Hypertension medication ingestion at bedtime improves asleep ABP and reduces CVD risk
Bedtime hypertension treatment improves cardiovascular risk reduction: the Hygia Chronotherapy Trial
Introduction and methods
Multiple prospective studies and meta-analyses have demonstrated that mean asleep BP determined by ambulatory BP monitoring (ABPM) is a more sensitive prognostic marker of CVD compared to daytime office BP measurements, ABPM-derived awake mean, or 24h BP mean [1-6]. It was shown that therapeutically induced reduction of asleep systolic BP (SBP) mean and enhancement of sleep-time relative SBP decline towards a normal dipper pattern result in reduced CVD risk [3,6]. Improved normalization of asleep BP and 24h BP patterning was observed when hypertension medications were ingested at bedtime instead of upon awakening [7,8].
Several studies assessed the effect of bedtime hypertension medication ingestion on CVD risk reduction, however a control group of patients ingesting medication in the morning was missing [7-12]. The MAPEC (Ambulatory Blood Pressure Monitoring for Prediction of Cardiovascular Events) study showed in a small cohort of 2156 hypertensive patients over a median follow-up of 5.6 years that bedtime ingestion of treatment resulted in significantly reduced asleep BP, reduced prevalence of non-dipping, and reduced incidence of CVD events compared to medication intake upon awakening . The current study investigated the effect of timing of hypertension medication ingestion on ABP control and CVD risk in a large cohort in a primary care clinical setting.
The Hygia Chronotherapy Trial is a multicenter, controlled, PROBE (prospective, randomized, open-label, blinded endpoint) study with 19084 (10614 men, 8470 women) hypertensive patients aged 60.5 ± 13.7 (mean ± SD) years. Patients were randomized to ingest the entire daily dose of ≥1 prescribed BP medications of the major therapeutic classes (ARB, ACEI, CCB, β-blocker, and/or diuretic) at either bedtime (n=9552) or upon awakening (n=9532). ABP was monitored for 48 h at baseline and each clinic visit (at least once a year). The median follow-up was 6.3 years (IQR 4.1-8.3 years).
The primary CVD outcome was myocardial infarction, coronary revascularization, heart failure, ischemic stroke, hemorrhagic stroke and CVD death.
- At baseline, 48h SBP of all patients was 131.6 ± 13.8 mmHg (mean ± SD) and 48h diastolic BP (DBP) was 77.4 ± 10.4.
- Bedtime-treatment regimen compared to regimen of treatment upon awakening resulted in a significantly lower asleep BP mean (asleep SBP 114.7 ± 14.6 vs. 118.0 ± 16.6, and asleep DBP 64.5 ± 9.3 vs. 66.1 ± 10.1, respectively, both P<0.001) without loss of awake BP-lowering efficacy. Larger relative BP decline was observed during sleep in the bedtime-treatment regimen compared to the awakening-treatment regimen (sleep-time relative SBP decline 12.2% ± 7.7% vs. 8.5% ± 8.4%, respectively, and sleep-time relative DBP decline 15.3% ± 8.6% vs. 13.3% ± 9.4%, respectively, both P <0.001), which led to a significantly lower prevalence of non-dipping (37.5% in the bedtime-treatment regimen vs. 50.3% in the awakening-treatment regimen, P<0.001).
- Patients in the bedtime-treatment regimen had a significantly lower HR of the primary CVD outcome, compared with patients in the awakening-treatment regimen (HR=0.55 [95% CI 0.50-0.61], P<0.001, adjusted for significant influential characteristics).
- Analysis of individual CVD events showed that ingestion at bedtime led to a significant risk reduction compared to ingestion at awakening for CVD death (HR=0.44 [0.34-0.56), P<0.001), hemorrhagic stroke (HR=0.39 [0.23–0.65], P< 0.001), heart failure (HR=0.58 [0.49–0.70], P< 0.001), and peripheral artery disease (HR=0.52 [0.41–0.67], P< 0.001).
- Patients in the bedtime-treatment regimen showed significantly lower creatinine and LDL-c, and higher HDL-c and eGFR compared to patients in the awakening-treatment regimen at the time of the final evaluation.
- No differences in prevalence of adverse effects were found between the bedtime and awakening-treatment regiments (6.0% vs. 6.7% respectively, P=0.061). Prevalence of poor adherence during the follow-up was similar in the bedtime and awakening-treatment regiments (2.9% vs. 2.8% respectively, P=0.813).
This study demonstrated that ingestion of the entire daily dose of hypertension medication at bedtime significantly improved asleep ABP and significantly reduced CVD morbidity and mortality. Time of ingestion of hypertension medication did not affect awake mean BP nor did it affect the prevalence of adverse effects.