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Does combining aspirin and warfarin decrease the risk of stroke for patients with nonvalvular atrial fibrillation?
Adjusted-dose warfarin (international normalized ratio [INR]=2.0–3.0) remains the most efficacious antithrombotic regimen for the primary and secondary prevention of cardioembolic stroke in high-risk patients with nonvalvular atrial fibrillation (NVAF) (strength of recommendation [SOR]: A, based on randomized controlled trials).
Aspirin therapy at a dose of 75 to 325 mg reduces the risk of stroke to a lesser degree and may be useful for low-risk patients with NVAF or patients at high risk for bleeding (SOR: A, based on randomized controlled trials).
Combination therapy with low, fixed-dose warfarin (1–2 mg) and aspirin has not been shown to be superior to aspirin therapy alone. Moreover, this combination appears to be inferior to adjusted-dose warfarin (SOR: A, based on randomized controlled trials). To date, no clinical trials have investigated the efficacy and safety of combining adjusted-dose warfarin and aspirin for the prevention of stroke from NVAF.
Evidence summary
Thromboprophylaxis with warfarin for patients with NVAF has been studied in 5 major clinical trials.1-5 Pooled analysis with more than 2900 patients revealed an annual stroke risk of 4.5% for control patients and 1.4% for patients receiving adjusted-dose warfarin (number needed to treat [NNT] for 1 year=32).6 Studies comparing aspirin with placebo for treatment of NVAF are less robust and have heterogeneous results. Combined data from the Atrial Fibrillation Aspirin Anticoagulation Study (AFASAK-1),1 the European Atrial Fibrillation Trial,7 and the Stroke Prevention in Atrial Fibrillation (SPAF) I studies2 revealed a small but statistically significant reduction in stroke rates (relative risk reduction [RRR]=21%; 8.1% vs 6.3% annual stroke rate; NNT=55), with no increase in major bleeding risk.8
The SPAF III investigators further compared adjusted-dose warfarin with low-intensity, fixed-dose warfarin plus aspirin in high-risk patients with NVAF.9 An interim analysis at 1.1 years revealed superiority in the reduction of ischemic strokes and systemic embolisms with adjusted-dose warfarin (7.9% vs 1.9% per year, respectively; NNT=16), which led to the trial’s termination. Rates of major hemorrhage did not differ between treatment groups (2.4% per year with combination vs 2.1% per year with warfarin).
Two similar studies published in 1998 were terminated early, in light of the SPAF III results. The Second Copenhagen Atrial Fibrillation, Aspirin, and Anticoagulation Study10 (AFASAK-2) completed 3 of the scheduled 6 years; it compared warfarin 1.25 mg/d, warfarin 1.25 mg/d plus aspirin 300 mg, aspirin 300 mg alone, and adjusted-dose warfarin (INR=2.0–3.0) to treat NVAF for patients with a median age of 74 years (range, 44–89). The cumulative stroke event rate after 1 year was 5.8% on fixed-dose warfarin, 7.2% on combination, 3.6% on aspirin, and 2.8% on adjusted-dose warfarin. The researchers concluded that while the difference was not statistically significant, adjusted-dose warfarin seemed superior to other treatments after 1 year.
In a similar fashion, Pengo et al11 randomized patients with NVAF aged >60 years to fixed-dose (1.25 mg/d) or adjusted-dose warfarin (INR=2.0–3.0) to evaluate ischemic stroke rates and major bleeding. This trial enrolled 303 patients who were followed up for 14.5 months before discontinuation of the trial. The rate of ischemic stroke was significantly higher in the fixed-dose warfarin group compared with the adjusted warfarin group (3.7% vs 0% per year; NNT=27). Major bleeds were more frequent in the adjusted warfarin group (2.6% vs 1% per year, number needed to harm=63). While the combined primary endpoint did not show a significant benefit for adjusted-dose warfarin, this study suggests that fixed-dose warfarin does not protect against ischemic stroke in NVAF patients.
