Warfarin Resumption after Intracranial Hemorrhage: A Systematic Review and Meta-Analysis
Authors: Chai-Adisaksopha Chatree , Hillis Christopher M , Witt Daniel M. , Schulman Sam , Crowther Mark , Iorio Alfonso 
Published: October 2019

Abstract

Objective: To assess the effect of warfarin resumption in patients who experienced warfarin-associated intracranial hemorrhage.
Study design: Systematic review and meta-analysis
Data sources:We searched MEDLINE (1966 to July 2016), EMBASE (1980 to July 2016) and Cochrane Library electronic database (up to July 2016).
Inclusion criteria:Studies were eligible for inclusion if (1) they were randomized controlled trials, prospective cohort or retrospective cohort studies, (2) studies that included adult patients (≥18 years), (3) studies that investigated the patients who experienced warfarin-associated intracranial bleeding, (4) studies that evaluated incidence of recurrent intracranial hemorrhage, thromboembolic events, and all-cause mortality, and (5) studies that reported on patients with warfarin resumption compared to controls (those who did not resume warfarin).
Main outcome and measures: Primary outcome was all-cause mortality. Secondary outcomes were ischemic stroke, thromboembolic events, recurrent intracranial hemorrhage and any bleeding. Pooled relative risks (RRs) were calculated using random-effects model.
Results: Seven studies were included in the meta-analysis, involving 623 patients who resumed warfarin and 1851 patients who did not resume warfarin after warfarin-associated intracranial hemorrhage. Majority of patients were anticoagulated due to atrial fibrillation, prosthetic heart valve and venous thrombosis. Median time to resume warfarin ranged form 11 days to 39.2 days. Warfarin resumption significantly reduced risk of all-cause mortality (17.06% vs 35.71%), RR 0.50, 95% confidence interval [CI];0.33-0.77, I-square=58.7%, Figure 1. Lower ischemic stroke was observed in patients who resumed warfarin (4.89% vs 7.64%), RR 0.67, 95%CI; 0.45-0.99, I-square=0%, Figure 2. Composite outcome of thromboembolic event was lower but not significant in patients who resumed warfarin (7.35% vs 11.48%), RR 0.61, 95%CI; 0.39-1.07, I-square=50.7%. Recurrent intracranial hemorrhage was not significantly different between patients who resumed and those who did not resume warfarin (7.33% vs 7.39%), RR 1.14, 95%CI; 0.57-2.27, I-square=51.0%, Figure 3. Any bleeding was not significantly different between 2 groups (8.23% vs 8.31%), RR 1.03, 95%CI; 0.73-1.43, I-square=50.4%.
Conclusions: Major limitation of this meta-analysis included potential selection bias of the original studies, specifically, patients with better prognosis tended be selected to restart warfarin. In summary, , warfarin resumption after warfarin-associated intracranial hemorrhage was associated with lower risk of all-cause mortality and ischemic stroke without a significant increase in recurrent intracranial hemorrhage.
Figure 1 Forest plot of all-cause mortality comparing patients who do and do not resume warfarin. Figure 1. Forest plot of all-cause mortality comparing patients who do and do not resume warfarin. Figure 2 Forest plot of ischemic stroke comparing between patients who do and do not resume warfarin. Figure 2. Forest plot of ischemic stroke comparing between patients who do and do not resume warfarin. Figure 3 Forest plot of recurrent intracranial hemorrhage comparing between patients who resume warfarin versus those who did not resume. Figure 3. Forest plot of recurrent intracranial hemorrhage comparing between patients who resume warfarin versus those who did not resume.

Disclosures
Hillis: Celgene: Consultancy; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria. Crowther:AKP America: Membership on an entity's Board of Directors or advisory committees; Alexion: Consultancy, Speakers Bureau; Bayer AG: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Boehringer-Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb - Pfizer alliance: Honoraria; Celgene: Honoraria; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Daichii: Honoraria; Leo Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ortho Clinical Diagnostics: Honoraria; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees.