dt from six rndomized plceo-controlled trils of ERAs sumitted to the US Food nd Drug Administrtion to elucidte heterogeneity in tretment response. We estimted the interction etween tretment ssignment (ERA vs plceo) nd sex nd etween tretment nd white or lck rce in terms of the chnge in 6-min wlk distnce from seline to 12 weeks. Results: Trils included 1,130 prticipnts with men ge of 49 yers; 21% were men, 74% were white, nd 6% were lck. The plceo-djusted response to ERAs ws 29.7 m (95% CI, m) greter in women thn in men ( P 5.03). The plceo-djusted response ws 42.2 m for whites nd m for lcks, difference of 43.6 m (95% CI, m) ( P 5.07). Similr results were found in sensitivity nlyses nd in secondry nlyses using the outcome of solute distnce wlked. Conclusions: Women with PAH otin greter responses to ERAs thn do men, nd whites my experience greter tretment enefit thn do lcks. This heterogeneity in tretment-response my reflect pthophysiologic differences etween sexes nd rces or distinct disese phenotypes. CHEST 2012; 141(1):20 26 Arevitions : 6MWD 5 6-min wlk distnce; ERA 5 endothelin receptor ntgonist; ET 5 endothelin; FDA 5 US Food nd Drug Administrtion; PAH 5 pulmonry rteril hypertension; RCT 5 rndomized controlled tril; RV 5 right ventriculr Pulmonry rteril hypertension (PAH) leds to decresed functionl sttus, right-sided hert filure, nd deth. 1 Recently studied therpies hve improved outcomes, yet sustntil heterogeneity remins in the risk of dverse clinicl outcomes nd the mgnitude of the tretment response. 2-4 Plsm levels of endothelin (ET)-1 re elevted mong ptients with PAH, contriuting to pulmonry vsculr remodeling. 5-7 Endothelin receptor ntgonists (ERAs) were the first orl therpies pproved y the US Food nd Drug Administrtion (FDA) for use in PAH nd remin mong the most commonly used drugs to tret it. Despite their effectiveness, experience hs shown tht certin 20 individuls my hve drmtic clinicl response to ERAs, wheres others my hve no response or my worsen. For editoril comment see pge 4 There re known iologic differences etween sexes nd mong different rces in the production nd hndling of ET-1, potent systemic nd pulmonry vsoconstrictor. Men hve higher concentrtions of circulting ET-1 thn do women, 8,9 nd men exhiit greter ET-medited coronry vsoconstriction.10 Blcks with systemic hypertension re known Originl Reserch

2 to hve higher plsm levels of ET-1 thn do whites nd greter increse in ET-1 in response to stress. 11 Further, lcks with systemic hypertension hve greter reduction in BP with ERAs compred with tht of whites. 12 The low enrollment of men nd lcks nd the reltively smll sizes of phse 2 nd 3 trils of ERAs in PAH hve until now precluded study-wide tests of heterogeneity in tretment response. We, therefore, sought to ssess whether sex nd rce modified the effects of ERA therpy in plceo-controlled trils of ERAs. Study Popultion Mterils nd Methods We otined dt on ll prticipnts included in the seven rndomized plceo-controlled trils of ERAs sumitted to the FDA. These seven clinicl trils (Amrisentn in Pulmonry Arteril Hypertension, Rndomized, Doule-Blind, Plceo- Controlled, Multicenter, Efficcy Studies [ARIES]-1; ARIES-2; Bosentn: Rndomized Tril of Endothelin Receptor Antgonist Therpy [BREATHE]-1; BREATHE-2; Sitxsentn To Relieve Impired Exercise [STRIDE]-1; STRIDE-2; nd STRIDE-4) exmined three gents (mrisentn, osentn, nd sitxsentn). We susequently excluded BREATHE-2 ecuse it included only 33 ptients, did not collect dt on severl potentil confounders, nd ws not phse 3 tril. Detils of the included trils re provided elsewhere Deidentified individul ptient dt for ll prticipnts were provided y the FDA. The included trils reported similr inclusion criteri, vrile collection, nd outcome ssessment t 12-week follow-up. Exposure Our primry exposure vrile ws tretment ssignment (ERA or plceo). Across trils, different gents nd doses yielded similr improvements in 6-min wlk distnce (6MWD) reltive to plceo nd were, therefore, nlyzed together. Covrites included ge, sex, PAH dignosis (idiopthic, connective Mnuscript received Ferury 16, 2011; revision ccepted August 1, Affilitions: From the Center for Clinicl Epidemiology nd Biosttistics nd the Deprtment of Biosttistics nd Epidemiology (Drs Gler, French, Strom, Kwut, nd Hlpern); the Pulmonry, Allergy, nd Criticl Cre Division (Drs Plevsky, Tichmn, Kwut, nd Hlpern); Penn Crdiovsculr Institute (Drs French, Plevsky, Tichmn, Kwut, nd Hlpern), Perelmn School of Medicine, University of Pennsylvni, Phildelphi, PA; nd the Deprtment of Biosttistics (Dr Liu), Indin University- Purdue University Indinpolis, Indinpolis, IN. Funding/Support: This work ws supported y n Americn Thorcic Society Fellows Creer Development Awrd nd n Actelion Phrmceuticls Entelligence Young Investigtor Awrd (Dr Hlpern ). Correspondence to: Scott D. Hlpern, MD, PhD, Perelmn School of Medicine, University of Pennsylvni, 723 Blockley Hll, 423 Gurdin Dr, Phildelphi, PA ; e-mil: shlpern@exchnge.upenn.edu. Reproduction of this rticle is prohiited without written permission from the Americn College of Chest Physicins ( site/misc/reprints.xhtml ). DOI: /chest tissue disese, HIV infection/norexigen use, or congenitl hert disese), height, weight, seline lortory nd hemodynmic mesures, nd concurrent mediction use. Outcomes The primry outcome of interest ws the chnge in 6MWD from seline to 12 weeks; 6MWD ws the primry end point in ll ut one of the trils nd ws selected for this reson. Bseline 6MWD ws otined t the time of, or within 2 weeks prior to, rndomiztion. In the primry nlyses, ptients who were missing 12-week 6MWD ecuse of study-ending clinicl events (n 543) were ssigned vlue of 0 m for their 12-week 6MWD ssessment. This choice ws mde priori sed on the ssumption tht ptients who were too sick to complete the study would lso e too sick to complete 6MWD ssessment. We lso performed sensitivity nlyses using 50, 100, 150, or 275 m (the men 12-week 6MWD mong ptients who sustined clinicl event ut still completed 12-week 6MWD ssessment) s the 12-week 6MWD. We conducted four secondry nlyses. First, we explored differences etween seline nd the finl recorded 6MWD, ccounting for the fct tht some trils lsted longer thn 12 weeks. These nlyses produced results similr to those of the primry nlyses nd re not reported. Second, we exmined differences in the solute distnce wlked t 12 weeks, which some hve considered etter predictor of clinicl outcomes. 18 Third, we repeted our primry nlysis in the suset of ptients with idiopthic PAH. Finlly, we compred the proportions of ptients in ech tretment-y-sex nd tretment-y-rce strtum who sustined clinicl events (deth, lung trnsplnt, tril septostomy, hospitliztion due to worsening PAH, withdrwl for worsening right-sided hert filure, or ddition of prostcyclin nlogs or phosphodiesterse inhiitors for PAH). We did not consider deteriortion in 6MWD in the clinicl event definition ecuse this represented our primry outcome vrile. Sttisticl Anlysis Prticipnt chrcteristics were summrized using medins nd interqurtile rnges for continuous vriles nd percentges for ctegoricl vriles. Primry nd secondry outcomes were nlyzed using liner or logistic regression for continuous or inry outcomes, respectively. We restricted the smple to lcks nd whites when nlyzing the interction of tretment ssignment with rce. Seprte models including ll ptients were used to estimte ll other effects. For the primry outcome, our most sic model included tretment (drug or plceo), sex, rce, nd the tretment-ysex or tretment-y-rce interction terms. This model lso djusted for PAH dignosis (idiopthic, connective tissue disese, HIV/norexigen use, or congenitl hert disese, entered s indictor vriles), seline 6MWD, ptient height, nd study. By including sex nd height in the model, we effectively modeled 6MWD % predicted without violting sttisticl ssumptions regrding rtio vlues. 19 In ddition, prtilly djusted model dditionlly included dignostic ctegory, ge, rce, nd sex. All other vriles were exmined s potentil confounders in third model tht included ny vriles tht ltered the coefficient for the interction term y 15%. A similr pproch ws used to model solute distnce wlked without djustment for seline wlk distnce. Achievement of certin threshold solute wlk distnce, if prognosticlly significnt, should e independent of seline wlk distnce. Multiple imputtion ws used to impute 12-week 6MWD for study prticipnts who did not hve study-ending clinicl event nd were missing 12-week 6MWD vlue (n 5 45). 20 The CHEST / 141 / 1 / JANUARY,

3 imputtion model included tretment, sex, nd rce, in ddition to vriles ssocited with missing 12-week 6MWD: study, seline wlk distnce, nd dignosis ctegory. Twenty imputed dt sets were generted to estimte the vriility mong imputed vlues. All nlyses were completed in SAS, version 9.2 (SAS Institute). The study ws pproved y the institutionl review ord of the University of Pennsylvni (Review Bord No. 4, pprovl ). All couthors hd ccess to the study dt, tke responsiility for the nlysis, nd hd uthority over mnuscript preprtion nd the decision to sumit for puliction. Results The six trils included 1,130 ptients. The prticipnts men ge ws 49 yers (rnge, 12-82), 21% were men, 836 (74%) were white, nd 65 (6%) were lck ( Tle 1 ). Seven hundred seventy-three ptients (68%) were rndomized to n ERA nd 357 (32%) to plceo. Forty-three ptients (4%) experienced study-ending clinicl events; n dditionl 10 ptients (1%) sustined clinicl events ut completed their 12-week 6MWD ssessment. Men seline wlk distnce ws 349 m (SD 87.0 m). Similr hemodynmic, lortory, nd severity of illness vlues were oserved for men nd women, nd for whites nd lcks (e-tles 1, 2). Tretment Response y Sex The plceo-djusted tretment response (men improvement in those who received ERAs vs plceo) ws 44.1 m mong women nd 16.7 m mong men in the se model ( Tle 2 ). Thus, tretment response ws 27.4 m (95% CI, m) greter in women thn in men. Women llocted to plceo showed decrement in 6MWD tht ws prevented y ssignment to ERAs. Men ssigned to plceo did not show decrement in 6MWD, ut lso did not show the enefit oserved in women with ssignment to ERAs (e-fig 1). As shown in the prtilly djusted model in Tle 2, djustment for ge, rce, nd dignosis ctegory did not chnge these results. Further djustment for potentil confounding vriles, such s lortory nd hemodynmic vlues, did not chnge the results (dt not shown). Women lso demonstrted greter solute wlk distnces t 12 weeks, with plceo-djusted 6MWD tht ws 27.5 m (95% CI, m) greter thn tht for men ( Tle 3 ). After djustment for confounders, the plceo-djusted improvement for women ws 44.9 m (95% CI, m) greter thn tht for men. Results were similr in sensitivity nlyses in which higher vlues were used for the 12-week 6MWD mong ptients experiencing intervl clinicl events (e-tles 3, 4), ut the mgnitudes of effect sizes Tle 1 Chrcteristics of Study Prticipnts Chrcteristic Active Tretment (n 5 773) Plceo (n 5 357) Age, y 50 (38-61) 49 (36-60) Mle sex, No. (%) 158 (20) 78 (22) Rce, No. (%) Blck 45 (6) 20 (6) White 577 (75) 259 (73) Other 151 (20) 78 (22) Height, cm 162 ( ) 163 ( ) Weight, kg 69 (59-82) 70 (59-85) BMI, kg/m ( ) 26.2 ( ) PAH dignosis, No. (%) Idiopthic 478 (62) 229 (64) Connective tissue disese 216 (28) 86 (24) HIV infection/norexigen use 23 (3) 11 (3) Congenitl hert disese 54 (7) 30 (8) New York Hert Assocition functionl clss, No. (%) I-II 256 (33) 114 (32) III-IV 516 (67) 243 (68) Bseline hemodynmics Men right tril 7.5 ( ) 7.5 ( ) pressure, mm Hg Men pulmonry rteril 50 (40-60) 51 (42-62) pressure, mm Hg Crdic output, L/min 4.2 ( ) 4.2 ( ) Crdic index, L/min/m ( ) 2.3 ( ) Pulmonry cpillry wedge 9 (7-12) 10 (7-12) pressure, mm Hg Pulmonry vsculr 10.2 ( ) 10.0 ( ) resistnce, Wood units Bseline lortory vlues Alumin, g/dl 4.2 ( ) 4.2 ( ) Cretinine, mg/dl 0.80 ( ) 0.80 ( ) Hemogloin, g/dl 14.8 ( ) 14.5 ( ) Sodium, meq/l 140 ( ) 140 ( ) Wrfrin use, No. (%) 466 (60) 230 (64) Bseline 6MWD, m 360 ( ) 366 ( ) Study, No. (%) ARIES (17) 67 (19) ARIES (16) 65 (18) BREATHE (19) 69 (19) STRIDE (15) 60 (17) STRIDE (24) 62 (17) STRIDE-4 64 (8) 34 (10) Dt re presented s medin (interqurtile rnge) unless indicted otherwise. 