Cardiovascular Outcomes of Alpha-Blockers Versus 5-Alpha Reductase Inhibitors Among Patients with Benign Prostatic Hyperplasia

Importance Alpha-blockers (AB) are widely prescribed for treatment of benign prostatic hyperplasia (BPH). However, the cardiovascular safety profile of these medications among patients with BPH is not well understood. Objective To compare the safety of ABs versus 5-alpha reductase inhibitors (5ARIs) for risk of adverse cardiovascular outcomes. Design We conducted an active comparator, new user, cohort study using insurance claims data from 2007-2019. Setting This study used data from a 20% random sample of Medicare (U.S.) beneficiaries. Participants Men between 66 and 90 years of age were indexed into the cohort at new use of an AB or 5ARI. We required 12 months of continuous enrollment and ≥1 diagnosis code for BPH within 12 months prior to initiation. Exposures Exposure was defined by a qualifying prescription fill for either an AB or 5ARI after at least 12 months without a prescription for these drug classes. Main Outcomes and Measures Follow-up began at a qualified refill for the study drug. The primary study outcomes were (1) hospitalization for heart failure (HF); (2) composite major adverse cardiovascular events (MACE) (hospitalization for stroke, myocardial infarction, or death); (3) composite MACE or hospitalization for HF; and (4) death. We estimated inverse probability of treatment and censoring weighted 1-year risks, risk ratios (RRs), and risk differences (RDs) for each outcome. Results We identified 163,846 and 26,040 initiators of ABs and 5ARIs, respectively. In our fully adjusted analyses, we found ABs, compared to 5ARIs, were associated with an increased 1-year risk of MACE (RR=1.08 [1.02, 1.13], RD=6.26 per 1,000 [2.15, 10.37]), composite MACE and HF (RR=1.07 [1.03, 1.12], RD=7.40 per 1,000 [2.88, 11.93]), and death (RR=1.07 [1.01, 1.14], RD=3.85 per 1,000 [0.40, 7.29]). We did not find a difference in risk for HF alone (RR=0.99 [0.92, 1.07], RD=-2.33 per 10,000 [-31.97, 27.31]). Conclusions and Relevance These results provide real-world evidence that ABs may be associated with an increased risk of adverse cardiovascular outcomes, though residual confounding may explain these findings. If replicated with detailed confounder data, these results could have important public health implications given the widespread use of these medications. Question What is the comparative risk of alpha-blockers versus 5-alpha reductase inhibitors for adverse cardiovascular outcomes among patients with benign prostatic hyperplasia? Findings We found that use of alpha-blockers was associated with a small increase in risk for multiple adverse cardiovascular outcomes compared to 5-alpha reductase inhibitors, among patients with benign prostatic hyperplasia. These results could be explained by unmeasured variables (e.g., blood pressure or body mass index). Meaning First-line use of alpha-blockers for BPH may result in a small increase in risk of adverse cardiovascular outcomes including death. Widescale use of alpha-blockers (>5 million prescriptions/year) could amplify this risk. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This research was partially supported by a National Research Service Award Pre-Doctoral/Post-Doctoral Traineeship from the Agency for Healthcare Research and Quality sponsored by The Cecil G. Sheps Center for Health Services Research, The University of North Carolina at Chapel Hill, Grant No. T32-HS000032 (CDL). TS receives investigator-initiated research funding and support as Principal Investigator (R01AG056479) from the National Institute on Aging (NIA), and as Co-Investigator (R01CA174453, R01HL118255, R01MD011680), National Institutes of Health (NIH). BCJ receives funding as Principal Investigator (2R01HL140067) and as Co-investigator (R01HL161456, R01HL148432, R01HL146701) from the National Institutes of Health. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study used ONLY openly available human data that were originally located in the database of Medicare (U.S.) beneficiaries. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present work are contained in the manuscript