STARTS-2: long-term survival with oral sildenafil monotherapy in treatment-naive pediatric pulmonary arterial hypertension.

STARTS-2: Long-Term Survival With Oral Sildenafil Monotherapy in Treatment-Naïve Pediatric Pulmonary Arterial Hypertension Robyn J. Barst, Maurice Beghetti, Tomas Pulido, Gary Layton, Irina Konourina, Min Zhang and D. Dunbar Ivy on behalf of the STARTS-2 investigators Circulation. published online March 17, 2014; Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 2014 American Heart Association, Inc. All rights reserved. Print ISSN: 0009-7322. Online ISSN: 1524-4539

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DOI: 10.1161/CIRCULATIONAHA.113.005698

STARTS-2: Long-Term Survival With Oral Sildenafil Monotherapy in Treatment-Naïve Pediatric Pulmonary Arterial Hypertension

Running title: Barst et al.; STARTS-2 Long-Term Sildenafil in Pediatric PAH Robyn J. Barst, MD1; Maurice Beghetti, MD2; Tomas Pulido, MD3; Gary Layton, MSc4; Irina Konourina, MD4; Min Zhang, MSc5; D. Dunbar Ivy, MD6 on behalf of the STARTS-2 investigators 1

Columbia University, New York, NY; 2Dept of the Child and Adolescent, University of

Gene Ge Geneva, neeva v , Ge G Geneva, neeva v , Switzerland; 3National Heart Heaartt IInstitute, nstitute, Mexico C City, ity, it y Mexico; 4Pfizer Ltd, y, Sandwich, Sandwi S a wich ch, UK (during ch (du duri ring ngg study stu udyy conduct); con ondu duct ct); ); 5Pf Pfizer Pfiz izeer IInc, nc, La JJolla, o laa, CA ol C CA;; 6De Dept ooff Pe Pedi Pediatrics, diat atri rics cs,, Th Thee U University niversity off Colo C Colorado olora raado S School ch hoo o l of of M Medicine ediccin ne an and nd Ch Children's hil ildr drren''s Hospital Hosspita tall Colorado, Color Col lorado rado, Aurora, Aurora, CO Aur

Addr Ad dres dr esss for es for Correspondence: Corr Co rres rr espo es pond po nden nd ence en ce:: ce Address D unba un barr Iv Ivy y, M D D.. D Dunbar Ivy, MD Department of Pediatrics The University of Colorado School of Medicine and Children's Hospital Colorado 13123 East 16th Ave, B100 Aurora, CO 80045 Tel: 720-777-3367 Fax: 720-777-3367 E-mail: [email protected]

Journal Subject Codes: Treatment:[27] Other treatment, Cardiovascular (CV) surgery:[41] Pediatric and congenital heart disease, including cardiovascular surgery, Hypertension:[193] Clinical studies, Hypertension:[14] Other hypertension

1 Downloaded from http://circ.ahajournals.org/ at USC Norris Medical Library on April 1, 2014


Abstract

Background—The double-blind, placebo-controlled STARTS-1 study assessed sildenafil in pediatric patients with pulmonary arterial hypertension (PAH); improved hemodynamics and exercise capacity occurred in medium- and high-dose groups. STARTS-2 was the extension study. Methods and Results—In STARTS-1, 234 children 8 kg were randomly assigned to low-, medium-, or high-dose sildenafil or placebo orally thrice daily; within-group dose depended on weight. In STARTS-2, sildenafil-treated patients continued STARTS-1 dosing; placebo-treated patients were randomized to 1 of the 3 sildenafil dose groups. Patients requiring additional PAHspecific therapy discontinued study treatment; survival follow-up was attempted. As of August 2011, all children received 3 years of treatment (unless discontinued) from STARTS-1 STA ART RTSS-11 Sbaseline; 37 deaths were reported (26 on study treatment), 1 of which occurred w itthi hinn th thee first firs fi rstt within year of treatment. Most patients who died (28/37) had idiopathic/heritable PAH (76% vs 33% ov ver eral all) al l) and and baseline bassel eliine in functional class III/IV disease disea ease ea se (38% vs 15% % ov ooverall); erral all) l); patients who died had overall) w orrse rs baseli line ne hhemodynamics. em mod odyn ynnam amic iccs. K ap plaann Me Meie ierr es ie eestimated tiimateed 33-ye year ye arr ssurvival urrvi v va vall ffrom rom om m sstart tart ta rt ooff si sild lden ld enaf en afil af il worse baseline Kaplan-Meier 3-year sildenafil w ass 94%, 9 %, 93%, 94 93% 3%, and an 88% 888% for for patients pa ien pati nts t randomized ran ndomi mizedd to mi o llow-, ow--, ow -, m ediu um-, and an nd high-dose high hi gh h-d -dosee sildenafil, sild sild dennafiil, was medium-, esp spec ecti ec tive ti vely ve ly; 87 ly 7%, % 889% 9% aand n 880% nd 0% w eree kn er know ownn to bbee aalive ow live li ve aatt 3 ye year arss. ar s. H azar az a d ra ar rati tios ti os ffor orr m orta or tali ta lity li ty respectively; 87%, were known years. Hazard ratios mortality were 3.95 (95% (9 95% % CI, CI, 1.46–10.65) 1.4 .46– 6 10 10.6 .65) .6 5)) for forr high hig gh vs low low an andd 1. 11.92 92 ((95% 95% 95 % CI C 0.65 65–5 65 –55.6 . 5)) for for medium med e ium vs CI,, 0. 0.65–5.65) low dose; however, multiple analyses raised uncertainty about the survival/dose relationship. Conclusions—Though children randomized to higher compared with lower sildenafil doses had an unexplained increased mortality, all sildenafil dose groups displayed favorable survival for children with PAH. Clinical Trial Registration Information—http://clinicaltrials.gov. Identifier: NCT00159874 (extension study of NCT00149913).

