Peter E. Pool

Efficacy of diltiazem in angina on effort: a multicenter trial.

During a multicenter study 57 patients with exercise-induced angina were evaluated with serial exercise testing to assess the efficacy of diltiazem, a calcium slow channel blocking agent, compared with a placebo. The study consisted of a 1 week single-blind placebo stabilization period followed by a double-blind triple crossover between diltiazem and placebo. Three dose levels were tested (120, 180 and 240 mg/day) in each patient. For the three time-related variables there was a significant dose-related response, with 240 mg/day being the most effective. The increases, over the washout placebo stabilization values, of the time-related variables for the 240 mg/day week compared with the corresponding placebo week were total duration of exercise 1.87 versus 1.05 minutes (p less than 0.002), time to onset of angina 1.81 versus 1.17 minutes (p less than 0.01) and time to appearance of 1 mm S-T segment depression 1.81 versus 1.01 minutes (p less than 0.002). Analysis of exercise variables indicated a significant reduction in heart rate, diastolic blood pressure, and pressure-rate product at submaximal exercise after administration of diltiazem. Diastolic blood pressure was significantly reduced at maximal exercise. Heart rate and pressure-rate product were unchanged at rest during submaximal or maximal exercise. Submaximal and maximal exercise S-T depression was not significantly altered by diltiazem. The reduction in pressure-rate product at submaximal exercise was a possible mechanism for the drugs beneficial effect in enhancing the three time-related variables.

Effects of diltiazem on serum lipids, exercise performance and blood pressure: Randomized, double-blind, placebo-controlled evaluation for systemic hypertension

Treatment of hypertension with diuretics, beta blockers and alpha blockers may be associated with adverse effects on exercise performance, serum lipids and blood chemistries, as well as with orthostatic effects and fluid retention. A randomized, double-blind, placebo-controlled trial of a sustained-release preparation of diltiazem as sole therapy for moderate essential hypertension was conducted. Diltiazem was administered 2 times a day (360 mg/day) to 16 patients and placebo to 14 patients in a 12-week study. Average supine blood pressure with diltiazem therapy fell from 161/100 to 144/87 mm Hg without fluid retention or orthostatic effects. In an open-label study, patients from the placebo and diltiazem groups continued with diltiazem therapy. At an average of over 8 months, supine blood pressure on diltiazem was 147/88 mm Hg, and after withdrawal to single-blind placebo, average supine blood pressure increased to 173/104 mm Hg. All changes were significant compared with baseline and placebo (p less than 0.01). On diltiazem therapy, maximal treadmill exercise was increased by an average of 55 seconds (p less than 0.01), whereas heart rate, blood pressure and double product (heart rate X blood pressure) were reduced at submaximal exercise, and heart rate and double product were reduced at maximal exercise. No changes in serum glucose, potassium or uric acid were found. No adverse effects on serum lipids occurred. Diltiazem treatment was associated with an increase in high-density lipoprotein cholesterol (52 to 60 mg/dl, p less than 0.006) and a decrease in total cholesterol:high-density lipoprotein cholesterol ratio (4.7 to 4.2, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Comparative study of encainide and quinidine in the treatment of ventricular arrhythmias

The antiarrhythmic efficacy and safety of oral encainide hydrochloride and quinidine sulfate were compared in a nine center double-blind crossover study in 187 outpatients with benign or potentially lethal ventricular arrhythmias. Patients with at least 30 premature ventricular complexes/h were randomized to receive either encainide, 25 mg four times/day, or quinidine, 200 mg four times/day, for 2 weeks. These doses were continued for another 2 weeks if a 75% or greater reduction in premature ventricular complexes was observed. If this reduction was not seen, encainide was increased to 50 mg four times/day or quinidine to 400 mg four times/day for an additional 2 weeks. Both drugs produced a statistically significant reduction in premature ventricular complex frequency compared with baseline values. Encainide produced a statistically significant greater mean reduction in total premature ventricular complexes than did quinidine during the initial dose phase and after dose adjustment. More patients required dose increases of quinidine (60%) than of encainide (51%). Early discontinuation of treatment resulting in advancement to the next study period occurred in 12 patients taking encainide and 38 patients taking quinidine (p less than 0.05). PR and QRS intervals increased significantly during encainide treatment, as did QTc and JT intervals during quinidine treatment. No adverse reactions resulted from these electrocardiographic changes. Adverse reactions were more common with quinidine than with encainide.(ABSTRACT TRUNCATED AT 250 WORDS)

Dose-response range of encainide for benign and potentially lethal ventricular arrhythmias

