Long-term Effect of Chronic Oral Anticoagulation with Warfarin after Acute Myocardial Infarction
Article Outline
Abstract
Background
Antiplatelet therapy is the principal component of the antithrombotic regimen after acute myocardial infarction. It remains unclear whether additional chronic oral anticoagulation (OAC) improves outcomes. We set out to evaluate the risk and benefit of long-term OAC after myocardial infarction.
Methods
We pooled 10 randomized clinical trials comparing warfarin-containing regimens (OAC) with or without aspirin with non-OAC regimens with or without aspirin (No OAC) for patients with recent infarction. The primary endpoint was all-cause mortality. Other endpoints included recurrent infarction, stroke, and major bleeding. We calculated the odds ratio (OR) (fixed effect, OR <1 indicates benefit for OAC) for death and other ischemic and hemorrhagic complications at the longest interval of follow-up available.
Results
Among 24,542 patients, 14,062 were assigned to OAC and 10,480 to no OAC. The patients were followed for 3-63 months, for 89,562 patient-years. Death occurred in 2424 patients (9.9%), 1279 OAC patients, and 1145 in the no OAC group, OR 0.97 (95% confidence interval [CI], 0.88-1.05), P
=.43. Similarly, there was no effect on recurrent infarction. Stroke occurred in 578 patients (2.4%), 271 in the OAC group and 307 in the no OAC group, OR 0.75 (95% CI, 0.63-0.89), P=.001. There was substantially more major bleeding (OR 1.83 [95% CI, 1.50-2.23], P <.001) in the OAC group. Separate analyses, performed for patients (n=11,920) randomized to aspirin versus aspirin and OAC yielded very similar results.
Conclusion
As compared with placebo or aspirin, OAC with or without aspirin does not reduce mortality or reinfarction, reduces stroke, but is associated with significantly more major bleeding.
Keywords: Anticoagulation, Bleeding, Death, Long-term effect, Myocardial infarction
Coronary artery disease remains the most common cause of death among adults in the United States. Anti-platelet therapy is the principal component of the antithrombotic regimen after acute myocardial infarction.1
There have been numerous studies over the last 4 decades attempting to address the utility of long-term oral anticoagulation (OAC) after myocardial infarction. Early studies suggested benefit in younger men only, while later ones found all patients to survive longer or to have lower rates of recurrent ischemic events, but not death.2, 3 In the last 20 years, several randomized controlled trials have been conducted to clarify the role of long-term OAC after myocardial infarction, with varying results.4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 They utilized different intensities of anticoagulation, starting at varying intervals from index event, and in a wide array of patients with respect to concomitant aspirin or reperfusion therapy.
As uncertainty about the benefit of OAC persists, we performed a meta-analysis of randomized clinical trials comparing OAC-based regimens (without or without aspirin) versus no OAC after myocardial infarction (with or without) ST-elevation, to determine whether there was any improvement in survival or other cardiovascular events in those taking OAC. We refined the analysis to evaluate the effect of OAC or placebo in addition to aspirin, which is the standard of care for patients with previous infarction.
Methods
We performed a comprehensive search of OVID SR and PubMed without any language restrictions. The keywords used included warfarin, myocardial infarction, and randomized controlled trials, in accordance with the Meta-analysis Of Observational Studies in Epidemiology guidelines.16 We retrieved 66 citations, which were reviewed at the title/abstract level. The inclusion criteria were: use of chronic OAC with warfarin post infarction, randomized controlled trial, at least 30-day follow-up, and death listed as outcome. The exclusion criteria were: retrospective study or registry and use of OAC for conditions other than myocardial infarction (Figure 1). Fourteen studies were analyzed in detail. The study by Cohen at al7 was excluded because it did not provide details about the 2 randomized arms and listed only the results comparing non-Q-wave infarction versus unstable angina. The study by Huynh et al11 was excluded because it studied a selected group of patients with unstable angina or non-ST-segment elevation myocardial infarction, with prior coronary bypass surgery, and who were poor candidates for a revascularization procedure. The third excluded study was a subgroup analysis of the original Coumadin Aspirin Reinfarction Study (CARS).17 The Organization to Assess Strategies for Ischemic Syndromes5 study reported use of aspirin in 85%-87% of patients, however, the study did not report the results separately for those receiving aspirin or not. This study was excluded because it did not report specifically number of deaths, but rather the combination of death, infarction, or stroke.
