Comparative Efficacy of Antihypertensive Chronotherapy Strategies on Cardiovascular Outcomes: A Systematic Review and Exploratory Network Meta-analysis

Abstract The optimal timing of antihypertensive medication administration remains controversial. Early chronotherapy trials suggested substantial cardiovascular benefit with bedtime dosing, whereas contemporary randomized trials demonstrated neutral findings. We conducted a systematic review and exploratory network meta-analysis comparing antihypertensive chronotherapy strategies on cardiovascular outcomes. A systematic search of PubMed, Embase, and Scopus was conducted from inception to May 2026 for randomized controlled trials evaluating antihypertensive administration timing and reporting cardiovascular outcomes. Distinct strategies were modeled as separate nodes: partial bedtime dosing (PBD), full bedtime dosing (FBD), evening dosing, pragmatic bedtime dosing, and frail bedtime dosing, with morning dosing as the common comparator. Hazard ratios (HR) were used when reported. Five randomized controlled trials involving 46,477 participants were included. Compared with morning dosing, PBD was associated with lower cardiovascular event rates (HR-equivalent incidence rate ratio: 0.43, 95% confidence interval [CI]: 0.31–0.59), as was FBD (HR: 0.55, 95% CI: 0.50–0.61). P-score ranking suggested the most favorable ranking for PBD (0.985), followed by FBD (0.815), frail bedtime dosing (0.658), evening dosing (0.316), and pragmatic bedtime dosing (0.281). The network was star-shaped without closed loops and inconsistency could not be assessed. Monitorización ambulatoria para predicción de eventos cardiovasculares (MAPEC) and Hygia were judged at high overall risk of bias, whereas treatment in morning versus evening (TIME), BedMed, and BedMed-Frail were judged as having some concerns overall. PBD was associated with lower cardiovascular event rates. Because of sparse star-shaped network geometry, nonestimable heterogeneity, indirect active-treatment comparisons, the network estimates and rankings should be considered exploratory and hypothesis-generating rather than definitive.