Jeffrey T. Ha, MBBS; Brendon L. Neuen, MBBS(Hons); Lap P. Cheng, MBBS; Min Jun, PhD; Tadashi Toyama, PhD; Martin P. Gallagher, PhD; Meg J. Jardine, PhD; Manish M. Sood, MD; Amit X. Garg, PhD; Suetonia C. Palmer, PhD; Patrick B. Mark, PhD; David C. Wheeler, MD; Vivekanand Jha, MD; Ben Freedman, PhD; David W. Johnson, PhD; Vlado Perkovic, PhD; Sunil V. Badve, PhD
Acknowledgment: The authors thank Professor John H. Alexander of Duke University School of Medicine for providing unpublished trial data from 1 trial for meta-analyses.
Financial Support: Dr. Ha is supported by a University Postgraduate Award from UNSW Sydney. Dr. Neuen is supported by a John Chalmers PhD Scholarship from The George Institute for Global Health, a University Postgraduate Award from UNSW Sydney, and an Oxford Australia Clarendon Scholarship from Oxford University. Dr. Jun is supported by a Scientia Fellowship from UNSW Sydney. Dr. Toyama is supported by the Japan Society for the Promotion of Science Program for Fostering Globally Talented Researchers. Dr. Jardine is supported by a Medical Research Future Fund Next Generation Clinical Researchers Program Career Development Fellowship. Dr. Palmer is supported by a Rutherford Discovery Fellowship from the Royal Society of New Zealand. Dr. Johnson is supported by an Australian Government National Health and Medical Research Council Practitioner Fellowship. Dr. Badve is supported by a John Chalmers Clinical Research Fellowship with the support of Servier from The George Institute for Global Health. These organizations and agencies had no role in the design or conduct of the study, analysis or interpretation of the data, review or approval of the manuscript, or the decision to submit the manuscript for publication.
Disclosures: Dr. Neuen has received travel support from Janssen outside the submitted work. Dr. Jun reports grants from AstraZeneca outside the submitted work. Dr. Gallagher reports personal fees from Amgen and other support from Bayer outside the submitted work. Dr. Jardine reports grants from Baxter, Amgen, Eli Lilly, and MSD and personal fees from Baxter, CSL, Akebia, Boehringer Ingelheim, Vifor Pharma, and Janssen outside the submitted work. All consultancy, honoraria, or travel support is paid to her employing institution. Dr. Mark reports grants from Boehringer Ingelheim; personal fees from Vifor Pharma, AstraZeneca, Pharmacosmos, Janssen, Novartis, Pfizer, and Bristol-Myers Squibb; and nonfinancial support from Pharmacosmos outside the submitted work. Dr. Wheeler reports personal fees from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, GlaxoSmithKline, Janssen, Mitsubishi, Mundipharma, Napp, Ono Pharmaceutical, Vifor Pharma, and MSD outside the submitted work. Dr. Jha reports grants from Baxter Healthcare, GSK, and Biocon and personal fees from NephroPlus outside the submitted work. Dr. Freedman reports grants from Bayer and BMS-Pfizer; personal fees from Bayer, BMS-Pfizer, and Daiichi Sankyo; and nonfinancial support from Bayer, BMS-Pfizer, Daiichi Sankyo, and AliveCor outside the submitted work. Dr. Johnson reports grants from Baxter Healthcare, Fresenius Medical Care, and the National Health and Medical Research Council of Australia; personal fees from Baxter Healthcare, Fresenius Medical Care, and AstraZeneca; and other support from Amgen during the conduct of the study. Dr. Perkovic reports personal fees from Retrophin, Janssen, Merck, Servier, AbbVie, Astellas, AstraZeneca, Bayer, Baxter, BMS, Boehringer Ingelheim, Dimerix, DURECT, Eli Lilly, Gilead, GSK, Mitsubishi Tanabe, Novartis, Novo Nordisk, Pfizer, PharmaLink, Relypsa, Sanofi, Vifor Pharma, and Tricida outside the submitted work. Dr. Badve reports grants from the National Health and Medical Research Council of Australia, personal fees from Bayer AG and Amgen Australia, and nonfinancial support from Bayer AG during the conduct of the study. Authors not named here have disclosed no conflicts of interest. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M19-0087.
Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that her spouse has stock options/holdings with Targeted Diagnostics and Therapeutics. Darren B. Taichman, MD, PhD, Executive Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Catharine B. Stack, PhD, MS, Deputy Editor, Statistics, reports that she has stock holdings in Pfizer, Johnson & Johnson, and Colgate-Palmolive. Christina C. Wee, MD, MPH, Deputy Editor, reports employment with Beth Israel Deaconess Medical Center. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Yu-Xiao Yang, MD, MSCE, Deputy Editor, reports that he has no financial relationships or interest to disclose.
Reproducible Research Statement: Study protocol: Available at www.crd.york.ac.uk/prospero/display_record.php?RecordID=79709. Statistical code and data set: Available from Dr. Badve (e-mail, firstname.lastname@example.org).
Corresponding Author: Sunil V. Badve, PhD, The George Institute for Global Health, UNSW Medicine, Level 5, 1 King Street, Newtown, NSW 2042, Australia; e-mail, email@example.com.
Current Author Addresses: Drs. Ha, Neuen, Cheng, Jun, Gallagher, Jardine, Perkovic, and Badve: The George Institute for Global Health, Level 5, 1 King Street, Newtown, NSW 2042, Australia.
Dr. Toyama: Kanazawa University Hospital, Kanazawa, 920-8641, Japan.
