Preventing Increases in Early-Morning Blood Pressure
Preventing Increases in Early-Morning Blood Pressure
Background: Therapeutic agents for the treatment of hypertension may differ in their efficacy during the early-morning period, a time when both morbid and mortal cardiovascular events are increased compared with other times of the day.
Methods: We studied the effects of a chronotherapeutic delivery system of verapamil (controlled-onset extended release [COER]-24 system) dosed at bedtime versus conventional morning administration of both enalapril and losartan on the blood pressure (BP), heart rate, and the heart rate systolic BP product during the first 4 hours after awakening in a placebo-controlled, forced-titration trial. There were 357 men and women enrolled in the trial with an untreated sitting diastolic BP of 95 to 114 mm Hg and ambulatory daytime diastolic BP ≥85 mm Hg. Patients were randomized to either COER-verapamil hydrochloride each evening (240 mg titrated to 360 mg), enalapril each morning (10 mg titrated to 20 mg), losartan each morning (50 mg titrated to 100 mg), or placebo. Early morning assessments of BP, heart rate, and the heart rate systolic BP product were performed by use of 24-hour ambulatory recordings after 4 weeks (low dose) and 8 weeks (high dose) of therapy.
Results: Results were similar at weeks 4 and 8 for all treatment groups except that the magnitude of change was greater at week 8. After 8 weeks of treatment, reductions in early morning BP by COER-verapamil were significantly greater (-15/-10 mm Hg) than enalapril (-9/-7 mm Hg, P < .01) and losartan (-8/-5 mm Hg, P < .001). COER-verapamil also led to greater reductions in morning heart rate, the rate-pressure product, and the rate-of-rise of BP compared with the other 2 active treatment groups. Reductions in mean 24-hour BP were greater in patients treated with COER-verapamil compared with placebo and losartan, and similar to reductions in patients treated with enalapril.
Conclusions: Bedtime administration of an agent designed to parallel the circadian rhythm of BP and heart rate led to significantly greater early morning hemodynamic effects compared with other conventional once-daily antihypertensive agents dosed in the morning.
Blood pressure (BP) and heart rate (HR) follow a highly reproducible circadian pattern in patients with systemic hypertension, characterized by higher values while awake and active and lower values during rest and sleep. There is also a substantial increase in the rate of acute myocardial infarction, ischemic and hemorrhagic stroke, and sudden cardiovascular death in the early morning periodespecially during the first 4 hours postawakening. In addition, a number of studies of older Japanese patients with systolic hypertension suggest that excessive reduction of systolic BP during sleep may result in a higher incidence of white matter lesions in the brain resulting from small cerebral vessel hypoperfusion (unpublished data). These pathophysiologic and epidemiologic associations have increased our recognition of the need to improve delivery of antihypertensive medications to attenuate the steep increases in BP and HR in the early morning period but not excessively decrease BP during sleep.
In this study we investigated the effects of 3 different therapeutic agents on the ambulatory BP, HR, and the HR-systolic pressure product in men and women with systemic hypertension. The chronotherapeutic delivery of verapamil (controlled-onset extended release [COER] system) administered at bedtime was compared with the conventional morning dosing of the angiotensin converting enzyme inhibitor enalapril, the angiotensin II receptor blocker losartan, and placebo. COER-verapamil has a novel delivery system that delays drug release for 4 to 5 hours after oral administration. Thus, if dosed at bedtime, there are relatively low plasma concentrations during sleep and maximal drug delivery during the first several postawakening hours. By use of automatic ambulatory monitoring, this study evaluated whether COER-verapamil had greater effects on the early morning BP, HR, and the rate pressure product compared with the other 3 treatment groups dosed during their conventional dosing time in the morning (enalapril, losartan, and placebo). The times of dosing of the 3 different agents conformed both to the labeling of these drugs as well as conventional practice guidelines for these antihypertensive regimens.
Background: Therapeutic agents for the treatment of hypertension may differ in their efficacy during the early-morning period, a time when both morbid and mortal cardiovascular events are increased compared with other times of the day.
Methods: We studied the effects of a chronotherapeutic delivery system of verapamil (controlled-onset extended release [COER]-24 system) dosed at bedtime versus conventional morning administration of both enalapril and losartan on the blood pressure (BP), heart rate, and the heart rate systolic BP product during the first 4 hours after awakening in a placebo-controlled, forced-titration trial. There were 357 men and women enrolled in the trial with an untreated sitting diastolic BP of 95 to 114 mm Hg and ambulatory daytime diastolic BP ≥85 mm Hg. Patients were randomized to either COER-verapamil hydrochloride each evening (240 mg titrated to 360 mg), enalapril each morning (10 mg titrated to 20 mg), losartan each morning (50 mg titrated to 100 mg), or placebo. Early morning assessments of BP, heart rate, and the heart rate systolic BP product were performed by use of 24-hour ambulatory recordings after 4 weeks (low dose) and 8 weeks (high dose) of therapy.
Results: Results were similar at weeks 4 and 8 for all treatment groups except that the magnitude of change was greater at week 8. After 8 weeks of treatment, reductions in early morning BP by COER-verapamil were significantly greater (-15/-10 mm Hg) than enalapril (-9/-7 mm Hg, P < .01) and losartan (-8/-5 mm Hg, P < .001). COER-verapamil also led to greater reductions in morning heart rate, the rate-pressure product, and the rate-of-rise of BP compared with the other 2 active treatment groups. Reductions in mean 24-hour BP were greater in patients treated with COER-verapamil compared with placebo and losartan, and similar to reductions in patients treated with enalapril.
Conclusions: Bedtime administration of an agent designed to parallel the circadian rhythm of BP and heart rate led to significantly greater early morning hemodynamic effects compared with other conventional once-daily antihypertensive agents dosed in the morning.
Blood pressure (BP) and heart rate (HR) follow a highly reproducible circadian pattern in patients with systemic hypertension, characterized by higher values while awake and active and lower values during rest and sleep. There is also a substantial increase in the rate of acute myocardial infarction, ischemic and hemorrhagic stroke, and sudden cardiovascular death in the early morning periodespecially during the first 4 hours postawakening. In addition, a number of studies of older Japanese patients with systolic hypertension suggest that excessive reduction of systolic BP during sleep may result in a higher incidence of white matter lesions in the brain resulting from small cerebral vessel hypoperfusion (unpublished data). These pathophysiologic and epidemiologic associations have increased our recognition of the need to improve delivery of antihypertensive medications to attenuate the steep increases in BP and HR in the early morning period but not excessively decrease BP during sleep.
In this study we investigated the effects of 3 different therapeutic agents on the ambulatory BP, HR, and the HR-systolic pressure product in men and women with systemic hypertension. The chronotherapeutic delivery of verapamil (controlled-onset extended release [COER] system) administered at bedtime was compared with the conventional morning dosing of the angiotensin converting enzyme inhibitor enalapril, the angiotensin II receptor blocker losartan, and placebo. COER-verapamil has a novel delivery system that delays drug release for 4 to 5 hours after oral administration. Thus, if dosed at bedtime, there are relatively low plasma concentrations during sleep and maximal drug delivery during the first several postawakening hours. By use of automatic ambulatory monitoring, this study evaluated whether COER-verapamil had greater effects on the early morning BP, HR, and the rate pressure product compared with the other 3 treatment groups dosed during their conventional dosing time in the morning (enalapril, losartan, and placebo). The times of dosing of the 3 different agents conformed both to the labeling of these drugs as well as conventional practice guidelines for these antihypertensive regimens.