Comparison of Effects of Controlled Onset Extended Release Verapamil at Bedtime and Nifedipine Gastrointestinal Therapeutic System on Arising on Early Morning Blood Pressure, Heart Rate, and the Heart Rate–Blood Pressure Product

We assessed the differential effects of a chronotherapeutic agent (controlled-onset extended release [COER] verapamil), administered at bedtime versus a conventional, homeostatic therapy (nifedipine gastrointestinal therapeutic system [GITS]) taken in the morning, on early morning and 24-hour blood pressure (BP), heart rate (HR), and the HR × systolic BP product. The study was a multicenter (n = 51), randomized, double-blind prospective clinical trial with a 10-week treatment period. Dose titration was performed by study investigators based on systolic and diastolic BP values at the doctor’s office. Ambulatory BP monitoring was performed at placebo baseline, after 4 weeks of stable double-blind therapy, and at end of the study. Twenty-four-hour BP profiles were studied in 557 hypertensive patients. Changes in BP, HR, slope of the rate of rise of BP and HR, and the HR-systolic BP product during the 4 hours from 1 hour before to 3 hours after awakening were evaluated. The study was powered to show equivalence between the 2 regimens, predefined as a difference between treatment groups in mean change from baseline in early morning BP of ±5 mm Hg systolic and ±3 mm Hg diastolic. Changes in the early morning BP fell within the definition of equivalence for the 2 treatment strategies (−12.0/−8.2 mm Hg for COER-verapamil and −13.9/−7.3 mm Hg for nifedipine GITS). Changes in both the early morning HR and rate–pressure product were significantly greater following COER-verapamil therapy versus nifedipine GITS (HR, −3.8 beats/minute vs +2.6 beats/minute, p <0.001 and HR-systolic BP product, −1,437 beats/min · mm Hg vs −703 beats/min · mm Hg, respectively, p <0.001). Changes in ambulatory BP demonstrated clinically similar reductions for the awake period, but nifedipine GITS lowered systolic BP to a greater extent than COER-verapamil during sleep (−11.0 vs −5.8 mm Hg, p <0.001). COER-verapamil and nifedipine GITS had equivalent effects (± 5/3 mm Hg) on early morning BP. In addition, both extended-release calcium antagonists effectively lowered 24-hour BP. However, COER-verapamil had greater effects than nifedipine GITS on early morning hemodynamics (HR, HR-systolic BP product, rate of rise of BP and HR) and lesser effects during sleep due to its intrinsic pharmacologic properties and chronotherapeutic delivery system.