Chronotherapy of Blood Pressure Medications to Improve Management of Hypertension and Reduce Vascular Risk

Abstract

Correlation between blood pressure (BP) and target organ damage, cardiovascular disease (CVD) risk, and long-term prognosis is greater for ambulatory BP monitoring (ABPM) than daytime in-clinic measurements. Additionally, consistent evidence from numerous studies substantiates that ABPM-determined asleep BP mean is an independent and stronger predictor of CVD risk than the awake or 24 h means. Hence, cost-effective adequate control of sleep-time BP is of marked clinical relevance. Ingestion time, according to circadian rhythms, of hypertension medications of six different classes and their combinations significantly impacts the beneficial and/or adverse effects of these drugs. For example, because the high-amplitude circadian rhythm of the renin-angiotensin-aldosterone system activates during nighttime sleep, bedtime versus morning ingestion of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers (ARB) better controls the asleep BP mean, with additional benefit, independent of medication terminal half-life, of converting the 24 h BP profile into more normal dipper patterning. The MAPEC Study, first prospective randomized treatment-time investigation testing the worthiness of bedtime chronotherapy with ≥1 conventional hypertension medications to specifically target attenuation of asleep BP, demonstrated, relative to conventional morning therapy, significantly better reduction of CVD risk: adjusted hazard ratio (HR) of total CVD events (HR = 0.39, 95 %CI [0.29–0.51]; P < 0.001) and major CVD events, i.e., CVD deaths, myocardial infarctions, and ischemic and hemorrhagic strokes (HR = 0.33 [0.19–0.55]; P < 0.001). CVD risk reduction was strongest when bedtime treatment included an ARB. The MAPEC Study documents that the asleep BP mean is the most significant prognostic marker of CVD and stroke morbidity and mortality. Moreover, the MAPEC study also substantiates attenuation of the asleep BP mean by a bedtime hypertension treatment strategy since the entire daily dose of ≥1 hypertension medications significantly reduces CVD risk, both in the general hypertension population and in patients of greater vulnerability and enhanced CVD risk, i.e., those diagnosed with chronic kidney disease, diabetes, and resistant hypertension