Association of BW with Thromboembolic and Bleeding Outcomes in Phase III Randomized Controlled Trials of Direct Oral Anticoagulants: Systematic Review and Meta-Analysis
Authors: Boonyawat Kochawan , Caron Francois , Li Ang , Chai-Adisaksopha Chatree , Lim Wendy , Alfonso Iorio , Lopes Renato Delascio , Garcia David A , Crowther Mark 
Published: October 2019

Abstract

Direct oral anticoagulants (DOACs) and low molecular weight heparin transitioned to warfarin are widely used for stroke prevention in AF (AF) and in acute venous thromboembolism (VTE) treatment. Concerns have arisen in DOAC treated patients about the safety and efficacy with extremely high or low body weight due to its fix-dose effect. Whether body weight is associated with an increased risk of thromboembolic or bleeding outcomes in anticoagulant treated patients remains unknown. We hypothesized that if the fix dose effect does not hold true, we would observe the higher risk of thromboembolism in high body weight patients and higher risk of bleeding in low body weight patients comparing with non-high or non-low body weight, respectively.
We performed a systematic review and meta-analysis of subgroups of phase III randomized controlled trials (RCTs) using DOACs for prevention of stroke in AF and in treatment of acute VTE. We searched the MEDLINE and EMBASE databases, PubMED, Clinicaltrial.gov, abstracts and conference proceedings up to February 2016. Two reviewers independently performed screening, assessing eligibility and assessing risk of bias of the included studies. Data on thromboembolic outcome including stroke and systemic embolism and venous thromboembolism and bleeding outcome by subgroups of body weight or body mass index for both the DOACs and comparison arm were abstracted. Relative risk and 95% confidence interval were calculated. The pooled estimate from all studies were performed using Mantel Haenszel random effects model.
A total of 9 phase III RCTs were included in the meta-analyses. In patients treated with DOACs and those treated with warfarin, low body weight was associated with increased risk of thromboembolism compared with non-low body weight (RR, 1.57; 95% CI, 1.34-1.85, P <0.0001). The subgroup of AF patients with high body weight had a lower risk of thromboembolism compared with non-high body weight (RR, 0.43; 95%CI, 0.28 to 0.67, p =0.002). Bleeding outcomes were comparable for all body weight comparisons.There were no interaction between types of anticoagulant in all body weight comparisons.
Low body weight was associated with an increased risk of thromboembolic outcomes despite anticoagulation. In contrast, AF patients with high BW had decreased risks. The pooled effect of both the DOAC and the comparison arm were likely attributable to differences in baseline risk of thromboembolism in each body weight category, rather than an effect of the fixed doses of DOAC used in each indication. This study supports the prior observation of an "obesity paradox" and provides supporting evidence of the fixed dose used of DOACs in AF and acute VTE patients.
Table 1. Characteristic of included studies Table 1. Characteristic of included studies Table 2. Forest plot of comparison: Low BW vs. Non-low BW, thromboembolic outcomes (-D, DOACs arm, -W, warfarin arm) Table 2. Forest plot of comparison: Low BW vs. Non-low BW, thromboembolic outcomes (-D, DOACs arm, -W, warfarin arm) Table 3. Forest plot of comparison: High BW vs. Non-high BW, thromboembolic outcomes, subgroup analysis based on indication of DOACs ( -D, DOACs arm, -W, warfarin arm) Table 3. Forest plot of comparison: High BW vs. Non-high BW, thromboembolic outcomes, subgroup analysis based on indication of DOACs ( -D, DOACs arm, -W, warfarin arm)