The intensity of warfarin therapy and stroke severity has recently been studied for patients with NVAF.12 A subtherapeutic INR (<2.0) on the day of admission was independently associated with severe stroke (odds ratio=1.9; 95% confidence interval [CI], 1.1–3.4), and risk of death at 30 days (hazard ratio, 3.4; 95% CI, 1.1–10.1) compared with an INR of 2.0 or greater. Furthermore, an admission INR of 1.5–1.9 had a similar mortality rate (18%) as an INR of <1.5 (15%), and for those patients on aspirin (15%).
These findings further support the importance of achieving therapeutic INR goals for patients with NVAF.
Recommendations from others
The American Heart Association, the American College of Cardiology,13 and the American College of Chest Physicians (ACCP)14 recommend adjusted-dose warfarin for nonvalvular atrial fibrillation patients at high risk for ischemic stroke. Risk stratification is a key component in order to maximize efficacy while minimizing bleeding risk.
The Table summarizes the ACCP guidelines for prevention of ischemic stroke based on patient risk factors.
TABLE
ACCP Stroke Prevention Guidelines 2001
| Atrial fibrillation stroke profile | Risk factors | Treatment guidelines |
|---|---|---|
| High risk | One or more of the following: | Warfarin (INR=2.5; range, 2–3) |
| Age 75 years | ||
| History of hypertension | ||
| Cerebrovascular accident/transient ischemic attack | ||
| Arterial thromboembolism | ||
| Poor left ventricular systolic dysfunction (ejection fraction <40%) | ||
| Rheumatic mitral valve disease or prosthetic heart valve | ||
| 2 or more moderate risk factors | ||
| Moderate risk | No high risk factors and 1 of the following: | Warfarin (INR=2.5, range, 2–3) or Aspirin 325 mg/d |
| Age 65–74 years | ||
| Diabetes | ||
| Coronary artery disease | ||
| Low risk | high or moderate risk factors and: | Aspirin 325 mg/d |
| Age <65 years | ||
| INR, international normalized ratio | ||
When warfarin is started, aspirin should be stopped
Rick Guthmann, MD
Illinois Masonic Family Practice Residency, University of Illinois at Chicago
The lack of evidence to support the combined use of aspirin and warfarin creates an excellent opportunity to remove an unnecessary drug from a patient’s medication list. Patients who were taking aspirin for thrombosis prophylaxis occasionally develop atrial fibrillation. Many patients who take aspirin for prophylaxis do so because they are already at moderate to high risk for embolic stroke. The onset of atrial fibrillation in these patients appropriately leads to the initiation of warfarin. At the time of warfarin initiation, the aspirin should be stopped. By stopping the aspirin at the initiation of the warfarin, one can reduce the number of medications that the patient must take, avoid the interactions of aspirin and warfarin, and eliminate the side the effects of the aspirin.
1. Peterson P, Boysen G, Godtfredsen J, et al. Placebo-controlled, randomized trial of warfarin and aspirin for prevention of thromboembolic complications in chronic atrial fibrillation: the Copenhagen AFASAK Study. Lancet 1989;1:175-179.
2. The Stroke Prevention in Atrial Fibrillation Investigators. The stroke prevention in atrial fibrillation study: final results. Circulation 1991;84:527-539.
3. The Boston Area Anticoagulation Trial for Atrial Fibrillation Investigators. The effect of low-dose warfarin on the risk of stroke in patients with nonrheumatic atrial fibrillation. N Eng J Med 1990;323:1505-1511.
4. Connolly SJ, Laupacis A, Gent M, et al. Canadian Atrial Fibrillation Anticoagulation (CAFA) Study. J Am Coll Cardiol 1991;18:349-355.
5. Ezekowitz MD, Bridgers SL, James KE, et al. Warfarin in the prevention of stroke associated with nonrheumatic atrial fibrillation: Veterans Affairs Stroke Prevention in Nonrheumatic Atrial Fibrillation Investigators. N Eng J Med 1992;327:1406-1412.
6. Atrial Fibrillation Investigators. Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation. Arch Intern Med 1994;154:1449-1457.
7. Secondary prevention in non-rheumatic atrial fibrillation after transient ischemic attack or minor stroke: EAFT (European Atrial Fibrillation Trial) study group. Lancet 1993;342:1255-1262.
8. Atrial Fibrillation Investigators. The efficacy of aspirin in patients with atrial fibrillation: analysis of pooled data from three randomized trials. Arch Intern Med 1997;157:1237-1240.
