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Review |

Oral Anticoagulant Therapy in Patients With Coronary Artery Disease: A Meta-analysis FREE

Sonia S. Anand, MD, MSc, FRCPC; Salim Yusuf, DPhil, FRCP
[+] Author Affiliations

Author Affiliations: Program of Preventive Cardiology and Therapeutics, Hamilton Civic Hospitals Research Centre and Division of Cardiology, McMaster University, Hamilton, Ontario.


JAMA. 1999;282(21):2058-2067. doi:10.1001/jama.282.21.2058.
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Published online

Context Despite years of use in coronary artery disease (CAD) and several studies of its effectiveness, the role of oral anticoagulants (OAs) remains controversial.

Objective To determine the effects of long-term OA therapy, stratified by the intensities of anticoagulation and aspirin therapy, on outcomes in patients with CAD.

Data Sources Studies were identified by MEDLINE, EMBASE, and CURRENT CONTENTS searches (1960-July 1999) and by reviewing reference lists and inquiring with experts and pharmaceutical companies.

Study Selection Studies were included if they were published between 1960 and July 1999, were randomized, had recruited patients with CAD, who had used OA therapy for at least 3 months. Of 43 articles identified, 30 articles (31 trials) were analyzed.

Data Extraction Information on type, duration, and method of monitoring OA therapy, as well as rates of death, myocardial infarction (MI), thromboembolic complications, stroke, and bleeding were abstracted by 2 independent observers.

Data Synthesis With high-intensity (international normalized ratio [INR], 2.8-4.8) OAs vs control (16 trials, 10,056 patients), clear reductions in mortality (odds reduction [ORed], 22%; 95% confidence interval [CI], 13%-31%), MIs (ORed, 42%; 95% CI, 34%-48%), and thromboembolic complications including stroke (ORed, 63%; 95% CI, 53-71%) were observed, but were associated with a 6.0-fold (95% CI, 4.4- to 8.2-fold) increase in major bleeding. For moderate OAs (INR, 2-3) vs control (4 trials, 1365 patients) the ORed for death was 18% (95% CI, −6% to 37%); for MI, 52% (95% CI, 37%-64%); and for stroke, 53% (95% CI, 19%-73%), but it increased bleeding by 7.7-fold (95% CI, 3.3- to 18-fold). For moderate- to high-intensity OAs (INR, ≥2) vs aspirin (7 trials, 3457 patients), no reduction in death, MI, or stroke was observed, and it was associated with a 2.4-fold (95% CI, 1.6- to 3.6-fold) increase in major bleeding. For moderate- to high-intensity OAs and aspirin vs aspirin alone (3 trials, 480 patients), the ORed for death, MI, or stroke was 56% (95% CI, 17%-77%) and major bleeding increased by 1.9-fold (0.6- to 6.0-fold). For low-intensity OAs (INR, <2.0) and aspirin vs aspirin alone (3 trials, 8435 patients), no significant reduction in death, MI, or stroke was observed, and major bleeding increased by 1.3-fold (95% CI, 1.0- to 1.8-fold).

Conclusions Among patients with CAD, high-intensity and moderate-intensity OA are effective in reducing MI and stroke but increase the risk of bleeding. In the presence of aspirin, low-intensity OA does not appear to be superior to aspirin alone, while moderate- to high-intensity OA and aspirin vs aspirin alone appears promising and the bleeding risk is modest, but this requires confirmation from ongoing trials.

Figures in this Article

Oral anticoagulants (OAs) have been used in patients with vascular disease for 40 years, but their role is still controversial because of multiple reasons. First, several small, randomized trials provided conflicting results in patients who had experienced a myocardial infarction (MI). Second, OAs are inconvenient to use as they require careful monitoring and dose adjustments. Third, there are concerns whether the risk of bleeding with OAs justify their use. Fourth, antiplatelet therapies have been proven to be effective in reducing vascular complications and to be safe.

Whether OAs are effective in reducing cardiovascular events in patients who had experienced an MI has been the subject of previous overviews.1,2 The International Anticoagulant Review group1 published a combined analysis of 9 trials (5 randomized), which were conducted between 1950 and 1965. Although they observed a statistically significant 40% risk reduction in mortality in men younger than 55 years using OAs, this group could not reach a consensus. In 1977, Chalmers et al2 published a more formal systematic overview of the available trials of OA in patients who had experienced an MI and reported a 21% reduction in mortality (P<.001), a 50% reduction in thromboembolic events including recurrent MI and ischemic stroke, and a 2-fold increase in bleeding events with OA.2 This analysis failed to gain acceptance partly because meta-analysis was new, and partly because trials that used historical or nonrandomized controls were included.

Subsequently, 2 important findings have directed research involving OA in vascular disease. First, the rates of recurrent vascular events in patients with established vascular disease remains high, despite the use of antiplatelet agents.3 Second, there is evidence of a persistent biochemical stimulus to thrombosis for several months after an acute coronary syndrome even in the presence of aspirin.4 This stimulated the conduct of a number of large, well-controlled trials testing OA at varying intensities with or without concomitant aspirin therapy. Initially, trials tested high-intensity OA (international normalized ratio [INR], 2.8-4.8) in the absence of aspirin,5,6 or high- and moderate-intensity OA (INR, 2-3) compared with aspirin or control.7 More recent trials have evaluated the combination of OA and aspirin vs aspirin alone in the moderate-intensity (INR, 2-3), and low-intensity (INR, <1.5)8,9 ranges. To more reliably determine the role of OA with and without antiplatelet therapy, we conducted an overview of all available trials of OA in established coronary artery disease (CAD), stratified by intensity (target INR) and by aspirin use. Our objectives were to comprehensively assess the effects of OA on death, recurrent MI, stroke, and bleeding in patients with established CAD, and to determine if the effects vary by intensity of OA and aspirin use.

We tried to identify all unconfounded randomized trials between 1960 and July 1999 by searching the conventional databases of MEDLINE, EMBASE, and CURRENT CONTENTS, reviewing reference lists, and inquiring with experts in the field, and pharmaceutical companies. Computer searches used combinations of key words related to OA (eg, warfarin sodium, coumarins) and vascular disease (eg, CAD, MI, unstable angina, coronary artery bypass graft surgery). Studies were included if they (1) were published after 1960, (2) were randomized, (3) recruited patients with established CAD, (4) used OA, and (5) continued treatment for 3 or more months. Data were extracted from the published reports independently by 2 reviewers and a consensus was achieved for any discrepancies. Extra information was requested from 2 trials,10,11 but only obtained for 1 trial.10

The reported events of death, MI, and stroke were taken from the published reports. In the trials that provided data on fatal and nonfatal events, a composite rate of death or nonfatal MI or nonfatal stroke was calculated. The reporting of bleeding events was incomplete, and the definitions of bleeding differed substantially in the trials conducted prior to 1980. However, all trials reported the rates of total bleeding, and wherever possible bleeds that required transfusion, surgical intervention, or hospitalization were identified and coded as major bleeding events.

Trials conducted prior to 1980 predated the widespread use of the INR.12 In trials that reported the prothrombin ratio and the type of thromboplastin used, the INR was reasonably approximated using a validated nomogram.13 In 3 trials in which the thromboplastin was not reported, the intensity of anticoagulation was classified based on the period in which the study was conducted.10,14,15 All INR classifications were independently reviewed by a thrombosis expert (Jack Hirsh, MD, September 1998).

Although a variety of OAs (eg, warfarin sodium, dicoumarol, marcoumar, phenprocoumon, acencoumarin, bishydroxycoumarin) were used across the trials, all agents work by inhibiting the production of vitamin K-dependent coagulation factors (factors VII, IX, X, II), and there are no data which suggest that the pharmacologic action of these agents differ from one another.13

The modified Mantel-Haenszel method was used to combine the data from individual trials.16 This method has been extensively used in previous meta-analyses17 and entailed calculating the observed (number of events in the treatment group) minus the expected (average number of events for treatment and control groups) events and determining the variance for each. Grand totals were calculated for each and the ratio of the 2 was used to estimate the odds ratio (OR). The OR (and its 95% confidence interval [CI]) was calculated for each trial. The odds reduction (ORed) was calculated using 1 minus the OR, and was expressed as a percentage. For each study event, patients were counted in each category (eg, a patient with fatal MI was counted in the MI category and in the total mortality category). For combined events (eg, death, MI, stroke), patients were counted only once. In unevenly randomized trials in which fewer patients were randomized to control, the number of patients randomized (and number of events reported) were adjusted to match the treatment group, using methods previously described.16 Trials were examined for heterogeneity by dividing them into strata based on the intensity of anticoagulation (low, moderate, high) and the concomitant use of aspirin. The χ2 tests for heterogeneity were approximated by summing the N separate χ2 test statistics (O-E2/V) for each trial and subtracting the overall χ2 value (GT2/SIV) from this, using N-1 degrees of freedom.18 The number of events prevented or caused per 1000 patients treated was calculated by subtracting the absolute event rate of the treatment group from the control or placebo group, and multiplying this number by 10.17

We identified 43 reports of 44 trials of patients with CAD that evaluated OA, and excluded 13 trials.1931 Two trials had duplicate reports,19,20 4 trials administered OA to both the treatment and control groups,2124 5 trials included patients with other vascular conditions (ie, coronary stents),2529 and 2 trials30,31 reported only surrogate outcomes. Of the remaining 30 reports of 31 trials included in the analysis, 20 were classified as high intensity (INR, >2.8),5,6,11,14,15,3246 8 as moderate intensity (INR, 2-3),7,10,4752 and 3 as low intensity (INR, <2).8,9,50

High Intensity

Twenty trials (N = 11,692) were classified as high intensity (Table 1).5,6,11,14,15,3246 In 16 trials (N = 10,056), no patients received aspirin and in 4 trials (N =1853),11,4446 OAs were compared directly with aspirin. Trials that evaluated OA vs control and OA vs aspirin were analyzed separately. Thirty-four percent of patients were treated with warfarin for up to 2 years, and 66% of patients were treated for longer duration. Thirty-two percent of patients discontinued OA therapy before the scheduled end of follow-up (Table 1).

Table Graphic Jump LocationTable 1. Baseline Characteristics in High-, Moderate- and Low-Intensity OA Trials*

For studies that compared high intensity vs control, 5044 patients received OAs and 5012 were randomized to placebo or control (totals adjusted for uneven randomization). The OReds for OA vs control for mortality, MI, and thromboembolic complications including stroke were 22% (95% CI, 13%-31%; P<.001; Table 2), 42% (95% CI, 34%-48%; P<.001; Table 3), and 63% (95% CI, 53%-71%; P<.001; Table 4), respectively (Figure 1). Where stroke was reported separately, an ORed of 48% (95% CI, 33%-60%; P<.001) in favor of OA was observed. For the combination of death, MI or stroke, data from 13 trials5,6,32,3442,44 indicated an ORed of 43% (95% CI, 37%-49%; P<.001; Table 5), although a relative increase in total and major bleeding occurred with OA; OR of 4.7 (95% CI, 4.0-5.6; P<.001; Table 6) and 6.0 (95% CI, 4.4-8.2; P<.001; Table 7), respectively. In the 3 trials (N = 5496)5,6,41 in which hemorrhagic stroke could be reliably separated from total stroke, a 5-fold (95% CI, 2.6-10.3; P<.001) relative increase in hemorrhagic strokes with OA was observed, although the absolute rates were low (1.1% vs 0.1%). However, given the substantial ORed reduction in nonhemorrhagic strokes of 65% (95% CI, 52%-74%; P<.001), overall, there was a 46% reduction (95% CI, 28%-59%; P<.001) in stroke with OA (Table 8). For every 1000 patients treated with high-intensity OA, 98 vascular events were prevented and 39 major bleeds were caused.

Table Graphic Jump LocationTable 2. Results of Prolonged Oral Anticoagulant (OA) Therapy Compared With Control in High-, Moderate-, and Low-Intensity Trials on Total Mortality*
Table Graphic Jump LocationTable 3. Results of Prolonged Oral Anticoagulant (OA) Therapy Compared With Control in High-, Moderate-, and Low-Intensity Trials on Fatal and Nonfatal Myocardial Infarction*
Table Graphic Jump LocationTable 4. Results of Prolonged Oral Anticoagulant (OA) Therapy Compared With Control in High-Intensity Trials on Thromboembolic Complications*
Figure 1. Rates of Major Cardiovascular Outcomes for High- and Moderate-Intensity Oral Anticoagulant vs Control
Graphic Jump Location
Table Graphic Jump LocationTable 5. Results of Prolonged Oral Anticoagulant (OA) Therapy Compared With Control in High-, Moderate-, and Low-Intensity Trials on the Combined Outcome of Death, Myocardial Infarction, or Stroke*
Table Graphic Jump LocationTable 6. Results of Prolonged Oral Anticoagulant (OA) Therapy Compared With Control in High-Intensity Trials on Total Bleeds*
Table Graphic Jump LocationTable 7. Comparisons of Results of Prolonged Oral Anticoagulant (OA) Therapy Compared With Control in High-, Moderate- and Low-Intensity Trials on Major Bleeding*
Table Graphic Jump LocationTable 8. Results of Prolonged Oral Anticoagulant (OA) Therapy Compared With Control in High-, Moderate-, and Low-Intensity Trials on Stroke*
Moderate Intensity

Eight trials were classified as moderate intensity (N = 3270) (Table 1). In 3 trials7,10,47 (N = 1562), OAs were compared with aspirin, 4 trials4749,52 (N = 1365) compared OA with control, and 2 trials50,52 (N = 361) compared OA and aspirin vs aspirin alone.

Moderate Intensity OA vs Control

Data from 1365 patients from 4 trials were available. The OA OReds for mortality, MI, and stroke were 18% (95% CI, −6% to 37%; P>.10; Table 2), 52% (95% CI, 37%-64%; P<.001; Table 3), and 53% (95% CI, 19%-73%; P = .02; Table 8), respectively (Figure 1). The relative increase in the odds of major bleeding with OA was 7.7 (95% CI, 3.3-18; P<.001; Table 7). For every 1000 patients treated, the number of vascular events prevented was 24 (with wide CIs), yet 35 major bleeds were caused.

Moderate- or High-Intensity OAs vs Aspirin

Data were available from 7 trials (3457 patients).7,10,11,4447 Nonsignificant OReds with OAs for death [7% (95% CI, −28% to 31%); P>.10; Table 2], and MI [12% (95% CI, −24% to 37%); P>.10; Table 3], and no reduction in the com bination of death, MI, or stroke were observed (Table 5). Stroke and major bleeding are increased 2.37 times (95% CI, 0.83-6.78; P>.10; Table 8), and 2.4 times (95% CI, 1.6-3.6; P<.001; Table 7), respectively (Figure 2).

Figure 2. Rates of Major Cardiovascular Outcomes by Oral Anticoagulant Intensity and Aspirin Use
Graphic Jump Location
Moderate- to High-Intensity OA and Aspirin Compared With Aspirin Alone

Data from 3 trials46,50,52 were combined although the total number of patients is small (n = 480). The point estimates favor the combination of OA and aspirin over aspirin alone, and differ markedly from the results of the direct comparison of OA with aspirin. For the combined outcome of death, MI, or stroke, the ORed was 56% (95% CI, 17%-77%; P = .01; Table 5). Separate analyses by individual outcomes indicate consistent mortality, MI, and stroke reductions of 26% (P>.10; Table 3), 45% (P>.10; Table 4), and 86%, (P = .08; Table 8), respectively, but the numbers are too small for each individual estimate to be reliable (Figure 2). The relative increase in major bleeding with OA and aspirin was 1.9 (95% CI, 0.6-6.0; P>.10; Table 7). For every 1000 patients treated, 54 vascular events were prevented, and 16 major bleeding events were caused.

Low Intensity

Three trials8,9,50 (N = 8435 patients) comparing low-intensity OA and aspirin with aspirin were identified (Table 1). The CARS trial8 was a 3-arm trial that compared fixed-dose 1-mg warfarin and aspirin with fixed-dose 3-mg warfarin and aspirin with aspirin alone. The INR values in the OA group receiving 1 milligram increased minimally, therefore data for only the arm receiving 3 milligrams was used and compared with the aspirin-only arm.8

No significant benefit in favor of OA and aspirin vs aspirin alone for mortality (OR, 1.03; 95% CI, 0.81-1.30; P>.10; Table 3), MI (OR, 0.93; 95% CI, 0.78-1.11; P>.10; Table 4), stroke (OR, 1.00; 95% CI, 0.65-1.55; P>.10; Table 8) or their combination (OR, 0.91; 95% CI, 0.79-1.06; P>.10; Table 5) is observed (Figure 2). Oral anticoagulants were associated with a relative increase in major bleeding (OR, 1.3; 95% CI, 1.0-1.7; P = .09; Table 7).

Compliance

We defined noncompliance as the discontinuation of OA prior to the intended duration of treatment. Discontinuation rates were reported inconsistently across the trials. The average rate of noncompliance with OA for high intensity was 32% (95% CI, 30.6-33.4), for moderate intensity was 20.0% (95% CI, 18.0-22.0), and for low intensity was 22.0% (95% CI, 19.1-24.9 ) (Table 1). The major reason for discontinuation was concern about bleeding.

Exploring Heterogeneity

We detected a significant degree of heterogeneity in the high-intensity vs control strata. Many of the trials included in this strata were small and were conducted in the early 1960s and 1970s; however, after 1980, 3 large and well-controlled trials testing high-intensity OA were conducted.5,6,41 To explore the causes of heterogeneity in the high-intensity strata, we divided all high-intensity trials into pre-1980 and post-1980 groups. Most of the variation in the treatment effect across individual trials was derived from the small, older trials in which the ORs vary from as small as 0.19 to as large as 8.6, compared with the modern trials in which the ORs are similar, and the variances smaller (available from authors on request). Therefore, given that the summary estimates of the modern trials are significant, not heterogeneous, and are consistent with the overall conclusions of the treatment effect in favor of high-intensity OA, the overall estimates are likely valid.

We also explored the heterogeneity of ORs between strata based on intensity of OA and subdivided the trials by whether the control group received aspirin. Three comparison groups were defined: trials that compared OA with control, trials that compared OA with aspirin, and trials in which the combination of OA and aspirin were compared with aspirin. Within each comparison group, strata were defined by level of intensity (high, moderate, and low) and compared for the outcome of death, MI, and bleeding. Overall, no significant heterogeneity was observed consistently across outcomes (Table 9).

Table Graphic Jump LocationTable 9. Summary of Results With the Analysis Stratified by Oral Anticoagulant (OA) Intensity and Aspirin Use*

Based on this meta-analysis of randomized trials that includes data from more than 21,319 patients, clear reductions in total mortality, MI, and stroke occur among CAD patients treated with OA at high intensity (INR, 2.8-4.8). Although a significant increase in major bleeding is also observed with high-intensity OA therapy, the benefits clearly outweigh the risks. By contrast, low-intensity OA (INR, <2.0) in the presence of aspirin is not beneficial, but increases bleeding. In a relatively smaller number of patients, we analyzed 3 categories of patients, moderate OA vs control, moderate to high OA vs aspirin, and moderate to high OA and aspirin vs aspirin alone. Moderate-intensity OAs are more effective than control in reducing recurrent ischemic events, moderate to high OA appear to be as effective but not superior to aspirin (although small [10% to 15%] but important differences between the therapies cannot be excluded), and some additional benefit appears to be gained when aspirin is added to moderate to high OA compared with aspirin alone. However, the CIs are wide and this hypothesis requires confirmation from other trials, many of which are ongoing.

The trials included in this systematic overview span a period of almost 40 years. Despite the variable practice of OA, and monitoring, our analysis of major vascular outcomes indicates the consistency of these results over time. In the early high-intensity trials, aspirin was not used. Aspirin has been clearly shown to reduce the vascular events (MI, stroke, vascular death) by about 25% to 30%, total mortality by 16%, vascular death by 18%, nonfatal reinfarction by 34%, and nonfatal stroke by 28%.17 The point estimates for the same outcomes when comparing OA with control appear to be generally larger. However, indirect comparisons can be misleading. By contrast, the direct comparison trials of OA with aspirin are too small to reliably detect a 15% to 20% difference between OA and aspirin. Therefore, the currently available data do not provide reliable information on the relative benefits of OA and aspirin. A more relevant question is the combined impact of OA and aspirin compared with aspirin alone in high-risk patients, as aspirin by itself is only of modest efficacy. Other antiplatelet agents or their combinations are also being evaluated in patients with CAD. Trials of new glycoprotein IIb/IIIa antiplatelet agents have not been demonstrated to be superior to aspirin during long-term treatment,53 whereas long-term use of clopidogrel (a thienopyridine compound) in patients with established vascular disease was associated with an 8.7% risk reduction in recurrent cardiovascular events when compared with aspirin.54 In addition, the combination of a thienopyridine (eg, ticlopidine and clopidogrel) and aspirin also appears to confer an additional benefit over aspirin alone in patients with coronary stents, and large trials testing the efficacy and safety profile of this combination in patients with prior cardiovascular disease are under way.

No benefit was observed in the large trials testing low-intensity OA and aspirin compared with aspirin, but major bleeding events increased. This result may seems at odds with the recent results of the Thrombosis Prevention Trial in which low-intensity OA and aspirin were evaluated in the primary prevention setting and resulted in a significant reduction in coronary death and MI.55 In this trial, 1268 patients were randomized to OA alone, 1268 to aspirin alone, 1277 to OA and aspirin, and 1272 to placebo. The mean INR in the OA group was 1.47 with an average dose of 4 mg/day. The combined treatment of OA and aspirin was found to be significantly more effective than placebo, and a modest but nonsignificant 15.5% risk reduction compared with aspirin was observed. In the Post-Coronary Artery Bypass Graft trial,9 the risk reduction with OA and aspirin compared with aspirin was modest and nonsignificant (11%), and a similar dosing schedule and mean INR of 1.4 was obtained. However, in the CARS trial,8 unlike the other 2, a fixed-dose regimen (3 mg/day) was used and a target INR intensity was not chosen. The mean INR was 1.19 and only a 3.1% risk reduction (P = NS), in favor of OA (3 mg) and aspirin vs aspirin alone was observed. Therefore, although it is clear that low-intensity OA with INR values of less than 1.5 are not effective in preventing ischemic events, the possibility remains of a beneficial effect of low-intensity OA (INR, 1.5-2.0) used together with aspirin, and this question requires further evaluation.

In contrast to the low-intensity strata, several small trials in which moderate-intensity OA and aspirin in patients with unstable angina or non-Q wave MI have suggested a moderate benefit51,53 when compared with aspirin alone. As well, there is evidence to support the efficacy of moderate intensity OA and aspirin compared with aspirin alone in patients with atrial fibrillation,56 and with mechanical valves.57 The additional benefit of moderate OA when added to aspirin in these trials is supportive of an independent mechanism of benefit of combined antiplatelet and antithrombotic treatment, but this requires confirmation. Ongoing trials include WARIS-2, ASPECT-2, and CHAMP, which are evaluating the efficacy of moderate-intensity OA (INR, 2-3) and aspirin compared with aspirin alone in patients following unstable angina or MI.

The risk of bleeding with OA is directly related to the intensity of anticoagulation, clinical factors, the duration of therapy, and the concomitant use of antiplatelet therapies.13 In our analysis we observed an increase in the absolute rate of major bleeding with an increase in INR intensity (Figure 3). No significant heterogeneity was identified in a formal comparison of ORs across intensity strata. The highest rate of bleeding was observed in the high-intensity stratum, in which the monitoring of anticoagulation was highly variable across studies, and the duration of treatment was significantly longer than in most modern trials. In both the low-intensity and moderate-intensity strata, OAs were used in combination with aspirin, however despite this, a graded increase in bleeding by INR intensity was observed. This suggests that in patients taking OAs, the more important predictor of bleeding is the INR and not whether aspirin was used concomitantly. However, at each intensity the rates of major bleeding with OA were significantly higher than in the comparison group (no OA or aspirin alone), and this is a justifiable concern when considering using OA and aspirin (Table 10).

Figure 3. Major Bleeding Rates in Patients With Vascular Disease
Graphic Jump Location
Table Graphic Jump LocationTable 10. Risk-Benefit per Thousand Patients Treated With Oral Anticoagulant (OA) Intensity*

Among patients with CAD, high-intensity (INR, 2.8-4.8) OAs are effective in reducing death, MI, and stroke, but are associated with a significant risk of bleeding. When compared with control, moderate-intensity OA (INR, 2-3) are effective in reducing MI, and stroke, but a significant increase in bleeding remains. When compared with aspirin, moderate- to high-intensity OAs appear equivalent, but the CIs are wide and are consistent with a moderate but clinically important difference. In the presence of aspirin, low-intensity OAs (INR<2.0) are not superior to aspirin alone, while moderate- to high-intensity OAs (INR, 2-3) and aspirin appear promising, but further trials are needed.

International Anticoagulation Review Group.  Collaborative analysis of long-term anticoagulant administration after acute myocardial infarction.  Lancet.1970;1:203-209.
Chalmers TC, Matta RJ, Smith Jr H, Kunzler AM. Evidence favoring the use of anticoagulants in the hospital phase of acute myocardial infarction.  N Engl J Med.1977;297:1091-1096.
Yusuf S, Flather M, Pogue J.  et al.  Variations between countries in invasive cardiac procedures and outcomes in patients with suspected unstable angina or MI without initial ST elevation.  Lancet.1998;352:507-514.
Merlini PA, Bauer KA, Oltrona L.  et al.  Persistant activiation of coagulation mechanism in unstable angina and myocardial infarction.  Circulation.1994;90:61-68.
Smith P, Arnesen H, Holme I. The effect of warfarin on mortality and reinfarction after myocardial infarction.  N Engl J Med.1990;323:147-152.
Anticoagulants in the Secondary Prevention of Events in Coronary Thrombosis (ASPECT) Research Group.  Effect of long-term oral anticoagulant treatment on mortality and cardiovascular morbidity after myocardial infarction.  Lancet.1994;343:499-503.
EPSIM Research Group.  A controlled comparison of aspirin and oral anticoagulants in prevention of death after myocardial infarction.  N Engl J Med.1982;307:701-708.
Coumadin Aspirin Reinfarction Study (CARS) Investigators.  Randomised double-blind trial of fixed low-dose warfarin with aspirin after myocardial infarction.  Lancet.1997;350:389-396.
Post Coronary Artery Bypass Graft Trial Investigators.  The effect of aggressive lowering of low-density lipoprotein cholesterol levels and low-dose anticoagulation on obstructive changes in saphenous vein coronary artery bypass grafts.  N Engl J Med.1997;336:153-162.
Kraska T, Malanowicz W, Skarzynska M, Tyminska K. Results of prevention of second myocardial infarct with syncumar or aspirin.  Kardiologia Polska.1981;24:593-597.
Eritsland J, Arnesen H, Gronseth K, Fjeld NB, Abdelnoor M. Effect of dietary supplementation with n-3 fatty acids on coronary artery bypass graft patency.  Am J Cardiol.1996;77:31-36.
Le D, Wiebert R, Sevilla B, Donnelly K, Rapaport S. The international normalized ratio (INR) for monitoring warfarin therapy: reliability and relationship to other monitoring methods.  Ann Intern Med.1994;120:552-558.
Hirsh J, Dalen J, Deykin D, Poller L, Bussey H. Oral anticoagulants.  Chest.1995;108(suppl):231-246.
MacMillan RL, Brown KW, Watt DL. Long-term anticoagulant therapy after myocardial infarction.  CMAJ.1960;83:567-570.
Wasserman AJ, Gutterman LA, Yoe KB, Kemp VE, Richardson DW. Anticoagulants in acute myocardial infarction.  Am Heart J.1966;71:43-49.
Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease.  J Natl Cancer Inst.1959;22:719-748.
Antiplatelet Trialist Collaboration.  Collaborative overview of randomized trials of antiplatelet therapy-1.  BMJ.1994;308:81-106.
Yusuf S, Peto R, Lewis J, Collins R, Sleight P. Beta blockade during and after myocardial infarction.  Prog Cardiovasc Dis.1985;27:335-371.
Medical Research Council Working Party.  An assessment of long-term anticoagulant administration after cardiac infarction.  BMJ.1959;1:803-810.
Drapkin A, Merskey C. Long-term anticoagulant therapy after myocardial infarction.  JAMA.1974;230:208-209.
Ritland S, Lygren T. Comparison of efficicacy of 3 and 12 months' anticoagulant therapy after myocardial infarction.  Lancet.1969;1:122-124.
Rothlin ME. Clinical experience with anti-platelet drugs in aorta-coronary bypass surgery.  Coron Artery Dis.1982;557:413-419.
Rajah SM, Salter M, Donaldson D.  et al.  Acetysalicylic acid and dipyridamole improve the early patentcy of aorta-coronary bypass grafts.  J Thorac Cardiovasc Surg.1985;90:373-377.
Ollivier JP.pour le group EPPAC.  Etude de la permeabilite des pontages aortocoronaries a 6 mois.  Arch Mal Coeur Vaiss.1991;84:537-542.
Brown KWG, MacMillan RL. Initial heparin therapy in acute myocardial infarction.  CMAJ.1964;90:1345-1348.
Schomig A, Neumann F, Kastrati A.  et al.  A randomized comparison of antiplatelet and anticoagulant therapy after the placement of coronary-artery stents.  N Engl J Med.1996;334:1084-1089.
Leon MB, Baim D, Cordon P.  et al.  Clinical and angiographic results from the Stent Anticoagulation Regimen Study (STARS).  Circulation.1996;94(suppl 1):I-685.
Hess H, Munich B. Proceedings of Colfarit Symposium III. Cologne, Germany: Bager; 1975:80-87.
Urban P, Buller N, Fox K.  et al.  Lack of effective warfarin on the restenosis rate or on clinical outcome after balloon coronary angioplasty.  Br Heart J.1988;60:485-488.
Tramarin R, Pozzoli M, Febo C.  et al.  Two-dimensional echocardiographic assessment of anticoagulant therapy in left ventricular thrombosis early after acute myocardial infarction.  Eur Heart J.1986;7:482-492.
Pantely GA, Goodnight SH, Rahimtoola SH.  et al.  Failure of antiplatelet and anticoagulant therapy to improve patency of grafts after coronary-artery bypass.  N Engl J Med.1979;301:962-966.
Borchegrevink CF. Long-term anticoagulant therapy in angina pectoris and myocardial infarction.  Acta Med Scand Suppl.1960;359:1-50.
Clausen J, Andersen PE, Andresen P.  et al.  Studies on long-term anticoagulant treatment after coronary occlusion.  Acta Med Scand.1961;123:987-994.
Harvald B, Hilden T, Letman H, Lund E, Thaysen EH, Worning H. Long-term anti-coagulant treatment in myocardial infarction.  Acta Med Scand.1961;21:983-987.
Apenstrom G, Korsan-Bengtsen K. A double blind study of dicumarol prophylaxis in coronary heart disease.  Acta Med Scand.1964;176:563-575.
Conrad LL, Kyriacopoulos JD, Wiggins CW, Honick GL. Prevention of recurrences of myocardial infarction.  Arch Intern Med.1964;114:348-358.
Loeliger EA, Hensen A, Kroes F.  et al.  A double-blind trial of long-term anticoagulant treatment after myocardial infarction.  Acta Med Scand.1967;182:549-566.
Lovell RR, Denborough MA, Nestel PJ, Goble AJ. A controlled trial of long-term treatment with anticoagulants after myocardial infarction in 412 male patients.  Med J Aust.1967;2:97-104.
Seaman AJ, Griswold HE, Reaume RB, Ritzmann L. Long-term anticoagulant prophylaxis after myocardial infarction.  N Engl J Med.1969;281:115-119.
Sorensen HO, Friis T, Jorgensen AW, Jorgensen MB, Nissen NI. Anticoagulant treatment of acute coronary thrombosis.  Acta Med Scand.1969;185:65-72.
Sixty Plus Reinfarction Study Research Group.  A double-blind trial to assess long-term oral anticoagulant therapy in elderly patients after myocardial infarction.  Lancet.1980;2:989-994.
Meuwissen OJ, Vervoorn AC, Cohen O, Jordan FL, Nelemans FA. Double blind trial of long-term anticoagulant treatment after myocardial infarction.  Acta Med Scand.1969;186:361-368.
Drapkin A, Merskey C. Anticoagulant therapy after acute myocardial infarction.  JAMA.1972;222:541-548.
Breddin K, Loew D, Lechner K, Oberla K, Walter E. The German-Austrian aspirin trial.  Circulation.1980;64:63-72.
van der Meer J, Hillege HL, Kootstra GJ.  et al.  Prevention of one-year vein-graft occlusion after aortocoronary-bypass surgery.  Lancet.1993;342:257-264.
Cohen M, Adams C, Hawkins L, Bach M, Fuster V. Usefulness of antithrombotic therapy in resting angina pectoris or non-Q-wave myocardial infarction in preventing death and myocardial infarction (a pilot study from the Antithrombotic Therapy in Acute Coronary Syndromes Study Group).  Am J Cardiol.1990;66:1287-1292.
McEnany MT, Salzman EW, Mundth ED.  et al.  The effect of antithrombotic therapy on patency rates of saphenous vein coronary artery bypass grafts.  J Thorac Cardiovasc Surg.1982;83:81-89.
Ebert RV. Long-term anticoagulant therapy after myocardial infarction.  JAMA.1969;207:2263-2267.
Medical Research Council Working Party.  An assessment of long-term anticoagulant administration after cardiac infarction.  BMJ.1964;2:837-843.
Williams DO, Kirby MG, McPherson K, Phear DN. Anticoagulant treatment in unstable angina.  Br J Clin Pract.1986;40:114-116.
Anand SS, Yusuf S, Pogue J, Weitz J, Flather M.for the OASIS Investigators.  Long-term oral anticoagulant therapy in patients with unstable angina or suspected non-Q-wave myocardial infarction.  Circulation.1998;98:1064-1070.
Cohen M, Adams PC, Parry G.  et al.  Combination antithrombotic therapy in unstable rest angina and non-Q-wave infarction in nonprior aspirin users.  Circulation.1994;89:81-88.
Ferguson JJ. Highlights of the 48th Scientific Sessions of the American College of Cardiology.  Circulation.1999;100:570-575.
CAPRIE Steering Committee.  A randomized, blinded, trial of clopidogrel versus aspirin in patients at risk of ischemia events (CAPRIE).  Lancet.1996;348:1329-1339.
The Medical Research Council's General Practice Research Framework.  Thrombosis prevention trial.  Lancet.1998;351:233-241.
Stroke Prevention in Atrial Fibrillation Investigators.  Adjusted-dose warfarin versus low-intensity, fixed dose warfarin plus aspirin in high-risk patients with atrial fibrillation.  Lancet.1996;348:633-638.
Turpie AG, Gent M, Laupacis A.  et al.  A comparison of aspirin with placebo in patients treated with warfarin after heart-valve replacement.  N Engl J Med.1993;329:524-529.

Figures

Figure 1. Rates of Major Cardiovascular Outcomes for High- and Moderate-Intensity Oral Anticoagulant vs Control
Graphic Jump Location
Figure 2. Rates of Major Cardiovascular Outcomes by Oral Anticoagulant Intensity and Aspirin Use
Graphic Jump Location
Figure 3. Major Bleeding Rates in Patients With Vascular Disease
Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Baseline Characteristics in High-, Moderate- and Low-Intensity OA Trials*
Table Graphic Jump LocationTable 2. Results of Prolonged Oral Anticoagulant (OA) Therapy Compared With Control in High-, Moderate-, and Low-Intensity Trials on Total Mortality*
Table Graphic Jump LocationTable 3. Results of Prolonged Oral Anticoagulant (OA) Therapy Compared With Control in High-, Moderate-, and Low-Intensity Trials on Fatal and Nonfatal Myocardial Infarction*
Table Graphic Jump LocationTable 4. Results of Prolonged Oral Anticoagulant (OA) Therapy Compared With Control in High-Intensity Trials on Thromboembolic Complications*
Table Graphic Jump LocationTable 5. Results of Prolonged Oral Anticoagulant (OA) Therapy Compared With Control in High-, Moderate-, and Low-Intensity Trials on the Combined Outcome of Death, Myocardial Infarction, or Stroke*
Table Graphic Jump LocationTable 6. Results of Prolonged Oral Anticoagulant (OA) Therapy Compared With Control in High-Intensity Trials on Total Bleeds*
Table Graphic Jump LocationTable 7. Comparisons of Results of Prolonged Oral Anticoagulant (OA) Therapy Compared With Control in High-, Moderate- and Low-Intensity Trials on Major Bleeding*
Table Graphic Jump LocationTable 8. Results of Prolonged Oral Anticoagulant (OA) Therapy Compared With Control in High-, Moderate-, and Low-Intensity Trials on Stroke*
Table Graphic Jump LocationTable 9. Summary of Results With the Analysis Stratified by Oral Anticoagulant (OA) Intensity and Aspirin Use*
Table Graphic Jump LocationTable 10. Risk-Benefit per Thousand Patients Treated With Oral Anticoagulant (OA) Intensity*

References

International Anticoagulation Review Group.  Collaborative analysis of long-term anticoagulant administration after acute myocardial infarction.  Lancet.1970;1:203-209.
Chalmers TC, Matta RJ, Smith Jr H, Kunzler AM. Evidence favoring the use of anticoagulants in the hospital phase of acute myocardial infarction.  N Engl J Med.1977;297:1091-1096.
Yusuf S, Flather M, Pogue J.  et al.  Variations between countries in invasive cardiac procedures and outcomes in patients with suspected unstable angina or MI without initial ST elevation.  Lancet.1998;352:507-514.
Merlini PA, Bauer KA, Oltrona L.  et al.  Persistant activiation of coagulation mechanism in unstable angina and myocardial infarction.  Circulation.1994;90:61-68.
Smith P, Arnesen H, Holme I. The effect of warfarin on mortality and reinfarction after myocardial infarction.  N Engl J Med.1990;323:147-152.
Anticoagulants in the Secondary Prevention of Events in Coronary Thrombosis (ASPECT) Research Group.  Effect of long-term oral anticoagulant treatment on mortality and cardiovascular morbidity after myocardial infarction.  Lancet.1994;343:499-503.
EPSIM Research Group.  A controlled comparison of aspirin and oral anticoagulants in prevention of death after myocardial infarction.  N Engl J Med.1982;307:701-708.
Coumadin Aspirin Reinfarction Study (CARS) Investigators.  Randomised double-blind trial of fixed low-dose warfarin with aspirin after myocardial infarction.  Lancet.1997;350:389-396.
Post Coronary Artery Bypass Graft Trial Investigators.  The effect of aggressive lowering of low-density lipoprotein cholesterol levels and low-dose anticoagulation on obstructive changes in saphenous vein coronary artery bypass grafts.  N Engl J Med.1997;336:153-162.
Kraska T, Malanowicz W, Skarzynska M, Tyminska K. Results of prevention of second myocardial infarct with syncumar or aspirin.  Kardiologia Polska.1981;24:593-597.
Eritsland J, Arnesen H, Gronseth K, Fjeld NB, Abdelnoor M. Effect of dietary supplementation with n-3 fatty acids on coronary artery bypass graft patency.  Am J Cardiol.1996;77:31-36.
Le D, Wiebert R, Sevilla B, Donnelly K, Rapaport S. The international normalized ratio (INR) for monitoring warfarin therapy: reliability and relationship to other monitoring methods.  Ann Intern Med.1994;120:552-558.
Hirsh J, Dalen J, Deykin D, Poller L, Bussey H. Oral anticoagulants.  Chest.1995;108(suppl):231-246.
MacMillan RL, Brown KW, Watt DL. Long-term anticoagulant therapy after myocardial infarction.  CMAJ.1960;83:567-570.
Wasserman AJ, Gutterman LA, Yoe KB, Kemp VE, Richardson DW. Anticoagulants in acute myocardial infarction.  Am Heart J.1966;71:43-49.
Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease.  J Natl Cancer Inst.1959;22:719-748.
Antiplatelet Trialist Collaboration.  Collaborative overview of randomized trials of antiplatelet therapy-1.  BMJ.1994;308:81-106.
Yusuf S, Peto R, Lewis J, Collins R, Sleight P. Beta blockade during and after myocardial infarction.  Prog Cardiovasc Dis.1985;27:335-371.
Medical Research Council Working Party.  An assessment of long-term anticoagulant administration after cardiac infarction.  BMJ.1959;1:803-810.
Drapkin A, Merskey C. Long-term anticoagulant therapy after myocardial infarction.  JAMA.1974;230:208-209.
Ritland S, Lygren T. Comparison of efficicacy of 3 and 12 months' anticoagulant therapy after myocardial infarction.  Lancet.1969;1:122-124.
Rothlin ME. Clinical experience with anti-platelet drugs in aorta-coronary bypass surgery.  Coron Artery Dis.1982;557:413-419.
Rajah SM, Salter M, Donaldson D.  et al.  Acetysalicylic acid and dipyridamole improve the early patentcy of aorta-coronary bypass grafts.  J Thorac Cardiovasc Surg.1985;90:373-377.
Ollivier JP.pour le group EPPAC.  Etude de la permeabilite des pontages aortocoronaries a 6 mois.  Arch Mal Coeur Vaiss.1991;84:537-542.
Brown KWG, MacMillan RL. Initial heparin therapy in acute myocardial infarction.  CMAJ.1964;90:1345-1348.
Schomig A, Neumann F, Kastrati A.  et al.  A randomized comparison of antiplatelet and anticoagulant therapy after the placement of coronary-artery stents.  N Engl J Med.1996;334:1084-1089.
Leon MB, Baim D, Cordon P.  et al.  Clinical and angiographic results from the Stent Anticoagulation Regimen Study (STARS).  Circulation.1996;94(suppl 1):I-685.
Hess H, Munich B. Proceedings of Colfarit Symposium III. Cologne, Germany: Bager; 1975:80-87.
Urban P, Buller N, Fox K.  et al.  Lack of effective warfarin on the restenosis rate or on clinical outcome after balloon coronary angioplasty.  Br Heart J.1988;60:485-488.
Tramarin R, Pozzoli M, Febo C.  et al.  Two-dimensional echocardiographic assessment of anticoagulant therapy in left ventricular thrombosis early after acute myocardial infarction.  Eur Heart J.1986;7:482-492.
Pantely GA, Goodnight SH, Rahimtoola SH.  et al.  Failure of antiplatelet and anticoagulant therapy to improve patency of grafts after coronary-artery bypass.  N Engl J Med.1979;301:962-966.
Borchegrevink CF. Long-term anticoagulant therapy in angina pectoris and myocardial infarction.  Acta Med Scand Suppl.1960;359:1-50.
Clausen J, Andersen PE, Andresen P.  et al.  Studies on long-term anticoagulant treatment after coronary occlusion.  Acta Med Scand.1961;123:987-994.
Harvald B, Hilden T, Letman H, Lund E, Thaysen EH, Worning H. Long-term anti-coagulant treatment in myocardial infarction.  Acta Med Scand.1961;21:983-987.
Apenstrom G, Korsan-Bengtsen K. A double blind study of dicumarol prophylaxis in coronary heart disease.  Acta Med Scand.1964;176:563-575.
Conrad LL, Kyriacopoulos JD, Wiggins CW, Honick GL. Prevention of recurrences of myocardial infarction.  Arch Intern Med.1964;114:348-358.
Loeliger EA, Hensen A, Kroes F.  et al.  A double-blind trial of long-term anticoagulant treatment after myocardial infarction.  Acta Med Scand.1967;182:549-566.
Lovell RR, Denborough MA, Nestel PJ, Goble AJ. A controlled trial of long-term treatment with anticoagulants after myocardial infarction in 412 male patients.  Med J Aust.1967;2:97-104.
Seaman AJ, Griswold HE, Reaume RB, Ritzmann L. Long-term anticoagulant prophylaxis after myocardial infarction.  N Engl J Med.1969;281:115-119.
Sorensen HO, Friis T, Jorgensen AW, Jorgensen MB, Nissen NI. Anticoagulant treatment of acute coronary thrombosis.  Acta Med Scand.1969;185:65-72.
Sixty Plus Reinfarction Study Research Group.  A double-blind trial to assess long-term oral anticoagulant therapy in elderly patients after myocardial infarction.  Lancet.1980;2:989-994.
Meuwissen OJ, Vervoorn AC, Cohen O, Jordan FL, Nelemans FA. Double blind trial of long-term anticoagulant treatment after myocardial infarction.  Acta Med Scand.1969;186:361-368.
Drapkin A, Merskey C. Anticoagulant therapy after acute myocardial infarction.  JAMA.1972;222:541-548.
Breddin K, Loew D, Lechner K, Oberla K, Walter E. The German-Austrian aspirin trial.  Circulation.1980;64:63-72.
van der Meer J, Hillege HL, Kootstra GJ.  et al.  Prevention of one-year vein-graft occlusion after aortocoronary-bypass surgery.  Lancet.1993;342:257-264.
Cohen M, Adams C, Hawkins L, Bach M, Fuster V. Usefulness of antithrombotic therapy in resting angina pectoris or non-Q-wave myocardial infarction in preventing death and myocardial infarction (a pilot study from the Antithrombotic Therapy in Acute Coronary Syndromes Study Group).  Am J Cardiol.1990;66:1287-1292.
McEnany MT, Salzman EW, Mundth ED.  et al.  The effect of antithrombotic therapy on patency rates of saphenous vein coronary artery bypass grafts.  J Thorac Cardiovasc Surg.1982;83:81-89.
Ebert RV. Long-term anticoagulant therapy after myocardial infarction.  JAMA.1969;207:2263-2267.
Medical Research Council Working Party.  An assessment of long-term anticoagulant administration after cardiac infarction.  BMJ.1964;2:837-843.
Williams DO, Kirby MG, McPherson K, Phear DN. Anticoagulant treatment in unstable angina.  Br J Clin Pract.1986;40:114-116.
Anand SS, Yusuf S, Pogue J, Weitz J, Flather M.for the OASIS Investigators.  Long-term oral anticoagulant therapy in patients with unstable angina or suspected non-Q-wave myocardial infarction.  Circulation.1998;98:1064-1070.
Cohen M, Adams PC, Parry G.  et al.  Combination antithrombotic therapy in unstable rest angina and non-Q-wave infarction in nonprior aspirin users.  Circulation.1994;89:81-88.
Ferguson JJ. Highlights of the 48th Scientific Sessions of the American College of Cardiology.  Circulation.1999;100:570-575.
CAPRIE Steering Committee.  A randomized, blinded, trial of clopidogrel versus aspirin in patients at risk of ischemia events (CAPRIE).  Lancet.1996;348:1329-1339.
The Medical Research Council's General Practice Research Framework.  Thrombosis prevention trial.  Lancet.1998;351:233-241.
Stroke Prevention in Atrial Fibrillation Investigators.  Adjusted-dose warfarin versus low-intensity, fixed dose warfarin plus aspirin in high-risk patients with atrial fibrillation.  Lancet.1996;348:633-638.
Turpie AG, Gent M, Laupacis A.  et al.  A comparison of aspirin with placebo in patients treated with warfarin after heart-valve replacement.  N Engl J Med.1993;329:524-529.
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