Attenuation of the circadian patterns of myocardial ischemia with nifedipine GITS in patients with chronic stable angina

Abstract

The Nifedipine Gastro-Intestinal Therapeutic System (GITS) Circadian Anti-ischemia Program (N-CAP) was designed to test the effect of nifedipine GITS as monotherapy or in combination with a beta-adrenergic blocking agent on the circadian pattern of angina and silent ischemia in patients with chronic stable angina. At 118 sites in the United States, 1,174 patients were screened for entry into this study. To be eligible for participation patients were required to have at least two episodes of angina a week and at least two episodes of myocardial ischemia during 48-h ambulatory electrocardiographic (ECG) monitoring during the baseline placebo period. A total of 207 patients completed all phases of the study. Beta-blockers were continued in those patients already receiving them. In this 7- to 10-week single-blind placebo withdrawal study, a 1-week placebo run-in was followed by up to 5 weeks of single-blind titration with nifedipine GITS, a 4-week efficacy phase with an established dose and a final single-blind 2-week placebo withdrawal period. Ambulatory ECG monitoring was performed at the end of each placebo phase and at the end of the efficacy phase with a digital monitoring device that was validated in a pilot study. Overall, nifedipine GITS significantly reduced the weekly number of anginal episodes from 5.7 to 1.8 (p = 0.0001) and the number of ischemic events from 7.3 to 4 (p = 0.0001) reported during the 48-h monitoring periods, with a significant increase in both during the placebo withdrawal period. The baseline circadian pattern of ischemia showed an early morning peak and a secondary peak in the afternoon. Nifedipine GITS significantly reduced ischemia during the 48-h period when administered as monotherapy or in combination with a beta-blocker. Patients were also randomized to receive nifedipine GITS in either a morning or an evening dose. The two regimens resulted in equal anti-ischemic benefit. The primary side effect of nifedipine GITS was edema, which was dose related. In summary, nifedipine GITS reduced the number of anginal and ischemic episodes when given alone or in combination with a beta-blocker. Nifedipine GITS had a sustained effect: a single daily dose was effective over 24 h regardless of whether it was administered in the morning or evening. This study also suggests that combination therapy with nifedipine GITS and a beta-blocker is especially efficacious in reducing ischemia.

2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS Guideline for the Diagnosis and Management of Patients With Stable Ischemic Heart Disease

“…Short-acting nifedipine seems to increase mortality in patients with hypertension, 860 but there is currently no evidence that these concerns apply to extended-release preparations. 861,862 Because of their effects on contractility, none of the calcium channel blockers are recommended for routine treatment of patients with current or prior symptoms of heart failure and a reduced LVEF. 21 Many drug interactions associated with calcium channel blockers occur because of rapid absorption or low bioavailability due to high first-pass metabolism by the cytochrome P450 (ie, CYP3A4) system.…”

Optimal Treatment of Stable Angina

“…Because of the known tolerance to ni trates, they could not be effectively studied over a 24-hour time period. Accordingly, we used the long-acting prepa ration of nifedipine GITS which provides a relatively con stant blood level of nifedipine over a 24-hour period [ 14], Patients were entered into the study if they had stable angina for at least 1 month, documentation of coronary artery disease, at least two episodes of symptomatic angi na each week and at least two episodes of myocardial isch emia on 48-hour ambulatory ECG monitoring. Approxi mately half the patients were already on (3-blockers and were continued on (3-blockers throughout the trial.…”

The Calcium Channel Blocker Controversy.

“…Long-Acting CCBs: Sustained-release verapamil significantly reduced ventricular ectopic activity in hypertensive patients whereas a diuretic did not (12). No increase in VEA was noted in the trials of nifedipine GITS (55) or amlodipine (57) in patients with coronary disease.…”