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Long-term sildenafil added to intravenous epoprostenol in patients with pulmonary arterial hypertension
http://www.jhltonline.org
ORIGINAL CLINICAL SCIENCE
Long-term sildenafil added to intravenous epoprostenol in patients with pulmonary arterial hypertension Gérald Simonneau, MD,a Lewis J. Rubin, MD,b Nazzareno Galiè, MD,c Robyn J. Barst, MD,,d Thomas R. Fleming, PhD,e Adaani Frost, MD,f Peter Engel, MD,g Mordechai R. Kramer, MD,h Marjana Serdarevic-Pehar, MD,i Gary R. Layton, MSc,j Olivier Sitbon, MD, PhD,a and David B. Badesch, MD,k on behalf of the PACES Study Group From the aUniversity Paris-Sud, National Reference Center for Severe Pulmonary Hypertension, Hôpital de Bicêtre, Le Kremlin-Bicêtre, France; the bDepartment of Medicine, University of California at San Diego, La Jolla, California; the cInstitute of Cardiology, Bologna University Hospital, Bologna, Italy; the dDivision of Pediatric Cardiology, Columbia University, New York, New York; the eDepartment of Biostatistics, University of Washington, Seattle, Washington; the fDepartment of Medicine, Section of Pulmonary and Critical Care, Baylor College of Medicine, Houston, Texas; the gPulmonary Hypertension Program, The Christ Hospital, Cincinnati, Ohio; the hPulmonary Institute, Rabin Medical Center, Petah Tikva, Israel; the iPfizer Inc, New York, New York; the jWorldwide Pharmaceutical Operations, Pfizer Ltd, Sandwich, Kent, United Kingdom; and the kDivision of Pulmonary Sciences and Critical Care Medicine, and Cardiology Director, Pulmonary Hypertension Program, University of Colorado Denver, Denver, Colorado.
KEYWORDS: sildenafil; epoprostenol; pulmonary arterial hypertension; survival; clinical trial
*
BACKGROUND: In pulmonary arterial hypertension (PAH), adding oral sildenafil to intravenous epoprostenol improved 6-minute walk distance (6MWD) and hemodynamics and delayed time to clinical worsening in a 16-week randomized, placebo-controlled trial (Pulmonary Arterial Hypertension Combination Study of Epoprostenol and Sildenafil [PACES-1]). METHODS: Patients completing PACES-1 could receive sildenafil (titrated to 80 mg, three times daily, as tolerated) in an open-label extension study (PACES-2) for Z 3 years; additional therapy was added according to investigator judgment. Survival and changes from PACES-1 baseline in World Health Organization Functional Class and 6MWD were captured. RESULTS: In an open-label setting, 6MWD, an effort-dependent outcome measure, was known to have improved or to have been maintained in 59%, 44%, and 33% of patients at 1, 2, and 3 years, respectively; functional class was known to have improved or to have been maintained in 73%, 59%, and 46%. At 3 years, 66% of patients were known to be alive, 24% were known to have died, and 10% were lost to follow-up. Patients with PACES-1 baseline 6MWD o 325 meters without 6MWD improvement during the first 20 weeks of sildenafil treatment subsequently had poorer survival. CONCLUSIONS: Although reliable assessments of safety and efficacy require a long-term randomized trial, the addition of sildenafil to background intravenous epoprostenol therapy appeared generally to be well tolerated in PAH patients. J Heart Lung Transplant ]]]];]:]]]–]]] r 2014 Published by Elsevier Inc. on behalf of International Society for Heart and Lung Transplantation. All rights reserved.
Deceased. Reprint requests: Gérald Simonneau, MD, Department of Pneumology and ICU, National Reference Center for Severe Pulmonary Hypertension, South Paris University, Hopital de Bicêtre, 78 rue du Général Leclerc, 94275 Le KremlinBicêtre, France. Telephone: 33-0-1-45-21-79-72. Fax: 33-0-1-45-21-79-71. E-mail address: [email protected]
Pulmonary arterial hypertension (PAH) is characterized by a progressive increase of pulmonary vascular resistance (PVR) leading to right heart failure and death.1,2 Pulmonary vasculature remodelling, vasoconstriction, and thrombosis in situ contribute to increased PVR; endothelial dysfunction appears to play a key role.2
1053-2498/$-see front matter r 2014 Published by Elsevier Inc. on behalf of International Society for Heart and Lung Transplantation. All rights reserved. http://dx.doi.org/10.1016/j.healun.2014.02.019
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Approved PAH-specific medical therapies target prostacyclin, nitric oxide (NO), and endothelin pathways. Prostacyclin promotes vascular smooth muscle relaxation through increased cyclic adenosine monophosphate production and also inhibits smooth muscle cell growth and platelet aggregation.2 NO diffusing through the endothelium signals an increase in the production of cyclic guanosine monophosphate (cGMP), which produces smooth muscle relaxation.3 Because phosphodiesterase type 5 (PDE5) metabolizes cGMP in endothelial cells, PDE5-inhibitor treatment increases the pool of cGMP, thereby increasing vasodilation. Endothelin-1 is a potent vasoconstrictor and mitogen, and endothelin-receptor antagonists (ETRAs) oppose these endothelin-1 actions.2 Oral sildenafil, a PDE5 inhibitor, and intravenous (IV) epoprostenol, a synthetic prostacyclin, each improve outcomes in patients with PAH as monotherapy.4,5 These 2 agents target separate pathways that appear to contribute to the pathobiology of PAH. The Pulmonary Arterial Hypertension Combination Study of Epoprostenol and Sildenafil (PACES-1) trial provided a 16-week, randomized, placebo-controlled evaluation of the addition of oral sildenafil (80 mg, three times daily, as tolerated) to background IV epoprostenol. This combination increased the 6-minute walk distance (6MWD), delayed the time to clinical worsening, and improved hemodynamic parameters compared with IV epoprostenol treatment alone.6 Patients who completed PACES-1 were eligible to enroll in PACES2, (ClinicalTrials.gov Identifier: NCT00147641), an openlabel extension (OLE) of PACES-1, in which all patients received sildenafil in addition to epoprostenol until the last enrolled patient received 3 years of sildenafil treatment. We report here the results for these patients.
Methods Local Institutional Review Boards or independent Ethics Committees approved the protocol.
Study design This study was conducted between November 2003 and April 2009 at 45 sites in 10 countries, ending when the last patient enrolled in the OLE completed 3 years of sildenafil treatment, including 16 weeks of PACES-1 sildenafil treatment (if receiving the active drug in PACES-1). Regardless of therapy received in PACES-1,6 all patients entering PACES-2 received sildenafil at 20 mg, three times daily, then titrated to 40, and then to 80 mg, three times daily, as tolerated, with doses separated by Z 6 hours. Patients could reduce the dose of sildenafil to a minimum of 20 mg, three times daily. Patients unable to tolerate sildenafil at 20 mg three times daily were withdrawn and monitored for survival. The epoprostenol dosage could be changed at the discretion of the investigator at any time during the study. The PACES-1 baseline constituted the baseline for the OLE. Follow-up assessments were conducted at 20 and 24 weeks and every 3 months thereafter. Laboratory safety assessments were performed at baseline, Week 16 of PACES-1, then at the first 3-month visit in PACES-2 (ie, Week 36 relative to the PACES-1 baseline), and every 6 months thereafter.
Patients Patients with idiopathic PAH (IPAH), heritable PAH (HPAH), or PAH associated with anorexigen use, connective tissue disease (CTD), or corrected congenital heart defect, who completed PACES-1 (or received an increased epoprostenol dose due to clinical deterioration in PACES-1 and completed all end-of-study assessments and Z 4 weeks of PACES-1) and gave informed consent were eligible to enter the OLE. Exclusion criteria have been published for PACES-1.6 Briefly, patients were not permitted to use nitrates or NO donors, protease inhibitors, or α-blockers. Oral anti-coagulants, digitalis, diuretics, calcium channel blockers in acute responders, and supplemental oxygen were permitted. After a protocol amendment in September 2007, patients could receive ETRAs and other prostacyclin analogs in PACES-2 if the investigator judged that additional therapy was warranted. Patients who permanently discontinued sildenafil study treatment were monitored for survival whenever possible.
Outcome measures At all visits, 6MWD and World Health Organization Functional Class (WHO FC) were assessed. The 6MWD test was performed as close to trough levels of sildenafil as possible. Descriptive summaries without significance testing are presented. Missing data for 6MWD and FC were imputed using the worst value for nonmissing adjacent values. “Missing” scores indicated that a score was missing at a target visit, and no subsequent score was recorded. The survival status of all patients, including those who discontinued study treatment (when possible), was documented yearly. Kaplan-Meier estimates of 1-, 2-, and 3-year survival were calculated overall and by PACES-1 baseline 6MWD (dichotomized as o 325 or Z 325 meters) and PAH etiology (both prespecified). Because missing follow-up data for some patients who discontinued treatment likely would lead to biased overestimates, the proportions of patients known to be alive at 1, 2, and 3 years were also calculated. A Cox regression was used to explore the relationship between change in the 6MWD during 20 weeks of sildenafil treatment and subsequent survival. In this latter analysis, change from baseline in 6MWD was defined as the change between Week 0 and Week 20 for patients randomized to sildenafil in PACES-1, and the change between Week 16 and Week 36 (i.e., Month 9 visit) for patients randomized to placebo in PACES-1. “Time 0” for survival, the dependent variable, was Week 20 for PACES-1 sildenafil patients and Week 36 for PACES-1 placebo patients. A post hoc Cox regression analysis was used to assess the association of 17 baseline covariates with survival: 6MWD, WHO FC, PAH etiology, mean pulmonary arterial pressure (PAP), mean PAP/mean arterial pressure, systolic and diastolic PAP, right atrial pressure, mixed venous oxygen saturation, heart rate, pulse pressure, mean systemic arterial pressure, PVR, PVR index, systemic vascular resistance (SVR), SVR index, PVR/SVR, cardiac index, cardiac output, and pulmonary capillary wedge pressure. “Time 0” for all patients was baseline of the PACES-1 study. Univariate and multivariate analyses were conducted. The number of patients with changes in intravenous epoprostenol dose was collected. The mean number of signs and symptoms of complications of epoprostenol (or alternative prostacyclin analog) use (e.g., headache, jaw pain, flushing) was recorded. Adverse events (AEs) were coded using the Medical Dictionary for Regulatory Activities and were assessed for severity and relation to
Simonneau et al.
