Timing of Antihypertensive Drug Therapy: A Systematic Review and Meta-Analysis of Randomized Clinical Trials

BACKGROUND: The timing of antihypertensive drugs administration is controversial. The aim was to compare the efficacy of dosing of antihypertensive drugs in the morning versus evening. METHODS: A PubMed, EMBASE, and clinicaltrials.gov databases search for randomized clinical trials of antihypertensive therapies where patients were randomized to morning versus evening dosing. The outcomes were ambulatory blood pressure (BP) parameters (day-time, night-time, and 24/48-hour systolic blood pressure [SBP] and diastolic blood pressure [DBP]) and cardiovascular outcomes. RESULTS: Of 72 randomized controlled trials included, evening dosing significantly reduced ambulatory BP parameters: 24/48-hour SBP (mean difference [MD]=1.41 mm Hg; [95% CI, 0.48-2.34]), DBP (MD=0.60 mm Hg [95% CI, 0.12-1.08]), night-time SBP (MD=4.09 mm Hg [95% CI, 3.01-5.16]), DBP (MD, 2.57 mm Hg [95% CI, 1.92-3.22]), with a smaller reduction in day-time SBP (MD=0.94 mm Hg [95% CI, 0.01-1.87]), and DBP (MD=0.87 mm Hg [95% CI, 0.10-1.63]), and numerically lower cardiovascular events compared with morning dosing. However, when controversial data by Hermida (23 trials, 25 734 patients) were omitted (P heterogeneity<0.05 for most outcomes), the above effect of evening dosing attenuated with no significant effect on 24/48-hour ambulatory blood pressure, day-time BP, and major adverse cardiac event and smaller reduction in night-time ambulatory SBP and DBP. CONCLUSIONS: Evening dosing of antihypertensive drugs significantly reduced ambulatory BP parameters and lowered cardiovascular events but the effect was mainly driven by trials by Hermida group. Unless the intention is to specifically lower night- time BP, antihypertensive drugs should be taken at a time of day that is convenient, optimizes adherence, and minimizes undesirable effects.