Figure 1.
Study inclusion and exclusion process. OAC
=oral anticoagulation.
The primary endpoint for each trial (except 1 trial that used all-cause mortality as endpoint8) was a composite of ischemic events, including death, infarction, stroke, or recurrent ischemia in various combinations. While our focus was on all-cause mortality, we examined individually each ischemic event (death, infarction, or stroke) because of the possibility of heterogeneity in response among the components of the composite endpoint. We also analyzed separately major bleeding and minor bleeding, according to the definition in each trial. Statistical analysis was performed using the weighted fixed and random effects methods for meta-analysis. After confirming that there were no substantial differences between the 2 methods, we reported only the pooled fixed-effect results. Heterogeneity was assessed using a standard chi-squared test (inverse variance method). For each event, the pooled result was presented as odds ratio (OR) with 95% confidence intervals. OR <1 signifies benefit for OAC-based therapy. The analyses were performed first for all patients and then only for patients randomized to aspirin versus aspirin and OAC. Statistical significance was set at P <.05, and all analyses were performed using STATA SE ver. 9.0 (StataCorp LP, College Station, Tex).
Results
Ten studies of long-term OAC versus no OAC, with or without aspirin, were included for final analysis. Table 1 highlights the studies identified: 1 study compared OAC versus placebo, without aspirin in either arm. There were 5 studies of patients on OAC and aspirin versus aspirin alone. Four studies had 3 arms that compared OAC alone versus aspirin alone versus OAC with aspirin. For the latter group, the groups were condensed into OAC-based regimens or no OAC regimens. The baseline characteristics of patients from all the studies are listed in Table 2. The number of patients enrolled in the studies ranged from 93 to 8803. Among the 24,542 patients, 14,062 were assigned to OAC and 10,480 to no OAC. The patients were followed for 3-63 months, with 89,562 patient-years of observation. The ejection fraction was listed in only one study.9 Reperfusion therapy was administered to 6009 patients (25%).
Table 1. Studies Included in the Meta-analysis
| Study Design and First Author/Study Name and Reference | Year | n |
|---|---|---|
| OAC vs. placebo | ||
| WARIS13 | 1990 | 1214 |
| OAC (± aspirin) vs. aspirin | ||
| AFTER12 | 1996 | 1036 |
| CHAMP8 | 2002 | 5059 |
| APRICOT 26 | 2002 | 274 |
| LoWASA9 | 2004 | 3300 |
| Zibaeenezhad et al15 | 2004 | 140 |
| OAC vs. aspirin vs. OAC+aspirin | ||
| ATACS7 | 1990 | 93 |
| CARS4 | 1997 | 8803 |
| ASPECT 214 | 2002 | 993 |
| Hurlen et al10 | 2002 | 3630 |
Table 2. Selected Baseline Characteristics
| Study/Year | Male (%) | Age (Years) | DM (%) | HTN (%) | Previous Angina/Infarction (%) | Time from Infarction | Lytics (%) | PTCA (%) | CABG (%) | BB (%) | Statins (%) |
|---|---|---|---|---|---|---|---|---|---|---|---|
| WARIS 199013 | |||||||||||
| No OAC | 77 | 61.6 | 8 | 35 | 25 | 4.6 | 48 | ||||
| OAC | 79 | 61.4 | 6 | 32 | 28 | 4.4 | 48 | ||||
