The role of combination therapy with an oral anticoagulant and aspirin for patients recovering from an acute coronary syndrome is still being debated. The results of our meta-analysis showed that treatment with aspirin plus warfarin at international normalized ratio values between 2 and 3 significantly reduces the risk of major adverse events compared with aspirin alone but also increases the risk of major bleeding. For every 100 patients receiving combination therapy, approximately 3 major adverse events are prevented and 1 major hemorrhage occurs.
Aspirin is a cornerstone of treatment for the secondary prevention of ischemic cardiovascular events, as it has been shown to reduce the risk of recurrence of acute coronary syndrome by almost one third.1 The benefits of adding long-term oral anticoagulant treatment to aspirin for patients recovering from an acute coronary syndrome are still being debated.2,3 Results of studies regarding this issue have been conflicting.4-7 Initial studies showed that the combined approach of aspirin plus warfarin sodium (Coumadin) offered no advantage compared with aspirin alone.4,5 More recently, however, the combination of aspirin plus warfarin appeared to be superior in preventing thrombotic events, despite an increased risk of bleeding.6,7
To accurately define the risk—benefit profile of aspirin plus warfarin (at different intensities of anticoagulation) vs aspirin alone, we performed a comprehensive meta-analysis of randomized controlled trials comparing these 2 strategies in patients recovering from an acute coronary syndrome. First, we considered all eligible studies regardless of the international normalized ratio (INR) value in the aspirin plus warfarin arm and then only those with a measured or target INR between 2 and 3.
We searched the MEDLINE and Cochrane Collaboration CENTRAL databases (updated to June 2006) without language restriction. Studies were included in the meta-analysis if a controlled comparison of aspirin plus warfarin vs aspirin alone in patients recovering from an acute coronary syndrome was made, randomized treatment allocation was used, and intention-to-treat analysis was performed. Studies with equivocal allocation, major imbalances in important baseline characteristics among study arms, and incomplete follow-up (< 80%)were excluded.
Subjects and methods
Major adverse events, including nonfatal thromboembolic stroke, myocardial infarction (MI), and all-cause mortality, as well as the rate of significant hemorrhage, including a ≥ 2 g/dL drop in hemoglobin level, bleeding necessitating transfusion, and intracranial hemorrhages, were the outcomes of interest.
Odds ratios (ORs) with 95% confidence intervals (CIs) for single end points, major bleeding, and major adverse events were determined. To begin with, analyses were performed by combining studies independently of INR values. Then, only studies using measured or target INR values between 2 and 3 were considered.
A total of 25,307 patients in 14 studies were included in the analysis. 4-16 Two substudies of the Organization to Assess Strategies for Ischemic Syndromes (OASIS) pilot study8 at different anticoagulation intensities were considered individually.
The major study characteristics have been previously reported.3 Admission diagnoses were ST- and non—ST-elevation MI and unstable angina. In most cases, study enrollment occurred within 1 week of the acute event, but in other cases, it occurred 6 or 8 weeks after the event. The follow-up period ranged from 3 months to 5 years, with a total of 52,936 patient years. In every study except 1, completeness of follow-up was more than 97%. The dose of aspirin ranged from 75 to 325 mg/day. Ten studies used measured or target INR values between 2 and 3 in the combined-treatment arm,6-8, 9-14,16 and the other 4 studies used INR values below 2,4,5,8,15
Overall, combination therapy with aspirin plus warfarin did not significantly affect the risk of major adverse events compared with aspirin alone, regardless of INR value (in absolute terms, 16.6% with aspirin plus warfarin vs 18.0% with aspirin alone; OR = 0.96; 95% confidence interval [CI] 0.90-1.03; = .30;
), although it increased the risk of major bleeding (in absolute terms, 2.5% with aspirin plus warfarin vs 1.4% with aspirin alone; OR = 1.77 [95% CI, 1.47-2.13]; < .001; Figure 2A). In particular, the OR of extracranial bleeding with aspirin plus warfarin was 2.20 (95% CI, 1.64-2.96; < .001;
), and the OR of intracranial bleeding was 1.37 (95% CI, 0.79-2.37; P = .27;
). The rate of all-cause mortality was not significantly reduced with combination therapy (in absolute terms, 7.2% with aspirin plus warfarin vs 8.5% with aspirin alone; OR = 1.00 [95% CI, 0.91-1.10]; P = .96), nor was the rate of nonfatal MI (7.4% with aspirin plus warfarin vs 9.0% with aspirin alone; OR = 0.96 [95% CI, 0.88-1.05]; P = .37). However, combination therapy significantly decreased the risk of thromboembolic stroke (1.6% with aspirin plus warfarin vs 2.1% with aspirin alone; OR = 0.81 [95% CI, 0.67-0.97]; P = .02). NB—The rates of single end points do not add up exactly to the overall rate of major adverse events because not all studies reported the incidence of single end points.
In the analysis limited to studies that used INR values between 2 and 3, aspirin plus warfarin was superior to aspirin alone in terms of decreasing the risk of major adverse events (in absolute terms, 9.4% with aspirin plus warfarin vs 12.3% with aspirin alone; OR = 0.73 [95% CI, 0.63-0.84]; P < .001;
), although it increased the risk of major bleeding (in absolute terms, 2.6% with aspirin plus warfarin vs 1.1% with aspirin alone; OR = 2.32 [95% CI, 1.63-3.29]; P < .001;
). In particular, the OR of extracranial bleeding with aspirin plus warfarin was 2.37 (95% CI, 1.37-4.10; P = .002;
), and the OR of intracranial bleeding was 3.02 (95% CI, 0.61-15.02; P = .18;
). Although combination therapy did not significantly reduce all-cause mortality compared with aspirin alone (2.8% with aspirin plus warfarin vs 2.9% with aspirin alone; OR = 0.99 [95% CI, 0.81-1.22]; P = .95), it was associated with a 28% decrease in the risk of nonfatal MI (in absolute terms, 4.7% with aspirin plus warfarin vs 6.5% with aspirin alone; OR = 0.70 [95% CI, 0.52-0.95]; P = .001) and a 59% decrease in the risk of nonfatal thromboembolic stroke (0.6% with aspirin plus warfarin vs 1.48% with aspirin alone; OR = 0.43 [95% CI, 0.27-0.70]; P = .001). The incidence of intracranial hemorrhage increased from 0.05% with aspirin alone to 0.25% with combination therapy. These results suggest that allocating 1000 patients to combination therapy at INR values between 2 and 3 would prevent approximately 30 major adverse events (20 nonfatal MIs and 10 nonfatal thromboembolic strokes) at the expense of 15 major hemorrhages (of which 2 would be intracranial), thus providing a benefit in favor of combination therapy.
The results of this meta-analysis showed that combination therapy with aspirin plus warfarin is superior to aspirin alone for the secondary prevention of acute coronary syndromes. Currently, the administration of oral anticoagulants to patients with ischemic heart disease is recommended for those with antiphospholipid syndrome, recurrent thromboembolism, intracardiac thrombi, valve prostheses, or atrial fibrillation; that is, for those in whom the risk of thromboembolic complications is greater than that of bleeding.3 In these clinical conditions, because of reservations over the risk—benefit profile of combination treatment, the prescription of vitamin K antagonists usually induces physicians to refrain from adding aspirin.
On the other hand, after non—ST-elevation acute coronary syndromes, 9 to 12 months of combination therapy with aspirin and a thienopyridine (ticlopidine hydrochloride [Ticlid] or clopidogrel [Plavix]) is recommended. Indeed, the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial showed that there was a 20% relative reduction in the combined rate of nonfatal stroke, nonfatal MI, and cardiovascular death with dual antiplatelet therapy compared with aspirin alone after 9 months.17 The benefit of adding clopidogrel to aspirin has also been shown by the recent Clopidogrel and Metoprolol in Myocardial Infarction Trial (COMMIT) 18 and Clopidogrel as Adjunctive Reperfusion Therapy (CLARITY) Thrombolysis in Myocardial Infarction (TIMI) 2819 study for patients with acute MI receiving thrombolytic therapy.
Our analysis indicates that there is an overall benefit for combination therapy with aspirin plus a moderate-intensity oral anticoagulant, compared with aspirin alone, in the prevention of major adverse events for survivors of an acute coronary syndrome, with an acceptable risk of bleeding complications. A head-to-head comparison of aspirin plus a dose-adjusted vitamin K antagonist against a dual antiplatelet regimen would be of interest.