9. The Stroke Prevention in Atrial Fibrillation Investigators. Adjusted-dose warfarin versus low-intensity, fixed-dose warfarin plus aspirin for high-risk patients with atrial fibrillation: Stroke Prevention in Atrial Fibrillation III randomized clinical trial. Lancet 1996;348:633-638.
10. Gullov AL, Koefoed BG, Petersen P, et al. Fixed minidose warfarin and aspirin alone and in combination vs adjusted-dose warfarin for stroke prevention in atrial fibrillation, Second Copenhagen Atrial Fibrillation, Aspirin, and Anticoagulation Study. Arch Intern Med 1998;158:1513-1521.
11. Pengo V, Zasso A, Barbero F, et al. Effectiveness of fixeddose minidose warfarin in the prevention of thromboembolism and vascular death in nonrheumatic atrial fibrillation. Am J Cardiol 1998;82:433-437.
12. Hylek EM, Go AS, Chang Y, et al. Effect of intensity of oral anticoagulation on stroke severity and mortality in atrial fibrillation. N Eng J Med 2003;349:1019-1026.
13. Hirsh J, Fuster V, Ansell J, et al. American Heart Association/American College of Cardiology Foundation guide to warfarin therapy. Circulation 2003;107:1692-1711.
14. Albers GW, Dalen JE, Laupacis A, et al. Antithrombotic therapy in atrial fibrillation. Chest 2001;119(Suppl 1):194S.-
Adjusted-dose warfarin (international normalized ratio [INR]=2.0–3.0) remains the most efficacious antithrombotic regimen for the primary and secondary prevention of cardioembolic stroke in high-risk patients with nonvalvular atrial fibrillation (NVAF) (strength of recommendation [SOR]: A, based on randomized controlled trials).
Aspirin therapy at a dose of 75 to 325 mg reduces the risk of stroke to a lesser degree and may be useful for low-risk patients with NVAF or patients at high risk for bleeding (SOR: A, based on randomized controlled trials).
Combination therapy with low, fixed-dose warfarin (1–2 mg) and aspirin has not been shown to be superior to aspirin therapy alone. Moreover, this combination appears to be inferior to adjusted-dose warfarin (SOR: A, based on randomized controlled trials). To date, no clinical trials have investigated the efficacy and safety of combining adjusted-dose warfarin and aspirin for the prevention of stroke from NVAF.
Evidence summary
Thromboprophylaxis with warfarin for patients with NVAF has been studied in 5 major clinical trials.1-5 Pooled analysis with more than 2900 patients revealed an annual stroke risk of 4.5% for control patients and 1.4% for patients receiving adjusted-dose warfarin (number needed to treat [NNT] for 1 year=32).6 Studies comparing aspirin with placebo for treatment of NVAF are less robust and have heterogeneous results. Combined data from the Atrial Fibrillation Aspirin Anticoagulation Study (AFASAK-1),1 the European Atrial Fibrillation Trial,7 and the Stroke Prevention in Atrial Fibrillation (SPAF) I studies2 revealed a small but statistically significant reduction in stroke rates (relative risk reduction [RRR]=21%; 8.1% vs 6.3% annual stroke rate; NNT=55), with no increase in major bleeding risk.8
The SPAF III investigators further compared adjusted-dose warfarin with low-intensity, fixed-dose warfarin plus aspirin in high-risk patients with NVAF.9 An interim analysis at 1.1 years revealed superiority in the reduction of ischemic strokes and systemic embolisms with adjusted-dose warfarin (7.9% vs 1.9% per year, respectively; NNT=16), which led to the trial’s termination. Rates of major hemorrhage did not differ between treatment groups (2.4% per year with combination vs 2.1% per year with warfarin).
Two similar studies published in 1998 were terminated early, in light of the SPAF III results. The Second Copenhagen Atrial Fibrillation, Aspirin, and Anticoagulation Study10 (AFASAK-2) completed 3 of the scheduled 6 years; it compared warfarin 1.25 mg/d, warfarin 1.25 mg/d plus aspirin 300 mg, aspirin 300 mg alone, and adjusted-dose warfarin (INR=2.0–3.0) to treat NVAF for patients with a median age of 74 years (range, 44–89). The cumulative stroke event rate after 1 year was 5.8% on fixed-dose warfarin, 7.2% on combination, 3.6% on aspirin, and 2.8% on adjusted-dose warfarin. The researchers concluded that while the difference was not statistically significant, adjusted-dose warfarin seemed superior to other treatments after 1 year.
In a similar fashion, Pengo et al11 randomized patients with NVAF aged >60 years to fixed-dose (1.25 mg/d) or adjusted-dose warfarin (INR=2.0–3.0) to evaluate ischemic stroke rates and major bleeding. This trial enrolled 303 patients who were followed up for 14.5 months before discontinuation of the trial. The rate of ischemic stroke was significantly higher in the fixed-dose warfarin group compared with the adjusted warfarin group (3.7% vs 0% per year; NNT=27). Major bleeds were more frequent in the adjusted warfarin group (2.6% vs 1% per year, number needed to harm=63). While the combined primary endpoint did not show a significant benefit for adjusted-dose warfarin, this study suggests that fixed-dose warfarin does not protect against ischemic stroke in NVAF patients.
The intensity of warfarin therapy and stroke severity has recently been studied for patients with NVAF.12 A subtherapeutic INR (<2.0) on the day of admission was independently associated with severe stroke (odds ratio=1.9; 95% confidence interval [CI], 1.1–3.4), and risk of death at 30 days (hazard ratio, 3.4; 95% CI, 1.1–10.1) compared with an INR of 2.0 or greater. Furthermore, an admission INR of 1.5–1.9 had a similar mortality rate (18%) as an INR of <1.5 (15%), and for those patients on aspirin (15%).
These findings further support the importance of achieving therapeutic INR goals for patients with NVAF.
Recommendations from others
The American Heart Association, the American College of Cardiology,13 and the American College of Chest Physicians (ACCP)14 recommend adjusted-dose warfarin for nonvalvular atrial fibrillation patients at high risk for ischemic stroke. Risk stratification is a key component in order to maximize efficacy while minimizing bleeding risk.
The Table summarizes the ACCP guidelines for prevention of ischemic stroke based on patient risk factors.
TABLE
ACCP Stroke Prevention Guidelines 2001
| Atrial fibrillation stroke profile | Risk factors | Treatment guidelines |
|---|---|---|
| High risk | One or more of the following: | Warfarin (INR=2.5; range, 2–3) |
| Age 75 years | ||
| History of hypertension | ||
| Cerebrovascular accident/transient ischemic attack | ||
| Arterial thromboembolism | ||
| Poor left ventricular systolic dysfunction (ejection fraction <40%) | ||
| Rheumatic mitral valve disease or prosthetic heart valve | ||
| 2 or more moderate risk factors | ||
| Moderate risk | No high risk factors and 1 of the following: | Warfarin (INR=2.5, range, 2–3) or Aspirin 325 mg/d |
| Age 65–74 years | ||
| Diabetes | ||
| Coronary artery disease | ||
| Low risk | high or moderate risk factors and: | Aspirin 325 mg/d |
| Age <65 years | ||
| INR, international normalized ratio | ||
When warfarin is started, aspirin should be stopped
Rick Guthmann, MD
Illinois Masonic Family Practice Residency, University of Illinois at Chicago
The lack of evidence to support the combined use of aspirin and warfarin creates an excellent opportunity to remove an unnecessary drug from a patient’s medication list. Patients who were taking aspirin for thrombosis prophylaxis occasionally develop atrial fibrillation. Many patients who take aspirin for prophylaxis do so because they are already at moderate to high risk for embolic stroke. The onset of atrial fibrillation in these patients appropriately leads to the initiation of warfarin. At the time of warfarin initiation, the aspirin should be stopped. By stopping the aspirin at the initiation of the warfarin, one can reduce the number of medications that the patient must take, avoid the interactions of aspirin and warfarin, and eliminate the side the effects of the aspirin.
Adjusted-dose warfarin (international normalized ratio [INR]=2.0–3.0) remains the most efficacious antithrombotic regimen for the primary and secondary prevention of cardioembolic stroke in high-risk patients with nonvalvular atrial fibrillation (NVAF) (strength of recommendation [SOR]: A, based on randomized controlled trials).
