Bedtime hypertension treatment improves cardiovascular risk reduction: the Hygia Chronotherapy Trial

Abstract

Aims The Hygia Chronotherapy Trial, conducted within the clinical primary care setting, was designed to test whether bedtime in comparison to usual upon awakening hypertension therapy exerts better cardiovascular disease (CVD) risk reduction. Methods and results In this multicentre, controlled, prospective endpoint trial, 19 084 hypertensive patients (10 614 men/8470 women, 60.5 ± 13.7 years of age) were assigned (1:1) to ingest the entire daily dose of ≥1 hypertension medications at bedtime (n = 9552) or all of them upon awakening (n = 9532). At inclusion and at every scheduled clinic visit (at least annually) throughout follow-up, ambulatory blood pressure (ABP) monitoring was performed for 48 h. During the 6.3-year median patient follow-up, 1752 participants experienced the primary CVD outcome (CVD death, myocardial infarction, coronary revascularization, heart failure, or stroke). Patients of the bedtime, compared with the upon-waking, treatment-time regimen showed significantly lower hazard ratio—adjusted for significant influential characteristics of age, sex, type 2 diabetes, chronic kidney disease, smoking, HDL cholesterol, asleep systolic blood pressure (BP) mean, sleep-time relative systolic BP decline, and previous CVD event—of the primary CVD outcome [0.55 (95% CI 0.50–0.61), P < 0.001] and each of its single components (P < 0.001 in all cases), i.e. CVD death [0.44 (0.34–0.56)], myocardial infarction [0.66 (0.52–0.84)], coronary revascularization [0.60 (0.47–0.75)], heart failure [0.58 (0.49–0.70)], and stroke [0.51 (0.41–0.63)]. Conclusion Routine ingestion by hypertensive patients of ≥1 prescribed BP-lowering medications at bedtime, as opposed to upon waking, results in improved ABP control (significantly enhanced decrease in asleep BP and increased sleep-time relative BP decline, i.e. BP dipping) and, most importantly, markedly diminished occurrence of major CVD events. Trial registration ClinicalTrials.gov, number NCT00741585.

Orthostatic hypotension and cardiovascular risk

“…58 In this context, bedtime administration of antihypertensive treatment, addressing both supine hypertension and an increased risk of BP fall during morning hours, seems to be less harmful, more optimal in reducing CV risk, and might be a standard approach in the future. 59 Finally, it is important to acknowledge that the identification of any optimum SBP therapeutic goal must Together with increased arterial stiffness, LVH is likely to be responsible for the impaired diastolic function in patients with OH.…”

Once versus twice daily antihypertensive medications for the control of nocturnal blood pressure: a comparative study

“…Drugs also demonstrate a circadian-rhythm that is dependent on the pharmacokinetics and pharmacodynamics. This is known as chronokinetics which may halt the desired 24H control of HTN [17]. Achieving 24H BP control may be considerably affected by the frequency of antihypertensive medications dosing.…”

What time is it? A tale of three clocks, with implications for personalized medicine

“…Therefore, mistiming light exposure by only ~2 hours may cause a circadian shift in the wrong direction. For other treatments (eg, light therapy for seasonal affective disorder or nonmotor symptoms of Parkinson's, melatonin for hypertension, chemotherapy timed by the circadian clock, small model pharmaceuticals to shift circadian phase), there are not enough data yet to determine the precision needed to be effective beyond the current prescriptions of “morning” or “evening” 17 or over a broad (eg, hours‐wide) time interval 18 . The precision needed for interventions can and should be tested.…”