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(Circulation. 1995;92:3194-3200.)
© 1995 American Heart Association, Inc.

Articles

Effect of Thromboxane A₂ Blockade on Clinical Outcome and Restenosis After Successful Coronary Angioplasty

Multi-Hospital Eastern Atlantic Restenosis Trial (M-HEART II)

Michael P. Savage, MD; Sheldon Goldberg, MD; Alfred A. Bove, MD; Ezra Deutsch, MD; George Vetrovec, MD; Robert G. Macdonald, MD; Theodore Bass, MD; James R. Margolis, MD; Hall B. Whitworth, MD; Andrew Taussig, MD; John W. Hirshfeld, MD; Michael Cowley, MD; James A. Hill, MD; Ronald G. Marks, PhD; David L. Fischman, MD; Eileen Handberg, RN MSN; Howard Herrmann, MD; Carl J. Pepine, MD; for the M-HEART II Study Group

From the Multi-Hospital Eastern Atlantic Restenosis Trialists (study chairman, Carl J. Pepine, MD). The participating sites and investigators are listed in the "Appendix."

Correspondence to Michael Savage, MD, Cardiac Catheterization Suite, 5360 Gibbon Building, Thomas Jefferson University Hospital, 111 S 11th St, Philadelphia, PA 19107.

	Abstract

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Background Antithromboxane therapy with aspirin reduces acute procedural complications of coronary angioplasty (PTCA) but has not been shown to prevent restenosis. The effect of chronic aspirin therapy on long-term clinical events after PTCA is unknown, and the utility of more specific antithromboxane agents is uncertain. The goal of this study was to assess the effects of aspirin (a nonselective inhibitor of thromboxane A₂ synthesis) and sulotroban (a selective blocker of the thromboxane A₂ receptor) on late clinical events and restenosis after PTCA.

Methods and Results Patients (n=752) were randomly assigned to aspirin (325 mg daily), sulotroban (800 mg QID), or placebo, started within 6 hours before PTCA and continued for 6 months. The primary outcome was clinical failure at 6 months after successful PTCA, defined as (1) death, (2) myocardial infarction, or (3) restenosis associated with recurrent angina or need for repeat revascularization. Neither active treatment differed significantly from placebo in the rate of angiographic restenosis: 39% (73 of 188) in the aspirin-assigned group, 53% (100 of 189) in the sulotroban group, and 43% (85 of 196) in the placebo group. In contrast, aspirin therapy significantly improved clinical outcome in comparison to placebo (P=.046) and sulotroban (P=.006). Clinical failure occurred in 30% (49 of 162) of the aspirin group, 44% (73 of 166) of the sulotroban group, and 41% (71 of 175) of the placebo group. Myocardial infarction was significantly reduced by antithromboxane therapy: 1.2% in the aspirin group, 1.8% in the sulotroban group, and 5.7% in the placebo group (P=.030).

Conclusions Thromboxane A₂ blockade protects against late ischemic events after angioplasty even though angiographic restenosis is not significantly reduced. While both aspirin and sulotroban prevent the occurrence of myocardial infarction, overall clinical outcome appears superior for aspirin compared with sulotroban. Therefore, aspirin should be continued for at least 6 months after coronary angioplasty.

Key Words: angioplasty • myocardial infarction • aspirin • platelets • restenosis

	Introduction

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Percutaneous transluminal coronary angioplasty (PTCA), used increasingly to ameliorate the clinical consequences of obstructive coronary atherosclerosis, remains hampered by limitations. Of central importance is the complex vascular response to balloon-induced injury that may lead to acute vessel closure and early complications in 2% to 10% of patients^{1 2 3 4 5} or to late restenosis and recurrent ischemic events in up to 50% of patients.^{6 7 8 9 10} Considerable evidence implicates platelet–thromboxane A₂ interactions in the vascular response to mechanical injury. In experimental studies, angioplasty is followed by rapid deposition of platelets at the site of injury.^{11 12 13} Platelet activation leads to the release of thromboxane A₂ and serotonin (which potentiate vasoconstriction and further platelet aggregation), thrombin activation, and release of mitogens such as platelet-derived growth factor. In clinical studies, aspirin pretreatment appears to reduce acute coronary thrombosis and myocardial infarction associated with the PTCA procedure.^{14 15 16 17 18} On the other hand, aspirin has failed to influence angiographic restenosis in randomized trials.^{17 18 19} However, the effect of aspirin on clinical events during long-term follow-up after successful PTCA has not been assessed. It also remains unknown whether more potent or more selective antithromboxane agents have greater efficacy in preventing restenosis.²⁰ Therefore, we conducted a prospective, multicenter, randomized study to evaluate the role of thromboxane A₂ blockade on late clinical outcome and angiographic restenosis after successful PTCA. Two forms of thromboxane A₂ blockade were evaluated: a nonselective inhibitor of thromboxane A₂ synthesis (aspirin) and a selective antagonist of the thromboxane A₂ receptor (sulotroban).

	Methods

Top Abstract Introduction Methods Results Discussion References

 
This was the second project developed by the Multi-Hospital Eastern Atlantic Restenosis Trialists (M-HEART II). The rationale and protocol have been presented in detail elsewhere.²⁰

Patient Selection
The M-HEART II institutions and investigators and satellite centers participating in the trial are listed in the "Appendix." Patients undergoing planned PTCA of at least one coronary lesion >60% in diameter stenosis were eligible for the study. Patients were excluded if any of the following were present: (1) history of Q-wave myocardial infarction or thrombolytic therapy within 3 days of PTCA, (2) hemorrhagic diathesis, (3) platelet count <100 000/mm², (4) significant gastrointestinal bleeding, (5) central nervous system disease, (6) allergy to aspirin, (7) blood pressure >180 mm Hg systolic or 120 mm Hg diastolic immediately before initiation of study medication, (8) creatinine clearance <40 mL/min, (9) women of childbearing potential, or (10) left main coronary artery stenosis >50%.

Study Design
M-HEART II used a double-blind, placebo-controlled design with three parallel arms: two antithromboxane therapies and placebo. The primary outcome variable was late clinical failure after an initially successful PTCA. The study protocol was approved by the institutional review board at each center. After giving informed consent, patients were randomly assigned to one of three treatment groups before PTCA: placebo, aspirin (325 mg daily), or sulotroban (800 mg every 6 hours). Treatment was continued for 6 months, at which time follow-up coronary angiography was performed.

Drug Administration
Study drugs were administered in a double-blind fashion with randomization performed off-site by a central facility to ensure that personnel at each institution remained blinded. Study treatment was initiated on the morning of scheduled PTCA at least 1 hour before the planned procedure. Medications were administered in double-dummy fashion with aspirin or comparable placebo administered once daily and sulotroban or comparable placebo administered every 6 hours. After initiation of the study drug, use of any antiplatelet medications or oral anticoagulants were prohibited. Antianginal medications were continued before and after PTCA at the discretion of the clinical investigators.

Angioplasty Procedure and Angiographic Analysis
All patients received aspirin 325 mg on the day before PTCA because of the proven efficacy of aspirin pretreatment in reducing acute procedural ischemic complications.^{14 15 16 17 18} PTCA was performed using conventional balloon catheter techniques. During the procedure, intravenous heparin was given as a bolus of 10 000 units followed by a continuous infusion at 1000 U/h. Successful PTCA was defined as a residual diameter stenosis <50% after dilatation.

Coronary artery stenoses were assessed before and after angioplasty in two or more orthogonal angiographic views after the administration of intracoronary nitroglycerin. Field magnification and projection angles were recorded before PTCA, and matching views were obtained for all subsequent angiograms. All cineangiograms were submitted to a core laboratory for analysis. Quantitative measurements of stenosis severity were made using a computer-based analysis as described elsewhere.²¹ For patients to qualify for inclusion in the study, PTCA had to be performed on at least one lesion with a 60% diameter stenosis confirmed by the core angiographic facility. Because the results achieved at the core lab were reproducible within ±4% for repeated measurements of percent diameter stenosis, patients found to have a baseline percent stenosis between 56% and 60% were allowed to continue in the study provided that the stenosis was improved by 10% after PTCA. Patients with no stenosis determined by the core laboratory to be 56% were discontinued from the study because the intent was to treat only those with significant stenoses. The baseline percent diameter stenosis was determined as the greatest diameter reduction observed in the single "worst" angiographic view. This same angiographic view was used for quantitative analysis of the post-PTCA and 6-month follow-up angiograms. Observers performing the quantitative coronary analysis were blinded to the assigned therapy.

Follow-up
Comprehensive clinical evaluations of patients were scheduled at 2, 6, 12, 18, and 26 weeks. An additional evaluation was repeated at 1 to 2 weeks in the posttreatment phase. Interim history, drug compliance, physical examination, 12-lead ECG, and clinical laboratory testing were performed at each follow-up visit. Pill counts were done to determine the actual number of tablets taken. Patients taking less than 80% of study medication on each of two consecutive visits were considered noncompliant and were withdrawn from the study. All patients prematurely withdrawn from the study, due to noncompliance or adverse side effects, were adjudicated in a blinded fashion by a data monitoring committee. In compliant patients, follow-up coronary angiography was performed at 26±2 weeks, at which time the study medication was discontinued. Early angiography before 24 weeks was performed when clinically indicated. Patients undergoing early restudy, in whom a 50% diameter stenosis at the site of dilatation was found, were considered to have a clinically significant restenosis, and study medication was discontinued. In patients undergoing coronary angiography before 24 weeks in whom no restenosis was found, the study drugs were continued and follow-up angiography was repeated at 6 months.

Assessment of Treatment Efficacy
The primary outcome variable was late clinical failure occurring after initially successful PTCA. This was defined as any of the following: (1) cardiovascular death, (2) myocardial infarction, (3) restenosis associated with recurrent angina, or (4) restenosis leading to a recommendation for additional myocardial revascularization procedures. For simplification of reporting, these later two categories are henceforth termed "clinically important restenosis." Myocardial infarctions were documented by elevation in cardiac enzymes accompanied by typical symptoms and ECG changes. Patients with acute ischemic complications associated with the initial PTCA were classified as procedural failures and thus were excluded from the primary outcome analysis of late clinical events. Angiographic restenosis was used as a secondary outcome variable. Restenosis was defined as diameter stenosis 50% measured on the follow-up angiogram. Restenosis rates were calculated both by lesion and by patient. All successfully dilated lesions were used in the analysis of the lesion restenosis rate. Patients who underwent multilesion PTCA were considered to have restenosis if any successfully dilated site demonstrated angiographic restenosis.

Sample Size Considerations and Statistical Analysis
To determine the sample size, it was assumed that the rate of late clinical failure would be approximately 30% in the placebo group and that a 50% reduction in the late clinical failure rate would be a clinically relative important change that would justify 6 months of therapy with one of the study agents. A three-armed trial with 500 patients completing the study and eligible for end point analysis was required in order to attain a ß error of 0.20 and a two-tailed error of 0.05 (with correction for multiple comparisons using the Bonferroni method). All clinical and angiographic data were collected on standardized forms and forwarded to the Coordinating Center for entry into a computerized database. Quantitative data are expressed as mean±SD.

Clinical outcome was converted into a binary response: treatment failure or treatment success. Analysis of the response variable was then performed in two ways: first using a parametric method, and second using a nonparametric method. Parametric analysis was performed using the maximum-likelihood log-linear model with effects due to center and treatment. The CATMOD procedure of the Statistical Analysis System (SAS) was used for this analysis. The probability values for the tests of significance correspond to generalized Wald statistic, which is approximately distributed as ². To justify pooling data across centers, the comparability of results across centers was examined by analyzing the data using a full model with effects due to center, treatment, and center-by-treatment interaction, and by examining the proportions of clinical failures by treatment and center. Since center-by-treatment interaction effect in these analyses was not significant, all probability values for treatment comparisons were obtained from analysis with only the main effects in the model. For nonparametric analysis, the Cochran-Mantel-Haenszel (CMH) ² statistic was used to test for differences in clinical failures between treatments groups controlling for center (investigator). This analysis was performed using PROC FREQ of SAS. The estimates of relative risk and 95% CMH test-based confidence intervals of relative risk for pairwise treatment comparisons were obtained from this analysis.²² A value of P<.05 was considered significant for differences in outcomes between treatment groups. Because of the large number of baseline variables compared, a value of P<.01 was considered significant for these comparisons.

	Results

Top Abstract Introduction Methods Results Discussion References

 
During a 24-month period, 752 patients were enrolled and received study medication before anticipated PTCA. Of these, 248 were randomized to receive aspirin, 249 to sulotroban, and 255 to placebo. As shown in Table 1, the three groups were not significantly different in terms of baseline clinical and angiographic characteristics.

View this table: [in this window] [in a new window]   Table 1. Baseline Characteristics of Treatment Groups

Fig 1 outlines the patient flow after enrollment and summarizes postrandomization status of subjects for outcomes analysis. A total of 112 patients were excluded because they failed to meet criteria of an initial successful PTCA, due to one of the following: no PTCA performed or no qualifying stenosis (n=43), unsuccessful PTCA procedure (n=37), or procedural success by clinical site but post-PTCA stenosis 50% by core laboratory quantitative analysis (n=32). These consequences were not significantly different among the three treatment arms. Procedural success rates were also similar among the three treatment groups. Of the 640 patients who were eligible after the procedure, 57 patients failed to complete follow-up due to side effects and an additional 74 patients were discontinued due to compliance failure as prospectively defined above. Early withdrawals due to drug side effects or noncompliance were not different between the treatment groups. An additional 6 patients were lost to follow-up. Thus, a total of 503 patients were considered eligible for follow-up angiography: 162 in the aspirin group, 166 in the sulotroban group, and 175 in the placebo group. Follow-up angiography was performed in 483 (96%) of these 503 eligible patients.

View larger version (30K): [in this window] [in a new window]   Figure 1. Patient flow diagram. PTCA indicates percutaneous transluminal coronary angioplasty.

Angiographic Outcome
The initial procedural success of PTCA was not affected by the study medication, which was started 1 to 6 hours beforehand. Primary angioplasty success without acute procedural complication was achieved in 89.4% of the aspirin group, 91.3% in the sulotroban group, and 90.2% in the placebo group (P=NS).

The angiographic restenosis rates by lesion and by patient are summarized in Table 2. Lesion restenosis occurred in 39% (73 of 188) of the aspirin group, 53% (100 of 189) of the sulotroban group, and 43% (85 of 196) of the placebo group. Differences in restenosis rates among the three treatment groups were statistically significant (P=.020 by Wald test; P=.019 by CMH test). Differences between sulotroban and placebo and between aspirin and placebo were not significant (both P=NS). However, the observed difference of 14% between sulotroban and aspirin was significant (P=.006). Differences in restenosis rates among the three treatment groups were also statistically significant when analyzed on a per-patient basis (P=.046 by Wald test; P=.050 by CMH test). Pairwise treatment comparisons indicate that differences in restenosis rates between sulotroban and placebo and between aspirin and placebo were not significant (both P=NS). However, the difference between sulotroban and aspirin was significant (P=.014).

View this table: [in this window] [in a new window]   Table 2. Restenosis Outcome

Primary Outcome
The results of treatment on the 6-month clinical outcome after initially successful PTCA are summarized in Table 3. Odds ratios for the primary outcome of treatment failure are presented in Fig 2. Treatment failure (death, myocardial infarction, or clinically important restenosis) occurred in 30% (40 of 162) of the aspirin group, 44% (73 of 166) of the sulotroban group, and 41% (71 of 175) of the placebo group. Differences in clinical outcome among the three treatment groups were statistically significant (P=.019 by Wald test, P=.021 by CMH test). There was no significant difference in the treatment failure rate comparing sulotroban with placebo (P=NS). On the other hand, aspirin was associated with reduced clinical failure rate compared with either placebo (P=.046) or sulotroban (P=.006). Importantly, antithromboxane treatment was associated with a significant reduction in acute myocardial infarction during the follow-up period. Myocardial infarction occurred in 1.2% (2 patients) of the aspirin group, 1.8% (3 patients) in the sulotroban group, and 5.7% (10 patients) in the placebo group (aspirin and sulotroban versus placebo, P=.030). Fig 3 depicts the time course during which myocardial infarction occurred over the 6-month follow-up period. Among the 17 patients with acute myocardial infarction or death after initially successful angioplasty, the mean interval between the PTCA procedure and the clinical event was 37±31 days. Thus, many of these acute clinical events occurred relatively late after the initial hospitalization.

View this table: [in this window] [in a new window]   Table 3. Clinical Outcomes

View larger version (14K): [in this window] [in a new window]   Figure 2. Treatment failure of antithromboxane therapies versus placebo. Results are displayed as odds ratio with 95% confidence intervals. In contrast to sulotroban, which was not significantly different from placebo, aspirin conferred a 37% reduction in treatment failure.

View larger version (10K): [in this window] [in a new window]   Figure 3. Time plot of myocardial infarctions occurring after initially successful coronary angioplasty. PTCA indicates percutaneous transluminal coronary angioplasty; MI, myocardial infarction.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
The results of this trial indicate that thromboxane A₂ blockade improves clinical outcome at 6 months after successful PTCA. Compared with placebo, aspirin was associated with a reduction in late clinical failure, defined as the occurrence of death, myocardial infarction, or clinically important restenosis. The selective thromboxane A₂ receptor antagonist sulotroban also reduced the risk of myocardial infarction during follow-up but was less effective than aspirin in preventing clinical failure. Importantly, a clinical benefit was observed with both antithromboxane treatments even though the rate of restenosis by quantitative coronary angiography was not significantly reduced.

Thromboxane A₂ and Vascular Injury After Angioplasty
The vascular response to balloon injury that leads to restenosis appears to be platelet mediated. Endothelial denudation and exposure of subendothelial collagen to circulating blood results in rapid adhesion of platelets at the site of arterial injury.^{11 12 13} Platelet adhesion and aggregation leads to the release of thromboxane A₂, a potent stimulus for vascular smooth muscle constriction and further platelet deposition. In addition, platelet deposition leads to the secretion of serotonin and platelet-derived growth factors, which promote the neointimal proliferation of smooth muscle cells. Thromboxane A₂ also may promote vascular smooth muscle cell proliferation through a direct mitogenic effect.²³ Thus, by promoting thrombus formation, local vasoconstriction, and cellular proliferation, platelet effects mediated by thromboxane A₂ may participate in the restenosis process that evolves in the weeks to months after coronary angioplasty.

The antiplatelet effect of aspirin is achieved by blockade of thromboxane A₂ synthesis through the nonselective irreversible acetylation of cyclooxygenase.²⁴ While aspirin blocks platelet cyclooxygenase and production of thromboxane A₂, it also blocks endothelial cyclooxygenase and production of prostacyclin. This later effect may be deleterious after angioplasty since prostacyclin inhibits platelet adhesion and promotes local vasodilation. Accordingly, use of more selective antithromboxane agents may be more efficacious in the postangioplasty setting. The selective agent used in this study, sulotroban (4,2-benzenesulfonamidoethyl phenoxyacetic acid), is a specific antagonist of the thromboxane A₂ receptor that does not interfere with prostacyclin production or activity.^{20 25 26 27 28 29}

Prior Studies
In 1984, Thornton and colleagues³⁰ reported results of a nonblinded trial of 248 patients who were randomly assigned after successful PTCA to either aspirin or warfarin. Angiographic restenosis after 6 months of therapy was observed in 27% of patients assigned aspirin and in 36% of patients assigned warfarin (P=NS). However, clinical events were not reported. Schwartz et al¹⁷ conducted a double-blind study of the antiplatelet regimen of aspirin (330 mg TID) plus dipyridamole (75 mg TID) compared with placebo beginning 24 hours before PTCA in 376 patients. Restenosis was found in 37% of lesions in both groups. Retrospective analysis of complications occurring within 48 hours of the procedure suggested a lower rate of myocardial infarction in the antiplatelet treated group (1.6%) versus the placebo group (6.9%) (P=.01). However, this was not a prospectively defined outcome, and clinical events occurring during later follow-up were not reported. Two other controlled trials that examined the combination of aspirin (650 to 975 mg per day) plus dipyridamole similarly suggested lower rates of acute procedure–related complications but no effect on late restenosis.^{18 19} Limited available data comparing high-dose aspirin versus low-dose aspirin (325 mg daily) have been inconclusive.³¹ One study of 216 patients, treated initially with aspirin and at 2 weeks assigned to either continued aspirin (100 mg daily) or placebo, suggested a reduction in restenosis with low-dose aspirin.³²

The impact of chronic aspirin therapy after PTCA on long-term clinical outcome after hospital discharge has not been addressed by previous restenosis trials. Late clinical outcome was evaluated as a secondary end point in the Coronary Artery Restenosis Prevention On Repeated Thromboxane-Antagonism (CARPORT) study, which compared the thromboxane A₂ receptor antagonist GR32191B with placebo.³³ No benefit for either angiographic restenosis or clinical events was reported. However, there was no concomitant aspirin-treated group in the CARPORT trial.

Implications of the Present Study
In the current trial, restenosis defined only by quantitative coronary angiography was not prevented by thromboxane A₂ blockade with either low-dose aspirin or a selective receptor antagonist. Although angiographic restenosis was not reduced, thromboxane blockade protected against late clinical events after successful PTCA. The discordance between the clinical and angiographic outcomes may reflect differential effects of thromboxane inhibition. Alternatively, this discordance may reflect the difference in assessment of a time integrated index (clinical events) versus a snapshot of a continuous variable (angiographic patency). The findings of this study has important implications for the design of future restenosis trials. Relying on angiographic end points to the exclusion of patient-related outcomes may result in important biological and clinical effects being overlooked. In contrast to prior angioplasty trials, our primary outcome variable was a censored clinical event rate, not angiographic restenosis. As our study demonstrates, major clinical events including myocardial infarction and death are not limited to the immediate postprocedural days but may occur throughout the following months. Thus, the post–hospital follow-up course of patients after successful PTCA should not be viewed as an inherently benign clinical interim.

The discordance between clinical and angiographic effects suggests that the clinical benefit derived from aspirin is independent of the cellular processes responsible for intimal proliferation. In animal studies, platelet accumulation has been demonstrated at the site of experimentally induced coronary stenoses.³⁴ Furthermore, thromboxane A₂ has been shown by Willerson and colleagues³⁵ to be an important mediator of intermittent coronary obstruction resulting from platelet aggregation and dynamic vasoconstriction. In the canine model of coronary stenosis with endothelial injury, these investigators have demonstrated that cyclical platelet aggregation can be prevented by thromboxane A₂ inhibition. It may be postulated that in patients, the nascent neointimal lesion associated with restenosis may become the nidus for platelet activation modulated by thromboxane A₂. Thus, while development of the restenotic lesion as the primary event may be relatively independent of thromboxane A₂, ischemic episodes and acute myocardial infarction may be secondary events triggered by thrombotic and vasoconstrictive processes that are thromboxane mediated. In this light, the vascular injury produced by angioplasty resembles plaque rupture occurring spontaneously in unstable ischemic syndromes. Three large randomized trials of aspirin in patients with unstable angina have shown a 49% to 72% relative reduction in risk of cardiovascular death or myocardial infarction.^{36 37 38} In the present study, one aspirin tablet taken daily for 6 months after successful PTCA was associated with a 79% reduction in the risk of myocardial infarction.

Limitations of the Study
All patients received aspirin before PTCA because of its documented benefit in reducing procedural complications including acute myocardial infarction.^{14 15 16 17 18 19} Since the objective of this study was to assess long-term benefits of thromboxane inhibition, our results underscore the importance of continued aspirin therapy after successful angioplasty. On the other hand, the effects of aspirin during the procedure may have mitigated a selective advantage of sulotroban, since prostacyclin synthesis may have been inhibited at the time of vascular injury. Thus, we cannot exclude the possibility that initial administration of aspirin diminished the benefit of thromboxane receptor blockade, since acute procedural events may have influenced later outcomes.

Recently, a unique thromboxane receptor isoform has been identified on endothelial cells.³⁹ This alternatively spliced version of the thromboxane receptor may serve a hemostatic function, inducing a rise in prostacyclin formation upon platelet activation. Accordingly, a thromboxane receptor antagonist that does not distinguish between platelet and endothelial receptors may not be truly selective as an antiplatelet agent. The relative affinity of sulotroban for these thromboxane receptor isoforms is unknown.

Another limitation was the lack of documentation of the degree of receptor blockade achieved with sulotroban and the degree of cyclooxygenase inhibition achieved with aspirin in the study patients. Although patient compliance with the drug protocol was assessed by careful and frequent pill counts, plasma drug levels and ex vivo platelet aggregation studies were not performed. However, we chose doses that had been shown active in previous studies. We also cannot exclude possible contamination of sulotroban or placebo treatment by surreptitious or casual aspirin use. However, the possibility of significant undetected aspirin use in these groups would have been unlikely, since patients were repeatedly instructed to avoid aspirin-containing products at the time of enrollment and at follow-up evaluations. Most importantly, significant differences in clinical outcomes were observed between the groups assigned to aspirin and placebo, indicating a therapeutic benefit of aspirin that would not have been observed if frequent aspirin use in the placebo group had occurred.

Conclusions
Our results indicate that thromboxane A₂ blockade protects against late ischemic events after coronary angioplasty, even though the angiographic restenosis rate is not reduced. While both aspirin and sulotroban reduce the incidence of acute myocardial infarction during follow-up, overall clinical outcome is superior with aspirin. Therefore, aspirin therapy should be maintained in patients for a minimum of 6 months after successful coronary angioplasty.

	Acknowledgments

 
The M-HEART II Study was supported in part by a grant from SmithKline Beecham Pharmaceuticals. We thank Laraine Bartlett for her excellent assistance in preparing the manuscript.

M-HEART II Study Group
M-HEART Study Chairman
Carl J. Pepine, MD, University of Florida, Gainesville.

M-HEART Study Group
Maritime Heart Hospital, Halifax, Nova Scotia, Canada: Robert G. Macdonald, MD, Principal Investigator; Mark A. Henderson, MD, and Judy M. Lomnicki, RCPT.

Florida Hospital, Orlando: Andrew Taussig, MD, Coprincipal Investigator; Hall Whitworth, MD, Coprincipal Investigator; William E. Story, MD, Michael Nocero, MD, and Suzanne Lee, RN.

Hospital of the University of Pennsylvania, Philadelphia: John W. Hirshfeld, Jr, MD, Principal Investigator; J. William G. Kussmaul, MD, Warren K. Laskey, MD, Elliot Barnathan, MD, and Howard Herrmann, MD.

West Hospital, Richmond, Va: George Vetrovec, MD, Coprincipal Investigator; Michael J. Cowley, MD, Coprincipal Investigator; Germano DiSciascio, MD, Amar Nath, MD, Evelyne Goudreau, MD, Kim Cooke, RN, and Mary Brodie, RN.

South Miami Hospital, South Miami, Fla: James R. Margolis, MD, Principal Investigator; Jose C. Martin, MD, Dan Krauthamer, MD, and Gerald Welcome, RN.

Temple University, Philadelphia, Pa: Alfred Bove, MD, Principal Investigator; Ezra Deutsch, MD, J. Patrick Kleaveland, MD.

Thomas Jefferson University Hospital, Philadelphia, Pa: Sheldon Goldberg, MD, Coprincipal Investigator; Michael P. Savage, MD, Coprincipal Investigator; Andrew Zalewski, MD, Paul Walinsky, MD, Gregory Natello, MD, Douglas Welsh, MD, David Fischman, MD, and Patricia Delacourt, MSN, RN.

University of Florida, and Gainesville Veterans Administration Medical Center, Gainesville, Fla: Carl J. Pepine, MD, Principal Investigator; James A. Hill, MD, Charles R. Lambert, MD, PhD, Barry Rose, MD, Thomas Wargovice, MD, Eileen Handberg, RN, and Ronald G. Marks, PhD.

University Hospital, Jacksonville, Fla: Theodore A. Bass, MD, Coprincipal Investigator; Paul S. Gilmore, MD, Coprincipal Investigator; Mark E. Johnson, MD, Alan B. Miller, MD, Gail Rohman, RN, and John Joslin, MSN, RN.

Satellite Sites and Investigators
University Hospital of Cleveland, Cleveland, Ohio: Ravi Nair, MD.

Foothills Hospital, Calgary, Alberta, Canada: Merril Knudtson, MD.

St Elizabeth's Hospital, Boston, Mass: Douglas Losordo, MD.

Cooper Hospital, Camden, NJ: William Groh, MD.

Evanston Hospital, Evanston, Ill: Michael Salinger, MD.

Rocky Mountain Heart Research Institute, Denver, Colo: Nampalli Vijay, MD.

San Antonio, Tex: Roger Lyons, MD.

University of Chicago Hospital, Chicago, Ill: Ted Feldman, MD.

St Joseph's Heart Institute, Tampa, Fla: Peter Alagona, MD.

VA Lakeside Hospital, Chicago, Ill: Pierre Abi-Mansour, MD.

Northwestern Memorial Hospital, Chicago, Ill: Barry Kramer, MD.

Quantitative Angiographic Center
Temple University, Philadelphia, Pa: Alfred A. Bove, MD, Principal Investigator.

Data Coordinating Center
SmithKline Beecham Pharmaceuticals, Philadelphia, Pa: Jeffrey Grannett, MD, and Gerald Parchman, PhD.

Received January 24, 1995; revision received May 18, 1995; accepted July 7, 1995.

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