Morning vs Bedtime Dosing and Nocturnal Blood Pressure Reduction in Patients With Hypertension

Importance Nocturnal blood pressure is difficult to manage in clinical practice. Antihypertensive chronotherapy may offer a potential approach for better control. However, the clinical evidence supporting this approach remains controversial. Objective To compare the effects of morning vs bedtime antihypertensive medication administration on nocturnal blood pressure reduction and circadian rhythm among patients with hypertension. Design, Setting, and Participants This randomized clinical trial was conducted at 15 hospitals in China from June 1, 2022, to April 30, 2024, with a 12-week follow-up. Patients with hypertension without prior antihypertensive treatment or who had discontinued antihypertensive agents for 2 weeks were randomized to the morning (6:00-10:00 am ) or bedtime (6:00-10:00 pm ) dosing group. Interventions Patients received a single pill containing olmesartan, 20 mg, and amlodipine, 5 mg, daily for 12 weeks, with dosage adjustments based on ambulatory and office blood pressure measurements at week 4 and week 8. Main Outcomes and Measures The primary outcome was the change in nighttime systolic blood pressure from baseline to 12 weeks. Key secondary outcomes included changes in office and other ambulatory blood pressure indicators. The primary and secondary outcomes were analyzed in the intention-to-treat and the per-protocol populations. Results A total of 720 patients (mean [SD] age, 55.5 [10.6] years; 409 men [56.8%]) were randomized to morning (n = 352) or bedtime (n = 368) dosing groups. The mean (SD) baseline blood pressure values for morning vs bedtime dosing at 24 hours were 148.0 (11.1)/91.4 (9.0) mm Hg vs 147.6 (11.0)/91.6 (9.2) mm Hg, for daytime were 152.3 (11.0)/94.0 (9.2) mm Hg vs 151.5 (11.6)/94.0 (9.8) mm Hg, for nighttime were 138.4 (15.1)/85.4 (10.4) mm Hg vs 138.3 (13.0)/85.8 (9.4) mm Hg, and in the office were 154.4 (12.1)/94.6 (10.3) mm Hg vs 154.3 (12.5)/95.1 (11.1) mm Hg. Compared with patients in the morning dosing group, those in the bedtime dosing group showed significantly greater reductions in nighttime systolic blood pressure (between-group difference, −3.0 mm Hg [95% CI, −5.1 to −1.0 mm Hg]; P = .004), and nighttime diastolic blood pressure (between-group difference, −1.4 mm Hg [95% CI, −2.8 to −0.1 mm Hg]; P = .04), with better nocturnal systolic blood pressure control (79.0% [244 of 309] vs 69.8% [208 of 298]; P = .01) and improved circadian rhythm. The incidence of nocturnal hypotension did not differ. Conclusions and Relevance In this randomized clinical trial of antihypertensive chronotherapy, bedtime dosing provided better control of nocturnal blood pressure and improved the circadian rhythm, without reducing the efficacy on mean daytime or 24-hour blood pressure, or increasing the risk of nocturnal hypotension. These findings support the potential advantages of bedtime administration and offer new evidence to guide future research on antihypertensive chronotherapy. Trial Registration Chinese Clinical Trial Registry Identifier: ChiCTR2200059719