Key words: pediatrics, pulmonary hypertension, clinical trial, sildenafil, survival



Introduction Pulmonary arterial hypertension (PAH) is a rare, progressive, and life-threatening disease. For many patients, steady deterioration ultimately culminates in reduced life expectancy.1 The phosphodiesterase type 5 inhibitor sildenafil is approved for the treatment of PAH in adults. Adult patients with PAH who received sildenafil monotherapy had significantly improved exercise capacity (measured by 6-minute walk distance [6MWD]) and hemodynamic parameters compared with placebo-treated patients in a randomized, double-blind clinical study (SUPER1).2 Sildenafil is approved in Europe for the treatment of PAH in children (20 kg, 10 mg three hree times daily [TID]; >20 kg, 20 mg TID). The 16-week, randomized, placebo placebo-controlled, bo o-c -con o tr trol olle ol led, le d, double-blind Sildenafil in Treatment-naive children, Aged 1–17 years, with pulmonaRy R ar arTerial Terial hypertenSion hype hy pert pe rteenS rt enSio ionn (S (STARTS-1) STA TART R S-1) study assessed the ef effects ffec fects of low, medi medium, d um di m, an and high doses of sildenafil ild den e afil in tr treatment-naïve rea eatm tmen tm ntt-na naaïve ïve pe pedi pediatric diaatr atric ric pa patients atien ntss wit with th PA PAH. AH.3 IImprovements mpro mpro oveme ment n s in nt n eexercise xerc xe rccis isee ccapacity apa paci city ity t (measured mea e su sure redd by ppeak eak ox oxygen xyg gen cconsumption o su on sump mpti mp tion on [[PVO PVO PV O2]) ]), ), Wo Worl World rldd H Health eal alth al th hO Organization rgan rg an nizzat atio ionn (W io (WHO (WHO) HO)) fu functional unc ncttio tional class, and hem em mod o yn ynam amic am iccs we were r oobserved b er bs erveed wi with th m edi d um u - an andd hi high gh-d gh -dos o e si os ssildenafil lden ld e af en afil ill ccompared ompa om p red with hemodynamics mediumhigh-dose placebo; sildenafil was well tolerated. Patients who completed STARTS-1 were eligible to enroll in the STARTS-2 extension study. For the results presented, all patients had the potential for 3 years of treatment with sildenafil.

Methods Study Design The design of the STARTS-1 study has been previously reported.3 Children (n=234) with PAH



weighing 8 kg were randomly assigned to low-, medium-, or high-dose sildenafil or placebo orally TID for 16 weeks. Actual TID doses within a group were dependent on weight (low: 10 mg; medium: 10, 20, or 40 mg; high: 20, 40, or 80 mg). In STARTS-2, patients who received sildenafil in STARTS-1 were maintained on their randomized sildenafil dose (low, medium, or high dose). Placebo-treated STARTS-1 patients were randomized (stratified by weight) to 1 of the 3 sildenafil dose groups at the beginning of STARTS-2. Patients in the >20–45 kg and >45 kg weight group strata were randomized in a 1:1:1 ratio; patients 8–20 kg were randomized to medium- or high-dose sildenafil in a 1:2 ratio. To prevent treatment unblinding in STARTS-1, the double-blind was maintained until the last was locked ast patient had completed STARTS-1 (June 2008) and the STARTS-1 databasee wa as lo lock cked ck ed (August August 2008); unless discontinued sooner, children therefore received 6 months to 5 years of double-blind do oub uble le-b le -bli bli lind nd treatment. treeat atm ment. STARTS-2 began in January Janu nuaary 2004. For this nu th his i interim int ntter erim i analysis, August 4, (see November safety 22011 011 was the ccutoff uttofff da ddate tee ffor or ssurvival or urviiva urvi vall ana aanalyses nalysses (se ee bbelow) ellow ow)) an andd No N ove vem mber 115, mbe 5, 22011 0111 fo forr sa afety fety t data. Alll on ongoing had 33 ye years data da ta.. Al ta A ngo goin ingg pati ppatients atien en nts ha ad th thee po ppotential ote teenttia iall to receive rec ecei eivve year arrs of of ssildenafil ilde il deenaafi fill tr ttreatment. e tm ea ment. en Throughout STARTS-2, upward disease progression Throug ugho ug h ut S ho TART TA RT TSS 2,, bboth otth up upwa ward wa rd ((for f r di fo dise s asse pr se prog ogre og ress re s io ionn or llack ackk of improvement) ac imp mpro r vement) ro and downward (for intolerability) dose titrations of sildenafil were permitted, per investigator judgment; titration was blinded until August 2008. A maximum of 2 uptitrations and 1 downtitration were allowed during the study. Doses received after dose titrations were equivalent to those in other dose groups (eg, a low-dose group patient who uptitrated once received a sildenafil dose equivalent to that of a medium-dose group patient in the same weight group). Dummy uptitrations were used (during the blinded portion of the study) for patients who were already receiving the highest dose within their weight group (ie, a high-dose group patient received only dummy uptitrations if the investigator wanted to increase the dose; medium-dose



