Department of Health Research Methods, Evidence, and Impact (HEI), McMaster University, 1280 Main Street West, Hamilton, Ontario, L8S 4K1, Canada.
Clinical Pharmacology & Toxicology, Research Institute, St Joseph's Healthcare Hamilton, 50 Charlton Avenue East, Hamilton, Ontario, L8N 4A6, Canada.
Br J Clin Pharmacol. 2021 Nov;87(11):4051-4100. doi: 10.1111/bcp.14833. Epub 2021 May 16.
The objective of this paper is to systematically review the literature on drug-drug interactions with warfarin, with a focus on patient-important clinical outcomes.
MEDLINE, EMBASE and the International Pharmaceutical Abstract (IPA) databases were searched from January 2004 to August 2019. We included studies describing drug-drug interactions between warfarin and other drugs. Screening and data extraction were conducted independently and in duplicate. We synthesized pooled odds ratios (OR) with 95% confidence intervals (CIs), comparing warfarin plus another medication to warfarin alone. We assessed the risk of bias at the study level and evaluated the overall certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.
Of 42 013 citations identified, a total of 72 studies reporting on 3 735 775 patients were considered eligible, including 11 randomized clinical trials and 61 observational studies. Increased risk of clinically relevant bleeding when added to warfarin therapy was observed for antiplatelet (AP) regimens (OR = 1.74; 95% CI 1.56-1.94), many antimicrobials (OR = 1.63; 95% CI 1.45-1.83), NSAIDs including COX-2 NSAIDs (OR = 1.83; 95% CI 1.29-2.59), SSRIs (OR = 1.62; 95% CI 1.42-1.85), mirtazapine (OR = 1.75; 95% CI 1.30-2.36), loop diuretics (OR = 1.92; 95% CI 1.29-2.86) among others. We found a protective effect of proton pump inhibitors (PPIs) against warfarin-related gastrointestinal (GI) bleeding (OR = 0.69; 95% CI 0.64-0.73). No significant effect on thromboembolic events or mortality of any drug group used with warfarin was found, including single or dual AP regimens.
This review found low to moderate certainty evidence supporting the interaction between warfarin and a small group of medications, which result in increased bleeding risk. PPIs are associated with reduced hospitalization for upper GI bleeding for patients taking warfarin. Further studies are required to better understand drug-drug interactions leading to thromboembolic outcomes or death.
本文旨在系统综述华法林药物-药物相互作用的文献，重点关注对患者有重要意义的临床结局。
检索 2004 年 1 月至 2019 年 8 月的 MEDLINE、EMBASE 和国际药学文摘（IPA）数据库，纳入描述华法林与其他药物之间药物-药物相互作用的研究。筛选和数据提取由两名独立的研究人员进行。我们采用 95%置信区间（CI）比较了华法林联合其他药物与华法林单药治疗的汇总比值比（OR）。我们评估了研究层面的偏倚风险，并采用 Grading of Recommendations Assessment, Development and Evaluation（GRADE）方法评估证据的总体确定性。
共检索到 42013 篇引文，其中共有 72 项研究（共 3735775 例患者）符合纳入标准，包括 11 项随机临床试验和 61 项观察性研究。与华法林联合治疗相比，抗血小板（AP）药物（OR=1.74；95%CI 1.56-1.94）、多种抗生素（OR=1.63；95%CI 1.45-1.83）、非甾体抗炎药（包括 COX-2 非甾体抗炎药）（OR=1.83；95%CI 1.29-2.59）、SSRIs（OR=1.62；95%CI 1.42-1.85）、米氮平（OR=1.75；95%CI 1.30-2.36）、袢利尿剂（OR=1.92；95%CI 1.29-2.86）等药物增加了临床相关出血的风险。我们发现质子泵抑制剂（PPIs）可降低华法林相关胃肠道（GI）出血的风险（OR=0.69；95%CI 0.64-0.73）。与华法林联合使用的任何药物组对血栓栓塞事件或死亡率均无显著影响，包括单一或双重 AP 方案。
本综述发现了支持华法林与少数药物相互作用的低至中等确定性证据，这些相互作用导致出血风险增加。PPIs 可降低华法林治疗患者上消化道出血的住院率。需要进一步研究以更好地了解导致血栓栓塞结局或死亡的药物-药物相互作用。