| ATACS 19907 | |||||||||||
| No OAC | 56 | 62 | 34 | 53 | 75 | 22 | 16 | 25 | |||
| OAC | 62 | 61-63 | 38 | 48 | 85 | 21 | 34 | 25 | |||
| AFTER 199612 | |||||||||||
| No OAC | 77 | 60.3 | <24 h | 100 | |||||||
| OAC | 76 | 60.3 | <24 h | 100 | |||||||
| CARS 19974 | |||||||||||
| No OAC | 76 | 18. | 18.2 | 3-21 days | |||||||
| OAC | 85 | 19 | 18.8 | 3-21 days | |||||||
| ASPECT-2 200214 | |||||||||||
| No OAC | 79 | 12 | 22 | 38 | 11 days | 7 | 4 | 79 | 30 | ||
| OAC | 75 | 8 | 24 | 36 | 10-11 days | 5 | 4 | 71 | 32 | ||
| Hurlen et al 200210 | |||||||||||
| No OAC | 74 | 60.7 | 9 | 12 | 54 | 19 | 18 | ||||
| OAC | 78 | 59.9 | 8 | 13 | 54 | 19 | 16 | ||||
| CHAMP 20018 | |||||||||||
| No OAC | 98 | 64 | 27 | 53 | 35 | <28 days | 30 | ||||
| OAC | 98 | 64 | 27 | 55 | 37 | <28 days | 31 | ||||
| APRICOT-2 20026 | |||||||||||
| No OAC | 81 | 58 | 6 | 31 | 12 | 48 h | 36 | ||||
| OAC | 82 | 57 | 6 | 23 | 11 | 48 h | 44 | ||||
| LoWASA 20049 | |||||||||||
| No OAC | 75 | 66 | 13 | 33 | 58 | <42 days | 2 | 4 | 84 | 17 | |
| OAC | 72 | 66 | 13 | 35 | 59 | 2 | 4 | 86 | 17 | ||
| Zibaeenezhad et al 200415 | |||||||||||
| No OAC | 63 | 58.9 | 5-7 days | ||||||||
| OAC | 68 | 63 | 5-7 days |
Table 3 lists the outcomes of patients. Death occurred in 2424 patients (9.9%), OR 0.97 (95% confidence interval [CI] 0.88-1.05), P=.43 (Pheterogeneity=.14) (Figure 2). All except one study reported myocardial infarction as an endpoint. A total of 2430 new infarctions occurred (9.9%), OR 0.94 (95% CI, 0.87-1.03), P=.18 (Pheterogeneity=.001). Stroke, reported in 7 of the 11 studies, occurred in a total of 578 patients (2.5%, Figure 3), OR 0.75 (95% CI, 0.63-0.89), P=.001 (Pheterogeneity=.001). In one study with angiographic follow-up, in which patients were treated with fibrinolytic therapy for their index infarction and had a patent artery at enrollment, OAC therapy added to aspirin significantly lowered rates of reocclusion and recurrent ischemic events.6 International normalized ratio (INR) target varied from 1.5 to 4.5, depending on the adjunctive antiplatelet therapy. The actual INR was <2 in 2 studies using low-dose warfarin.4, 9 Most studies reported both major (all 10) and minor (8 studies) bleeding. The definition of major bleeding varied among the different studies. A total of 482 major bleeding events occurred (2.0%, Figure 4), OR 1.83 (95% CI, 1.50-2.23), P <.001 (Pheterogeneity=.14). Minor bleeding was reported in 1025 patients (4.2%), OR 3.46 (95% CI, 2.95-4.05), P <.001 (Pheterogeneity=.001). Odds ratios for ischemic events and major bleeding complications are summarized in Table 4. Because it is important to assess the effect of OAC on the background of obligatory aspirin background recommended in patients with previous infarction, we also analyzed the subset of patients (n=11,920) randomized to aspirin versus aspirin and OAC. OAC did not affect mortality or reinfarction, reduced stroke by 30% (without evidence for heterogeneity), and markedly increased the odds of major bleeding (Table 5). There was no evidence for publication bias for the entire population (P=.72) or the aspirin background cohort (P=.73) by funnel plot analysis (Egger's test).
