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Warfarin plus Aspirin after Myocardial Infarction or the Acute Coronary Syndrome: Meta-Analysis with Estimates of Risk and Benefit FREE

Michael B. Rothberg, MD, MPH; Carmel Celestin, MD; Louis D. Fiore, MD, MPH; Elizabeth Lawler, MPH; and James R. Cook, MD, MPH
[+] Article and Author Information

From Baystate Medical Center, Springfield, Massachusetts, and Tufts University School of Medicine, Massachusetts Veterans Epidemiology Research and Information Center, Veterans Affairs Boston Healthcare System, Boston, Massachusetts.


Potential Financial Conflicts of Interest: None disclosed.

Requests for Single Reprints: Michael B. Rothberg, MD, MPH, Division of General Medicine and Geriatrics, Baystate Medical Center, 759 Chestnut Street, Springfield, MA 01199; e-mail, Michael.Rothberg@bhs.org.

Current Author Addresses: Dr. Rothberg: Division of General Medicine and Geriatrics, Baystate Medical Center, 759 Chestnut Street, Springfield, MA 01199.

Dr. Celestin: Baystate Medical Center, 759 Chestnut Street, Springfield, MA 01199.

Dr. Fiore and Ms. Lawler: Massachusetts Veterans Epidemiology Research and Information Center, 150 South Huntington Avenue, Boston, MA 02130.

Dr. Cook: Cardiac Services, Baystate Medical Center, 759 Chestnut Street, Springfield, MA 01199.

Author Contributions: Conception and design: M.B. Rothberg, C. Celestin.

Analysis and interpretation of the data: M.B. Rothberg, L.D. Fiore, E. Lawler, J.R. Cook.

Drafting of the article: M.B. Rothberg, J.R. Cook.

Critical revision of the article for important intellectual content: M.B. Rothberg, C. Celestin, L.D. Fiore, E. Lawler, J.R. Cook.

Final approval of the article: M.B. Rothberg, C. Celestin, L.D. Fiore, E. Lawler, J.R. Cook.

Provision of study materials or patients: L.D. Fiore, E. Lawler.

Statistical expertise: J.R. Cook.

Collection and assembly of data: M.B. Rothberg, C. Celestin, L.D. Fiore.


Ann Intern Med. 2005;143(4):241-250. doi:10.7326/0003-4819-143-4-200508160-00005
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Editors' Notes
Context

Continued thrombin generation persists for several months after acute cardiac events.

Contribution

Data from 10 randomized trials involving 5938 patients with the acute coronary syndrome who were not stented showed that, compared with aspirin alone, warfarin plus aspirin decreased annual rates of myocardial infarction, ischemic stroke, and revascularization and increased major bleeding rates. In patients with low or average bleeding risks, numbers of cardiovascular events prevented by warfarin plus aspirin exceeded numbers of major bleeding episodes caused by it.

Implications

Benefits of warfarin plus aspirin may exceed harms in patients with the acute coronary syndrome who are not stented and do not have high bleeding risks.

–The Editors

Myocardial infarction is a leading cause of illness and death in the United States (1). Patients with a history of myocardial infarction are at increased risk for recurrent infarction, stroke, and death (23). Several interventions have proven beneficial in the secondary prevention of myocardial infarction, including β-blockers (4), angiotensin-converting enzyme inhibitors (5), lipid-lowering therapy (6), and aspirin (7). In addition, after acute cardiac events, a marked thrombin generation persists for months after clinical stabilization (8), suggesting a role for anticoagulation beyond the initial use of low-molecular-weight heparin (9). Although some studies have shown that addition of warfarin to aspirin decreases subsequent risk for cardiovascular events (1014), other studies have not (1516). In a meta-analysis, Anand and Yusuf (17) suggested that only moderate- to high-intensity anticoagulation, with a target international normalized ratio (INR) more than 2.0, decreased cardiovascular events more than aspirin alone. A large randomized trial conducted in a primary care setting showed that adding warfarin to aspirin decreased combined cardiovascular end points of myocardial infarction, stroke, and death by 29% (12). Despite these findings, warfarin use has not been widely adopted, perhaps because of concern that the increased bleeding risk may counter the cardiovascular benefit (18) or that the benefits are too small to justify the inconvenience (19).

The risks and benefits that are probably associated with warfarin therapy are not equally distributed. Patients at the highest risk for recurrent cardiovascular events should derive the most benefit, which may be offset in those with increased bleeding risk. To better quantify the risks and benefits of warfarin therapy for individuals, we conducted a meta-analysis of randomized trials and then calculated the expected benefit for groups at varying risk for cardiovascular disease and bleeding.

Study Selection

We searched MEDLINE using the following Medical Subject Heading (MeSH) terms and text words: anticoagulant or anticoagulation or warfarin and aspirin, combined with myocardial infarction, unstable angina, coronary arteriosclerosis, or coronary artery disease. We limited our search to original, English-language articles published between 1 January 1990 and 1 October 2004; earlier trials were not likely to reflect current standards of care for secondary prevention, including lipid therapy and β-blockers.

Two reviewers scanned the titles independently for relevant randomized trials. We checked abstracts and then manuscripts of all potentially appropriate references. We included studies if they were randomized, controlled trials of warfarin and aspirin in patients with an acute coronary syndrome. We excluded studies of percutaneous coronary stenting (for which warfarin is generally not considered appropriate therapy) (20) and low-intensity warfarin therapy (target INR < 2.0). We assessed studies for proper randomization, blinding of patients and investigators to treatment allocation, and completeness of follow-up.

Data Extraction

The 2 reviewers extracted the following data independently: study size and duration; aspirin dose; target INR; and demographic characteristics of trial participants, including age, sex, number of patients with diabetes, smoking status, systolic blood pressure, and whether the patient had a Q-wave infarction or received thrombolysis. We evaluated 7 end points: myocardial infarction, ischemic stroke, revascularization, death, minor bleeding, major bleeding, and intracranial hemorrhage. Each study's authors defined major and minor bleeding, and most studies reported all 7 end points. When results were presented only as combined end points or were ambiguous, we contacted the study authors to obtain primary data.

In the Organization to Assess Strategies for Ischemic Syndromes (OASIS) study (13), a multicenter, international trial, investigators noted 35 days into the trial that compliance as measured by achievement of target INR was better in some countries than in other countries and designated a subset analysis of countries with good compliance before data collection was complete. We included only the compliant countries in our analysis.

We contacted the OASIS authors for select data on compliant countries from OASIS (13) and individual end points from the OASIS pilot study (21), which were published only as combined end points. We contacted the authors of Huynh and colleagues' study (22), because the published results for all end points were incorrect.

Statistical Analysis

We used Stata, version 8.2 (Stata Corp., College Station, Texas), for all analyses. We calculated the rate ratios and 95% CIs for recurrent myocardial infarction, stroke, and bleeding (major or minor) for each study. We used a half-integer correction if no events occurred in 1 group of the study. We pooled rate ratios by using random-effects models that used weighting based on the inverse-variance model according to DerSimonian and Laird (23). We used the Mantel–Haenszel test to evaluate heterogeneity among trial outcomes. We considered statistical significance at a P value less than 0.05. We performed an influence analysis in which we computed the summary rate ratio, omitting the largest trial (Warfarin, Aspirin, Reinfarction Study [WARIS II] [12]), to assess for any single study dominance in the analysis. We used the Begg and Mazumdar adjusted rank correlation test (24) and the Egger regression asymmetry test (25) to evaluate publication bias.

Weighing Risks and Benefits

To demonstrate the relative benefits of warfarin plus aspirin for individual patients at different degrees of risk, we calculated the number of myocardial infarctions, strokes, and major bleeding episodes expected to result from aspirin therapy, with or without warfarin, for 9 combinations of cardiovascular and bleeding risk. We calculated events in each risk group taking warfarin plus aspirin by multiplying the rate for the corresponding group of patients taking aspirin by the rate ratio derived from the meta-analysis. The absolute differences between these rates represent the number of myocardial infarctions and strokes prevented by adding warfarin to aspirin. Because the timing of events may be important in treatment decisions, we calculated outcomes at 3 months and 1 year. On the basis of 5059 patients in the Combination Hemotherapy and Mortality Prevention (CHAMP) study (16), we estimated that 51% of myocardial infarctions, 54% of strokes, and 50% of bleeding episodes in the first year after acute myocardial infarction would occur in the first 3 months. Event rates for all 3 outcomes continue to decrease over time. Thus, considering events in the first 2 years after an acute coronary syndrome, approximately 70% of all outcomes occur in the first year. To directly compare event rates across studies of differing duration, we converted all results into first-year rates by using the proportions just described.

Cardiovascular Risk

Many published instruments are available for determining short- and long-term risk for reinfarction, stroke, and mortality. To demonstrate the clinical usefulness of estimating both cardiovascular and bleeding risk before prescribing warfarin, we chose clinical examples of low-, medium-, and high-risk patients. We derived our estimates of the rates for recurrent myocardial infarction and stroke for patients receiving aspirin by using the computed hazard ratios from a large population-based study of 2700 patients surviving hospitalization after a first myocardial infarction and followed for an average of 3.4 years (26). We chose this study for its large size, long follow-up period, emphasis on easily measured clinical predictors, and inclusion of stroke as an outcome. The following variables were associated with increased risk for recurrent myocardial infarction and stroke: age, treated diabetes, chronic congestive heart failure, angina, and serum creatinine level greater than 123.76 µmol/L (>1.4 mg/dL). We created examples of low-, medium-, and high-risk patients by applying the hazard ratios for specific risk variables to a baseline risk of 49 per 1000 patient-years of observation. Infarction rates per 1000 patient-years were 40 for a low-risk patient (no risk factors), 82 for a medium-risk patient (for example, diabetes and serum creatinine level >123.76 µmol/L [>1.4 mg/dL]), and 188 for a high-risk patient (for example, diabetes and congestive heart failure). Stroke rates for the same patients were 13, 32, and 79, respectively. Other risk stratification tools, based on the Thrombolysis In Myocardial Infarction (TIMI II) (27), Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico (GISSI) (28), Secondary Prevention Reinfarction Israeli Nifedipine Trial (SPRINT) (29), or Global Registry of Acute Coronary Events (GRACE) (30) studies, produce similar ranges of low-, medium-, and high-risk patients. A detailed calculator based on the GRACE model is available at http://www.outcomes-umassmed.org/grace.

Bleeding Risk

Several instruments are also available for predicting bleeding risk for patients taking warfarin (3134). We chose examples of low, medium, and high risk for bleeding by using the Outpatient Bleeding Risk Index devised by Landefeld and Goldman (35), which is the only prediction tool prospectively validated in clinical practice (3637). Landefeld and Goldman identified 5 independent risk factors for major bleeding in outpatients: age 65 years or older, history of stroke, history of gastrointestinal bleeding, a specific comorbid condition (renal insufficiency, recent myocardial infarction, or severe anemia), and atrial fibrillation. Incidence of major bleeding in 2 prospective validation sets in the first 12 months was 1% for low-risk patients (no risk factors), 7% for medium-risk patients (1 or 2 risk factors), and 30% for high-risk patients (≥3 risk factors) (3637). Approximately half of all bleeding events occurred in the first 3 months of therapy. We derived predicted rates of bleeding with aspirin alone by dividing the bleeding rates with warfarin and aspirin by the relative risk for warfarin plus aspirin versus aspirin. The difference between these rates represents the absolute number of bleeding episodes attributable to the addition of warfarin.

Study Selection

The initial search yielded 656 articles (Appendix Figure 1). Ten studies met the inclusion criteria, involving a total of 5938 patients (11 334 patient-years). All studies reported rates for myocardial infarction and major and minor bleeding. Nine studies reported rates for intracerebral hemorrhage and death, 8 studies reported revascularization rates, and 7 studies reported rates of ischemic stroke.

Study Design

Appendix Table 1 shows the study designs. There was a mix of large and small studies, with 3 studies including more than 600 patients. Follow-up ranged from 3 months to 4 years; most studies lasted 12 months or less. Aspirin dose varied from 80 to 325 mg daily. Target INR for most studies was 2.0 to 2.5. All studies were intention-to-treat analyses, and compliance measured by target INR achieved ranged from 2.0 to 3.0. All studies used proper randomization techniques and had end points adjudicated by investigators blinded to treatment allocation. Because of the difficulty in maintaining placebo warfarin therapy, only 2 studies were double-blind. Seven studies had greater than 99% clinical follow-up, and all studies had follow-up of at least 90%.

Myocardial Infarction

The annualized rate of myocardial infarction in the aspirin group ranged from 0.03 to 0.93 (Table 1). Nine of 10 studies found a risk reduction attributable to warfarin, but only 2 studies were sufficiently powered for the reduction to reach statistical significance. Reductions in relative risk ranged from 29% to 100%, with an overall risk reduction of 44% (Figure 1). Excluding the 2 largest studies had little effect on the risk reduction, which increased to 45% (95% CI, 18% to 63%). Event-free survival curves continued to diverge for at least 5.5 years of therapy. Pairwise correlation analysis suggested that studies showing greater risk reductions with warfarin therapy tended to have more bleeding complications as well (r = 0.7; P < 0.036).

Table Jump PlaceholderTable 1.  Baseline Events and Rates for 6 Outcomes in the Aspirin and Combination Aspirin and Warfarin Groups
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Figure 1.
Forest plot showing rate ratios of myocardial infarction for warfarin plus aspirin compared with aspirin alone.

