Lip Gregory Y H
University Department of Medicine, City Hospital, Birmingham B18 7QH, UK.
Pathophysiol Haemost Thromb. 2005;34 Suppl 1:25-30. doi: 10.1159/000083081.
Atrial fibrillation (AF) is the most common cardiac risk factor for stroke. Oral anticoagulants such as the vitamin K antagonist warfarin have been proven effective in reducing the risk of stroke in AF. Warfarin, however, has many disadvantages including the need for coagulation monitoring, a narrow therapeutic index, inter-/intra-patient variability and food-drug interactions. As a result, warfarin is underused in clinical practice and a viable alternative is needed. Ximelagatran, the first oral direct thrombin inhibitor, is given as a fixed dose, does not have a narrow therapeutic index, has low potential for drug interactions, has no significant food interactions and does not require coagulation monitoring. Ximelagatran has been evaluated in the Stroke Prevention using an ORal direct Thrombin Inhibitor in atrial Fibrillation (SPORTIF) trial programme, the largest clinical trials of antithrombotic therapy for stroke prevention in AF to date. The phase III trials, SPORTIF III and V, compared ximelagatran (36 mg twice daily) with well-controlled warfarin (international normalized ratio 2.0-3.0) in a combined population of more than 7,000 moderate- to high-risk AF patients. Data from SPORTIF III show an absolute reduction in stroke and systemic embolic events with ximelagatran compared with warfarin at 21 months (1.6 vs. 2.3% per year, respectively; p = 0.10). Preliminary data from SPORTIF V appear to further support non-inferiority between the two agents. On-treatment analysis of the rate of major bleeding events shows an absolute, nonsignificant reduction in the event rate per year with ximelagatran versus warfarin in both studies. The results of SPORTIF III and V demonstrate that a fixed oral dose of ximelagatran, without coagulation monitoring, is comparable to dose-adjusted warfarin in preventing stroke and other thromboembolic complications among moderate- to high-risk AF patients and has a lower rate of both major and minor bleeding. With its positive benefit-risk ratio, ximelagatran may increase the population of eligible patients for anticoagulation with AF and maximize the potential of anticoagulation in the prevention of stroke.
心房颤动（AF）是卒中最常见的心脏危险因素。口服抗凝剂，如维生素K拮抗剂华法林，已被证明可有效降低AF患者的卒中风险。然而，华法林有许多缺点，包括需要进行凝血监测、治疗指数狭窄、患者间/患者内变异性以及食物-药物相互作用。因此，华法林在临床实践中未得到充分使用，需要一种可行的替代药物。希美加群是首个口服直接凝血酶抑制剂，采用固定剂量给药，治疗指数不窄，药物相互作用可能性低，无明显食物相互作用，且无需凝血监测。希美加群已在心房颤动口服直接凝血酶抑制剂预防卒中（SPORTIF）试验项目中进行了评估，该项目是迄今为止针对AF患者预防卒中的抗栓治疗规模最大的临床试验。III期试验SPORTIF III和V，在7000多名中高危AF患者的合并人群中，将希美加群（每日两次，每次36 mg）与控制良好的华法林（国际标准化比值2.0 - 3.0）进行了比较。SPORTIF III的数据显示，与华法林相比，21个月时希美加群使卒中和全身性栓塞事件的绝对发生率降低（每年分别为1.6%和2.3%；p = 0.10）。SPORTIF V的初步数据似乎进一步支持了两种药物的非劣效性。两项研究中对主要出血事件发生率的治疗中分析显示，与华法林相比，希美加群每年的事件发生率绝对降低，但差异无统计学意义。SPORTIF III和V的结果表明，固定口服剂量的希美加群在不进行凝血监测的情况下，在预防中高危AF患者的卒中和其他血栓栓塞并发症方面与剂量调整的华法林相当，且大出血和小出血发生率均较低。鉴于其良好的效益风险比，希美加群可能会增加符合抗凝治疗条件的AF患者人数，并使抗凝预防卒中的潜力最大化。
