Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation. Analysis of pooled data from five randomized controlled trials.
Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation. Analysis of pooled data from five randomized controlled trials.
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DOI：
10.1001/archinte.154.13.1449
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发表时间：
1994
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背景和方法房颤与缺血性卒中风险增加相关。个体患者的数据来自最近完成的5项随机试验，这些试验比较了华法林（所有研究）或阿司匹林（房颤、阿司匹林、抗凝研究和房颤卒中预防研究）与对照组房颤患者的数据。分析的目的是（1）确定预测卒中高风险或低风险的患者特征，（2）评估抗血栓治疗在主要患者亚组（例如，女性）中的疗效，（3）获得房颤抗血栓治疗疗效和风险的最精确估计值。对于华法林对照组比较，有1889例患者-年接受华法林治疗，对照组为1802例患者-年。对于阿司匹林-安慰剂比较，有1132例患者-年接受阿司匹林，1133例患者-年接受安慰剂。房颤、阿司匹林、抗凝研究中阿司匹林的日剂量为75 mg，房颤卒中预防研究中为325 mg。为了监测华法林剂量，三项研究使用凝血酶原时间比值，两项使用国际标准化比值。最低目标强度为凝血酶原时间比值1.2 - 1.5，最高目标强度为国际标准化比值2.8 - 4.2。主要终点是缺血性卒中和大出血，由每项研究评估。结果在随机分组时，平均年龄为69岁，平均血压为142/82 mm Hg。46%的患者有高血压史，6%的患者有短暂性脑缺血发作或中风史，14%的患者有糖尿病史。在对照组患者中，多变量分析预测卒中的危险因素是年龄增加、高血压病史、既往短暂性脑缺血发作或卒中和糖尿病。年龄小于65岁且无其他预测因素的患者（占所有患者的15%）的卒中年发生率为1.0%，95%置信区间（CI）为0.3%-3.0%。对照组的卒中年发生率为4.5%，华法林组为1.4%（风险降低，68%; 95%CI，50%至79%）。华法林的疗效在所有研究和患者亚组中一致。在女性中，华法林使卒中风险降低了84%（95% CI，55%至95%），而男性中为60%（95% CI，35%至76%）。阿司匹林的疗效并不一致。在房颤、阿司匹林、抗凝研究中，75 mg阿司匹林的风险降低18%（95% CI，60%-58%），在房颤卒中预防研究中，325 mg阿司匹林的风险降低44%（95% CI，7%-66%）。当两项研究结合时，风险降低36%（95% CI，4%至57%）。对照组、阿司匹林组和华法林组的严重出血（颅内出血或需要住院或2个单位血液的出血）年发生率分别为1.0%、1.0%和1.3%。结论在这五项随机试验中，华法林可持续降低房颤患者的中风风险（风险降低68%），而大出血的频率几乎没有增加。年龄小于65岁且无高血压、既往卒中或短暂性脑缺血发作或糖尿病史的房颤患者，即使未接受治疗，卒中风险也非常低。阿司匹林的疗效不太一致。阿司匹林在房颤中的作用还需要进一步研究。
BACKGROUND AND METHODS Atrial fibrillation is associated with an increased risk of ischemic stroke. Data on individual patients were pooled from five recently completed randomized trials comparing warfarin (all studies) or aspirin (the Atrial Fibrillation, Aspirin, Anticoagulation Study and the Stroke Prevention in Atrial Fibrillation Study) with control in patients with atrial fibrillation. The purpose of the analysis was to (1) identify patient features predictive of a high or low risk of stroke, (2) assess the efficacy of antithrombotic therapy in major patient subgroups (eg, women), and (3) obtain the most precise estimate of the efficacy and risks of antithrombotic therapy in atrial fibrillation. For the warfarin-control comparison there were 1889 patient-years receiving warfarin and 1802 in the control group. For the aspirin-placebo comparison there were 1132 patient-years receiving aspirin and 1133 receiving placebo. The daily dose of aspirin was 75 mg in the Atrial Fibrillation, Aspirin, Anticoagulation Study and 325 mg in the Stroke Prevention in Atrial Fibrillation Study. To monitor warfarin dosage, three studies used prothrombin time ratios and two used international normalized ratios. The lowest target intensity was a prothrombin time ratio of 1.2 to 1.5 and the highest target intensity was an international normalized ratio of 2.8 to 4.2. The primary end points were ischemic stroke and major hemorrhage, as assessed by each study. RESULTS At the time of randomization the mean age was 69 years and the mean blood pressure was 142/82 mm Hg. Forty-six percent of the patients had a history of hypertension, 6% had a previous transient ischemic attack or stroke, and 14% had diabetes. Risk factors that predicted stroke on multivariate analyses in control patients were increasing age, history of hypertension, previous transient ischemic attack or stroke, and diabetes. Patients younger than 65 years who had none of the other predictive factors (15% of all patients) had an annual rate of stroke of 1.0%, 95% confidence interval (CI) 0.3% to 3.0%. The annual rate of stroke was 4.5% for the control group and 1.4% for the warfarin group (risk reduction, 68%; 95% CI, 50% to 79%). The efficacy of warfarin was consistent across all studies and subgroups of patients. In women, warfarin decreased the risk of stroke by 84% (95% CI, 55% to 95%) compared with 60% (95% CI, 35% to 76%) in men. The efficacy of aspirin was not as consistent. The risk reduction with 75 mg of aspirin in the Atrial Fibrillation, Aspirin, Anticoagulation Study was 18% (95% CI, 60% to 58%), and with 325 mg of aspirin in the Stroke Prevention in Atrial Fibrillation Study the risk reduction was 44% (95% CI, 7% to 66%). When both studies were combined the risk reduction was 36% (95% CI, 4% to 57%). The annual rate of major hemorrhage (intracranial bleeding or a bleed requiring hospitalization or 2 units of blood) was 1.0% for the control group, 1.0% for the aspirin group, and 1.3% for the warfarin group. CONCLUSION In these five randomized trials warfarin consistently decreased the risk of stroke in patients with atrial fibrillation (a 68% reduction in risk) with virtually no increase in the frequency of major bleeding. Patients with atrial fibrillation younger than 65 years without a history of hypertension, previous stroke or transient ischemic attack, or diabetes were at very low risk of stroke even when not treated. The efficacy of aspirin was less consistent. Further studies are needed to clarify the role of aspirin in atrial fibrillation.