Evening anti-hypertensive dosing, blood pressure and cardiovascular events in hypertensive: Updated meta-analysis of 41 trials in 65,271 patients
Authors: Sunjaya A F , Sunjaya A P 
Published: November 2023

Abstract

Introduction
In 2022, the International Society of Hypertension and World Hypertension League released a position paper noting that there is limited evidence on the impact of bedtime versus other time dosing of antihypertensives on 24-h BP profile and on cardiovascular morbidity and mortality. Since then, the Treatment In Morning versus Evening (TIME) trial results which enrolled over 20 thousand participants was published. This study aims to update our prior meta-analysis in 2020 (Sunjaya et al. EHJ. Vol. 41:S2) in light of this new results.

Purpose
In patients with hypertension does evening dosing of anti-hypertensive compared to morning dosing led to better reduction in pressure, blood pressure control and reduced cardiovascular morbidity.

Methods
A meta-analysis was performed based on randomized controlled trials obtained from Cochrane Central Register of Controlled Trials (CENTRAL), EMBASE, Medline and Medline ahead of print published between 2000 and February 2023. Main outcome measures include mean 24 hour systolic and diastolic blood pressure, cardiovascular events as well as prevalence of blood pressure in control. Data synthesis and analysis was done using RevMan 5.3 using a random effects model.

Results
A total of 41 randomized controlled trials, representing 65,271 patients were included in this meta-analysis. Most studies evaluate the administration of mixed anti-hypertensive with ≥1 medication ingested at bedtime, calcium channel blockers (CCBs) or angiotensin receptor blockers (ARBs) with sample sizes ranging from 30 to 21,104 patients. Evening administration of anti-hypertensive was found to significantly lower 24-hour systolic blood pressure (Mean difference = -1.09, 95% CI -1.97 to -0.20, p = 0.02) and 24-hour diastolic blood pressure (Mean difference = -1.05, 95% CI -1.60 to -0.51, p = 0.0002). Significant reduction in cardiovascular events were found in the evening dosing group (RR = 0.53, 95% CI 0.38 to 0.73, p = 0.0001).
Discussion: While evening administration was found to result in significantly lower systolic and diastolic blood pressure, both reductions were found to not be clinically meaningful (At least 5 mmHg for systolic and at least 3 mmHg as per 2022 Hypertension Academic Research Consortium consensus). Few studies have reported the impact on cardiovascular events (7 studies), mostly contributed by one research group (Hermida et al. 4 studies). Sensitivity analyses conducted removing studies conducted by this research group resulted in a non-significant pooled risk being found, though with result from only 3 studies.

Conclusion
For patients with hypertension, current evidence suggests no significant impact on blood pressure levels. While a reduction in the risk for cardiovascular events was found, this result was strongly contributed by that from one setting. Further studies remain required to answer this important question due to its possible widespread impact on clinical practice.Figure 1MACEFigure 2Systolic Blood Pressure