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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)
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.
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Abstract |
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 Top Abstract IntroductionMethods Results Discussion References |
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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
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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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 patients1 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).
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Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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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.
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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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.
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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.
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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).
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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.
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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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.
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Acknowledgments |
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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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