A multicenter, 2-week, double-blind, placebo-controlled, parallel group study was performed to determine the dose-response relation of encainide administered 3 times daily and to determine its onset of action. To be included in the study, patients with benign or potentially lethal ventricular arrhythmias were required to have an average of at least 30 ventricular premature complexes (VPCs) per hour on 48-hour Holter monitoring after a 48-hour washout period without antiarrhythmic drug treatment. Patients were randomly assigned to receive either placebo or 10, 25 or 50 mg of encainide 3 times daily (tid) for 2 weeks. Of the 125 patients who entered the study, 122 were available for efficacy analysis. Efficacy was determined using 24-hour Holter monitoring on days 1, 7 and 14. There was no difference in frequency of VPCs or of ventricular tachycardia events in the placebo and 10-mg-tid encainide arms. At doses of 25 and 50 mg of tid, encainide was effective in suppressing VPCs and in reducing the number of episodes of ventricular tachycardia. A positive dose-response relation was identified. The onset of effect of encainide was apparent at 3 hours and lasted for 24 hours with tid dosing. No difference in on-therapy conditions were found among the 4 study arms. No patients were discontinued from the study because of electrocardiographic changes. There was no statistically significant change in vital signs or physical examination data. In 1 patient an elevated serum glucose level developed. No symptomatic proarrhythmic events occurred and none required discontinuation of study medication.(ABSTRACT TRUNCATED AT 250 WORDS)

Metabolic effects of antihypertensive therapy with a calcium antagonist

The effect of diuretics to increase serum glucose, low-density lipoprotein cholesterol and triglycerides, as well as the adverse changes in triglycerides and high-density lipoprotein cholesterol produced by nonselective beta blockers, have been largely ignored in the treatment of hypertension. However, a number of trials have shown that reductions in serum lipids can alter cardiovascular mortality. Calcium antagonists have become major drugs in the treatment of hypertension, and some data suggest that calcium antagonists may increase serum glucose levels. Significantly less data on lipid effects have been published. Lipid and glucose effects were examined in an 8-week antihypertensive study using a sustained-release preparation of diltiazem titrated from 240 to 360 mg/day in a twice-daily regimen in a randomized, double-blind, placebo-controlled parallel trial in 96 patients. Average supine blood pressure at week 8 was 156/98 mm Hg, standing blood pressure with placebo 152/100 mm Hg, and with diltiazem 147/91 and 144/93 mm Hg. There were no statistically significant changes in serum lipids or glucose in the diltiazem or placebo group or between the groups. Mean values (mg/dl) at baseline and week 8 in the diltiazem group were, respectively, for cholesterol 215 and 218, high-density lipoprotein cholesterol 50 and 51, low-density lipoprotein cholesterol 128 and 133, triglycerides 169 and 175, and glucose 113 and 110. Thus, this large and placebo-controlled study shows that diltiazem is among the antihypertensives with no adverse long-term lipid or glucose effects.

Sustained‐Release Diltiazem: Duration of Antihypertensive Effect

The antihypertensive activity of a sustained‐release preparation of diltiazem (given each 12 hours) was assessed in 96 patients with supine diastolic blood pressure (BP) between 95 and 110 mm Hg in a multicenter, randomized, double‐blind, placebo run‐in, parallel‐group trial comparing optimally titrated doses of diltiazem and placebo. The aim was to assess the onset of action as well as the extent and variability of BP control of this formulation during the 12‐hour interval. Diltiazem was titrated from 120 mg bid to 180 mg bid as necessary to lower BP. At baseline, on the first day of titration, and at the end of 8 weeks, BP was evaluated at 0, 1, 2, 3, 4, 5, 6, 8, 10, and 12 hours after dosing. The onset of action was within 2 hours, and the effect was maintained throughout the 12‐hour period. Mean BP for the diltiazem group at baseline was 154/101 mm Hg. At week 8, BP was 148/93 mm Hg at hour “0” (P < .02 and P = .0001 for systolic and diastolic BP vs. placebo), 139/84 mm Hg at the nadir at hour 5 (P = .0001), and 149/91 mm Hg at the end of the 12‐hour period (P < .02 and P = .0001 for systolic and diastolic BP). Diltiazem was significantly more effective than placebo (P = .0001) with 50% of patients controlled to a diastolic pressure of <90 mm Hg at 7 of the 10 evaluation points, including the evaluation point of 12 hours post‐dose. There was no exaggeration of the magnitude of daily BP fluctuation nor any increase in orthostatic effect noted.

Treatment of supraventricular arrhythmias with encainide

Encainide has been used to treat 230 patients with supraventricular arrhythmias, including patients with reentry supraventricular tachycardia of the atrioventricular reentry (Wolff-Parkinson-White syndrome) and the atrioventricular nodal reentry types associated with atrial fibrillation, paroxysmal supraventricular tachycardia or both, as well as incessant supraventricular tachycardia. The available data are summarized in this review. The short- and long-term response to encainide for preventing recurrence or lessening symptoms was excellent in most cases. There was little arrhythmia aggravation, and side effects, which were mostly central nervous system and visual in nature, did not cause discontinuation of the drug. Anterograde accessory pathway block was clearly an important effect. Whether retrograde block or refractoriness in the accessory pathway is the most important mechanism remains to be resolved. Pediatric patients with tachycardia-related cardiomyopathy responded well to encainide. Oral encainides absence of effect on blood pressure or myocardial contractility is an added benefit.