Aspirin therapy at a dose of 75 to 325 mg reduces the risk of stroke to a lesser degree and may be useful for low-risk patients with NVAF or patients at high risk for bleeding (SOR: A, based on randomized controlled trials).
Combination therapy with low, fixed-dose warfarin (1–2 mg) and aspirin has not been shown to be superior to aspirin therapy alone. Moreover, this combination appears to be inferior to adjusted-dose warfarin (SOR: A, based on randomized controlled trials). To date, no clinical trials have investigated the efficacy and safety of combining adjusted-dose warfarin and aspirin for the prevention of stroke from NVAF.
Evidence summary
Thromboprophylaxis with warfarin for patients with NVAF has been studied in 5 major clinical trials.1-5 Pooled analysis with more than 2900 patients revealed an annual stroke risk of 4.5% for control patients and 1.4% for patients receiving adjusted-dose warfarin (number needed to treat [NNT] for 1 year=32).6 Studies comparing aspirin with placebo for treatment of NVAF are less robust and have heterogeneous results. Combined data from the Atrial Fibrillation Aspirin Anticoagulation Study (AFASAK-1),1 the European Atrial Fibrillation Trial,7 and the Stroke Prevention in Atrial Fibrillation (SPAF) I studies2 revealed a small but statistically significant reduction in stroke rates (relative risk reduction [RRR]=21%; 8.1% vs 6.3% annual stroke rate; NNT=55), with no increase in major bleeding risk.8
The SPAF III investigators further compared adjusted-dose warfarin with low-intensity, fixed-dose warfarin plus aspirin in high-risk patients with NVAF.9 An interim analysis at 1.1 years revealed superiority in the reduction of ischemic strokes and systemic embolisms with adjusted-dose warfarin (7.9% vs 1.9% per year, respectively; NNT=16), which led to the trial’s termination. Rates of major hemorrhage did not differ between treatment groups (2.4% per year with combination vs 2.1% per year with warfarin).
Two similar studies published in 1998 were terminated early, in light of the SPAF III results. The Second Copenhagen Atrial Fibrillation, Aspirin, and Anticoagulation Study10 (AFASAK-2) completed 3 of the scheduled 6 years; it compared warfarin 1.25 mg/d, warfarin 1.25 mg/d plus aspirin 300 mg, aspirin 300 mg alone, and adjusted-dose warfarin (INR=2.0–3.0) to treat NVAF for patients with a median age of 74 years (range, 44–89). The cumulative stroke event rate after 1 year was 5.8% on fixed-dose warfarin, 7.2% on combination, 3.6% on aspirin, and 2.8% on adjusted-dose warfarin. The researchers concluded that while the difference was not statistically significant, adjusted-dose warfarin seemed superior to other treatments after 1 year.
In a similar fashion, Pengo et al11 randomized patients with NVAF aged >60 years to fixed-dose (1.25 mg/d) or adjusted-dose warfarin (INR=2.0–3.0) to evaluate ischemic stroke rates and major bleeding. This trial enrolled 303 patients who were followed up for 14.5 months before discontinuation of the trial. The rate of ischemic stroke was significantly higher in the fixed-dose warfarin group compared with the adjusted warfarin group (3.7% vs 0% per year; NNT=27). Major bleeds were more frequent in the adjusted warfarin group (2.6% vs 1% per year, number needed to harm=63). While the combined primary endpoint did not show a significant benefit for adjusted-dose warfarin, this study suggests that fixed-dose warfarin does not protect against ischemic stroke in NVAF patients.
The intensity of warfarin therapy and stroke severity has recently been studied for patients with NVAF.12 A subtherapeutic INR (<2.0) on the day of admission was independently associated with severe stroke (odds ratio=1.9; 95% confidence interval [CI], 1.1–3.4), and risk of death at 30 days (hazard ratio, 3.4; 95% CI, 1.1–10.1) compared with an INR of 2.0 or greater. Furthermore, an admission INR of 1.5–1.9 had a similar mortality rate (18%) as an INR of <1.5 (15%), and for those patients on aspirin (15%).
These findings further support the importance of achieving therapeutic INR goals for patients with NVAF.
