Hrebickova Lenka, Nawarskas James J, Anderson Joe R
University of New Mexico College of Pharmacy, Albuquerque, NM 87131, USA.
Heart Dis. 2003 Nov-Dec;5(6):397-408. doi: 10.1097/01.hdx.0000099777.39577.e8.
Although there have been many significant advances over the last 50 years with regards to anticoagulant therapy, warfarin remains the definitive standard for the long-term prevention of thromboembolic events in many patients at risk for these complications. Although effective, warfarin has a narrow therapeutic window, necessitating frequent laboratory monitoring for anticoagulant effect. Ximelagatran is an investigational anticoagulant that directly inhibits thrombin, unlike heparin or warfarin, which are indirect inhibitors. Although indirect thrombin inhibitors are mainly only effective at inhibiting circulating thrombin, direct thrombin inhibitors are able to inhibit both free and clot-bound thrombin, thereby producing more effective anticoagulation. Ximelagatran is the first orally available direct thrombin inhibitor to reach phase 3 clinical trials. Ximelagatran is a prodrug for the active metabolite melagatran, and has been demonstrated to have a relatively wide therapeutic window in terms of bleeding and antithrombotic effect compared with warfarin. Clinical studies have demonstrated ximelagatran to be comparable in efficacy to warfarin and low-molecular-weight heparins (LMWH) for prophylaxis of venous thromboembolism, comparable to warfarin for stroke prevention in the setting of atrial fibrillation, and, when combined with aspirin, possible more effective than aspirin alone at preventing major adverse cardiovascular events in patients with a recent myocardial infarction. Adverse effects with ximelagatran primarily involve bleeding complications, which are more frequent than with placebo, but appear comparable to those occurring with standard anticoagulant treatment (ie, warfarin and LMWH). Ximelagatran has also been demonstrated to cause transient increases in liver enzymes, the significance of which will need to be addressed in ongoing phase 3 studies. Should ongoing trials prove ximelagatran to have at least similar therapeutic efficacy and safety as warfarin, ximelagatran may become a first-line anticoagulant due to its ease of administration and lack of a need for drug monitoring. The results of these trials are eagerly awaited in helping to defining the place in therapy for this promising new agent.
尽管在过去50年里抗凝治疗取得了许多重大进展，但华法林在许多有血栓栓塞事件风险的患者中，仍是长期预防这些并发症的决定性标准。华法林虽然有效，但治疗窗狭窄，需要频繁进行实验室监测以评估抗凝效果。希美加群是一种正在研究的抗凝剂，它直接抑制凝血酶，这与肝素或华法林不同，肝素和华法林是间接抑制剂。虽然间接凝血酶抑制剂主要仅对抑制循环中的凝血酶有效，但直接凝血酶抑制剂能够抑制游离和与血栓结合的凝血酶，从而产生更有效的抗凝作用。希美加群是首个进入3期临床试验的口服直接凝血酶抑制剂。希美加群是活性代谢产物美拉加群的前体药物，与华法林相比，在出血和抗血栓形成方面已证明具有相对较宽的治疗窗。临床研究表明，在预防静脉血栓栓塞方面，希美加群的疗效与华法林和低分子量肝素（LMWH）相当；在房颤患者预防中风方面，与华法林相当；并且，在近期心肌梗死患者中，与阿司匹林联合使用时，在预防主要不良心血管事件方面可能比单独使用阿司匹林更有效。希美加群的不良反应主要涉及出血并发症，比安慰剂更常见，但似乎与标准抗凝治疗（即华法林和LMWH）的出血并发症相当。希美加群还被证明会导致肝酶短暂升高，其意义需要在正在进行的3期研究中解决。如果正在进行的试验证明希美加群至少具有与华法林相似的治疗疗效和安全性，由于其给药方便且无需药物监测，希美加群可能会成为一线抗凝剂。人们急切期待这些试验的结果，以帮助确定这种有前景的新药在治疗中的地位。
