Placebo-controlled, randomised trial of warfarin and aspirin for prevention of thromboembolic complications in chronic atrial fibrillation. The Copenhagen AFASAK study. Primary prevention of arterial thromboembolism in non-rheumatic atrial fibrillation in primary care: randomised controlled trial comparing two intensities of coumarin with aspirin. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial. Comparative effects of antiplatelet, anticoagulant, or combined therapy in patients with valvular and nonvalvular atrial fibrillation: a randomized multicenter study. Warfarin versus aspirin for prevention of thromboembolism in atrial fibrillation: Stroke Prevention in Atrial Fibrillation II Study. 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. Primary prevention of arterial thromboembolism in the oldest old with atrial fibrillation--a randomized pilot trial comparing adjusted-dose and fixed low-dose coumadin with aspirin.
From November, 1985, to June, 1988, 1007 outpatients with chronic non-rheumatic atrial fibrillation (AF) entered a randomised trial; 335 received anticoagulation with warfarin openly, and in a double-blind study 336 received aspirin 75 mg once daily and 336 placebo. Each patient was followed up for 2 years or until termination of the trial. The primary endpoint was a thromboembolic complication (stroke, transient cerebral ischaemic attack, or embolic complications to the viscera and extremities). The secondary endpoint was death. The incidence of thromboembolic complications and vascular mortality were significantly lower in the warfarin group than in the aspirin and placebo groups, which did not differ significantly. 5 patients on warfarin had thromboembolic complications compared with 20 patients on aspirin and 21 on placebo. 21 patients on warfarin were withdrawn because of non-fatal bleeding complications compared with 2 on aspirin and none on placebo. Thus, anticoagulation therapy with warfarin can be recommended to prevent thromboembolic complications in patients with chronic non-rheumatic AF. To investigate the effectiveness of aspirin and coumarin in preventing thromboembolism in patients with non-rheumatic atrial fibrillation in general practice.
                Randomised controlled trial.
                729 patients aged >/=60 years with atrial fibrillation, recruited in general practice, who had no established indication for coumarin. Mean age was 75 years and mean follow up 2. 7 years.
                Primary care in the Netherlands.
                Patients eligible for standard intensity coumarin (international normalised ratio 2.5-3.5) were randomly assigned to standard anticoagulation, very low intensity coumarin (international normalised ratio 1.1-1.6), or aspirin (150 mg/day) (stratum 1). Patients ineligible for standard anticoagulation were randomly assigned to low anticoagulation or aspirin (stratum 2).
                Stroke, systemic embolism, major haemorrhage, and vascular death.
                108 primary events occurred (annual event rate 5.5%), including 13 major haemorrhages (0.7% a year). The hazard ratio was 0.91 (0.61 to 1.36) for low anticoagulation versus aspirin and 0.78 (0.34 to 1.81) for standard anticoagulation versus aspirin. Non-vascular death was less common in the low anticoagulation group than in the aspirin group (0.41, 0.20 to 0.82). There was no significant difference between the treatment groups in bleeding incidence. High systolic and low diastolic blood pressure and age were independent prognostic factors.
                In a general practice population (without established indications for coumarin) neither low nor standard intensity anticoagulation is better than aspirin in preventing primary outcome events. Aspirin may therefore be the first choice in patients with atrial fibrillation in general practice. Oral anticoagulation therapy reduces risk of vascular events in patients with atrial fibrillation. However, long-term monitoring is necessary and many patients cannot achieve optimum anticoagulation. We assessed whether clopidogrel plus aspirin was non-inferior to oral anticoagulation therapy for prevention of vascular events.
                Patients were enrolled if they had atrial fibrillation plus one or more risk factor for stroke, and were randomly allocated to receive oral anticoagulation therapy (target international normalised ratio of 2.0-3.0; n=3371) or clopidogrel (75 mg per day) plus aspirin (75-100 mg per day recommended; n=3335). Outcome events were adjudicated by a blinded committee. Primary outcome was first occurrence of stroke, non-CNS systemic embolus, myocardial infarction, or vascular death. Analyses were by intention-to-treat. This study is registered with ClinicalTrials.gov, number NCT00243178.
