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Tumor Necrosis Factor-α Inhibitor Use and the Risk of Incident Hypertension in Patients with Rheumatoid Arthritis

Desai, Rishi J.; Solomon, Daniel H.; Schneeweiss, Sebastian; Danaei, Goodarz; Liao, Katherine P.; Kim, Seoyoung C.

doi: 10.1097/EDE.0000000000000446
Cardiovascular Disease

Objective: To compare the risk of incident hypertension between initiators of tumor necrosis factor (TNF)-α inhibitors and initiators of nonbiologic disease modifying antirheumatic drugs (hereafter referred to as nonbiologics) in rheumatoid arthritis patients taking methotrexate monotherapy.

Methods: We conducted a cohort study using insurance claims data (2001–2012) from the US. We identified initiators of use of either TNF-α inhibitors or nonbiologics. Subsequent exposure to these agents was measured monthly in a time-varying manner. The outcome of interest was incident hypertension, defined by a diagnosis and a prescription for an antihypertensive drug. Marginal structural models estimated hazard ratios (HRs) adjusted for both baseline and time-varying confounders. To validate the primary analysis, we designed a verification analysis to evaluate a known association between leflunomide (a nonbiologic disease modifying agent) and hypertension.

Results: We identified 4,822 initiations of TNF-α inhibitor use and 2,400 of nonbiologic use. Crude incidence rates of hypertension per 1,000 person-years of follow-up were 36 (95% CI [confidence interval]: 32, 41) for the TNF-α inhibitor group and 42 (95% CI: 34, 51) for the nonbiologics group. The crude HR of TNF-α inhibitors versus nonbiologics for the risk of incident hypertension was 0.85 (95% CI: 0.67, 1.1). After adjusting for both baseline and time-varying covariates using marginal structural models, the HR was 0.95 (95% CI: 0.74, 1.2). In the verification analysis, the adjusted HR of incident hypertension was 2.3 (95% CI: 1.7, 3.0) in leflunomide initiators compared with methotrexate initiators.

Conclusion: Treatment with TNF-α inhibitors was not associated with a reduced risk of incident hypertension compared with nonbiologics in rheumatoid arthritis patients.

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From the aDivision of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women’s Hospital & Harvard Medical School, Boston, MA; bDivision of Rheumatology, Immunology and Allergy, Brigham and Women’s Hospital, Boston, MA; and cDepartment of Global Health and Population, Harvard School of Public Health, Boston, MA.

Submitted 9 March 2015; accepted 19 January 2016.

This study was funded from internal sources of the Division of Pharamcoepidemiology and Pharmacoeconomics. Dr. Solomon is supported by National Institutes of Health (NIH) Grants K24 AR055989, P60 AR047782, and R01 AR056215. He receives research grants from Amgen and Lilly. He serves in unpaid roles on studies sponsored by Pfizer, Novartis, Lilly, and Bristol Myers Squibb. He also receives royalties from Dr. Kim is supported by NIH Grant K23 AR059677. She received research support from Pfizer and Lilly. Dr. Liao is supported by NIH Grant K08 AR060257 and the Harold and Duval Bowen Fund. Dr. Schneeweiss is principal investigator of the Harvard-Brigham Drug Safety and Risk Management Research Center funded by the US Food and Drug Administration (FDA). His work is partially funded by grants/contracts from PCORI, FDA, and National Heart, Lung, and Blood Institute. Schneeweiss is consultant to WHISCON, LLC, and Aetion, Inc., of which he also owns shares. He is principal investigator of investigator-initiated grants to the Brigham and Women’s Hospital from Novartis, and Boehringer-Ingelheim unrelated to the topic of this study.

The authors report no conflicts of interest.

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Correspondence: Rishi J. Desai, Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, 1620 Tremont Street, Suite 3030-R, Boston, MA 02120. E-mail:

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