Recommendations from others
The American Heart Association, the American College of Cardiology,13 and the American College of Chest Physicians (ACCP)14 recommend adjusted-dose warfarin for nonvalvular atrial fibrillation patients at high risk for ischemic stroke. Risk stratification is a key component in order to maximize efficacy while minimizing bleeding risk.
The Table summarizes the ACCP guidelines for prevention of ischemic stroke based on patient risk factors.
TABLE
ACCP Stroke Prevention Guidelines 2001
| Atrial fibrillation stroke profile | Risk factors | Treatment guidelines |
|---|---|---|
| High risk | One or more of the following: | Warfarin (INR=2.5; range, 2–3) |
| Age 75 years | ||
| History of hypertension | ||
| Cerebrovascular accident/transient ischemic attack | ||
| Arterial thromboembolism | ||
| Poor left ventricular systolic dysfunction (ejection fraction <40%) | ||
| Rheumatic mitral valve disease or prosthetic heart valve | ||
| 2 or more moderate risk factors | ||
| Moderate risk | No high risk factors and 1 of the following: | Warfarin (INR=2.5, range, 2–3) or Aspirin 325 mg/d |
| Age 65–74 years | ||
| Diabetes | ||
| Coronary artery disease | ||
| Low risk | high or moderate risk factors and: | Aspirin 325 mg/d |
| Age <65 years | ||
| INR, international normalized ratio | ||
When warfarin is started, aspirin should be stopped
Rick Guthmann, MD
Illinois Masonic Family Practice Residency, University of Illinois at Chicago
The lack of evidence to support the combined use of aspirin and warfarin creates an excellent opportunity to remove an unnecessary drug from a patient’s medication list. Patients who were taking aspirin for thrombosis prophylaxis occasionally develop atrial fibrillation. Many patients who take aspirin for prophylaxis do so because they are already at moderate to high risk for embolic stroke. The onset of atrial fibrillation in these patients appropriately leads to the initiation of warfarin. At the time of warfarin initiation, the aspirin should be stopped. By stopping the aspirin at the initiation of the warfarin, one can reduce the number of medications that the patient must take, avoid the interactions of aspirin and warfarin, and eliminate the side the effects of the aspirin.
1. Peterson P, Boysen G, Godtfredsen J, et al. Placebo-controlled, randomized trial of warfarin and aspirin for prevention of thromboembolic complications in chronic atrial fibrillation: the Copenhagen AFASAK Study. Lancet 1989;1:175-179.
2. The Stroke Prevention in Atrial Fibrillation Investigators. The stroke prevention in atrial fibrillation study: final results. Circulation 1991;84:527-539.
3. The Boston Area Anticoagulation Trial for Atrial Fibrillation Investigators. The effect of low-dose warfarin on the risk of stroke in patients with nonrheumatic atrial fibrillation. N Eng J Med 1990;323:1505-1511.
4. Connolly SJ, Laupacis A, Gent M, et al. Canadian Atrial Fibrillation Anticoagulation (CAFA) Study. J Am Coll Cardiol 1991;18:349-355.
5. Ezekowitz MD, Bridgers SL, James KE, et al. Warfarin in the prevention of stroke associated with nonrheumatic atrial fibrillation: Veterans Affairs Stroke Prevention in Nonrheumatic Atrial Fibrillation Investigators. N Eng J Med 1992;327:1406-1412.
6. Atrial Fibrillation Investigators. Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation. Arch Intern Med 1994;154:1449-1457.
7. Secondary prevention in non-rheumatic atrial fibrillation after transient ischemic attack or minor stroke: EAFT (European Atrial Fibrillation Trial) study group. Lancet 1993;342:1255-1262.
8. Atrial Fibrillation Investigators. The efficacy of aspirin in patients with atrial fibrillation: analysis of pooled data from three randomized trials. Arch Intern Med 1997;157:1237-1240.
9. The Stroke Prevention in Atrial Fibrillation Investigators. Adjusted-dose warfarin versus low-intensity, fixed-dose warfarin plus aspirin for high-risk patients with atrial fibrillation: Stroke Prevention in Atrial Fibrillation III randomized clinical trial. Lancet 1996;348:633-638.
