Efficacy and safety of a once-daily graded-release diltiazem formulation dosed at bedtime compared to placebo and to morning dosing in chronic stable angina pectoris.

BACKGROUND: The efficacy and safety of a once-daily graded-release diltiazem hydrochloride (GRD) formulation dosed at 10 PM in doses of 180, 360, and 420 mg were compared with placebo and with GRD 360 mg dosed once daily at 8 AM in patients (n = 311) with chronic stable angina pectoris. METHODS: This was a 3-week multicenter, randomized, double-blind, double-dummy, parallel-group, placebo-controlled trial. Standard Bruce protocol treadmill stress test was performed at baseline and end point between 6 and 8 PM (trough for evening doses) and between 7 and 11 AM (trough for morning doses). RESULTS: All GRD evening doses showed a significant (P < or = .0201) increase in total duration of exercise at trough and a greater significant increase (P < or = .0002) at peak, compared with placebo. The GRD 360-mg evening dose showed the greatest increase at trough. In contrast, GRD 360-mg morning dose showed an increase in total duration of exercise at trough that was not significantly different (P = .0555) from placebo AM. GRD 360-mg evening dose showed a 4-fold placebo-adjusted improvement compared with GRD 360-mg morning dose between 7 and 11 AM. Significant increases (P < or = .0240) in time to onset of angina were obtained for all evening doses at trough and peak. All GRD doses were well tolerated, and incidence of adverse events for all GRD groups combined was less than that for placebo. CONCLUSIONS: Bedtime GRD significantly increases exercise tolerance in patients with angina pectoris over the 24-hour dosing interval. A greater 4-fold placebo-adjusted improvement occurred between 7 and 11 AM compared with the same morning dose, coinciding with the period of increased cardiovascular risk. GRD was safe and well tolerated.

Antihypertensive efficacy of night-time graded-release diltiazem versus morning amlodipine in African Americans.

BACKGROUND: The effect of a once daily night-time (10 pm) graded-release diltiazem (GRD) on early morning blood pressure (BP), heart rate (HR), and rate-pressure product (RPP) were compared with the effect of morning (8 am) amlodipine in 262 African American individuals with hypertension. METHODS: The multicenter, randomized, double-blind, parallel-group, dose-to-effect trial evaluated changes from baseline in BP, HR, and RPP (HR x systolic BP) by ambulatory BP monitoring during the first 4 h after awakening (diastolic BP = primary), between 6 am and 12 noon, and over a 24-h period. Patients were randomized to night-time GRD 360 mg (n = 132) or morning amlodipine 5 mg (n = 130) for 6 weeks, and were titrated to GRD 540 mg or amlodipine 10 mg after 6 weeks if clinic systolic BP/diastolic BP (SBP/DBP) was > or = 130/85 mm Hg. RESULTS: Compared with amlodipine, GRD showed significantly greater DBP reductions of 3.5 mm Hg (P < .0049) and 3.2 mm Hg (P < .0019) during the first 4 h after awakening and between 6 am and 12 noon respectively, as well as comparable reduction for the 24-h mean DBP. The SBP reductions during the morning periods were comparable, but the reduction in the 24-h mean SBP was 3.4 mm Hg greater (P < .0022) for amlodipine. Mean reductions in HR and RPP were significantly greater (P < or = .0008) for GRD during all intervals; amlodipine increased whereas diltiazem reduced HR with mean differences of 6.7 to 9.3 beats/min. Both treatments were well tolerated. CONCLUSIONS: Night-time GRD was more effective than morning amlodipine in reducing early morning DBP, HR, and RPP, as well as 24-h HR and RPP in African American individuals with hypertension. Amlodipine was more effective in reducing SBP over the 24-h period.