In the first Copenhagen Atrial Fibrillation, Aspirin, and Anticoagulant Therapy Study (AFASAK I), 1007 patients aged 18 or over with chronic nonvalvular AF documented by electrocardiogram (ECG) were randomized to openly receive warfarin (international normalized ratio [INR] 2.8–4.2, n=335), or, blindly, aspirin (75mg/day, n=336) or placebo (n=336).10 The following were exclusion criteria: cerebrovascular events within the past month, previous anticoagulant therapy for more than six months, hypertension above 180/100mmHg, valvular heart disease, valve replacement, or current therapy or contraindication to aspirin or warfarin treatment. The primary endpoint was stroke, TIA or systemic embolism. The secondary event was death.

The mean follow-up was two years. In the warfarin group, compared to the aspirin group and placebo, there was a significantly lower incidence of embolic complications (5, 20 and 21 events, respectively, p<0.05) and mortality from cardiovascular causes or stroke (3, 12 and 15 events, respectively, p<0.02). The annual incidence of thromboembolic complications was 2.0% with warfarin and 5.5% with aspirin and placebo. Nonfatal bleeding complications occurred in 21 patients with warfarin (7%), in two patients with aspirin (2%) and in no patients on placebo (0%). Some of the main results are shown in Table 1.

The Boston Area Anticoagulation Trial for Atrial Fibrillation (BAATAF) was an unblinded trial in which 420 adult patients with chronic or paroxysmal nonvalvular AF documented by ECG were randomized to receive low-dose warfarin (n=212; prothrombin-time ratio 1.2 to 1.5, corresponding to an INR between 1.5 and 2.7) or no anticoagulant treatment (n=208; aspirin or nothing).11 Exclusion criteria were intracardiac thrombus, left ventricular aneurysm, severe CHF, valve replacement, stroke in the previous 6 months, increased bleeding risk, planned cardioversion, indication for aspirin therapy or indication or contraindication for anticoagulation. The primary endpoint was ischemic stroke. Systemic embolism was also an endpoint. Bleeding complications and deaths were recorded.

The mean follow-up was 2.2 years. The annual rate of stroke was 2.98% in the placebo group and 0.41% in the warfarin group (RR 0.14, p=0.0022). The annual mortality rate was 5.97% for placebo and 2.25% for warfarin (RR 0.38, p=0.005). There was only one fatal hemorrhage in each group, and three major bleeding events (two with warfarin and one with placebo). There were 38 minor bleeding episodes with warfarin and 21 episodes with placebo (RR 1.62, 95% confidence interval [CI] 0.95–2.74). Some of the main results are shown in Table 2.

In the Stroke Prevention in Atrial Fibrillation (SPAF) multicenter randomized trial, 1330 patients with permanent or paroxysmal nonvalvular AF diagnosed by ECG 12 months previously were enrolled in order to compare aspirin (325mg daily, double-blind) or warfarin (INR 2.0–4.5) with placebo.12 Patients with ischemic stroke and TIA more than two years before the study were included. Patients were excluded if they had valve replacement, mitral stenosis, or other requirements or contraindication for aspirin or warfarin therapy. Two groups were formed. In group 1, patients received warfarin openly (n=210) or, blindly, aspirin (n=206) or placebo (n=211). In group 2, patients received aspirin (n=346) or placebo (n=357). The primary endpoint was ischemic stroke and systemic embolism.

During a median follow-up of 1.3 years, there was a 42% reduction in the primary event rate in group 2 (3.6%/year [aspirin] vs. 6.3%/year [placebo], p=0.02) and a 67% reduction in group 1 (2.3%/year [warfarin] vs. 7.4%/year [placebo], p=0.01). The primary event and mortality decreased by 58% (p=0.01) with warfarin and 32% (p=0.02) with aspirin. The risk of significant bleeding was similar in all groups. Some of the main results are shown in Table 3.

The Canadian Atrial Fibrillation Anticoagulant Study (CAFA) was stopped before completion of its planned recruitment of 630 patients,13 after the publication of evidence from two different studies10,12 demonstrating the efficacy of warfarin in reducing systemic thromboembolism. In this trial, 187 patients were randomized to warfarin (INR 2–3) and 191 to placebo. The primary outcome events were ischemic stroke (except lacunar), systemic embolism and intracranial or fatal hemorrhage. The results indicated a reduction in the number of primary events in the warfarin group, but none of the results were statistically significant.

In the Stroke Prevention in Nonrheumatic Atrial Fibrillation (SPINAF) trial,14 a double-blind, randomized, placebo-controlled study, 571 male patients of any age with chronic nonvalvular AF documented by ECG received warfarin (INR 1.2–1.5) or placebo (n=265). Patients were excluded if they had paroxysmal AF and indication for treatment or contraindication to treatment with antiplatelet agents or anticoagulants. The primary endpoint was cerebral infarction and the secondary endpoints were cerebral hemorrhage and death. The mean follow-up was 1.7 years for the placebo group and 1.8 years for the warfarin group.

