Oral rivaroxaban versus enoxaparin with vitamin K antagonist for the treatment of symptomatic venous thromboembolism in patients with cancer (EINSTEIN-DVT and EINSTEIN-PE): a pooled subgroup analysis of two randomised controlled trials
Oral rivaroxaban versus enoxaparin with vitamin K antagonist for the treatment of symptomatic venous thromboembolism in patients with cancer (EINSTEIN-DVT and EINSTEIN-PE): a pooled subgroup analysis of two randomised controlled trials
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DOI：
10.1016/s2352-3026(14)70018-3
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发表时间：
2014-10-01
影响因子：
24.7
通讯作者：
Prandoni, Paolo
中科院分区：
文献类型：
--
作者：
Prins, Martin H.;Lensing, Anthonie W. A.;Prandoni, Paolo
背景静脉血栓栓塞和癌症患者在抗凝治疗期间有复发静脉血栓栓塞和出血的巨大风险。尽管在这些患者中推荐使用低分子量肝素单药治疗，但在临床实践中，许多患有静脉血栓栓塞和癌症的患者没有接受这种治疗。我们的目的是评估口服利伐沙班与依诺肝素随后维生素K拮抗剂的单药治疗方案在EINSTEIN-DVT和EINSTEIN-PE随机对照试验中入组的癌症患者亚组中的疗效和安全性。（基线时或研究期间诊断）、癌症史或无癌症的受试者。符合条件的深静脉血栓形成（EINSTEIN-DVT）或肺栓塞（EINSTEIN-PE）患者以1：1的比例随机分配接受利伐沙班（15 mg每日2次，持续21天，随后20 mg每日1次）或标准治疗（依诺肝素1.0 mg/kg每日2次和华法林或醋硝香豆素;国际标准化比率2.0-3.0）。根据国家和预期治疗持续时间（3、6或12个月），使用计算机语音应答系统对随机化进行分层。试验和本次分析的预先规定的主要疗效和安全性结局分别为症状性复发性静脉血栓栓塞和临床相关出血。我们在意向治疗人群中进行了疗效和死亡率分析，并在安全性人群（所有接受至少一剂研究药物的患者）中对接受治疗的时间加2天进行了出血分析。EINSTEIN-DVT和EINSTEIN-PE研究在www.example.com上注册ClinicalTrials.gov，编号为NCT 00440193和NCT 00439777。（在基线或治疗期间诊断），354例分配至利伐沙班组的患者中有16例（5%）和301例分配至依诺肝素和维生素K拮抗剂组的患者中有20例（7%）发生复发性静脉血栓栓塞（风险比[HR] 0.67，95% CI 0.35 - 1.30）。353例接受利伐沙班治疗的患者中有48例（14%）发生临床相关出血，298例接受标准治疗的患者中有49例（16%）发生临床相关出血（HR 0.80，95% CI 0.54 - 1.20）。接受利伐沙班治疗的353例患者中有8例（2%）发生大出血，接受标准治疗的298例患者中有15例（5%）发生大出血（HR 0.42，95% CI 0.18 - 0.99）。仅有癌症病史的患者复发性静脉血栓栓塞的总体频率（利伐沙班组233例患者中有5例[2%]，标准治疗组236例患者中有5例[2%]; HR 0.98，95%CI 0.28-3.43）与非癌症患者相似（分别为3563例中的65例[2%]和3594例中的70例[2%]; HR 0.93，95% CI 0.66-1.30），但基线时活动性癌症患者的频率增加（分别为258例中的6例[2%]和204例中的8例[4%]; HR 0.62，95%CI 0.21-1.79），在研究期间诊断为癌症的患者中最明显增加（96例中的10例[10%] vs 97例中的12例[12%]; HR 0.80，95% CI 0.34-1.88）。仅有癌症病史的患者中大出血的总体频率（利伐沙班组1例[< 1%]患者vs标准治疗组4例[2%]患者; HR 0.23，95% CI 0.03-2.06）与非癌症患者相似（分别为31 [1%] vs 53 [1%]; HR 0.58，95% CI 0.37-0.91），但在基线时活动性癌症患者中增加（分别为5 [2%]对8 [4%]; HR 0.47，95% CI 0.15-1.45），在研究期间诊断为癌症的患者中最高（分别为3 [3%]对7 [7%]; HR 0.33，95%CI 0.08-1.31）。解释在患有活动性癌症和静脉血栓栓塞的患者中，与用依诺肝素和维生素K拮抗剂治疗相比，利伐沙班在预防静脉血栓栓塞复发和减少大出血事件的数量方面具有相似的功效，尽管两组之间临床相关出血没有差异。基于这些结果，有必要在癌症患者中进行利伐沙班与长期低分子量肝素的头对头比较。
Background Patients with venous thromboembolism and cancer have a substantial risk of recurrent venous thromboembolism and bleeding during anticoagulant therapy. Although monotherapy with low-molecular-weight heparin is recommended in these patients, in clinical practice many patients with venous thromboembolism and cancer do not receive this treatment. We aimed to assess the efficacy and safety of a single-drug regimen with oral rivaroxaban compared with enoxaparin followed by vitamin K antagonists, in the subgroup of patients with cancer enrolled in the EINSTEIN-DVT and EINSTEIN-PE randomised controlled trials.Methods We did a subgroup analysis of patients with active cancer (either at baseline or diagnosed during the study), a history of cancer, or no cancer who were enrolled in the EINSTEIN-DVT and EINSTEIN-PE trials. Eligible patients with deep-vein thrombosis (EINSTEIN-DVT) or pulmonary embolism (EINSTEIN-PE) were randomly assigned in a 1: 1 ratio to