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Associations Between Methotrexate Use and the Risk of Cardiovascular Events in Patients with Elderly-onset Rheumatoid Arthritis

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Widdifield J1, Abrahamowicz M1, Paterson JM1, Huang A1, Thorne JC1, Pope JE1, Kuriya B1, Beauchamp ME1, Bernatsky S1. J Rheumatol. 2018 Dec 1. pii: jrheum.180427. doi: 10.3899/jrheum.180427. [Epub ahead of print]

Abstract

Author information 1 From the Sunnybrook Research Institute, Holland Bone and Joint Research Program, Toronto, Ontario; McGill University, Department of Epidemiology, Biostatistics and Occupational Health; Research Institute of the McGill University Health Centre, Department of Clinical Epidemiology, and Centre for Outcomes Research and Evaluation, Montreal, Quebec; ICES; University of Toronto, Institute of Health Policy, Management and Evaluation, Toronto; McMaster University, Department of Family Medicine, Hamilton; Southlake Regional Health Centre, Department of Medicine, Newmarket; Western University, Department of Epidemiology and Biostatistics; St. Joseph's Health Care, Department of Medicine, London; Mount Sinai Hospital, Department of Medicine, Toronto, Ontario, Canada. This analysis was supported by the Canadian Network for Advanced Interdisciplinary Methods for comparative effectiveness research, which is funded by the Canadian Institutes of Health Research Drug Safety and Effectiveness Network (funding reference no. TD3-137716). JW was supported by fellowship awards from The Arthritis Society and the Canadian Institutes of Health Research (Banting) during the course of this work; SB holds a career award from the Fonds de la recherche en santé du Québec; MA is a James McGill Professor of Biostatistics at McGill University. This study was supported by the ICES, a nonprofit research corporation funded by the Ontario Ministry of Health and Long-Term Care. Parts of this material are based on data and/or information compiled and provided by the Canadian Institutes of Health Information (CIHI). However, the analyses, conclusions, opinions, and statements expressed in the material are those of the authors and not necessarily those of CIHI. J. Widdifield, PhD, Sunnybrook Research Institute, Holland Bone and Joint Research Program, and McGill University, Department of Epidemiology, Biostatistics and Occupational Health, and Research Institute of the McGill University Health Centre, Department of Clinical Epidemiology, ICES, and University of Toronto, Institute of Health Policy, Management and Evaluation; M. Abrahamowicz, PhD, McGill University, Department of Epidemiology, Biostatistics and Occupational Health, and Research Institute of the McGill University Health Centre, Centre for Outcomes Research and Evaluation; J.M. Paterson, MSc, ICES, and University of Toronto, Institute of Health Policy, Management and Evaluation, and McMaster University, Department of Family Medicine; A. Huang, MSc, ICES; J.C. Thorne, MD, FRCPC, Southlake Regional Health Centre, Department of Medicine; J.E. Pope, MD, FRCPC, MPH, Western University, Department of Epidemiology and Biostatistics, and St. Joseph's Health Care, Department of Medicine; B. Kuriya, MD, FRCPC, SM, Mount Sinai Hospital, Department of Medicine; M.E. Beauchamp, PhD, Research Institute of the McGill University Health Centre, Centre for Outcomes Research and Evaluation; S. Bernatsky, MD, FRCPC, PhD, McGill University, Department of Epidemiology, Biostatistics and Occupational Health, and Research Institute of the McGill University Health Centre, Centre for Outcomes Research and Evaluation. Address correspondence J. Widdifield, Holland Bone and Joint Research Program, Sunnybrook Research Institute MG 352, 2075 Bayview Ave., Toronto, Ontario M4N 3M5, Canada. E-mail: jessica.widdifield@utoronto.ca. Accepted for publication August 22, 2018.

Abstract

OBJECTIVE: We evaluated the associations between time-varying methotrexate (MTX) use and risk of cardiovascular events (CVE) in patients with rheumatoid arthritis (RA).

METHODS: We studied an inception cohort of 23,994 patients with RA diagnosed after their 65th birthday. Multivariable Cox regression models were fit to evaluate the associations between time-varying MTX use, controlling for other risk factors, and time to CVE. Alternative models assessed the cumulative duration of MTX use over the (1) first year, (2) previous year (recent use), and (3) entire duration of followup. We also assessed whether the strength of the association varied over time.

RESULTS: Over 115,453 patient-years (PY), 3294 (13.7%) patients experienced a CVE (28.5 events per 1000 PY; 95% CI 27.6-29.5). In the multivariable analyses, the model assessing time-varying continuous use in the most recent year yielded the best fit. Increasing recent MTX use was associated with lower CVE risks (HR 0.79 for continuous use vs no use in past 12 months, 95% CI 0.70-0.88; p < 0.0001). Greater MTX use in the first year after cohort entry was also protective (HR 0.84, 95% CI 0.72-0.96; p = 0.0048), but this effect decreased with increasing followup. In contrast, longer MTX use during the entire followup was not clearly associated with CVE risk (HR 0.98, 95% CI 0.95-1.01; p = 0.1441).

CONCLUSION: We observed about a 20% decrease in CVE associated with recent continuous MTX use. Greater MTX use in the first year of cohort entry also appeared to be important in the association between MTX and CVE risk.