6MWD 5 6-min wlk distnce; ARIES 5 Amrisentn in Pulmonry Arteril Hypertension, Rndomized, Doule- Blind, Plceo-Controlled, Multicenter, Efficcy Studies; BREATHE 5 Bosentn: Rndomized Tril of Endothelin receptor Antgonist Therpy; PAH 5 pulmonry rteril hypertension; STRIDE 5 Sitxsentn To Relieve Impired Exercise. Reference ctegory for nlysis. diminished when lrger vlues were entered for these 12-week wlk distnces. Likewise, nlysis of only ptients with dignosis of idiopthic PAH yielded similr overll results (e-tle 5), mking it less likely tht unmesured differences in disese sutypes etween women nd men explined the results. Tretment with ERAs (vs plceo) did not influence 22 Originl Reserch

4 Tle 2 Chnge in 6MWD From Bseline to 12-wk Follow-up y Sex Model Women (n 5 894) Men (n 5 236) Difference-in-Difference (95% CI) P Vlue for Interction Bse model Tretment Plceo (tretment-plceo) ( ).04 Prtilly djusted model Tretment Plceo (tretment-plceo) ( ).03 See Tle 1 legend for expnsion of revition. Adjusted for study, height, nd seline wlk distnce. Adjusted for study, height, seline wlk distnce, ge, rce, nd dignosis ctegory; dditionl regression output provided in e-tle 9. the risk of clinicl events mong men fter djusting for study nd seline wlk distnce (OR ; 95% CI, ), ut significntly reduced the risk of clinicl events mong women (OR ; 95% CI, ) ( P vlue for interction 5.11). Tretment Response y Rce The plceo-djusted tretment response ws 41.5 m mong whites nd m mong lcks in the se model ( Tle 4 ), tretment response difference of 45.0 m (95% CI, m) (e-fig 2). Results were similr in the models djusting for dignosis ctegory, ge, nd sex. Further djustment for potentil confounding vriles did not chnge these results. Plceo-djusted solute wlk distnces t 12 weeks were 41.6 m for whites nd 11.1 m for lcks, difference of 30.5 m (95% CI, m) ( Tle 5 ). Similr results were found in prtilly djusted models including ge, sex, nd dignostic ctegory, ut n ttenution of effects ws oserved when including New York Hert Assocition clss in fully djusted models. Results were similr in sensitivity nlyses (e-tles 6, 7) nd in nlyses restricted to ptients with idiopthic PAH (e-tle 8). There were no clinicl events mong lcks in the plceo groups precluding clcultion of rce-y-tretment interction. Discussion This study suggests tht sex nd rce my influence the response to ERA tretment of PAH. Specificlly, we found tht women hd significntly greter responses in terms of chnge in 6MWD thn did men. The differences etween rces did not meet the criteri for significnce t the 0.05 level, lthough they hd lrge effect estimtes nd CIs tht just included the null vlue. These findings were consistent cross different prmeteriztions of 6MWD, nd were unlikely to e due to difference in illness severity ecuse of comprle seline hemodynmic nd lortory mesures. We lso found n indiction of greter reductions in clinicl events with ERAs mong women nd whites, ut these differentil effects were either not sttisticlly significnt or were unle to e quntified ecuse of the low numers of events. Tle 3 Asolute Distnce Wlked t 12-wk Follow-up y Sex Model Women (n 5 894) Men (n 5 236) Difference-in-Difference (95% CI) P Vlue for Interction Bse model Tretment Plceo (tretment-plceo) ( ).13 Prtilly djusted model Tretment Plceo (tretment-plceo) ( ).06 Fully djusted model c Tretment Plceo (tretment-plceo) ( ).01 Adjusted for study nd height. Adjusted for study, height, ge, rce, nd dignosis ctegory. c Adjusted for study, height, ge, rce, dignosis ctegory, crdic index, nd pulmonry cpillry wedge pressure; dditionl regression output provided in e-tle CHEST / 141 / 1 / JANUARY,