Disclosures
Lim: Pfizer: Honoraria; Leo Pharma: Honoraria, Research Funding. Alfonso:Pfizer: Consultancy; NovoNorkdisk: Consultancy; Bayer: Consultancy; University of Perugia: Employment; McMaster University: Employment. Lopes:Bayer: Consultancy; Boehringer Ingleheim: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Glaxo Smith Kline: Consultancy, Research Funding; Merck: Consultancy; Pfizer: Consultancy; Portola: Consultancy. Garcia:Pfizer: Consultancy; Boehringer Ingelheim: Consultancy; Daiichi Sankyo: Consultancy, Research Funding; BMS: Consultancy; Janssen: Consultancy, Research Funding. Crowther:Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Daichii: Honoraria; Celgene: Honoraria; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Daichii: Honoraria; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ortho Clinical Diagnostics: Honoraria; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb - Pfizer alliance: Honoraria; Bristol-Myers Squibb - Pfizer alliance: Honoraria; Daichii: Honoraria; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ortho Clinical Diagnostics: Honoraria; Boehringer-Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees; Daichii: Honoraria; Bristol-Myers Squibb - Pfizer alliance: Honoraria; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ortho Clinical Diagnostics: Honoraria; Boehringer-Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees; Leo Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb - Pfizer alliance: Honoraria; Daichii: Honoraria; Bristol-Myers Squibb - Pfizer alliance: Honoraria; Leo Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Leo Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alexion: Consultancy, Speakers Bureau; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Ortho Clinical Diagnostics: Honoraria; Boehringer-Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees; Alexion: Consultancy, Speakers Bureau; Celgene: Honoraria; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer AG: 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; Celgene: Honoraria; Celgene: Honoraria; Boehringer-Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees; Boehringer-Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb - Pfizer alliance: Honoraria; Boehringer-Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb - Pfizer alliance: Honoraria; Bristol-Myers Squibb - Pfizer alliance: Honoraria; Alexion: Consultancy, Speakers Bureau; Alexion: Consultancy, Speakers Bureau; AKP America: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb - Pfizer alliance: Honoraria; Alexion: Consultancy, Speakers Bureau; AKP America: Membership on an entity's Board of Directors or advisory committees; AKP America: Membership on an entity's Board of Directors or advisory committees; Bayer AG: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bayer AG: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bayer AG: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer-Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ortho Clinical Diagnostics: Honoraria; Ortho Clinical Diagnostics: Honoraria; Ortho Clinical Diagnostics: Honoraria; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; 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; Bayer AG: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria; Bayer AG: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bayer AG: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bayer AG: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria; Celgene: Honoraria; AKP America: Membership on an entity's Board of Directors or advisory committees; Bayer AG: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bayer AG: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AKP America: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AKP America: Membership on an entity's Board of Directors or advisory committees; AKP America: Membership on an entity's Board of Directors or advisory committees; Alexion: Consultancy, Speakers Bureau; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion: Consultancy, Speakers Bureau; AKP America: Membership on an entity's Board of Directors or advisory committees; Alexion: Consultancy, Speakers Bureau; Bristol-Myers Squibb - Pfizer alliance: Honoraria; Alexion: Consultancy, Speakers Bureau; Daichii: Honoraria; AKP America: Membership on an entity's Board of Directors or advisory committees; AKP America: Membership on an entity's Board of Directors or advisory committees; Boehringer-Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb - Pfizer alliance: Honoraria; Ortho Clinical Diagnostics: Honoraria; Ortho Clinical Diagnostics: Honoraria; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Boehringer-Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer-Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer AG: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; 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; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria; Daichii: Honoraria; Celgene: Honoraria; AKP America: Membership on an entity's Board of Directors or advisory committees; Daichii: Honoraria; Bayer AG: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Ortho Clinical Diagnostics: Honoraria; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ortho Clinical Diagnostics: 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; Leo Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer AG: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Ortho Clinical Diagnostics: Honoraria; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb - Pfizer alliance: Honoraria; Leo Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees; Alexion: Consultancy, Speakers Bureau; Daichii: Honoraria; Leo Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb - Pfizer alliance: Honoraria; Celgene: Honoraria; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees; Boehringer-Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees; AKP America: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Ortho Clinical Diagnostics: Honoraria; Ortho Clinical Diagnostics: Honoraria; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees; AKP America: Membership on an entity's Board of Directors or advisory committees; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Leo Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Daichii: Honoraria; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daichii: Honoraria; AKP America: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer AG: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb - Pfizer alliance: Honoraria; Daichii: Honoraria; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Alexion: Consultancy, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees; Alexion: Consultancy, Speakers Bureau; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; 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; Leo Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Leo Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Ortho Clinical Diagnostics: Honoraria; Ortho Clinical Diagnostics: Honoraria; AKP America: Membership on an entity's Board of Directors or advisory committees; Alexion: Consultancy, Speakers Bureau; AKP America: Membership on an entity's Board of Directors or advisory committees; Bayer AG: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ortho Clinical Diagnostics: Honoraria; Daichii: Honoraria; Daichii: Honoraria; Boehringer-Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Leo Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Daichii: Honoraria; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer-Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ortho Clinical Diagnostics: Honoraria; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; 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; Leo Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alexion: Consultancy, Speakers Bureau; Celgene: Honoraria; Celgene: Honoraria; Alexion: Consultancy, Speakers Bureau; Alexion: Consultancy, Speakers Bureau; Boehringer-Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Boehringer-Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ortho Clinical Diagnostics: Honoraria; Leo Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria; Bristol-Myers Squibb - Pfizer alliance: Honoraria; Bristol-Myers Squibb - Pfizer alliance: 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.