华法林与阿司匹林预防非瓣膜性心房颤动患者血栓栓塞的随机对照研究

The randomized study of efficiency and safety of antithrombotic therapy in nonvalvular atrial fibrillation: warfarin compared with aspirin

目的 通过前瞻性、随机、多中心研究比较阿司匹林与调整剂量华法林预防非瓣膜性心房颤动（房颤）患者发生血栓栓塞的有效性和安全性.方法 在18个中心,根据入选标准将非瓣膜性房颤患者随机分配至阿司匹林组（150～160 mg/d）和调整剂量华法林组（初始剂量2 mg/d）,目标国际标准化比值（INR）为2.0～3.0（年龄≥75岁者的INR为1.6～2.5）.常规门诊随访,调整华法林剂量并记录两组患者的终点事件和不良反应发生情况.主要终点事件为缺血性脑卒中和死亡,次要终点事件包括短暂性脑缺血发作、腔隙性脑梗死、外周动脉栓塞、急性心肌梗死和严重出血.结果 共704例患者进入分析,阿司匹林组369例,华法林组335例.男性420例（59.7%）,平均年龄（63.3±9.9）岁,两组患者基线特征（包括合并疾病和伴随用药）差异无统计学意义.随访时间中位数19个月（2～24个月）.与阿司匹林比较,调整剂量华法林明显降低主要终点事件发生率[2.7%比6.0%,P=0.03,OR 0.44,95%可信区间（CI）为0.198～0.960],相对危险下降54%;缺血性脑卒中的相对危险下降62%（1.8%比4.6%,P=0.04,OR 0.38,95% CI为0.147～0.977）;总血栓栓塞事件相对危险下降52%（10.6%比5.4%,P=0.01,OR 0.48,95% CI为0.269～0.858）.次要终点事件两组间差异无统计学意义.华法林组轻微出血和严重出血发生率均高于阿司匹林组（P＜0.05）.华法林组总死亡率低于阿司匹林组[4例（1.2%）比8例（2.2%）],但差异无统计学意义（P＞0.05）;包括主要和次要终点的联合终点事件华法林组低于阿司匹林组（8.4%比13.0%,P=0.047）. 结论 与阿司匹林相比,华法林可明显降低国人非瓣膜性房颤患者脑卒中的发生率,华法林组出血的发生率高于阿司匹林组,但多数出血并发症发生在INR＞3.0.严密监测（INR 2.0～3.0）下的调整剂量华法林安全有效.

Objective To investigate whether warfarin is more effective and superior to aspirin for the prevention of thrombeembolism in nonvalvular atrial fibrillation in Chinese. Methods In a multicenter randomized trial, the patients diagnosed as nonvalvular atrial fibrillation were randomized to receive aspirin 150 mg- 160 mg once daily or adjusted-dose warfarin （international normalized ratio, 2.0 - 3.0）. We compared the effect of the two therapy on the primary end point of ischemic stroke or death from any cause and on the combined end-point （stroke, death, peripheral arteries embolism, TIA, acute myocardial infarction, serious bleeding） during a median follow-up period of 19 months. Results Of the 704 patients, 420 （59.7%） were male. The average patient age was （63.3 ±9.9） years. The median follow-up period is 19 months. The mean dose of warfarin was （3.2 ±0.7） rag. Compared with aspirin, the primary end point of death or ischemic stroke was reduced by warfarin （2.7% vs 6.0% , P =0.03, OR 0. 44,95% CI 0. 198 -0.960） and the relative risk decreased by 56%. The thrombeembolism event in the aspirin group was significantly higher than that in warfarin group （ 10.6% vs 5.4%, P = 0. 01, OR 0. 48,95% CI 0. 269 - 0.858）. There was no significant differences of the mortality rate between the two groups（ 1.2% vs 2.2%,P 〉0.05）. The secondary end point was nonsignificantly reduced in warfarin group than that in aspirin group, while the combined end point is statistically decreased by adjusted-dose warfarin（8.4% vs 13.0% , P =0. 047）. Warfarin treatment was associated with increased bleeding rate compared to aspirin （6.9% vs 2.4%, P 〈 0.05 ）, although the major bleeding rate is rather low （1.5%）. All the major bleeding events occurred with INR above 3.0. Conclusions Randomized control study demonstrated that anticoagulation with adjusted-dosed warfarin （ INR 2.0 - 3.0） can significantly reduced the risk of thromboembolism event with slightly increased hemorrhage, compared to aspirin in Chinese population. Under intensive monitoring, warfarin is effective and safe for the moderate to high risk atrial fibrillation patients.