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How does the intraocular risk of bleeding differ between patients receiving warfarin compared with the newer novel oral anticoagulants?
In this systematic review and meta-analysis of phase 3 randomized clinical trials involving 102 627 patients, use of novel oral anticoagulants was associated with a reduced risk of intraocular bleeding by one-fifth compared with warfarin.
Patients requiring anticoagulation for atrial fibrillation or venous thromboembolism at high risk of spontaneous intraocular bleeding may benefit from novel oral anticoagulant therapy.
It is unclear if the risk of intraocular bleeding with novel oral anticoagulants differs compared with warfarin.
To characterize the risk of intraocular bleeding with novel oral anticoagulants compared with warfarin.
A systematic review and meta-analysis was undertaken in an academic medical setting. MEDLINE and ClinicalTrials.gov were searched for randomized clinical trials published up until August 2016. This search was supplemented by manual bibliography searches of identified trials and other review articles.
Studies were eligible for inclusion if they were phase 3 randomized clinical trials, enrolled patients with atrial fibrillation or venous thromboembolism, compared a novel oral anticoagulant (dabigatran, rivaroxaban, apixaban, or edoxaban) with warfarin, and recorded event data on intraocular bleeding. Data on intraocular bleeding were pooled using inverse-variance, weighted, fixed-effects meta-analysis.
Data Extraction and Synthesis
The PRISMA guidelines were used for abstracting data and assessing quality. Independent extraction was performed by 2 investigators.
Main Outcomes and Measures
Intraocular bleeding events and associated risk ratio for novel oral anticoagulants compared with warfarin.
Twelve trials investigating 102 627 patients were included. Randomization to novel oral anticoagulants was associated with a 22% relative reduction in intraocular bleeding compared with warfarin (risk ratio, 0.78; 95% CI, 0.61-0.99). There was no significant heterogeneity observed (I2 = 4.8%, P = .40). Comparably lower risks of intraocular bleeding with novel oral anticoagulants were seen in subgroup analyses, with no significant difference according to the indication for anticoagulation (P for heterogeneity = .49) or the novel oral anticoagulant type (P for heterogeneity = .15). Summary estimates did not differ materially when random-effects meta-analytic techniques were used.
Conclusions and Relevance
These results suggest that novel oral anticoagulants reduce the risk of intraocular bleeding by approximately one-fifth compared with warfarin. Similar benefits were seen in both patients with atrial fibrillation and venous thromboembolism. Our data have particular relevance for patients at higher risk of spontaneous retinal and subretinal bleeding. These findings may also have important implications in the perioperative period, in which the use of novel oral anticoagulants may be superior. Future studies are required to better characterize the optimal management of patients with both ophthalmic disease and cardiovascular comorbidities requiring anticoagulation.
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Accepted for Publication: May 22, 2017.
Corresponding Author: Michelle T. Sun, MBBS, South Australian Institute of Ophthalmology, The University of Adelaide and Royal Adelaide Hospital, Level 8, East Wing, Adelaide, South Australia, Australia 5000 (email@example.com).
Published Online: July 6, 2017. doi:10.1001/jamaophthalmol.2017.2199
Author Contributions: Drs Sun and Wong had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Sun, Chan, Selva, Sanders, Wong.
Acquisition, analysis, or interpretation of data: Wood, Casson, Wong.
Drafting of the manuscript: Sun, Wood, Wong.
Critical revision of the manuscript for important intellectual content: Sun, Chan, Selva, Sanders, Casson, Wong.
Statistical analysis: Sun, Wong.
Administrative, technical, or material support: Wood, Casson.
Study supervision: Sun, Chan, Selva, Sanders, Casson, Wong.
Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Sanders reported having served on the advisory board of Biosense-Webster, Medtronic, and St Jude Medical; reported having received lecture or consulting fees from Biosense-Webster, Medtronic, and St Jude Medical; and reported having received research funding from Medtronic, St Jude Medical, Boston Scientific, Biotronik, and Sorin. Dr Wong reported having received lecture or travel funding from Novartis, Servier, Boehringer-Ingelheim, and Medtronic. No other disclosures were reported.
Funding/Support: The study was sponsored by The University of Adelaide, South Australian Institute of Ophthalmology, and Centre for Heart Rhythm Disorders. Dr Sun is supported by an Australian Postgraduate Award. Dr Sanders is supported by a Practitioner Fellowship from the National Health and Medical Research Council of Australia (NHMRC) and The Heart Foundation of Australia. Dr Wong is supported by a Rhodes Scholarship and a Neil Hamilton Fairley Fellowship from the NHMRC.
Role of the Funder/Sponsor: The design, approval, and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, and approval of the manuscript; and the decision to submit the manuscript for publication was executed through the authors as employees of The University of Adelaide and overseen by it.
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