Table 3. Summary of Ischemic and Hemorrhagic Events
| Study | n | Death | Infarction | Stroke | Major Bleeding | Minor Bleeding |
|---|---|---|---|---|---|---|
| WARIS13 | ||||||
| No OAC | 607 | 20.3% | 20.4% | 7.2% | 0.0% | 4.1% |
| OAC | 607 | 15.5% | 13.5% | 3.3% | 1.3% | 7.2% |
| ATACS7 | ||||||
| ASA | 32 | 0.0% | 3.1% | 0.0% | 0.0% | 3.1% |
| OAC+ASA | 61 | 1.6% | 4.9% | 0.0% | 0.0% | 1.6% |
| AFTER12 | ||||||
| ASA | 519 | 8.9% | 3.3% | 0.0% | 1.0% | 0.0% |
| OAC | 517 | 8.1% | 5.0% | 0.0% | 2.5% | 0.0% |
| CARS4 | ||||||
| ASA | 3393 | 3.0% | 6.8% | 0.6% | 1.7% | 0.0% |
| OAC+ASA | 5410 | 3.3% | 7.2% | 1.1% | 2.2% | 0.0% |
| ASPECT 214 | ||||||
| ASA | 336 | 4.5% | 4.2% | 1.5% | 0.9% | 4.8% |
| OAC+ASA | 657 | 1.8% | 3.5% | 0.2% | 1.5% | 11.6% |
| Hurlen et al10 | ||||||
| ASA | 1206 | 7.6% | 9.7% | 2.7% | 0.7% | 3.2% |
| OAC+ASA | 2424 | 7.9% | 6.6% | 1.4% | 2.5% | 9.7% |
| CHAMP8 | ||||||
| ASA | 2537 | 17.3% | 13.1% | 3.5% | 2.0% | 3.0% |
| OAC+ASA | 2522 | 17.6% | 13.3% | 3.1% | 3.4% | 13.8% |
| APRICOT 26 | ||||||
| ASA | 139 | 0.0% | 7.9% | 0.0% | 1.4% | 1.4% |
| OAC+ASA | 135 | 0.7% | 2.2% | 0.0% | 1.5% | 3.7% |
| LoWASA9 | ||||||
| ASA | 1641 | 19.7% | 16.3% | 7.1% | 1.0% | 2.6% |
| OAC+ASA | 1659 | 18.7% | 17.1% | 4.7% | 2.2% | 5.8% |
| Zibaeenezhad et al15 | ||||||
| ASA | 70 | 8.6% | 8.6% | 0.0% | 2.9% | 2.9% |
| OAC+ASA | 70 | 2.9% | 5.7% | 0.0% | 7.1% | 18.6% |
| Total | ||||||
| No OAC | 10,480 | 10.9% | 10.7% | 2.9% | 1.4% | 2.0% |
| OAC | 14,062 | 9.1% | 9.3% | 1.9% | 2.4% | 5.8% |
Figure 2.
Forester plot of effect of long-term oral anticoagulation on mortality (point estimate proportional to number of events, odds ratio <1 indicates benefit for oral anticoagulation). OAC
=oral anticoagulation; ATACS=Antithrombotic Therapy in Acute Coronary Syndromes Study; WARIS=Warfarin Aspirin Re-infarction Study; AFTER=Aspirin/Anticoagulants Following Thrombolysis with Eminase in Recurrent infarction study; CARS=Coumadin Aspirin Reinfarction Study; ASPECT=Aspirin and Coumadin after Acute Coronary Syndromes study; CHAMP=Combination Hemotherapy and Mortality Prevention study; APRICOT=Antithrombotics in the Prevention of Reocclusion In Coronary Thrombolysis; LoWASA=Effect of fixed low-dose warfarin added to aspirin in the long term after acute myocardial infarction study.
Figure 3.
Forester plot of effect of long-term oral anticoagulation on nonfatal stroke (point estimate proportional to number of events, odds ratio <1 indicates benefit for oral anticoagulation). OAC
=oral anticoagulation; WARIS=Warfarin Aspirin Re-infarction Study; CARS=Coumadin Aspirin Reinfarction Study; ASPECT=Aspirin and Coumadin after Acute Coronary Syndromes study; CHAMP=Combination Hemotherapy and Mortality Prevention study; LoWASA=Effect of fixed low-dose warfarin added to aspirin in the long term after acute myocardial infarction study.
Figure 4.
Forester plot of effect of long-term oral anticoagulation on nonfatal major bleeding (point estimate proportional to number of events, odds ratio >1 indicates excess with oral anticoagulation). OAC
=oral anticoagulation; WARIS=Warfarin Aspirin Re-infarction Study; ATACS=Antithrombotic Therapy in Acute Coronary Syndromes Study; CARS=Coumadin Aspirin Reinfarction Study; ASPECT=Aspirin and Coumadin after Acute Coronary Syndromes study; CHAMP=Combination Hemotherapy and Mortality Prevention study; APRICOT=Antithrombotics in the Prevention of Reocclusion In Coronary Thrombolysis; LoWASA=Effect of fixed low-dose warfarin added to aspirin in the long term after acute myocardial infarction study.
