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

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1 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 Downloaded from by guest on April 16, 2017 Robyn J. Barst, MD 1 ; Maurice Beghetti, MD 2 ; Tomas Pulido, MD 3 ; Gary Layton, MSc 4 ; Irina Konourina, MD 4 ; Min Zhang, MSc 5 ; D. Dunbar Ivy, MD 6 on behalf of the STARTS-2 investigators 1 Columbia University, New York, NY; 2 Dept of the Child and Adolescent, University of Geneva, Geneva, Switzerland; 3 National Heart Institute, Mexico City, Mexico; 4 Pfizer Ltd, Sandwich, UK (during study conduct); ct); 5 Pfizer Inc, La Jolla, la, CA; 6 Dept of Pediatrics, The University of Colorado School of Medicine and Children's Hospital Colorado, Aurora, CO Address dres for Correspondence: ence D. Dunbar Ivy, MD Department of Pediatrics The University of Colorado School of Medicine and Children's Hospital Colorado East 16 th Ave, B100 Aurora, CO Tel: Fax: dunbar.ivy@childrenscolorado.org 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

2 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 S-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 PAH (76% vs 33% overall) l) and baseline functional class III/IV disease (38% vs 15% overall); l); patients who died had worse baseline hemodynamics. Kaplan-Meier estimated 3-year survival val from start of sildenafil was 94%, 93%, and 88% for patientsts randomized to low-, medium-, and high-dose sildenafil, respectively; ecti 87%, 89% and 80% were known to be alive at 3 years. Hazard ar ratios for mortality ty were 3.95 (95% CI, ) ) for high vs low and 1.92 (95% CI, ). 5) for medium vs 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 Identifier: NCT (extension study of NCT ). Key words: pediatrics, pulmonary hypertension, clinical trial, sildenafil, survival 2

3 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 (SUPER- 1). 2 Sildenafil is approved in Europe for the treatment of PAH in children ( 20 kg, 10 mg three times daily [TID]; >20 kg, 20 mg TID). The 16-week, randomized, placebo-controlled, o olle led, double-blind Sildenafil in Treatment-naive children, Aged 1 17 years, with pulmonary arterial hypertension ensio (STARTS-1) S-1) study assessed the effects fects of low, medium, and high doses of sildenafil in treatment-naïve tment-naïv pediatric patients with PAH. 3 Improvements ment in exercise capacity city (measured by peak oxygen consumption [PVO 2 ]), World Health Organization atio ion (WHO) 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, 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 3

4 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 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 lind treatment. STARTS-2 began in January For this interim i analysis, August 4, 2011 was the cutoff date for survival val analyses (see below) and November 15, 2011 for safety data. All l ongoing patients ts had the potential to receive eive 3 years of sildenafil treatment. tment. Throughout ho ut STARTS-2, S- both upward (for disease progression ress 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 4

5 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. During mandated review of study data, the Data Monitoring Committee (DMC) recommended discontinuation of the 40 and 80 mg TID doses, as well as the 20 mg TID dose in children 20 kg. The study protocol was amended in August 2011 (the reason for the cutoff date for the survival analyses); s); patients ts who were receiving these doses were downtitrated. ted. Patients 8 20 kg received ed a maximum dose of 10 mg TID; patients ts >20 45 kg received eiveded 10 or 20 mg TID, per investigator judgment; and patients >45 kg received eive a maximum m m dose of 20 mg TID. 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. 5

6 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 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 ts were censored on the last date they were known to be alive. The number of patients ts known to be alive at different ent times was also summarized, mari and is the most conservative estimate te of survival because it assumes sume that patients who were lost to follow-up ow-u had died. Cox proportional orti onal hazard a models, stratified tifi by baseline weight ( 20 vs >20 kg), were used 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, 6

7 functional class, PVO 2, ventilation to carbon dioxide output (VE/VCO 2 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 [MVO 2 ], 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] pro- BNP). 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 best predicted mortality (based on chi-square statistic). The influence of these variables on the treatment tment comparisons was assessed by including them in the stratified t Cox proportional hazard 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, ) 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 7

8 20±15 Wood units m 2 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 received (if any) following discontinuation, including possible treatment with commercial ci sildenafil, was not specifically collected. Deaths Thirty-seven patients were known to have died before August ust 4, 2011 (Supplementary Table 1). One death occurred red within in the first year of study treatment (STARTS-1 TS-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 (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. 8