In the 525 patients without a previous history of stroke, the annual primary event rate was 4.3% in the placebo group (n=265) and 0.9% in the warfarin group (n=260; risk reduction 0.79, p=0.001). In patients over 70 years, the corresponding rate was 4.8% in the placebo group and 0.9% in the warfarin group (risk reduction: 0.79, p=0.02). In the patients with prior stroke, stroke was more common (9.3% for placebo and 6.1% for warfarin; risk reduction 0.40, p=0.63). The only episode of cerebral hemorrhage in patients with no history of previous stroke occurred in a 73-year-old patient in the warfarin group. All other major bleeds were gastrointestinal events, with an annual rate of 0.9% in the placebo group and 1.3% in the warfarin group (p=0.54). The annual minor bleeding rate was 10.5% with placebo and 14.0% with warfarin (p=0.04). In patients without prior stroke, the annual mortality rate was 5.0% with placebo and 3.3% with warfarin (risk reduction 0.3; p=0.19). The risk of stroke or death was 53% lower in the warfarin group (p=0.003). Some of the main results are shown in Table 4.

In the multicenter randomized European Atrial Fibrillation Trial (EAFT),15 1007 patients aged over 25 with nonvalvular AF documented by ECG and with TIA or minor ischemic stroke in the previous three months were divided into two groups. The first group received open anticoagulation with warfarin (INR 2.5–4.0, n=225), or double-blind treatment with either aspirin (300mg/day, n=230) or placebo (n=214). Group 2 included patients with contraindications to anticoagulation, who were randomized to receive double-blind treatment with aspirin (n=174) or placebo (n=164). Exclusion criteria included secondary causes of AF, current antiplatelet or anticoagulant therapy, other cardiac embolic sources (such as prosthetic valves, cardiac aneurysm, atrial myxoma or MI in the preceding three months), and contraindication to, or absolute indication for, aspirin. Patients were excluded from receiving anticoagulant treatment if they had high bleeding risk, hypertension (>180/100mmHg), chronic alcoholism, hemorrhagic retinopathy or previous intracranial hemorrhage. The primary endpoint was death from vascular disease, nonfatal stroke (ischemic and hemorrhagic), nonfatal MI, or systemic embolism. Secondary events were death from all causes, all strokes (fatal and nonfatal) and other major thromboembolic events.

The mean follow-up was 2.3 years. In group 1, the annual primary event rate was 8% with warfarin and 17% with placebo (hazard ratio [HR] 0.53, p=0.001). The risk of stroke was reduced from 12% to 4%/year (HR 0.34, p<0.001). Combining the results of both groups, the annual primary event rate was 15% with aspirin and 19% with placebo (HR 0.83, p=0.12). The annual rate of stroke was 10% with aspirin and 12% with placebo (HR 0.86, p=0.31). Regarding mortality, there was no statistically significant difference between warfarin and placebo (8%/year vs. 9%/year, HR 0.82, p=0.37) or between aspirin and placebo (11%/year vs. 12%/year, HR 0.91, p=0.48). With respect to the primary event, warfarin was more effective than aspirin (HR 0.60, p=0.008), largely due to the decreased rate of stroke (HR 0.38, p<0.001). The annual rate of bleeding was higher with warfarin compared to aspirin (HR 2.8, 95% CI 1.7–4.8, p<0.001) and to placebo (HR 3.4, 95% CI 1.9–6.0, p<0.001). Some of the main results are shown in Table 5.

In the multicenter, randomized, unblinded Stroke Prevention in Atrial Fibrillation II study (SPAFII), 715 adult patients aged 75 years or less and 385 patients aged over 75 years with nonvalvular AF documented by ECG were enrolled to receive aspirin (325mg/day) or warfarin (INR 2.0–4.5).16 Patients were excluded if they had prosthetic heart valves, mitral stenosis, or requirements for or contraindication to warfarin or aspirin, lone AF in patients under 60 years old, or ischemic stroke or TIA in the previous two years. The primary event was ischemic stroke and systemic embolism in n patients aged 75 or less, the annual primary event rate was 1.9% with aspirin and 1.3% with warfarin (RR 0.67, p=0.24, mean prothrombin time ratio=1.5). In patients older than 75 years, the annual primary event rate was 4.8% with aspirin and 3.6% with warfarin (RR 0.73, p=0.39), mean prothrombin (time ratio=1.4). The overall annual primary event rate was 2.7% with aspirin and 1.9% with warfarin (RR 0.70, p=0.15). Patients with risk factors for thromboembolism (history of hypertension, prior thromboembolism, recent heart failure) assigned to aspirin had a higher primary event rate than those without risk factors (p<0.001). In patients aged 75 or less, the annual major bleeding rate was 0.9% with aspirin and 1.7% with warfarin (p=0.17) and in patients over 75 years, the annual bleeding rate was respectively 1.6% and 4.2% (p=0.04). The major bleeding rate with warfarin was higher in older patients, despite similar intensity of coagulation (p=0.008). The rate of intracranial hemorrhage (ICH) was higher in patients aged over 75 with warfarin than in younger patients (1.8% vs. 0.5%, p=0.05). Some of the main results are shown in Table 6.

This study (Stroke Prevention in Atrial Fibrillation III) randomized 1044 patients with AF and at least one thromboembolic risk factor to openly receive fixed low-dose warfarin (0.5–3.0mg/day, INR 1.2–1.5) plus aspirin (325mg/day) (n=521), or adjusted-dose warfarin (INR 2.0–3.0, n=523).17 Selection criteria included the presence of AF diagnosed six months earlier and at least one of the following: CHF or left ventricular fractional shortening≤25%, TIA, previous ischemic stroke or systemic embolism (in the previous 30 days), systolic blood pressure higher than 160mmHg, or female gender over 75 years old. Patients were excluded if they had valve replacement, mitral stenosis, indication or contraindication to the use of warfarin or aspirin, or inability to give informed consent. The primary endpoint was stroke and systemic embolism and the secondary events were major bleeding and death.

The study was stopped after a median follow-up of 1.1 years due to a higher rate of ischemic stroke and systemic embolism in the group with combined therapy (7.9%/year vs. 1.9%/year; p<0.0001). The same conclusions were found for the annual rates of disabling or fatal stroke (5.6%/year vs. 1.7%/year, p=0.0007) and rates of primary event or death from cardiovascular causes (11.8%/year vs. 6.4%/year, p=0.002). The major bleeding rate was similar in both groups (2.4%/year for the group with combined therapy vs. 2.1%/year for the warfarin group). The mean INR in the combined therapy group was 1.3 compared to 2.4 in the group with adjusted-dose warfarin. Some of the main results are shown in Table 7.

In this multicenter study (Studio Italiano Fibrilazzione Atriale),18 916 patients aged over 30 with chronic or paroxysmal nonvalvular atrial fibrillation and a recent episode (in the previous 15 days) of cerebral ischemia (TIA or stroke), were randomized to receive indobufen (462 patients, 100mg [if creatinine clearance <80ml/min] or 200mg) or warfarin (454 patients, INR=2–3.5) over 12 months. Exclusion criteria included rheumatic or congenital valvular disease, valvular prostheses, cardioversion in the previous two weeks, intracardiac thrombus or tumor, left ventricular aneurysm, heart failure (NYHA class >III), MI or unstable angina in the previous month, severe hypertension, and carotid endarterectomy or coronary or peripheral revascularization procedures in the previous six months. The primary endpoint was nonfatal stroke (ischemic and hemorrhagic), systemic embolism, nonfatal MI and death from cardiovascular causes.

The incidence of the primary outcome was 10.6% for the indobufen group and 9% in the warfarin group, with no statistically significant difference between the groups. The incidence of noncerebral bleeding was 0.6% for the indobufen group and 5.1% in the warfarin group, the difference being statistically significant (p<0.01). Some of the main results are shown in Table 8.

The second Copenhagen Atrial Fibrillation, Aspirin, and Anticoagulant Therapy Study (AFASAK II)19 was terminated prematurely after the publication of evidence from a different study17 demonstrating the ineffectiveness of low-intensity anticoagulation plus aspirin. In this trial, 677 patients with chronic nonvalvular AF were randomized to receive, unblinded, fixed low-dose warfarin (1.25mg/day), fixed low-dose warfarin (1.25mg/day) plus aspirin (300mg/day), aspirin (300mg/day) or adjusted-dose warfarin (INR 2.0–3.0). The cumulative primary event rate (stroke or systemic thromboembolic event) after one year was 5.8%, 7.2%, 3.6% and 2.8% for fixed low-dose warfarin, warfarin plus aspirin, aspirin, and adjusted-dose warfarin, respectively (p=0.67). The cumulative mortality rate after three years was 3.9%, 5.9%, 13.4% and 10.3%, respectively (p=0.27).

In another report from the same study20 to an evaluation was carried out of bleeding events. During treatment with fixed low-dose warfarin, warfarin plus aspirin, aspirin, and adjusted-dose warfarin, the annual major bleeding rate was 0.8%, 0.3%, 1.4% and 1.1%, respectively (p=0.20). After three years of treatment, the cumulative bleeding rate was 24.7%, 24.4%, 30.0% and 41.1%, respectively (p=0.003).

This study was stopped early after the publication of evidence17 indicating that low-dose warfarin puts patients at high risk of stroke compared to those with an INR adjusted to 2–3. In this open-labeled multicenter study,21 303 patients aged over 60 and with chronic nonrheumatic AF were randomized to receive fixed low-dose (1.25mg/day) or adjusted-dose warfarin (INR 2–3). The primary event rate was 6.2% for the fixed low-dose warfarin and 3.6% in the group with adjusted-dose warfarin (p=0.29). The rate of ischemic stroke was higher in the group with fixed low-dose warfarin (3.7%/year vs. 0%/year, p=0.025). Major bleeding occurred in 2.6%/year in the group with adjusted-dose warfarin and 1%/year in the group with fixed low-dose warfarin (p=0.19).

