Congenital Heart Disease. STARTS-2 Long-Term Survival With Oral Sildenafil Monotherapy in Treatment-Naive Pediatric Pulmonary Arterial Hypertension

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1 Congenital Heart Disease STARTS-2 Long-Term Survival With Oral Sildenafil Monotherapy in Treatment-Naive Pediatric Pulmonary Arterial Hypertension Robyn J. Barst, MD ; Maurice Beghetti, MD; Tomas Pulido, MD; Gary Layton, MSc; Irina Konourina, MD; Min Zhang, MSc; D. Dunbar Ivy, MD; on behalf of the STARTS-2 Investigators Background The double-blind, placebo-controlled Sildenafil in Treatment-Naive Children, Aged 1 to 17 Years, With Pulmonary Arterial Hypertension (STARTS-1) study assessed sildenafil in pediatric patients with pulmonary arterial hypertension; 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 pulmonary arterial hypertension specific 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 baseline; 37 deaths were reported (26 on study treatment), 1 of which occurred within the first year of treatment. Most patients who died (28/37) had idiopathic/heritable pulmonary arterial hypertension (76% versus 33% overall) and baseline functional class III/IV disease (38% versus 15% overall); patients who died had worse baseline hemodynamics. Kaplan- Meier estimated 3-year survival rates from start of sildenafil were 94%, 93%, and 88% for patients randomized to low-, medium-, and high-dose sildenafil, respectively; 87%, 89%, and 80% were known to be alive at 3 years. Hazard ratios for mortality were 3.95 (95% confidence interval, ) for high versus low and 1.92 (95% confidence interval, ) for medium versus low dose; however, multiple analyses raised uncertainty about the survival/dose relationship. Conclusions Although children randomized to higher compared with lower sildenafil doses had an unexplained increased mortality, all sildenafil dose groups displayed favorable survival for children with pulmonary arterial hypertension. Clinical Trial Registration URL: (extension study of NCT ). Unique identifier: NCT (Circulation. 2014;129: ) Key Words: clinical trial pediatrics pulmonary hypertension sildenafil survival 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) and hemodynamic parameters compared with placebo-treated patients in a randomized, double-blind clinical study (Sildenafil Use in Pulmonary Arterial Hypertension [SUPER-1]). 2 Editorial see p 1905 Clinical Perspective on p 1923 Sildenafil is approved in Europe for the treatment of PAH in children ( 20 kg, 10 mg 3 times a day; >20 kg, 20 mg 3 times a day). The 16-week, randomized, placebo-controlled, doubleblind Sildenafil in Treatment-Naive Children, Aged 1 to 17 Years, With Pulmonary Arterial Hypertension (STARTS-1) study assessed the effects of low, medium, and high doses of sildenafil in treatment-naive pediatric patients with PAH. 3 Improvements in exercise capacity (measured by peak oxygen consumption), World Health Organization functional class, and hemodynamics were observed with medium- and high-dose sildenafil compared with placebo; sildenafil was well tolerated. Patients who completed STARTS-1 were eligible to enroll in the STARTS-2 extension study. For the results presented, Continuing medical education (CME) credit is available for this article. Go to to take the quiz. Received October 12, 2012; accepted February 18, From Columbia University, New York, NY (R.J.B.); Department of the Child and Adolescent, University of Geneva, Geneva, Switzerland (M.B.); National Heart Institute, Mexico City, Mexico (T.P.); Pfizer Ltd, Sandwich, UK (during study conduct) (G.L., I.K.); Pfizer Inc, La Jolla, CA (M.Z.); and Department of Pediatrics, University of Colorado School of Medicine and Children s Hospital Colorado, Aurora (D.D.I.). Deceased. The online-only Data Supplement is available with this article at /-/DC1. Correspondence to D. Dunbar Ivy, MD, E 16th Ave, B100, Aurora, CO dunbar.ivy@childrenscolorado.org 2014 American Heart Association, Inc. Circulation is available at DOI: /CIRCULATIONAHA

2 Barst et al STARTS-2 Long-Term Sildenafil in Pediatric PAH 1915 all patients had the potential for 3 years of treatment with sildenafil. Methods Study Design The design of the STARTS-1 study has been reported previously. 3 Children (n=234) with PAH weighing 8 kg were randomly assigned to low-, medium-, or high-dose sildenafil or placebo orally 3 times a day for 16 weeks. Actual 3-times-a-day 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 to 45 kg and >45 kg weight group strata were randomized in a 1:1:1 ratio; patients 8 to 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 patient had completed STARTS-1 (June 2008) and the STARTS-1 database was locked (August 2008); unless discontinued sooner, children therefore received 6 months to 5 years of double-blind treatment. STARTS-2 began in January For this interim analysis, August 4, 2011, was the cutoff date for survival analyses (see below), and November 15, 2011, was the cutoff date for safety data. All ongoing patients had the potential to receive 3 years of sildenafil treatment. Throughout STARTS-2, both upward (for disease progression or lack of improvement) and downward (for intolerability) dose titrations of sildenafil were permitted, per investigator judgment; titration was blinded until August 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 and not by the dose resulting from uptitration or downtitration. 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 PAHspecific therapy (ie, prostacyclin analogues, endothelin receptor antagonists) was deemed appropriate by the investigator. Information regarding therapy received after discontinuation (eg, no therapy, commercial sildenafil, others) was not specifically collected. During mandated review of study data, the Data Monitoring Committee recommended discontinuation of the 40- and 80-mg 3-times-a-day doses, as well as the 20-mg 3-times-a-day dose in children 20 kg. The study protocol was amended in August 2011 (the reason for the cutoff date for the survival analyses); patients who were receiving these doses were downtitrated. Patients 8 to 20 kg received a maximum dose of 10 mg 3 times a day; patients >20 to 45 kg received 10 or 20 mg 3 times a day, per investigator judgment; and patients >45 kg received a maximum dose of 20 mg 3 times a day. 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 versus >20 kg). Analyses of survival were by randomized dose group; hence, upward and downward titrations were not taken into account in analyses. As noted, patients who discontinued the study were followed for survival whenever possible; patients were censored on the last date they were known to be alive. The number of patients known to be alive at different times was also summarized and is the most conservative estimate of survival because it assumes that patients who were lost to follow-up had died. Cox proportional hazards models, stratified by baseline weight ( 20 versus >20 kg), were used to make comparisons between treatment groups. Hazard ratios are presented with 95% confidence intervals. The P value for comparison of the treatment groups was calculated with the use of 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 with Cox proportional hazards models. Parameters evaluated in univariate analyses included PAH etiology, functional class, peak oxygen consumption, ventilation to carbon dioxide output, hemodynamic parameters (mean pulmonary arterial pressure, pulmonary vascular resistance [PVR], PVR index, systemic vascular resistance, systemic vascular resistance index, cardiac index, right atrial pressure [RAP], pulmonary capillary wedge pressure, mixed venous oxygen saturation, heart rate, PVR/systemic vascular resistance, diastolic pulmonary arterial pressure, systolic pulmonary arterial pressure, systemic pulse pressure, mean arterial pressure, mean pulmonary arterial pressure/mean arterial pressure), and biomarkers (brain natriuretic peptide and N-terminal pro brain natriuretic peptide). 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 hazards models were also used to examine all 2- and 3-parameter combinations of factors (ignoring the treatment effect) to select the model(s) that best predicted mortality (based on χ 2 statistic). The influence of these variables on the treatment comparisons was assessed by including them in the stratified Cox proportional hazards 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 reported previously. 3 STARTS-1 patients were predominantly female (62%). PAH was idiopathic (IPAH) or heritable (HPAH) in 33% and associated with congenital heart defect in 67%; mean time from diagnosis was 1.7 (range, ) years and 6.0 (range, 0 17) years, respectively. Disease was World Health Organization functional class I or II in 83% of patients. Mean (±SD) PVR index was 15±10 and 20±15 Wood units m 2 for placebo-treated and sildenafil-treated patients, respectively.