9 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 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 ve estimates of 3-year survival (assuming that all patients t lost to follow-up had died), are shown in Tables 4 and 5. Estimates were lowest in the high-dose h-dose group. Survival From Initiation iation of Sildenafil Treatment Kaplan-Meierer estimated ed 3-year survival from the start t of sildenafil l treatment tmen ent (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 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 9

10 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, ogy, PVRI, and RAP, when assessed from STARTS-1 baseline. This set of variables was also one of the best combinations ions when assessing survival from the start of sildenafil, l, although several different sets of variables (including ing different 3-variable combinations ns of etiology, PVR, RAP, WHO functional class, systolic stolic PAP, diastolic PAP and systemic s pulse pressure) e) performed rmed similarly. ilar To assess the influence nce of baseline variables on the treatment tmen ent comparisons, ons, 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 majority of 10

11 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: etiology, baseline RAP, and baseline PVRI) for mortality for high- and medium-dose sildenafil versus placebo and high versus lower sildenafil doses (Table 6), while others did not (ex: covariates of etiology, baseline RAP and systolic PAP). 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; Supplementary Table 3 shows AEs occurring in 10% of patients in any group. The majority of AEs were of mild or moderate intensity. nsit ity. The most common treatment-related AEs were headache (15%) and vomiting (6%). Serious AEs were reported for 41% of patients (n=97), most commonly monl infections ions (n=43 [including ng pneumonia, n=16, upper per respiratory tract infection, ion, n=7]), respiratory disorders (n=32 [including worsening ng of pulmonary hypertension, n, n=12, and worsening ng 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 due 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). 11

12 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 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 treatment groups (Table 6), but do not fully account for the increased mortality observed with high-dose sildenafil. il. This study was unique for being a large, randomized, d, dose-ranging study of a single monotherapy in treatment-naïve aïve patients. Overall, l, survival val in all dose groups was favorable able compared with other reports rts 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-naïve patients. Some studies 7, 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 therapy and the median 10-month survival reported for the natural history of IPAH

13 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 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 parameters predicted pediatric PAH mortality in previous studies, specifically RAP (in IPAH patients ts 12, 18 and in children with mixed PAH etiology, some of whom received epoprostenol 19 ) and PVRI (in a large US registry, ry, 9 in UK children, 11 and in 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, WHO functional class is predictive of outcome ome in pediatric ic patients with IPAH, 11 in children with PAH treated ted with bosentan, 7 and in pediatric patients enrolled in registries. 10, di i PAH i 20 No other pediatric i study examining predictors of mortality assessed an exercise capacity endpoint, likely because of difficulties with performing such studies in pediatric patients Exercise capacity was prognostic in univariate analysis of STARTS-1/-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 17, 29 PAH, including those treated with sildenafil. 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 13

14 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, dosing was doubled within each dose group for patients >45 vs kg. However, pharmacokinetic modeling using samples obtained in STARTS-1 indicated that clearance plateaued at ~30 kg; therefore, e patients >45 kg would achieve higher-than-anticipated nticipip ated exposure in medium- m- and high- dose groups. Despite these higher her exposures, s 14% of patients >45 kg at baseline are known to have died versus 21% of patients ts kg; no imbalance was evident ent 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, 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 14

15 baseline clinical characteristics than patients randomized to sildenafil in STARTS-1 (mpap, PVRI, CI; 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 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 dosing for pediatric sildenafil (patients 20 kg, 10 mg TID; >20 kg, 20 mg TID), which was based on population pharmacokinetics of STARTS-1 patients and known adult data, as well as efficacy fica cy data from STARTS-1. 3, 30 In this study, 5/5555 (9%), 7/60 (12%), and 25/114 (22%) patients ts died who were randomized to doses of sildenafil that were below, at, or above the EMA dosing instructions, tions, respectively. ely. An additional iona 5 deaths (on study treatment, n=2; after discontinuation, inua tion 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 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 15

16 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 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 apparent (for example, if sildenafil were to unexpectedly accelerate heart failure, the physician ian 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 sildenafil l dose group had an unexplained ned increased mortality compared with the lower sildenafil dose groups, multiple le analyses raised uncertainty ty about the survival/dose val/ se relationship; ip; all l 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 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 16