APRICOT-2 = Antithrombotics in the Prevention of Reocclusion In Coronary Thrombolysis-2; ASPECT-2 = Antithrombotics in the Secondary Prevention of Events in Coronary Thrombosis-2; ATACS = Antithrombotic Therapy in Acute Coronary Syndromes; OASIS = Organization to Assess Strategies for Ischemic Syndromes; WARIS II = Warfarin, Aspirin, Reinfarction Study.

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Stroke

The annualized risk for ischemic stroke in the aspirin group ranged from 0.0 to 0.08, with a weighted average of 0.008. All 5 studies in which at least 1 stroke was reported found a risk reduction for the warfarin plus aspirin group, but only 1 risk reduction was statistically significant (Figure 2). Reductions in relative risk ranged from 50% to 100%, with an overall risk reduction of 54% (CI, 23% to 73%). Removing the largest study improved the risk reduction to 82% (CI, −1% to 97%).

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Figure 2.
Forest plot showing rate ratios of ischemic stroke for warfarin plus aspirin compared with aspirin alone.

Studies with excluded rate ratios had no events in either group. ASPECT-2 = Antithrombotics in the Secondary Prevention of Events in Coronary Thrombosis-2; OASIS = Organization to Assess Strategies for Ischemic Syndromes; WARIS II = Warfarin, Aspirin, Reinfarction Study.

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Hemorrhagic strokes were counted separately and included in the estimates of major bleeding. Overall, 4 hemorrhagic strokes occurred in the warfarin group and 1 occurred in the aspirin group, translating to 1 additional intracranial hemorrhage per 1800 patient-years of combined anticoagulation.

Revascularization

The annualized risk for revascularization ranged from 0.076 to 1.3. Five of 7 studies showed decreased rates of percutaneous transluminal coronary angioplasty or coronary artery bypass grafting for patients receiving warfarin therapy, but only 1 rate reached statistical significance (Appendix Figure 2). Hazard ratios ranged from 0.51 to 1.70, with an overall relative risk reduction of 20% (CI, 5% to 33%).

Death

No study showed a statistical difference in mortality (Figure 3). The combined studies showed a 4% decrease in overall mortality in the warfarin group, but this did not reach statistical significance.

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Figure 3.
Forest plot showing rate ratios of death for warfarin plus aspirin compared with aspirin alone.

The study with an excluded rate ratio had no events in either group. APRICOT-2 = Antithrombotics in the Prevention of Reocclusion In Coronary Thrombolysis-2; ASPECT-2 = Antithrombotics in the Secondary Prevention of Events in Coronary Thrombosis-2; ATACS = Antithrombotic Therapy in Acute Coronary Syndromes; OASIS = Organization to Assess Strategies for Ischemic Syndromes; WARIS II = Warfarin, Aspirin, Reinfarction Study.

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Bleeding

Nine studies showed an increased risk for major bleeding associated with warfarin therapy (Figure 4). The annualized risk for major bleeding in the warfarin group ranged from 0.6% to 18.0%, with an overall risk of 1.5%. The relative risk for major bleeding with warfarin compared with aspirin was 2.5 (CI, 1.7 to 3.7). The relative risk for minor bleeding was 2.6 (CI, 2.0 to 3.3) (Appendix Figure 3).

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Figure 4.
Forest plot showing rate ratios of major bleeding for warfarin plus aspirin compared with aspirin alone.

The study with an excluded rate ratio had no events in either group. APRICOT-2 = Antithrombotics in the Prevention of Reocclusion In Coronary Thrombolysis-2; ASPECT-2 = Antithrombotics in the Secondary Prevention of Events in Coronary Thrombosis-2; ATACS = Antithrombotic Therapy in Acute Coronary Syndromes; OASIS = Organization to Assess Strategies for Ischemic Syndromes; WARIS II = Warfarin, Aspirin, Reinfarction Study.

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Study Diagnostics

The Mantel–Haenszel test showed no statistically significant heterogeneity for any end point among the studies (Appendix Table 2). An influence analysis excluding 1 study at a time and finally the 2 largest studies simultaneously (WARIS II [12] and OASIS [13]) had no substantial effect on the summary rate ratio. No evidence suggested publication bias for any end point, with the exception of stroke, and only the Egger regression asymmetry test suggested some bias. Stroke was not a primary end point in any trial.

Timing and Risk Groups

As expected, studies lasting 3 months had the highest rates of myocardial infarction, stroke, and bleeding. Rates for all 3 outcomes decreased with increasing study duration. Projected first-year rates of myocardial infarction and major bleeding episodes varied considerably among the studies, but relative risk reductions from warfarin were the same for all outcomes, regardless of study duration or indication (Table 2).

Table Jump PlaceholderTable 2.  Projected 1-Year Rates for Myocardial Infarction and Bleeding, by Indication
Table Jump PlaceholderAppendix Table 1.  Design of Trials Included in the Meta-Analysis
Table Jump PlaceholderAppendix Table 2.  Tests of Heterogeneity

Figure 5 shows the cardiovascular events averted and excess bleeding episodes caused by adding warfarin to aspirin for 1 year for different combinations of cardiovascular and bleeding risk. For most studies, the benefit of warfarin clearly outweighs the risk. Individuals at the highest risk for cardiovascular events (for example, a patient with diabetes and congestive heart failure) could avert 83 myocardial infarctions and 43 strokes per 1000 patient-years of warfarin therapy, while those at the lowest cardiovascular risk would avoid 18 myocardial infarctions and 7 strokes. Regardless of cardiovascular risk, adding warfarin to aspirin will cause an excess of 6 to 180 major bleeding episodes per 1000 patient-years, depending on the individual's bleeding risk. Because rates for all outcomes decrease over time, approximately half of the benefit and risk in the first year of therapy accrues in the first 3 months. Conversely, both benefits and risks are reduced by 60% in the second year of therapy.

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Figure 5.
Predicted myocardial infarctions (MIs) and thrombotic strokes averted and excess bleeding episodes caused in 1000 patients as a result of adding warfarin to aspirin for 1 year, stratified by bleeding and MI risk.

Numbers of cardiovascular events are the differences between the MI rates (aspirin rate − aspirin rate × risk ratio) plus the difference in stroke rates (baseline rates not shown) multiplied by 1000 patient-years. The number of bleeding episodes represents the difference in bleeding rates (combination rate − combination rate/risk ratio for major bleeding episode) multiplied by 1000. Letters and corresponding dots represent actual combinations of bleeding and cardiovascular risk from Table 2. The shaded area in the parallelogram represents unfavorable risk or benefit. APRICOT-2 = Antithrombotics in the Prevention of Reocclusion In Coronary Thrombolysis-2; ASPECT-2 = Antithrombotics in the Secondary Prevention of Events in Coronary Thrombosis-2; ATACS = Antithrombotic Therapy in Acute Coronary Syndromes; OASIS = Organization to Assess Strategies for Ischemic Syndromes; WARIS II = Warfarin, Aspirin, Reinfarction Study.