3 1916 Circulation May 13, 2014 From STARTS-1 baseline, 206 (88%), 184 (79%), and 166 patients (71%) 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 of 42 (93%), 53 of 55 (96%), 68 of 77 (88%), and 55 of 60 patients (92%) 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). Information on therapy received (if any) after discontinuation, including possible treatment with commercial sildenafil, was not specifically collected. Deaths Thirty-seven patients were known to have died before August 4, 2011 (Table I in the online-only Data Supplement). One death occurred within the first year of study treatment (STARTS-1 baseline), 9 during the second year, 9 during the third year, and 18 after the third year. Of these 37 deaths, 26 died 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 patients (76%) 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 unrepaired PAH associated with congenital heart defect. Baseline disease was functional class III/IV in 38% of the deaths (versus 15% overall). The majority of patients who died had worse than median STARTS-1 baseline hemodynamic values: 68%, 76%, 68%, and 73% for mean pulmonary arterial pressure, PVR index, cardiac index, and RAP, respectively (Table 2); 78% (25 of 32 patients with available baseline data) had N-terminal pro brain natriuretic peptide greater than the median value. Table 1. Summary of Dose Changes Sildenafil Dose Low (n=55) Medium (n=74) High (n=100) Downtitrations, n (%)* 0 2 (3) 4 (4) At least 1 uptitration, n (%) 28 (51) 11 (15) 13 (13) 1 uptitration 20 (36) 8 (11) 8 (8) 2 uptitrations 8 (15) 3 (4) 5 (5) Dose increases attributable to weight increases 19 (35) 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 Sildenafil in Treatment-Naive Children, Aged 1 to 17 Years, With Pulmonary Arterial Hypertension (STARTS-1) but not randomized in STARTS-2. 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. Includes 1 patient who was downtitrated in STARTS-1. Dummy uptitrations were used for patients who were already receiving the highest dose within their weight group (see Methods). Table 2. Distribution of STARTS-1 Baseline Characteristics Associated With Survival* Patients, n (%) Placebo (n=60) Low (n=42) Sildenafil Dose Medium (n=55) High (n=77) Weight, kg (30) 0 15 (27) 35 (46) >20 42 (70) 42 (100) 40 (73) 42 (55) Etiology IPAH/HPAH 21 (35) 12 (29) 19 (35) 26 (34) Repaired CHD 16 (27) 14 (33) 16 (29) 25 (33) Unrepaired CHD 23 (38) 16 (38) 20 (36) 26 (34) WHO functional class, n (%) I 25 (42) 9 (21) 20 (36) 21 (27) II 29 (48) 23 (55) 25 (45) 43 (56) III/IV 6 (10) 9 (21) 9 (16) 12 (16) Missing 0 1 (2) 1 (2) 1 (1) PVR index, Wood units m 2 < (58) 14 (33) 26 (47) 36 (47) (37) 26 (62) 26 (47) 37 (48) Missing 3 (5) 2 (5) 3 (5) 4 (5) Mean±SD 14.6± ± ± ±16.1 mpap, mm Hg < (58) 18 (43) 25 (45) 35 (45) (40) 24 (57) 30 (55) 40 (52) Missing 1 (2) (3) Mean±SD 58.9± ± ± ±23.7 RAP, mm Hg < (43) 17 (41) 23 (42) 27 (35) (55) 25 (60) 32 (58) 48 (62) Missing 1 (2) (3) Mean±SD 8.0± ± ± ±4.8 Cardiac index, L min 1 m 2 < (37) 21 (50) 33 (60) 39 (51) (62) 20 (48) 19 (35) 35 (45) Missing 1 (2) 1 (2) 3 (5) 3 (4) Mean±SD 3.9± ± ± ±1.6 NT pro-bnp, pg/ml < (40) 18 (43) 24 (44) 28 (36) (40) 14 (33) 21 (38) 34 (44) Missing 12 (20) 10 (24) 10 (18) 15 (20) Mean±SD 878± ± ± ±4934 CHD indicates congenital heart defect; HPAH, heritable pulmonary arterial hypertension; IPAH, idiopathic pulmonary arterial hypertension; mpap, mean pulmonary artery pressure; NT pro-bnp, N-terminal pro brain natriuretic peptide; PVR, pulmonary vascular resistance; RAP, right atrial pressure; STARTS-1, Sildenafil in Treatment-Naive Children, Aged 1 to 17 Years, With Pulmonary Arterial Hypertension; and WHO, World Health Organization. *Better survival was associated with weight 20 kg; CHD etiology; lower functional class, PVR index, mpap, RAP, and NT pro-bnp; and higher cardiac index. Median value. NT pro-bnp information was available for only a subset of patients (n=30/35 patients who died and 157/199 who were alive at last follow-up).

4 Barst et al STARTS-2 Long-Term Sildenafil in Pediatric PAH 1917 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 to 20 or >45 kg. Post hoc analyses performed with the use of different definitions of actual dose (ie, other than randomized dose) also showed a higher percentage of deaths in patients receiving high-dose sildenafil (Table II in the online-only Data Supplement). 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 Kaplan-Meier estimated 3-year survival from STARTS-1 baseline for patients randomized to low-, medium-, and high-dose sildenafil and placebo in STARTS-1, as well as the most conservative estimates of 3-year survival (assuming that all patients lost to follow-up had died), are shown in Tables 4 and 5. Estimates were lowest in the high-dose group. Survival From Initiation of Sildenafil Treatment Kaplan-Meier estimated 3-year survival from the start of sildenafil treatment (ie, baseline 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 the Figure (A). Estimates were lowest in the high-dose group. Greater separation between doses was observed in patients weighing >20 kg, becoming evident after year 2 (Figure [B and C]). Table 3. Deaths by Sildenafil Dose Group, Weight,* and Etiology Group Sildenafil Dose Low Medium High Total Overall 5/55 (9) 10/74 (14) 22/100 (22) 37/229 (16) Weight, kg* 8 to 20 NA 1/20 (5) 5/44 (11) 6/64 (9) > /40 (8) 7/40 (18) 15/41 (37) 25/121(21) >45 2/15 (13) 2/14 (14) 2/15 (13) 6/44 (14) Etiology IPAH/HPAH 3/18 (17) 9/24 (38) 16/35 (46) 28/77 (36) PAH-CHD 2/37 (5) 1/50 (2) 6/65 (9) 9/152 (6) Unrepaired 0/21 (0) 0/29 (0) 4/34 (12) 4/84 (5) Repaired 2/16 (13) 1/21 (5) 2/31 (6) 5/68 (7) Values are No. dead/no. total (%). CHD indicates congenital heart defect; HPAH, heritable pulmonary arterial hypertension; IPAH, idiopathic pulmonary arterial hypertension; NA, not applicable; and PAH, pulmonary arterial hypertension. *At the start of sildenafil treatment (Sildenafil in Treatment-Naive Children, Aged 1 to 17 Years, With Pulmonary Arterial Hypertension [STARTS-1] baseline for patients randomized to sildenafil treatment in STARTS-1; week 16 for patients randomized to placebo in STARTS-1). Of 234 patients randomized and treated in STARTS-1, 5 patients randomized to placebo did not enter STARTS-2 and hence did not receive sildenafil. Table 4. Kaplan-Meier 3-Year Survival Estimates Placebo Sildenafil Low Dose Randomized Group Sildenafil Medium Dose Sildenafil High Dose From start of STARTS-1 Overall kg 100 NA >20 kg Known alive* From start of sildenafil Overall kg NA >20 kg Known alive* IPAH/HPAH 94 (n=18) 78 (n=24) 82 (n=35) 20 kg NA >20 kg PAH-CHD 94 (n=37) 100 (n=50) 92 (n=65) 20 kg NA >20 kg Values are percentages. CHD indicates congenital heart defect; HPAH, heritable pulmonary arterial hypertension; IPAH, idiopathic pulmonary arterial hypertension; NA, not applicable; PAH, pulmonary arterial hypertension; and STARTS-1, Sildenafil in Treatment-Naive Children, Aged 1 to 17 Years, With Pulmonary Arterial Hypertension. *Patients known to be alive at 3 years (vs known to be dead or lost to follow-up); the most conservative estimate of survival. Patients 20 kg at baseline were randomized to placebo and sildenafil medium- and high-dose groups (ie, there was no low-dose sildenafil group). 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 placebotreated STARTS-1 patients were not randomized. Children with PAH associated with congenital heart defect 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 (P<0.05) associated with mortality in univariate analyses. For individual variables, the difference in patients baseline values associated with a 10% reduction in mortality was derived (ie, for each difference value given, divergence in patients baseline values by that amount confers [or is associated with] a 10% lower risk of death; Table 7). The combination of variables with the highest predictive ability included etiology, PVR index, and RAP when assessed from STARTS-1 baseline. This set of variables was also one of the best combinations when survival was assessed from the start of sildenafil, although several different sets of variables (including different 3-variable combinations