17 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, GlaxoSmithKline, Novartis, and Pfizer and has received investigator-initiated research funding from Actelion and Bayer-Schering; the institution employing T.P. has received research ea rch grants from United Therapeutics, Actelion Pharmaceuticals, Pfizer, Gilead (formerly Myogen Ltd), and Encysive Pharmaceuticals; T.P. has received lecture fees from Pfizer, Actelion, and Lilly, and has been e a consultant for Pfizer, Actelion, Bayer-Schering, GlaxoSmithKline, and Lilly; ly; The University of Colorado receives eive fees es for D.D.I. to be a consultant for Actelion, Gilead, Pfizer, and United Therapeutics; D.D.I..I. has received investigator-initiated igat ated research earch funding ng from Gilead and United Therapeutics; G.L. and I.K. are former r Pfizer employees ees and hold shares of Pfizer stock. References: 1. McLaughlin VV, Archer SL, Badesch DB, Barst RJ, Farber HW, Lindner JR, Mathier MA, McGoon MD, Park MH, Rosenson RS, Rubin LJ, Tapson VF, Varga J, Harrington RA, Anderson JL, Bates ER, Bridges CR, Eisenberg MJ, Ferrari VA, Grines CL, Hlatky MA, Jacobs AK, Kaul S, Lichtenberg RC, Moliterno DJ, Mukherjee D, Pohost GM, Schofield RS, Shubrooks SJ, Stein JH, Tracy CM, Weitz HH, Wesley DJ. ACCF/AHA 2009 expert consensus document on pulmonary hypertension: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association: developed in collaboration with the American College of Chest Physicians, American Thoracic Society, Inc., and the Pulmonary Hypertension Association. Circulation. 2009;119: Galie N, Ghofrani HA, Torbicki A, Barst RJ, Rubin LJ, Badesch D, Fleming T, Parpia T, Burgess G, Branzi A, Grimminger F, Kurzyna M, Simonneau G. Sildenafil citrate therapy for 17

18 pulmonary arterial hypertension. N Engl J Med. 2005;353: Barst RJ, Ivy DD, Gaitan G, Szatmari A, Rudzinski A, Garcia AE, Sastry BK, Pulido T, Layton GR, Serdarevic-Pehar M, Wessel DL. A randomized, double-blind, placebo-controlled, dose-ranging study of oral sildenafil citrate in treatment-naive children with pulmonary arterial hypertension. Circulation. 2012;125: Yung D, Widlitz AC, Rosenzweig EB, Kerstein D, Maislin G, Barst RJ. Outcomes in children with idiopathic pulmonary arterial hypertension. Circulation. 2004;110: Lammers AE, Hislop AA, Flynn Y, Haworth SG. Epoprostenol treatment in children with severe pulmonary hypertension. Heart. 2007;93: Hislop AA, Moledina S, Foster H, Schulze-Neick I, Haworth SG. Long-term efficacy of bosentan in treatment of pulmonary arterial hypertension in children. Eur Respir J. 2011;38: Ivy DD, Rosenzweig EB, Lemarie JC, Brand M, Rosenberg D, Barst RJ. Long-term outcomes omes in children with pulmonary arterial hypertension treated with bosentan in real-world ld clinical cal settings. Am J Cardiol. 2010;106: Haworth SG, Hislop AA. Treatment and survival in children with pulmonary arterial hypertension: ensi the UK Pulmonary Hypertension Service for Children Heart. 2009;95: ;95: Barst RJ, McGoon MD, Elliott liott CG, Foreman AJ, Miller DP, Ivy DD. Survival v in childhood od pulmonary arterial rial hypertension: n: insights ight from the registry ry to evaluate early and long-term pulmonary arterial r al hypertension disease management. m nt. Circulation. ion. 2012;125: : van Loonon RL, Roofthooft oft MT, Delhaas T, van Osch-Gevers ers M, ten Harkel AD, Strengers ers JL, Backx A, Hillege HL, Berger RM. Outcome of pediatric patients with pulmonary arterial hypertension in the era of new medical therapies. Am J Cardiol. 2010;106: Moledina S, Hislop AA, Foster H, Schulze-Neick I, Haworth SG. Childhood idiopathic pulmonary arterial hypertension: a national cohort study. Heart. 2010;96: Barst RJ, Maislin G, Fishman AP. Vasodilator therapy for primary pulmonary hypertension in children. Circulation. 1999;99: Houde C, Bohn DJ, Freedom RM, Rabinovitch M. Profile of paediatric patients with pulmonary hypertension judged by responsiveness to vasodilators. Br Heart J. 1993;70: Simpson CM, Penny DJ, Cochrane AD, Davis AM, Rose ML, Wilson SE, Weintraub RG. Preliminary experience with bosentan as initial therapy in childhood idiopathic pulmonary arterial hypertension. J Heart Lung Transplant. 2006;25:

19 15. Fuster V, Steele PM, Edwards WD, Gersh BJ, McGoon MD, Frye RL. Primary pulmonary hypertension: natural history and the importance of thrombosis. Circulation. 1984;70: D'Alonzo GE, Barst RJ, Ayres SM, Bergofsky EH, Brundage BH, Detre KM, Fishman AP, Goldring RM, Groves BM, Kernis JT, Levy PS, Pietra GG, Reid LM, Reeves JT, Rich S, Vreim CE, Williams GW, Wu M. Survival in patients with primary pulmonary hypertension. Results from a national prospective registry. Ann Intern Med. 1991;115: Rubin LJ, Badesch DB, Fleming TR, Galie N, Simonneau G, Ghofrani HA, Oakes M, Layton G, Serdarevic-Pehar M, McLaughlin VV, Barst RJ, Group S-S. Long-term treatment with sildenafil citrate in pulmonary arterial hypertension: the SUPER-2 study. Chest. 2011;140: Sandoval J, Bauerle O, Gomez A, Palomar A, Martinez Guerra ML, Furuya ME. Primary pulmonary hypertension in children: clinical characterization and survival. J Am Coll Cardiol. 1995;25: Clabby ML, Canter CE, Moller JH, Bridges ND. Hemodynamic data and survival val in children with pulmonary hypertension. J Am Coll Cardiol. 1997;30: van Loon RL, Roofthooft MT, Hillege HL, ten Harkel AD, van Osch-Gevers M, Delhaas T, Kapusta L, Strengers JL, Rammeloo L, Clur SA, Mulder BJ, Berger RM. Pediatric pulmonary hypertension ensi in the Netherlands: epidemiology and characterization during the period 1991 to Circulation. ion. 2011;124: McLaughlin VV, Presberg erg KW, Doyle RL, Abman SH, McCrory DC, Fortin T, Ahearn G. Prognosis of pulmonary arterial hypertension: ensi ACCP CP evidence-based e- clinical ical practice guidelines. e Chest. 2004;126:78S-92S. 04;126:78S 22. Benza RL, Miller DP, Gomberg-Maitland and M, Frantz RP, Foreman AJ, Coffey fey CS, Frost A, Barst RJ, Badesch DB, Elliott CG, Liou TG, McGoon MD. Predicting survival in pulmonary arterial hypertension: insights from the Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL). Circulation. 2010;122: Barst RJ, Ertel SI, Beghetti M, Ivy DD. Pulmonary arterial hypertension: a comparison between children and adults. Eur Respir J. 2011;37: Haworth SG, Beghetti M. Assessment of endpoints in the pediatric population: congenital heart disease and idiopathic pulmonary arterial hypertension. Curr Opin Pulm Med. 2010;16 Suppl 1:S Lammers AE, Diller GP, Odendaal D, Tailor S, Derrick G, Haworth SG. Comparison of 6- min walk test distance and cardiopulmonary exercise test performance in children with pulmonary hypertension. Arch Dis Child. 2011;96: Galie N, Hoeper MM, Humbert M, Torbicki A, Vachiery JL, Barbera JA, Beghetti M, Corris 19