group patients who uptitrated received 1 actual uptitration and, if further uptitration was required, 1 dummy uptitration). Analyses are presented by randomized sildenafil dose group, not by the dose resulting from up- or down-titration. Alterations in dosing were also made in accordance with changes in weight; however, dose changes in response to changed weight resulted in a patient receiving the relevant dose for that weight within the same dose group. Patients discontinued study treatment if additional PAH-specific therapy (ie, prostacyclin analogues, endothelin receptor antagonists) was deemed appropriate by the investigator. Information regarding therapy received following discontinuation (eg, no therapy, commercial sildenafil, others) was not specifically collected. (DMC) During mandated review of study data, the Data Monitoring Committee (D DMC MC)) recommended ecommended discontinuation of the 40 and 80 mg TID doses, as well as the 20 mg TID dose in children amended ch hilldr dren en 20 20 kg. kg.. The The study protocol was amende deed iin n August 20111 (the hee rreason eason for the cutoff date patients who were doses were Patients ffor or the th survival al aanalyses); naly yses) s);; pa s) pati tien ti ents tss w ho w eree rreceiving eceeiv vingg thes tthese hesse do dos sess we wer re ddowntitrated. ow wntit ntitra rate ra teed. d Pat atie at ient ns nt 8–20 TID, 8– –20 kg kg received rece re ceiived ce ived d a maximum maxim axim i um m dose dos osee of 10 10 mg TID; TID ID;; patients patiien pati nts >20–45 >20 20––45 20 –45 kg k received recei eivved d 10 10 oorr 220 0 mg gT ID investigator maximum mg TID. per investig gat ator or jjudgment; udgm ud gmen gm e t;; aand en n ppatients nd a ieent at n s >4 >455 kg rreceived ecei ec eive ei v d a ma ve maxi ximu xi m m do dose se ooff 20 m g TI T D. Adverse events (AEs) were recorded throughout STARTS-1 and -2, and are presented for the entire STARTS program. Survival status was recorded every 3 months. All patients enrolled in STARTS-1, regardless of whether they enrolled in STARTS-2 or discontinued from either STARTS-1 or -2, were followed for survival whenever possible (contactable and consented). STARTS-1 took place at 32 centers in 16 countries. Local institutional review boards approved the protocol; written informed consent was obtained from each child’s guardian; child assent was obtained when applicable.



Statistical Analysis Comparison of Treatment Groups Kaplan-Meier estimates of survival were assessed 1) from baseline of the STARTS-1 study and 2) from the start of sildenafil treatment, to account for the 16-week delay in receipt of sildenafil for patients randomized to placebo in STARTS-1. Thus, for the second analysis, survival was assessed from STARTS-2 baseline in placebo-treated STARTS-1 patients who were rerandomized to sildenafil treatment groups in STARTS-2; for all other patients, survival was assessed from STARTS-1 baseline. Analyses were conducted for patients overall, and because of differences in allocation ratios, by weight strata (20 vs >20 kg). Analyses of survival were by randomized andomized dose group; hence, upward and downward titrations were not taken into into o account acc ccou ount ou nt in in analyses. As noted, patients who discontinued the study were followed for survival whenever possible; po oss ssib ible ib le;; patients le pati pa tieents ti tss were were censored on the last datee they theey were known n to bee aalive. l ve. The number of li patients pati ien e ts known wn to to be alive aliive at at different diff di ffer ereent er ent times tiimess was was also also summarized, als summa umma mari rize zeed, and and iss the th he mo most st cconservative on nseerva rvativ a t ve estimate essti tima mate ma t of te of survival surv su rviiva ival al because bec ecau a se it au it assumes assu as sum su mes that mes that patients paati t en nts who whoo were werre lost lo ostt to to follow-up folllow llow w-u up had had died. diied d. weight Cox proportional prop pr opor op orti or tion ti on nal a hazard haz azar a d models, mode mo d ls ls,, stratified stra st rati ra tifi ti fied fi ed d by by baseline baase seli l ne w li e gh ei ghtt ((20 20 vs vs >20 >20 kg), kg) were usedd to make comparisons between treatment groups. Hazard ratios are presented with 95% confidence intervals. The p-value for the comparison of the treatment groups was calculated by using a stratified log-rank test. Alternative models were used to explore the influence of individual covariates on the treatment comparisons. Exploratory Analyses to Investigate the Relationship Between Baseline Parameters and Survival The association between baseline parameters and survival was investigated using Cox proportional hazard models. Parameters evaluated in univariate analyses included PAH etiology,



functional class, PVO2, ventilation to carbon dioxide output (VE/VCO2 ratio), hemodynamic parameters (mean pulmonary arterial pressure [mPAP], pulmonary vascular resistance [PVR], PVR index, systemic vascular resistance [SVR], SVR index, cardiac index, right atrial pressure [RAP], pulmonary capillary wedge pressure, mixed venous oxygen saturation [MVO2], heart rate, PVR/SVR, diastolic PAP, systolic PAP, systemic pulse pressure, mean arterial pressure [MAP], mPAP/MAP), and biomarkers (brain natriuretic peptide [BNP] and N-terminal [NT] proBNP). Because hazard ratios are scale dependent, the difference in baseline parameters that corresponded to a fixed hazard ratio of 0.9 was estimated. Cox proportional hazard models were also used to examine all 2- and 3-parameter combinations of factors (ignoring the treatment effect) to select the model(s) that att bbest et es predicted mortality (based on chi-square statistic). The influence of these variables on the reaatm tmeent ent co com mpar aris ar isoons was assessed by includin is ng th hem in the stra ati t fied ed d Cox Cox proportional hazard treatment comparisons including them stratified m oddels. de models.

Results Of the 234 patients who were randomized and treated in STARTS-1, 6 patients discontinued STARTS-1 and an additional 8 did not enter STARTS-2; of these 14, 5 patients receiving placebo in STARTS-1 did not enter STARTS-2 and therefore never received sildenafil treatment. Baseline characteristics of STARTS-1 patients have been previously reported.3 STARTS-1 patients were predominantly female (62%). PAH was idiopathic or heritable (IPAH/HPAH) in 33% and associated with congenital heart defect (PAH-CHD) in 67%; mean time from diagnosis was 1.7 (range, 0–12.4) years and 6.0 (range, 0–17) years, respectively. Disease was WHO functional class I or II in 83% of patients. Mean (± SD) PVRI was 15±10 and