10. Gullov AL, Koefoed BG, Petersen P, et al. Fixed minidose warfarin and aspirin alone and in combination vs adjusted-dose warfarin for stroke prevention in atrial fibrillation, Second Copenhagen Atrial Fibrillation, Aspirin, and Anticoagulation Study. Arch Intern Med 1998;158:1513-1521.
11. Pengo V, Zasso A, Barbero F, et al. Effectiveness of fixeddose minidose warfarin in the prevention of thromboembolism and vascular death in nonrheumatic atrial fibrillation. Am J Cardiol 1998;82:433-437.
12. Hylek EM, Go AS, Chang Y, et al. Effect of intensity of oral anticoagulation on stroke severity and mortality in atrial fibrillation. N Eng J Med 2003;349:1019-1026.
13. Hirsh J, Fuster V, Ansell J, et al. American Heart Association/American College of Cardiology Foundation guide to warfarin therapy. Circulation 2003;107:1692-1711.
14. Albers GW, Dalen JE, Laupacis A, et al. Antithrombotic therapy in atrial fibrillation. Chest 2001;119(Suppl 1):194S.-
1. Peterson P, Boysen G, Godtfredsen J, et al. Placebo-controlled, randomized trial of warfarin and aspirin for prevention of thromboembolic complications in chronic atrial fibrillation: the Copenhagen AFASAK Study. Lancet 1989;1:175-179.
2. The Stroke Prevention in Atrial Fibrillation Investigators. The stroke prevention in atrial fibrillation study: final results. Circulation 1991;84:527-539.
3. The Boston Area Anticoagulation Trial for Atrial Fibrillation Investigators. The effect of low-dose warfarin on the risk of stroke in patients with nonrheumatic atrial fibrillation. N Eng J Med 1990;323:1505-1511.
4. Connolly SJ, Laupacis A, Gent M, et al. Canadian Atrial Fibrillation Anticoagulation (CAFA) Study. J Am Coll Cardiol 1991;18:349-355.
5. Ezekowitz MD, Bridgers SL, James KE, et al. Warfarin in the prevention of stroke associated with nonrheumatic atrial fibrillation: Veterans Affairs Stroke Prevention in Nonrheumatic Atrial Fibrillation Investigators. N Eng J Med 1992;327:1406-1412.
6. Atrial Fibrillation Investigators. Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation. Arch Intern Med 1994;154:1449-1457.
7. Secondary prevention in non-rheumatic atrial fibrillation after transient ischemic attack or minor stroke: EAFT (European Atrial Fibrillation Trial) study group. Lancet 1993;342:1255-1262.
8. Atrial Fibrillation Investigators. The efficacy of aspirin in patients with atrial fibrillation: analysis of pooled data from three randomized trials. Arch Intern Med 1997;157:1237-1240.
9. The Stroke Prevention in Atrial Fibrillation Investigators. Adjusted-dose warfarin versus low-intensity, fixed-dose warfarin plus aspirin for high-risk patients with atrial fibrillation: Stroke Prevention in Atrial Fibrillation III randomized clinical trial. Lancet 1996;348:633-638.
10. Gullov AL, Koefoed BG, Petersen P, et al. Fixed minidose warfarin and aspirin alone and in combination vs adjusted-dose warfarin for stroke prevention in atrial fibrillation, Second Copenhagen Atrial Fibrillation, Aspirin, and Anticoagulation Study. Arch Intern Med 1998;158:1513-1521.
11. Pengo V, Zasso A, Barbero F, et al. Effectiveness of fixeddose minidose warfarin in the prevention of thromboembolism and vascular death in nonrheumatic atrial fibrillation. Am J Cardiol 1998;82:433-437.
12. Hylek EM, Go AS, Chang Y, et al. Effect of intensity of oral anticoagulation on stroke severity and mortality in atrial fibrillation. N Eng J Med 2003;349:1019-1026.
13. Hirsh J, Fuster V, Ansell J, et al. American Heart Association/American College of Cardiology Foundation guide to warfarin therapy. Circulation 2003;107:1692-1711.
14. Albers GW, Dalen JE, Laupacis A, et al. Antithrombotic therapy in atrial fibrillation. Chest 2001;119(Suppl 1):194S.-
Evidence-based answers from the Family Physicians Inquiries Network