Long-term Sildenafil Plus Epoprostenol Therapy
treatment. AE data were summarized; all PACES-1 randomized patients who received Z 1 dose of study drug were included in the safety population.
Results
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Anti-coagulants (97%), diuretics (85%), and supplemental oxygen treatment (58%) were the most common concomitant therapies; 38% of patients received systemic antihypertensive drugs. After a protocol amendment, 27 patients received bosentan; 10, ambrisentan; and 1, sitaxentan.
Patients 6MWD results Of the 265 patients randomized and treated in PACES-1 (placebo, n ¼ 131; sildenafil, n ¼ 134), 242 received openlabel sildenafil in addition to continued IV epoprostenol therapy in PACES-2. Of these 242, 23 entered the OLE without completing all 16 weeks of PACES-1 (n ¼ 16 [14 placebo, 2 sildenafil] for Z 10% increase in epoprostenol dose because of perceived deterioration). Most patients were female, were white, and had IPAH/HPAH (Table 1). Most patients on the study drug were receiving the dose of 80 mg, three times daily, at Years 1, 2, and 3 (71%, 70%, and 68%, respectively); median sildenafil exposure was 3.2 years (range, 3 days–5.4 years) in PACES-1 and -2.
Table 1 PACES-1 Baseline Demographics and Clinical Characteristics Variablea Sex Women Men Age, years Ethnicity White Black Asian Other PAH classification Idiopathic Duration since first diagnosis, years Associated with CTD Duration since first diagnosis, years Epoprostenol treatment Dose, ng/kg/min Duration, years 6MWD,b meters WHO functional class I II III IV Borg dyspnea scorec
Placebo (n ¼ 131)
Sildenafil (n ¼ 134)
102 (78) 29 (22) 48 ⫾ 13
110 (82) 24 (18) 48 ⫾ 13
106 (81) 7 (5) 6 (5) 12 (9)
105 (78) 10 (8) 5 (4) 14 (10)
104 (79) 5.1 (0.3–37.2)
107 (80) 4.2 (0.3–25.8)
27 (21) 4.5 (0.5–13.1)
27 (20) 3.7 (0.3–8.8)
31.98 ⫾ 22.43 32.89 ⫾ 22.11 (3–179) (4–181) 2.9 (0.3–11.7) 2.8 (0.2–10.5) 349 ⫾ 73 350 ⫾ 69 2 (2) 35 (27) 88 (67) 6 (5) 3.3 ⫾ 2.0 3 (0–10)
1 (1) 34 (25) 89 (66) 10 (7) 3.5 ⫾ 2.0 3 (0–10)
6MWD, 6-minute walk distance; CTD, connective tissue disease; PAH, pulmonary arterial hypertension; WHO, World Health Organization. a Continuous data are shown as mean ⫾ standard deviation, mean (range), and discrete data as number (%). b Placebo, n ¼ 119; sildenafil, n ¼ 131. c Placebo, n ¼ 115; sildenafil, n ¼ 123.
At 1, 2, and 3 years, 6MWD was known to have improved or to have been maintained in 59%, 44%, and 33% of patients, respectively, and 28%, 25%, and 19% of patients improved 6MWD Z 60 meters (Table 2). Greater improvements were observed in patients with baseline 6MWD Z 325 meters in PACES-1 compared with 6MWD o 325 meters and in patients with IPAH/HPAH vs PAH-CTD (Table 2).
WHO FC assessment WHO FC at 1, 2, and 3 years was known to have been maintained in 44%, 37%, and 29% of patients, respectively, and known to have improved in 29%, 23%, and 18% (Table 3). Improvements were greater for patients with baseline 6MWD Z325 meters in PACES-1 compared with patients with 6MWD o 325 meters and for patients with IPAH/HPAH vs PAH-CTD (Table 3). Of 133 patients with data available for analysis at Year 3, 60 (45%) were WHO FC II. Of these patients, 32 (53%) were FC III, and 28 (47%) were FC II at PACES-1 baseline.
Survival Overall Kaplan-Meier estimates of survival at 1, 2, and 3 years were 91%, 81%, and 74%, respectively; estimates were 92%, 81%, and 74% for sildenafil-treated and 89%, 80%, and 74% for placebo-treated PACES-1 patients (Figure 1). These estimates are likely upwardly biased due to informative missingness. At 3 years, 66% of patients were known to be alive, 24% were known to have died, and 10% were lost to follow-up after discontinuation. Seven patients received lung (n ¼ 3) or heart/lung transplants (n ¼ 4). Survival was longer for patients with PACES-1 baseline 6MWD Z 325 meters than patients with baseline 6MWD o 325 meters (Figure 2A). Survival also appeared better for patients with IPAH/HPAH vs PAH-CTD (Figure 2B). A substantial interaction was seen between PACES-1 baseline walk and change in 6MWD. For patients whose PACES-1 baseline walk was o 325 meters, deterioration in 6MWD during the first 20 weeks of sildenafil treatment (whether started in PACES-1 or -2) was associated with subsequent poorer survival (hazard ratio [HR], 0.274; 95% confidence interval [CI], 0.141–0.531; Figure 3A). There was a weaker association between change in 6MWD and survival for those whose PACES-1 baseline 6MWD was Z325 meters (HR, 0.910; 95% CI, 0.463–1.790; Figure 3B).
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4 Table 2
Categorized Change in 6-Minute Walk Distance From PACES-1 Baseline PACES-1 Baseline 6MWD Overall (N ¼ 265)
Variablea
1y
6MWD change from baseline Improvement Z60 meters 430 to 60 meters 0 to 30 meters Worsening 40 to 30 meters 430 to 60 meters 460 meters Discontinued Died Missing
2y
o325 m (n ¼ 85) 3y
1y
2y
3y
Etiology Z325 m (n ¼ 180)
IPAH/HPAH (n ¼ 211)
PAH-CTD (n ¼ 54)
1y
1y
1y
2y
3y
2y
73 (28) 67 (25) 51 (19) 20 (24) 18 (21) 11 (13) 53 (29) 49 (27) 40 (22) 63 (30) 46 (17) 26 (10) 19 (7) 12 (14) 6 (7) 5 (6) 34 (19) 20 (11) 14 (8) 39 (18) 38 (14) 23 (9) 18 (7) 7 (8) 6 (7) 3 (4) 31 (17) 17 (9) 15 (8) 32 (15) 22 12 12 36 24 2
(8) (5) (5) (14) (9) (1)
27 9 14 48 48 3
(10) (3) (5) (18) (18) (1)
20 10 13 68 64 2
(8) 4 (5) 2 (2) 1 (1) 18 (10) (4) 1 (1) 4 (5) 2 (2) 11 (6) (5) 5 (6) 0 1 (1) 7 (4) (26) 17 (20) 18 (21) 26 (31) 19 (11) (24) 18 (21) 29 (34) 35 (41) 6 (3) (1) 1 (1) 2 (2) 1 (1) 1 (1)
25 5 14 30 19 1
(14) (3) (8) (17) (11) (1)
19 8 12 42 29 1
(11) (4) (7) (23) (16) (1)
14 8 10 28 16 1
3y
2y
58 (27) 45 (21) 10 (19) 24 (11) 16 (8) 7 (13) 19 (9) 16 (8) 6 (11)
(7) 23 (11) 15 (7) (4) 7 (3) 6 (3) (5) 8 (4) 8 (4) (13) 38 (18) 58 (27) (8) 32 (15) 45 (21) (o1) 2 (1) 2 (1)
8 4 2 8 8 1
3y
9 (17) 2 (4) 4 (7)
6 (11) 3 (6) 2 (4)
(15) 4 (7) 5 (9) (7) 2 (4) 4 (7) (4) 6 (11) 5 (9) (15) 10 (19) 10 (19) (15) 16 (30) 19 (35) (2) 1 (2) 0
6MWD, 6-minute walk distance; CTD, connective tissue disease; HPAH, heritable pulmonary arterial hypertension; IPAH, idiopathic pulmonary arterial hypertension; PAH, pulmonary arterial hypertension. a Data are shown as number (%).
Predictive Variables
Safety
The univariate analysis found 13 PACES-1 baseline characteristics that were associated with survival (Table 4). The best-fit multivariate model included 3 PACES-1 baseline factors: 6MWD, FC, and right atrial pressure (Table 4).