                The study was stopped early because of clear evidence of superiority of oral anticoagulation therapy. There were 165 primary events in patients on oral anticoagulation therapy (annual risk 3.93%) and 234 in those on clopidogrel plus aspirin (annual risk 5.60%; relative risk 1.44 (1.18-1.76; p=0.0003). Patients on oral anticoagulation therapy who were already receiving this treatment at study entry had a trend towards a greater reduction in vascular events (relative risk 1.50, 95% CI 1.19-1.89) and a significantly (p=0.03 for interaction) lower risk of major bleeding with oral anticoagulation therapy (1.30; 0.94-1.79) than patients not on this treatment at study entry (1.27, 0.85-1.89 and 0.59, 0.32-1.08, respectively).
                Oral anticoagulation therapy is superior to clopidogrel plus aspirin for prevention of vascular events in patients with atrial fibrillation at high risk of stroke, especially in those already taking oral anticoagulation therapy. This trial evaluated the efficacy and safety of the combination of antiplatelet and moderate-intensity anticoagulation therapy in patients with atrial fibrillation associated with recognized risk factors or mitral stenosis.
                Warfarin was more effective than aspirin in preventing stroke in these patients; combined therapy with low anticoagulant intensity was ineffective. Mitral stenosis patients were not investigated.
                We performed a multicenter randomized trial in 1,209 patients at risk. The intermediate-risk group included patients with risk factors or age >60 years: 242 received the cyclooxygenase inhibitor triflusal, 237 received acenocumarol, and 235 received a combination of both. The high-risk group included patients with prior embolism or mitral stenosis: 259 received anticoagulants and 236 received the combined therapy. Median follow-up was 2.76 years. Primary outcome was a composite of vascular death and nonfatal stroke or systemic embolism.
                Primary outcome was lower in the combined therapy than in the anticoagulant arm in both the intermediate- (hazard ratio [HR] 0.33 [95% confidence interval (CI)0.12 to 0.91]; p = 0.02) and the high-risk group (HR 0.51 [95% CI 0.27 to 0.96]; p = 0.03). Primary outcome plus severe bleeding was lower with combined therapy in the intermediate-risk group. Nonvalvular and mitral stenosis patients had similar embolic event rates during anticoagulant therapy.
                The combined antiplatelet plus moderate-intensity anticoagulation therapy significantly decreased the vascular events compared with anticoagulation alone and proved to be safe in atrial fibrillation patients. Warfarin is an established treatment for prevention of ischaemic stroke in patients with atrial fibrillation, but the value of this agent relative to aspirin in unclear. In the first Stroke Prevention in Atrial Fibrillation (SPAF-I) study, direct comparison of warfarin with aspirin was limited by the small number of thromboembolic events. SPAF-II aims to address this issue and also to assess the differential effects of the two treatments according to age. We compared warfarin (prothrombin time ratio 1.3-1.8, international normalised ratio 2.0-4.5) with aspirin 325 mg daily for prevention of ischaemic stroke and systemic embolism (primary events) in two parallel randomised trials involving 715 patients aged 75 years or less and 385 patients older than 75; we sought reductions in the absolute rate of primary events by warfarin compared with aspirin of 2% per year and 4% per year, respectively. In the younger patients, warfarin decreased the absolute rate of primary events by 0.7% per year (95% CI-0.4 to 1.7). The primary event rate per year was 1.3% with warfarin and 1.9% with aspirin (relative risk [RR] 0.67, p = 0.24). The absolute rate of primary events in low-risk younger patients (without hypertension, recent heart failure, or previous thromboembolism) on aspirin was 0.5% per year (95% CI 0.1 to 1.9). Among older patients, warfarin decreased the absolute rate of primary events by 1.2% per year (95% CI-1.7 to 4.1). The primary event rate per year was 3.6% with warfarin and 4.8% with aspirin (RR 0.73, p = 0.39). In this older group, the rate of all stroke with residual deficit (ischaemic or haemorrhagic) was 4.3% per year with aspirin and 4.6% per year with warfarin (RR 1.1). Warfarin may be more effective than aspirin for prevention of ischaemic stroke in patients with atrial fibrillation, but the absolute reduction in stroke rate by warfarin is small. Younger patients without risk factors had a low rate of stroke when treated with aspirin. In older patients the rate of stroke (ischaemic and haemorrhagic) was substantial, irrespective of which agent was given. Patient age and the inherent risk of thromboembolism should be considered in the choice of antithrombotic prophylaxis for patients with atrial fibrillation. Despite the efficacy of warfarin sodium therapy for stroke prevention in atrial fibrillation, many physicians hesitate to prescribe it to elderly patients because of the risk for bleeding complications and because of inconvenience for the patients.