Table 4. Pooled (Fixed) Effect of OAC for Ischemic and Hemorrhagic Events (OR <1 Indicates Benefit for OAC)
| Event | OR | CI | P Value | P (Heterogeneity) |
|---|---|---|---|---|
| Death | 0.97 | 0.88-1.05 | .43 | .14 |
| Infarction | 0.94 | 0.87-1.03 | .18 | .001 |
| Stroke | 0.75 | 0.63-0.89 | .001 | .001 |
| Major bleeding | 1.83 | 1.50-2.23 | <.001 | .14 |
Table 5. Pooled (Fixed) Effect of OAC for Ischemic and Hemorrhagic Events (OR <1 Indicates Benefit for OAC) in 11,920 Patients Randomized to Aspirin Alone or Aspirin and OAC
| Event | OR | CI | P Value | P (Heterogeneity) |
|---|---|---|---|---|
| Death | 0.98 | 0.89-1.09 | .74 | .50 |
| Infarction | 0.93 | 0.83-1.04 | .20 | .007 |
| Stroke | 0.71 | 0.58-0.87 | .001 | .19 |
| Major bleeding | 2.03 | 1.56-2.64 | <.001 | .65 |
Discussion
The principal finding of our meta-analysis is that among nearly 25,000 patients with recent acute myocardial infarction followed for nearly 90,000 patient-years, OAC does not reduce the risk of all-cause death (the focus of this analysis) or reinfarction. There was a substantial reduction in the incidence of stroke (30%). OAC doubled the risk of major bleeding. There was substantial heterogeneity among the studies for some endpoints (infarction and stroke), but not for the principal efficacy and safety endpoints (all-cause mortality and major bleeding). Unlike in previous meta-analyses, we chose to examine the strategy of OAC-based versus no OAC treatments, rather than to separate the individual arms of the studies when 3 regimens were compared. These results indicate that for every 100 patients treated with warfarin after a myocardial infarction, 1 major bleeding (number needed to harm=100) and 4 minor bleeding (number needed to harm=25) are caused, while 1 stroke was prevented (number needed to treat=100). An analysis geared towards a more homogenous population receiving background aspirin therapy confirmed the directionality and magnitude of these findings.
Epidemiological data support the association between elevated concentrations of factor VII and the risk of a primary vascular thrombotic event or recurrence after one had occurred. A potential benefit might be obtained by lowering factor VII concentrations. Some had suggested therapy with a low fixed-dose warfarin, which in pilot studies lowered factor VII levels, and decreased the risk of bleeding complications compared with full anticoagulation. The Warfarin Aspirin Re-infarction Study (WARIS)13 specifically addressed this question and found that OAC improved mortality in the setting of acute myocardial infarction compared with placebo, in the absence of aspirin therapy. However, when OAC was compared with no OAC, on aspirin background therapy, the largest trial to date, CARS,4 did not find any difference in mortality among 8803 patients randomized to OAC alone, aspirin alone, or combination of the 2. The INR achieved in CARS was 1.2-1.5. Our meta-analysis confirms these results in a much larger cohort of patients, with a more heterogeneous level of anticoagulation.
It is well recognized that platelets play an important role in vascular thrombosis at the ruptured coronary atherosclerotic plaque, leading to acute ischemic episodes.18 Antiplatelet strategies have contributed substantially to improve the outcome of patients with acute coronary syndromes.1 However, some studies reinforced the doubt about the putative benefit of adding OAC to aspirin for some groups of patients. The current American College of Cardiology/American Heart Association guidelines for ST-elevation myocardial infarction recommend warfarin alone (INR 2.5 to 3.5) or warfarin with aspirin (75 to 162 mg) (INR 2.0 to 3.0) as Class IIa indication for secondary prevention.19 Similar recommendations were promoted by the American College of Chest Physicians.20 They distinguish between the majority of patients with recent infarction who can monitor INR and for whom warfarin is weakly indicated (Class IIb) and those at high risk (large anterior myocardial infarction, thrombus in left ventricle) for whom warfarin is recommended for at least 3 months at moderate intensity and in addition to aspirin (Class IIA).