All patients, regardless of PACES-1 treatment, experienced at least 1 AE during the OLE. The most common AEs were headache (64%), diarrhea (47%), dyspnea (45%), nausea (45%), fatigue (40%), dizziness (39%), upper respiratory tract infection (36%), and flushing (32%). Most AEs were mild or moderate in severity (Table 5). The most common treatment-related AEs were headache (49%), flushing (22%), and nausea (17%), and most of these were mild or moderate. At least 1 serious AE occurred in 77% of patients; however, only 7% of patients had a serious AE that was considered to be treatment related. AEs leading to premature discontinuation occurred in 19% of patients. Treatment-related serious AEs that resulted in discontinuation included, in 1 patient each, cardiac failure; cardiac arrest; thrombotic thrombocytopenic purpura; rectal hemorrhage; skin reaction; suicide attempt; and tachycardia, dyspnea, and hypoxia (patient received placebo only). There were no discontinuations because of laboratory test abnormalities during the study.
Epoprostenol Dosage and Complications Considering any epoprostenol dosage change, more patients in PACES-1 and -2 decreased, stopped, or did not change their dose than increased their epoprostenol therapy (relative to PACES-1 baseline), although dose increases were more frequent after 2 years (Supplementary Figure 1, available on the jhltonline.org Web site). Most patients remaining in the OLE did not have changes in epoprostenol dosage that were maintained Z 6 months (Supplementary Figure 1, available on the jhltonline.org Web site). No trends were observed in the mean number of complications of epoprostenol dosing during the study.
Table 3
Categorized Change in World Health Organization Functional Class From PACES-1 Baseline PACES-1 Baseline 6MWD Overall (N ¼ 265)
Variablea
1y
Change from baseline in WHO FC Improved 2 classes 5 (2) Improved 1 class 73 (28) No change 116 (44) Worsened 1 class 10 (4) Worsened 2 classes 1 (o1) Discontinued 36 (14) Died 24 (9)
2y
3y
5 (2) 55 (21) 97 (37) 12 (5) 0 48 (18) 48 (18)
5 42 76 9 1 68 64
(2) (16) (29) (3) (o1) (26) (24)
Etiology
o325 m (n ¼ 85)
Z325 m (n ¼ 180)
IPAH/HPAH (n ¼ 211)
PAH-CTD (n ¼ 54)
1y
1y
1y
1y
2y
3y
2y
3y
0 0 0 5 (3) 5 (3) 5 10 (12) 6 (7) 5 (6) 63 (35) 49 (27) 37 37 (44) 31 (36) 17 (20) 79 (44) 66 (37) 59 2 (2) 1 (1) 2 (2) 8 (4) 11 (6) 7 1 (1) 0 0 0 0 1 17 (20) 18 (21) 26 (31) 19 (11) 30 (17) 42 18 (21) 29 (34) 35 (41) 6 (3) 19 (11) 29
(3) (21) (33) (4) (1) (23) (16)
4 61 94 7 1 28 16
(2) (29) (45) (3) (o1) (13) (8)
2y
3y
4 (2) 48 (23) 81 (38) 8 (4) 0 38 (18) 32 (15)
4 36 59 8 1 58 45
2y
3y
(2) 1 (2) 1 (2) 1 (2) (17) 12 (22) 7 (13) 6 (11) (28) 22 (41) 16 (30) 17 (31) (4) 3 (6) 4 (7) 1 (2) (o1) 0 0 0 (27) 8 (15) 10 (19) 10 (19) (21) 8 (15) 16 (30) 19 (35)
6MWD, 6-minute walk distance; CTD, connective tissue disease HPAH, heritable pulmonary arterial hypertension; IPAH, idiopathic pulmonary arterial hypertension; PAH, pulmonary arterial hypertension; WHO FC, World Health Organization Functional Class. a Data are shown as number (%).
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Long-term Sildenafil Plus Epoprostenol Therapy
Figure 1
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Kaplan-Meier overall survival.
Among the 83 patients who discontinued by 3 years, 15 were confirmed to have died before 3 years, 41 were confirmed to be alive at 3 years, and 27 were lost to follow-up. An additional 49 deaths occurred in patients receiving sildenafil treatment (or r 7 days of the last dose) for 64 known deaths
by Year 3. The investigator considered 2 deaths, both from cardiac arrest, to be related to study treatment; both patients (aged 40 and 62) were randomized to sildenafil in PACES-1 (final sildenafil doses of 40 and 80 mg, three times daily, respectively, and treatment duration of 505 and 722 days).
Figure 2 Kaplan-Meier survival by (Top) PACES-1 baseline 6-minute walk distance (6MWD) and (Bottom) etiology. CTD, connective tissue disease; HPAH, heritable pulmonary artery hypertension; IPAH, idiopathic pulmonary artery hypertension.
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Figure 3 Kaplan-Meier survival after 20 weeks of sildenafil treatment by change in 6-minute walk distance (6MWD) during the initial 20 weeks of sildenafil. Change in 6MWD r 0 meters or 4 0 meters for patients whose PACES-1 baseline 6MWD was o325 meters or Z 325 meters.
Discussion In this extension study of PACES-1, 6MWD was known to have improved or to have been maintained in 59%, 44%, and 33% of patients receiving sildenafil added to IV epoprostenol therapy at 1, 2, and 3 years, respectively; however, the influence of open-label assessment on an Table 4
effort-dependent outcome measure such as 6MWD should be recognized. WHO FC was known to have improved or to have been maintained in 74%, 59%, and 46% of patients at 1, 2, and 3 years, respectively. At 3 years, 66% of patients were known to be alive, 24% were known to have died, and 10% were lost to follow-up. Patients with PACES-1 baseline 6MWD o 325 meters who did not improve in
Baseline Parameters Significantly Associated With Survival From PACES-1 Baseline
Parameter Univariate analysis 6MWD, meters Right atrial pressure, mm Hg WHO functional class Mixed venous oxygen saturation, % Heart rate, beats/min Systolic systemic arterial pressure, mm Hg PVR/SVR Mean systemic arterial pressure, mm Hg Pulse pressure, mm Hg PVR, dyn sec/cm5 PVR index, dyn sec/cm5/m2 Cardiac index, liters/min/m2 Cardiac output, liters/min Multivariate analysisc 6MWD, meters WHO functional class Right atrial pressure, mm Hg
No.
Unit difference for HR
HR (95% CI)a
Unit difference for 10% reduction in deathb
265 265 265 247 263 262 238 246 262 256 255 261 262
30 –1 –1 5 –10 –10 –0.05 –10 5 –100 –100 0.1 0.1
0.77 0.90 0.32 0.74 0.70 1.27 0.92 1.31 0.90 0.94 0.97 0.97 0.98
12.2 –1 –0.1 1.8 –2.9 4.4 –0.1 3.9 5.4 –184.4 –305.7 0.3 0.7
265 265 265
30 –1 –1
0.81 (0.74–0.89) 0.48 (0.30–0.75) 0.91 (0.88–0.95)
(0.71–0.84) (0.87–0.93) (0.21–0.51) (0.66–0.84) (0.59–0.83) (1.09–1.47) (0.87–0.97) (1.07–1.62) (0.83–0.99) (0.90–0.99) (0.94–1.00) (0.94–1.00) (0.97–1.00)
15.4 –0.1 –1.2
6MWD, 6-minute walk distance; CI, confidence interval; HR, hazard ratio; PVR, pulmonary vascular resistance; SVR, systemic vascular resistance; WHO, World Health Organization. a Parameters (i.e., nominally clinically significant unit differences) for which the CIs exclude 1 (within rounding) are statistically significant (p o 0.05). b Because HRs are scale-dependent, the difference in baseline parameters that corresponded to a fixed HR of 0.9 was estimated and 95% CIs were generated; for example, each 12.2-m increase in 6MWD between patients at baseline confers (or is associated with) a 10% lower risk of death. c Includes all significant univariate baseline parameters.