                The Second Copenhagen Atrial Fibrillation, Aspirin, and Anticoagulation Study was a randomized, controlled trial examining the following therapies: warfarin sodium, 1.25 mg/d; warfarin sodium, 1.25 mg/d, plus aspirin, 300 mg/d; and aspirin, 300 mg/d. These were compared with adjusted-dose warfarin therapy (international normalized ratio of prothrombin time [INR], 2.0-3.0). Stroke or a systemic thromboembolic event was the primary outcome event. Transient ischemic attack, acute myocardial infarction, and death were secondary events. Data were handled as survival data, and risk factors were identified using the Cox proportional hazards model. The trial was scheduled for 6 years from May 1, 1993, but due to scientific evidence of inefficiency of low-intensity warfarin plus aspirin therapy from another study, our trial was prematurely terminated on October 2, 1996.
                We included 677 patients (median age, 74 years). The cumulative primary event rate after 1 year was 5.8% in patients receiving minidose warfarin; 7.2%, warfarin plus aspirin; 3.6%, aspirin; and 2.8%, adjusted-dose warfarin (P = .67). After 3 years, no difference among the groups was seen. Major bleeding events were rare.
                Although the difference was insignificant, adjusted-dose warfarin seemed superior to minidose warfarin and to warfarin plus aspirin after 1 year of treatment. The results do not justify a change in the current recommendation of adjusted-dose warfarin (INR, 2.0-3.0) for stroke prevention in atrial fibrillation. Anticoagulation therapy remains largely underused in older people with atrial fibrillation (AF). The aim of this pilot trial was to investigate the effects of low-intensity adjusted-dose and fixed-dose coumadin on the incidence of arterial thromboembolism and bleeding, as well as the efficacy of anticoagulation monitoring in elderly AF patients.
                In this open-label, randomized trial we recruited patients over 75 years of age without previous stroke or systemic embolism. Patients were randomized into three groups, with group A receiving aspirin 100 mg/day, group B fixed-dose coumadin 1 mg/day; and group C adjusted-dose coumadin with a target range of international normalized ratios (INR) between 1.6 and 2.5. Primary endpoints (ischemic strokes and systemic embolisms) and secondary endpoints (deaths, myocardial infarctions, and major bleeding events) were prospectively documented.
                The study was discontinued 6 months after the enrollment of the first patient for safety reasons. During this period, 45 patients were recruited (15 patients in group A, 14 in group B, and 16 in group C). Over a mean follow-up period of 3.7 months (range: 1-6 months), two patients from group B developed a dangerous prolongation of the INR (7.0 and 4.2), which led to the discontinuation of fixed-dose coumadin. Another patient from the same group experienced a major bleeding event 1 month after enrollment in the study (INR: 5.5). The percentage of INR measurements within the target range was significantly (p<0.001) lower in group B (48.7%) than in group C (83.7%).
                Older people receiving fixed-dose oral anticoagulants may be at risk of developing a dangerous prolongation of their INR.
Adjusted-dose warfarin and related oral anticoagulants reduce stroke, disabling stroke and other major vascular events for those with non-valvular AF by about one third when compared with antiplatelet therapy.