Combination Antithrombotic Therapy with Antiplatelet Agents and Anticoagulants for Patients with Atherosclerotic Heart Disease (

ABSTRACT: We reviewed the efficacy and safety of combination antithrombotic therapy with aspirin plus warfarin versus aspirin alone in patients with atherosclerotic heart disease. We performed a comprehensive MEDLINE search of English-language reports published between 1966 and 2002 and search of references and relevant papers. Only clinical research studies on primary or secondary prevention of cardiovascular events in patients at high risk for coronary artery disease or patients experiencing unstable angina or myocardial infarction were included. Despite daily aspirin treatment, many patients “break through” aspirin treatment and experience cardiovascular events. Individuals at high risk for coronary disease or with established disease benefit from combination therapy with aspirin plus warfarin, if compliance with warfarin is greater than 70% and the target international normalized ratio (INR) of 2.0–2.5 is achieved. Combination therapy within these parameters leads to a 29–45% reduction in the risk of death, reinfarction and/or ischemic stroke. There is a significant increase in the rate of minor and a slight increase in the rate of major bleeding with combination therapy. Other potential indications for combination therapy include myocardial infarction associated with acute left ventricular aneurysm or significant left ventricular systolic dysfunction. In spite of reluctance to use oral anticoagulants, several large, randomized clinical trials support combination therapy with aspirin plus warfarin (INR, 2.0–2.5) in high-risk patients with atherosclerotic heart disease. Combination therapy increases the risk of minor and major bleeding, but not intracranial bleeding. J INVAS CARDIOL 2004;16:271–278 Key words: antithrombotic therapy, aspirin, coronary artery disease, warfarin Arterial thrombosis is responsible for many of the acute manifestations of atherosclerotic heart disease (ASHD) and contributes to the progression of atherosclerotic plaques. Activation of both the coagulation and platelet aggregation pathways are responsible for arterial thrombosis. These two mechanisms of thrombogenesis are closely linked. Thrombin, a key clotting enzyme generated by blood coagulation, is a potent platelet activator, and activated platelets provide a platform for (and augment) the coagulation process. Therefore, combination therapy with antiplatelet agents plus anticoagulants should be very effective in the prevention and treatment of arterial thrombosis.^1,2 We searched the MEDLINE database for English-language reports published up to September 2002 by using the key words antithrombotic therapy, aspirin, warfarin, coronary artery disease (CAD), ischemic heart disease, sudden death, unstable angina (UA) and myocardial infarction (MI). In addition, we searched references from relevant articles. Studies on primary prevention of cardiovascular events in patients at risk for CAD as well as studies on secondary prevention of recurrent cardiovascular events in patients with prior history of UA and MI were reviewed and clinical information was extracted. Studies were included if they were randomized, evaluated combination therapy with aspirin plus warfarin, had a reasonably large sample size (200 patients or more with the exception of one hallmark pilot trial), and continued treatment for 3 or more months. For recent trials not yet published, related abstracts and synopses of original scientific presentations were reviewed and relevant data were extracted. We did not include studies evaluating combination therapy with ticlopidine, since it is not often used in the United States in view of recent data on clopidogrel. We did not review the data on antiplatelet therapy with dipyridamole since this agent has no broad support in patients with coronary disease. Efficacy of combination therapy with aspirin plus warfarin in primary prevention of cardiovascular events Several trials have evaluated the efficacy of aspirin in prevention of cardiovascular events in asymptomatic individuals without prior history of vascular disease.^3–7 The largest of these studies, the United States Physician Health Study, of 22,071 male physicians, revealed a 44% reduction in the risk of MI (p 4 In the Thrombosis Prevention Trial (TPT), a total of 5,499 men at high risk for CAD were randomized to combination therapy with low-dose aspirin (75 mg daily) plus low-intensity warfarin anticoagulation [international normalized ratio (INR) 7 The mean INR of those receiving warfarin was 1.47 (range, 1.3–1.8). Compared to placebo, the combination of aspirin plus warfarin reduced the rate of combined fatal and nonfatal ischemic events by 34% [71/1,277 (8.7/1,000 person years) versus 107/1,272 (13.3/1,000 person years); p = 0.003] (Table 1).