Effect of Morning Versus Evening Dosing of Diltiazem on Myocardial Ischemia Detected by Ambulatory Electrocardiographic Monitoring in Chronic Stable Angina Pectoris

Myocardial ischemia occurs frequently during daily life and has a circadian pattern similar to that reported for myocardial infarction and sudden death. Because of the increased risk of myocardial ischemia in the morning hours, it has been suggested that the administration of anti-ischemic medication before bedtime may be more effective than the traditional morning dosing. This randomized, double-blind, placebo-controlled, crossover study evaluated the effects of 480-mg/day diltiazem (given either in the A.M. or the P.M.) on myocardial ischemia using ambulatory electrocardiographic monitoring in 68 patients with chronic stable angina and > or = 2 minutes of ischemia per 48 hours. During treatment with diltiazem, the duration and number of myocardial ischemic episodes were reduced by 45% (94 to 52 minutes, p <0.004) and by 40% (4.5 to 2.7 episodes, p <0.003), respectively. The duration and number of myocardial ischemic episodes during daytime (6 A.M. to 6 P.M.) hours were also reduced by 52% (74 to 36 minutes, p <0.002) and by 48% (3.1 to 1.6 episodes, p <0.001), respectively. There was no significant difference between A.M. and P.M. dosing. Morning ischemia (6 A.M. to noon), considered separately from daytime ischemia, was also significantly reduced by both A.M. and P.M. dosing regimens, with no difference between the regimens. The results of this study showed that both A.M. and P.M. dosing of long-acting diltiazem were equally effective in suppressing episodes of ambulatory myocardial ischemia at all times.

Isradipine in the treatment of angina pectoris

Abstract Isradipine (PN 200-110) is a second-generation dihydropyridine derivative calcium antagonist. This study compares isradipine with nifedipine in 29 patients with chronic stable angina in a randomized double-blind cross-over trial with sequential treadmill exercise evaluations (modified Bruce) and anginal diaries. The study plan included a two-week, single-blind placebo washout period and four weeks of titration and treatment with each drug interrupted by one week of placebo treatment. Dosing goals were 7.5 mg three times per day for isradipine and 30 mg three times per day for nifedipine. Both treatments reduced systolic and diastolic blood pressure and increased heart rate while resting to a similar degree. Average study endpoints were, for baseline, isradipine, and nifedipine, respectively: total exercise time in seconds, 447, 581, and 578; time to onset angina in seconds, 344, 512, and 498; number of anginal episodes per two weeks, 20, 12, and 9; and number of nitroglycerin tablets taken in two weeks, 11, 8, and 6. No difference between the treatments was statistically significant. There were significant differences in adverse reactions with cardiovascular discomfort for those patients receiving nifedipine outnumbering discomfort for those patients receiving isradipine 22 to 9; neurologic discomfort 38 to 16; and gastrointestinal discomfort 13 to 10. Two patients discontinued nifedipine treatment for adverse reactions, and none withdrew from isradipine treatment. Thus, isradipine proved to be equal to nifedipine in improving exercise performance and reducing the incidence of angina in patients with chronic stable angina. At the same time, isradipine was better tolerated.

Antihypertensive monotherapy with tablet (Prompt-release) diltiazem: Multicenter controlled trials

SummaryThe tablet formulation of diltiazem has been available for the treatment of angina pectoris but has not been comprehensively evaluated in hypertension. This studys aim was to evaluate the efficacy, dose-response characteristics, and duration of action of tablet (prompt-release) diltiazem in mild to moderate hypertension. Three placebocontrolled trials were designed. The first (trial #1) evaluated the dose response of 120, 240, and 360 mg/day (q12h regimen) of diltiazem in parallel fixed-dose fashion using hourly blood pressures. The second (trial #2) evaluated a q12h titration from 240 to 360 mg/day, which could be switched to q8h. The third (trial #3) evaluated a q8h titration from 180 to 270 to 360 mg/day, followed by conversion to a q12h regimen. The goal was a supine diastolic blood pressure of <90 mmHg and 10 mmHg less than baseline. With doses of diltiazem increasing from 120 to 240 to 360 mg/day, there was a progressive decrease in the average mean arterial pressure, describing a dose response with 120 mg/day as the ineffective dose. The peak effect for each dose regimen was found at 6 hours, with significant reductions lasting over 10 hours in the 240 mg/day and 360 mg/day groups. Peak plasma concentrations occurred at 3 hours. The residual effect at the trough of the 240 mg/day and 360 mg/day doses was 48% and 53% of the peak effect, respectively. When titration was carried out on a q8h regimen, both systolic and diastolic blood pressures were significantly decreased. When the regimen was switched from q8h to q12h, the effect was not maintained. Thus, the prompt-release preparation is not as effective as the sustained-release preparation in a q12h regimen, since it shows some loss of effect near the end of the 12-hour dosing period. However, the prompt-release preparation clearly produces adequate control of blood pressure in most patients in a q8h regimen.