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Appendix Figure 2.
Forest plot showing rate ratios of percutaneous transluminal coronary angioplasty or coronary artery bypass grafting for warfarin plus aspirin compared with aspirin alone.

The study with an excluded rate ratio had no events in either group. APRICOT-2 = Antithrombotics in the Prevention of Reocclusion In Coronary Thrombolysis-2; ASPECT-2 = Antithrombotics in the Secondary Prevention of Events in Coronary Thrombosis-2; ATACS = Antithrombotic Therapy in Acute Coronary Syndromes; OASIS = Organization to Assess Strategies for Ischemic Syndromes; WARIS II = Warfarin, Aspirin, Reinfarction Study.

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Appendix Figure 3.
Forest plot showing rate ratios of minor bleeding for warfarin plus aspirin compared with aspirin alone.

APRICOT-2 = Antithrombotics in the Prevention of Reocclusion In Coronary Thrombolysis-2; ASPECT-2 = Antithrombotics in the Secondary Prevention of Events in Coronary Thrombosis-2; ATACS = Antithrombotic Therapy in Acute Coronary Syndromes; OASIS = Organization to Assess Strategies for Ischemic Syndromes; WARIS II = Warfarin, Aspirin, Reinfarction Study.

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Our meta-analysis bolsters the finding that after an acute coronary syndrome, warfarin plus aspirin decreases the rate of myocardial infarction or stroke more than aspirin alone. Although the probability of major bleeding is also increased, the benefits far outweigh the risks for many patients. For individuals at high cardiovascular risk but at low risk for bleeding (for example, a 58-year-old man with diabetes and congestive heart failure), adding warfarin to standard aspirin therapy could avert 83 myocardial infarctions and 43 strokes per 1000 patient-years of therapy at a cost of just 6 major bleeding episodes. The number needed to treat for 3 months to prevent 1 major cardiovascular event is 16, while the number needed to harm for the same period is 333. Even when it is not possible to fully separate bleeding risk from cardiovascular risk, warfarin still seems beneficial, as long as patients at the highest risk for bleeding are excluded from therapy.

We found no difference in relative risk reduction over time, but the absolute rates of all end points decrease steadily. As a result, the greatest benefits and risks occur in the first 3 months of therapy. Still, the curves for the combined end points continue to diverge for at least 5 years. For patients at high cardiovascular risk, the gains beyond 1 year are likely to be substantial, whereas those at low risk may choose to stop therapy after 3 months.

Despite an almost 3-fold increase in major bleeding, overall bleeding rates among patients taking warfarin and aspirin during 5500 patient-years of observation were low, similar to the rate seen in patients with atrial fibrillation or deep venous thrombosis (4243). The low rate in WARIS II (0.6% per year) may have resulted from the intention-to-treat design (12). Some patients presumably did not have bleeding episodes because they received inadequate anticoagulation or had stopped taking warfarin altogether. An annual bleeding rate of 1.5% is probably more representative of adherent patients. Similarly, adherent patients could expect fewer myocardial infarctions and strokes than were seen in the intention-to-treat analysis, as was found in both the OASIS trial (13) and the Thrombosis Prevention Trial (44) when each was analyzed according to adherence to warfarin.

Our study has several limitations. Although the designs of the individual studies were similar, they were not identical. All meta-analyses contain some degree of heterogeneity, as do multicenter randomized trials. Despite minor variations in eligibility criteria, study duration, and aspirin dosage, the studies selected were remarkably similar. Although 2 large trials accounted for most patients, without these, the relative risk reduction for myocardial infarction was almost identical, emphasizing the homogeneity of the trials.

We chose to include only the compliant countries from the OASIS trial (13) because including countries where fewer than 70% of the patients took the therapy would bias our results heavily in favor of the null hypothesis. Although this violates the strictest interpretation of intention to treat, the designation of compliant countries was made only 35 days into the study and without examining clinical outcomes. Because entire countries were excluded, patient-specific bias could not occur. It is also encouraging that the effect size seen in compliant countries from OASIS (13) was almost identical to that seen in WARIS II (12).

All studies were conducted in the 1990s before coronary artery stenting became widespread. As a result of several comparative trials, warfarin is not considered a standard of care in stented patients (4547). However, outside of large metropolitan areas in the United States, most patients with myocardial infarction still do not undergo stenting. Moreover, none of these studies examined long-term anticoagulation after the initial stenting period.

Finally, we assumed that the decrease in relative risk for myocardial infarction and stroke would be consistent across risk groups. Although this assumption has been found to be true with clopidogrel (48), simvastatin (49), and aspirin (50), additional trials of moderate- to high-risk patients, including those with diabetes and heart failure, would be helpful, especially because warfarin may not benefit diabetic patients (51) and aspirin may be harmful in patients with heart failure (52).

Despite the clear benefits demonstrated in WARIS II (12), no recommendations have been made for use of warfarin to prevent reinfarction and stroke. The most recent American College of Cardiology/American Heart Association guidelines (53) for treatment of myocardial infarction were published before the results of WARIS II were available. Three general objections have been raised to warfarin: The increased bleeding risk offsets any potential cardiovascular benefit (18), the cardiovascular gains are too small to justify the inconvenience of warfarin therapy (19), and studies have not demonstrated a mortality benefit (54).

On the basis of our analysis, the benefits of warfarin should outweigh the harms for most patients. Even those for whom the absolute numbers of major bleeding episodes and cardiovascular events are similar may benefit because cardiovascular events are usually more serious than bleeding events. Approximately 25% of reinfarctions are fatal, and among patients who survive, risk for congestive heart failure and disability increases. Ischemic stroke is even more likely to result in permanent disability. An atrial fibrillation study showed that warfarin therapy reduces not only the frequency but also the severity of strokes (55). Apart from intracranial hemorrhage, bleeding episodes rarely result in long-term sequelae. In our meta-analysis, warfarin resulted in 1 excess nonfatal intracranial hemorrhage per 1800 patient-years of therapy.

While the absolute benefit to participants in WARIS II was small because of their low overall risk (3% per year for myocardial infarction and 1% per year for stroke), patients were mostly young and nondiabetic and had Q-wave infarctions with preserved left ventricular function. Our study demonstrated that warfarin produces the same relative risk reduction in high-risk patients, such as those in the Antithrombotic Therapy in Acute Coronary Syndromes (ATACS) (3839) and Antithrombotics in the Prevention of Reocclusion In Coronary Thrombolysis-2 (APRICOT-2) (11) studies, yielding considerable absolute benefit. Whether this benefit is worth the inconvenience of frequent blood draws and dietary restrictions is a decision that is best left to individual patients and their physicians.

Despite decreasing myocardial infarctions and strokes, warfarin had no demonstrable mortality benefit. However, mortality in all groups was relatively low, making it difficult to detect a difference. Moreover, study durations were short and mortality due to congestive heart failure may be delayed several years. A similar reduction in nonfatal myocardial infarction was shown in the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial (56), which also did not demonstrate a mortality benefit among 12 500 patients who were followed for up to 1 year.