5 Tle 4 Chnge in 6MWD From Bseline to 12-wk Follow-up y Rce Model White (n 5 836) Blck (n 5 65) Difference-in-Difference (95% CI) P Vlue for Interction Bse model Tretment Plceo (tretment-plceo) ( ).06 Prtilly djusted model Tretment Plceo (tretment-plceo) ( ).07 See Tle 1 legend for expnsion of revitions. Adjusted for study, height, nd seline wlk distnce. Adjusted for study, height, seline wlk distnce, ge, sex, nd dignosis ctegory; dditionl regression output provided in e-tle 11. Interestingly, women nd whites experienced deteriortions in 6MWD when ssigned to plceo, wheres men nd lcks did not nd even showed some improvement on plceo. Women experienced greter enefits from ERAs compred with men, nd whites my hve enefitted more thn lcks. Bsed on these oservtions, future studies re needed to explore the mechnisms ccounting for why women nd whites my show greter response to ERA tretment. For exmple, such differences might e explined, in prt, y known differences in estrogen concentrtions or signling 21,22 or in right ventriculr (RV) contrctility 23 etween men nd women. Women with idiopthic PAH hve higher RV ejection frction t seline, independent of vriety of confounders, including pulmonry vsculr resistnce. 23 Indeed, studies hve shown improved survivl mong women with PAH in longterm treted cohorts. 24 It is possile tht RV dpttion could llow women to hve greter or more rpid response to PAH tretment, while hving more severe trjectory without trgeted therpy. Alterntively, off-trget (ie, mechnisticlly unpredicted) drug effects could ccount for some of the oserved vrition etween sexes. Finlly, it is possile tht these oserved differences re due to vritions in disese expression on 6MWD etween men nd women, nd whites nd lcks. Blcks hve incresed levels of circulting ET-1 11,25 nd greter increses in ET-1 in response to stress. 12 It is possile tht these higher ET-1 levels re not sufficiently inhiited y currently ville ERAs. A possily reduced tretment response in lcks is consistent with literture reporting higher mortlity mong lcks with idiopthic PAH, 26 nd with studies suggesting tht lcks with crdiovsculr nd pulmonry illnesses often hve worse outcomes thn do whites The identifiction of tretment-response heterogeneity cn improve helth cre. First, pinpointing ptient chrcteristics tht modify seline risks for dverse events nd/or fvorle therpeutic response cn inform individul tretment decisions. 2,31 Second, isolting sources of tretment-response heterogeneity cn enhnce knowledge of the iologic mechnisms of disese pthogenesis in PAH. Third, recognizing differences in supopultions with PAH could mximize the efficiency of future rndomized Tle 5 Asolute Distnce Wlked t 12-wk Follow-up y Rce Model White (n 5 836) Blck (n 5 65) Difference-in-Difference (95% CI) P Vlue for Interction Bse model Tretment Plceo (tretment-plceo) ( ).37 Prtilly djusted model Tretment Plceo (tretment-plceo) ( ).39 Fully djusted model c Tretment Plceo (tretment-plceo) ( ).66 Adjusted for study nd height. Adjusted for study, height, ge, sex, nd dignosis ctegory. c Adjusted for study, height, ge, sex, dignosis ctegory, nd New York Hert Assocition clss; dditionl regression output provided in e-tle Originl Reserch

6 controlled trils (RCTs) y providing metrics upon which to strtify ptients t enrollment. Therefore, extrpolting the summry result of n RCT to ll ptients my e inpproprite ecuse the risks of dverse events my exceed the proilities of clinicl enefits for certin ptients. 2,32,33 Quntifying tretment s risk-enefit rtio for n individul with given seline risk my promote sfer, more rtionl, nd cost-effective drug use. 34 Severl limittions of this nlysis were lso limittions of the trils in our study. These include the use of 6MWD s the primry end point, the inclusion of mostly women nd whites, nd the short exposure times to ctive drug nd plceo. Whether 6MWD should e viewed s n intermedite end point of clinicl import (s it is y the FDA) or s surrogte requires further reserch. 