Simonneau et al. Table 5
Long-term Sildenafil Plus Epoprostenol Therapy
Adverse Events Occurring in 15% or More of Patients
Adverse event Headache Diarrhea Dyspnea Nausea Fatigue Dizziness Upper respiratory tract infection Flushing Cough Pain in extremity Peripheral edema Vomiting Chest pain Palpitations Rash Pulmonary hypertension Epistaxis Catheter-related infection Dyspepsia Back pain Abdominal pain Anemia Bronchitis Edema Hypokalemia Arthralgia Pain in jaw Pyrexia Hypotension Nasopharyngitis
Total (N ¼ 265) Mild Moderate Severe No. (%) (No.) (No.) (No.) 170 125 119 118 105 103 96
(64) (47) (45) (45) (40) (39) (36)
61 56 27 54 40 67 52
72 49 64 52 53 35 42
37 20 28 12 12 1 2
84 77 77 77 74 68 66 66 61 58 56
(32) (29) (29) (29) (28) (26) (25) (25) (23) (22) (21)
39 51 37 43 31 27 38 36 5 30 9
36 22 32 29 40 31 24 28 30 23 28
9 4 8 5 3 10 4 2 26 5 19
52 49 47 47 44 44 43 43 42 42 40 40
(20) (18) (18) (18) (17) (17) (16) (16) (16) (16) (15) (15)
25 18 10 15 17 23 28 8 20 23 12 23
23 22 27 22 24 14 11 26 22 17 17 16
4 9 10 10 3 7 4 9 0 2 11 1
6MWD during the first 20 weeks of sildenafil treatment subsequently had poorer survival. The most common AEs reported were generally those previously observed with epoprostenol and/or sildenafil treatment4,6,7 or were not unexpected in patients with PAH. Comparing the results from this study with other longterm PAH studies examining sildenafil or epoprostenol therapy alone is difficult. A study of sildenafil monotherapy noted Kaplan-Meier 3-year survival of 79% and greater percentages of patients who maintained or improved 6MWD and WHO FC than in PACES-2; however, patients in that study were treatment-naive and were healthier at baseline.8 Three-year survival rates with epoprostenol infusion monotherapy range from 48% to 63%,9–14 though patient populations have differed substantially (Supplementary Table 1, available on the jhltonline.org Web site). Although PACES-2 survival compares favorably with survival observed with epoprostenol monotherapy, findings for PACES-2 may be influenced by survivor bias15 because only prevalent patients were recruited into PACES-2. Assessments of 6MWD and WHO FC are likewise not comparable between PACES-2 and historical studies
7
because information from patients who died or discontinued epoprostenol infusion monotherapy in these studies was not considered in reporting,9,10 biasing toward patients who responded to administered therapy.16 How the combination of sildenafil added to epoprostenol therapy compares with other combinations of PAH-specific therapies is unclear. Combination therapy is frequently used in clinical practice despite limited supporting data,17 because of the possibility of additive or synergistic effects on disease control.18 Randomized controlled studies of combination therapy show improved exercise capacity vs monotherapy in short-term studies,19,20 but long-term outcomes are scarce. Small patient numbers plague uncontrolled assessments of combination therapy, including studies where sildenafil was added to prostanoids.21–24 An impressive 2-year survival was noted in the OLE study of the inhaled prostacyclin analog treprostinil with a PDE5 inhibitor (sildenafil, 31% of patients) or an ETRA (bosentan, 69%)25; unlike the treatment sequence in PACES-2, this prostacyclin analog was added to stable oral therapy.26 When additional therapies should be added to a patient’s treatment is debated because no randomized trials address this issue. Patients who failed to improve 6MWD during initial treatment with sildenafil had poorer subsequent survival, especially those with a PACES-1 baseline 6MWD o 325 meters. A similar finding occurred with sildenafil monotherapy in the SUPER-2 study,8 an extension of the Sildenafil Use in Pulmonary Arterial Hypertension (SUPER-1) study, suggesting that patients who have a lower baseline 6MWD and fail to improve 6MWD with active PAH treatment have the poorest outcomes. However, although these data provide insight about prognosis, they are not direct evidence about when or how to add therapies. The best-fit multivariate model assessing baseline predictors of survival in PACES-2 included 3 parameters— exercise capacity, WHO FC, and right atrial pressure— previously identified as predictive in patients with IPAH treated with long-term epoprostenol9,10 and in registries of patients with PAH of varying etiology.27,28 The United States registry, with 40% of patients on combination therapy, additionally found resting systolic blood pressure and heart rate were predictive of survival,27 as in our univariate analysis. In treprostinil-treated patients, PVR index and mixed venous oxygen saturation (in addition to FC) were similarly identified as prognostic.29 Additional univariate factors identified in our study (e.g., cardiac index) have been significant in some studies but not others, perhaps reflecting differences in patient numbers, populations, and/or analyses. Epoprostenol management during long-term therapy is rarely described.7 Few patients stopped epoprostenol treatment in this OLE. Slightly more patients had epoprostenol dose decreases rather than increases over the first 2 years; this trend reversed by Year 3, suggesting disease progression between 2 and 3 years. The OLE design, which allowed investigators to adjust epoprostenol dosage as needed, mimics clinical practice more than traditional studies, which generally prohibit additional medication until patients have significantly worsened; however, this design also limits the conclusions that can be drawn.
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Notably, PACES-2, as in other long-term OLE studies, provides useful descriptive information, but without a randomized control group, causal relationships cannot be reliably assessed. Although the ability to change therapy (i.e., epoprostenol dosing) mimics clinical disease management, this and the ability of the investigator to add other PAH-specific medications complicates interpretation of the results. The sildenafil dose used by 4 69% of patients at the end of the study, 80 mg three times daily, is 4-fold higher than the approved dose of 20 mg three times daily; therefore, outcomes with lower doses of sildenafil are unknown. Further, patients who discontinued sildenafil in this study but who may have received commercial sildenafil were not tracked, with the exception of survival whenever possible. In conclusion, although a reliable assessment of safety as well as efficacy would require a long-term randomized controlled trial, the addition of oral sildenafil to background IV epoprostenol therapy appears generally well tolerated in PAH patients. At 3 years, in an open-label setting, 33% of patients maintained or improved 6MWD and 46% maintained or improved FC.
Disclosure statement This study was funded by Pfizer Inc, New York, New York. Pfizer worked with all PACES-2 investigators to collect data. Pfizer statisticians and contractors performed the analyses; summary Tables were sent to authors for review. Editorial assistance was provided by Tiffany Brake, PhD, at Complete Healthcare Communications, Inc., and was funded by Pfizer Inc. L.J.R. serves as a consultant for Pfizer, GlaxoSmithKline, Actelion, United Therapeutics, Bayer, Gilead, GeNO, Aires, and MondoBiotech, serves on a scientific board of United Therapeutics, and has served as an expert witness in diet drug litigation. D.B.B. has received honoraria (for steering committees and/or advisory board services) from Actelion, Arena, Bayer, Ikaria, Gilead, Encysive Pharmaceuticals, Pfizer, GlaxoSmithKline, Lung Rx, United Therapeutics, Eli Lilly & Co., Biogen Idec, and mondoBIOTECH; has received grants from Actelion, Gilead, Encysive Pharmaceuticals, Pfizer, United Therapeutics, Lung Rx, Eli Lilly & Co., Bayer, Ikaria, and the National Institutes of Health/ National Heart, Lung, and Blood Institute; has been deposed previously in appetite suppressant litigation, serving as both a treating physician and an expert witness; and has provided consultation to legal counsel for Actelion. A.F. has received research support from Actelion, Gilead, United Therapeutics, Lilly, Aires, Ikaria, Novartis, Pfizer, Bayer, and VentriPoint and has received honoraria for participation in steering committees, advisory boards, and/or speaker’s bureaus from United Therapeutics, Gilead, and Bayer. P.E. has received honoraria from Actelion and Gilead, research support from Actelion, and symposium support from Actelion, Gilead, and United Therapeutics, and has been a member of a speaker’s bureau for United Therapeutics. M.S.-P. is a Pfizer employee. G.R.L. was a Pfizer employee at the time the study was conducted and is a consultant for Aires and Actelion. R.J.B., who died before finalization of the manuscript, had received honoraria (for steering committees and/or advisory board services) from Actelion, Bayer, Eli Lilly, GSK, Gilead, Ikaria, Novartis, Pfizer and VentriPoint, was deposed previously in appetite suppressant litigation, serving as both a treating physician and an expert witness, and owned stock in VentriPoint. None of the
other authors has a financial relationship with a commercial entity that has an interest in the subject of the presented manuscript or other conflicts of interest to disclose.
Supplementary data Supplementary data are available in the online version at jhltonline.org.
References 1. Galiè N, Torbicki A, Barst R, et al. Guidelines on diagnosis and treatment of pulmonary arterial hypertension. The Task Force on Diagnosis and Treatment of Pulmonary Arterial Hypertension of the European Society of Cardiology. Eur Heart J 2004;25:2243-78. 2. Humbert M, Sitbon O, Simonneau G. Treatment of pulmonary arterial hypertension. N Engl J Med 2004;351:1425-36. 3. Mehta S. Sildenafil for pulmonary arterial hypertension: exciting, but protection required. Chest 2003;123:989-92. 4. Galie N, Ghofrani HA, Torbicki A, et al. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med 2005;353:2148-57. 5. Barst RJ, Rubin LJ, Long WA, et al. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. The Primary Pulmonary Hypertension Study Group. N Engl J Med 1996;334:296-302. 6. Simonneau G, Rubin LJ, Galie N, et al. Addition of sildenafil to longterm intravenous epoprostenol therapy in patients with pulmonary arterial hypertension: a randomized trial. Ann Intern Med 2008;149: 521-30. 7. Barst RJ. How has epoprostenol changed the outcome for patients with pulmonary arterial hypertension? PVRI Rev 2009;1:150-6. 8. Rubin LJ, Badesch DB, Fleming TR, et al. Long-term treatment with sildenafil citrate in pulmonary arterial hypertension: the SUPER-2 study. Chest 2011;140:1274-83. 9. McLaughlin VV, Shillington A, Rich S. Survival in primary pulmonary hypertension: the impact of epoprostenol therapy. Circulation 2002; 106:1477-82. 10. Sitbon O, Humbert M, Nunes H, et al. Long-term intravenous epoprostenol infusion in primary pulmonary hypertension: prognostic factors and survival. J Am Coll Cardiol 2002;40:780-8. 11. Barst RJ, Rubin LJ, McGoon MD, et al. Survival in primary pulmonary hypertension with long-term continuous intravenous prostacyclin. Ann Intern Med 1994;121:409-15. 12. Shapiro SM, Oudiz RJ, Cao T, et al. Primary pulmonary hypertension: improved long-term effects and survival with continuous intravenous epoprostenol infusion. J Am Coll Cardiol 1997;30:343-9. 13. Badesch DB, McGoon MD, Barst RJ, et al. Longterm survival among patients with scleroderma-associated pulmonary arterial hypertension treated with intravenous epoprostenol. J Rheumatol 2009;36:2244-9. 14. Kuhn KP, Byrne DW, Arbogast PG, et al. Outcome in 91 consecutive patients with pulmonary arterial hypertension receiving epoprostenol. Am J Respir Crit Care Med 2003;167:580-6. 15. Humbert M, Sitbon O, Yaici A, et al. Survival in incident and prevalent cohorts of patients with pulmonary arterial hypertension. Eur Respir J 2010;36:549-55. 16. Gomberg-Maitland M, Dufton C, Oudiz RJ, Benza RL. Compelling evidence of long-term outcomes in pulmonary arterial hypertension? A clinical perspective. J Am Coll Cardiol 2011;57:1053-61. 17. Rubin LJ. Combination therapy for pulmonary artery hypertension: what is the evidence? Cardiology 2011;120:172-3. 18. Levinson AT, Klinger JR. Combination therapy for the treatment of pulmonary arterial hypertension. Ther Adv Respir Dis 2011;5:419-30. 19. Fox BD, Shimony A, Langleben D. Meta-analysis of monotherapy versus combination therapy for pulmonary arterial hypertension. Am J Cardiol 2011;108:1177-82. 20. Bai Y, Sun L, Hu S, Wei Y. Combination therapy in pulmonary arterial hypertension: a meta-analysis. Cardiology 2011;120:157-65.