⁷ Compared to aspirin alone or warfarin alone, combination therapy with aspirin plus warfarin reduced the risk of fatal and nonfatal ischemic events by 15%. There was no significant increase in the risk of major bleeding in patients treated with a combination of aspirin plus warfarin, as compared to aspirin alone (12/1,277 versus 8/1,268; p = NS). However, the combination of aspirin plus warfarin increased the risk of hemorrhagic stroke (7/1,277 versus 2/12,688; p 7 It is important to note that systolic blood pressure was significantly higher in patients who had cerebral bleeding as compared to those who did not have cerebral bleeding. Efficacy of combination therapy with aspirin plus warfarin in secondary prevention of cardiovascular events In patients with CAD, aspirin has clearly been shown to reduce vascular events (recurrent MI, stroke and vascular death) by about 25–35%.⁸ However, the rates of recurrent cardiovascular events remain high despite the use of aspirin.⁹ Patients who present with an acute coronary syndrome (ACS), in spite of being on aspirin, are at a higher risk for recurrent ischemic events compared to nonprior aspirin users.^10–12 Even in the presence of aspirin, a persistent biochemical stimulus to thrombosis exists for several months after an ACS.¹³ Several trials have evaluated the role of long-term anticoagulation therapy in patients with CAD and MI.^14–16 In the Warfarin Reinfarction Study (WARIS-1), a total of 1,214 patients who had sustained an MI were randomized to high-intensity warfarin (INR, 2.8–4.8) or placebo and were advised not to take aspirin.¹⁵ Therapy with warfarin resulted in a significant reduction in all-cause mortality (15% versus 20%; p = 0.026) and reinfarction (14% versus 20%; p = 0.0007). However, major bleeding episodes were significantly more frequent with warfarin than placebo (1.3% versus 0%; p = 0.005).15 The Anticoagulation in the Secondary Prevention of Events in Coronary Thrombosis-1 (ASPECT-1) research group randomized 3,404 patients who had sustained an MI to oral anticoagulants (INR, 2.8–4.8) or placebo.¹⁶ Oral anticoagulation was associated with a favorable trend for reduction of all-cause mortality and significant reductions in reinfarction (6.7% versus 14.2%; p 16 Despite being effective at reducing death, recurrent MI and stroke, high-intensity anticoagulation (INR > 2.8) has been abandoned secondary to increased risk of major bleeding. Subsequently, several trials have evaluated the combination of aspirin plus low-intensity warfarin (INR, 1.5–1.9) or moderate-intensity warfarin (INR, 2.0–2.8) in secondary prevention (Table 1, Figure 1).^17–27 Aspirin plus low-intensity anticoagulation with warfarin. The Coumadin Aspirin Reinfarction Study (CARS) trial was a large randomized trial comparing the efficacy of low-dose aspirin (80 mg/day) plus fixed, low-dose warfarin (1 or 3 mg/day), versus aspirin alone (160 mg/day) in 8,803 patients after acute MI.¹⁷ The median INR attained in the combination group was 1.5 at week 1, and 1.19 at month 6. One-year life table estimates for the primary endpoint (composite of death, reinfarction or ischemic stroke) were 8.8% for the aspirin plus warfarin 1 mg/day group, 8.4% for the aspirin plus warfarin 3 mg/day group, and 8.6% for the aspirin 160 mg/day group.17 The 1-year life-table estimates of spontaneous major bleeding were 1.4% in the combination group and 0.74% in the aspirin group (p = 0.14) (Figure 2).17 In the Post Coronary Artery Bypass Graft (Post CABG) trial, aspirin plus low-dose anticoagulation with warfarin (mean INR, 1.4) had no benefit over aspirin alone in preventing saphenous vein graft disease. However, aggressive lipid-lowering with lovastatin, as compared with moderate lipid-lowering, resulted in significantly less progression of atherosclerosis in saphenous vein bypass grafts.¹⁸ The Combination Hemotherapy and Mortality Prevention (CHAMP) trial was a large, open-label, multicenter study conducted in 78 Veterans Affairs medical centers.¹⁹ A total of 5,059 patients were randomized to aspirin (81 mg daily) plus warfarin (titrated to achieve INR of 1.5–2.5), or aspirin alone (162 mg daily) within 14 days of acute MI. The mean INR achieved was 1.8. At a median follow-up of 2.7 years, the primary endpoint, all cause mortality, was similar between the two groups: 17.6% (444/2,522) in the aspirin plus warfarin group and 17.3% (438/2,537) in the aspirin group (p = 0.76).¹⁹ Major bleeding complications occurred more frequently in the aspirin plus warfarin cohort (1.28/100 versus 0.72/100 person years; p 20 The median INR in the warfarin group was 2.3. At 14 days, the primary endpoint composite of death, MI or recurrent angina occurred in 10.5% (11/105) of patients in the combination group and 27% (29/109) of patients in the aspirin alone group (p = 0.004). By 12 weeks, there was still a large risk reduction with combination therapy (19% versus 28%), but it did not reach statistical significance (p = 0.09). The lack of significant effect of combination therapy at late follow-up was due to small sample size.²⁰ In the warfarin substudy of the Organization to Assess Strategies for Ischemic Syndromes (OASIS) pilot trial, the effect of long-term warfarin at 2 intensities was studied in patients with non-ST elevation ACS.²¹ In phase one, combination therapy with aspirin plus low-dose warfarin (mean INR, 1.5) did not reduce the risk of recurrent ischemic events compared to aspirin, but in phase two (mean INR, 2.3), combination therapy reduced the risk of death, MI and stroke, compared to aspirin (5.1% versus 13.1%; p = 0.05).