In the Primary prevention of Arterial Thromboembolism in nonrheumatic Atrial Fibrillation (PATAF) trial,22 729 patients aged over 60 years with chronic or paroxysmal AF, diagnosed by ECG up to two years prior to selection, were divided into two groups. Patients in group 1 were randomized to receive adjusted-dose anticoagulant (n=131, INR 2.5–3.5), low-dose anticoagulant (n=122, INR 1.1–1.6) or aspirin (n=141, 150mg/day). Patients in group 2 received aspirin (n=178, 150mg/day) or low-dose anticoagulant (n=157, INR 1.1–1.6). The following were exclusion criteria: AF with a treatable cause, previous stroke, rheumatic valvular disease, MI or cardiovascular surgery in the previous year, cardiomyopathy (left ventricular ejection fraction [LVEF] <40%), chronic heart failure, previous systemic embolism, coumarin use in the previous 3 months, contraindication to aspirin or coumarin, life expectancy less than 2 years and the presence of a pacemaker. Patients were excluded from standard anticoagulation if they were older than 78, or had retinopathy, duodenal ulcer, history of gastrointestinal or genitourinary bleeding, or hypertension (>185/105mmHg). The primary endpoint was ischemic or hemorrhagic stroke, systemic embolism, major bleeding and vascular death. Secondary outcome events were nonfatal MI, retinal infarction, TIA, minor bleeding or non-vascular death.

There were 108 primary events (annual rate of 5.5%), with no significant differences between patients with dose-adjusted (HR 0.78, 95% CI 0.34–1.8) or low-dose anticoagulant therapy (HR 0.91, 95% CI 0.61–1.4) compared to aspirin. There were 45 deaths from vascular causes (annual rate of 2%) and there were also no significant differences between patients with dose-adjusted anticoagulant therapy (HR 0.76, 95% CI 0.23–2.5) or low-dose therapy (HR 1.1, 95% CI 0.58–2.0) compared to aspirin. The annual rate of bleeding was 3.9%, with no significant differences between patients with dose-adjusted (HR 1.3, 95% CI 0.59–3.0) or with low-dose anticoagulation (HR 1.02, 95% CI 0.58–1.8) compared to aspirin. Some of the main results are shown in Table 9.

This study (by the Japanese Nonvalvular Atrial Fibrillation-Embolism Secondary Prevention Cooperative Study Group) randomized 115 patients younger than 80 years old with nonvalvular AF and with a history of stroke or TIA (1–6 months previously) to receive conventional-dose warfarin (INR 2.2–3.5, n=55) or low-dose warfarin (INR 1.5–2.1, n=60).23 Exclusion criteria included intracardiac thrombus, left ventricular aneurysm, CHF (NYHA class IV), heart valve disease, previous episode of ICH, severe kidney or liver disease and cancer. The primary endpoint was stroke, systemic embolism, TIA and amaurosis fugax, and the secondary event was bleeding.

The study was stopped after a median follow-up of 658±423 days, due to the occurrence of major bleeding complications in six patients with conventional-dose warfarin, which represents an occurrence rate of 6.6% per year, compared to 0%/year in patients treated with low-dose warfarin. These six patients, with a mean age of 73.7±3.7 years, had an INR within the range established prior to the events (median INR=2.8). The annual rate of recurrent ischemic stroke was low in both groups (1.1% with conventional-dose and 1.7% with low-dose warfarin, p>0.99). Some of the main results are shown in Table 10.

In the open multicenter Swedish Atrial Fibrillation Trial,24 668 patients aged over 60 with persistent or permanent nonvalvular AF were randomized to receive fixed-dose warfarin (1.25mg) plus aspirin (75mg, n=334), or no antithrombotic treatment (n=334). Exclusion criteria were prior stroke or TIA, heart valve prosthesis, cardiac valvular disease, hypertension (>190/110mmHg), reversible causes of atrial fibrillation, severe heart failure (NYHA III-IV), hypertension, bradycardia, renal failure, liver disease, chronic obstructive pulmonary disease, bleeding disorder, and indication for or contraindication to anticoagulation or antiplatelet agents. The primary endpoint was stroke and secondary endpoints were death from any cause, cardiovascular morbidity, TIA, MI, peripheral embolism and bleeding.

The mean follow-up was 33 months. The rate of stroke was 9.6% with combined therapy and 12.3% in controls (HR 0.78, p=0.28). The rate of TIA was 3.3% with combined therapy and 4.5% in controls (HR 0.73, p=0.42) while the rate of MI was 4.2% with combined therapy and 5.4% in controls (HR 0.77, p=0.46). During follow-up there were 63 deaths, 9.3% in the group treated with antithrombotics and 10.8% in the untreated group (p=0.55). Bleeding was more frequent with combined therapy (5.7% vs. 1.2%, p=0.003). Some of the main results are shown in Table 11.

In this multicenter open-label study (National Study for Prevention of Embolism in Atrial Fibrillation),25 1209 patients with chronic or paroxysmal AF were randomized in two groups. The high-risk group included patients without mitral stenosis and with previous embolism or patients with mitral stenosis with or without prior embolism. The remaining patients were included in an intermediate risk group (patients with risk factors or aged over 60 years). In the intermediate risk group, 242 patients received triflusal (600mg/day), 237 received acenocoumarol (INR 2–3) and 235 received a combination of both drugs (INR 1.25–2). In the high-risk group, 259 patients received acenocoumarol (INR 2–3) and 236 patients received combined therapy (INR of 1.4–2.4). Patients were excluded if they had mechanical valve prosthesis, stroke within the previous 6 months, serum creatinine >3mg/dl, alcohol or drug abuse, severe uncontrolled hypertension, diffuse arteriosclerosis, indication for therapy with anti-inflammatory drugs or indication for or contraindication to antiplatelet or anticoagulant therapy. The primary endpoint was death from cardiovascular causes, TIA, nonfatal stroke or systemic embolism.

