Sleep BP, a significantly more sensitive prognostic marker of cardiovascular disease (CVD) risk than daytime office BP or 24hr mean BP, is normalized to a relatively more normal dipper profile when medication is ingested at bedtime than upon awakening. The multicenter controlled PROBE (prospective, randomized, open-label, blinded endpoint) Hygia Chronotherapy Trial tested the effects of bedtime ingestion vs. morning upon waking ingestion of >1 hypertension medications on ABP control and CVD risk reduction. Overall, 19,084 hypertensive patients (mean age 60.5 years)  were allocated in a 1:1 ratio to 2 parallel arms:  bedtime (bedtime-treatment regimen; n= 9552) or awakening (awakening-treatment regimen; n=9532). Treatment included >1 prescribed BP-lowering medications of the major therapeutic classes (ARB, ACEI, CCB, b-blocker, and/or diuretic). The protocol required avoiding division of prescribed medications for ingestion as split doses. The complete electronic clinical records of every participant was reviewed at least annually and at least 1 year following his/her last ABPM evaluation. ARBs/ACEIs, ARB/ACEI + Diuretic/CCB and ARB/ACEI–diuretic–CCB were the most commonly used mono, dual and triple therapies.

Compared to the awakening-treatment regimen, the patients in the bedtime-treatment regimen had significantly -

Lower office SBP/DBP,  mean asleep SBP /DBP and 48h mean SBP/DBP

Greater relative decline in sleep time SBP/DBP

Lower LDL-C and creatinine with higher HDL-C and eGFR.

Only 37% patients in the bedtime-treatment regimen had a non dipper pattern vs. 50% in the awakening-treatment regimen.

Bedtime treatment regimen resulted in a lower CV morbidity and mortality. A 45% significantly lower risk of the primary CVD outcome (myocardial infarction, coronary revascularization, heart failure, stroke, CVD death) was observed in patients on the bedtime-treatment regimen vs. the awakening regimen, during the median follow-up period of 6.3 years. Bedtime dosing was associated with 43% lower CVD events, 49% lower stroke, 44% lower coronary events, 43% lower cardiac events and 40% lower minor events.

 The lower HR of CVD events was significant regardless of sex, age, hypertension treatment, baseline ABP level and patterning, and absence/ presence of diabetes, CKD, and/or previous CVD event.

 Bedtime hypertension therapy is safe with a similar patient compliance and adherence as upon-waking therapy. The Hygia Chronotherapy trial thus concludes that ingesting the entire dose of > 1 BP lowering medications at bedtime improves asleep ABP control and significantly reduces CV morbidity and mortality as compared to awakening-treatment regimen.

Reference: Hermida RC, Crespo JJ, Domínguez-Sardiña M, et al. Bedtime hypertension treatment improves cardiovascular risk reduction: the Hygia Chronotherapy Trial [published online ahead of print, 2019 Oct 22]. Eur Heart J. 2019;ehz754.

BP: Blood Presure, ANP: Ambulatory Blood Pressure, ARB: Angiotensin Receptor Blockers, ACE: Angiotensin-Converting Enzyme, CCB: Calcium Channel Blockers, SBP: Systolic Blood Pressure, DBP: Diastolic Blood Pressure, HDL-C: High-Density lipoprotein (HDL) cholesterol, LDL-C: Low-Density Lipoprotein-Cholesterol, HR: Heart Rate

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