²¹ In the subsequent OASIS-2 substudy, after acute phase treatment with hirudin or heparin for 12–48 hours, the effects of aspirin plus warfarin (target INR, 2.5), compared to aspirin alone and when given for up to 5 months, was evaluated in 3,712 patients.²² The composite outcome of cardiovascular death, MI or stroke occurred in 7.6% (140/1,848) of patients in the aspirin plus warfarin group versus 8.3% (155/1,864) of patients in the aspirin group (p = 0.4). However, when analysis was restricted to patients with good compliance rates (> 70%), there was a significant reduction in the risk of cardiovascular death, MI and stroke (6.1% versus 8.9%; p = 0.02).²² Various factors, including the need for invasive procedures, bleeding and patient refusal, led to poor compliance with warfarin therapy. In the OASIS-2 study, there was an excess of major bleeding with the combination therapy (2.7% versus 1.3%; p = 0.004), but the rate of intracranial bleeding was similar in both groups.²² The efficacy of combination therapy with aspirin plus moderate-intensity anticoagulation with warfarin in reducing recurrent cardiovascular events was further shown by Williams,23 Antithrombotics in the Prevention of Reocclusion in Coronary Thrombolysis-2 (APRICOT-2),²⁴ Anticoagulation in the Secondary Prevention of Events in Coronary Thrombosis (ASPECT-2)²⁵ and the Warfarin-Aspirin Re-Infarction Study-2 (WARIS-2) trials.²⁶ The APRICOT-2 trial²⁴ was an angiographic follow-up trial involving 308 MI patients with successful fibrinolysis who were randomized to a combination of aspirin plus warfarin (mean INR, 2.6) versus aspirin alone. Combination therapy produced a 40% reduction (18% versus 30%; p = 0.02) in the 3-month infarct artery reocclusion rate. Clinical outcomes were also significantly improved.²⁴ In ASPECT-2 trial, a total of 668 MI patients were randomized to aspirin plus warfarin (target INR, 2.0–2.5) versus aspirin alone.²⁵ The mean INR attained in the combination group was 2.4 and mean follow-up was 12 months. Even though the study was prematurely discontinued because of slow recruitment, there was a significant reduction in the composite endpoint of death, reinfarction and stroke with the combination of aspirin plus moderate-intensity warfarin (5.0% versus 9.0%; p = 03).²⁵ The most recent trial of combination therapy, the WARIS-2 trial, was a large multicenter trial of 3,630 post-MI patients, conducted in 20 Norwegian hospitals.²⁶ Patients were randomized in an open-label fashion to one of three arms: 1) combination of aspirin (75 mg/day) plus warfarin (target INR, 2.0–2.5); 2) aspirin alone (160 mg/day); or 3) warfarin alone (target INR, 2.8–4.2). The level of anticoagulation attained was a mean INR of 2.2 in the combination group and 2.8 in the warfarin alone group. The mean age was 60 years and 77% were male. Overall, Q-wave MI occurred in 59%, and 54% received thrombolytic therapy. The rate of other concomitant therapy, such as statins, beta-blockers and ACE inhibitors, was similar in all groups. Patients were enrolled between January 1994 and June 1998 and followed for a mean of about 4 years. The primary composite endpoint of death, nonfatal reinfarction and thromboembolic stroke occurred in 15% of the aspirin plus warfarin group versus 20% of the aspirin-alone group [odds ratio (OR), 0.71; 95% confidence interval (CI), 0.58–0.86; p = 0.00005]. The composite endpoint occurred in 16.7% of the warfarin-alone patients; therefore, warfarin was also significantly more effective than aspirin (OR, 0.81). However, the benefit of aspirin plus warfarin over warfarin alone did not reach statistical significance (OR, 0.88; 95% CI: 0.72–1.07; p = 0.20).²⁶ There was no significant difference between the groups in the rate of bypass surgery or angioplasty procedures over the follow-up. In WARIS-2, major bleeding was slightly but not significantly more frequent in the combination of aspirin plus warfarin group (0.52% per year) compared to aspirin alone (0.15% per year), but the absolute numbers were very low in both groups (Figure 2). In a small trial, Huynh et al. evaluated the potential benefits of secondary prevention with warfarin in a group of patients with UA or non-ST elevation MI and prior coronary bypass surgery who were poor candidates for revascularization.²⁷ In this small trial, a total of 135 patients were randomized to aspirin plus warfarin (target INR, 2.0–2.5), aspirin alone or warfarin alone for 12 months. The primary endpoints of death, MI or UA occurred in 11.3% of the aspirin plus warfarin group, 11.5% of the aspirin alone group and 14.6% of the warfarin alone group (p = 0.76). However, no conclusion can be drawn from these data since the sample size was very small. In a recent meta-analysis by Anand and Yusuf,28 the combination of aspirin plus low-intensity warfarin therapy (INR, 1.5–2.0) was not superior to aspirin alone, while aspirin plus moderate-intensity warfarin (INR, 2.0–2.8), as compared to aspirin alone, was more effective in reducing the risk of recurrent cardiovascular events. Continued on next page