The mean follow-up was 2.76 years. In the intermediate-risk group, there was a lower incidence of the primary outcome with combined therapy compared to the group with triflusal (HR 0.24, p=0.001) and to the acenocoumarol group (HR 0.33, p=0.02). There was no significant difference between the acenocoumarol and triflusal groups (HR 0.72, p=0.32). Regarding the high-risk group, combined therapy led to a 49% reduction in the primary event rate compared to therapy with acenocoumarol (HR 0.51, p=0.03). Patients in the intermediate-risk group treated with triflusal had a significantly lower bleeding risk than patients treated with acenocoumarol or combined therapy. Patients with mitral stenosis and anticoagulant treatment of embolism had similar rates of embolism, compared to patients without valvular pathology. Some of the main results are shown in Table 12.

Ximelagatran is an oral direct thrombin inhibitor. Although it had shown promising results,26,27 with similar antithrombotic efficacy to warfarin, research on this drug has ceased because of its potential hepatotoxicity. The SPORTIF III and SPORTIF V clinical trials, although of historical interest concerning antithrombotic therapy of AF, will therefore not be described here due to space limitations.

In this open study (Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events),28 6706 patients were randomized to receive oral anticoagulant therapy (OAC) (n=3371; INR 2.0–3.0) or clopidogrel (75mg daily) in combination with aspirin (75–100mg/day, n=3335). Selection criteria included the presence of AF and of at least one of the following characteristics: age ≥75 years; undergoing treatment for arterial hypertension; previous TIA, stroke or systemic embolism; LVEF<45%; peripheral arterial disease; age between 55 and 74 years; and diabetes or CAD. Patients were excluded if they had a contraindication to clopidogrel or OAC, peptic ulcer disease in the previous 6 months, prior ICH, significant thrombocytopenia or mitral stenosis. The primary endpoint was stroke, systemic embolism, MI and death from cardiovascular causes.

The mean follow-up was 1.28 years. The study was discontinued due to clear evidence of the superiority of OAC. There were 165 primary events in patients with OAC (annual risk 3.90%) and 234 events in patients with combined antiplatelet therapy (annual risk 5.60%, RR 1.44, p=0.0003). The risk reduction with OAC therapy was more evident in the prevention of stroke (RR 1.72 with clopidogrel+aspirin, p=0.001) and systemic embolism (RR 4.66 with clopidogrel+aspirin, p=0.005). The rate of MI was less than 1% in both groups. There were no significant differences between the mortality rates in the two groups. The combination of the primary event and major bleeding was more favorable with OAC (RR 1.41 with clopidogrel+aspirin, p<0.0001). The major bleeding rates were similar between the two groups, but minor bleeding were more frequent with combination therapy (RR 1.23, p=0.0009). Patients with OAC who had received this treatment prior to the study (77%) had a greater reduction in cardiovascular events (RR 1.50 with clopidogrel+aspirin, 95% CI 1.19–1.80) and a significantly lower risk of major bleeding (p=0.03). Some of the main results are shown in Table 13.

In this randomized study, carried out in 704 Chinese patients with nonvalvular AF, adjusted-dose warfarin (INR 2.0–3.0) was shown to significantly reduce thromboembolic risk compared to 150–160mg/day aspirin.29 The median follow-up was 19 months. Death or ischemic stroke was reduced by warfarin (2.7% vs. 6.0%, p=0.03) and relative risk decreased by 56%. However, there was no significant difference in mortality, and warfarin treatment was associated with an increased bleeding rate (6.9% vs. 2.4%, p<0.05).

In the open-label Birmingham Atrial Fibrillation treatment of the Aged Study,30 973 patients over 75 years of age followed in primary care and with AF diagnosed by ECG were randomized to receive warfarin (INR 2–3) or aspirin (75mg/day). Patients were excluded if they had rheumatic heart disease, major nontraumatic hemorrhage in the previous five years, ICH, peptic disease in the previous year, esophageal varices, allergic hypersensitivity to warfarin or aspirin, terminal illness, surgery in the previous three months or hypertension (>180/110mmHg). The primary endpoint was fatal or disabling stroke (ischemic or hemorrhagic) and systemic embolism. The secondary events were major extracranial bleeding, other major vascular events (stroke, MI, pulmonary embolism and death from cardiovascular causes) and death. Evaluation of the events was blinded.

The mean follow-up was 2.7 years. The primary event rate was 1.8% in the warfarin group and 3.8% in the aspirin group (RR 0.48, p=0.0027). There was a decrease in the incidence of ischemic stroke in the warfarin group (0.8% vs. 2.5%, p=0.0004). Major vascular events were less frequent in the warfarin group (5.9% vs. 8.1%, RR 0.73, p=0.03). The combination of the primary event with major bleeding was also less frequent in the warfarin group (3.0% vs. 5.1%, RR 0.59, p=0.008). There were no significant differences between warfarin and aspirin regarding total mortality (8.0% vs. 8.4%, p=0.73) or major bleeding (1.9% vs. 2.0%, p=0.90). Some of the main results are shown in Table 14.

