Oral Anticoagulants in Patients With Coronary Artery Disease

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1 Journal of the American College of Cardiology Vol. 41, No. 4 Suppl S 2003 by the American College of Cardiology Foundation ISSN /03/$30.00 Published by Elsevier Science Inc. doi: /s (02) Oral Anticoagulants in Patients With Coronary Artery Disease Sonia S. Anand, MD, MSC, FRCP(C), Salim Yusuf, FRCP, DPHIL Hamilton, Ontario, Canada Oral anticoagulants have been used in patients with vascular disease for over 40 years, yet their role in the secondary prevention of recurrent cardiovascular (CV) events remains controversial. The objectives of this systematic review are to more reliably determine the role of oral anticoagulants with and without antiplatelet therapy in patients with established coronary artery disease (CAD). Randomized trials in which oral anticoagulants were tested in CAD patients who were treated for at least three months were identified, and each trial was classified by the targeted level of intensity of anticoagulation. Data from the trials were combined using the modified Mantel-Haenszel method, and odds ratios were computed. Data from over 20,000 patients indicated that high-intensity oral anticoagulation (international normalized ratio [INR] 2.8) significantly reduced CV complications and increased bleeding compared with controls. Moderate-intensity oral anticoagulation (INR 2 to 3) also reduced CV complications compared with controls. The combination of moderate-intensity oral anticoagulation and aspirin is more effective and equally as safe as aspirin alone. Low-intensity oral anticoagulation (INR 2) in the presence of aspirin does not reduce CV complications and increases bleeding compared with aspirin alone. (J Am Coll Cardiol 2003;41:62S 69S) 2003 by the American College of Cardiology Foundation Oral anticoagulation (OA) has been used in patients with vascular disease for more than 40 years, yet its role is still controversial (1 3). This is because randomized trials have produced conflicting results, some showing a clear benefit, and some showing no benefit and increased harm. Furthermore, OA is inconvenient to use because it requires careful monitoring and dose adjustment to prevent overanticoagulation. This contrasts with antiplatelet agents, which are easier to administer, have been clearly proven to reduce cardiovascular (CV) complications in patients with established vascular disease (4), and are relatively safe. In order to more reliably determine the role of OA with and without antiplatelet therapy, we recently conducted an overview of all available trials that tested OA in patients with established coronary artery disease (CAD) (3). All trials were stratified by the targeted level of intensity of anticoagulation and by aspirin use. In this initial review there was strong evidence that high-intensity OA (international normalized ratio [INR] 2.8) reduced CV complications and low-intensity OA (INR 2.0) did not. However, few data existed to produce reliable results for the effects of moderate-intensity OA (INR 2 to 3), with or without aspirin use. Since this original publication, six randomized clinical trials that tested moderate-intensity OA in CAD patients have been completed (5 11). In this Please refer to the Trial Appendix at the back of this supplement for the complete list of clinical trials. From the Department of Medicine, Division of Cardiology and Population Health Research Institute, McMaster University, Hamilton, Ontario, Canada. Dr. Anand is a recipient of a Canadian Institutes of Health Research Clinician Scientist Award. Dr. Yusuf is a recipient of a Canadian Institutes of Health Research Senior Scientist Award and holds a Heart and Stroke Foundation of Ontario Research Chair. Manuscript received May 31, 2002; revised manuscript received October 15, 2002, accepted October 31, article, the results of these recent trials are presented, and the role of moderate-intensity OA in CAD patients