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21. Ruiz MJ, Escribano P, Delgado JF, et al. Efficacy of sildenafil as a rescue therapy for patients with severe pulmonary arterial hypertension and given long-term treatment with prostanoids: 2-year experience. J Heart Lung Transplant 2006;25:1353-7. 22. Ikeda D, Tsujino I, Ohira H, et al. Addition of oral sildenafil to beraprost is a safe and effective therapeutic option for patients with pulmonary hypertension. J Cardiovasc Pharmacol 2005;45: 286-9. 23. Ghofrani HA, Rose F, Schermuly RT, et al. Oral sildenafil as long-term adjunct therapy to inhaled iloprost in severe pulmonary arterial hypertension. J Am Coll Cardiol 2003;42:158-64. 24. Stiebellehner L, Petkov V, Vonbank K, et al. Long-term treatment with oral sildenafil in addition to continuous IV epoprostenol in patients with pulmonary arterial hypertension. Chest 2003;123:1293-5. 25. Benza RL, Seeger W, McLaughlin VV, et al. Long-term effects of inhaled treprostinil in patients with pulmonary arterial hypertension: the Treprostinil Sodium Inhalation Used in the Management of Pulmonary
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9 Arterial Hypertension (TRIUMPH) study open-label extension. J Heart Lung Transplant 2011;30:1327-33. McLaughlin VV, Benza RL, Rubin LJ, et al. Addition of inhaled treprostinil to oral therapy for pulmonary arterial hypertension: a randomized controlled clinical trial. J Am Coll Cardiol 2010;55:1915-22. Benza RL, Miller DP, Gomberg-Maitland M, et al. Predicting survival in pulmonary arterial hypertension: insights from the Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL). Circulation 2010;122:164-72. Humbert M, Sitbon O, Chaouat A, et al. Survival in patients with idiopathic, familial, and anorexigen-associated pulmonary arterial hypertension in the modern management era. Circulation 2010;122:156-63. Benza RL, Gomberg-Maitland M, Naeije R, Arneson CP, Lang IM. Prognostic factors associated with increased survival in patients with pulmonary arterial hypertension treated with subcutaneous treprostinil in randomized, placebo-controlled trials. J Heart Lung Transplant 2011;30:982-9.
ORIGINAL CLINICAL SCIENCE
Long-term sildenafil added to intravenous epoprostenol in patients with pulmonary arterial hypertension Gérald Simonneau, MD,a Lewis J. Rubin, MD,b Nazzareno Galiè, MD,c Robyn J. Barst, MD,,d Thomas R. Fleming, PhD,e Adaani Frost, MD,f Peter Engel, MD,g Mordechai R. Kramer, MD,h Marjana Serdarevic-Pehar, MD,i Gary R. Layton, MSc,j Olivier Sitbon, MD, PhD,a and David B. Badesch, MD,k on behalf of the PACES Study Group From the aUniversity Paris-Sud, National Reference Center for Severe Pulmonary Hypertension, Hôpital de Bicêtre, Le Kremlin-Bicêtre, France; the bDepartment of Medicine, University of California at San Diego, La Jolla, California; the cInstitute of Cardiology, Bologna University Hospital, Bologna, Italy; the dDivision of Pediatric Cardiology, Columbia University, New York, New York; the eDepartment of Biostatistics, University of Washington, Seattle, Washington; the fDepartment of Medicine, Section of Pulmonary and Critical Care, Baylor College of Medicine, Houston, Texas; the gPulmonary Hypertension Program, The Christ Hospital, Cincinnati, Ohio; the hPulmonary Institute, Rabin Medical Center, Petah Tikva, Israel; the iPfizer Inc, New York, New York; the jWorldwide Pharmaceutical Operations, Pfizer Ltd, Sandwich, Kent, United Kingdom; and the kDivision of Pulmonary Sciences and Critical Care Medicine, and Cardiology Director, Pulmonary Hypertension Program, University of Colorado Denver, Denver, Colorado.
KEYWORDS: sildenafil; epoprostenol; pulmonary arterial hypertension; survival; clinical trial
*
BACKGROUND: In pulmonary arterial hypertension (PAH), adding oral sildenafil to intravenous epoprostenol improved 6-minute walk distance (6MWD) and hemodynamics and delayed time to clinical worsening in a 16-week randomized, placebo-controlled trial (Pulmonary Arterial Hypertension Combination Study of Epoprostenol and Sildenafil [PACES-1]). METHODS: Patients completing PACES-1 could receive sildenafil (titrated to 80 mg, three times daily, as tolerated) in an open-label extension study (PACES-2) for Z 3 years; additional therapy was added according to investigator judgment. Survival and changes from PACES-1 baseline in World Health Organization Functional Class and 6MWD were captured. RESULTS: In an open-label setting, 6MWD, an effort-dependent outcome measure, was known to have improved or to have been maintained in 59%, 44%, and 33% of patients at 1, 2, and 3 years, respectively; functional class was known to have improved or to have been maintained in 73%, 59%, and 46%. At 3 years, 66% of patients were known to be alive, 24% were known to have died, and 10% were lost to follow-up. Patients with PACES-1 baseline 6MWD o 325 meters without 6MWD improvement during the first 20 weeks of sildenafil treatment subsequently had poorer survival. CONCLUSIONS: Although reliable assessments of safety and efficacy require a long-term randomized trial, the addition of sildenafil to background intravenous epoprostenol therapy appeared generally to be well tolerated in PAH patients. J Heart Lung Transplant ]]]];]:]]]–]]] r 2014 Published by Elsevier Inc. on behalf of International Society for Heart and Lung Transplantation. All rights reserved.
Deceased. Reprint requests: Gérald Simonneau, MD, Department of Pneumology and ICU, National Reference Center for Severe Pulmonary Hypertension, South Paris University, Hopital de Bicêtre, 78 rue du Général Leclerc, 94275 Le KremlinBicêtre, France. Telephone: 33-0-1-45-21-79-72. Fax: 33-0-1-45-21-79-71. E-mail address: [email protected]
Pulmonary arterial hypertension (PAH) is characterized by a progressive increase of pulmonary vascular resistance (PVR) leading to right heart failure and death.1,2 Pulmonary vasculature remodelling, vasoconstriction, and thrombosis in situ contribute to increased PVR; endothelial dysfunction appears to play a key role.2
1053-2498/$-see front matter r 2014 Published by Elsevier Inc. on behalf of International Society for Heart and Lung Transplantation. All rights reserved. http://dx.doi.org/10.1016/j.healun.2014.02.019
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Approved PAH-specific medical therapies target prostacyclin, nitric oxide (NO), and endothelin pathways. Prostacyclin promotes vascular smooth muscle relaxation through increased cyclic adenosine monophosphate production and also inhibits smooth muscle cell growth and platelet aggregation.2 NO diffusing through the endothelium signals an increase in the production of cyclic guanosine monophosphate (cGMP), which produces smooth muscle relaxation.3 Because phosphodiesterase type 5 (PDE5) metabolizes cGMP in endothelial cells, PDE5-inhibitor treatment increases the pool of cGMP, thereby increasing vasodilation. Endothelin-1 is a potent vasoconstrictor and mitogen, and endothelin-receptor antagonists (ETRAs) oppose these endothelin-1 actions.2 Oral sildenafil, a PDE5 inhibitor, and intravenous (IV) epoprostenol, a synthetic prostacyclin, each improve outcomes in patients with PAH as monotherapy.4,5 These 2 agents target separate pathways that appear to contribute to the pathobiology of PAH. The Pulmonary Arterial Hypertension Combination Study of Epoprostenol and Sildenafil (PACES-1) trial provided a 16-week, randomized, placebo-controlled evaluation of the addition of oral sildenafil (80 mg, three times daily, as tolerated) to background IV epoprostenol. This combination increased the 6-minute walk distance (6MWD), delayed the time to clinical worsening, and improved hemodynamic parameters compared with IV epoprostenol treatment alone.6 Patients who completed PACES-1 were eligible to enroll in PACES2, (ClinicalTrials.gov Identifier: NCT00147641), an openlabel extension (OLE) of PACES-1, in which all patients received sildenafil in addition to epoprostenol until the last enrolled patient received 3 years of sildenafil treatment. We report here the results for these patients.
Methods Local Institutional Review Boards or independent Ethics Committees approved the protocol.