This randomized open-label prospective study was designed to evaluate the differences between risks and benefits of adjusted-dose warfarin (INR 2.0–3.0) and aspirin 300mg/day in octogenarians.31 A total of 75 octogenarian patients were included (36 to receive warfarin and 39 to receive aspirin), ambulant and diagnosed as having permanent AF. Patients were excluded if they had any of the following: history of falls or syncopal episode within the previous 12 months; epileptiform seizures; alcoholic liver disease; previous history of thromboembolism; gastrointestinal or genitourinary bleeding in the previous six months; previous intracranial hemorrhage; blood pressure >180/100mmHg; abnormal prothrombin time; Folstein mini mental state score <26; previous intolerance/allergy to warfarin or aspirin; patients already taking warfarin. The follow-up was 12 months and the primary outcome included death, thromboembolism, serious bleeding and withdrawal from the study. There were no significant differences between the two groups regarding the primary outcome. A total of 17 patients reached an endpoint in the aspirin group vs. 9 patients in the warfarin group (p=0.114). However there were significantly fewer adverse reactions with warfarin than with aspirin (p=0.002) and adherence to treatment was equivalent. There was no serious bleeding in the warfarin group, in contrast to aspirin (three events).

In this study,32 subcutaneous idraparinux (a long-acting activated coagulation factor X inhibitor; 2.5mg/week) was compared to adjusted-dose vitamin K antagonists (INR 2–3), in patients with nonvalvular AF. The trial was terminated because of excess bleeding in the idraparinux group.

In this clinical trial (Randomized Evaluation of Long-Term Anticoagulation Therapy),33 18113 patients with AF were randomized to receive fixed-dose dabigatran (a direct thrombin inhibitor; 110mg or 150mg twice daily) or warfarin (doses of 1, 3 or 5mg; adjusted to obtain an INR between 2.0–3.0). An update of major results was published in 2010.34 Selection criteria included the presence of AF diagnosed by ECG at the time of selection or in the previous six months and at least one of the following: prior TIA or stroke; LVEF <40%; NYHA class II or symptoms of severe heart failure less than 6 months prior to selection; age ≥75 years or between 65 and 74 years; and diabetes, hypertension or CAD. Patients were excluded if they had severe valvular heart disease, stroke in the previous 14 days, increased bleeding risk, creatinine clearance <30ml/min, active liver disease or pregnancy. The primary endpoint was stroke or systemic embolism.

The mean follow-up was 2 years. The annual rate of the primary outcome was 1.71% with warfarin, 1.54% with 110mg dabigatran (RR 0.90, p=0.30) and 1.11% with 150mg dabigatran (RR 0.65 compared with warfarin, p<0.001).34 The annual rate of MI was 0.64% with warfarin, 0.82% with 110mg dabigatran (RR 1.29, p=0.09) and 0.81% with 150mg dabigatran (RR 1.27, p=0.12). The annual major bleeding rate was 3.57% with warfarin, 2.87% with 110mg dabigatran (RR 0.80, p=0.003) and 3.32% with 150mg dabigatran (RR 0.93, p=0.32).

In the 2009 report, the following findings were presented: (1) The annual mortality rate from cardiovascular causes was 2.69% with warfarin, 2.43% with 110mg dabigatran (RR 0.90, p=0.21) and 2.28% with 150mg dabigatran (RR 0.85, p=0.04); (2) The annual rate of hemorrhagic stroke was 0.38% with warfarin, 0.12% with 110mg dabigatran (RR 0.31, p<0.001) and 0.10% with 150mg dabigatran (RR 0.26, p<0.001); (3) There was a higher rate of major gastrointestinal bleeding with 150mg dabigatran (1.51%/year) compared to warfarin (1.02%/year) (RR 1.50, p<0.001); (4) Compared to 110mg dabigatran, 150mg led to a greater reduction in the risk of stroke or systemic embolism (p=0.005); (5) There was no significant difference between the rate of cardiovascular death (p=0.44) or death from any cause (p=0.66); (6) However, 150mg dabigatran was associated with an increased risk of major (p=0.052), minor (p<0.001), gastrointestinal (p=0.007) and any bleeding33; (7) Dyspepsia occurred in 5.8% of patients treated with warfarin, 11.8% in those treated with 110mg dabigatran and 11.3% in those treated with 150mg dabigatran (p<0.001 for both comparisons); (8) There were no significant modifications in creatinine clearance in the groups with dabigatran; (9) The incidence of alanine aminotransferase and aspartate aminotransferase elevated three times above the normal limit was similar in all groups.33 Some of the main results are shown in Table 15.

In a further report from the same study,35 the effects of dabigatran were studied in relation to the time in therapeutic range (TTR) for warfarin reached in each centre. The effects of dabigatran “vs. warfarin were consistent irrespective of centres’ quality of INR control”. The authors also noted that the “advantages of dabigatran were greater at sites with poor INR control than at those with good INR control”.