5 1918 Circulation May 13, 2014 Figure. Kaplan-Meier estimated survival from start of sildenafil treatment in Sildenafil in Treatment-Naive Children, Aged 1 to 17 Years, With Pulmonary Arterial Hypertension (STARTS-1) and STARTS-2 overall (A) and in patients weighing 20 kg (B) or >20 kg (C). Patients were censored at the last date they were known to be alive; if a patient received a transplant, he or she was censored the day before transplant (however, if the transplanted patient later died, the death was counted as an event). Patients at risk are those who are ongoing in the study or known to be alive at the specified time (ie, not dead, not lost to follow-up, or not in study long enough to reach time point). of etiology, PVR, RAP, World Health Organization functional class, systolic pulmonary arterial pressure, diastolic pulmonary arterial pressure, and systemic pulse pressure) performed similarly. To assess the influence of baseline variables on the treatment comparisons, the impact of different combinations on the hazard ratios was investigated (see below). Additional Analyses of Deaths Additional analyses were undertaken to attempt to understand the higher incidence of deaths observed in the high-dose sildenafil group versus low- and medium-dose groups. Primary analyses were performed by randomized (not received) sildenafil dose. Using randomized doses is less prone to bias but is insensitive to imbalances between groups in dose alterations during the study; additionally, no information was collected on PAH-specific therapy received (if any) after patients discontinued the study. Examination of patterns of titration revealed that the majority of uptitrations occurred in patients randomized to low-dose sildenafil (51% versus 15% and 13% in medium- and high-dose groups, respectively; Table 1). Imbalances were observed between treatment groups in baseline variables identified as prognostic of survival (Table 2). Adjustment for some 3-variable combinations identified as being prognostic reduced hazard ratios (covariates of etiology, baseline RAP, and baseline PVR index) for mortality for high- and medium-dose sildenafil versus placebo and high versus lower sildenafil doses (Table 6), whereas others did not (eg, covariates of etiology, baseline RAP, and systolic pulmonary arterial pressure). Adverse Events Most patients reported 1 AE during STARTS-1 and -2. The most frequently reported AEs were upper respiratory tract infection, headache, and vomiting; Table III in the online-only Date Supplement shows AEs occurring in 10% of patients in any group. The majority of AEs were of mild or moderate intensity. The most common treatment-related AEs were headache (15%) and vomiting (6%). Serious AEs were reported for 41% of patients (n=97), most commonly infections (n=43 [including pneumonia, n=16; upper respiratory tract infection, n=7]), respiratory disorders (n=32 [including worsening of pulmonary hypertension, n=12; worsening of PAH, n=7]), and cardiac disorders (n=26; most commonly cardiac failure [n=11]). Five patients had serious AEs that were assessed as treatment related (low-dose group: enterocolitis, n=1; medium-dose group: convulsion, n=1; high-dose group: hypersensitivity and stridor, n=1; hypoxia, n=1; ventricular arrhythmia, n=1). Seventeen patients permanently discontinued STARTS-1 or -2 because of AEs; most were considered to be related to the disease under study. The 5 discontinuations attributable to AEs that were assessed as treatment related included decreased weight (n=1), convulsion (n=1), stridor (n=1), dyspnea and hypoxia (n=1), and macular rash (n=1).