Study design This study was conducted between November 2003 and April 2009 at 45 sites in 10 countries, ending when the last patient enrolled in the OLE completed 3 years of sildenafil treatment, including 16 weeks of PACES-1 sildenafil treatment (if receiving the active drug in PACES-1). Regardless of therapy received in PACES-1,6 all patients entering PACES-2 received sildenafil at 20 mg, three times daily, then titrated to 40, and then to 80 mg, three times daily, as tolerated, with doses separated by Z 6 hours. Patients could reduce the dose of sildenafil to a minimum of 20 mg, three times daily. Patients unable to tolerate sildenafil at 20 mg three times daily were withdrawn and monitored for survival. The epoprostenol dosage could be changed at the discretion of the investigator at any time during the study. The PACES-1 baseline constituted the baseline for the OLE. Follow-up assessments were conducted at 20 and 24 weeks and every 3 months thereafter. Laboratory safety assessments were performed at baseline, Week 16 of PACES-1, then at the first 3-month visit in PACES-2 (ie, Week 36 relative to the PACES-1 baseline), and every 6 months thereafter.
Patients Patients with idiopathic PAH (IPAH), heritable PAH (HPAH), or PAH associated with anorexigen use, connective tissue disease (CTD), or corrected congenital heart defect, who completed PACES-1 (or received an increased epoprostenol dose due to clinical deterioration in PACES-1 and completed all end-of-study assessments and Z 4 weeks of PACES-1) and gave informed consent were eligible to enter the OLE. Exclusion criteria have been published for PACES-1.6 Briefly, patients were not permitted to use nitrates or NO donors, protease inhibitors, or α-blockers. Oral anti-coagulants, digitalis, diuretics, calcium channel blockers in acute responders, and supplemental oxygen were permitted. After a protocol amendment in September 2007, patients could receive ETRAs and other prostacyclin analogs in PACES-2 if the investigator judged that additional therapy was warranted. Patients who permanently discontinued sildenafil study treatment were monitored for survival whenever possible.
Outcome measures At all visits, 6MWD and World Health Organization Functional Class (WHO FC) were assessed. The 6MWD test was performed as close to trough levels of sildenafil as possible. Descriptive summaries without significance testing are presented. Missing data for 6MWD and FC were imputed using the worst value for nonmissing adjacent values. “Missing” scores indicated that a score was missing at a target visit, and no subsequent score was recorded. The survival status of all patients, including those who discontinued study treatment (when possible), was documented yearly. Kaplan-Meier estimates of 1-, 2-, and 3-year survival were calculated overall and by PACES-1 baseline 6MWD (dichotomized as o 325 or Z 325 meters) and PAH etiology (both prespecified). Because missing follow-up data for some patients who discontinued treatment likely would lead to biased overestimates, the proportions of patients known to be alive at 1, 2, and 3 years were also calculated. A Cox regression was used to explore the relationship between change in the 6MWD during 20 weeks of sildenafil treatment and subsequent survival. In this latter analysis, change from baseline in 6MWD was defined as the change between Week 0 and Week 20 for patients randomized to sildenafil in PACES-1, and the change between Week 16 and Week 36 (i.e., Month 9 visit) for patients randomized to placebo in PACES-1. “Time 0” for survival, the dependent variable, was Week 20 for PACES-1 sildenafil patients and Week 36 for PACES-1 placebo patients. A post hoc Cox regression analysis was used to assess the association of 17 baseline covariates with survival: 6MWD, WHO FC, PAH etiology, mean pulmonary arterial pressure (PAP), mean PAP/mean arterial pressure, systolic and diastolic PAP, right atrial pressure, mixed venous oxygen saturation, heart rate, pulse pressure, mean systemic arterial pressure, PVR, PVR index, systemic vascular resistance (SVR), SVR index, PVR/SVR, cardiac index, cardiac output, and pulmonary capillary wedge pressure. “Time 0” for all patients was baseline of the PACES-1 study. Univariate and multivariate analyses were conducted. The number of patients with changes in intravenous epoprostenol dose was collected. The mean number of signs and symptoms of complications of epoprostenol (or alternative prostacyclin analog) use (e.g., headache, jaw pain, flushing) was recorded. Adverse events (AEs) were coded using the Medical Dictionary for Regulatory Activities and were assessed for severity and relation to
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treatment. AE data were summarized; all PACES-1 randomized patients who received Z 1 dose of study drug were included in the safety population.
Results
3
Anti-coagulants (97%), diuretics (85%), and supplemental oxygen treatment (58%) were the most common concomitant therapies; 38% of patients received systemic antihypertensive drugs. After a protocol amendment, 27 patients received bosentan; 10, ambrisentan; and 1, sitaxentan.
Patients 6MWD results Of the 265 patients randomized and treated in PACES-1 (placebo, n ¼ 131; sildenafil, n ¼ 134), 242 received openlabel sildenafil in addition to continued IV epoprostenol therapy in PACES-2. Of these 242, 23 entered the OLE without completing all 16 weeks of PACES-1 (n ¼ 16 [14 placebo, 2 sildenafil] for Z 10% increase in epoprostenol dose because of perceived deterioration). Most patients were female, were white, and had IPAH/HPAH (Table 1). Most patients on the study drug were receiving the dose of 80 mg, three times daily, at Years 1, 2, and 3 (71%, 70%, and 68%, respectively); median sildenafil exposure was 3.2 years (range, 3 days–5.4 years) in PACES-1 and -2.
Table 1 PACES-1 Baseline Demographics and Clinical Characteristics Variablea Sex Women Men Age, years Ethnicity White Black Asian Other PAH classification Idiopathic Duration since first diagnosis, years Associated with CTD Duration since first diagnosis, years Epoprostenol treatment Dose, ng/kg/min Duration, years 6MWD,b meters WHO functional class I II III IV Borg dyspnea scorec
Placebo (n ¼ 131)
Sildenafil (n ¼ 134)
102 (78) 29 (22) 48 ⫾ 13
110 (82) 24 (18) 48 ⫾ 13
106 (81) 7 (5) 6 (5) 12 (9)
105 (78) 10 (8) 5 (4) 14 (10)
104 (79) 5.1 (0.3–37.2)
107 (80) 4.2 (0.3–25.8)
27 (21) 4.5 (0.5–13.1)
27 (20) 3.7 (0.3–8.8)
31.98 ⫾ 22.43 32.89 ⫾ 22.11 (3–179) (4–181) 2.9 (0.3–11.7) 2.8 (0.2–10.5) 349 ⫾ 73 350 ⫾ 69 2 (2) 35 (27) 88 (67) 6 (5) 3.3 ⫾ 2.0 3 (0–10)
1 (1) 34 (25) 89 (66) 10 (7) 3.5 ⫾ 2.0 3 (0–10)
6MWD, 6-minute walk distance; CTD, connective tissue disease; PAH, pulmonary arterial hypertension; WHO, World Health Organization. a Continuous data are shown as mean ⫾ standard deviation, mean (range), and discrete data as number (%). b Placebo, n ¼ 119; sildenafil, n ¼ 131. c Placebo, n ¼ 115; sildenafil, n ¼ 123.
At 1, 2, and 3 years, 6MWD was known to have improved or to have been maintained in 59%, 44%, and 33% of patients, respectively, and 28%, 25%, and 19% of patients improved 6MWD Z 60 meters (Table 2). Greater improvements were observed in patients with baseline 6MWD Z 325 meters in PACES-1 compared with 6MWD o 325 meters and in patients with IPAH/HPAH vs PAH-CTD (Table 2).
WHO FC assessment WHO FC at 1, 2, and 3 years was known to have been maintained in 44%, 37%, and 29% of patients, respectively, and known to have improved in 29%, 23%, and 18% (Table 3). Improvements were greater for patients with baseline 6MWD Z325 meters in PACES-1 compared with patients with 6MWD o 325 meters and for patients with IPAH/HPAH vs PAH-CTD (Table 3). Of 133 patients with data available for analysis at Year 3, 60 (45%) were WHO FC II. Of these patients, 32 (53%) were FC III, and 28 (47%) were FC II at PACES-1 baseline.
Survival Overall Kaplan-Meier estimates of survival at 1, 2, and 3 years were 91%, 81%, and 74%, respectively; estimates were 92%, 81%, and 74% for sildenafil-treated and 89%, 80%, and 74% for placebo-treated PACES-1 patients (Figure 1). These estimates are likely upwardly biased due to informative missingness. At 3 years, 66% of patients were known to be alive, 24% were known to have died, and 10% were lost to follow-up after discontinuation. Seven patients received lung (n ¼ 3) or heart/lung transplants (n ¼ 4). Survival was longer for patients with PACES-1 baseline 6MWD Z 325 meters than patients with baseline 6MWD o 325 meters (Figure 2A). Survival also appeared better for patients with IPAH/HPAH vs PAH-CTD (Figure 2B). A substantial interaction was seen between PACES-1 baseline walk and change in 6MWD. For patients whose PACES-1 baseline walk was o 325 meters, deterioration in 6MWD during the first 20 weeks of sildenafil treatment (whether started in PACES-1 or -2) was associated with subsequent poorer survival (hazard ratio [HR], 0.274; 95% confidence interval [CI], 0.141–0.531; Figure 3A). There was a weaker association between change in 6MWD and survival for those whose PACES-1 baseline 6MWD was Z325 meters (HR, 0.910; 95% CI, 0.463–1.790; Figure 3B).