receive rivaroxaban (15 mg twice daily for 21 days, followed by 20 mg once daily) or standard therapy (enoxaparin 1.0 mg/kg twice daily and warfarin or acenocoumarol; international normalised ratio 2.0-3.0). Randomisation with a computerised voice-response system was stratified according to country and intended treatment duration (3, 6, or 12 months). The prespecified primary efficacy and safety outcomes of both the trials and this subanalysis were symptomatic recurrent venous thromboembolism and clinically relevant bleeding, respectively. We did efficacy and mortality analyses in the intention-to-treat population, and bleeding analyses for time spent receiving treatment plus 2 days in the safety population (all patients who received at least one dose of study drug). The EINSTEIN-DVT and EINSTEIN-PE studies are registered at ClinicalTrials.gov, numbers NCT00440193 and NCT00439777.Findings In patients with active cancer (diagnosed at baseline or during treatment), recurrent venous thromboembolism occurred in 16 (5%) of 354 patients allocated to rivaroxaban and 20 (7%) of 301 patients allocated to enoxaparin and vitamin K antagonist (hazard ratio [HR] 0.67, 95% CI 0.35 to 1.30). Clinically relevant bleeding occurred in 48 (14%) of 353 patients receiving rivaroxaban and in 49 (16%) of 298 patients receiving standard therapy (HR 0.80, 95% CI 0.54 to 1.20). Major bleeding occurred in eight (2%) of 353 patients receiving rivaroxaban and in 15 (5%) of 298 patients receiving standard therapy (HR 0.42, 95% CI 0.18 to 0.99). The overall frequency of recurrent venous thromboembolism in patients with only a history of cancer (five [2%] of 233 patients in the rivaroxaban group vs five [2%] of 236 in the standard therapy group; HR 0.98, 95% CI 0.28-3.43) was similar to that of patients without cancer (65 [2%] of 3563 vs 70 [2%] of 3594, respectively; HR 0.93, 95% CI 0.66-1.30), but the frequency was increased in patients with active cancer at baseline (six [2%] of 258 vs eight [4%] of 204, respectively; HR 0.62, 95% CI 0.21-1.79) and most markedly increased in patients whose diagnosis of cancer was made during the study (ten [10%] of 96 vs 12 [12%] of 97, respectively; HR 0.80, 95% CI 0.34-1.88). The overall frequency of major bleeding in patients with only a history of cancer (one [< 1%] patient in the rivaroxaban group vs four [2%] patients in the standard therapy group; HR 0.23, 95% CI 0.03-2.06) was similar to that of patients without cancer (31 [1%] vs 53 [1%], respectively; HR 0.58, 95% CI 0.37-0.91), but was increased in patients with active cancer at baseline (five [2%] vs eight [4%], respectively; HR 0.47, 95% CI 0.15-1.45) and was highest in those with cancer diagnosed during the study (three [3%] vs seven [7%], respectively; HR 0.33, 95% CI 0.08-1.31).Interpretation In patients with active cancer and venous thromboembolism, rivaroxaban had similar efficacy to prevent recurrence of venous thromboembolism and reduced the number major bleeding events compared with treatment with enoxaparin and a vitamin K antagonist, although there was no difference between groups for clinically relevant bleeding. Based on these results, a head-to-head comparison of rivaroxaban with long-term low-molecular-weight heparin in patients with cancer is warranted.