Warfarin, aspirin, or both after myocardial infarction - WARIS-II

Description:

Warfarin (target International Normalized Ratio 2.8-4.2) vs. aspirin (160 mg/day) vs. Warfarin (target International Normalized Ratio 2.0 -2.5) and aspirin 75 mg/day for the secondary prevention of myocardial infarction

Hypothesis:

Combined anticoagulant therapy with warfarin and aspirin in the secondary prevention of myocardial infarction would be superior when compared to either warfarin or aspirin alone.

Study Design

Patients Enrolled: 3630
Mean Follow Up: 1445 day =-- 592
Mean Patient Age: 60 (mean)
Female: 23

Patient Populations:

1. Age 20-74 years 2. Outpatients 3. AMI as defined by 2 of the following 3 criteria: History of chest pain, EKG changes typical of AMI, CK >250 U/L and or AST >50 U/L of probable cardiac origin

Exclusions:

1. History of serious, spontaneous bleeding on aspirin or warfarin 2. Bleeding diathesis 3. Any contraindication to aspirin or warfarin 4. Any indication for warfarin or aspirin 5. Malignant disease interfering with life expectancy 6. Anticipated poor compliance

Primary Endpoints:

Combined endpoint of death, nonfatal reinfarction and nonfatal thromboembolic stroke

Drug/Procedures Used:

Upon discharge from the hospital for myocardial infarction, patients were randomized to receive either Warfarin (target INR 2.8-4.2) or aspirin (160 mg/day) or Warfarin (target INR 2.0 -2.5) and aspirin 75 mg/day.

Concomitant Medications:

Statins 76.5%, beta-blockers 73.8%, ACE inhibitors 28.5%, calcium channel blockers 12.9%, nitrates 21.9%, diuretics 14.3%, digitalis 2.3%

Principal Findings:

The average INR was 2.8 in the warfarin alone group and 2.2 in the warfarin plus aspirin group. 35% of patients underewent coronary revascularization (CABG or PCI). The incidence of the primary outcome, a composite of death, nonfatal reinfarction, or thromboembolic stroke, occurred in 241 of 1206 patients receiving aspirin (20.0 %), 203 of 1216 receiving warfarin (16.7 %; RR compared with aspirin, 0.81; 95 % CI 0.69 to 0.95; P=0.03), and 181 of 1208 receiving warfarin and aspirin (15.0 %, RR compared with aspirin, 0.71; 95 % CI, 0.60 to 0.83; P=0.001). There was no significant difference between the two warfarin groups. Episodes of major, nonfatal bleeding were significantly higher in patients per treatment-year among patients treated with warfarin (0.62%) compared to 0.17 % of patients receiving aspirin (P<0.001).

Interpretation:

Among patients who have sustained an acute MI, warfarin, in combination with aspirin or given alone, was superior to aspirin alone in reducing the incidence of death / recurrent MI/ and thromboembolic stroke. This came at the cost of an approximately 0.5% higher rate of bleeding. Despite these therapies, patients with a recent myocardial infarction continue to be at an increased risk of additional cardiovascular events. An important consideration is that in the United States, primary PCI with stenting is performed in 15 to 20 percent of patients who present with ST-segment elevation myocardial infarction, and an additional 20 - 40 % undergo PCI within the subsequent six weeks. Thus over 50% or more individuals will receive clopidogrel for at least four weeks and up to nine months after myocardial infarction. There is currently no data on the safety of the combination of aspirin, clopidogrel and warfarin together and previous trials have conclusively shown that warfarin is not effective in preventing stent thrombosis. Thus, for more than 50% of patients in the US, an aspirin and warfarin combination may not be applicable. A future trial comparing aspirin plus clopidogrel versus aspirin plus warfarin may be more useful to determine optimal antiplatelet / antithrombotic secondary prevention therapy.

References:

1. Hurlen M, Abdelnoor M., Smith P, Erikssen J, Arnesen H, New England J of Medicine 2002;347:969-974. 2. Hurlen M, Smith P, Arnesen H. Effects of warfarin, aspirin and the two combined, on mortality and thromboembolic morbidity after myocardial infarction. The WARIS-II (Warfarin-Aspirin Reinfarction Study) design. Scand Cardiovasc J 2000;34(2):168-71. 3. Arnesen H. Results of the WARIS-II Trial. Presented at the European Society of Cardiology. Stockholm, Sweden. September 2001.

Clinical Topics: Anticoagulation Management, Invasive Cardiovascular Angiography and Intervention, Prevention

Keywords: Myocardial Infarction, Stroke, Platelet Aggregation Inhibitors, Warfarin, Coronary Disease, Ticlopidine, Electrocardiography, Purinergic P2Y Receptor Antagonists, Stents, International Normalized Ratio, Secondary Prevention, Thrombosis, Chest Pain, Hemorrhage


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