Department of Technology Marketing, Sapir College, Sderot, Israel.
Department of Public Health, School of Public Health, Faculty of Health Sciences, Ben-Gurion University of the Negev, Be'er-Sheva, Israel.
Am J Med. 2019 Jul;132(7):847-855.e3. doi: 10.1016/j.amjmed.2019.01.025. Epub 2019 Feb 15.
Direct oral anticoagulants (DOACs) reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation but may result in serious bleeding complications. Off-label dose-reduced use of DOACs to mitigate bleeding is common in routine clinical practice although data about its consequences on patient outcomes are limited. Therefore, our objective was to evaluate the effectiveness and safety of off-label dose-reduced vs per-label standard-dose DOAC treatment.
The study cohort included newly diagnosed patients with nonvalvular atrial fibrillation that had initiated DOAC therapy between 2011 and 2017 in Clalit Health Services (Tel Aviv, Israel). Effectiveness was defined as the composite outcome of all-cause mortality, stroke, or myocardial infarction. The safety outcome was defined as bleeding events requiring hospitalization. Patients were followed until March 30, 2018 or until occurrence of an outcome event. Hazard ratios (HR) were adjusted for 21 variables, including comorbidities, concomitant medications, and socioeconomic factors, using multivariate regression.
A total of 8425 patients met the study criteria; 5140 (61%) patients were treated with DOACs at per-label dosing and 3285 (39%) patients were treated with off-label dose-reduced DOAC. Off-label dose-reduced treatment was associated with a higher rate of the composite effectiveness outcome: adjusted HR 1.57 (95% confidence interval, 1.34-1.83; P < .001) and a higher rate of bleeding: adjusted HR 1.63 (95% confidence interval, 1.14-2.34; P = .008).
Almost 4 of 10 patients were treated with off-label dose-reduced DOAC, which was associated with reduced effectiveness without a safety benefit. Compliance with per-label dosage may significantly improve outcomes of this population.
直接口服抗凝剂（DOACs）可降低非瓣膜性心房颤动患者中风和全身性栓塞的风险，但可能导致严重的出血并发症。尽管关于其对患者结局影响的数据有限，但在常规临床实践中，DOAC 减少剂量的超适应证使用以减轻出血是很常见的。因此，我们的目的是评估超适应证剂量减少与标签标准剂量 DOAC 治疗的有效性和安全性。
研究队列包括 2011 年至 2017 年在 Clalit 医疗保健服务（以色列特拉维夫）开始 DOAC 治疗的新诊断为非瓣膜性心房颤动的患者。有效性定义为全因死亡率、中风或心肌梗死的复合结局。安全性结局定义为需要住院治疗的出血事件。患者随访至 2018 年 3 月 30 日或发生结局事件。使用多变量回归，通过调整 21 个变量（包括合并症、同时使用的药物和社会经济因素）来调整危险比（HR）。
共有 8425 名患者符合研究标准；5140 名（61%）患者以标签剂量接受 DOAC 治疗，3285 名（39%）患者接受超适应证剂量减少的 DOAC 治疗。超适应证剂量减少治疗与复合有效性结局的发生率较高相关：调整后的 HR 为 1.57（95%置信区间，1.34-1.83；P<0.001），出血发生率较高：调整后的 HR 为 1.63（95%置信区间，1.14-2.34；P=0.008）。
近 10 名患者中有 4 名接受超适应证剂量减少的 DOAC 治疗，其有效性降低，而安全性无获益。遵循标签剂量可能会显著改善这部分人群的结局。
