Thread: Warfarin vs Aspirin in Atrial Fibrillation

Best Evidence Review
Warfarin vs Aspirin in Atrial Fibrillation -- New Perspectives: A Best Evidence Review



Introduction

Stroke is one of the most significant risks associated with atrial fibrillation, yet many patients with an indication for poststroke warfarin therapy do not receive this treatment. In part, this is because of uncertainty regarding the balance of risks and benefits of warfarin therapy, especially in high-risk populations. A recent meta-analysis and randomized trial provide new insights into this issue.

Commentary

Approximately 2.2 million people in the United States have atrial fibrillation. It is a common problem that increases in prevalence as patients grow older -- from 2.3% among adults over age 40 to 5.9% among people older than 65 years, with the median age being 75. There does not appear to be a predilection based on gender, although the absolute number of women older than 75 with atrial fibrillation exceeds the number of men at those ages.[1]

Atrial fibrillation is the most common cause of cardioembolic stroke. The current meta-analysis suggests that the annual risk for stroke among patients with atrial fibrillation and no history of anticoagulation or prior cerebrovascular disease is between 2.5% and 4%.

A recent systematic review found that the risk for stroke in the setting of atrial fibrillation was most significantly elevated by a history of prior stroke or transient ischemic attack.[2] Other factors that increased the risk for stroke in patients with atrial fibrillation were advanced age and a history of hypertension or diabetes mellitus. However, female sex and a history of heart failure or coronary artery disease were not conclusively linked with an increased risk for stroke.

Current guidelines recommend warfarin adjusted to achieve an international normalized ratio (INR) between 2 and 3 to prevent stroke among patients with atrial fibrillation and a history of prior cerebrovascular disease, prosthetic heart valve, or mitral stenosis.[3] Warfarin therapy should also be considered for patients age 75 or over and those with hypertension, diabetes, heart failure, or a documented left ventricular ejection fraction of less than 35%. Other patients with atrial fibrillation may receive aspirin for stroke prevention.

There is evidence that many patients with atrial fibrillation do not receive their recommended treatment. In a study of 405 patients with atrial fibrillation, only 51% were discharged from the hospital with a prescription for warfarin, and fewer than half of patients over age 80 received warfarin.[4] This phenomenon may be in part the result of previous reviews of randomized controlled trials that questioned whether anticoagulation provides a significant clinical benefit compared with antiplatelet therapy for patients with atrial fibrillation. A meta-analysis of 5 studies of patients with nonrheumatic atrial fibrillation found no benefit of anticoagulation with warfarin vs all antiplatelet therapy in terms of overall mortality or death resulting from stroke.[5] The 32% reduction in the risk for nonfatal stroke in the warfarin vs antiplatelet treatment groups was of borderline statistical significance, and this result was not significant when a trial with weak methodology was excluded. Moreover, warfarin was associated with a nonsignificant 45% increase in the risk of major bleeding events vs antiplatelet therapy.

Another review that limited its meta-analysis to treatment with warfarin vs aspirin for patients with atrial fibrillation found a more robust protective effect against stroke with warfarin, which also produced superior results for all cardiovascular outcomes.[6] The difference is that the other meta-analysis examined all antiplatelet therapy, not just aspirin. However, warfarin also increased the risk of major bleeding vs aspirin, meaning that for every 1000 patients with atrial fibrillation treated with warfarin instead of aspirin, 23 additional ischemic strokes would be prevented at the cost of 9 additional cases of major bleeding.

The current meta-analysis of warfarin vs antiplatelet therapy includes data from 8 trials involving a total of 9598 patients with atrial fibrillation. Six trials used aspirin as the antiplatelet agent, and 1 trial used dual antiplatelet therapy with aspirin and clopidogrel. The dose of aspirin ranged between 75 mg and 325 mg daily. The minimal target INR for warfarin therapy was 1.5, and 6 trials reported that at least 50% of their study cohort achieved the target INR.

Treatment with warfarin reduced the risk of all strokes by 32% compared with antiplatelet therapy (P = .0007). This means that 13 additional strokes would be prevented by treating 1000 patients with warfarin instead of antiplatelet agents for 1 year. Warfarin also reduced the risk of ischemic stroke by nearly half compared with antiplatelet therapy.

Warfarin was not superior to antiplatelet therapy in terms of prevention of disabling or fatal strokes or vascular death. Overall rates of mortality were also similar between the 2 treatments. However, warfarin reduced the risk of myocardial infarction by 31% compared with antiplatelet therapy (P = .06). There were 41 intracranial hemorrhages reported during the trials, and warfarin increased the risk of hemorrhage by 98% compared with antiplatelet treatment.

Although older adults bear the greatest risk for stroke in atrial fibrillation, the choice for stroke prevention in this important patient group has not been as scrutinized as it has among younger patients. The authors of the Birmingham Atrial Fibrillation Treatment of the Aged Study (BAFTA) note that the average age in previous studies of stroke prevention among patients with atrial fibrillation is 69 years. Therefore, they compared warfarin and aspirin therapy among patients age 75 or older.

The trial recruited patients from 260 general practices in England and Wales. A total of 973 patients with atrial fibrillation and no risk factors for major bleeding were randomized in an open-label design to receive either aspirin 75 mg daily or warfarin; the target INR range was 2 to 3. The primary study outcome was the combined rate of stroke, intracranial hemorrhage, and clinically significant arterial embolism.

The average age of study subjects was 81.5 years, and 20% of participants were at least 85 years old. There was a history of stroke or transient ischemic attack in 12% of participants, and similar proportions of patients in the 2 treatment groups were receiving aspirin or warfarin at baseline.

The average follow-up time for study outcomes was 2.7 years. One third of patients randomized to receive warfarin stopped taking it, and the remaining patients were in the target INR range two thirds of the time. The use of blood pressure and lipid-lowering medications was similar between treatment groups.

Warfarin reduced the rate of the combined primary outcome by 52% compared with aspirin. Warfarin was as effective in the primary outcome among patients at age 85 or older as it was in younger patients and was also more effective when examining patient subgroups based on gender, previous history of stroke, or baseline risk of stroke. At the same time, warfarin was not more effective than aspirin in the prevention of nonstroke vascular events or overall mortality rates.

A surprising finding was that there was no significant increase in the risk of major hemorrhage with warfarin vs aspirin therapy. However, the confidence intervals in this finding were wide, suggesting that a larger patient cohort or greater adherence to randomized therapy could have demonstrated a significant difference between treatments. The researchers also note that their target INR was lower than in previous studies, which could also account for lower rates of hemorrhage among participants receiving warfarin.

Reducing the risk of stroke is one of the most important aspects of caring for patients with atrial fibrillation, and improvements in therapy beyond anticoagulation or antiplatelet therapy may have lessened the risk for stroke over the last decade. In BAFTA, the annual rate of stroke among patients with at least a moderate baseline risk was 3.3%, which compared favorably with a predicted rate of 9.9% based on previous reports. In addition, a recent trial of clopidogrel plus aspirin vs warfarin for stroke prevention among patients with atrial fibrillation and at least 1 other risk factor for stroke also found a lower than expected rate of vascular events, with an annual rate of stroke of 3.93% in the warfarin arm of the trial.[7] This trial was stopped early because of the apparent superiority of warfarin compared with aspirin plus clopidogrel in vascular outcomes.

Whereas the risk of stroke and vascular events among patients with atrial fibrillation may be decreasing, the risk of mortality among patients with this condition appears to be stagnant. In a study that followed a cohort of patients with atrial fibrillation in a Minnesota community, the risk of mortality was essentially unchanged between 1980 and 2000.[8] During the first 4 months after diagnosis with atrial fibrillation, the mean hazard ratio of overall mortality was 9.62 when comparing patients with atrial fibrillation vs age- and gender-matched control subjects without atrial fibrillation, and this risk fell to 1.66 thereafter.

Could greater adherence to recommendations for warfarin therapy in atrial fibrillation improve the rate of mortality associated with this condition? The current articles do not find a direct mortality benefit of warfarin vs antiplatelet treatment, but it would be reasonable to believe that greater adherence to guidelines among thousands of patients could reduce not only the rate of stroke in atrial fibrillation, but also the death rate. Physicians should consider this possibility when evaluating patients with atrial fibrillation.



Some Short notes


The prevalence of atrial fibrillation among adults over the age of 65 is 5.9%
Approximately 2.2 million people in the United States have atrial fibrillation, and the median age of these patients is 75. The prevalence of atrial fibrillation increases from 2.3% among adults over age 40 to 5.9% among people older than 65 years. There does not appear to be a predilection for atrial fibrillation based on gender, although the absolute number of women older than 75 with atrial fibrillation exceeds the number of men.

Which factor most significantly increases the risk of stroke in the setting of atrial fibrillation?

Answer: Prior history of stroke or transient ischemic attack
A recent systematic review found that the risk for stroke in the setting of atrial fibrillation was most significantly elevated by a history of prior stroke or transient ischemic attack. However, female sex and a history of heart failure or coronary artery disease were not conclusively linked with an increased risk for stroke.

According to the current meta-analysis by Aguilar and colleagues, which outcome was most improved among patients receiving warfarin instead of anti-platelet therapy for atrial fibrillation?

Answer: All strokes

In the current meta-analysis, treatment with warfarin reduced the risk of all strokes by 32% compared with anti-platelet therapy (P = .0007).

Warfarin was not superior to antiplatelet therapy in terms of prevention of disabling or fatal strokes or vascular death. Overall rates of mortality were also similar between the 2 treatments.


Warfarin improved the risk of the combined vascular outcome vs aspirin, and the risk of major bleeding was similar between treatment groups
Warfarin reduced the rate of the combined primary outcome by 52% compared with aspirin. Warfarin was as effective in the primary outcome among patients age 85 or older as it was in younger patients. A surprising finding was that there was no significant increase in the risk of major hemorrhage with warfarin vs aspirin therapy.