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Renin–Angiotensin–Aldosterone System-based Antihypertensive Agents and the Risk of Colorectal Cancer Among Medicare Beneficiaries

Htoo, Phyo T.a; Stürmer, Tila; Jonsson-Funk, Michelea; Pate, Virginiaa; Simpson, Ross J. Jrb; Lund, Jennifer L.a

doi: 10.1097/EDE.0000000000001065

Background: Biologic evidence suggests that angiotensin II may play a role in tumor progression or growth. We compared the short-term colorectal cancer (CRC) risk among initiators of angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) versus guideline-recommended clinical alternatives (beta blockers, calcium channel blockers [CCB], and thiazides).

Methods: We conducted a new-user cohort study on U.S. Medicare beneficiaries aged over 65 years, who initiated antihypertensive monotherapy during 2007–2013 and were free of cancer diagnosis before drug initiation. Follow-up began 6 months postinitiation to allow time for the diagnostic delay. We estimated hazard ratios (HR) with 95% confidence intervals (CI) using propensity score weighted Cox regression, overall and stratified by time since drug initiation, and 5-year cumulative risk differences (RD) using Kaplan–Meier estimator. We assessed the potential for unmeasured confounding using supplemental data from Medicare Current Beneficiary Survey.

Results: For analyses without censoring for treatment changes, we observed 532 CRC events among 111,533 ACEI/ARB initiators. After a median follow-up of 2.2 years (interquartile range: 1.0–3.7), CRC risk was similar between ACEI/ARB and active comparators, with adjusted HRs of 1.0 (95% CI = 0.85, 1.1) for ACEI/ARB versus beta blockers, 1.2 (95% CI = 0.97, 1.4) for ACEI/ARB versus CCB and 1.0 (95% CI = 0.80, 1.3) for ACEI/ARB versus thiazide. Five-year RDs and as-treated analyses, which censored follow-up at medication changes, produced similar findings.

Conclusions: Based on real-world antihypertensive utilization patterns in Medicare beneficiaries, our study suggests no association between ACEI/ARB initiation and the short-term CRC risk.

From the aDepartment of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC

bDivision of Cardiology, Department of Medicine, University of North Carolina at Chapel Hill, NC.

Submitted April 23, 2018; accepted July 18, 2019.

T.S. reports salary support from Center for Pharmacoepidemiology in the Department of Epidemiology, Gillings School of Global Public Health (current members: GlaxoSmithKline, UCB BioSciences, Merck), research support from AstraZeneca, Amgen, and ownership interest in Novartis, Roche, BASF, AstraZeneca, Johnson & Johnson, and Novo Nordisk. M.J.-F. reports salary support from NIH National Center for Advancing Translational Sciences (NCATS, 1UL1TR001111), consulting fee paid to the UNC via GlaxoSmithKline, Center for Pharmacoepidemiology in the Department of Epidemiology, Gillings School of Global Public Health and other research support from AstraZeneca. The results reported herein correspond to specific aims of grant R01 AG056479 to investigator T.S. from National Institute of Aging. The database infrastructure used for this project was funded by the Pharmacoepidemiology Gillings Innovation Lab (PEGIL) for the population-based evaluation of drug benefits and harms in older U.S. adults (GIL200811.0010); the Center for Pharmacoepidemiology, Department of Epidemiology, UNC Gillings School of Global Public Health; the Comparative Effectiveness Research Strategic Initiative of UNC’s Clinical and Translational Science Award (UL1TR002489); the Cecil G. Sheps Center for Health Services Research, UNC; and the UNC School of Medicine.

R.J.S. is a paid consultant to Amgen, Pfizer and Merck.

P.T.H., J.L.L., M.J.-F., and T.S. were involved in study design and conception. P.T.H. and V.P. had access to the data and performed data cleaning and statistical programming. P.T.H. was responsible for literature searches, statistical analyses, data interpretation, and preparation of the initial manuscript. All co-authors were involved in reviewing, providing feedback, and revising the manuscript. All authors have given permission to be named in the manuscript.

The computing code required to reproduce our findings is available upon request. We cannot provide Medicare data due to data user agreement but the data could be requested from the Centers for Medicare and Medicaid Services.

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Correspondence: Phyo T. Htoo, Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, 135 Dauer Drive, 2101 McGavran-Greenberg Hall, CB #7435, Chapel Hill, NC. E-mail:

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