The “Rivaroxaban once-daily oral direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation” study was a randomized, double-blind, double-dummy trial.36 Patients were included if they had at least two risk factors (heart failure, hypertension, age 75 years or over, diabetes), or a past history of stroke, TIA or systemic embolism. Patients (14264) were randomized to take either rivaroxaban (20mg/day, or 15mg in patients with creatinine clearance of 30–49ml/min), or warfarin (INR target of 2.0–3.0). The mean age of the patients was 73 years. The primary endpoint was stroke or systemic embolism; in the per-protocol, as-treated population analysis (rivaroxaban 6958 patients, warfarin 7004 patients), “stroke or systemic embolism occurred in 188 patients in the rivaroxaban group (1.7% per year) and in 241 patients in the warfarin group (2.2% per year) (HR in the rivaroxaban group, 0.79; 95% CI 0.66–0.96; p<0.001 for noninferiority)”36; in the intention-to-treat population (rivaroxaban 7081 patients, warfarin 7090 patients), “primary events occurred in 269 patients in the rivaroxaban group (2.1% per year) and in 306 patients in the warfarin group (2.4% per year) (HR 0.88; 95% CI 0.74–1.03; p<0.001 for noninferiority; p=0.12 for superiority)”36 (Table 16). Secondary efficacy outcomes included the following: myocardial infarction occurred in 101 patients under rivaroxaban therapy, compared to 126 patients in the warfarin group; 208 patients died in the rivaroxaban group, compared to 250 deaths in the warfarin group (as-treated safety population; both comparisons were non-significantly different). The incidence of major and clinically relevant nonmajor bleeding was not significantly different in the two groups, but intracranial hemorrhage and fatal bleeding were less common with rivaroxaban, whereas major bleeding from a gastrointestinal site was more common with rivaroxaban.

The “Apixaban for reduction in stroke and other thromboembolic events in atrial fibrillation” study was a randomized, double-blind, double-dummy trial.37 Patients were included if they had at least one risk factor (age at least 75 years; previous stroke, TIA or systemic embolism; heart failure; diabetes; hypertension). Patients (18201) with atrial fibrillation were randomized to take either apixaban (a direct factor Xa inhibitor; 5mg twice daily, or 2.5mg in patients with two or more of the following criteria: age at least 80 years, body weight no more than 60kg, plasma creatinine 1.5mg/dl or more; 9120 patients), or warfarin (INR target of 2.0–3.0; 9081 patients). The mean age of the patients was 70 years. The primary endpoint was stroke or systemic embolism, and this endpoint “occurred in 212 patients in the apixaban group (1.27% per year) as compared with 265 patients in the warfarin group (1.60% per year) (HR in the apixaban group, 0.79; 95% CI 0.66–0.95; p<0.001 for noninferiority and p=0.01 for superiority)” (Table 17).

Secondary efficacy outcomes included the following: death from any cause was significantly less common in the apixaban group (603 vs. 669 patients, 3.52%/year vs. 3.94% per year; HR 0.89; 95% CI 0.80–0.99; p=0.047); hemorrhagic stroke was significantly less common in the apixaban group (40 vs. 78 patients, HR 0.51; 95% CI 0.35–0.75, p<0.001), as were all cases of stroke; the incidence of myocardial infarction was not significantly different in the two groups (90 vs. 102 cases, apixaban/warfarin; HR 0.88; 95% CI 0.66–1.17, p=0.37).

Major bleeding occurred in 327 patients under apixaban therapy, compared to 462 under warfarin (HR 0.69; 95% CI 0.60–0.80; p<0.001). Intracranial hemorrhage was also significantly less frequent in the apixaban group (0.33% per year vs. 0.80% per year, HR 0.42; 95% CI 0.30–0.58; p<0.001).

In this prospective cohort multicenter study,38 892 patients with AF received a daily dose of aspirin (325mg). The selected patients had atrial fibrillation and low risk of stroke, based on the absence of four thromboembolic risk factors: CHF or left ventricular fractional shortening ≤25%, prior thromboembolism, systolic blood pressure above 160mmHg, or female gender older than 75 years. The study excluded patients with lone AF, valve replacement, mitral stenosis, contraindications for aspirin or indication for anticoagulants. The primary endpoint was ischemic stroke and systemic embolism.

The mean follow-up was 2 years. The annual primary event rate was 2.2% (95% CI 1.6–3.0%). The annual rate of ischemic stroke was 2.0% (95% CI 1.5–2.8%). The primary event rate was higher in patients with hypertension than in those without (3.6% vs. 1.1%, p<0.001). The rate of disabling ischemic stroke was low in both patients with or without hypertension (1.4% vs. 0.5%). Major bleeding occurred at a rate of 0.7% per year. A history of hypertension (RR 3.3, p=0.001) and age (RR 1.7 increase per 10 years, p=0.01) were independent risk factors for stroke.

