INFLUENCE OF CIRCADIAN TIME OF ANTIHYPERTENSIVE TREATMENT ON CARDIOVASCULAR RISK: RESULTS OF THE MAPEC STUDY: PP.16.102

Objectives: Clinical studies have documented morning-evening, administration-time differences in antihypertensive efficacy, duration of action, safety profile and/or effects on the circadian blood pressure (BP) pattern of several different classes of BP-lowering medications. Despite these findings, most hypertensive subjects ingest all their BP-lowering agents in a single morning dose. The MAPEC study investigated if chronotherapy of hypertension has any influence in cardiovascular morbidity and mortality. Methods: This prospective study investigated 3344 subjects (1718 men), 52.6 ± 14.5 years of age. At baseline, BP was measured every 20-min intervals 07:00 to 23:00 h and every 30-min at night for 48 h. Physical activity was simultaneously monitored every minute by wrist actigraphy. The same evaluation procedure was scheduled yearly or more frequently (quarterly) if treatment adjustment was required to improve BP control. The Cox proportional-hazard model was used to estimate relative risks of cardiovascular events associated with use of antihypertensive treatment and circadian time of treatment. Results: At the last evaluation, 625 subjects were normotensive and 606 untreated hypertensives according to ambulatory BP criteria. Among the remaining subjects, 1068 were receiving all antihypertensive medication on awakening, and 1045 were ingesting some antihypertensive agent at bedtime. Compared with normotensive subjects, the relative risk of cardiovascular events was highest for patients ingesting all drugs on awakening (3.84 [2.48–5.95]) and lowest for those receiving all medication at bedtime (0.95 [0.44–2.07]; P = 0.907 compared to normotensive subjects; P < 0.001 compared to all other groups). Compared with untreated subjects, cardiovascular risk was significantly higher with increasing number of drugs on awakening, but consistently lower, independently of the number of drugs, when medication was ingested at bedtime. Non-dipping was significantly lower (28 vs. 61%) among subjects treated at bedtime. Conclusions: In subjects with essential hypertension, pharmacologic therapy should take into account when to treat with respect to the rest-activity pattern of each patient. Treatment at bedtime not only improves BP control and decreases the prevalence of non-dipping, but also significantly reduces cardiovascular risk to the level of normotension.