Epidemiological studies have shown a prominent 24 h variation, with a significant increase during the early morning hours, in the rate of myocardial infarction, angina, cardiac arrest, sudden cardiac death, and pulmonary embolism. Several studies have also documented a relationship between elevated blood pressure (BP) in the early morning hours and higher incidence of stroke, microalbuminuria, and cardiovascular mortality. Despite these findings, effects on the morning BP of antihypertensive medication have been reported only occasionally. We investigated the effects on morning BP of ramipril administered at different circadian times in hypertensive subjects.
We studied 115 previously untreated hypertensive subjects (52 men), 46.7 ± 11.2 years of age, assigned to receive ramipril (5 mg/day) as a monotherapy either on awakening or at bedtime. BP was measured every 20-min from 07:00 to 23:00 h and every 30-min at night for 48 h before and after 6 weeks of treatment. Physical activity was simultaneously monitored every minute by wrist actigraphy to accurately determine the beginning and end of daytime activity and nocturnal sleep. Morning BP was calculated as the average BP during the first 2 h after wake-up time.
There was lack of significant differences in morning BP at baseline between treatment-groups (P = 0.994). The reduction in morning BP was significantly higher when ramipril was administered at bedtime (13.0 and 10.4 mmHg reduction in systolic and diastolic BP; P < 0.001), compared to the effects of ingestion upon awakening (5.8 and 4.0 mmHg, respectively; P < 0.001 between treatment-groups). Duration of antihypertensive efficacy was a full 24 h after bedtime dosing, but only 16 h when ramipril was ingested on awakening.
The regulation of morning BP is significantly better achieved with bedtime as compared to morning administration of ramipril. This might be clinically important, as elevated morning BP has been shown to be a marker of cardiovascular risk. The improved efficacy in controlling morning BP and extended duration of antihypertensive action suggest ramipril should be preferably administered at bedtime in subjects with essential hypertension.
1University of Vigo, Vigo, Spain
2Urgencias Sanitarias 061 Galicia, Santiago, Spain