Bedtime vs Morning Antihypertensive Medications in Frail Older Adults: The BedMed-Frail Randomized Clinical Trial

Abstract

Importance: The effect of antihypertensive administration time on major adverse cardiovascular events is unclear, and has never been studied in frail older adults, for whom risks and benefits may differ from the general population.

Objective: To determine, in frail seniors, the effect of bedtime vs morning administration of antihypertensive medications on major cardiovascular events and death, as well as on potentially ischemic or hypotensive adverse events.

Design, setting, and participants: This multicenter, open-label, pragmatic randomized clinical trial recruited from 13 continuing care facilities in Canada (17 wards; 14 long-term care and 3 supportive-living wards) from May 25, 2020, to September 18, 2023, with follow-up until February 29, 2024. Residents with hypertension and at least 1 once-daily antihypertensive medication were included. Data analysis was from March to August 2024.

Interventions: Patients were randomized 1:1 to taking all once-daily antihypertensive medications either at bedtime (intervention) or per usual care control (largely morning use).

Main outcomes and measures: The composite primary outcome was first occurrence of all-cause death or either hospitalization or emergency department (ED) visit for stroke, acute coronary syndrome, or heart failure. All-cause unplanned hospitalization or ED visits, falls and fractures, decubitus ulcers, and worsening cognition or behavioral problems were also assessed.

Results: A total of 776 older adults (median [IQR] age, 88 [81-92] years; 562 female [72.4%]; 664 [85.6%] with some degree of dementia; 367 [47.3%] with diabetes; 307 [39.6%] with coronary artery disease) were randomized to bedtime (394 participants) vs usual care (382 participants) administration and were followed-up for a median (IQR) of 415 (251-735) days. Of 320 primary outcome events, 293 (91.6%) were deaths; there was no difference in primary outcomes for bedtime vs usual care in a modified intention-to-treat analysis (29.4 vs 31.5 events per 100 patient-years; adjusted hazard ratio [aHR], 0.88; 95% CI, 0.71-1.11; P = .28). Other outcomes were similarly no different between groups, excepting all-cause unplanned hospitalization and ED visits, which favored bedtime (22.6 vs 30.0 events per 100 patient-years; aHR, 0.74; 95% CI, 0.57-0.96; P = .02).

Conclusions and relevance: In this randomized clinical trial of antihypertensive medication timing, switching antihypertensives to bedtime failed to reduce a composite of death or major cardiovascular events that were primarily all-cause death, and had no effect on potentially ischemic and hypotensive adverse events, suggesting that in a population of frail older adults, administration time had little or no influence on the benefits and risks of antihypertensive medication.

Trial registration: ClinicalTrials.gov Identifier: NCT04054648.

Figure 1.. Randomization and Follow-Up in the BedMed-Frail Trial

BP indicates blood pressure.

Figure 2.. Effect of Medication Timing on Cardiovascular Events and Death

Figure shows the cumulative incidence of a first composite primary outcome event (all-cause death or hospitalization/emergency department visit for stroke, acute coronary syndrome, or heart failure) for the comparison of bedtime vs usual care (largely morning) antihypertensive use. HR indicates hazard ratio.

Figure 3.. Subgroup Analyses: Primary Outcome and All-Cause Unplanned Hospitalization or Emergency Department (ED) Visit

For all-cause death or major cardiovascular event (A) and unplanned hospitalization or ED visit (B), interaction P values for the prespecified subgroup analyses shown were obtained from a Cox model employing all covariates preidentified in the statistical analysis plan, and including both the characteristic of interest, and an interaction term between that characteristic and the randomization group. All confidence intervals are adjusted using the same rules for covariate selection as defined in the statistical analysis plan (which fully define order of covariates and number of covariates for inclusion according to the number of events observed). Resistant hypertension was defined as 3 or more antihypertensive medications. ACE indicates angiotensin-converting enzyme; HR, hazard ratio; NA, not applicable.