20 P, Gaine S, Gibbs JS, Gomez-Sanchez MA, Jondeau G, Klepetko W, Opitz C, Peacock A, Rubin L, Zellweger M, Simonneau G, Guidelines ESCCfP. Guidelines for the diagnosis and treatment of pulmonary hypertension: the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Eur Heart J. 2009;30: Miyamoto S, Nagaya N, Satoh T, Kyotani S, Sakamaki F, Fujita M, Nakanishi N, Miyatake K. Clinical correlates and prognostic significance of six-minute walk test in patients with primary pulmonary hypertension. Comparison with cardiopulmonary exercise testing. Am J Respir Crit Care Med. 2000;161: Wensel R, Opitz CF, Anker SD, Winkler J, Hoffken G, Kleber FX, Sharma R, Hummel M, Hetzer R, Ewert R. Assessment of survival in patients with primary pulmonary hypertension: importance of cardiopulmonary exercise testing. Circulation. 2002;106: Simonneau G, Rubin L, Galie N, Fleming T, Gillies H, Barst R, PACES study group. Longterm follow-up of patients with pulmonary arterial hypertension receiving sildenafil plus intravenous epoprostenol therapy. Presented at: American Thoracic Society International nal Conference; May 14 19, 2010; New Orleans, LA, USA. 30. European Medicines Agency. Assessment report rt for Revatio (Procedure No. EMEA/H/C/000638/II/0028). EA/H /C/0 /00063 Available at: tp:/ / ww.e.eur a eu/d ocs/ en_g document_library ry/e /EPAR_-_ Assese ssment nt_r _Report_ t_- _Variation/human/000638/WC pdf. 06 /WC Table 1. Summary of Dose Changes Sildenafil Dose Low (n=55) Medium (n=74) High (n=100) Down titrations, 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 due 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 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. 20

21 Table 2. Distribution of STARTS-1 Baseline Characteristics Associated With Survival* Placebo (N=60) Low (N=42) Sildenafil Dose Medium (N=55) High (N=77) Patients, n (%) Weight 20 kg 18 (30) 0 15 (27) 35 (46) >20 kg 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) PVRI <15.1 Wood units m 2 35 (58) 14 (33) 26 (47) 36 (47) 15.1 Wood units m 2 22 (37) 26 (62) 26 (47) 37 (48) Missing 3 (5) 2 (5) 3 (5) 4 (5) Mean ± SD 14.6± ± ± ±16.1 mpap <62.0 mmhg mh 35 (58) 18 (43) 25 (45) 35 (45) mmhg 24 (40) 24 (57) 30 (55) 40 (52) Missing 1 (2) (3) Mean ± SD 58.9± ± ± ±23.7 RAP <7.0 mmhg mhg 26 (43) 17 (41) 23 (42) 27 (35) mmhg 33 (55) 25 (60) 32 (58) 48 (62) Missing 1 (2) (3) Mean ± SD 8.0± ± ± ±4.8 Cardiac index <3.2 L/min/m 2 22 (37) 21 (50) 33 (60) 39 (51) 3.2 L/min/m 2 37 (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 <233 pg/ml 24 (40) 18 (43) 24 (44) 28 (36) 233 pg/ml 24 (40) 14 (33) 21 (38) 34 (44) Missing 12 (20) 10 (24) 10 (18) 15 (20) Mean ± SD 878± ± ± ±4934 CHD=congenital heart disease; IPAH=idiopathic pulmonary arterial hypertension; HPAH=heritable pulmonary arterial hypertension; mpap=mean pulmonary artery pressure; NT probnp=n-terminal pro-brain natriuretic peptide; PVRI=pulmonary vascular resistance index; RAP=right atrial pressure; WHO=World Health Organization. *Better survival was associated with weight 20 kg; CHD etiology; lower functional class, PVRI, mpap, RAP, and NT-proBNP; 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). 21

22 Table 3. Deaths by Sildenafil Dose Group, Weight,* and Etiology Group Sildenafil Dose (No. Dead/No. Total, %) Low Medium High Total Overall 5/55 (9) 10/74 (14) 22/100 (22) 37/229 (16) Weight* 8 to 20 kg NA 1/20 (5) 5/44 (11) 6/64 (9) >20 to 45 kg 3/40 (8) 7/40 (18) 15/41 (37) 25/121(21) >45 kg 2/15 (13) 2/14 (14) 2/15 (13) 6/44 (14) Etiology Idiopathic/heritable PAH 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) CHD=congenital heart defect; NA=not applicable; PAH=pulmonary arterial hypertension. *At the start of sildenafil treatment (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 Randomized Group Placebo Sildenafil Low Dose Sildenafil Medium Dose Sildenafil High Dose From start of STARTS-1 Overall 96% 93% 91% 87% 20 kg 100% 0% NA* 93% 91% >20 kg 95% 93% 90% 84% Known alive 88% 86% 87% 77% From start of sildenafil Overall 94% 93% 88% 20 kg NA* 94% 93% >20 kg 94% 93% 84% Known alive 87% 89% 80% IPAH/HPAH 94% (n=18) 78% (n=24) 82% (n=35) 20 kg NA* 86% 87% >20 kg 94% 75% 79% PAH-CHD 94% (n=37) 100% (n=50) 92% (n=65) 20 kg NA* 100% 96% >20 kg 94% 100% 88% *Patients 20 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. 22