20±15 Wood units·m2 for placebo-treated and sildenafil-treated patients, respectively. From STARTS-1 baseline, 206 (88%), 184 (79%), and 166 (71%) patients received therapy for >1, >2, and >3 years, respectively. Median treatment exposure across all patients was 4.1 years (range, 3 days to 7.4 years). Survival status at 3 years was known (ie, patients were ongoing or not lost to follow-up after discontinuation) for 39/42 (93%), 53/55 (96%), 68/77 (88%), and 55/60 (92%) of patients in sildenafil low-, medium-, and high-dose groups and the placebo group, respectively. Dose uptitrations, which resulted in doses received being equivalent to those in other dose groups (see Methods), occurred most frequently in the low-dose group (Table 1). Therapy eceived (if any) following discontinuation, including possible treatment with co omm mmerrci c al received commercial ildenafil, was not specifically collected. sildenafil, De Deat aths at hs Deaths T hir irrty-seven ppatients attie ient ntss we eree kknown nown no wnn tto o hav hhave ave ddied ieed be efo ore A ug gus ustt 4,, 22011 0111 (S 01 Suppl Sup ppleme lemeent ntar arry Ta Tabl be bl Thirty-seven were before August (Supplementary Table 1). ). O ne ddeath eaath ooccurred ccurre urredd within within with in the the first fir irst st year yea earr off study stu udyy treatment trreat reat atm ment (STARTS-1 ment (ST STAR A TS-1 AR S-1 ba base s liine se ne), ), 9 dduring urin ur in ng One baseline), he second year, yeaar, 9 during dur urin ingg the in the third thir th irdd year, ir yearr, and ye and 18 after afte terr th thee th thir irdd ye ir year a . Of th thes esee 377 ddeaths, es eath ea th hs, s 26 died the third year. these while on treatment and 11 died after withdrawal from treatment (defined as >7 days after last study dose; median [range], 287 [9–1202] days after last dose). Twenty-eight (76%) patients who died had IPAH/HPAH (n=19 female) versus 33% of patients overall; 5 (n=4 female) had surgically repaired and 4 (n=3 female) had non-repaired PAH-CHD. Baseline disease was functional class III/IV in 38% of the deaths (vs 15% overall). The majority of patients who died had worse-than-median STARTS-1 baseline hemodynamic values: 68%, 76%, 68%, and 73% for mPAP, PVRI, CI, and RAP, respectively (Table 2); 78% (25 of 32 patients with available baseline data) had NT-proBNP greater than the median value.



The percentage of deaths in the overall cohort was higher for the high-dose sildenafil group (22%) than for the medium- and low-dose groups (13.5% and 9%, respectively; Table 3). This imbalance in the number of deaths in the high-dose group was apparent in children in the middle-weight category (>20–45 kg), but not in children 8–20 or >45 kg. Posthoc analyses performed using different definitions of “actual” dose (ie, other than randomized dose) also showed a higher percentage of deaths in patients receiving high-dose sildenafil (Supplementary Table 2). Most deaths were assessed by the investigator as associated with disease progression. No deaths were considered by the investigator to be causally related to study treatment. Survival From STARTS-1 Baseline randomized Kaplan-Meier estimated 3-year survival from STARTS-1 baseline for patients ran an ndoomi mize zed ed to low-, ow-, medium-, and high-dose sildenafil and placebo in STARTS-1, as well as the most conservative co ons nser errvati vati tive v estimates ve esttim imat a es of 3-year survival (assuming (assum mingg that all patients patien en nts t lost los osst to to follow-up had died), are Tables Estimates were lowest ar re sshown hown in Ta Tabl bles bl es 4 aand nd 55.. Esti E stiimate ma es wer re low wesst in n tthe he hhigh-dose i h-dose ig s ggroup. ro oupp. Survival From Initiation Sildenafil Treatment Su Surv r iv rv ival al F rom ro m In Init itia ia ati tioon on off S ilde il den de nafi nafi fil Tr Tre eatm eatm tmeentt 3-year survival the Kaplan-Meier err eestimated stim st imat im ated ed 3-y -y yea e r su surv rv viv i al ffrom rom ro m th he st sstart a t of ssildenafil ar i de il dena nafi na f l tr ttreatment eatm ea tmen tm entt (i en (ie, e, bbaseline asel as e ine for patients who received placebo in STARTS-1 was the beginning of STARTS-2) for patients randomized to low-, medium-, and high-dose sildenafil in STARTS-2, as well as conservative estimates of 3-year survival, are shown in Table 4 and Figure 1A. Estimates were lowest in the high-dose group. Greater separation between doses was observed in patients weighing >20 kg, becoming evident after year 2 (Figures 1B and 1C). Children with PAH-CHD had better Kaplan-Meier estimated 3-year survival than children with IPAH/HPAH (Table 4). Cox Regression Analysis



The hazard ratios from the Cox regression analyses indicated a greater risk of death with higher compared with lower sildenafil doses or placebo (ie, a 16-week delay in sildenafil treatment; Table 6). Risk of Mortality Eleven baseline characteristics were significantly (P20 kg, and in patients with IPAH/HPAH. The differences observed between treatment groups were unexpected because in the double-blind portion of this study, medium and high sildenafil doses were associated with improved exercise capacity, functional class, and hemodynamic parameters, whereas low-dose sildenafil appeared to be ineffective.3 There were imbalances between treatment groups in baseline characteristics identified as predictive of mortality (Table 2). Adjustment for some of these factors influenced the hazard ratios comparing g ttreatment reeatme m nt ggroups r up ro (Table Table 6), but do not fully account for the increased mortality observed with high-dose sildenafil. ild den enaf afil af il. il This stu study tudy d was wass unique uni niqu quee for qu for being bein be in ng a large, laarg ge, ran randomized, andomi an m ze mi zed, d, dose-ranging dose-raanggin ng study study stu udy of a single sin ngl glee monotherapy Overall, was mo ono noth ther th erap apyy in ttreatment-naïve ap reeat atm ment ment n -naï aïve aï vee ppatients. atie at ien nts. nts. s O v ra ve ralll, l, ssurvival urvi v va vi vall in n aall lll ddose osee gro os ggroups roups oups w ass ffavorable avoora orable able compared with wit ithh other o he ot herr reports r po re p rt rtss in i children chi h ld dre r n using usiing PAH-specific us PAH AH-s -sspe peci cifi ci ficc drugs fi drug dr ugs that ug that were wer eree only only approved app ppro r ved for adult PAH.4-10 Indeed, an alternate hypothesis is that there was little survival benefit with higher doses of sildenafil and that lower doses displayed an unexplained improvement in survival. Few10 of the reported studies and registries included treatment-naïve patients. Some studies7, 11 and all registries did not assess monotherapy (therapies could be added and/or changed), whereas 71% of STARTS patients were alive and receiving monotherapy for >3 years. The observed survival in all dose groups was higher than 3-year survival rates for pediatric PAH patients before the availability of PAH-specific therapy12-15 and the median 10-month survival reported for the natural history of IPAH.16



This study is inconsistent with results obtained using sildenafil monotherapy in adults with PAH (SUPER-1 study and SUPER-2 extension). Not unexpectedly, adult patients who received placebo in the 12-week SUPER-12 study had poorer long-term survival than patients treated with sildenafil in SUPER-1.17 However, pediatric PAH patients who received placebo in the 16-week STARTS-1 study and subsequently received sildenafil had better long-term survival than children who began sildenafil in STARTS-1. In the current study, RAP, PVRI, and etiology were found to be the combination of baseline factors with the highest prognostic potential in multivariate analysis when assessing survival from the start of STARTS-1; when assessing survival from the start of sildenafil, this was also one of the best combinations of variables. Hemodynamic patients parameters predicted pediatric PAH mortality in previous studies, specifically RAP (in IPAH patien ents ts12,, 18an andd in children hildren with mixed PAH etiology, some of whom received epoprostenol19) and PVRI (in a large ge U US S re regi registry, gist gi stry st ry,9 in ry in UK children,11 and in univariate analysis off patients treated with bosentan7) but it is unclear whether these factors were we eree eexamined xami xa mine mi nedd iin ne n oother t er th er studies.10, 20 Hemodynamic parameters, param meter et rs, including RAP P andd PVR, PVR, VR similarly predict outcome 21, 22 22 in PAH. n adult ad du patients dult patient ntss with with P AH.21, AH

Regarding Rega ard rdin ng uni univariate ivariate tee ppredictors redi re d cttor orss ooff su survival, urvivaal,, si urv simi similar millar mi lar to o ou our ur sstudy, tudyy, WH WHO HO fu ffunctional ncttionnal class claass is pred pr edic ed icti ic tive ti ve ooff outcome outc ou tcom tc omee in ppediatric om edia ed iatr ia tric tr ic ppatients atie at ient ie ntss wi nt with th IIPAH, PAH PA H,11 iinn children H, chil ch ildr il dren dr en with wit ithh PAH PAH treated trea tr eate ea tedd with te with predictive 10, 20 bbosentan,7 and d iin pediatric di i patients i enrolled ll d iin PAH registries. i i 10 No other N h pediatric di i study d

examining predictors of mortality assessed an exercise capacity endpoint, likely because of difficulties with performing such studies in pediatric patients.23-25 Exercise capacity was prognostic in univariate analysis of STARTS-1/-2, despite being assessed in a limited subset of patients. Both functional class26 and exercise capacity27, 28 predict survival in adult patients with PAH, including those treated with sildenafil.17, 29 Importantly, all analyses for this study assessed randomized, not received, sildenafil dose and therefore are insensitive to imbalances between groups in dose alterations during the study (Table 1). Randomized doses are unbiased to confounding events that may occur during the



study (example: final dose would be influenced by disease progression if failing patients preferentially uptitrated). Assessment using differing definitions of dose received were not more enlightening; high-dose sildenafil was associated with an increased risk of mortality when final or modal (most frequent) dose was assessed (Supplementary Table 2). An explanation of the higher incidence of deaths observed after 2 years of STARTS-1/2 treatment in patients randomized to higher sildenafil doses remains elusive. Several observations suggest that other factors are influencing the survival comparisons. No deaths were considered by the investigator to be treatment related and the majority of the causes of death were known sequelae of PAH. Further, there was an inconsistency of the relationship between survival and exposure. Because sildenafil clearance was anticipated to increase with weight, ddosing osin os i g wa in wass doubled within each dose group for patients >45 vs 20–45 kg. However, pharmacokinetic modeling clearance mode mo deli de linng li ng uusing sing ssamples sin amples obtained in STARTS-11 iindicated am nddicated that clea e ranc ea ncce pl pplateaued ateaued at ~30 kg; therefore, >45 would higher-than-anticipated mediumherref e ore, patients patie ient nts >4 45 kg w ould ou ld aachieve ch hieeve hig gher-tthan-aantic nticip i at ip ated ed d eexposure xpoosure in m xp ed diu um- aand nd hhighnd ig ghdose Despite exposures, dose ggroups. r up ro ups. s. D esspiite tthese heese hhigher ighe ig herr ex he expo po osuure ress, 114% 4% of of ppatients attie ienntss >4 >45 kg aatt base bbaseline aseeli line n aare ne ree kknown nown nown w tto o versus patients imbalance evident across groups have died ve erssus u 221% 1% % ooff pa atiien e ts 220–45 0 45 0– 5 kkg; g; nno o im mba bala lanc ncee wa nc wass ev evid den entt ac acro ross ro s ddose ss osee gr os grou o ps for patients >45 kg (Table 3). Additionally, exposure-response analysis (data on file) showed that within the high-dose group, improved survival was associated with higher exposures. Patients randomized to placebo in STARTS-1 (who then received sildenafil in STARTS2) had better survival than patients receiving sildenafil throughout. As noted above, placebotreated patients in clinical studies of adults with PAH had poorer long-term survival than patients treated with sildenafil.17 There is no plausible explanation why a 16-week delay in the start of sildenafil treatment would confer a long-term survival advantage in pediatric patients, other than chance baseline imbalances between groups. Placebo-treated STARTS-1 patients had better