is clarified. The original overview included all randomized studies that were published between 1960 and July 1999, recruited patients with established CAD, and continued OA treatment for at least three months. For this update, data for published and unpublished randomized trials that met these same criteria are included. Each trial was classified by the targeted intensity of OA, using methods previously described (3). Considering the variable outcomes reported across the recently completed trials, for this review, the primary efficacy outcome is the composite of CV death, myocardial infarction (MI), and stroke, and the primary safety outcome is major bleeding. The events were counted as they were defined in the individual trials. In general, the definitions of the primary outcome events were similar. Major bleeding events were defined by most trials as bleeding episodes that required blood transfusion or surgical intervention. The statistical method used to combine data from individual trials is the modified Mantel-Haenszel method (11). This method has been used extensively in the previous meta-analyses (3,4). The odds ratio (OR) (and its 95% confidence interval [CI]) is calculated for each trial. The odds reduction (ORed) is calculated using 1 minus the OR and is expressed as a percent. The six additional trials involved 14,587 patients (5 10). Three of these trials compared three treatments: moderateintensity OA plus aspirin, moderate-high-intensity OA alone, and aspirin alone (8 10). The other three trials compared moderate-intensity OA and aspirin to aspirin alone (5 7). The characteristics of the six new trials are

2 JACC Vol. 41, No. 4 Suppl S February 19, 2003:62S 69S Anand and Yusuf 63S Abbreviations and Acronyms ACS acute coronary syndrome(s) CAD coronary artery disease CV cardiovascular INR international normalized ratio MI myocardial infarction OA oral anticoagulation ORed odds reduction found in Table 1, and their results are summarized in the following text. ASPECT II. The Antithrombotics in the Secondary Prevention of Events in Coronary Thrombosis (ASPECT)-II trial was a multicenter open trial involving 53 sites randomizing 993 patients who had suffered an acute coronary syndrome (ACS) (9). Patients were randomly assigned within eight weeks of hospital discharge to receive combined moderate-intensity OA (target INR 2 to 2.5) and low-dose aspirin (80 mg/day) (n 333), high-intensity OA (target INR 3 to 4) (n 330), or low-dose aspirin (80 mg/day) (n 336). Patients were followed up for a maximum of 26 months (median of 12 months). The primary outcome was the first occurrence of MI, stroke, or death. A significant 50% risk reduction was observed when the combination OA and aspirin (4.8%) was compared with aspirin alone (9.2%; p 0.05). Also a significant 45% risk reduction was observed when OA (5.2%) was compared with aspirin alone (9.2%; p 0.05) (9). Although the composite outcome was lower in the combination group than in the OA-alone group, this difference was not significant. Significantly more major bleeding episodes were observed among patients receiving the combination of OA and aspirin (2.1%) than among those receiving OA alone (0.9%) or aspirin alone (0.9%). Therefore, in patients who were hospitalized with an ACS, aspirin combined with OA at either moderate or high intensity is more effective than aspirin alone in reducing subsequent CV events. Table 1. Characteristics of Recent Trials Trial Population Randomized Comparisons BAAS. A total of 1,058 patients were randomized in the Balloon Angioplasty and Anticoagulation Study (BAAS) (6). Of these, 530 patients were randomly assigned to warfarin (INR 2.1 to 4.8) plus aspirin (100 mg/day), and 528 patients were randomized to receive aspirin alone (100 mg/day). Patients were pre-treated with warfarin (median of 6 days before percutaneous coronary intervention) and aspirin before angioplasty. The mean INR before angioplasty was , and during follow-up it was At 30 days, the composite