Dr. Sood: Ottawa Hospital Research Institute, Civic Campus, 2-014 Administrative Services Building, 1053 Carling Avenue, Box 693, Ottawa, Ontario K1Y 4E9, Canada.
Dr. Garg: Institute for Clinical Evaluative Sciences Western Facility (ICES Western), 800 Commissioners Road, Victoria Hospital, Room ELL-215, London, Ontario N6A 5W9, Canada.
Dr. Palmer: University of Otago Christchurch, 2 Riccarton Avenue, Christchurch 8140, New Zealand.
Dr. Mark: Institute of Cardiovascular and Medical Sciences, University of Glasgow, 126 University Place, Glasgow G12 8TA, United Kingdom.
Dr. Wheeler: Centre for Nephrology, University College London, Rowland Hill Street, London NW3 2PF, United Kingdom.
Dr. Jha: The George Institute for Global Health, 310–11 Splendor Forum, Jasola, New Delhi 110025, India.
Dr. Freedman: Heart Research Institute, Charles Perkins Centre, Building D17, Level 3, Room 3114, University of Sydney, Camperdown, NSW 2006, Australia.
Dr. Johnson: Ambulatory Renal and Transplant Services (ARTS) Building, 199 Ipswich Road, Woolloongabba, QLD 4102, Australia.
Author Contributions: Conception and design: J.T. Ha, L.P. Cheng, D.C. Wheeler, D.W. Johnson, S.V. Badve.
Analysis and interpretation of the data: J.T. Ha, B.L. Neuen, M. Jun, T. Toyama, M.P. Gallagher, M.J. Jardine, M.M. Sood, A.X. Garg, S.C. Palmer, V. Jha, B. Freedman, S.V. Badve.
Drafting of the article: J.T. Ha, L.P. Cheng, P.B. Mark, D.C. Wheeler, V. Jha, D.W. Johnson, V. Perkovic, S.V. Badve.
Critical revision of the article for important intellectual content: J.T. Ha, B.L. Neuen, L.P. Cheng, M. Jun, M.P. Gallagher, M.J. Jardine, M.M. Sood, A.X. Garg, S.C. Palmer, P.B. Mark, D.C. Wheeler, V. Jha, B. Freedman, D.W. Johnson, V. Perkovic, S.V. Badve.
Final approval of the article: J.T. Ha, B.L. Neuen, L.P. Cheng, M. Jun, T. Toyama, M.P. Gallagher, M.J. Jardine, M.M. Sood, A.X. Garg, S.C. Palmer, P.B. Mark, D.C. Wheeler, V. Jha, B. Freedman, D.W. Johnson, V. Perkovic, S.V. Badve.
Statistical expertise: M.M. Sood, S.C. Palmer.
Obtaining of funding: D.C. Wheeler.
Administrative, technical, or logistic support: J.T. Ha, T. Toyama, M.P. Gallagher, S.C. Palmer.
Collection and assembly of data: J.T. Ha, B.L. Neuen.
Effects of oral anticoagulation in chronic kidney disease (CKD) are uncertain.
To evaluate the benefits and harms of vitamin K antagonists (VKAs) and non–vitamin K oral anticoagulants (NOACs) in adults with CKD stages 3 to 5, including those with dialysis-dependent end-stage kidney disease (ESKD).
English-language searches of MEDLINE, EMBASE, and Cochrane databases (inception to February 2019); review bibliographies; and ClinicalTrials.gov (25 February 2019).
Randomized controlled trials evaluating VKAs or NOACs for any indication in patients with CKD that reported efficacy or bleeding outcomes.
Two authors independently extracted data, assessed risk of bias, and rated certainty of evidence.
Forty-five trials involving 34 082 participants who received anticoagulation for atrial fibrillation (AF) (11 trials), venous thromboembolism (VTE) (11 trials), thromboprophylaxis (6 trials), prevention of dialysis access thrombosis (8 trials), and cardiovascular disease other than AF (9 trials) were included. All but the 8 trials involving patients with ESKD excluded participants with creatinine clearance less than 20 mL/min or estimated glomerular filtration rate less than 15 mL/min/1.73 m2. In AF, compared with VKAs, NOACs reduced risks for stroke or systemic embolism (risk ratio [RR], 0.79 [95% CI, 0.66 to 0.93]; high-certainty evidence) and hemorrhagic stroke (RR, 0.48 [CI, 0.30 to 0.76]; moderate-certainty evidence). Compared with VKAs, the effects of NOACs on recurrent VTE or VTE-related death were uncertain (RR, 0.72 [CI, 0.44 to 1.17]; low-certainty evidence). In all trials combined, NOACs seemingly reduced major bleeding risk compared with VKAs (RR, 0.75 [CI, 0.56 to 1.01]; low-certainty evidence).
Scant evidence for advanced CKD or ESKD; data mostly from subgroups of large trials.
In early-stage CKD, NOACs had a benefit–risk profile superior to that of VKAs. For advanced CKD or ESKD, there was insufficient evidence to establish benefits or harms of VKAs or NOACs.
None. (PROSPERO: CRD42017079709)
Ha JT, Neuen BL, Cheng LP, Jun M, Toyama T, Gallagher MP, et al. Benefits and Harms of Oral Anticoagulant Therapy in Chronic Kidney Disease: A Systematic Review and Meta-analysis. Ann Intern Med. [Epub ahead of print 16 July 2019]171:181–189. doi: 10.7326/M19-0087
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Published: Ann Intern Med. 2019;171(3):181-189.
Published at www.annals.org on 16 July 2019
Cardiology, Chronic Kidney Disease, Nephrology, Renal Replacement Therapy, Rhythm Disorders and Devices.
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