Rothberg et al performed a meta-analysis of studies comparing warfarin plus aspirin versus aspirin alone after myocardial infarction or acute coronary syndromes.3 They evaluated 10 trials (5938 patients), reported until 2004, and demonstrated no benefit in mortality for OAC and aspirin versus aspirin alone, but there was significant reduction in reinfarction, revascularization, and stroke. The incidence of major bleeding was significantly higher in the OAC group (1.5% per year), as found in our updated meta-analysis. There was a 2.5-fold (95% CI, 1.7-3.7, P <.01) higher rate of major bleeding and 2.6-fold (95% CI, 2.0-3.3, P <.01) higher rate of minor bleeding. Nevertheless, the authors did recommend warfarin in patients at low or intermediate risk for bleeding, stating that the benefits may outweigh the risk of bleeding because of a significant reduction in reinfarction (from 4.1% per year to 2.2%, P <.01) and in thrombotic stroke (from 0.84% per year to 0.34%, P <.01). Three of the largest trials completed since, CARS (8803 patients),4 Combination Hemotherapy and Mortality Prevention study (CHAMP, 5059 patients),8 and Effect of fixed low-dose warfarin added to aspirin in the long term after acute myocardial infarction study (LoWASA, 3,300 patients),9 are included in our analysis. These studies quadrupled the number of patients analyzed and reinforced the lack of benefit in mortality and excess of bleeding associated with OAC added to aspirin background therapy. The reduction in stroke remained highly statistically significant and clinically relevant. In these trials, one quarter to one third of patients had anterior infarction, and in 2 of them (CHAMP and LoWASA), prespecified analyses showed no evidence of benefit in patients with anterior infarction. As new studies accumulate, it appears that the benefit of OAC for cardiac protection is less and less evident, reflecting the pathophysiology of acute coronary syndromes and concomitant therapies offered to patients in more recent trials. The rupture of a stable plaque results in platelet activation and aggregation, which decreases blood flow, and possibly results in myocardial infarction. Thus, there appears to be a limited role for warfarin-like compounds, as they would not prevent the initiation of the thrombotic cascade related to the disruption of the atherosclerotic plaque. Furthermore, more modern postinfarction therapy, including statins and angiotensin-converting enzyme inhibitors, used infrequently in older trials, may decrease the potential for additional ischemic events.21, 22, 23, 24 Not least important is the advantage of more frequent reperfusion with pharmacological or mechanical means that decreases the likelihood of death and severe heart failure after infarction.25 In 2006, Andreotti et al performed an updated meta-analysis of aspirin plus warfarin versus aspirin alone in patients recovering from acute coronary syndromes.26 Their analysis focused on the combination of major adverse events (MAE), rather than death alone in our study, and excluded studies in which aspirin was not given. They concluded that, among 25,307 patients randomized, warfarin added to aspirin did not reduce the incidence of MAE (fixed OR 0.96, P=.30 with considerable heterogeneity). When only studies with INR 2-3 were included, the OR was 0.73, P<.001 and without heterogeneity. The authors concluded that addition of intermediate-intensity warfarin to aspirin is indicated to prevent MAE in patients willing “to face the logistic hurdles” and accept the inherent bleeding risk associated with chronic OAC. Nevertheless, when mortality alone is analyzed, as is the primary focus of our analysis, there was no benefit for the combination therapy over aspirin alone, even in studies targeting INR of 2-3 (2.8% vs 2.9%).
Limitations
While our data are derived from a large cohort of patients, we did not have access to patient-specific data and could not identify subsets of patients in whom OAC may be beneficial. Specifically, we could not find evidence that subsets of patients, such as those with large anterior infarctions and those in whom thrombus was present in the left ventricle benefited from the addition of OAC. We could not reliably detect an interaction between intensity of anticoagulation and prevention of ischemic events, particularly death, and could not find a therapeutic window for which anticoagulation prevents ischemic events without affecting safety. Furthermore, because randomized clinical trials frequently represent a relatively healthier population than those treated in daily practice, it is possible that our findings underestimate the benefit of chronic OAC in patients with multiple co-morbidities.
Conclusion
Notwithstanding these limitations, we concluded that chronic OAC with warfarin does not reduce mortality or reinfarction after myocardial infarction, regardless of concomitant aspirin administration. There was a significantly higher rate of bleeding in patients receiving OAC, balanced by a significant protective effect for stroke. Dedicated clinical trials may be able to identify selected subsets of patients who could still benefit from OAC in the current era. These results do not exclude the possibility that carefully monitored INR at a moderate intensity may prevent the combination of ischemic events analyzed separately in this study. We see a need, based on our findings, for revisiting the American College of Cardiology/American Heart Association guidelines for postinfarction care with respect to OAC.
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Funding: There were no funding sources for this manuscript.
Conflict of Interest: All authors state that they have no conflict of interest to disclose.
Authorship: All authors had complete access to the data and the analytical process. All authors contributed significantly to data collection, analysis, and manuscript review, and participated meaningfully in manuscript writing and editing.
PII: S0002-9343(09)00818-3
doi:10.1016/j.amjmed.2009.08.016
© 2010 Elsevier Inc. All rights reserved.