end point of death, MI, target revascularization, and stroke occurred in 3.4% patients treated with warfarin plus aspirin, compared with 6.4% of patients treated with aspirin alone, which is associated with a relative risk reduction of 47% (95% CI, 8% to 70%; p 0.04). At one year, the event rate was 14.3% in the combination group vs. 20.3% in the aspirin-alone group, for a relative risk reduction of 29% (95% CI, 7% to 46%). The incidence of major bleeding during hospitalization was 3.2% in the combination group versus 1.0% in the aspirin-alone group. In this study, therefore, warfarin combined with aspirin, begun before angioplasty and continued for at least six months, appears to be more effective than aspirin alone in the prevention of acute and late complications after coronary angioplasty. CHAMP. The Combination Hemotherapy And Mortality Prevention (CHAMP) study was a randomized, openlabelled trial comparing warfarin (target INR 1.5 to 2.5) combined with aspirin (81 mg/day) to aspirin monotherapy (162 mg/day) in patients after acute MI. Within 14 days of MI, 5,059 patients were enrolled and followed for a median of 2.7 years (7). The primary outcome was total mortality. This occurred in 17.6% of the patients randomized to OA and aspirin versus 17.3% of patients randomized to aspirin alone (p 0.76). Recurrent MI occurred in 13.3% of patients receiving OA and aspirin versus 13.1% receiving aspirin alone (p 0.78). Stroke occurred in 3.1% of patients receiving OA and aspirin versus 3.5% receiving aspirin, (p Management Achieved INR Compliance End of Study Duration of Study ASPECT-2 (9) ACS OA (2 2.5) A (80 mg) n % Max 26 months OA (3 4.0) n % A (80 mg) n % BAAS (6) Angioplasty OA ( ) A (100 mg) n NA 12 months A (100 mg) n 528 CHAMP (7) AMI OA ( ) A (81 mg) n 2, % 2.7 years A (162 mg) n 2,537 Huynh et al. (8) ACS prior CABG OA (2 2.5) A (80 mg) n 44 NA 86% 12 months OA (2 2.5) n 45 A (80 mg) n 46 OASIS (5) ACS OA (2 2.5) A (325 mg) n 1, % 5 months A (325 mg) n 1,864 WARIS-2 (10) AMI OA ( ) A (75 mg) n 1, NA 4 years OA ( ) n 1, A (160 mg) n 1,206 A aspirin; ACS acute coronary syndromes; AMI acute myocardial infarction; CABG coronary artery bypass graft; INR international normalization ratio; NA not available; OA oral anticoagulants. Trials are defined in appendix of this supplement.

3 64S Anand and Yusuf JACC Vol. 41, No. 4 Suppl S Figure 1. High intensity oral anticoagulation versus control. Outcomes are cardiovascular death, myocardial infarction, or stroke. ASPECT Antithrombotics in the Secondary Prevention of Events in Coronary Thrombosis; CI confidence interval; df degrees of freedom; N study population; n subset population; OA oral anticoagulation; OR odds ratio; WARIS Warfarin-Aspirin ReInfarction Study. 0.52). No significant differences in the composite of CV death, stroke, and MI were observed. Major bleeding occurred more frequently with combination therapy versus aspirin, with 1.28 versus 0.72 events per 100 persons per year (p 0.001). The mean INR achieved in the anticoagulant group was 1.8. By the end of the trial, 30% of patients had discontinued OA therapy. Huynh et al. (8). This study, undertaken by Huynh et al. (8), was a double-blind, randomized trial of patients with a non-st-segment elevation ACS who had undergone previous coronary artery bypass graft surgery. The duration of treatment was 12 months. Patients (n 135) with this condition were randomized to receive either warfarin plus aspirin (target INR 2 to 2.5) (n 44), warfarin alone (n 45), or aspirin alone (n 46). The primary outcome was the composite of any death, MI, or unstable angina requiring hospitalization. This occurred in 11.3% randomized to combination therapy, 14.6% in the OA-alone group, and 11.5% in the aspirin-alone group (overall p 0.76). This trial was stopped early due to poor recruitment and was underpowered to show a statistical difference between the treatment groups. OASIS-II. In the Organization to Assess Strategies for Ischemic Syndromes-II study, 3,712 subjects with ACS were randomized within 12 to 48 h of receiving intravenous antithrombotic treatment to receive OA therapy (n 1,848) or standard therapy (n 1,864) (5). All patients were encouraged to take aspirin (mean 325 mg/day). Patients were followed-up for five months after entry into the study. Of the patients in the combination group, 7.6% suffered CV death, MI, or stroke, versus 8.3% of the patients in the standard therapy group, for a relative risk reduction of 10% (95% CI, 14% to 28%; p 0.40). Overall, there was an excess of major bleeding (2.7% vs. 1.3%) experienced in the combination group compared with the aspirin-alone group (p 0.004). The mean INR among patients receiving OA was , and compliance to OA was 64% at the end of the trial. A retrospective subgroup analysis indicated that among countries with good compliance, there was an apparent benefit (risk reduction of 32; 95% CI, 5 to 52), compared with no benefit in countries with poor compliance (relative risk, 1.17; 95% CI, 0.86 to 1.60). WARIS-II. The Warfarin-Aspirin ReInfarction-II Study (WARIS-II) was a randomized open-label trial. Over 3,600 patients with acute MI from 20 hospitals in Norway were assigned to one of three treatment arms, which included warfarin (INR 2 to 2.5) plus aspirin 75 mg/day (n 1208), warfarin (INR 2.8 to 4.2; n 1216), or aspirin 160 mg/day (n 1206) (10). Patients were enrolled between January 1994 and June 1998 and monitored for four years. The average age of the patients was 60 years, and 77% were men. In addition, about half of these patients received thrombolytic therapy as treatment for their acute MI. The primary end point of the study was the combination of death, recurrent MI, or stroke. Treatment with OA (mean INR 2.2) plus aspirin compared with aspirin alone reduced CV death, MI, and stroke by 29% (95% CI, 14 to 42; p ). Oral anticoagulation alone (mean INR 2.8) compared with aspirin reduced CV death, MI, and stroke by 19% (95% CI, 1 to 33; p 0.028). Major bleeding was significantly increased in patients treated with OA and

4 JACC Vol. 41, No. 4 Suppl S Anand and Yusuf 65S Figure 2. Major bleeding rates in patients with vascular disease. A aspirin; C control; INR international normalized ratio; N study population; n subset population; OA oral anticoagulation. (Adapted from Anand SS, Yusuf S. Oral anticoagulant therapy in patients with coronary artery disease: a meta-analysis. JAMA 1999;282: Copyrighted 2002, American Medical Association.) aspirin (0.58% per year) and OA alone (0.52% per year), compared with patients who received aspirin alone (0.15% per year). High-intensity OA (INR >2.8) versus control. Data from 13 trials (12 24) involving 8,140 patients were available to compare high-intensity OA to control. Cardiovascular death, MI, or stroke occurred in 20.3% of patients treated with OA, versus 30.3% of patients who received no therapy, translating into an ORed of 43% (95% CI, 37 to 49; p ) (Fig. 1). Among 11 trials involving 7,933 patients (12 16,18,19,21 25), major bleeding occurred in 4.6% of OA patients versus 0.7% of control patients, for an odds increase of 4.5 (95% CI, 2.5 to 6.0; p ) (Fig. 2). Moderate-intensity OA (INR 2 to 3) versus control. Data from three trials are available (26 28). A nonsignificant 16% (95% CI, 11 to 37; p 0.20) reduction in CV death, MI, and stroke was observed among patients receiving OA versus controls (Fig. 3). Major bleeding occurred in 3.5% of the patients receiving OA, versus no patients in the control groups, for an odds increase of 7.67 (95% CI, 3.3 to 18; p ) (Fig. 2). Moderate- or high-intensity OA versus aspirin. Data from six trials and 4,155 patients in which OA and aspirin Figure 3. Moderate intensity oral anticoagulation versus control. Outcomes are cardiovascular death, myocardial infarction, or stroke. CI confidence interval; COOP Veterans Administration COOPerative study; df degrees of freedom; OA oral anticoagulation; N study population; n subset population; OR odds ratio.

5 66S Anand and Yusuf JACC Vol. 41, No. 4 Suppl S Figure 4. Moderate-to-high-intensity oral anticoagulation versus aspirin. Outcomes are cardiovascular death, myocardial infarction, or stroke. ASPECT Antithrombotics in the Secondary Prevention of Events in Coronary Thrombosis; ATACS Antithrombotic Therapy in Acute Coronary Syndrome; CI confidence interval; df degrees of freedom; EPSIM Enquete de Prevention Secondaire de I Infarctus du Myocarde; N study population; n subset population; OR odds ratio; WARIS Warfarin-Aspirin ReInfarction Study. were directly compared were available to evaluate the outcome of death, MI, or stroke (9,10,24,26,29,30). This outcome occurred in 13.5% of patients receiving OA, versus 16.3% among patients receiving aspirin alone, resulting in an ORed of 21% (95% CI, 6 to 33; p 0.008) (Fig. 4). In an analysis of data from 10 trials involving 6,655 patients (8 10,24,26,30 33), major bleeding was found to increase 2.1-fold (95% CI, 1.7 to 2.1; p ) among patients receiving OA (Fig. 2). Moderate-to-high-intensity OA plus aspirin versus aspirin alone. Data were available from seven trials (5,7,9,10,34 36) involving 12,333 patients for assessing the combined outcome of CV death, MI, or stroke. This outcome occurred in 15.9% of patients who received OA plus aspirin, versus 12.6% who received aspirin alone, resulting in a significant 12% ORed (95% CI, 3 to 20; p 0.01) (Fig. 5). Another analysis of data from nine trials involving 13,498 patients (5 10,34 36) found that major bleeding occurred in 3.0% of patients receiving the combination, versus 1.7% of patients receiving aspirin only, for a relative increase of 1.74 (95% CI, 1.39 to 2.17; p 0.10) (Fig. 2). Moderate-to-high-intensity OA and aspirin versus OA alone. Data from three trials involving 3,142 patients were available to compare the occurrence of CV death, MI, and stroke (9,10,34). These events occurred in 12.5% of subjects receiving the combination therapy versus 14.3% of people receiving OA alone. A modest reduction of 14% in favor of OA and aspirin compared with OA alone was observed (95% CI, 6% to 30%; p 0.15) (Fig. 6). In four trials Figure 5. Moderate-to-high-intensity oral anticoagulation plus aspirin versus aspirin alone. Outcomes are cardiovascular death, myocardial infarction, or stroke. ASPECT Antithrombotics in the Secondary Prevention of Events in Coronary Thrombosis; ATACS Antithrombotic Therapy in Acute Coronary Syndrome; CHAMP Combination Hemotherapy And Mortality Prevention; CI confidence interval; df degrees of freedom; OA oral anticoagulation; OASIS Organization to Assess Strategies for Ischemic Syndromes; OR odds ratio; WARIS Warfarin-Aspirin ReInfarction Study.

6 JACC Vol. 41, No. 4 Suppl S Anand and Yusuf 67S Figure 6. Moderate intensity oral anticoagulation plus aspirin versus moderate-to-high-intensity oral anticoagulation. Outcomes are cardiovascular death, myocardial infarction, or stroke. ASPECT Antithrombotics in the Secondary Prevention of Events in Coronary Thrombosis; ATACS Antithrombotic Therapy in Acute Coronary Syndrome; CI confidence interval; df degrees of freedom; OA oral anticoagulation; OR odds ratio; WARIS Warfarin-Aspirin ReInfarction Study. involving 3,231 patients (8,9,10,34), no substantial difference in major bleeding episodes was observed between the combination therapy (2.2%) and OA alone (2.3%) (OR, 0.95; 95% CI, 0.60 to 1.51; p 0.80) (Fig. 2). Low-intensity OA (INR <2.0). Three trials (35,37,38) (n 8,435) compared low-intensity OA plus aspirin to aspirin alone. The Coumadin Aspirin Reinfarction Study (CARS) trial design included three arms that compared fixed-dose 1 mg warfarin plus aspirin with fixed-dose 3 mg warfarin plus aspirin, and with aspirin alone. The INR values in the 1 mg OA group increased minimally; therefore, data for only the 3-mg arm were used for comparison with the aspirin-alone arm (37). No significant benefit was observed in favor of OA and aspirin versus aspirin alone for the combination of CV death, MI, and stroke (OR, 0.91; 95% CI, 0.79 to 1.06; p 0.10). This outcome occurred in 8.8% of patients who received combination therapy, versus 9.6% who received aspirin (Fig. 7). Major bleeding occurred in 2.3% of the patients receiving combination therapy versus 1.8% of the patients who received aspirin, resulting in a non-significant 25% increase in bleeding (Fig. 2). Discussion, implications, and conclusions. This metaanalysis of randomized trials includes data from more than 20,000 patients with established CAD. Clear reductions in total mortality, MI, and stroke occurred among patients treated with OA at high intensity (INR 2.8 to 4.8), although this therapy was also associated with a significant increase in major bleeding. Conversely, low-intensity OA (INR 2.0) in the presence of aspirin does not confer any benefit over aspirin alone but still increases major bleeding episodes. Moderate-intensity OA reduced recurrent ischemic events by 16% compared with controls. For moderateor high-intensity OA, the reduction in CV events was 21% compared with aspirin, and when used together with aspirin, moderate-to-high-intensity OA reduced recurrent ischemic events by 12% compared with aspirin alone. A comparison of moderate- or high-intensity OA alone versus the combination of moderate-intensity OA plus aspirin may be more effective than moderate-to-high-intensity OA alone, although with the paucity of current data, this cannot be confirmed. Certainly there is no apparent significant increase in bleeding with the combination of moderate- Figure 7. Low intensity oral anticoagulation plus aspirin versus aspirin alone. Outcomes are cardiovascular death, myocardial infarction, or stroke. CABG coronary artery bypass graft; CARS Coumadin Aspirin Reinfarction Study; CI confidence interval; df degrees of freedom; N study population; n subset population; OA oral anticoagulation; OASIS Organization to Assess Strategies for Ischemic Syndrome; OR odds ratio.

7 68S Anand and Yusuf JACC Vol. 41, No. 4 Suppl S intensity OA and aspirin compared with OA alone. This supports other evidence that it is the INR intensity rather than the simultaneous use of antiplatelet agents with OA that leads to bleeding episodes and justifies careful monitoring of the INR for patients who are receiving OA (39). The data presented in this overview represent the observed treatment effects because the summary estimates included all patients whether they were actually compliant with the intended therapy or not. Therefore, these estimates are conservative, represent an intention-to-treat analysis, and are likely to be an underestimate of the true risk reduction achievable with OA when compliance is maximized and the target INR is achieved. An example of the effect of non-compliance on the overall estimate of treatment effect comes from the OASIS-2 trial (5). In this trial, OA and aspirin versus aspirin alone was associated with a small non-significant reduction in CV death, MI, and stroke (7.6% vs. 8.3%; risk reduction, 0.90; 95% CI, 0.72 to 1.14; p 0.40) (5). However, at the end of the follow-up period, only 63.7% of patients who had been randomized to receive OA and aspirin were actually receiving their OA. Compliance with OA varied significantly between the 14 countries participating in the trial. The good compliance countries were those in which compliance with OA was at least 70% at 35 days; poor compliance countries had 70% at 35 days. In the good compliance countries, the combination of OA and aspirin was associated with a significant 32% reduction in CV death, MI, and stroke (6.1% vs. 8.9%; risk reduction, 0.68; 95% CI, 0.48 to 0.95; p 0.02) compared with aspirin alone. Conversely, in poor compliance countries, no reduction in the composite outcome of CV death, MI or stroke was observed. As expected, there was a larger relative increase in major bleeding among the good compliance countries compared with the poor compliance countries (2.71 vs. 1.58). Therefore, in the high compliance subgroup, OA and aspirin use was associated with a relative risk reduction three times that observed with OA and aspirin using the intent-to-treat approach. This review provides evidence that among CAD patients the combination of moderate-intensity OA plus aspirin is more effective than aspirin alone and is relatively safe. This combination should be considered for high-risk patients with CAD, including those who suffer a CV event while receiving aspirin monotherapy (e.g., an aspirin failure). The potential benefits of OA therapy in reducing serious clinical events such as MI, stroke, and death should be weighed against the risk that OA might cause life-threatening bleeding. Clinical algorithms can assist clinicians in making such judgments. 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