Pamela F. Blakely, MD

ABSTRACT

BACKGROUND: Aspirin alone, and warfarin alone, benefit survivors of acute myocardial infarction. However, it is not known whether combination therapy is more effective in preventing subsequent cardiovascular events.

POPULATION STUDIED: Investigators enrolled 5059 patients from 78 VA medical centers, who were diagnosed with acute myocardial infarction. Screening was to be done within 14 days of the initial event. Exclusion criteria included life expectancy less than 2 years, active bleeding or risk of bleeding, treatment with high-dose aspirin or nonsteroidal anti-inflammatory drugs, other indications for anticoagulants, substance abuse, or living far from the medical center. Mean age was 64 years; 98% were men, 37% had history of previous myocardial infarction, 8% had prior congestive heart failure, 27% had diabetes mellitus, 55% had hypertension, and 45% were current smokers.

STUDY DESIGN AND VALIDITY: This was a randomized, unblinded, controlled trial. After acute myocardial infarction, subjects were assigned to receive an antithrombotic therapy, either aspirin (162 mg daily) alone, or aspirin (81 mg daily) plus warfarin, adjusted to keep the international normalized ratio at 1.5 to 2.5. Delayed treatment was allowed for patients requiring invasive procedures. Hazard ratios were calculated to determine if a delay resulted in differences in mortality. An end-points committee, blinded to treatment assignment, adjudicated cause of death and major hemorrhage. The study was sufficiently large to detect a 15% reduction in annual mortality.

OUTCOMES MEASURED: The primary outcome measured was all-cause mortality; secondary outcomes included recurrent myocardial infarction, stroke, and major hemorrhage.

RESULTS: There were 438 deaths (17.3%) in the aspirin group and 444 deaths (17.6%) in the combination group, after a median follow-up of 2.7 years. Recurrent myocardial infarction or stroke occurred in 13.1% and 3.5% of those taking aspirin and in 13.3% and 13.1% of those taking combination therapy, respectively. A delay in initiating treatment increased risk, although this risk was not significantly different between study groups. Fifteen percent of reported recurrent myocardial infarctions were not confirmed as such. Eighteen strokes that occurred in the aspirin group and 21 in the combination therapy group were not confirmed ischemic strokes. Major bleeding events per 100 patient-years of follow-up were 0.72 in the aspirin group and 1.28 in the combination therapy group, resulting in a statistically significant rate ratio of 1.78 (95% confidence interval [CI], 1.27–2.72), with the majority being gastrointestinal tract bleeding. The rate ratio for minor bleeding events was 4.63% (95% CI, 3.78–6.94). No difference was noted in the rate of confirmed intracranial hemorrhage between the 2 groups.

ABSTRACT

BACKGROUND: Aspirin alone, and warfarin alone, benefit survivors of acute myocardial infarction. However, it is not known whether combination therapy is more effective in preventing subsequent cardiovascular events.

POPULATION STUDIED: Investigators enrolled 5059 patients from 78 VA medical centers, who were diagnosed with acute myocardial infarction. Screening was to be done within 14 days of the initial event. Exclusion criteria included life expectancy less than 2 years, active bleeding or risk of bleeding, treatment with high-dose aspirin or nonsteroidal anti-inflammatory drugs, other indications for anticoagulants, substance abuse, or living far from the medical center. Mean age was 64 years; 98% were men, 37% had history of previous myocardial infarction, 8% had prior congestive heart failure, 27% had diabetes mellitus, 55% had hypertension, and 45% were current smokers.

STUDY DESIGN AND VALIDITY: This was a randomized, unblinded, controlled trial. After acute myocardial infarction, subjects were assigned to receive an antithrombotic therapy, either aspirin (162 mg daily) alone, or aspirin (81 mg daily) plus warfarin, adjusted to keep the international normalized ratio at 1.5 to 2.5. Delayed treatment was allowed for patients requiring invasive procedures. Hazard ratios were calculated to determine if a delay resulted in differences in mortality. An end-points committee, blinded to treatment assignment, adjudicated cause of death and major hemorrhage. The study was sufficiently large to detect a 15% reduction in annual mortality.

OUTCOMES MEASURED: The primary outcome measured was all-cause mortality; secondary outcomes included recurrent myocardial infarction, stroke, and major hemorrhage.

RESULTS: There were 438 deaths (17.3%) in the aspirin group and 444 deaths (17.6%) in the combination group, after a median follow-up of 2.7 years. Recurrent myocardial infarction or stroke occurred in 13.1% and 3.5% of those taking aspirin and in 13.3% and 13.1% of those taking combination therapy, respectively. A delay in initiating treatment increased risk, although this risk was not significantly different between study groups. Fifteen percent of reported recurrent myocardial infarctions were not confirmed as such. Eighteen strokes that occurred in the aspirin group and 21 in the combination therapy group were not confirmed ischemic strokes. Major bleeding events per 100 patient-years of follow-up were 0.72 in the aspirin group and 1.28 in the combination therapy group, resulting in a statistically significant rate ratio of 1.78 (95% confidence interval [CI], 1.27–2.72), with the majority being gastrointestinal tract bleeding. The rate ratio for minor bleeding events was 4.63% (95% CI, 3.78–6.94). No difference was noted in the rate of confirmed intracranial hemorrhage between the 2 groups.

ABSTRACT

BACKGROUND: Aspirin alone, and warfarin alone, benefit survivors of acute myocardial infarction. However, it is not known whether combination therapy is more effective in preventing subsequent cardiovascular events.

POPULATION STUDIED: Investigators enrolled 5059 patients from 78 VA medical centers, who were diagnosed with acute myocardial infarction. Screening was to be done within 14 days of the initial event. Exclusion criteria included life expectancy less than 2 years, active bleeding or risk of bleeding, treatment with high-dose aspirin or nonsteroidal anti-inflammatory drugs, other indications for anticoagulants, substance abuse, or living far from the medical center. Mean age was 64 years; 98% were men, 37% had history of previous myocardial infarction, 8% had prior congestive heart failure, 27% had diabetes mellitus, 55% had hypertension, and 45% were current smokers.

STUDY DESIGN AND VALIDITY: This was a randomized, unblinded, controlled trial. After acute myocardial infarction, subjects were assigned to receive an antithrombotic therapy, either aspirin (162 mg daily) alone, or aspirin (81 mg daily) plus warfarin, adjusted to keep the international normalized ratio at 1.5 to 2.5. Delayed treatment was allowed for patients requiring invasive procedures. Hazard ratios were calculated to determine if a delay resulted in differences in mortality. An end-points committee, blinded to treatment assignment, adjudicated cause of death and major hemorrhage. The study was sufficiently large to detect a 15% reduction in annual mortality.

OUTCOMES MEASURED: The primary outcome measured was all-cause mortality; secondary outcomes included recurrent myocardial infarction, stroke, and major hemorrhage.

RESULTS: There were 438 deaths (17.3%) in the aspirin group and 444 deaths (17.6%) in the combination group, after a median follow-up of 2.7 years. Recurrent myocardial infarction or stroke occurred in 13.1% and 3.5% of those taking aspirin and in 13.3% and 13.1% of those taking combination therapy, respectively. A delay in initiating treatment increased risk, although this risk was not significantly different between study groups. Fifteen percent of reported recurrent myocardial infarctions were not confirmed as such. Eighteen strokes that occurred in the aspirin group and 21 in the combination therapy group were not confirmed ischemic strokes. Major bleeding events per 100 patient-years of follow-up were 0.72 in the aspirin group and 1.28 in the combination therapy group, resulting in a statistically significant rate ratio of 1.78 (95% confidence interval [CI], 1.27–2.72), with the majority being gastrointestinal tract bleeding. The rate ratio for minor bleeding events was 4.63% (95% CI, 3.78–6.94). No difference was noted in the rate of confirmed intracranial hemorrhage between the 2 groups.