Abstract
Sitaxsentan may benefit patients with pulmonary arterial hypertension by blocking the vasoconstrictor effects of endothelin-A while maintaining the vasodilator/clearance functions of endothelin-B receptors. Patients with pulmonary arterial hypertension that was idiopathic, related to connective tissue disease or congenital heart disease, were randomized to receive placebo (n = 60), sitaxsentan 100 mg (n = 55), or sitaxsentan 300 mg (n = 63) orally once daily for 12 weeks. The primary endpoint was change in peak V̇O2 at Week 12. Secondary endpoints included 6-minute walk, New York Heart Association class, V̇O2 at anaerobic threshold, V̇E per carbon dioxide production at anaerobic threshold, hemodynamics, quality of life, and time to clinical worsening. Although the 300-mg group increased peak V̇O2 compared with placebo (+3.1%, p < 0.01), none of the other endpoints derived from cardiopulmonary exercise testing were met. However, both the 100-mg dose and the 300-mg dose, compared with placebo, increased 6-minute walk distance (100 mg: +35 m, p < 0.01; 300 mg: +33 m, p < 0.01); functional class, cardiac index, and pulmonary vascular resistance also improved (p < 0.02 for each parameter at both doses). The incidence of elevated aminotransferase values (> three times normal) was 3% for the placebo group, 0% for the 100-mg group, and 10% for the 300-mg group.
Pulmonary arterial hypertension (PAH), characterized by vasoconstriction and structural changes in the small pulmonary muscular arteries and arterioles, is a devastating disease with progressive elevation of pulmonary artery pressure (Ppa) and pulmonary vascular resistance, ultimately producing right heart failure and death (1).
Endothelin (ET) is an endogenous peptide with potent vasoconstrictor, mitogenic, and profibrotic effects (2) and appears to play a significant role in the pathophysiology of PAH. Patients with PAH have increased plasma ET levels and increased expression of ET in the pulmonary vasculature (3, 4). In a small cohort of patients with idiopathic PAH, plasma concentrations of ET correlated with Ppa and pulmonary vascular resistance, as well as with exercise capacity (5).
Two distinct ET receptor isoforms have been identified, ETA and ETB (6). Activation of ETA receptors facilitates sustained vasoconstriction and proliferation of vascular smooth muscle cells (6). In contrast, ETB receptors are believed to be principally involved in the clearance of ET, particularly in the vascular beds of the lung and kidney (6). To date, bosentan, the oral ETA and ETB receptor antagonist, is the only approved ET receptor antagonist for the treatment of PAH (7, 8).
Selective antagonism of ETA receptors may be more beneficial than antagonism of both ETA and ETB receptors for the treatment of PAH by blocking the vasoconstrictor effects of ETA while maintaining the vasodilator and clearance functions of ETB receptors (9). Sitaxsentan sodium is a potent ET receptor antagonist that has oral bioavailability and a long duration of action (t1/2, 5–7 hours) (10). Sitaxsentan is approximately 6,500-fold more selective as an antagonist for ETA compared with ETB receptors (10). The primary objectives of the Sitaxsentan To Relieve Impaired Exercise (STRIDE-1) Trial were to evaluate the safety and efficacy of sitaxsentan in patients with symptomatic PAH. Some of the results from this study have been previously reported in abstract form (11, 12).
Patients between the ages of 16 and 75 years with symptomatic PAH despite treatment with anticoagulants, vasodilators, diuretics, cardiac glycosides, or supplemental oxygen were eligible for study participation if they met the following criteria: (1) PAH that was idiopathic, related to connective tissue disease, or related to congenital systemic-to-pulmonary shunts (repaired or unrepaired); (2) peak V̇o2 that was between 25 and 75% of predicted; and (3) mean pulmonary artery pressure (P̅p̅a̅) higher than 25 mm Hg at rest, pulmonary capillary wedge pressure or left ventricular end-diastolic pressure lower than 15 mm Hg, and pulmonary vascular resistance higher than or equal to 240 dynes/second/cm−5. Patients were excluded if they had significant parenchymal lung disease, portal hypertension, chronic liver disease, history of human immunodeficiency virus infection, hepatic dysfunction (serum aminotransferase level > three times upper limit of normal), chronic renal insufficiency, or received any chronic prostaglandin (PG), PG analog, or ET receptor antagonist therapy within 30 days before study entry.
The study was conducted according to the ethical principles stated in the Declaration of Helsinki (1996) and applicable guidelines on Good Clinical Practice. The protocol was approved by local institutional review committees, and written informed consent was obtained from all patients.
The study was a randomized, double-blind, placebo-controlled trial that enrolled 178 patients between July 2001 and May 2002 at 23 centers (22 in the United States, 1 in Canada). Patients were randomized to receive placebo, sitaxsentan 100 mg, or sitaxsentan 300 mg once daily given orally for 12 weeks. Randomization was performed centrally and stratified by center in blocks according to a computer-generated random number table. All patients who completed the 12-week study were eligible to enter a blinded extension study and receive sitaxsentan 100 or 300 mg.
Patients were evaluated at Study Weeks 1 and 2 and every 2 weeks thereafter through Week 12. The primary endpoint was: percent of predicted peak V̇o2 (measured during cycle ergometry) (13). Secondary endpoints were: 6-minute walk distance, New York Heart Association (NYHA) functional class, V̇o2 at anaerobic threshold (AT), V̇e per carbon dioxide production (V̇e/V̇co2) at AT, hemodynamic parameters (P̅p̅a̅, mean right atrial pressure, cardiac index, and pulmonary vascular resistance), quality of life (as measured by the Medical Outcomes Study Short-Form 36) (14), and time to events of clinical worsening defined as death, epoprostenol use, atrial septostomy, or transplantation. Safety was assessed by adverse events and laboratory evaluations.
Peak V̇o2, V̇o2 at AT, and V̇e/V̇co2 at AT were measured during cycle ergometry conducted at baseline, Week 6, and Week 12. Right heart catheterization was performed at baseline and Week 12. For hemodynamic calculations, V̇o2 was measured in all patients with residual or unrepaired congenital systemic-to-pulmonary shunts. Clinical laboratories and trough plasma sitaxsentan concentrations were evaluated at baseline and every 2 weeks thereafter through Week 12, with more extensive pharmacokinetic sampling performed in a subset of patients at Days 2 (first day of dosing in this subset) and 84. Patients were discontinued from the study if they had deterioration of NYHA functional class, an elevation in total bilirubin more than two times the upper limit of normal plus a serum aminotransferase value more than three times the upper limit of normal, or a serum aminotransferase value more than five times the upper limit of normal.
Percent of predicted peak V̇o2 was defined as observed peak V̇o2 divided by the predicted peak V̇o2 on the basis of normalization by weight, height, age, and sex, multiplied by 100 ([peak V̇o2/predicted peak V̇o2] × 100) (13). The efficacy analysis was prospectively defined and conducted according to the intent-to-treat principle, consisting of analysis of all patients who received any dose of study drug and according to the group randomized. All efficacy endpoints were analyzed by comparison of the placebo group with each sitaxsentan group separately. Changes in the primary efficacy endpoint were separately analyzed by a parametric analysis of covariance model (15) and a nonparametric analysis of covariance (based on ranks) (15), with baseline value as the covariate. Changes in secondary endpoints were analyzed as follows: (1) for continuous endpoints, e.g., 6-minute walk distance, the parametric analysis of covariance model described previously was used; (2) for categoric endpoints, e.g., NYHA class, a Cochran–Mantel–Haenszel procedure (16) was used; and (3) for time to event endpoints, Kaplan–Meier methodology was used. Safety data were analyzed according to actual treatment received.
Based on prespecified rules, missing values were replaced using the last observation carried forward data imputation method. If no postbaseline value was available, the baseline value was carried forward.
An independent, external Data and Safety Monitoring Board conducted two interim safety evaluations based on adverse events and laboratory data after 45 and 90 patients completed Week 12 assessments. In addition, the Sponsor and Data and Safety Monitoring Board reviewed serious adverse events and elevated liver function enzyme values by blinded, masked treatment groups from both the current study and the extension trial on an ongoing basis. Only the Data and Safety Monitoring Board was authorized to request unblinding of safety data by treatment groups.
A total of 178 patients were enrolled: 60 received placebo and 118 received sitaxsentan (55 patients, 100 mg; 63 patients, 300 mg). Twelve patients prematurely discontinued the study. Reasons for discontinuation in the placebo group (n = 5) were three patients for worsening PAH, one for liver enzyme elevation, and one was lost to follow-up. In the 300-mg group (n = 7), three patients discontinued for worsening PAH, three for liver enzyme elevation, and one for renal insufficiency. None of the patients in the 100-mg group discontinued prematurely.
Characteristic | Placebo (n = 60) | Sitaxsentan 100 mg (n = 55) | Sitaxsentan 300 mg (n = 63) | Overall (n = 178) |
|---|---|---|---|---|
| Sex, n (%) | ||||
| Female | 47 (78) | 47 (85) | 47 (75) | 141 (79) |
| Age, yr | ||||
| Mean | 48 ± 14 | 45 ± 14 | 44 ± 12 | 46 ± 13 |
| Range | 17–72 | 18–74 | 22–70 | 17–74 |
| Ethnicity, n (%) | ||||
| White | 42 (70) | 39 (71) | 44 (70) | 125 (70) |
| Cause of pulmonary arterial hypertension, n (%) | ||||
| Idiopathic | 37 (62) | 23 (42) | 34 (54) | 94 (53) |
| Related to connective tissue disease | 9 (15) | 16 (29) | 17 (27) | 42 (24) |
| Related to congenital systemic-to-pulmonary shunts | 14 (23) | 16 (29) | 12 (19) | 42 (24) |
| Previous or concomitant treatment, n (%)* | ||||
| Warfarin | 50 (83) | 43 (78) | 49 (78) | 142 (80) |
| Diuretics | 39 (65) | 36 (65) | 41 (65) | 116 (65) |
| Calcium-channel blockers | 27 (45) | 25 (45) | 31 (49) | 83 (47) |
| Digoxin | 23 (38) | 22 (40) | 23 (37) | 68 (38) |
| Supplemental oxygen | 15 (25) | 17 (31) | 17 (27) | 49 (28) |
| NYHA functional class, n (%) | ||||
| II | 22 (37) | 16 (29) | 21 (33) | 59 (33) |
| III | 36 (60) | 39 (71) | 42 (67) | 117 (66) |
| IV | 2 (3) | 0 (0) | 0 (0) | 2 (1) |
| Percent of predicted peak V̇O2 | 48 ± 14 | 45 ± 14 | 45 ± 16 | 46 ± 14 |
| 6-Minute walk distance, m | 413 ± 105 | 394 ± 114 | 387 ± 110 | 398 ± 110 |
| P̅p̅a̅, mm Hg | 52 ± 16 | 54 ± 17 | 54 ± 14 | 54 ± 15 |
| Mean right atrial pressure, mm Hg | 8 ± 5 | 7 ± 5 | 9 ± 5 | 8 ± 5 |
| Cardiac index, L/min/m2 | 2.4 ± 0.8 | 2.4 ± 0.8 | 2.3 ± 0.7 | 2.4 ± 0.8 |
| Pulmonary vascular resistance, dyn/s/cm5 | 911 ± 504 | 1,026 ± 694 | 946 ± 484 | 958 ± 560 |
After 12 weeks, the primary endpoint, i.e., percent of predicted peak V̇o2, increased in the 300-mg group compared with placebo (+3.1%; p < 0.01); no improvement occurred in the 100-mg group (Table 2)
Placebo (n = 60) | Sitaxsentan 100 mg (n = 55) | Sitaxsentan 300 mg (n = 63) | |
|---|---|---|---|
| % of predicted peak V̇O2 | |||
| Baseline | |||
| Mean (SD) | 48 (14) | 45 (14) | 45 (16) |
| Change at Week 12 | |||
| Mean (SD) | −0.1 (9.10) | −0.4 (8.92) | 3.0 (11.08) |
| Median | 0.0 | 0.5 | 3.1 |
| Minimum: maximum | −26.3: 21.1 | −22.8: 27.0 | −64.6: 18.1 |
| p Value* | 0.847 | 0.219 | |
| p Value† | 0.835 | 0.005 | |
| % of predicted V̇O2 at AT | |||
| Baseline | |||
| Mean (SD) | 36 (11) | 33 (10) | 32 (12) |
| Change at Week 12 | |||
| Mean (SD) | −0.7 (8.22) | −0.7 (8.77) | 0.9 (10.63) |
| Minimum: maximum | −29.9: 19.9 | −25.3: 22.4 | −47.8: 26.0 |
| p Value* | 0.859 | 0.912 | |
| V̇E/V̇CO2 score at AT | |||
| Baseline | |||
| Mean (SD) | 50 (12) | 60 (55) | 50 (12) |
| Change at Week 12 | |||
| Mean (SD) | 4 (8) | −7 (63) | −2 (10) |
| Minimum: maximum | 10:32 | −412:75 | −29:33 |
| p Value* | 0.999 | 0.096 |
However, both the 100-mg dose and the 300-mg dose increased the 6-minute walk distance after 12 weeks (Figure 1)
Figure 1. Mean (± SE) change in 6-minute walk distance from baseline to Week 12 in placebo and sitaxsentan groups. Pairwise (vs. placebo) p values are from analysis of covariance including baseline response in the model and are adjusted for multiple comparisons using Dunnett's method (17). p Values less than 0.01 for the comparison between each sitaxsentan dose (100 and 300 mg) and placebo.
[More] [Minimize]Both doses of sitaxsentan improved pulmonary vascular resistance (p < 0.001 for both doses) and cardiac index (p = 0.013 for 100 mg and p < 0.001 for 300 mg) compared with placebo. Pulmonary vascular resistance decreased with sitaxsentan treatment from baseline to Week 12 (mean ± SD for 100 mg: 1,025 ± 694 to 805 ± 553 dynes/second/cm−5; mean ± SD for 300 mg: 946 ± 484 to 753 ± 524 dynes/second/cm−5) and increased with placebo (911 ± 484 to 960 ± 535 dynes/second/cm−5). Cardiac index did not change in the placebo group after 12 weeks of treatment (2.4 ± 0.8 to 2.4 ± 0.9 L/minute/m2) but increased with sitaxsentan treatment (100 mg: 2.4 ± 0.8 to 2.7 ± 0.8 L/minute/m2; 300 mg: 2.3 ± 0.7 to 2.7 ± 0.9 L/minute/m2). P̅p̅a̅ improved after 12 weeks with the 300-mg dose (54 ± 14 to 49 ± 15 mm Hg), compared with placebo treatment (52 ± 16 to 53 ± 15 mm Hg); no significant improvement was seen in the 100-mg–dose group (54 ± 17 to 51 ± 16 mm Hg) compared with placebo (Table 3)
Placebo (n = 60) | Sitaxsentan 100 mg (n = 55) | Sitaxsentan 300 mg (n = 63) | |
|---|---|---|---|
| P̅p̅a̅, mm Hg | 0 (8) | −3 (8) | −5 (11)* |
| Mean right atrial pressure, mm Hg | 1 (4) | 0 (4)† | −1 (4)* |
| Cardiac index , L/min/m2 | 0.0 (0.5) | 0.3 (0.6)‡ | 0.4 (0.6)* |
| Pulmonary vascular resistance, dyn/s/cm5 | 49 (244) | −221 (442)* | −194 (330)* |
Both doses of sitaxsentan, compared with placebo, improved NYHA functional class after 12 weeks of treatment (p < 0.02). NYHA functional class improved in 16/55 (29%) patients in the 100-mg group and in 19/63 (30%) patients in the 300-mg group. In contrast, only 9/60 (15%) patients in the placebo group had improvement in NYHA functional class. Worsening of NYHA functional class at Week 12 was infrequent in all three groups, likely due to the absence of patients with severe disease at baseline. NYHA functional class worsened in 4/60 (7%) patients receiving placebo, in none of the 55 patients receiving 100 mg, and in 1/63 (2%) patient receiving 300 mg. There were no significant differences between groups in quality of life assessment.
Only four patients had events of clinical worsening as defined in the protocol, i.e., death, epoprostenol use, atrial septostomy, or transplantation, consistent with a high percentage of patients with mild-to-moderate disease at baseline. Clinical worsening at Week 12 occurred in 3/60 (5%) patients in the placebo group, in none of the 55 patients in the sitaxsentan 100-mg group, and in 1/63 (2%) patient in the sitaxsentan 300-mg group. No significant differences were seen between treatment groups in time to clinical worsening.
Comparison of the maximum-concentration-of-drug (Cmax) and area-under- curve for Days 2 (AUC∞) and 84 (AUC0–24) indicates significant accumulation of sitaxsentan over the dosing period for sitaxsentan 300 mg but not 100 mg. Pharmacokinetic analyses showed that sitaxsentan 100 mg resulted in no increase in mean Cmax and a 1.3-fold increase in mean AUC values from baseline to Week 12. In contrast, sitaxsentan 300 mg resulted in a 1.4-fold increase in mean Cmax and a 3.1-fold increase in mean AUC values from baseline to Week 12. The ratio of geometric mean values for area under the plasma level–time curve at steady state (AUCss) at Week 12 for 300 mg/100 mg was 11.3, reflecting nonlinearity in the elimination of sitaxsentan when administered at a dose of 300 mg.
No clinically meaningful differences were seen between groups in the total number of adverse events reported or in the incidence of patients with adverse events. The incidence of serious adverse events was infrequent, with no significant differences among treatment groups (placebo, 15%; sitaxsentan 100 mg, 5%; sitaxsentan 300 mg, 16%). One death, judged by the investigator to be due to worsening PAH and unrelated to study drug, occurred in the 300-mg group.
The most frequently reported clinical adverse events with sitaxsentan treatment (and more frequent than with placebo) were headache, peripheral edema, nausea, nasal congestion, and dizziness (Table 4)
Adverse Event | Placebo (n = 59) | Sitaxsentan 100 mg (n = 56) | Sitaxsentan 300 mg (n = 63) | Sitaxsentan Combined (n = 118) |
|---|---|---|---|---|
| Headache | 20 (34) | 25 (45) | 29 (46) | 54 (45) |
| Peripheral edema | 10 (17) | 9 (16) | 16 (25) | 25 (21) |
| Nausea | 11 (19) | 13 (23) | 11 (18) | 24 (20) |
| Increased INR or PT | 3 (5) | 8 (14) | 15 (24)* | 23 (19)* |
| Nasal congestion | 6 (10) | 9 (16) | 13 (20) | 22 (18) |
| Dizziness | 6 (10) | 8 (14) | 6 (10) | 14 (12) |
Liver abnormalities have been recognized as a class effect associated with ET receptor antagonists (7, 8, 18). The incidence of liver enzyme abnormalities (aminotransferase values > 3 times upper limit of normal), which reversed in all cases, was 3% (2/59) for the placebo group, 0% for the sitaxsentan 100-mg group, and 10% (6/63) for the sitaxsentan 300-mg group. When results were combined with an extension trial that randomized all patients to receive sitaxsentan 100 or 300 mg, the incidence of liver enzyme abnormalities increased to 5% (4/77) for the sitaxsentan 100-mg group and 21% (19/91) for the sitaxsentan 300-mg group for exposure as long as 58 weeks (median, 26 weeks). Using Kaplan–Meier estimates for the time to first occurrence of aminotransferase values more than three times the upper limit of normal for all patients in the 12-week study and in the extension phase, the cumulative risk of an aminotransferase value more than three times the upper limit of normal at 6 months was 8% for the 100-mg group and 26% for the 300-mg group; at 9 months, this incidence remained 8% for the 100-mg group but increased to 32% for the 300-mg group.
Modest dose-related changes occurred in serum hemoglobin concentration. Decreases in hemoglobin in sitaxsentan-treated groups were observed as early as Week 2 and remained stable throughout the study (mean change from baseline to Week 12; placebo, 0.2 g/dl; 100 mg, −1.0 g/dl; 300 mg, −1.6 g/dl). None of the hemoglobin changes was clinically significant.
The Data and Safety Monitoring Board did not request data to be unblinded during the two interim safety evaluations and deemed that no change to the conduct of the trial was warranted.
This trial is the first placebo-controlled multicenter study to evaluate a selective ETA receptor antagonist, i.e., sitaxsentan, in PAH. Although the 300-mg group met the primary endpoint, i.e., increased peak V̇o2 compared with placebo, none of the other endpoints derived from CPET, i.e., V̇o2 at AT and V̇e/V̇co2 at AT, were met. However, both the 100 and 300 mg doses, compared with placebo, improved 6-minute walk distance, functional class, cardiac index, and pulmonary vascular resistance. The reasons for the discrepancy between results obtained from CPET versus other measures that have been validated in previous PAH trials (i.e., 6-minute walk test, functional class, pulmonary vascular resistance, and cardiac index) are unclear. However, the possibility of greater technical expertise required to conduct CPET testing, intrasubject variability, and lack of validation of CPET parameters as efficacy endpoints in PAH trials may be important considerations.
The 6-minute walk test has been the most widely used measure of exercise capacity in PAH clinical trials (19) and has shown benefits from treatment with epoprostenol (20), bosentan (7, 8), treprostinil (21), and beraprost (22, 23). We elected to use peak V̇o2 as the primary endpoint on the basis of the correlation reported between 6-minute walk distance and peak V̇o2 and literature suggesting that peak V̇o2 is an independent predictor of survival in patients with idiopathic PAH (24, 25). Despite protocol-specified guidelines for the conduct of CPET testing, it is possible that the discrepancy between 6-minute walk distance and peak V̇o2 data in the present multicenter study could have been minimized by validation of each center's CPET facilities and use of a core laboratory for data acquisition and interpretation. Alternatively, 6-minute walk distance, i.e., exercise endurance, may be a better index of the ability of a patient with chronic heart and/or lung disease to perform daily activities than peak V̇o2, i.e., exercise tolerance (26). Interestingly, in a recently published PAH study that also used both the 6-minute walk test and CPET as efficacy endpoints, it is noteworthy that treatment with the active study drug, i.e., beraprost, resulted in significant improvement in 6-minute walk distance at 3 and 6 months, with no associated improvement in peak V̇o2 (23).
To date, clinical trials in PAH that have used the 6-minute walk test as the primary endpoint have traditionally limited enrollment to those with functional Class III or IV disease, either idiopathic or connective tissue disease etiology, and baseline 6-minute walk distances less than or equal to 450 m (7, 8, 20). In contrast, this trial included patients with PAH with functional Class II disease, congenital heart defects, and baseline 6-minute walk distances more than 450 m. The 6-minute walk distance for patients in this trial (mean ± SD: 398 ± 110 m, range 79–657 m) was 20 to 30% higher than in previous trials with other agents for PAH, (7, 8, 20–22) in part due to inclusion of patients with mild (NYHA Class II) functional status. To evaluate whether a “ceiling effect” masked efficacy, we conducted a post hoc analysis of those patients meeting traditional enrollment criteria, i.e., Class III/IV PAH (idiopathic or related to connective tissue disease) with a baseline 6-minute walk of 450 m or more. For these analyses, although two sitaxsentan doses were evaluated in this trial, i.e., 100 and 300 mg, the data were pooled on the basis of similar treatment effects on the 6-minute walk test, functional class, cardiac index, and pulmonary vascular resistance for both doses (all p < 0.02). Using these traditional enrollment criteria, the treatment effect for 6-minute walk increased from 34 m in the entire STRIDE-1 population to 65 m in the STRIDE-1 patients meeting traditional inclusion criteria. Similarly, the hemodynamic improvement also increased when analyzed in the patients meeting the traditional trial design enrollment criteria compared with the broader inclusion criteria used in this trial. Therefore, patients with functional Class II limitations, PAH related to congenital heart disease, or a baseline 6-minute walk more than 450 m may have a relatively lower treatment effect related to this “masking effect.” As a result, comparisons between PAH trials with differing enrollment criteria (7, 8, 19–23) require caution. The advantages of a selective ETA receptor antagonist, (e.g., sitaxsentan) compared with a combined ETA and ETB antagonist (e.g., bosentan) can best be determined in comparator trials.
In summary, although the selective ETA receptor antagonist, sitaxsentan, did not meet the endpoints derived from CPET (i.e., V̇o2, V̇o2 at AT, or V̇e/V̇co2 at AT), it did improve 6-minute walk distance, functional class, pulmonary vascular resistance, and cardiac index after 12 weeks of treatment in patients with PAH. The similar effects on the latter efficacy endpoints suggest that significant saturation of ETA receptors occurred with both sitaxsentan doses. In contrast, the incidence of liver function abnormalities was much lower for the 100-mg dose compared with the 300-mg dose, suggesting a distinct dose response for safety and tolerability. Future trials are needed to confirm efficacy with sitaxsentan in the treatment of PAH as well as to determine the optimal dose on the basis of overall risk–benefit considerations.
The authors thank the following additional STRIDE Study Group investigators and their staff members, who enrolled patients at the following institutions: Sir Mortimer B. Davis Jewish General Hospital, Montreal, Quebec, Canada (Andrew Hirsch, Eileen Shalit); Cleveland Clinic Foundation, Cleveland, OH (Alejandro Arroliga, Robert Schilz); Ohio State University Medical Center, Columbus (Curt Daniels); Louisiana State University School of Medicine, New Orleans (Bennett deBoisblanc); University of California, San Francisco (Teresa De Marco); Stanford University Medical Center, Stanford, CA (Ramona Doyle); Massachusetts General Hospital, Boston (Leo Ginns); Johns Hopkins Hospital, Baltimore, MD (Reda Girgis); Medical College of Georgia, Augusta (James Gossage); Children's Hospital, Denver, CO (Dunbar Ivy); Mayo Clinic, Rochester, MN (Sudhir Kushwaha); University of Pittsburgh Medical Center, Pittsburgh, PA (Srinivas Murali); University of Michigan, Ann Arbor (Melvyn Rubenfire); Maine Medical Center, Portland (Joel Wirth); Data and Safety Monitoring Board—Bruce Brundage (Chair), Kanu Chatterjee, Roger Flora, Harold Palevsky; ICOS Corporation—Michael Deeley, Pam Walentynowicz; Encysive Pharmaceuticals—Phil Brown, Bruce Given. The authors also thank William Kramer, Willis Maddrey, and Karlman Wasserman for their expertise and collaboration.
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