6 Barst et al STARTS-2 Long-Term Sildenafil in Pediatric PAH 1919 Table 5. Survival Disposition Over Time (From Start of STARTS-1) Group Year Sildenafil low dose (n=42) Ongoing 37 (88) 32 (76) 30 (71) Died on treatment* 0 1 (2) 2 (5) Discontinued 5 (12) 9 (21) 10 (24) Alive 4 (10) 7 (17) 6 (14) Died after treatment 0 1 (2) 1 (2) Lost to follow-up 1 (2) 1 (2) 3 (7) Sildenafil medium dose (n=55) Ongoing 52 (95) 46 (84) 41 (75) Died on treatment* 0 1 (2) 2 (4) Discontinued 3 (6) 8 (15) 12 (22) Alive 2 (4) 4 (7) 7 (13) Died after treatment 0 2 (4) 3 (6) Lost to follow-up 1 (2) 2 (4) 2 (4) Sildenafil high dose (n=77) Ongoing 68 (88) 59 (77) 54 (70) Died on treatment* 1 (1) 5 (7) 7 (9) Discontinued 8 (10) 13 (17) 16 (21) Alive 5 (7) 6 (8) 5 (7) Died after treatment (3) Lost to follow-up 3 (4) 7 (9) 9 (12) Placebo (n=60) Ongoing 49 (82) 47 (78) 41 (68) Died on treatment* (2) Discontinued 11 (18) 13 (22) 18 (30) Alive 7 (12) 8 (13) 12 (20) Died after treatment (2) Lost to follow-up 4 (7) 5 (8) 5 (8) Values are n (%). STARTS-1 indicates Sildenafil in Treatment-Naive Children, Aged 1 to 17 Years, With Pulmonary Arterial Hypertension. *Death within 7 days of last study dose. Includes STARTS-1 patients who never entered STARTS-2. Discussion In pediatric patients with PAH, treatment with high-dose sildenafil was associated with an increased risk of mortality compared with lower doses of sildenafil. A higher risk of death specifically was observed in patients with greater disease severity at baseline, in patients >20 kg, and in patients with IPAH/HPAH. The differences observed between treatment groups were unexpected because in the doubleblind 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 treatment groups (Table 6) but does not fully account for the increased mortality observed with high-dose sildenafil. This study was unique for being a large, randomized, dose-ranging study of a single monotherapy in treatment-naive patients. Overall, survival in all dose groups was favorable compared with other reports in children using PAH-specific drugs that were only approved for adult PAH 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. Few 10 of the reported studies and registries included treatment-naive patients. Some studies 7,11 and all registries did not assess monotherapy (therapies could be added 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 therapy 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-1 2 study had poorer long-term survival than patients treated with sildenafil in SUPER 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 present study, RAP, PVR index, and etiology were found to be the combination of baseline factors with the highest prognostic potential in multivariate analysis when survival from the start of STARTS-1 was assessed; when survival from the start of sildenafil treatment was assessed, this was also one of the best combinations of variables. Hemodynamic parameters predicted pediatric PAH mortality in previous studies, specifically RAP (in IPAH patients 12,18 and in children with mixed PAH etiology, some of whom received epoprostenol) 19 and PVR index (in a large US registry, 9 in UK children, 11 and in a univariate analysis of patients treated with bosentan 7 ), but it is unclear whether these factors were examined in other studies. 10,20 Hemodynamic parameters, including RAP and PVR, similarly predict outcome in adult patients with PAH. 21,22 Regarding univariate predictors of survival, similar to our study, World Health Organization functional class is predictive of outcome in pediatric patients with IPAH, 11 in children with PAH treated with bosentan, 7 and in pediatric patients enrolled in PAH registries. 10,20 No other pediatric study examining predictors of mortality assessed an exercise capacity end point, likely because of difficulties with such studies being performed in pediatric patients Exercise capacity was prognostic in univariate analysis of STARTS-1 and -2, despite being assessed in a limited subset of patients. Both functional class 26 and exercise capacity 27,28 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

7 1920 Circulation May 13, 2014 Table 6. Stratified Hazard Ratios (95% Confidence Intervals) for Mortality Mortality during the study (Table 1). Randomized doses are unbiased to confounding events that may occur during the study (eg, final dose would be influenced by disease progression if failing patients preferentially uptitrated). Assessments with the use of 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 (Table II in the online-only Data Supplement). An explanation of the higher incidence of deaths observed after 2 years of STARTS-1 and -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. Furthermore, there was an inconsistency in the relationship between survival and exposure. Because sildenafil clearance was anticipated to increase with weight, dosing was doubled within each dose group for patients >45 versus 20 to 45 kg. However, pharmacokinetic modeling with the use of samples obtained in STARTS-1 indicated that clearance plateaued at 30 kg; therefore, patients >45 kg would achieve higher-than-anticipated exposure in medium- and high-dose groups. Despite Sildenafil Dose Low Medium High P Value* From start of STARTS vs placebo 1.40 ( ) 2.44 ( ) 4.73 ( ) vs low dose NA 1.74 ( ) 3.38 ( ) vs medium dose NA NA 1.94 ( ) From start of sildenafil treatment vs low dose NA 1.92 ( ) 3.95 ( ) vs medium dose NA NA 2.06 ( ) From start of STARTS-1 Base-stratified model (no covariates) vs placebo 1.44 ( ) 2.57 ( ) 4.69 ( ) vs low dose NA 1.78 ( ) 3.26 ( ) vs medium dose NA NA 1.83 ( ) With covariates added to model vs placebo 1.36 ( ) 2.01 ( ) 3.05 ( ) vs low dose NA 1.49 ( ) 2.25 ( ) vs medium dose NA NA 1.52 ( ) From start of sildenafil treatment Base-stratified model (no covariates) vs low dose NA 1.95 ( ) 3.84 ( ) vs medium dose NA NA 1.97 ( ) With covariates added to model vs low dose NA 2.11 ( ) 3.35 ( ) vs medium dose NA NA 1.59 ( ) NA indicates not applicable; and STARTS-1, Sildenafil in Treatment-Naive Children, Aged 1 to 17 Years, With Pulmonary Arterial Hypertension. *Stratified log-rank test for difference between treatment groups. Analysis of patients for whom baseline data for covariates were available. these higher exposures, 14% of patients >45 kg at baseline are known to have died versus 21% of patients 20 to 45 kg; no imbalance was evident across dose groups 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 STARTS-2) had better survival than patients receiving sildenafil throughout. As noted above, placebo-treated patients in clinical studies of adults with PAH had poorer long-term survival than patients treated with sildenafil. 17 There is no plausible explanation in regard to 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 (mean pulmonary arterial pressure, PVR index, cardiac index; see Table 7 and Barst et al 3 ); across dose groups, sildenafil-treated STARTS-1 patients were clinically comparable, as were sildenafil dose groups in STARTS-2 (ie, including the rerandomized placebotreated STARTS-1 patients). Adjustment for etiology, PVR index, and RAP, parameters identified as being prognostic

8 Barst et al STARTS-2 Long-Term Sildenafil in Pediatric PAH 1921 Table 7. Differences in Significant Baseline Characteristics Associated With 10% Reduction in Mortality in Univariate Analysis Sildenafil Placebo n Difference Wald P Value n Difference Wald P Value Mean RAP, mm Hg < Etiology < Mean PAP, mm Hg < Systolic PAP, mm Hg < Pro-BNP, pg/ml < PVR, Wood units < Diastolic PAP, mm Hg < PVR index, Wood units m < BNP, pg/ml < WHO functional class Mean PAP/MAP Peak VO 2, ml/kg/min* Systemic pulse pressure, mm Hg SVR index, Wood units m Cardiac index, L min 1 m SVR, Wood units BNP indicates brain natriuretic peptide; MAP, mean arterial pressure; PAP, pulmonary arterial pressure; PVR, pulmonary vascular resistance; RAP, right atrial pressure; SVR, systemic vascular resistance; VO 2, oxygen uptake; and WHO, World Health Organization. *Based on subset of patients who were developmentally able to exercise (n=115). 