van den Dries Carline J, van Doorn Sander, Souverein Patrick, Pajouheshnia Romin, Moons Karel G M, Hoes Arno W, Geersing Geert-Jan, van den Ham Hendrika A
Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht and Utrecht University, Utrecht, The Netherlands.
Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
TH Open. 2020 Dec 23;4(4):e417-e426. doi: 10.1055/s-0040-1721499. eCollection 2020 Oct.
The benefit of direct oral anticoagulants (DOACs) versus vitamin K antagonists (VKAs) on major bleeding was less prominent among atrial fibrillation (AF) patients with polypharmacy in post-hoc randomized controlled trials analyses. Whether this phenomenon also exists in routine care is unknown. The aim of the study is to investigate whether the number of concomitant drugs prescribed modifies safety and effectiveness of DOACs compared with VKAs in AF patients treated in general practice. Adult, nonvalvular AF patients with a first DOAC or VKA prescription between January 2010 and July 2018 were included, using data from the United Kingdom Clinical Practice Research Datalink. Primary outcome was major bleeding, secondary outcomes included types of major bleeding, nonmajor bleeding, ischemic stroke, and all-cause mortality. Effect modification was assessed using Cox proportional hazard regression, stratified for the number of concomitant drugs into three strata (0-5, 6-8, ≥9 drugs), and by including the continuous variable in an interaction term with the exposure (DOAC vs. VKA). A total of 63,600 patients with 146,059 person-years of follow-up were analyzed (39,840 person-years of DOAC follow-up). The median age was 76 years in both groups, the median number of concomitant drugs prescribed was 7. Overall, the hazard of major bleeding was similar between VKA-users and DOAC-users (hazard ratio [HR] 0.98; 95% confidence interval [CI] 0.87-1.11), though for apixaban a reduction in major bleeding was observed (HR 0.81; 95% CI 0.68-0.98). Risk of stroke was comparable, while risk of nonmajor bleeding was lower in DOAC users compared with VKA users (HR 0.92; 95% CI 0.88-0.97). We did not observe any evidence for an impact of polypharmacy on the relative risk of major bleeding between VKA and DOAC across our predefined three strata of concomitant drug use ( -value for interaction = 0.65). For mortality, however, risk of mortality was highest among DOAC users, increasing with polypharmacy and independent of the type of DOAC prescribed ( -value for interaction <0.01). In this large observational, population-wide study of AF patients, risk of bleeding, and ischemic stroke were comparable between DOACs and VKAs, irrespective of the number of concomitant drugs prescribed. In AF patients with increasing polypharmacy, our data appeared to suggest an unexplained yet increased risk of mortality in DOAC-treated patients, compared with VKA recipients.
在事后随机对照试验分析中，直接口服抗凝剂（DOACs）与维生素K拮抗剂（VKAs）相比，在合并用药的心房颤动（AF）患者中，其预防大出血的益处不太显著。这种现象在常规治疗中是否也存在尚不清楚。本研究的目的是调查在全科医疗中接受治疗的AF患者中，与VKAs相比，合并用药的数量是否会改变DOACs的安全性和有效性。
纳入了2010年1月至2018年7月期间首次开具DOAC或VKA处方的成年非瓣膜性AF患者，数据来自英国临床实践研究数据链。主要结局是大出血，次要结局包括大出血类型、非大出血、缺血性卒中和全因死亡率。使用Cox比例风险回归评估效应修正，根据合并用药数量分为三个层次（0 - 5种、6 - 8种、≥9种药物），并通过将连续变量纳入与暴露因素（DOAC与VKA）的交互项中进行评估。
共分析了63,600例患者，随访时间为146,059人年（DOAC随访39,840人年）。两组的中位年龄均为76岁，合并用药的中位数为7种。总体而言，VKA使用者和DOAC使用者大出血的风险相似（风险比[HR] 0.98；95%置信区间[CI] 0.87 - 1.11），不过观察到阿哌沙班可减少大出血（HR 0.81；95% CI 0.68 - 0.98）。卒中风险相当，而DOAC使用者的非大出血风险低于VKA使用者（HR 0.92；95% CI 0.88 - 0.97）。在我们预先定义的三个合并用药层次中，未观察到合并用药对VKA和DOAC之间大出血相对风险有任何影响的证据（交互作用P值 = 0.65）。然而，对于死亡率，DOAC使用者的死亡风险最高，随合并用药增加而增加，且与所开具的DOAC类型无关（交互作用P值 < 0.01）。
在这项针对AF患者的大型观察性全人群研究中，无论合并用药数量多少，DOACs和VKAs的出血风险和缺血性卒中风险相当。在合并用药增多的AF患者中，我们的数据似乎表明，与VKA接受者相比，DOAC治疗的患者存在无法解释但增加的死亡风险。