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4 Table 2
Categorized Change in 6-Minute Walk Distance From PACES-1 Baseline PACES-1 Baseline 6MWD Overall (N ¼ 265)
Variablea
1y
6MWD change from baseline Improvement Z60 meters 430 to 60 meters 0 to 30 meters Worsening 40 to 30 meters 430 to 60 meters 460 meters Discontinued Died Missing
2y
o325 m (n ¼ 85) 3y
1y
2y
3y
Etiology Z325 m (n ¼ 180)
IPAH/HPAH (n ¼ 211)
PAH-CTD (n ¼ 54)
1y
1y
1y
2y
3y
2y
73 (28) 67 (25) 51 (19) 20 (24) 18 (21) 11 (13) 53 (29) 49 (27) 40 (22) 63 (30) 46 (17) 26 (10) 19 (7) 12 (14) 6 (7) 5 (6) 34 (19) 20 (11) 14 (8) 39 (18) 38 (14) 23 (9) 18 (7) 7 (8) 6 (7) 3 (4) 31 (17) 17 (9) 15 (8) 32 (15) 22 12 12 36 24 2
(8) (5) (5) (14) (9) (1)
27 9 14 48 48 3
(10) (3) (5) (18) (18) (1)
20 10 13 68 64 2
(8) 4 (5) 2 (2) 1 (1) 18 (10) (4) 1 (1) 4 (5) 2 (2) 11 (6) (5) 5 (6) 0 1 (1) 7 (4) (26) 17 (20) 18 (21) 26 (31) 19 (11) (24) 18 (21) 29 (34) 35 (41) 6 (3) (1) 1 (1) 2 (2) 1 (1) 1 (1)
25 5 14 30 19 1
(14) (3) (8) (17) (11) (1)
19 8 12 42 29 1
(11) (4) (7) (23) (16) (1)
14 8 10 28 16 1
3y
2y
58 (27) 45 (21) 10 (19) 24 (11) 16 (8) 7 (13) 19 (9) 16 (8) 6 (11)
(7) 23 (11) 15 (7) (4) 7 (3) 6 (3) (5) 8 (4) 8 (4) (13) 38 (18) 58 (27) (8) 32 (15) 45 (21) (o1) 2 (1) 2 (1)
8 4 2 8 8 1
3y
9 (17) 2 (4) 4 (7)
6 (11) 3 (6) 2 (4)
(15) 4 (7) 5 (9) (7) 2 (4) 4 (7) (4) 6 (11) 5 (9) (15) 10 (19) 10 (19) (15) 16 (30) 19 (35) (2) 1 (2) 0
6MWD, 6-minute walk distance; CTD, connective tissue disease; HPAH, heritable pulmonary arterial hypertension; IPAH, idiopathic pulmonary arterial hypertension; PAH, pulmonary arterial hypertension. a Data are shown as number (%).
Predictive Variables
Safety
The univariate analysis found 13 PACES-1 baseline characteristics that were associated with survival (Table 4). The best-fit multivariate model included 3 PACES-1 baseline factors: 6MWD, FC, and right atrial pressure (Table 4).
All patients, regardless of PACES-1 treatment, experienced at least 1 AE during the OLE. The most common AEs were headache (64%), diarrhea (47%), dyspnea (45%), nausea (45%), fatigue (40%), dizziness (39%), upper respiratory tract infection (36%), and flushing (32%). Most AEs were mild or moderate in severity (Table 5). The most common treatment-related AEs were headache (49%), flushing (22%), and nausea (17%), and most of these were mild or moderate. At least 1 serious AE occurred in 77% of patients; however, only 7% of patients had a serious AE that was considered to be treatment related. AEs leading to premature discontinuation occurred in 19% of patients. Treatment-related serious AEs that resulted in discontinuation included, in 1 patient each, cardiac failure; cardiac arrest; thrombotic thrombocytopenic purpura; rectal hemorrhage; skin reaction; suicide attempt; and tachycardia, dyspnea, and hypoxia (patient received placebo only). There were no discontinuations because of laboratory test abnormalities during the study.
Epoprostenol Dosage and Complications Considering any epoprostenol dosage change, more patients in PACES-1 and -2 decreased, stopped, or did not change their dose than increased their epoprostenol therapy (relative to PACES-1 baseline), although dose increases were more frequent after 2 years (Supplementary Figure 1, available on the jhltonline.org Web site). Most patients remaining in the OLE did not have changes in epoprostenol dosage that were maintained Z 6 months (Supplementary Figure 1, available on the jhltonline.org Web site). No trends were observed in the mean number of complications of epoprostenol dosing during the study.
Table 3
Categorized Change in World Health Organization Functional Class From PACES-1 Baseline PACES-1 Baseline 6MWD Overall (N ¼ 265)
Variablea
1y
Change from baseline in WHO FC Improved 2 classes 5 (2) Improved 1 class 73 (28) No change 116 (44) Worsened 1 class 10 (4) Worsened 2 classes 1 (o1) Discontinued 36 (14) Died 24 (9)
2y
3y
5 (2) 55 (21) 97 (37) 12 (5) 0 48 (18) 48 (18)
5 42 76 9 1 68 64
(2) (16) (29) (3) (o1) (26) (24)
Etiology
o325 m (n ¼ 85)
Z325 m (n ¼ 180)
IPAH/HPAH (n ¼ 211)
PAH-CTD (n ¼ 54)
1y
1y
1y
1y
2y
3y
2y
3y
0 0 0 5 (3) 5 (3) 5 10 (12) 6 (7) 5 (6) 63 (35) 49 (27) 37 37 (44) 31 (36) 17 (20) 79 (44) 66 (37) 59 2 (2) 1 (1) 2 (2) 8 (4) 11 (6) 7 1 (1) 0 0 0 0 1 17 (20) 18 (21) 26 (31) 19 (11) 30 (17) 42 18 (21) 29 (34) 35 (41) 6 (3) 19 (11) 29
(3) (21) (33) (4) (1) (23) (16)
4 61 94 7 1 28 16
(2) (29) (45) (3) (o1) (13) (8)
2y
3y
4 (2) 48 (23) 81 (38) 8 (4) 0 38 (18) 32 (15)
4 36 59 8 1 58 45
2y
3y
(2) 1 (2) 1 (2) 1 (2) (17) 12 (22) 7 (13) 6 (11) (28) 22 (41) 16 (30) 17 (31) (4) 3 (6) 4 (7) 1 (2) (o1) 0 0 0 (27) 8 (15) 10 (19) 10 (19) (21) 8 (15) 16 (30) 19 (35)
6MWD, 6-minute walk distance; CTD, connective tissue disease HPAH, heritable pulmonary arterial hypertension; IPAH, idiopathic pulmonary arterial hypertension; PAH, pulmonary arterial hypertension; WHO FC, World Health Organization Functional Class. a Data are shown as number (%).
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Long-term Sildenafil Plus Epoprostenol Therapy
Figure 1
5
Kaplan-Meier overall survival.
Among the 83 patients who discontinued by 3 years, 15 were confirmed to have died before 3 years, 41 were confirmed to be alive at 3 years, and 27 were lost to follow-up. An additional 49 deaths occurred in patients receiving sildenafil treatment (or r 7 days of the last dose) for 64 known deaths
by Year 3. The investigator considered 2 deaths, both from cardiac arrest, to be related to study treatment; both patients (aged 40 and 62) were randomized to sildenafil in PACES-1 (final sildenafil doses of 40 and 80 mg, three times daily, respectively, and treatment duration of 505 and 722 days).
Figure 2 Kaplan-Meier survival by (Top) PACES-1 baseline 6-minute walk distance (6MWD) and (Bottom) etiology. CTD, connective tissue disease; HPAH, heritable pulmonary artery hypertension; IPAH, idiopathic pulmonary artery hypertension.
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6
Figure 3 Kaplan-Meier survival after 20 weeks of sildenafil treatment by change in 6-minute walk distance (6MWD) during the initial 20 weeks of sildenafil. Change in 6MWD r 0 meters or 4 0 meters for patients whose PACES-1 baseline 6MWD was o325 meters or Z 325 meters.
Discussion In this extension study of PACES-1, 6MWD was known to have improved or to have been maintained in 59%, 44%, and 33% of patients receiving sildenafil added to IV epoprostenol therapy at 1, 2, and 3 years, respectively; however, the influence of open-label assessment on an Table 4
effort-dependent outcome measure such as 6MWD should be recognized. WHO FC was known to have improved or to have been maintained in 74%, 59%, and 46% of patients at 1, 2, and 3 years, respectively. At 3 years, 66% of patients were known to be alive, 24% were known to have died, and 10% were lost to follow-up. Patients with PACES-1 baseline 6MWD o 325 meters who did not improve in
Baseline Parameters Significantly Associated With Survival From PACES-1 Baseline
Parameter Univariate analysis 6MWD, meters Right atrial pressure, mm Hg WHO functional class Mixed venous oxygen saturation, % Heart rate, beats/min Systolic systemic arterial pressure, mm Hg PVR/SVR Mean systemic arterial pressure, mm Hg Pulse pressure, mm Hg PVR, dyn sec/cm5 PVR index, dyn sec/cm5/m2 Cardiac index, liters/min/m2 Cardiac output, liters/min Multivariate analysisc 6MWD, meters WHO functional class Right atrial pressure, mm Hg
No.