Like insulin, warfarin engenders resistance in primary care physicians and patients alike. Despite ample evidence for more than a decade that warfarin reduces stroke in atrial fibrillation, as well as clear guidelines from the American College of Cardiology/American Heart Association, only one half of eligible patients receive warfarin therapy (57), an increase from one third in 1993 (58). In the face of similar resistance, acceptance of warfarin in patients with the acute coronary syndrome may take years, by which time less cumbersome, albeit more expensive, alternatives should be available. Routine use of clopidogrel for at least 9 months is quickly becoming the standard of care, despite studies that found the practice to be non–cost-effective (5960). Moreover, the 23% reduction in myocardial infarction shown with clopidogrel is considerably smaller than the 44% reduction shown with warfarin (56). Although newer oral anticoagulants that do not require monitoring may someday replace warfarin, the benefits of warfarin therapy are available to patients today.

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Fiore LD, Ezekowitz MD, Brophy MT, Lu D, Sacco J, Peduzzi P. et al.  Department of Veterans Affairs Cooperative Studies Program Clinical Trial comparing combined warfarin and aspirin with aspirin alone in survivors of acute myocardial infarction: primary results of the CHAMP study. Circulation. 2002; 105:557-63. PubMed
 
Anand SS, Yusuf S.  Oral anticoagulant therapy in patients with coronary artery disease: a meta-analysis. JAMA. 1999; 282:2058-67. PubMed
 
Topol EJ.  Warfarin alone or with aspirin was superior to aspirin alone after acute myocardial infarction but increased bleeding. ACP J Club. 2003; 138:34. PubMed
 
Pullicino P, Thompson JL.  Warfarin, aspirin, or both after myocardial infarction [Letter]. N Engl J Med. 2003;348:256-7; author reply 256-7. [PMID: 12529470]
 
Leon MB, Baim DS, Popma JJ, Gordon PC, Cutlip DE, Ho KK. et al.  A clinical trial comparing three antithrombotic-drug regimens after coronary-artery stenting. Stent Anticoagulation Restenosis Study Investigators. N Engl J Med. 1998; 339:1665-71. PubMed
 
Anand SS, Yusuf S, Pogue J, Weitz JI, Flather M.  Long-term oral anticoagulant therapy in patients with unstable angina or suspected non-Q-wave myocardial infarction: organization to assess strategies for ischemic syndromes (OASIS) pilot study results. Circulation. 1998; 98:1064-70. PubMed
 
Huynh T, Théroux P, Bogaty P, Nasmith J, Solymoss S.  Aspirin, warfarin, or the combination for secondary prevention of coronary events in patients with acute coronary syndromes and prior coronary artery bypass surgery. Circulation. 2001; 103:3069-74. PubMed
 
DerSimonian R, Laird N.  Meta-analysis in clinical trials. Control Clin Trials. 1986; 7:177-88. PubMed
 
Begg CB, Mazumdar M.  Operating characteristics of a rank correlation test for publication bias. Biometrics. 1994; 50:1088-101. PubMed
 
Egger M, Davey Smith G, Schneider M, Minder C.  Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997; 315:629-34. PubMed
 
Kaplan RC, Heckbert SR, Furberg CD, Psaty BM.  Predictors of subsequent coronary events, stroke, and death among survivors of first hospitalized myocardial infarction. J Clin Epidemiol. 2002; 55:654-64. PubMed
 
Wiviott SD, Morrow DA, Frederick PD, Giugliano RP, Gibson CM, McCabe CH. et al.  Performance of the thrombolysis in myocardial infarction risk index in the National Registry of Myocardial Infarction-3 and -4: a simple index that predicts mortality in ST-segment elevation myocardial infarction. J Am Coll Cardiol. 2004; 44:783-9. PubMed
 
Marchioli R, Avanzini F, Barzi F, Chieffo C, Di Castelnuovo A, Franzosi MG. et al.  Assessment of absolute risk of death after myocardial infarction by use of multiple-risk-factor assessment equations: GISSI-Prevenzione mortality risk chart. Eur Heart J. 2001; 22:2085-103. PubMed
 
Kornowski R, Goldbourt U, Boyko V, Behar S.  Clinical predictors of reinfarction among men and women after a first myocardial infarction. SPRINT Study Group. Secondary Prevention Reinfarction Israeli Nifedipine Trial. Cardiology. 1995; 86:163-8. PubMed
 
Eagle KA, Lim MJ, Dabbous OH, Pieper KS, Goldberg RJ, Van de Werf F. et al.  A validated prediction model for all forms of acute coronary syndrome: estimating the risk of 6-month postdischarge death in an international registry. JAMA. 2004; 291:2727-33. PubMed
 
Kuijer PM, Hutten BA, Prins MH, Büller HR.  Prediction of the risk of bleeding during anticoagulant treatment for venous thromboembolism. Arch Intern Med. 1999; 159:457-60. PubMed
 
Gitter MJ, Jaeger TM, Petterson TM, Gersh BJ, Silverstein MD.  Bleeding and thromboembolism during anticoagulant therapy: a population-based study in Rochester, Minnesota. Mayo Clin Proc. 1995; 70:725-33. PubMed
 
van der Meer FJ, Rosendaal FR, Vandenbroucke JP, Briët E.  Assessment of a bleeding risk index in two cohorts of patients treated with oral anticoagulants. Thromb Haemost. 1996; 76:12-6. PubMed
 
McMahan DA, Smith DM, Carey MA, Zhou XH.  Risk of major hemorrhage for outpatients treated with warfarin. J Gen Intern Med. 1998; 13:311-6. PubMed
 
Landefeld CS, Goldman L.  Major bleeding in outpatients treated with warfarin: incidence and prediction by factors known at the start of outpatient therapy. Am J Med. 1989; 87:144-52. PubMed
 
Wells PS, Forgie MA, Simms M, Greene A, Touchie D, Lewis G. et al.  The outpatient bleeding risk index: validation of a tool for predicting bleeding rates in patients treated for deep venous thrombosis and pulmonary embolism. Arch Intern Med. 2003; 163:917-20. PubMed
 
Beyth RJ, Quinn LM, Landefeld CS.  Prospective evaluation of an index for predicting the risk of major bleeding in outpatients treated with warfarin. Am J Med. 1998; 105:91-9. PubMed
 
Cohen M, Adams PC, Parry G, Xiong J, Chamberlain D, Wieczorek I. et al.  Combination antithrombotic therapy in unstable rest angina and non-Q-wave infarction in nonprior aspirin users. Primary end points analysis from the ATACS trial. Antithrombotic Therapy in Acute Coronary Syndromes Research Group. Circulation. 1994; 89:81-8. PubMed
 
Cohen M, Adams PC, 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; 66:1287-92. PubMed
 
Williams MJ, Morison IM, Parker JH, Stewart RA.  Progression of the culprit lesion in unstable coronary artery disease with warfarin and aspirin versus aspirin alone: preliminary study. J Am Coll Cardiol. 1997; 30:364-9. PubMed
 
Zibaeenezhad MJ, Mowla A, Sorbi MH.  Warfarin and aspirin versus aspirin alone in patients with acute myocardial infarction: a pilot study. Angiology. 2004; 55:17-20. PubMed
 
.  Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation. Analysis of pooled data from five randomized controlled trials. Arch Intern Med. 1994; 154:1449-57. PubMed
 
Palareti G, Leali N, Coccheri S, Poggi M, Manotti C, D'Angelo A. et al.  Bleeding complications of oral anticoagulant treatment: an inception-cohort, prospective collaborative study (ISCOAT). Italian Study on Complications of Oral Anticoagulant Therapy. Lancet. 1996; 348:423-8. PubMed
 
Rudnicka AR, Ashby D, Brennan P, Meade T.  Thrombosis prevention trial: compliance with warfarin treatment and investigation of a retained effect. Arch Intern Med. 2003; 163:1454-60. PubMed
 
Schömig A, Neumann FJ, Kastrati A, Schühlen H, Blasini R, Hadamitzky M. et al.  A randomized comparison of antiplatelet and anticoagulant therapy after the placement of coronary-artery stents. N Engl J Med. 1996; 334:1084-9. PubMed
 
Bertrand ME, Legrand V, Boland J, Fleck E, Bonnier J, Emmanuelson H. et al.  Randomized multicenter comparison of conventional anticoagulation versus antiplatelet therapy in unplanned and elective coronary stenting. The full anticoagulation versus aspirin and ticlopidine (fantastic) study. Circulation. 1998; 98:1597-603. PubMed
 
Leon MB, Baim DS, Popma JJ, Gordon PC, Cutlip DE, Ho KK. et al.  A clinical trial comparing three antithrombotic-drug regimens after coronary-artery stenting. Stent Anticoagulation Restenosis Study Investigators. N Engl J Med. 1998; 339:1665-71. PubMed
 
Budaj A, Yusuf S, Mehta SR, Fox KA, Tognoni G, Zhao F. et al.  Benefit of clopidogrel in patients with acute coronary syndromes without ST-segment elevation in various risk groups. Circulation. 2002; 106:1622-6. PubMed
 
.  MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002; 360:7-22. PubMed
 
.  Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ. 2002; 324:71-86. PubMed
 
Smith P, Hurlen M, Abdelnoor M, Arnesen H.  No benefit by warfarin in post-MI patients with diabetes mellitus [Abstract]. Pathophysiol Haemost Thromb. 2002; 32:S76.
 
Cleland JG, Findlay I, Jafri S, Sutton G, Falk R, Bulpitt C. et al.  The Warfarin/Aspirin Study in Heart failure (WASH): a randomized trial comparing antithrombotic strategies for patients with heart failure. Am Heart J. 2004; 148:157-64. PubMed
 
Ryan TJ, Antman EM, Brooks NH, Califf RM, Hillis LD, Hiratzka LF. et al.  1999 update: ACC/AHA guidelines for the management of patients with acute myocardial infarction: executive summary and recommendations: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Acute Myocardial Infarction). Circulation. 1999; 100:1016-30. PubMed
 
Hoey J.  Warfarin, acetylsalicylic acid or both? CMAJ. 2002; 167:1036. PubMed
 
Hylek EM, Go AS, Chang Y, Jensvold NG, Henault LE, Selby JV. et al.  Effect of intensity of oral anticoagulation on stroke severity and mortality in atrial fibrillation. N Engl J Med. 2003; 349:1019-26. PubMed
 
Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK. et al.  Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001; 345:494-502. PubMed
 
Go AS, Hylek EM, Borowsky LH, Phillips KA, Selby JV, Singer DE.  Warfarin use among ambulatory patients with nonvalvular atrial fibrillation: the anticoagulation and risk factors in atrial fibrillation (ATRIA) study. Ann Intern Med. 1999; 131:927-34. PubMed
 
Stafford RS, Singer DE.  National patterns of warfarin use in atrial fibrillation. Arch Intern Med. 1996; 156:2537-41. PubMed
 
Gaspoz JM, Coxson PG, Goldman PA, Williams LW, Kuntz KM, Hunink MG. et al.  Cost effectiveness of aspirin, clopidogrel, or both for secondary prevention of coronary heart disease. N Engl J Med. 2002; 346:1800-6. PubMed
 
Marshall T.  Coronary heart disease prevention: insights from modelling incremental cost effectiveness. BMJ. 2003; 327:1264. PubMed
 

Figures

Grahic Jump Location
Figure 1.
Forest plot showing rate ratios of myocardial infarction for warfarin plus aspirin compared with aspirin alone.

APRICOT-2 = Antithrombotics in the Prevention of Reocclusion In Coronary Thrombolysis-2; ASPECT-2 = Antithrombotics in the Secondary Prevention of Events in Coronary Thrombosis-2; ATACS = Antithrombotic Therapy in Acute Coronary Syndromes; OASIS = Organization to Assess Strategies for Ischemic Syndromes; WARIS II = Warfarin, Aspirin, Reinfarction Study.

Grahic Jump Location
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Figure 2.
Forest plot showing rate ratios of ischemic stroke for warfarin plus aspirin compared with aspirin alone.

Studies with excluded rate ratios had no events in either group. ASPECT-2 = Antithrombotics in the Secondary Prevention of Events in Coronary Thrombosis-2; OASIS = Organization to Assess Strategies for Ischemic Syndromes; WARIS II = Warfarin, Aspirin, Reinfarction Study.

Grahic Jump Location
Grahic Jump Location
Figure 3.
Forest plot showing rate ratios of death for warfarin plus aspirin compared with aspirin alone.

The study with an excluded rate ratio had no events in either group. APRICOT-2 = Antithrombotics in the Prevention of Reocclusion In Coronary Thrombolysis-2; ASPECT-2 = Antithrombotics in the Secondary Prevention of Events in Coronary Thrombosis-2; ATACS = Antithrombotic Therapy in Acute Coronary Syndromes; OASIS = Organization to Assess Strategies for Ischemic Syndromes; WARIS II = Warfarin, Aspirin, Reinfarction Study.

Grahic Jump Location
Grahic Jump Location
Figure 4.
Forest plot showing rate ratios of major bleeding for warfarin plus aspirin compared with aspirin alone.

The study with an excluded rate ratio had no events in either group. APRICOT-2 = Antithrombotics in the Prevention of Reocclusion In Coronary Thrombolysis-2; ASPECT-2 = Antithrombotics in the Secondary Prevention of Events in Coronary Thrombosis-2; ATACS = Antithrombotic Therapy in Acute Coronary Syndromes; OASIS = Organization to Assess Strategies for Ischemic Syndromes; WARIS II = Warfarin, Aspirin, Reinfarction Study.

Grahic Jump Location
Grahic Jump Location
Figure 5.
Predicted myocardial infarctions (MIs) and thrombotic strokes averted and excess bleeding episodes caused in 1000 patients as a result of adding warfarin to aspirin for 1 year, stratified by bleeding and MI risk.

Numbers of cardiovascular events are the differences between the MI rates (aspirin rate − aspirin rate × risk ratio) plus the difference in stroke rates (baseline rates not shown) multiplied by 1000 patient-years. The number of bleeding episodes represents the difference in bleeding rates (combination rate − combination rate/risk ratio for major bleeding episode) multiplied by 1000. Letters and corresponding dots represent actual combinations of bleeding and cardiovascular risk from Table 2. The shaded area in the parallelogram represents unfavorable risk or benefit. APRICOT-2 = Antithrombotics in the Prevention of Reocclusion In Coronary Thrombolysis-2; ASPECT-2 = Antithrombotics in the Secondary Prevention of Events in Coronary Thrombosis-2; ATACS = Antithrombotic Therapy in Acute Coronary Syndromes; OASIS = Organization to Assess Strategies for Ischemic Syndromes; WARIS II = Warfarin, Aspirin, Reinfarction Study.

Grahic Jump Location
Grahic Jump Location
Appendix Figure 2.
Forest plot showing rate ratios of percutaneous transluminal coronary angioplasty or coronary artery bypass grafting for warfarin plus aspirin compared with aspirin alone.

The study with an excluded rate ratio had no events in either group. APRICOT-2 = Antithrombotics in the Prevention of Reocclusion In Coronary Thrombolysis-2; ASPECT-2 = Antithrombotics in the Secondary Prevention of Events in Coronary Thrombosis-2; ATACS = Antithrombotic Therapy in Acute Coronary Syndromes; OASIS = Organization to Assess Strategies for Ischemic Syndromes; WARIS II = Warfarin, Aspirin, Reinfarction Study.

Grahic Jump Location
Grahic Jump Location
Appendix Figure 3.
Forest plot showing rate ratios of minor bleeding for warfarin plus aspirin compared with aspirin alone.

APRICOT-2 = Antithrombotics in the Prevention of Reocclusion In Coronary Thrombolysis-2; ASPECT-2 = Antithrombotics in the Secondary Prevention of Events in Coronary Thrombosis-2; ATACS = Antithrombotic Therapy in Acute Coronary Syndromes; OASIS = Organization to Assess Strategies for Ischemic Syndromes; WARIS II = Warfarin, Aspirin, Reinfarction Study.

Grahic Jump Location

Tables

Table Jump PlaceholderTable 1.  Baseline Events and Rates for 6 Outcomes in the Aspirin and Combination Aspirin and Warfarin Groups
Table Jump PlaceholderTable 2.  Projected 1-Year Rates for Myocardial Infarction and Bleeding, by Indication
Table Jump PlaceholderAppendix Table 1.  Design of Trials Included in the Meta-Analysis
Table Jump PlaceholderAppendix Table 2.  Tests of Heterogeneity

References

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Kornowski R, Goldbourt U, Zion M, Mandelzweig L, Kaplinsky E, Levo Y. et al.  Predictors and long-term prognostic significance of recurrent infarction in the year after a first myocardial infarction. SPRINT Study Group. Am J Cardiol. 1993; 72:883-8. PubMed
 
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Yusuf S, Mehta SR, Xie C, Ahmed RJ, Xavier D, Pais P. et al.  Effects of reviparin, a low-molecular-weight heparin, on mortality, reinfarction, and strokes in patients with acute myocardial infarction presenting with ST-segment elevation. JAMA. 2005; 293:427-35. PubMed
 
van Es RF, Jonker JJ, Verheugt FW, Deckers JW, Grobbee DE.  Aspirin and coumadin after acute coronary syndromes (the ASPECT-2 study): a randomised controlled trial. Lancet. 2002; 360:109-13. PubMed
 
Brouwer MA, van den Bergh PJ, Aengevaeren WR, Veen G, Luijten HE, Hertzberger DP. et al.  Aspirin plus coumarin versus aspirin alone in the prevention of reocclusion after fibrinolysis for acute myocardial infarction: results of the Antithrombotics in the Prevention of Reocclusion In Coronary Thrombolysis (APRICOT)-2 Trial. Circulation. 2002; 106:659-65. PubMed
 
Hurlen M, Abdelnoor M, Smith P, Erikssen J, Arnesen H.  Warfarin, aspirin, or both after myocardial infarction. N Engl J Med. 2002; 347:969-74. PubMed
 
.  Effects of long-term, moderate-intensity oral anticoagulation in addition to aspirin in unstable angina. The Organization to Assess Strategies for Ischemic Syndromes (OASIS) Investigators. J Am Coll Cardiol. 2001; 37:475-84. PubMed
 
.  Thrombosis prevention trial: randomised trial of low-intensity oral anticoagulation with warfarin and low-dose aspirin in the primary prevention of ischaemic heart disease in men at increased risk. The Medical Research Council's General Practice Research Framework. Lancet. 1998; 351:233-41. PubMed
 
.  Randomised double-blind trial of fixed low-dose warfarin with aspirin after myocardial infarction. Coumadin Aspirin Reinfarction Study (CARS) Investigators. Lancet. 1997; 350:389-96. PubMed
 
Fiore LD, Ezekowitz MD, Brophy MT, Lu D, Sacco J, Peduzzi P. et al.  Department of Veterans Affairs Cooperative Studies Program Clinical Trial comparing combined warfarin and aspirin with aspirin alone in survivors of acute myocardial infarction: primary results of the CHAMP study. Circulation. 2002; 105:557-63. PubMed
 
Anand SS, Yusuf S.  Oral anticoagulant therapy in patients with coronary artery disease: a meta-analysis. JAMA. 1999; 282:2058-67. PubMed
 
Topol EJ.  Warfarin alone or with aspirin was superior to aspirin alone after acute myocardial infarction but increased bleeding. ACP J Club. 2003; 138:34. PubMed
 
Pullicino P, Thompson JL.  Warfarin, aspirin, or both after myocardial infarction [Letter]. N Engl J Med. 2003;348:256-7; author reply 256-7. [PMID: 12529470]
 
Leon MB, Baim DS, Popma JJ, Gordon PC, Cutlip DE, Ho KK. et al.  A clinical trial comparing three antithrombotic-drug regimens after coronary-artery stenting. Stent Anticoagulation Restenosis Study Investigators. N Engl J Med. 1998; 339:1665-71. PubMed
 
Anand SS, Yusuf S, Pogue J, Weitz JI, Flather M.  Long-term oral anticoagulant therapy in patients with unstable angina or suspected non-Q-wave myocardial infarction: organization to assess strategies for ischemic syndromes (OASIS) pilot study results. Circulation. 1998; 98:1064-70. PubMed
 
