Bedtime Versus Morning Dosing of Anti-hypertensives: A GRADE-Assessed Meta-Analysis of Randomized Controlled Trials with Trial Sequential Evidence.

Abstract

Introduction: The timing of anti-hypertensive medication may influence cardiovascular outcomes and blood pressure control, yet the evidence remains inconclusive.

Aim: We conducted a meta-analysis to compare the effects of bedtime versus morning dosing of anti-hypertensives on mortality, cardiovascular events, and ambulatory blood pressure.

Methods: We conducted a meta-analysis of randomized controlled trials (RCTs) comparing bedtime versus morning administration of antihypertensive therapy. A comprehensive literature search was performed in PubMed, Embase, Cochrane Library, Scopus, and Web of Science databases up to June 2025. Pooled risk ratios (RRs) were calculated for categorical outcomes, and mean differences (MDs) for continuous variables. All statistical analyses were performed using R version 4.3.3. PROSPERO registration ID: CRD420251113957.

Results: Pooled analysis of six RCTs with 49,983 patients was included. Bedtime dosing of anti-hypertensive medications resulted in a lower incidence of heart failure (1.3% vs. 2.0%; RR 0.63, 95% CI 0.47-0.85) but not myocardial infarction (1.4% vs. 1.6%; RR 0.87, 95% CI 0.64-1.17), stroke or transient ischemic attack (0.9% vs. 1.3%; RR 0.71, 95% CI 0.49-1.05), all-cause mortality (2.6% vs. 3.1%; RR 0.75, 95% CI 0.53-1.06), or cardiovascular mortality (1.0% vs. 1.5%; RR 0.52, 95% CI 0.22-1.21). For blood pressure, bedtime dosing significantly reduced evening systolic blood pressure (MD - 4.71 mmHg, 95% CI - 6.64 to - 2.78) and evening diastolic blood pressure (MD - 1.66 mmHg, 95% CI - 1.92 to - 1.40), with no significant differences observed in morning readings.

Conclusion: Bedtime administration of anti-hypertensive medications may be associated with reduction in MACE and heart failure incidence. No significant effect was observed in mortality, myocardial infarction, or stroke.