23 Table 5. Survival Disposition Over Time (From Start of STARTS-1). Year Group, n (%) 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 posttreatment 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 posttreatment 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 i 8 (10) 13 (17) 16 (21) Alive 5 (7) 6 (8) 5 (7) Died posttreatment (3) Lost to follow-up ow-u 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 posttreatment (2) Lost to follow-up 4 (7) 5 (8) 5 (8) *Death within 7 days of last study dose. Includes STARTS-1 patients who never entered STARTS-2. 23

24 Table 6. Stratified Hazard Ratios (95% CI) for Mortality. Sildenafil Dose Mortality Low Medium High P Value* From start of STARTS vs placebo 1.40 (0.37, 5.23) 2.44 (0.75, 7.92) 4.73 (1.60, 13.97) vs low dose NA 1.74 (0.58, 5.23) 3.38 (1.23, 9.27) vs medium dose NA NA 1.94 (0.87, 4.33) From start of sildenafil treatment vs low dose NA 1.92 (0.65, 5.65) 3.95 (1.46, 10.65) vs medium dose NA NA 2.06 (0.97, 4.38) From start of STARTS-1 Base-stratified model (no covariates) vs placebo 1.44 (0.39, 5.39) 2.57 (0.79, 8.34) 4.69 (1.59, 13.86) vs low dose NA 1.78 (0.59, 5.35) 3.26 (1.19, 8.93) vs medium m dose NA NA 1.83 (0.82, 4.08) With covariates added d to model vs placebo 1.36 (0.36, 5.14) 2.01 (0.60, 0, 6.75) 3.05 (0.98, 9.53) vs low dose NA 1.49 (0.48, 4.57) 2.25 (0.80, 0, 6.34) vs medium dose NA NA 1.52 (0.66, 3.49) From start of sildenafil treatment Base-stratified model (no covariates) vs low dose NA 1.95 (0.66, 5.74) 3.84 (1.42, 10.35) vs medium dose NA NA 1.97 (0.92, 4.19) With covariates added to model vs low dose NA 2.11 (0.71, 6.25) 3.35 (1.23, 9.11) vs medium dose NA NA 1.59 (0.73, 3.45) NA=not applicable. *Stratified log rank test for difference between treatment groups. Analysis of patients for whom baseline data for covariates was available. 24

25 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, mmhg < Etiology < Mean PAP, mmhg < Systolic PAP, mmhg < Pro-BNP, pg/ml < PVR, Wood units < Diastolic PAP, mmhg < PVR index, Wood units m < BNP, pg/ml < WHO functional class mpap/map P/M Peak VO 2, ml/kg/min* /min Systemic pulse pressure, e, mmhg mh SVR index, Wood units m Cardiac ac index, L min 1 m SVR, Wood o units BNP=bone natriuretic tic peptide; MAP=mean arterial pressure; PAP=pulmonary arterial pressure; e; PVR=pulmonary vascular resistance; RAP=right atrial pressure; SVR=systemic vascular resistance; VO 2 =oxygen uptake; WHO=World Wo Health Organization. a ion. *Based d on subset of patients who were developmentally e ly able to exercise (n=115). 15). 25

26 Figure Legend: Figure 1. Kaplan-Meier Estimated Survival From Start of Sildenafil Treatment in STARTS-1 and -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, they were 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 on study long enough to reach time point). 26

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30 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 Copyright 2014 American Heart Association, Inc. All rights reserved. Print ISSN: Online ISSN: The online version of this article, along with updated information and services, is located on the World Wide Web at: Data Supplement (unedited) at: Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Circulation can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. Further information about this process is available in the Permissions and Rights Question and Answer document. Reprints: Information about reprints can be found online at: Subscriptions: Information about subscribing to Circulation is online at: