Early versus Delayed, Provisional Eptifibatide in Acute Coronary Syndromes

Study Design

Our trial was a collaboration involving the Virtual Coordinating Center for Global Collaborative Cardiovascular Research (VIGOUR), the Thrombolysis in Myocardial Infarction (TIMI) Study Group, and a steering committee of investigators. An independent data and safety monitoring board reviewed the trial's progress and adverse events. Investigators at the Duke Clinical Research Institute (DCRI) coordinated the trial, collected and managed the data, provided statistical support, and classified clinical events. Treatment codes were generated and held by a statistician at the DCRI who was aware of study-group assignments. The final trial database and treatment codes were transferred to one of the two initial sponsors, Schering-Plough, at the end of the trial on December 17, 2008. All analyses were performed by the DCRI with the use of the complete database. The academic authors on the executive committee (with input from the steering committee) prepared all drafts of the manuscript, decided to submit the article for publication, and assume responsibility for the accuracy and completeness of the reported data.

The original protocol and amendments were approved by the ethics committee at each center. All patients provided written informed consent.

Study Population

We randomly assigned 9492 patients who had high-risk acute coronary syndromes without ST-segment elevation and were assigned to an invasive strategy to receive either early, routine administration of eptifibatide or early placebo with delayed, provisional administration of eptifibatide after angiography but before the patient underwent a percutaneous coronary intervention (PCI). Patients who were at least 18 years of age were eligible if they had cardiac ischemia at rest lasting for at least 10 minutes and occurring within 24 hours before randomization and if they underwent randomization within 8 hours after presentation, with a planned invasive strategy no sooner than the next calendar day after randomization. Patients were considered to have a high-risk condition if they met two or more of the following criteria: ischemic changes on electrocardiography (ST-segment depression of 0.1 mV or more or transient [<30-minute] ST-segment elevation of 0.1 mV or more in two or more contiguous leads), a level of troponin or creatine kinase MB that was above the upper limit of the normal range, and an age of 60 years or more.

Key exclusion criteria were an increased risk of bleeding, an allergy to heparin or eptifibatide, pregnancy, renal dialysis within the previous 30 days, the intention of the investigator to use a nonheparin anticoagulant, recent use of a glycoprotein IIb/IIIa inhibitor, and any other condition that posed an increased risk.⁵

A protocol amendment on June 3, 2005, expanded the randomization period to 12 hours after presentation, clarified the timing of angiography (≥12 hours after randomization), and permitted the enrollment of patients who were designated as high risk and who were between the ages of 50 and 59 years with elevated levels of troponin or creatine kinase MB if they had documented coronary, cerebrovascular, or peripheral artery disease. On March 24, 2008, a protocol amendment reduced the sample size to 9500 patients.

Study Procedures

Eligible patients were randomly assigned in a 1:1 ratio to receive either early, routine administration of eptifibatide or early administration of placebo with delayed, provisional administration of eptifibatide. Randomization was performed in blocks according to the study center and was stratified according to the intention of the investigator to administer early clopidogrel (i.e., at or before randomization). Randomization was managed through an interactive voice-response system.

After randomization, patients received either early eptifibatide in two boluses, each containing 180 μg per kilogram of body weight, or matching placebo boluses administered 10 minutes apart. A standard infusion of 2.0 μg of eptifibatide or matching placebo per kilogram per minute (or 1.0 μg per kilogram per minute if the creatinine clearance was less than 50 ml per minute) was administered concurrently with the first bolus. In cases of bleeding, the Investigator could decrease the dose of the study-drug infusion by one third.

After coronary angiography but before PCI, investigators could request a PCI study-drug kit for patients who they deemed would benefit from eptifibatide on the basis of the clinical evidence and angiographic findings. The first bolus of the PCI study-drug kit contained eptifibatide for patients who had previously received placebo and placebo for patients who had previously received eptifibatide. Concurrently, the blinded administration of the initial study drug (either eptifibatide or placebo) was stopped, and an open-label infusion of eptifibatide was begun and continued for 18 to 24 hours after the PCI procedure.

If a provisional dose of a study drug was not administered before PCI, the initial infusion was continued without a change for 18 to 24 hours after PCI. During PCI, if a thrombotic complication occurred after the catheter guidewire crossed the lesion, investigators could request a kit that contained bolus therapy opposite to the initial study-group assignment (termed a bailout kit). The use of bailout kits for any one of seven predefined procedural complications⁵ was considered “thrombotic bailout,” and such cases were reviewed by the clinical events committee.

For patients undergoing PCI, the duration of the infusion was 96 hours or less; longer infusions were permitted to ensure a minimum 18-hour infusion after PCI. For patients undergoing coronary-artery bypass grafting (CABG), the infusion continued until 2 hours before surgery (maximum infusion time, 120 hours). Patients who were not undergoing revascularization received an infusion for no more than 96 hours.

Concomitant Medications

Aspirin (at a dose of 162 to 325 mg orally or 150 to 500 mg intravenously) was required on enrollment, followed by at least 75 mg daily thereafter. Thienopyridine was substituted in patients who could not tolerate aspirin.

The protocol mandated the administration of either weight-based unfractionated heparin or enoxaparin adjusted for weight and creatinine clearance (with the possible substitution of dalteparin or nadroparin if enoxaparin was unavailable), according to the investigator's choice. For patients undergoing PCI who received unfractionated heparin, the target for the activated clotting time was 250 seconds; for patients receiving enoxaparin, additional enoxaparin (0.3 mg per kilogram) was administered intravenously if PCI was performed 8 to 12 hours after the last dose. Switching between unfractionated heparin and low-molecular-weight heparins was discouraged because of the potentially increased risk of bleeding.⁶ The initial protocol amendment permitted the use of bivalirudin during PCI. The March 24, 2008, amendment allowed the use of bivalirudin and fondaparinux as baseline antithrombotic therapy.

If early clopidogrel was used, the recommended loading dose was 300 mg. A 600-mg loading dose was permitted during PCI if no previous loading dose had been administered. The recommended maintenance dose of clopidogrel was 75 mg daily. Other medical therapies were administered according to standard practice and guidelines.

Key End Points

The primary efficacy composite end point was death from any cause, myocardial infarction, recurrent ischemia requiring urgent revascularization, or thrombotic bailout at 96 hours (for details, see Section 2 in the Supplementary Appendix, available with the full text of this article at NEJM.org).⁷ The key secondary efficacy end point was a composite of death from any cause or myocardial infarction within the first 30 days. Safety end points included rates of hemorrhage, transfusion, surgical reexploration, stroke, thrombocytopenia, and serious adverse events at 120 hours after randomization. Stroke and all efficacy components, except death, were adjudicated by an independent clinical events committee whose members were unaware of study-group assignments. If classification of TIMI bleeding could not be determined by a programmed algorithm, blinded adjudication was performed.

Statistical Analysis

Efficacy analyses were performed according to the intention-to-treat principle. In patients with multiple events, the earliest end point was counted. Event rates were compared with the use of the Cochran–Mantel–Haenszel test, with adjustment for intended early use of clopidogrel. Odds ratios with 95% confidence intervals were calculated. Prespecified subgroup analyses were performed on the basis of sex, geographic region, baseline troponin level, type of hospital (primary care or tertiary care), presence or absence of diabetes, age (<75 years or ≥75 years), the type of antithrombin that was used, TIMI risk score, and the time from presentation to randomization (≤4 hours or >4 hours). Logistic-regression models tested for interaction with study-group assignments in selected subgroups. The Breslow–Day test was used to assess for heterogeneity of the odds ratios within clopidogrel strata and subgroups.

Safety end points were summarized for the as-treated population (with the exclusion of 77 patients who did not receive any study drug). Between-group comparisons were performed with the use of Pearson's chi-square test to analyze the rate of stroke, and the Cochran–Mantel–Haenszel test with adjustment for intended early use of clopidogrel was used to analyze end points that involved bleeding.

The initial sample size (10,500 patients) provided a power of 85% to detect a 22.5% relative reduction in the rate of the primary efficacy end point in the early-eptifibatide group, as compared with the delayed-eptifibatide group, assuming a 96-hour event rate of 5.8% in the latter group. This sample size preserved a power of 85% to detect a 15% reduction in the rate of death or myocardial infarction at 30 days in the early-eptifibatide group. The executive committee regularly reviewed pooled event rates in a blinded fashion. Since the rate of the observed composite primary end point was nearly twice the initial projection (5.2%) after the enrollment of 6822 patients, the executive committee recommended a sample-size reduction to 9500 patients, which provided a power of 98% for the composite primary end point and 81% for the composite secondary end point.

One prespecified interim efficacy analysis was conducted after approximately 50% of the patients had been enrolled. O'Brien–Fleming stopping boundaries were generated for between-group comparisons, with a one-sided nominal alpha level of 0.0026. Thus, the final primary analysis compared the study groups at a two-sided alpha level of 0.048. The protocol specified a step-down testing procedure, requiring that the test of the primary end point be significant before the key secondary end point was tested (also at an alpha level of 0.048).

Patients

Figure 1. Figure 1. Enrollment and Outcomes.

Data from 64 patients from a single hospital could not be confirmed and were excluded for all analyses. Among the patients in the delayed-eptifibatide group, 747 received active eptifibatide after angiography but before percutaneous coronary intervention (PCI), and an additional 336 received active eptifibatide after PCI had begun.

Table 1. Table 1. Baseline Characteristics, Treatments, and Temporal Data.

Between May 2004 and August 2008, a total of 9492 patients underwent randomization at 440 study centers in 29 countries (Figure 1). The intention-to-treat cohort included 9406 patients after the exclusion of 22 patients who did not provide consent and 64 patients from a single hospital for whom data could not be verified independently from source documents. Eleven patients were lost to follow-up, and three patients had less than 27 days of follow-up. Baseline characteristics in the two study groups are shown in Table 1.

Clopidogrel Stratification

Investigators intended to provide early administration of clopidogrel for 7057 patients (75.0%), although 5% of these patients did not receive the drug as intended. Investigators intended to defer a decision on the use of clopidogrel until after angiography for 2349 patients (25.0%), although 14% of these patients actually received the drug before angiography. The rate of intended early use of clopidogrel was lower in North America than elsewhere (50.8% vs. 85.8%).

Study Procedures

The median time from presentation to randomization was 5.6 hours. Nearly all patients (97.5%) underwent coronary angiography (median interval after randomization, 21.4 hours). PCI was performed in 59.1% of patients, CABG in 13.0%, and medical therapy without revascularization in 28.3% (Table 1).

Of 5559 patients who underwent PCI, 1434 (25.8%) received PCI kits (with transition to open-label eptifibatide infusion) after angiography but before the wire crossed the lesion. Of these patients, 687 were in the early-eptifibatide group, and 747 were in the delayed-eptifibatide group. The rates of use of PCI kits were 54.7% in North America and 15.1% elsewhere. An additional 648 patients (11.7%) received bailout kits (312 in the early-eptifibatide group and 336 in the delayed-eptifibatide group) after the wire crossed the lesion.

Efficacy End Points

Table 2. Table 2. Efficacy End Points and Adverse Events.

The early administration of eptifibatide did not significantly reduce the rate of the primary composite end point, as compared with the delayed, provisional administration of the drug (9.3% vs. 10.0%; odds ratio, 0.92; 95% confidence interval [CI], 0.80 to 1.06; P=0.23), nor did it significantly reduce the rate of the composite secondary end point of death or myocardial infarction at 30 days (11.2% vs. 12.3%; odds ratio, 0.89; 95% CI, 0.79 to 1.01; P=0.08) (Table 2, and Sections 3 and 4 in the Supplementary Appendix). There were no significant differences between the study groups in the rate of death from any cause; in the rate of a composite of death, myocardial infarction, or recurrent ischemia requiring urgent revascularization; in the rate of myocardial infarction alone; or in the rate of recurrent ischemia requiring urgent revascularization alone.

Figure 2. Figure 2. Odds Ratios and Rates of the Composite Primary End Point, According to Prespecified Subgroups.

Data for the composite primary end point — death from any cause, myocardial infarction, recurrent ischemia requiring urgent revascularization, or the occurrence of a thrombotic complication during percutaneous coronary intervention (PCI) that required bolus therapy opposite to the initial study-group assignment (thrombotic bailout) — are shown. The percentages are the observed rates of the composite primary end point at 96 hours. For each subgroup, the size of the square is proportional to the number of patients and represents the odds ratio estimate for the treatment effect with adjustment for Cochran–Mantel–Haenszel analysis. The horizontal lines indicate 95% confidence intervals. The overall treatment effect in the early-eptifibatide group, as compared with that in the delayed-eptifibatide group, is represented by the diamond, and the dashed vertical line represents the corresponding overall odds ratio point estimate. None of the P values for interactions were significant.

Figure 3. Figure 3. Odds Ratios and Rates of the Composite Secondary End Point, According to Prespecified Subgroups.

Data for the key secondary end points — death or myocardial infarction — are shown. The percentages are the observed rates of the key secondary composite end point at 30 days. For each subgroup, the size of the square is proportional to the number of patients and represents the odds ratio estimate for the treatment effect with adjustment for Cochran–Mantel–Haenszel analysis. The horizontal lines indicate 95% confidence intervals. The overall treatment effect in the early-eptifibatide group, as compared with that in the delayed-eptifibatide group, is represented by the diamond, and the dashed vertical line represents the corresponding overall odds ratio point estimate. The only significant P value for interaction was for sex (P=0.046 by the Breslow–Day test).

There were no significant between-group interactions with respect to prespecified baseline characteristics (including the investigator's intention to administer clopidogrel early), the composite primary end point (Figure 2), or the composite secondary end point (Figure 3).

Figure 4. Figure 4. Primary End-Point Events during Medical Therapy and after PCI or CABG.

Kaplan–Meier (KM) estimates of the rates of the primary efficacy end point are shown for patients who received medical therapy alone, those who underwent percutaneous coronary intervention (PCI), and those who underwent coronary-artery bypass grafting (CABG). Data on the interventional strategies were missing for eight patients (four in each study group). One death in the delayed-eptifibatide group that occurred 16 days after randomization was not included because data were missing regarding the use of revascularization. The 47 patients who underwent both CABG and PCI were categorized according to the procedure that was performed first. In the table below the flow chart, all events that occurred before PCI or CABG are included in the total number of events that occurred during medical therapy. All events that are shown are the first occurrence of the primary end point. The summaries are shown as the total number of events, along with the number at risk and Kaplan–Meier rate estimates. For event rates after revascularizations, events were counted after procedures were actually performed.

No significant between-group differences in the rates of the primary or secondary end points were observed for patients who received only medical treatment or for those who received medical treatment before PCI or CABG (Figure 4, and Section 5 in the Supplementary Appendix). Among patients who underwent PCI, those in the early-eptifibatide group had fewer primary and secondary end points than those in the delayed-eptifibatide group.

Safety End Points

Among patients in the early-eptifibatide group, 118 patients had a TIMI major hemorrhage (2.6%), as compared with 83 in the delayed-eptifibatide group (1.8%) (odds ratio, 1.42; 95% CI, 1.07 to 1.89; P=0.02). With the severity of bleeding defined according to the GUSTO (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries) criteria, the rate of moderate bleeding was 6.8% in the early-eptifibatide group and 4.3% in the delayed-eptifibatide group (P<0.001); less severe bleeding was also significantly more frequent in the early-eptifibatide group. There was no significant between-group difference in the rate of severe bleeding (0.8% in the early-eptifibatide group and 0.9% in the delayed-eptifibatide group, P= 0.97) (Table 2). The need for red-cell transfusion was increased in the early-eptifibatide group (8.6%, as compared with 6.7% in the delayed-eptifibatide group; P=0.001). There were no significant between-group differences in the rates of thrombocytopenia, stroke, or surgical reexploration for bleeding; in the total volume of chest-tube drainage during the first 8 hours and 24 hours after CABG; or in the rate of serious adverse events (see Section 6 in the Supplementary Appendix).

We evaluated early administration of a glycoprotein IIb/IIIa inhibitor, eptifibatide, in patients who had high-risk acute coronary syndromes without ST-segment elevation and who were undergoing invasive therapies, with angiography mandated at 12 to 96 hours after randomization. In comparison with earlier placebo-controlled trials of glycoprotein IIb/IIIa inhibitors in such patients,^7-10 the patients in our trial were older, had higher-risk profiles, and were treated with more aggressive concomitant medical therapy and revascularization. In this context, the early, routine administration of double-bolus eptifibatide followed by a standard eptifibatide infusion was not superior to a strategy of early administration of placebo followed by delayed, provisional administration of eptifibatide after angiography but before PCI. Among patients in the early-eptifibatide group, the trend toward fewer recurrent ischemic complications at 30 days was counterbalanced by more frequent episodes of bleeding and need for transfusions.

Previous studies investigating the use of glycoprotein IIb/IIIa inhibitors before PCI have had mixed results. As compared with placebo, the use of glycoprotein IIb/IIIa inhibitors reduced ischemic complications (predominantly periprocedural myocardial infarction) whether treatment was initiated early¹¹ or just before PCI,³ even when 600 mg of clopidogrel was administered.¹² However, two small, randomized trials involving patients with acute coronary syndromes had conflicting findings regarding the effect of the early use of glycoprotein IIb/IIIa inhibitors, as compared with the use of such drugs immediately before PCI, on markers of myocardial necrosis.^4,13 Furthermore, in the Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trial (ClinicalTrials.gov number, NCT00093158),¹⁴ investigators could not rule out a benefit of as much as 29% with the early administration of glycoprotein IIb/IIIa inhibitors, nor did they show noninferiority of a strategy of delayed administration on the composite ischemic end point.

In our trial, we used a superiority design to test strategies of early, routine use of eptifibatide versus early placebo before angiography, allowing a convergence of therapy in selected patients undergoing PCI (39% of patients in the delayed-eptifibatide group received eptifibatide during PCI). This convergence precluded assessment of the benefit of eptifibatide, as compared with placebo. Therefore, our findings do not contradict earlier studies showing the superiority of glycoprotein IIb/IIIa inhibitors over placebo in patients with acute coronary syndromes. In addition, there were important differences between our study and the ACUITY trial. In our study, randomization was required within 12 hours after presentation, the duration of exposure to a study drug before angiography was longer (21 hours vs. 4 hours), and bivalirudin was used less frequently, since it was not required by design, as in the ACUITY trial.

A meta-analysis of six large, randomized trials comparing glycoprotein IIb/IIIa inhibitors with placebo in patients with acute coronary syndromes in whom an invasive strategy was not mandated by protocol showed a relative reduction in the rate of death or myocardial infarction of 9% (95% CI, 2 to 16) at 30 days.¹⁵ These findings are similar in magnitude to those that we report. Although due caution must be used in interpreting treatment comparisons according to post-randomization treatment strategies,¹⁶ among patients who had undergone PCI within 5 days after presentation, the relative reduction in the rate of death or myocardial infarction at 30 days was a more robust 23% (95% CI, 8 to 36), a finding that was similar to our observations after accounting for events before and after the invasive procedure. Furthermore, in this meta-analysis, the use of glycoprotein IIb/IIIa inhibitors was not associated with benefit for patients who did not have an elevated troponin level. Similarly, we observed no treatment benefit among patients with normal troponin levels; however, the treatment effect among patients with elevated levels was not as large as previously reported.

We postulate several explanations for the lack of significant treatment benefit with early, routine use of eptifibatide in our study. First, the convergence of use of eptifibatide during PCI in the two study groups probably reduced the difference in efficacy. However, we could not assign patients to a strict placebo group, since guidelines at the time that we were planning the trial strongly endorsed the use of glycoprotein IIb/IIIa inhibitors during PCI,^17,18 and some regulatory agencies thought it would be unethical to withhold such drugs during PCI, given their efficacy in previous placebo-controlled trials.^3,19 It is also possible that interventionalists simply identified correctly many of the patients who would benefit from delayed, provisional use of eptifibatide. Furthermore, patients were treated with aggressive contemporary cotherapies, including frequent use of clopidogrel (in >90% of patients), low-molecular-weight heparin (60%), and statins (85%), which may have reduced the potential incremental effect of the early use of eptifibatide. Also, a greater-than-anticipated contribution to the primary end points of events that may not be modifiable by antiplatelet therapy (e.g., procedural complications) may have limited the benefit in the early-eptifibatide group. In addition, such a benefit may have been attenuated by the shorter time between presentation and PCI than in earlier placebo-controlled studies and by the substantial number of patients who were treated with CABG or medical therapy only. Finally, 1-year follow-up data in our trial are pending and may provide additional insights, as occurred in a similar study.²⁰

Although subgroup analyses should be interpreted with caution,²¹ our analysis of selected subgroups of patients (e.g., those who had a normal baseline troponin level, who did not have diabetes, and who were over the age of 75 years) showed no evidence of a benefit with early eptifibatide but did show an increased risk of bleeding. Our results argue against routine early initiation of treatment with glycoprotein IIb/IIIa inhibitors in such subgroups. Patients in our study who received early eptifibatide had fewer ischemic complications after PCI than those who received delayed eptifibatide, a finding that is consistent with current guidelines^1,2 and previous studies²² and that supports a continued role for such drugs in patients undergoing PCI.

Our results have important implications for the use of eptifibatide in patients with acute coronary syndromes. First, the early, routine use of eptifibatide was not superior to provisional use during PCI. Second, patients in the early-eptifibatide group had an increased risk of bleeding by a factor of 1.5 to 2.0. Even if subgroups of patients who might benefit from early eptifibatide treatment could be identified, the risk of bleeding would have to be weighed against potential benefits. If clinical or noninvasive assessments could reliably identify which patients with acute coronary syndromes would have a substantially improved outcome after PCI (as was recently shown in patients with stable angina²³), selected subgroups might be considered for the early use of glycoprotein IIb/IIIa inhibitors.

In conclusion, in high-risk patients with acute coronary syndromes, the early, routine use of eptifibatide before PCI, as compared with early placebo followed by provisional eptifibatide, did not reduce the rate of the composite primary efficacy end point at 96 hours and was associated with a higher rate of non–life-threatening bleeding and transfusion. However, in the early-eptifibatide group, there was a trend toward fewer recurrent ischemic events at 30 days. On the basis of these results, a routine strategy of administering eptifibatide in patients early after presentation cannot be recommended.

The members of the executive and steering committees and the data and safety monitoring board of the EARLY ACS trial and key representatives of the trial coordinating center were as follows (with principal investigators at participating centers listed separately, in the Supplementary Appendix): Executive Committee: TIMI Study Group, Brigham and Women's Hospital, Boston — E. Braunwald (chair), R.P. Giugliano; Duke Clinical Research Institute , Durham, NC — R.M. Califf (cochair), R.A. Harrington, L.K. Newby, J.A. White (lead biostatistician); Belgium — F. Van de Werf (cochair); Canada — P.W. Armstrong; France — G. Montalescot. Sponsor: Schering-Plough Research Institute — E. Veltri, S. Hildemann, J.T. Strony, A. Kilian, B. Yang; Millennium, Inc. — J. Gilbert. Steering Committee: Austria — K. Huber; Australia — P. Aylward; Canada — M. Labinaz, A. Langer, J.-F. Tanguay; Czech Republic — P. Widimsky; Denmark — P. Grande; Finland — M. Lindroos; France — P.G. Steg; Germany — C. Bode, U. Zeymer; Hungary — M. Keltai; India — D. Prabhakaran; Israel — B.S. Lewis; Italy — D. Ardissino; the Netherlands — A. Van `t Hof; New Zealand — H. White; Norway — D. Atar; Poland — W. Ruzyllo; Portugal — P. Canas da Silva; Russia — V. Sulimov; South Africa — A. Dalby; Spain — A. Betriu; Switzerland — F. Mach; Sweden — S. James; United Kingdom — K. Fox, K. Karsch; United States — G. Brogan, J. Ferguson (through 2007), B. Gibler, H. Herrmann, J. Hochman, J. Hoekstra, N. Kleiman, E.M. Ohman, W. O'Neill, C. Pollack, Jr., M. Schweiger. Duke Clinical Research Institute Coordinating Center: Physician leadership — L.K. Newby (principal investigator), R.A. Harrington, P. Tricoci; Project leadership — L. Berdan; Lead statistician — J. White; Faculty statistician — K. Lee; Unblinded statistician — J. Leimberger; Clinical end-point committee (CEC) lead physician — M. Roe; CEC lead coordinator — D. Montgomery; CEC event adjudication team — J. Alexander, M. Brennan, C. Bushnell, M. Chan, R. Lopes, D. Laskowitz, K. Mahaffey, R. Mehta, C. Melloni, J. Mills, G. Oliveira, M. Patel, J. Petersen, J. Piccini, B. Shah, P. Tricoci, T. Wang, K. Williams, S. Wiviott. Data management leads — C. Campbell, A. Heath. Data and Safety Monitoring Board: D. Weaver (chair), J. Alpert, E. Cohen, D. Faxon, L. Fisher, F. Verheugt. Angiographic Core Laboratory: V. Kunadian, C. Zorkun (readers), S. Williams, L. Biller, A. Palmer, K. Ogando, B. Blank (quality-control assurance technicians).