Service d'Hématologie Biologique, Hôpital Tenon, Hôpitaux Universitaires Est Parisien Assistance Publique Hôpitaux de Paris, Paris, France ; ER2UPMC, Faculté de Médecine Pierre et Marie Curie, Université Paris VI, Paris, France.
Service de Médecine interne, Hôpital Louis Mourier, Université Paris 7, Assistance Publique Hôpitaux de Paris, EA REMES, Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
Ther Clin Risk Manag. 2014 Jun 13;10:423-36. doi: 10.2147/TCRM.S49063. eCollection 2014.
Patients with cancer have a 6-7-fold higher risk of venous thromboembolism (VTE) as compared with non-cancer patients. Effective and safe anticoagulation for the prevention and treatment of VTE is the cornerstone of the management of patients with cancer, aiming to decrease morbidity and mortality and to improve quality of life. Unfractionated heparin, low molecular weight heparins, fondaparinux and vitamin K antagonists (VKAs) are used in the prevention and treatment of VTE in cancer patients. Heparins and fondaparinux are administered subcutaneously. VKAs are orally active, but they have a narrow therapeutic window, numerous food and drug interactions, and treatment requires regular laboratory monitoring and dose adjustment. These limitations among others have important negative impact on the quality of life of patients and decrease adherence to the treatment. New orally active anticoagulant (NOAC) agents are specific inhibitors of activated factor Xa (FXa) (rivaroxaban and apixaban) or thrombin (dabigatran). It is expected that NOACs will improve antithrombotic treatment. Cancer patients are a particular group that could benefit from treatment with NOACs. However, NOACs present some significant interactions with drugs frequently used in cancer patients, which might influence their pharmacokinetics, compromising their efficacy and safety. In the present review, we analyzed the available data from the subgroups of patients with active cancer who were included in Phase III clinical trials that assessed the efficacy and safety of NOACs in the prevention and treatment of VTE. The data from the Phase III trials in prophylaxis of VTE by rivaroxaban or apixaban highlight that these two agents, although belonging to the same pharmacological group (direct inhibitors of factor Xa), have substantially different profiles of efficacy and safety, especially in hospitalized acutely ill medical patients with active cancer. A limited number of patients with VTE and active cancer were included in the Phase III trials (EINSTEIN, AMPLIFY, and RE-COVER) which evaluated the efficacy and safety of NOACs in the acute phase and secondary prevention of VTE. Although, from a conceptual point of view, NOACs could be an attractive alternative for the treatment of VTE in cancer patients, the available data do not support this option. In addition, due to the elimination of the NOACs by the liver and renal pathway as well as because of their pharmacological interactions with drugs which are frequently used in cancer patients, an eventual use of these drugs in cancer patients should be extremely cautious and be restricted only to patients presenting with contraindications for low molecular weight heparins, fondaparinux, or VKAs. The analysis of the available data presented in this review reinforces the request for the design of new Phase III clinical trials for the assessment of the efficacy and safety of NOACs in specific populations of patients with cancer.
癌症患者发生静脉血栓栓塞症（VTE）的风险比非癌症患者高 6-7 倍。有效的、安全的抗凝治疗是癌症患者 VTE 预防和治疗的基石，目的是降低发病率和死亡率，并改善生活质量。普通肝素、低分子肝素、磺达肝癸钠和维生素 K 拮抗剂（VKA）用于癌症患者 VTE 的预防和治疗。肝素和磺达肝癸钠是皮下给药。VKA 是口服活性药物，但治疗窗较窄，有许多食物和药物相互作用，且需要定期进行实验室监测和剂量调整。这些局限性对患者的生活质量有重要的负面影响，并降低了患者对治疗的依从性。新型口服抗凝剂（NOAC）是活化因子 Xa（FXa）（利伐沙班和阿哌沙班）或凝血酶（达比加群）的特异性抑制剂。预计 NOAC 将改善抗血栓治疗。癌症患者是特别可能受益于 NOAC 治疗的人群。然而，NOAC 与癌症患者经常使用的药物有一些显著的相互作用，可能影响其药代动力学，从而影响其疗效和安全性。在本综述中，我们分析了在评估 NOAC 预防和治疗 VTE 的疗效和安全性的 III 期临床试验中纳入的活动期癌症患者亚组的现有数据。利伐沙班或阿哌沙班预防 VTE 的 III 期临床试验数据表明，这两种药物虽然属于同一药理学组（直接 FXa 抑制剂），但在急性住院重病癌症患者中具有明显不同的疗效和安全性特征。III 期临床试验（EINSTEIN、AMPLIFY 和 RE-COVER）纳入了少数 VTE 和活动期癌症患者，评估了 NOAC 在 VTE 急性期和二级预防中的疗效和安全性。尽管从概念上讲，NOAC 可能是癌症患者 VTE 治疗的一种有吸引力的选择，但现有数据并不支持这种选择。此外，由于 NOAC 通过肝脏和肾脏途径消除，并且由于与癌症患者经常使用的药物发生药理学相互作用，因此在癌症患者中使用这些药物应极其谨慎，并且仅应限于存在低分子肝素、磺达肝癸钠或 VKA 禁忌证的患者。本综述中对现有数据的分析进一步强调了设计新的 III 期临床试验的必要性，以评估特定癌症患者人群中 NOAC 的疗效和安全性。