35 Acceptle type 1 error rtes for interction terms re controversil nd full picture of effect modifiction involves more thn just the interction P vlue. 36 Our nlyses showed lrge point estimtes of the interctions etween tretment ssignment nd oth sex nd rce; however, the results for rce were not sttisticlly significnt t the P,.05 level. The identifiction of white nd lck ws not uniform in the RCTs included in our study, nd such misclssifiction would tend to is results towrd the null. We were unle to control for site differences within ech study ecuse of the low numer of prticipnts t ech site. Finlly, lthough our study ws limited to the trils sumitted to the FDA for drug pprovl, these re the precise studies upon which ERA tretment recommendtions re mde y the FDA. Dr Plevsky: contriuted to dt nlysis, mnuscript preprtion, Dr Tichmn: contriuted to dt nlysis, mnuscript preprtion, Dr Kwut: contriuted to dt nlysis, mnuscript preprtion, Dr Hlpern: contriuted to dt nlysis, mnuscript preprtion, Finncil/nonfinncil disclosures: The uthors hve reported to CHEST the following conflicts of interest: Dr Kwut hs received consulting fees, dvisory ord fees, speking fees, unrestricted eductionl grnts, nd/or reserch funding from Pfizer, Actelion, Byer, Novrtis, Merck, Giled, United Therpeutics, nd Lung Rx. Dr Gler hs prticipted in reserch projects funded y Pfizer. Dr Strom hs served in oth reserch nd consultnt roles for Pfizer nd hs received gifts from Pfizer for his phrmcoepidemiology trining progrm. Dr Tichmn hs received reserch grnt support to the University of Pennsylvni from Actelion, Inc, for prticiption in the REVEAL Registry. Dr Plevsky hs served s speker nd/or consultnt to Actelion Phrmceuticls, Giled, nd Pfizer, the compnies with the rights to the three endothelin receptor ntgonists nlyzed in this study. These roles in no wy impcted on this nlysis of the results of previously pulished studies. Dr Hlpern hs received reserch grnts relted to this work from the Americn Thorcic Society, Pfizer, nd Actelion. Drs French nd Liu hve reported tht no potentil conflicts of interest exist with ny compnies/orgniztions whose products or services my e discussed in this rticle. Role of sponsors: Neither the FDA nor the funding source hd role in the design of this study nor in the decision to sumit it for puliction. The FDA did review the study prior to sumission s condition of the originl contrct, ut did not request ny chnges. Drs Normn Stockridge nd Slm Lemtouni of the FDA hve provided written permission for us to cknowledge them s we hve. Other contriutions: We re grteful to Mximilin Herlim for invlule help in prepring the dt for nlysis nd to Normn Stockridge, MD, PhD, nd Slm Lemtouni, MD, MPH, t the US FDA for providing us with the dt to conduct this study. Additionl informtion: The e-tles nd e-figures cn e found in the Online Supplement t org/content/141/1/20/suppl/dc1. Conclusions In conclusion, our results indicte tht women with PAH derive greter tretment responses to ERAs thn do men. Whites with PAH my lso hve etter responses thn do lcks. Further studies re needed to determine whether these differences re ttriutle to heterogeneous responses to ERAs specificlly or to more generlized differences in seline risks for clinicl deteriortion mong groups defined y rce nd sex. Acknowledgments Author contriutions: Dr Gler: contriuted to dt nlysis, mnuscript preprtion, Dr French: contriuted to dt nlysis, mnuscript preprtion, Dr Strom: contriuted to dt nlysis, mnuscript preprtion, Dr Liu: contriuted to dt nlysis, mnuscript preprtion, nd decision to sumit for puliction. References 1. Tichmn DB, Mndel J. Epidemiology of pulmonry rteril hypertension. Clin Chest Med ;28(1): Krvitz RL, Dun N, Brslow J. Evidence-sed medicine, heterogeneity of tretment effects, nd the troule with verges. Milnk Q ;82(4): Hrch S, Whitford H, McLen C. Filure of medicl therpy in pulmonry rteril hypertension. Is there n lterntive dignosis? Chest ;135(6): McLughlin VV, Archer SL, Bdesch DB, et l. 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