Huynh T, Théroux P, Bogaty P, Nasmith J, Solymoss S.  Aspirin, warfarin, or the combination for secondary prevention of coronary events in patients with acute coronary syndromes and prior coronary artery bypass surgery. Circulation. 2001; 103:3069-74. PubMed
 
DerSimonian R, Laird N.  Meta-analysis in clinical trials. Control Clin Trials. 1986; 7:177-88. PubMed
 
Begg CB, Mazumdar M.  Operating characteristics of a rank correlation test for publication bias. Biometrics. 1994; 50:1088-101. PubMed
 
Egger M, Davey Smith G, Schneider M, Minder C.  Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997; 315:629-34. PubMed
 
Kaplan RC, Heckbert SR, Furberg CD, Psaty BM.  Predictors of subsequent coronary events, stroke, and death among survivors of first hospitalized myocardial infarction. J Clin Epidemiol. 2002; 55:654-64. PubMed
 
Wiviott SD, Morrow DA, Frederick PD, Giugliano RP, Gibson CM, McCabe CH. et al.  Performance of the thrombolysis in myocardial infarction risk index in the National Registry of Myocardial Infarction-3 and -4: a simple index that predicts mortality in ST-segment elevation myocardial infarction. J Am Coll Cardiol. 2004; 44:783-9. PubMed
 
Marchioli R, Avanzini F, Barzi F, Chieffo C, Di Castelnuovo A, Franzosi MG. et al.  Assessment of absolute risk of death after myocardial infarction by use of multiple-risk-factor assessment equations: GISSI-Prevenzione mortality risk chart. Eur Heart J. 2001; 22:2085-103. PubMed
 
Kornowski R, Goldbourt U, Boyko V, Behar S.  Clinical predictors of reinfarction among men and women after a first myocardial infarction. SPRINT Study Group. Secondary Prevention Reinfarction Israeli Nifedipine Trial. Cardiology. 1995; 86:163-8. PubMed
 
Eagle KA, Lim MJ, Dabbous OH, Pieper KS, Goldberg RJ, Van de Werf F. et al.  A validated prediction model for all forms of acute coronary syndrome: estimating the risk of 6-month postdischarge death in an international registry. JAMA. 2004; 291:2727-33. PubMed
 
Kuijer PM, Hutten BA, Prins MH, Büller HR.  Prediction of the risk of bleeding during anticoagulant treatment for venous thromboembolism. Arch Intern Med. 1999; 159:457-60. PubMed
 
Gitter MJ, Jaeger TM, Petterson TM, Gersh BJ, Silverstein MD.  Bleeding and thromboembolism during anticoagulant therapy: a population-based study in Rochester, Minnesota. Mayo Clin Proc. 1995; 70:725-33. PubMed
 
van der Meer FJ, Rosendaal FR, Vandenbroucke JP, Briët E.  Assessment of a bleeding risk index in two cohorts of patients treated with oral anticoagulants. Thromb Haemost. 1996; 76:12-6. PubMed
 
McMahan DA, Smith DM, Carey MA, Zhou XH.  Risk of major hemorrhage for outpatients treated with warfarin. J Gen Intern Med. 1998; 13:311-6. PubMed
 
Landefeld CS, Goldman L.  Major bleeding in outpatients treated with warfarin: incidence and prediction by factors known at the start of outpatient therapy. Am J Med. 1989; 87:144-52. PubMed
 
Wells PS, Forgie MA, Simms M, Greene A, Touchie D, Lewis G. et al.  The outpatient bleeding risk index: validation of a tool for predicting bleeding rates in patients treated for deep venous thrombosis and pulmonary embolism. Arch Intern Med. 2003; 163:917-20. PubMed
 
Beyth RJ, Quinn LM, Landefeld CS.  Prospective evaluation of an index for predicting the risk of major bleeding in outpatients treated with warfarin. Am J Med. 1998; 105:91-9. PubMed
 
Cohen M, Adams PC, Parry G, Xiong J, Chamberlain D, Wieczorek I. et al.  Combination antithrombotic therapy in unstable rest angina and non-Q-wave infarction in nonprior aspirin users. Primary end points analysis from the ATACS trial. Antithrombotic Therapy in Acute Coronary Syndromes Research Group. Circulation. 1994; 89:81-8. PubMed
 
Cohen M, Adams PC, 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; 66:1287-92. PubMed
 
Williams MJ, Morison IM, Parker JH, Stewart RA.  Progression of the culprit lesion in unstable coronary artery disease with warfarin and aspirin versus aspirin alone: preliminary study. J Am Coll Cardiol. 1997; 30:364-9. PubMed
 
Zibaeenezhad MJ, Mowla A, Sorbi MH.  Warfarin and aspirin versus aspirin alone in patients with acute myocardial infarction: a pilot study. Angiology. 2004; 55:17-20. PubMed
 
.  Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation. Analysis of pooled data from five randomized controlled trials. Arch Intern Med. 1994; 154:1449-57. PubMed
 
Palareti G, Leali N, Coccheri S, Poggi M, Manotti C, D'Angelo A. et al.  Bleeding complications of oral anticoagulant treatment: an inception-cohort, prospective collaborative study (ISCOAT). Italian Study on Complications of Oral Anticoagulant Therapy. Lancet. 1996; 348:423-8. PubMed
 
Rudnicka AR, Ashby D, Brennan P, Meade T.  Thrombosis prevention trial: compliance with warfarin treatment and investigation of a retained effect. Arch Intern Med. 2003; 163:1454-60. PubMed
 
Schömig A, Neumann FJ, Kastrati A, Schühlen H, Blasini R, Hadamitzky M. et al.  A randomized comparison of antiplatelet and anticoagulant therapy after the placement of coronary-artery stents. N Engl J Med. 1996; 334:1084-9. PubMed
 
Bertrand ME, Legrand V, Boland J, Fleck E, Bonnier J, Emmanuelson H. et al.  Randomized multicenter comparison of conventional anticoagulation versus antiplatelet therapy in unplanned and elective coronary stenting. The full anticoagulation versus aspirin and ticlopidine (fantastic) study. Circulation. 1998; 98:1597-603. PubMed
 
Leon MB, Baim DS, Popma JJ, Gordon PC, Cutlip DE, Ho KK. et al.  A clinical trial comparing three antithrombotic-drug regimens after coronary-artery stenting. Stent Anticoagulation Restenosis Study Investigators. N Engl J Med. 1998; 339:1665-71. PubMed
 
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Summary for Patients

Benefits and Harms of Warfarin plus Aspirin after Acute Coronary Events

The summary below is from the full report titled “Warfarin plus Aspirin after Myocardial Infarction or the Acute Coronary Syndrome: Meta-Analysis with Estimates of Risk and Benefit.” It is in the 16 August 2005 issue of Annals of Internal Medicine (volume 143, pages 241-250). The authors are M.B. Rothberg, C. Celestin, L.D. Fiore, E. Lawler, and J.R. Cook.

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