In the Low-dose Aspirin, Stroke, and Atrial Fibrillation (LASAF) study, an open, multicenter, randomized study,39 285 patients with AF were divided into three groups. Group A1 was treated with 125mg of aspirin daily (n=104). Group A2 was treated with 125mg of aspirin on alternate days (n=90). Group C (control) was not treated with either OAC or antiplatelet agents (n=91). Exclusion criteria were contraindication to aspirin use or indication for OAC or antiplatelet therapy prior to the beginning of the study. The primary events were cardiovascular death and death from any cause, thrombotic, embolic or hemorrhagic stroke, other embolic events, myocardial infarction, need for coronary surgery and hospital admission for an episode of unstable angina. Stroke, myocardial infarction, death from cardiovascular causes and need for coronary surgery were considered major cardiovascular events.

The follow-up was 1–62 months. The mortality rate from cardiovascular causes was 4.8% in group A1 and 6.6% in group C (relative risk reduction [RRR] 27%). The rate of major cardiovascular events was 7.7% in group A1 and 11% in group C (RRR 43%). The rate of stroke was 3.8% in group A1 and 3.3% in group C (RRR 13%). None of these differences was statistically significant. In group A2, there was a 65% reduction in the risk of stroke compared to group C (1.1% vs. 3.3%, p=0.05). Furthermore, the mortality rate from cardiovascular causes (1.1% vs. 6.6%, p=0.02) and incidence of major cardiovascular events (2.2% vs. 11%, p=0.001) were 80% lower in group A2 compared to group C. The reduction in major cardiovascular events between groups A1 and A2 was statistically significant (7.7% vs. 2.2%, absolute risk reduction [ARR] 5.5%, p<0.05). The differences regarding other endpoints were not statistically significant. Some of the main results are shown in Table 18.

In this open, multicenter study (Japan Atrial Fibrillation Stroke Trial),40 871 Japanese patients with chronic or paroxysmal nonvalvular AF documented by ECG were randomized to receive aspirin (150–200mg, n=426) or no antithrombotic treatment (n=445). Exclusion criteria were prosthetic heart valve, rheumatic heart disease, mitral valve disease, uncontrolled hypertension; reversible causes of AF, severe HF, prior thromboembolism, previous gastrointestinal or intracranial bleeding (in the previous 6 months), and indication for anticoagulation or antiplatelet agents. The primary endpoint was TIA, stroke and death from cardiovascular causes.

The mean follow-up was 768±403 days. The study was terminated early due to the occurrence of 27 primary events in the aspirin group (3.1%/year) compared to 23 events in the control group (2.4%/year), p=0.458, suggesting a low probability of aspirin being superior to no treatment in the prevention of primary events. There were seven major bleeding events in the aspirin group (1.6%) and two events in the control group (0.4%, p=0.101). Some of the main results are shown in Table 19.

A post-hoc subgroup analysis of the double-blind randomized study CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance) was published but will not be discussed here since treatment of AF was not the primary aim of the study.41

In this study,42 7554 patients with AF and high risk of stroke for whom therapy with vitamin K antagonists was not indicated were randomized to receive, blindly, clopidogrel (3772 patients, 75mg/day) or placebo (3782 patients), in addition to aspirin (75–100mg/day). The inclusion and exclusion criteria were the same as in the ACTIVE-W study, but in this trial patients were excluded if they required a vitamin K antagonist or clopidogrel or had bleeding risk factors. The primary endpoint was any major vascular event (stroke, MI, systemic embolism or death from vascular causes).

After a mean follow-up of 3.6 years, 832 events had occurred in patients receiving clopidogrel (6.8% per year) and 924 events in patients receiving placebo (7.6% per year) (RR 0.89, p=0.01). Stroke occurred in 296 patients receiving clopidogrel+aspirin (2.4% per year) and in 408 patients receiving placebo+aspirin (3.3%/year) (RR 0.72, p<0.001). MI occurred in 90 patients who received clopidogrel+aspirin (0.7%/year) and in 115 patients receiving placebo+aspirin (0.9%/year) (RR 0.78, p=0.08). The annual rates of systemic embolism and mortality from cardiovascular causes were similar between the two groups. Major bleeding occurred in 251 patients receiving clopidogrel+aspirin (2.0%/year) and in 162 patients receiving placebo+aspirin (1.3%/year) (RR 1.57, p<0.001). Some of the main results are shown in Table 20.

In the Apixaban vs. ASA to reduce the risk of stroke (AVERROES) trial,43 patients with AF and at least one risk factor for stroke, unsuitable for OAC, were randomized to take either aspirin (81–324mg/day) or apixaban, an oral activated factor X inhibitor (5 or 2.5mg twice daily). A total of 5600 patients were enrolled. The study was terminated due to evidence favoring apixaban. Major results of the study included (Table 21): (1) The annual rate of stroke or systemic embolism (the primary outcome) was 3.7% per year on aspirin and 1.6% per year on apixaban (HR 0.45, 95% CI 0.32–0.62, p<0.001); (2) The rate of major bleeding was 1.2%/year on aspirin and 1.4%/year on apixaban (HR 1.13, 95% CI 0.74–1.75, p=0.57); (3) Major intracranial bleeding events occurred in 11 patients treated with apixaban, compared to 13 patients under aspirin therapy; (4) There was no evidence of hepatic toxicity or other major adverse events (Table 21).