[OP.4A.06] CARDIOVASCULAR RISK IS BETTER REDUCED BY BEDTIME THAN UPON AWAKENING HYPERTENSION TREATMENT-REGIMEN

Objective: In hypertension, ingesting blood pressure (BP)-lowering medications at bedtime, compared to upon awakening, is usually associated with significantly improved reduction of sleep-time BP mean, a sensitive prognostic marker of cardiovascular disease (CVD) risk. The Hygia Project, a research network presently composed of 292 investigators of 40 clinical sites, was specifically designed to test the hypothesis that bedtime chronotherapy entailing the entire daily dose of >1 conventional hypertension medications exerts better ambulatory BP control and CVD risk reduction than all such medications ingested upon awakening. Design and method: We conducted a prospective, randomized, open-label, blinded endpoint trial of 15,674 hypertensive patients (8,682 men/6,992 women, 60.4 ± 13.7 years of age) according to ambulatory BP (ABPM) criteria. Participants were randomized to ingest all their prescribed hypertension medications upon awakening (n = 7,848) or the entire daily dose of at least one of them at bedtime (n = 7,826). Among the later, 3,918 participants were ingesting all medications at bedtime and the remaining 3,908 ingested some medications at bedtime and others upon awakening. At inclusion and at every scheduled clinic visit for ABPM (at least annually) during follow-up, BP was assessed for 48 h. The primary CVD-outcome was the composite of CVD death, myocardial infarction, coronary revascularization, heart failure, and stroke. Results: During a median 5.1-year follow-up, we documented 1,154 major CVD events. Patients of the bedtime, compared with the upon-waking, treatment group showed significantly lower hazard ratio of CVD events, adjusted for significant influential characteristics of age, sex, type 2 diabetes, chronic kidney disease, cigarette smoking, HDL-cholesterol, asleep systolic BP (SBP) mean, sleep-time relative SBP decline, and previous CVD event (0.47 [95%CI 0.42–0.54], P < 0.001). CVD risk was further reduced among patients who ingested not just some, but all their BP-lowering medications at bedtime (0.27 [0.21–0.34], P < 0.001, compared with ingestion of all medications upon awakening). Conclusions: In hypertensive patients, ingestion of some (preferably all) BP-lowering medications at bedtime, compared with ingestion of all such medications upon-awakening, results in improved ambulatory BP control (significantly enhanced decrease of asleep BP and increase of sleep-time relative BP decline) and, most importantly, markedly reduced risk of major CVD events.