baseline clinical characteristics than patients randomized to sildenafil in STARTS-1 (mPAP, PVRI, CI; see Table 7 and Barst et al3); across dose groups, sildenafil-treated STARTS-1 patients were clinically comparable, as were sildenafil dose groups in STARTS-2 (ie, including the re-randomized placebo-treated STARTS-1 patients). Adjustment for etiology, PVRI, and RAP, parameters identified as being prognostic for mortality, reduced hazard ratios comparing high and medium doses with placebo. Taken together, these observations raise uncertainty concerning the strength of the relationship between sildenafil dose groups and survival. The dose recommendations of the STARTS DMC were consistent with approved EMA ), wh whic ch wa wass dosing for pediatric sildenafil (patients 20 kg, 10 mg TID; >20 kg, 20 mg TID) TID), which based on population pharmacokinetics of STARTS-1 patients and known adult data, as well as ef ffiica cacy cy ddata ataa from at om mS TARTS-1.3, 30 In this study, 55/55 /55 (9%), 7/60 (1 ((12%), 2% %), ) aand nd 25/114 (22%) efficacy STARTS-1. pati patients ien e ts died who whho were werre we re randomized ran ndo domi mize zeed to doses dosess of of sildenafil sild ldeenaafi afil il that that hat were weeree bbelow, ellow w, at, at, or or ab abo above ove th ove the he EM EMA dosing do dosi sing si ng iinstructions, nstr ns truc tr ucti tioonss, s, rrespectively. espe pect pe c iv velly. An add additional dddittio ona nall 5 de ddeaths aths at hs ((on on sstudy t dy ttreatment, tu reat re atme at m nt me n , n= nn=2; 2;; aafter fter ft er ddiscontinuation, isco is co ont ntin inua in uati ua tion ti o , n= on nn=3) 3) w were ere reported in STARTS-2 after August 2011. Of these 5 deaths, 3 occurred in patients randomized to the medium-dose group and 2 occurred in patients re-randomized to the high-dose group in STARTS-2 (after receiving placebo in STARTS-1). Four of the 5 patients downtitrated following DMC recommendations; deaths occurred in 2 patients on treatment (2 months and approximately 1 year after down-titration) and 2 patients off treatment (1 patient received downtitrated sildenafil for approximately 1 month and died approximately 2 months after discontinuing; 1 patient received downtitrated sildenafil for approximately 5 months and died 2 weeks after discontinuing). Notably, the 0, 3, and 2 new deaths reported (post-August 2011 interim cutoff



date) for patients randomized to low-, medium-, and high-dose sildenafil, respectively, shows that deaths in the low-dose group remain below the other dose groups despite the prevalence of dose uptitrations in the low-dose group. This study was limited by its essentially open-label nature after STARTS-1 was closed and unblinded. It is possible that uptitrations occurred after STARTS-1 data, which favored higher doses of sildenafil, were made public in 2009. Additionally, patients could have received commercial sildenafil and/or alternative PAH therapies after withdrawal; this information was not collected. Although no deaths were investigator-assessed as being related to sildenafil, such judgements are subjective; it is possible that sildenafil may cause harm in a way that is not easily failure, the physician apparent (for example, if sildenafil were to unexpectedly accelerate heart failure e, th he ph phys ysic ys icia ic iann is ia likely ikely to attribute death to underlying PAH). Additionally, it is unclear whether (or at which dose) combination therapy. do ose se)) sildenafil sild si lden ld enaf en a il might af might ig be effective as part of com mbi b nation therapy y. summary, In sum mmary, al aalthough th hou ough gh cchildren hild hi ldrren ld ren rrandomized andom omizeed tto om o th thee hig hhigh igh ssildenafil ilddena denafi f l do dose se ggroup roup ro up hhad a aan ad n unexplained mortality compared with the lower groups, multiple unex un e pl ex plai aine need increased incrreaase incr sedd mort m or al alit ityy co com mpar mpar ared ed w itth th he lo lowe werr sild we ssildenafil i den enaf affil ddose osee gr grou oups ou ps,, mu ps m lttiplle le raised uncertainty survival/dose analyses raise seed un unce cert ce rttain i ty y about abo b ut tthe he sur urvi ur viva vi val/ va l/do l/ d se rrelationship; do e ati el tion onsh on ship sh ip;; al ip aalll do dose se ggroups roup ro upps displayed d sp di spla l yed la favorable survival for children with PAH. STARTS-1 efficacy results3 and the long-term survival rates favor use of lower sildenafil doses. After reviewing STARTS-2 survival data, it was recommended to downtitrate all patients remaining in the study to lower sildenafil doses, which are those approved in the European Union.

Acknowledgments: It is with sadness that the authors inform the reader that Dr Barst has passed away. We grieve the loss of a clinician so dedicated to improving the understanding and management of pulmonary arterial hypertension. Her contributions on behalf of pediatric patients were essential for the STARTS studies, and represent only a small portion of her work on behalf



of all patients with PAH. The authors also would like to thank Helen Richardson, MSc, for her contributions to the STARTS studies and assistance in the preparation of this manuscript.

Funding Sources: This research was funded by Pfizer Inc. Editorial support was provided by Tiffany Brake, PhD, and Janet E. Matsuura, PhD, from Complete Healthcare Communications Inc. and was funded by Pfizer Inc.

Conflict of Interest Disclosures: Financial support and potential conflicts of interest: R.J.B. has served as a consultant and/or advisory board member to Actelion, Bayer, Lilly, GlaxoSmithKline, GE, Gilead, Ikaria, Merck, Novartis, Pfizer and Ventripoint; M.B. has served as consultant and/or advisory board member for Actelion, Bayer-Schering, Lilly, g GlaxoSmithKline,, Novartis,, and Pfizer and has received investigator-initiated research fundingg from Actelion and Bayer-Schering; the institution employing T.P. has received rresearch esea e rcch gr ea gran ants an ts grants from United Therapeutics, Actelion Pharmaceuticals, Pfizer, Gilead (formerly Myogen Ltd), and Ency ysive Pharmaceuticals; T.P. has received lecture fees from Pfizer, Actelion, and Lilly, and Encysive haas be been e a cconsultant on ult onsu ltan ant fo for Pf Pfizer er, Ac cteli l onn, Baye yerr-Sc Sccheriing ng,, Glax xoS o mi mith thK Kline, e aand n Lil nd lly ly; Th T has Pfizer, Actelion, Bayer-Schering, GlaxoSmithKline, Lilly; Thee Uniiversity iv of Co Colo oraado d rreceives eccei eive vess fe ve fee es ffor es or D.D D.II. to o bbee a cons cconsultant onssulta tannt for for Actelion, Actel elio ionn, io n, Gilead, Gil i ea ead, d, Pfizer, Pfi fize zeer,, University Colorado fees D.D.I. an nd Un U ited T h rapeut he peutiicss; D .D D.I .I. ha as re eceeiv iveed iinvestigator-initiated nveestig nv igaator ator-i -iiniitiat atted d resea earrch ea h ffunding u di un ding ng fr rom G ileead and United Therapeutics; D.D.I. has received research from Gilead Uniited Un ed Therapeutics; The hera r pe peut utiics; G.L. G.L L. and and I.K. are are former for o me merr Pfizer Pfi fize zerr employees empl em ployyee eess and an hold hold shares sha haress of of Pfizer Pfi fize zer andd United tock. stock.

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Table Summary Dose Changes Tabl blee 11.. Su Summ maryy of Dos se Ch Chan ange g s

Low (n=55) 0 28 (51) 20 (36) 8 (15) 19 (35)

Down titrations, n (%)* At least 1 uptitration, n (%) 1 uptitration 2 uptitrations Dose increases due to weight increases§

Sildenafil Si Sild lden enaf afil il Dose Dos osee Medium High (n=74) (n=100) 2† (3) 4 (4) 11 (15) 13 (13)‡ 8 (11) 8 (8)‡ 3 (4)‡ 5 (5)‡ 36 (49) 40 (40)

A maximum of 2 uptitrations and 1 downtitration were allowed during the study. Doses received after dose titrations were equivalent to those in other dose groups (see Methods). *An additional 2 downtitrations occurred in patients who were treated with placebo in STARTS-1 but not randomized in STARTS-2. † Includes 1 patient who downtitrated in STARTS-1. ‡ Dummy uptitrations were used for patients who were already receiving the highest dose within their weight group (see Methods). § A change in weight to a new weight category resulted in a patient receiving the dose for the new weight category within that treatment group and was not regarded as a titration.



Table 2. Distribution of STARTS-1 Baseline Characteristics Associated With Survival*

Patients, n (%) Weight 20 kg >20 kg Etiology IPAH/HPAH Repaired CHD Unrepaired CHD WHO functional class, n (%) I II III/IV Missing PVRI 20 kg ʊ‡ PAH-CHD ʊ‡ ʊ‡ d20 kg >20 kg ʊ‡

Randomized R andomized Group Grou Gr up Sildenafil Sil i de dena nafill na Sildenafil S Sild ild lden e af en afil il Low Dose Lo Do Medium Me edium D Dose osee os

Sild Si Sildenafil ld den enaf afil af il Hig H High igh Dose Dosse

93% 9 % 93 N A A* NA* 93% 93% 86% 86 %

91% 91% 993% 3% 90% 90% 87% 87 %

87% 87% 91% 1% 84% 77% 77 %

94% NA* 94% 87% 94% (n=18) NA* 94% 94% (n=37) NA* 94%

93% 94% 93% 89% 78% (n=24) 86% 75% 100% (n=50) 100% 100%

88% 93% 84% 80% 82% (n=35) 87% 79% 92% (n=65) 96% 88%

*Patients d20 kg at baseline were randomized to placebo and sildenafil medium- and high-dose groups (ie, there was no low-dose sildenafil group). † Patients known to be alive at 3 years (vs known to be dead or lost to follow-up); the most conservative estimate of survival. ‡ Placebo-treated STARTS-1 patients were randomized to low (n=13), medium (n=19), and high (n=23) doses of sildenafil in STARTS-2; 5 placebo-treated STARTS-1 patients were not randomized.



Table 5. Survival Disposition Over Time (From Start of STARTS-1).

Group, n (%) Sildenafil low dose (n=42) Ongoing Died on treatment* Discontinued Alive Died posttreatment Lost to follow-up Sildenafil medium dose (n=55) Ongoing Died on treatment* Discontinued Alive Died posttreatment Lost to follow-up Sildenafil high dose (n=77) Ongoing Onggoing Die iedd on ttreatment* reaatme re mennt* me nt Died Discontin is i ueed Discontinued A ive Al Alive Died pos stt ttreaatm mennt Died posttreatment Lost to to follow-up foll fo llow ow-u ow -upp -u Lost † Plac Pl aceb ac eboo (n=60) eb (n= n 60 60)) Placebo Ongoing Onggoing g Died on treatment* Discontinued Alive Died posttreatment Lost to follow-up

1

Year 2

3

37 (88) 0 5 (12) 4 (10) 0 1 (2)

32 (76) 1 (2) 9 (21) 7 (17) 1 (2) 1 (2)

30 (71) 2 (5) 10 (24) 6 (14) 1 (2) 3 (7)

52 (95) 0 3 (6) ( ) 2 (4) 0 1 (2)

46 (84) 1 (2) 8 (15) ( ) 4 (7) 2 (4)) 2 (4))

41 (75) 2 (4) 12 (22) ( ) 7 (13) (6) 3 (6) (4) 2 (4)

68 (88) 1 (1 1) (1) (10) 8 (10) (7)) 5 (7) 0 (4 4) 3 (4)

59 (77) 5 (7) (17) 7) 133 (1 (8) 6 (8) 0 (9) 7 (9)

54 (70) 7 (9) 116 6 (21) (21) (77) 5 (7) (3) 3) 2 (3) (12) 9 (12)

49 (82) (822) 0 11 (18) 7 (12) 0 4 (7)

47 47 ((78) 78)) 78 0 13 (22) 8 (13) 0 5 (8)

41 (68) (68)) 1 (2) 18 (30) 12 (20) 1 (2) 5 (8)

*Death within 7 days of last study dose. Includes STARTS-1 patients who never entered STARTS-2.

†



Table 6. Stratified Hazard Ratios (95% CI) for Mortality.