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 Data Monitoring Committee were consistent with approved European Medicines Agency dosing for pediatric sildenafil (patients 20 kg, 10 mg 3 times a day; >20 kg, 20 mg 3 times a day), which was based on population pharmacokinetics of STARTS-1 patients and known adult data, as well as efficacy data from STARTS-1. 3,30 In this study, 5 of 55 (9%), 7 of 60 (12%), and 25 of 114 patients (22%) died who were randomized to doses of sildenafil that were below, at, or above the European Medicines Agency dosing instructions, respectively. An additional 5 deaths (on study treatment, n=2; after discontinuation, n=3) were reported in STARTS-2 after August Of these 5 deaths, 3 occurred in patients randomized to the medium-dose group, and 2 occurred in patients rerandomized to the high-dose group in STARTS-2 (after receiving placebo in STARTS-1). Four of the 5 patients downtitrated following Data Monitoring Committee recommendations; deaths occurred in 2 patients on treatment (2 months and 1 year after downtitration) and 2 patients off treatment (1 patient received downtitrated sildenafil for 1 month and died 2 months after discontinuing; 1 patient received downtitrated sildenafil for 5 months and died 2 weeks after discontinuing). Notably, the 0, 3, and 2 new deaths reported (after the August 2011 interim cutoff date) for patients randomized to low-, medium-, and high-dose sildenafil, respectively, show that deaths in the low-dose group remain below those in 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 Additionally, patients could have received commercial sildenafil or alternative PAH therapies after withdrawal; this information was not collected. Although no deaths were investigator-assessed as being related to sildenafil, such judgments are subjective; it is possible that sildenafil may cause harm in a way that is not easily apparent (for example, if sildenafil were to unexpectedly accelerate heart failure, the physician is likely to attribute death to underlying PAH). Additionally, it is unclear whether (or at which dose) sildenafil might be effective as part of combination therapy. In summary, although children randomized to the high-dose sildenafil group had an unexplained increased mortality compared with the lower-dose sildenafil groups, multiple analyses raised uncertainty about the survival/dose relationship; all dose groups displayed favorable survival for children with PAH. STARTS-1 efficacy results 3 and the long-term survival rates favor use of lower sildenafil doses. After STARTS-2 survival data were reviewed, 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 we 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 PAH. Her contributions on

9 1922 Circulation May 13, 2014 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. We also thank Helen Richardson, MSc, for her contributions to the STARTS studies and assistance in the preparation of this manuscript. Sources of Funding 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. Disclosures Dr Barst has served as a consultant and/or advisory board member for Actelion, Bayer, Lilly, GlaxoSmithKline, GE, Gilead, Ikaria, Merck, Novartis, Pfizer, and Ventripoint. Dr Beghetti has served as a consultant and/or advisory board member for Actelion, Bayer-Schering, Lilly, GlaxoSmithKline, Novartis, and Pfizer and has received investigator-initiated research funding from Actelion and Bayer-Schering. The institution with which Dr Pulido is affiliated has received research grants from United Therapeutics, Actelion Pharmaceuticals, Pfizer, Gilead (formerly Myogen Ltd), and Encysive Pharmaceuticals; Dr Pulido has received lecture fees from Pfizer, Actelion, and Lilly and has been a consultant for Pfizer, Actelion, Bayer-Schering, GlaxoSmithKline, and Lilly. The University of Colorado receives fees for Dr Ivy to be a consultant for Actelion, Gilead, Pfizer, and United Therapeutics; Dr Ivy has received investigator-initiated research funding from Gilead and United Therapeutics. G. Layton and Dr Konourina are former Pfizer employees and hold shares of Pfizer stock; G. Layton is a consultant for Aires Pharmaceuticals, Inc. and Actelion and Dr Konourina is an employee of Actelion. References 1. 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