Unit difference for HR
HR (95% CI)a
Unit difference for 10% reduction in deathb
265 265 265 247 263 262 238 246 262 256 255 261 262
30 –1 –1 5 –10 –10 –0.05 –10 5 –100 –100 0.1 0.1
0.77 0.90 0.32 0.74 0.70 1.27 0.92 1.31 0.90 0.94 0.97 0.97 0.98
12.2 –1 –0.1 1.8 –2.9 4.4 –0.1 3.9 5.4 –184.4 –305.7 0.3 0.7
265 265 265
30 –1 –1
0.81 (0.74–0.89) 0.48 (0.30–0.75) 0.91 (0.88–0.95)
(0.71–0.84) (0.87–0.93) (0.21–0.51) (0.66–0.84) (0.59–0.83) (1.09–1.47) (0.87–0.97) (1.07–1.62) (0.83–0.99) (0.90–0.99) (0.94–1.00) (0.94–1.00) (0.97–1.00)
15.4 –0.1 –1.2
6MWD, 6-minute walk distance; CI, confidence interval; HR, hazard ratio; PVR, pulmonary vascular resistance; SVR, systemic vascular resistance; WHO, World Health Organization. a Parameters (i.e., nominally clinically significant unit differences) for which the CIs exclude 1 (within rounding) are statistically significant (p o 0.05). b Because HRs are scale-dependent, the difference in baseline parameters that corresponded to a fixed HR of 0.9 was estimated and 95% CIs were generated; for example, each 12.2-m increase in 6MWD between patients at baseline confers (or is associated with) a 10% lower risk of death. c Includes all significant univariate baseline parameters.
Simonneau et al. Table 5
Long-term Sildenafil Plus Epoprostenol Therapy
Adverse Events Occurring in 15% or More of Patients
Adverse event Headache Diarrhea Dyspnea Nausea Fatigue Dizziness Upper respiratory tract infection Flushing Cough Pain in extremity Peripheral edema Vomiting Chest pain Palpitations Rash Pulmonary hypertension Epistaxis Catheter-related infection Dyspepsia Back pain Abdominal pain Anemia Bronchitis Edema Hypokalemia Arthralgia Pain in jaw Pyrexia Hypotension Nasopharyngitis
Total (N ¼ 265) Mild Moderate Severe No. (%) (No.) (No.) (No.) 170 125 119 118 105 103 96
(64) (47) (45) (45) (40) (39) (36)
61 56 27 54 40 67 52
72 49 64 52 53 35 42
37 20 28 12 12 1 2
84 77 77 77 74 68 66 66 61 58 56
(32) (29) (29) (29) (28) (26) (25) (25) (23) (22) (21)
39 51 37 43 31 27 38 36 5 30 9
36 22 32 29 40 31 24 28 30 23 28
9 4 8 5 3 10 4 2 26 5 19
52 49 47 47 44 44 43 43 42 42 40 40
(20) (18) (18) (18) (17) (17) (16) (16) (16) (16) (15) (15)
25 18 10 15 17 23 28 8 20 23 12 23
23 22 27 22 24 14 11 26 22 17 17 16
4 9 10 10 3 7 4 9 0 2 11 1
6MWD during the first 20 weeks of sildenafil treatment subsequently had poorer survival. The most common AEs reported were generally those previously observed with epoprostenol and/or sildenafil treatment4,6,7 or were not unexpected in patients with PAH. Comparing the results from this study with other longterm PAH studies examining sildenafil or epoprostenol therapy alone is difficult. A study of sildenafil monotherapy noted Kaplan-Meier 3-year survival of 79% and greater percentages of patients who maintained or improved 6MWD and WHO FC than in PACES-2; however, patients in that study were treatment-naive and were healthier at baseline.8 Three-year survival rates with epoprostenol infusion monotherapy range from 48% to 63%,9–14 though patient populations have differed substantially (Supplementary Table 1, available on the jhltonline.org Web site). Although PACES-2 survival compares favorably with survival observed with epoprostenol monotherapy, findings for PACES-2 may be influenced by survivor bias15 because only prevalent patients were recruited into PACES-2. Assessments of 6MWD and WHO FC are likewise not comparable between PACES-2 and historical studies
7
because information from patients who died or discontinued epoprostenol infusion monotherapy in these studies was not considered in reporting,9,10 biasing toward patients who responded to administered therapy.16 How the combination of sildenafil added to epoprostenol therapy compares with other combinations of PAH-specific therapies is unclear. Combination therapy is frequently used in clinical practice despite limited supporting data,17 because of the possibility of additive or synergistic effects on disease control.18 Randomized controlled studies of combination therapy show improved exercise capacity vs monotherapy in short-term studies,19,20 but long-term outcomes are scarce. Small patient numbers plague uncontrolled assessments of combination therapy, including studies where sildenafil was added to prostanoids.21–24 An impressive 2-year survival was noted in the OLE study of the inhaled prostacyclin analog treprostinil with a PDE5 inhibitor (sildenafil, 31% of patients) or an ETRA (bosentan, 69%)25; unlike the treatment sequence in PACES-2, this prostacyclin analog was added to stable oral therapy.26 When additional therapies should be added to a patient’s treatment is debated because no randomized trials address this issue. Patients who failed to improve 6MWD during initial treatment with sildenafil had poorer subsequent survival, especially those with a PACES-1 baseline 6MWD o 325 meters. A similar finding occurred with sildenafil monotherapy in the SUPER-2 study,8 an extension of the Sildenafil Use in Pulmonary Arterial Hypertension (SUPER-1) study, suggesting that patients who have a lower baseline 6MWD and fail to improve 6MWD with active PAH treatment have the poorest outcomes. However, although these data provide insight about prognosis, they are not direct evidence about when or how to add therapies. The best-fit multivariate model assessing baseline predictors of survival in PACES-2 included 3 parameters— exercise capacity, WHO FC, and right atrial pressure— previously identified as predictive in patients with IPAH treated with long-term epoprostenol9,10 and in registries of patients with PAH of varying etiology.27,28 The United States registry, with 40% of patients on combination therapy, additionally found resting systolic blood pressure and heart rate were predictive of survival,27 as in our univariate analysis. In treprostinil-treated patients, PVR index and mixed venous oxygen saturation (in addition to FC) were similarly identified as prognostic.29 Additional univariate factors identified in our study (e.g., cardiac index) have been significant in some studies but not others, perhaps reflecting differences in patient numbers, populations, and/or analyses. Epoprostenol management during long-term therapy is rarely described.7 Few patients stopped epoprostenol treatment in this OLE. Slightly more patients had epoprostenol dose decreases rather than increases over the first 2 years; this trend reversed by Year 3, suggesting disease progression between 2 and 3 years. The OLE design, which allowed investigators to adjust epoprostenol dosage as needed, mimics clinical practice more than traditional studies, which generally prohibit additional medication until patients have significantly worsened; however, this design also limits the conclusions that can be drawn.
8
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Notably, PACES-2, as in other long-term OLE studies, provides useful descriptive information, but without a randomized control group, causal relationships cannot be reliably assessed. Although the ability to change therapy (i.e., epoprostenol dosing) mimics clinical disease management, this and the ability of the investigator to add other PAH-specific medications complicates interpretation of the results. The sildenafil dose used by 4 69% of patients at the end of the study, 80 mg three times daily, is 4-fold higher than the approved dose of 20 mg three times daily; therefore, outcomes with lower doses of sildenafil are unknown. Further, patients who discontinued sildenafil in this study but who may have received commercial sildenafil were not tracked, with the exception of survival whenever possible. In conclusion, although a reliable assessment of safety as well as efficacy would require a long-term randomized controlled trial, the addition of oral sildenafil to background IV epoprostenol therapy appears generally well tolerated in PAH patients. At 3 years, in an open-label setting, 33% of patients maintained or improved 6MWD and 46% maintained or improved FC.
Disclosure statement This study was funded by Pfizer Inc, New York, New York. Pfizer worked with all PACES-2 investigators to collect data. Pfizer statisticians and contractors performed the analyses; summary Tables were sent to authors for review. Editorial assistance was provided by Tiffany Brake, PhD, at Complete Healthcare Communications, Inc., and was funded by Pfizer Inc. L.J.R. serves as a consultant for Pfizer, GlaxoSmithKline, Actelion, United Therapeutics, Bayer, Gilead, GeNO, Aires, and MondoBiotech, serves on a scientific board of United Therapeutics, and has served as an expert witness in diet drug litigation. D.B.B. has received honoraria (for steering committees and/or advisory board services) from Actelion, Arena, Bayer, Ikaria, Gilead, Encysive Pharmaceuticals, Pfizer, GlaxoSmithKline, Lung Rx, United Therapeutics, Eli Lilly & Co., Biogen Idec, and mondoBIOTECH; has received grants from Actelion, Gilead, Encysive Pharmaceuticals, Pfizer, United Therapeutics, Lung Rx, Eli Lilly & Co., Bayer, Ikaria, and the National Institutes of Health/ National Heart, Lung, and Blood Institute; has been deposed previously in appetite suppressant litigation, serving as both a treating physician and an expert witness; and has provided consultation to legal counsel for Actelion. A.F. has received research support from Actelion, Gilead, United Therapeutics, Lilly, Aires, Ikaria, Novartis, Pfizer, Bayer, and VentriPoint and has received honoraria for participation in steering committees, advisory boards, and/or speaker’s bureaus from United Therapeutics, Gilead, and Bayer. P.E. has received honoraria from Actelion and Gilead, research support from Actelion, and symposium support from Actelion, Gilead, and United Therapeutics, and has been a member of a speaker’s bureau for United Therapeutics. M.S.-P. is a Pfizer employee. G.R.L. was a Pfizer employee at the time the study was conducted and is a consultant for Aires and Actelion. R.J.B., who died before finalization of the manuscript, had received honoraria (for steering committees and/or advisory board services) from Actelion, Bayer, Eli Lilly, GSK, Gilead, Ikaria, Novartis, Pfizer and VentriPoint, was deposed previously in appetite suppressant litigation, serving as both a treating physician and an expert witness, and owned stock in VentriPoint. None of the
other authors has a financial relationship with a commercial entity that has an interest in the subject of the presented manuscript or other conflicts of interest to disclose.
Supplementary data Supplementary data are available in the online version at jhltonline.org.
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