Mortality From start of STARTS-1 vs placebo vs low dose vs medium dose From start of sildenafil treatment vs low ow dose vs medium dose From start of STARTS-1 Base-stratified e-stratified model (no covariates)† vss placebo pla lace cebo bo vss low low ddose ose os vss medium mediu ed di m dosee With covariates added model th cova ov riates add ed d tto o mo m dell† de placebo a vss placebo low ddose oe os vss low vss medium med ediu ium iu m dose dose From start r off sild sildenafil den e afill treatment treattme ment nt Base-stratified e-stratified mod model odel el ((no n ccovariates) no ovar ov aria ar iaate t s))† vss low low ddose osee os vs medium dose With covariates added to model† vs low dose vs medium dose

Sildenafil Dose Medium

Low

High

1.40 (0.37, 5.23) NA NA

2.44 (0.75, 7.92) 1.74 (0.58, 5.23) NA

4.73 (1.60, 13.97) 3.38 (1.23, 9.27) 1.94 (0.87, 4.33)

NA NA

1.92 (0.65, 5.65) NA

(1.46, 3.95 (1.4 .46, 6 110.65) 0 65 0. 65)) (0.97, 4.38) 2.06 (0. 0.97 97, 7, 4. .38 3 )

1.44 (0.39, 5.39) 5.39 5. 399) NA NA

2.57 (0.79, 8.34) 1.78 (0.59, 55.35) .3 35) NA A

4.69 (1.59, 13.86) 3.26 (1.19, 8.93) 1.83 1. .83 ((0.82, 0.82 82,, 4. 44.08) 08)) 08

1.3 .36 (0.36, 0 6 5.14) 5.114)) 1.36 NA NA

2.0 .011 (0 (0.6 . 0, 66.75) .75) 7 2.01 (0.60, 11.49 .499 (0 .4 (0.4 . 8, 44.57) .57) 5 ) (0.48, NA

33.05 .05 05 (0 ((0.98, .98, 8 99.53) .53) 3 22.25 .255 (0 .2 (0.8 . 0, 0 66.34) .34) 4 (0.80, 1.52 1. 52 ((0.66, 0.66 0.66 66, 3. 33.49) 49)) 49

NA NA

11.95 95 (0 (0.66, 66 55.74) 74) NA

33.84 84 (1 (1.42, 42 110.35) 0 35 35)) 1.97 (0.92, 4.19)

NA NA

2.11 (0.71, 6.25) NA

3.35 (1.23, 9.11) 1.59 (0.73, 3.45)

P Value* 0.0047

0.0078 00. 00

NA=not applicable. *Stratified log rank test for difference between treatment groups. † Analysis of patients for whom baseline data for covariates was available.



Table 7. Differences in Significant Baseline Characteristics Associated With 10% Reduction in Mortality in Univariate Analysis

Mean RAP, mmHg Etiology Mean PAP, mmHg Systolic PAP, mmHg Pro-BNP, BNP, pg/mL PVR, Wood units Diastolic olic PAP, mmHg PVR index, Wood units·m2 BNP, pg/mL WHO class O functional fu unc ncti tion on nal a cla ass mPAP/MAP P/MAP /M MAP Peak VO VO2, mL/kg mL/kg/min* /min mi * Systemic micc ppulse ulse pressure, pressurre, mmHg mmH m g 2 i dex, in ex Wood units·m unnits·m m SVR index, – –1 – Cardiac ac inde index, nd x, L·m L·min min n ·m m–2 SVR, W Wood ood oo od un uunits itss it

N 174 174 174 174 139 167 174 167 121 174 174 85 174 1774 169 1699 1169 6 69 169 69

Sildenafil Difference –1.1 0.1 –3.2 –4.1 –1068.0 –3.4 –2.7 –3.1 –36.0 –0.1 0 00.5 .5 1.8 1.8 –2.8 –2. 28 00.2 .2 –4.5 –4 .5 5

Wald P value

Sildenafil improves renal function in patients with pulmonary arterial hypertension.

Pediatric pulmonary arterial hypertension.

Efficacy of sildenafil in HIV-related pulmonary arterial hypertension.

Oral Tadalafil in Children with Pulmonary Arterial Hypertension.

Lower Doses of Bosentan in Combination With Sildenafil Might be Beneficial in Pulmonary Arterial Hypertension.

Comparison of preventive effect of sildenafil and therapeutic effect of sildenafil treatment in rats with monocrotaline-induced pulmonary arterial hypertension.

Preventive effect of sildenafil on right ventricular function in rats with monocrotaline-induced pulmonary arterial hypertension.

Survival with sildenafil and inhaled iloprost in a cohort with pulmonary hypertension: an observational study.

Sildenafil for the Treatment of Pulmonary Arterial Hypertension in Infants with Bronchopulmonary Dysplasia.

Safety and tolerability considerations in the use of sildenafil for children with pulmonary arterial hypertension.

Sildenafil dosed concomitantly with bosentan for adult pulmonary arterial hypertension in a randomized controlled trial.

A new START for Sildenafil in pediatric pulmonary hypertension: reframing the dose-survival relationship in the STARTS-2 trial.

Efficacy and safety of oral sildenafil in children with Down syndrome and pulmonary hypertension.

Sildenafil in heart transplant candidates with pulmonary hypertension.

Conversion from sildenafil to tadalafil: results from the sildenafil to tadalafil in pulmonary arterial hypertension (SITAR) study.

Treatment of pulmonary arterial hypertension using extemporaneous formulation of sildenafil in Mexican children.

The limits of oral therapy in pulmonary arterial hypertension management.

Reversal of right-ventricular dysfunction in pulmonary arterial hypertension following sildenafil therapy.

Sildenafil versus nitric oxide for acute vasodilator testing in pulmonary arterial hypertension.

Efficacy and safety of sildenafil treatment in pulmonary arterial hypertension: a systematic review.

Sildenafil add-on therapy in paediatric pulmonary arterial hypertension, experiences of a national referral centre.

Sildenafil for pulmonary hypertension complicating bronchopulmonary dysplasia.

Sildenafil in heart failure with reactive pulmonary hypertension (Sildenafil HF) clinical trial (rationale and design).

Effect of preoperative oral sildenafil on severe pulmonary artery hypertension in patients undergoing mitral valve replacement.