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(Circulation. 2001;103:3069.)
© 2001 American Heart Association, Inc.
Clinical Investigation and Reports |
Aspirin, Warfarin, or the Combination for Secondary Prevention of Coronary Events in Patients With Acute Coronary Syndromes and Prior Coronary Artery Bypass Surgery
From the Montreal General Hospital (T.H., S.S.), the Montreal Heart Institute (P.T.), and Sacré-Coeur Hospital (J.N.), Montreal, Quebec, and the Quebec Heart Institute (P.B.), Quebec, Quebec, Canada.
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Abstract |
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Background—Patients with a non–ST-elevation acute coronary syndrome and prior CABG are at high risk of a recurrent ischemic event despite aspirin therapy. This trial investigated the potential benefit of secondary prevention with warfarin.
Methods and Results—In a double-blind randomized trial, 135 patients with unstable angina or non–ST-segment elevation myocardial infarction, with prior CABG, and who were poor candidates for a revascularization procedure received therapy with aspirin and placebo+warfarin, warfarin and placebo+aspirin, or aspirin and warfarin for 12 months. Warfarin was titrated to an international normalized ratio of 2.0 to 2.5. The primary end point (death or myocardial infarction or unstable angina requiring hospitalization 1 year after randomization) occurred in 14.6% of the patients in the warfarin-alone group, in 11.5% of patients in the aspirin-alone group, and in 11.3% of patients randomized to the combination therapy (P=0.76). Subgroup analyses by risk features provided no indications that warfarin alone or in combination with aspirin could be of benefit over aspirin alone. Bleeding was more frequent in the 2 groups of patients administered warfarin.
Conclusions—Moderate-intensity oral anticoagulation alone or combined with low-dose aspirin does not appear to be superior to low-dose aspirin in the prevention of recurrent ischemic events in patients with non–ST-elevation acute coronary syndromes and previous CABG.
Key Words: warfarin sodium • anticoagulants • aspirin • coronary disease
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Cardiac events are frequent in patients with previous CABG and are associated with an impaired prognosis.1 2 3 4 Aspirin prevents graft closure during the first year after surgery,5 6 7 8 9 10 11 12 but its long-term benefit in this specific setting has not been documented. Warfarin had been evaluated in unstable angina,13 but no studies have addressed the specific population of patients with unstable coronary syndromes without ST elevation developing late after CABG. Because of the high frequency of flow stasis, thrombi, and fibrin-rich thrombi associated with venous graft disease,14 15 16 long-term anticoagulation with warfarin may be particularly beneficial in this situation. We tested the hypothesis that moderate-intensity warfarin (international normalized ratio [INR] 2 to 2.5) either alone or in combination with low-dose aspirin will be more effective than aspirin alone for the secondary prevention of coronary events in patients with previous CABG.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Selection of Patients
The present study was conducted at 4 referral cardiology centers in Quebec, Canada. All patients who presented with a diagnosis of unstable angina or non–ST-elevation myocardial infarction and prior CABG were considered for the study. The diagnosis of unstable angina was based on an accelerating pattern of chest pain occurring at rest or with minimal exertion or of a prolonged chest pain and normal serum levels of creatine kinase (CK). A non–ST-segment elevation myocardial infarction was diagnosed when serum CK-MB increased above the upper normal limit of the site in the absence of new Q waves on the ECG. Patients who had coronary angioplasty or repeat CABG during the index hospitalization were excluded; therefore, the study population was limited to patients who were poor candidates for a revascularization procedure. Other exclusion criteria were as follows: contraindication to the use of aspirin or warfarin, a treatable cause for angina pectoris, any major concomitant illness, congestive heart failure class 3 or 4 (New York Heart Association), uncontrolled systemic hypertension (blood pressure >180/95 mm Hg), recent major trauma, alcohol or drug abuse, females with child-bearing potential, coronary angioplasty within the last 6 months, conditions mandating treatment with aspirin (such as previous stroke) or with warfarin (such as metallic valve prosthesis), atrial fibrillation, or intracardiac thrombi. All patients gave informed consent to participate, and the institutional review board at each participating hospital approved the protocol.
Study Protocol
In a double-blind parallel-group study design,
patients were randomized to 1 of 3 parallel study groups: (1) aspirin
plus placebo-warfarin, (2) warfarin plus placebo-aspirin, or (3)
aspirin plus warfarin. Aspirin was administered as a daily dose of 80
mg in nonenteric coated form. Warfarin was given as crystalline
warfarin sodium tablets (Coumadin). Placebo tablets were supplied by
Dupont Pharma Canada. In-hospital follow-up visits were scheduled at 1,
3, 6, and 12 months of treatment. The study drugs were terminated at
the 12-month follow-up visit, and aspirin (325 mg daily) was prescribed
to all patients. Patients were reevaluated 1 month after the
discontinuation of the study drugs.
Study Monitoring
Measurements of INR were performed 3 days and 1 week
after study drug initiation. Subsequent visits were scheduled depending
on INR stability. Hemoglobin and hematocrit were monitored at the time
of INR determination. Unblinded pharmacists or physicians, not
otherwise involved in the study and patient care, adjusted warfarin to
a target INR of 2.0 to 2.5 by using a predefined algorithm. To maintain
the double-blind integrity, patients assigned to aspirin plus
placebo-warfarin therapy also had regular blood tests and mock
placebo-warfarin adjustments. Major bleeding was defined as a fall in
hemoglobin of 
2 g/L or requiring blood product transfusion. Minor
bleeding was defined as all other bleeding events reported by the
patients and/or health care professionals. In the event of clinically
significant bleeding, the study drugs were discontinued, and patients
were transfused as necessary. Compliance was defined as 100% of study
medication taken (pills were counted by research coordinators). Study
drugs could be temporarily interrupted for major illnesses, elective
surgeries, and dental treatment. The study code was broken only when it
was essential for optimal patient management.
Other Therapies
Concomitant medications could be prescribed at the
discretion of the attending physicians, but drugs known to interact
with warfarin or to increase the bleeding risk (barbiturates, NSAIDs,
and salicylates) were prohibited during the whole study period. All
patients received aspirin at the end of the 12-month study period, when
study drugs were discontinued.
Study End Points
The primary study end point was a composite end point
of any-cause death, myocardial infarction, or unstable angina requiring
a new hospitalization. Other end points were performance of
reperfusion procedure (either percutaneous or open
chest). Myocardial infarction was defined as typical chest pain or
discomfort lasting 30 minutes and associated with elevated serum
CK-MB levels (above the upper normal limit of the site) or with new Q
waves. Unstable angina was considered as a study end point only when it
was severe enough to require hospitalization and there was a confirmed
diagnosis at hospital discharge. Atypical chest pain requiring
hospitalization was not counted as an end point. All events were
classified before conditions of the blind study were
revealed.
Statistical Analyses
The study was terminated prematurely after enrollment
of half the planned number of patients because of difficulty in
recruiting because of the high rate of conventional or investigative
procedures performed in otherwise qualifying patients. The baseline
characteristics of the 3 study groups were compared by
2 and Student tests. End-point events
were group-classified by the intention-to-treat principle. Intergroup
differences for event rates were compared by the
2 statistics with the use of 2x3 tables.
The event rates for the primary end point of death, myocardial
infarction, and documented recurrent unstable angina were displayed by
the Kaplan-Meier survival method and tested for statistical
significance by the log-rank statistic. Events rates were also compared
in subgroups with higher risk features identified by
univariate and multivariate
analyses of the baseline characteristics associated with an
impaired prognosis. Statistical significance was defined by a value of
P<0.05. The SPSS Base 10.0
(SPSS Advanced Models 10.0 statistical software) served for the
statistical analyses.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The baseline clinical characteristics of patients in the 3 study groups are shown in Table 1
. Mean age, left ventricular
systolic function (left ventricular ejection
fraction [LVEF]), and time elapsed after CABG were similar
among the patients. Although no statistically significant differences
existed between the 3 groups, there were more patients that were female
and had prior MI, diabetes, and functional impairment by angina in the
group assigned to aspirin+warfarin and fewer patients with depressed
LVEF (<40%) in the group assigned to aspirin+placebo than in the
other 2 groups. More than 60% of the patients had prior myocardial
infarction. Cardiac catheterization was performed in
60% of patients during the index hospitalization. The time elapsed
between the last CABG and occurrence of the index acute
coronary event averaged 7.5 years.
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Table 2 shows the medical treatment received at the time of
randomization. Patients in the warfarin+placebo group more often
received ACE inhibitors and lipid-lowering drugs and less
often received ß-blockers; patients assigned to aspirin+placebo less
often received diuretics and ACE inhibitors; and
patients in the combination group more often received
nitrates.
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Table 3 presents the study end points for the 3
treatment arms, and the
Figure
presents the cumulative event rates. No statistically significant
differences existed between groups in the incidence of the primary end
point. End points regrouped or considered individually and secondary
end points were all less frequent in the aspirin-alone arm than in the
2 other arms. A percutaneous procedure during follow-up
was also performed more frequently in the 2 groups of patients
randomized to receive warfarin.
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Baseline characteristics associated with an impaired
prognosis were as follows: age 65 years (relative risk [RR] 1.65,
P=0.19), male sex (RR 2.32,
P=0.11), diabetes (RR 2.23,
P=0.07), and Canadian
Cardiovascular Society (CCS) angina class 3 (RR 1.83,
P=0.31). Treatment effects in
all subgroups showed no trends to a benefit with Coumadin alone or in
combination with aspirin over aspirin alone. Thus, the event rates in
the warfarin-alone, aspirin-alone, and warfarin+aspirin groups were,
respectively, as follows: in patients aged <65 years, 40%, 22.7%,
and 19%; in patients aged 65 years, 41.7%, 34.8%, and 36.8%;
among women, 9%, 0%, and 10%; among men, 15.7%, 15.3%, and 13.8%;
among diabetics, 13%, 18%, and 30%; among patients with LVEF <40%,
11%, 8%, and 12%; and among patients in CCS class 3 or 4 at
randomization, 6.3%, 0%, and 9.1%. Patients using diuretics
at the time of entry into the study had rates of 15.6%, 6.5%, and
13.6%, respectively, and those using ACE inhibitors had
rates of 13.3%, 8.7%, and 9.1%, respectively.
Table 4 shows the distribution of complications among the 3
treatment arms. Minor bleeds were more frequent in patients receiving
warfarin (P=0.02), either as
single therapy (8.9%) or in combination (9.8%), than in those
receiving only aspirin (1.5%). Major bleeding occurred only in
patients receiving the anticoagulant. Two patients on warfarin+ placebo
and 2 patients on warfarin+aspirin required blood transfusions. In the
present study, compared with warfarin alone, the addition of 80 mg
of aspirin to warfarin treatment resulted in no excess bleeding. No
significant excess in clinical events occurred in the month after
cessation of the study drugs, with all patients administered open-label
aspirin
(Figure
).
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The rate of completion of protocol was high among the 3 groups. The reasons for premature cessation of study medications were diverse; most of the reasons for cessation were medical conditions requiring nonstudy use of warfarin or aspirin. Three patients had to stop the study drugs because of bleeding. Nonstudy use of warfarin was required in 5 patients on warfarin+placebo, 2 patients on aspirin+placebo, and 2 patients on aspirin+warfarin. Three patients (1 in each treatment group) were lost to follow-up.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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No benefit of warfarin alone or of warfarin+aspirin compared with aspirin alone could be documented for the secondary prevention of ischemic events in the present study of patients with previous CABG and an acute coronary syndrome (ACS). The composite end point and the various components of the end point were all less frequent in the aspirin-alone group. More frequent interventions were also performed during follow-up in patients receiving Coumadin, although they were poor candidates for surgery, suggesting a lack of a benefit of the anticoagulation in preventing severe angina as well as recurrent ischemic events.
ACS in patients with previous CABG is usually associated with fibrin-rich blood clot,14 15 16 more extensive coronary artery disease, and an impaired prognosis.2 3 4 Other specific features of high risk in the study population included mean age >65 years, a high incidence of previous myocardial infarction and of diabetes mellitus, a low LVEF (30±2%), and, most important, selection of patients evaluated as poor candidates for a new revascularization procedure by coronary angiography and, for noncatheterized patients, by a coronary anatomy known to be poorly suitable for revascularization.
Despite these high-risk features, the primary end point in the present study was relatively infrequent, less than expected, and composed primarily of recurrent unstable angina with a relatively low rate of death or myocardial infarction. These figures are in contrast to those of previous studies, including one from our center, in which rates as high as 30% to 40% were reported.2 4 The improved prognosis possibly reflects a more aggressive use of conventional and investigative intervention procedures in patients with severe angina as well as the progress made in medical therapy in recent years, with emphasis on drugs that achieve plaque passivation and better control of the disease process. Such drugs include lipid-lowering agents, ACE inhibitors, and antithrombotic therapy. Yet, medical management in the study remained suboptimal, with 20% of the hyperlipemic patients not being on lipid-lowering therapy at the time of randomization, 25% of patients with depressed LVEF not being on ACE inhibitors, and 25% of the patients remaining active smokers.
With the premature discontinuation of the study and an observed event rate less than expected, the sample size of the present study was suboptimal. It provided 60% power to detect a 15% risk difference, 70% power to detect a 20% risk difference, and 88% power to detect a 25% difference between groups at a value of P<0.05. However, Coumadin alone, compared with aspirin alone, was associated with an increased absolute risk of 2.6%, and the combination of Coumadin with aspirin was associated with a minimal decrease of 0.1% (RR reduction of 0.87%), providing a low probability of a significant gain with Coumadin. A sample size >50 000 of patients would be required to document an eventual benefit of the combination Coumadin+aspirin over aspirin for a high futility index, assuming that the observed event rates were not confounded by an imbalance in the baseline characteristics of patients. Differences were indeed observed between groups, although they were not statistically significant. Subanalysis of the results by variables influencing prognosis did not influence results, and no favorable trends emerged in any end point favoring Coumadin alone or in combination. However, it remains possible that the differences observed, a combination of various differences, or other undetected differences could have had an impact on the results. Indeed, the univariate and multivariate analyses of determinants of prognosis suffered a similar lack of power as the outcome end points. Therefore, the present results should be interpreted as highly suggestive but not conclusive.
Although no studies with aspirin and Coumadin have previously specifically addressed the specific population of patients with previous CABG developing an ACS, a large body of experience has been gained with aspirin, warfarin, and the combination in unstable angina and in CABG in general. The efficacy of aspirin in the prevention of death and myocardial infarction in patients with unstable angina has been well documented, as has the efficacy of aspirin in maintaining venous graft patency when initiated at the time of surgery.5 6 7 8 9 10 11 12 However, long-term benefits to maintain graft patency are less well documented. Warfarin used alone can prevent recurrence of unstable angina13 but has not been shown to be more effective than aspirin in maintaining graft patency.8 9 10 11 12
The combination of antiplatelet and antithrombotic therapy has been extensively studied. In a primary prevention trial in high-risk men,17 low-intensity oral anticoagulation (INR 1.5) and low-dose aspirin (75 mg daily) had additive benefit. However, a low-intensity regimen was ineffective in large secondary prevention trials addressing patients with previous CABG18 and patients with a recent myocardial infarction,19 although post-CABG patients appeared to have derived some benefit, years after the discontinuation of Coumadin.20 The combination therapy with moderate-intensity anticoagulation to INR 2 to 3 might be more interesting. In a small angiographic study, Williams and Stewart21 suggested less progression in the severity of the culprit coronary lesions with combination therapy compared with aspirin alone. Another small study by Cohen et al22 showed a trend to a reduction in coronary events with the combination therapy. Favorable trends were also found in the Organization to Assess Strategies for Ischemic Syndromes (OASIS) program, with fewer deaths, myocardial infarctions, strokes, and rehospitalizations in patients receiving the combination therapy compared with those receiving aspirin alone.23 24 All together, the results of the previous studies and of the present study do not suggest a major benefit of Coumadin in ACS. One explanation could be a deficiency in important natural anticoagulants such as tissue plasminogen activator/inhibitor and thrombomodulin in the coronary circulation and in vein grafts submitted to arterial flow that contribute to create a thrombogenic state.25 26 27 28
Clinical Implications
Although pathophysiological
considerations make a strong case for the prolonged use of combined
antiplatelet and anticoagulant drugs, the various attempts made so
far in that direction have not been rewarding. The present study,
although not conclusive because it was underpowered by a low event
rate, was composed of high-risk patients with venous graft disease most
likely to benefit from anticoagulation. The prolonged administration of
low-molecular-weight heparins recently tested in 4 trials yielded no
benefit,28 although 1 of the
trials showed a benefit in the first few months of treatment that was
not maintained, however, at the 6-month
follow-up.29 Specific
inhibitors of coagulation factor Xa, oral heparins, and oral
antithrombin drugs represent new therapeutic opportunities that
need to be explored. However, more potent antiplatelet therapy may
be a better approach to secondary prevention. Oral
glycoprotein IIb/IIa receptor antagonists have
failed in this regard, but the Clopidogrel in the Unstable Angina to
Prevent Recurrent Ischemic Events (CURE) trial recently showed
that combination of aspirin and clopidogrel added significant benefit
to aspirin alone in the prevention of recurrent ischemic events
in patients with non–ST-elevation
ACS.30
Therapeutic measures addressing other pathophysiological mechanisms of the disease are also very much rewarding. The low event rates observed in our population compared with historical controls support this hypothesis. In the Post Coronary Artery Bypass Graft trial of the National Heart, Lung, and Blood Institute, the number of grafts with progression of atherosclerosis and the need for revascularization over a 4-year period were significantly reduced with aggressive lowering of LDL cholesterol levels.18 20 Therefore, the treatment currently recommended for the management of ACS in high-risk patients with previous CABG is aspirin, clopidogrel, ACE inhibitors, and an aggressive control of risk factors aided by lipid-lowering drugs.
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Acknowledgments |
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The authors wish to thank Susan Nguyen for the statistical analyses, Marie-Andrée Séguin for data compilation, and the research coordinators for patient recruitment and follow-up.
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Footnotes |
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Reprint requests to Pierre Theroux, MD, Montreal Heart Institute, 5000 Belanger East St, Montreal, Quebec, Canada H1T 1C8.
Received October 12, 2000; revision received April 9, 2001; accepted April 9, 2001.
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