Martin J. O'Hara

Objective evaluation of three dose levels of diltiazem in patients with chronic stable angina.

Twenty-one patients with chronic stable angina were treated with the calcium antagonist diltiazem. Dose titration studies involving 180, 270 and 360 mg/day were conducted using a blinded objective protocol. Improvement in exercise tolerance was observed at all dose levels, but the best reduction of anginal attacks and glyceryl trinitrate consumption, enhancement of exercise capacity and improvement of objective ischemic variables were observed with the 360 mg/day dose. The mean exercise time to produce grade II angina on treadmill walking increased from 5.6 +/- 0.7 minutes on placebo to 7.9 +/- 0.8 minutes on diltiazem 180 mg/day (probability [p] less than 0.001), 8.0 +/- 0.8 minutes on 270 mg/day and 9.5 +/- 0.9 minutes on 360 mg/day (p less than 0.001 as compared with 270 mg/day). One patient was withdrawn at the 360 mg/day dosage because of pedal edema. The 24 hour Holter monitoring data confirmed the findings on exercise testing, and left ventricular function was not altered with any dose level. Diltiazem in doses ranging from 180 to 360 mg/day is another powerful antianginal agent in the calcium antagonist group producing excellent therapeutic benefit in chronic stable angina with no adverse effects on left ventricular function.

Randomized double-blind comparison of gallopamil and propranolol in stable angina pectoris

A new calcium ion antagonist, gallopamil, 150 mg/day, was compared with propranolol, 240 mg/day, in 20 patients with stable chronic angina. The patients were studied in a randomized, placebo-controlled, double-blind, crossover trial. Multistage treadmill exercise with computer-assisted electrocardiographic analysis was performed after 2 weeks of placebo therapy and at the end of each 4-week active treatment period. The mean (+/- standard error of the mean) exercise time to development of angina was 5.4 +/- 0.3 minutes with placebo; this increased to 9.4 +/- 0.7 minutes with propranolol (p less than 0.001) and 10.1 +/- 0.7 minutes with gallopamil (p less than 0.001 vs placebo; difference not significant vs propranolol). Both drugs significantly prolonged the time to development of 1 mm of ST depression. Five patients became free of angina during treadmill testing with gallopamil therapy and 2 with propranolol. Both drugs decreased the heart rate at rest; propranolol also decreased the maximal exercise heart rate, which was slightly increased with gallopamil. With the exception of 1 patient in whom raised liver enzymes developed, gallopamil was well tolerated. Thus, gallopamil is an effective antianginal agent that has few of the unwanted effects associated with other calcium channel-blocking drugs.

Reproducibility of multistage graded exercise testing in patients with chronic stable angina

Exercise testing is widely used for the diagnosis of ischaemic heart disease and for the evaluation of antianginal drugs. To assess reproducibility, analysis was carried out on 128 paired graded exercise tests from 103 patients performed at the same time of day and under identical conditions. Six different parameters were evaluated and compared between the basal test (no treatment) and the placebo test. During the basal period the mean (+/- SEM) exercise time to the development of angina was 6.0 (+/- 0.2) min and the 1 mm ST depression time was 4.1 (+/- 0.2) min. After 2 weeks of placebo the exercise time was 6.1 (+/- 0.2) min (P = NS) and the 1 mm ST depression time was 4.2 (+/- 0.2) min (P = NS). There was no significant difference between the resting or maximum heart rate on either test and the maximum ST segment depression (leads CM5 and CC5) was unaltered. In a second group of 17 patients where the basal tests were performed in the afternoon and the placebo tests in the morning, heart rate and ST segment were found to be reproducible but there was a significant difference in exercise time: 5.7 (+/- 0.7) min for the basal test and 8.3 (+/- 0.5) min for the placebo test (P less than 0.001); and of the 1 mm ST depression time: 2.7 (+/- 0.4) min for the basal test, and 5.4 (+/- 0.5) min for the placebo test (P less than 0.001). We conclude that exercise tests done under standardised conditions in the morning are highly reproducible in patients with chronic stable angina and therefore provide a valuable test for the evaluation of antianginal drugs.

Long-term efficacy of diltiazem assessed with multistage graded exercise tests in patients with chronic stable angina pectoris

The long-term efficacy of diltiazem, 360 mg/day, in patients with grade II or III stable exertional angina pectoris (Canadian Cardiovascular Society criteria) was assessed by multistage graded exercise tests. Seventeen patients undertook a placebo-controlled, double-blind, dose-titration protocol and all received long-term therapy. Exercise tests were performed at the end of 2 weeks of placebo treatment and after 6, 18, 26, 40 and 52 weeks of diltiazem, 360 mg/day. All patients had angina during treadmill testing with placebo and the mean (+/- standard error of the mean) exercise time was 5.8 +/- 0.7 minutes. This increased to 10.8 +/- 1.0 minutes after 6 weeks, 11.3 +/- 1.1 minutes after 18 weeks, 11.4 +/- 1.1 minutes after 26 weeks, 12.9 +/- 1.2 minutes after 40 weeks and 11.6 +/- 1.3 minutes after 52 weeks of continuous diltiazem therapy (p less than 0.001 vs placebo at all stages). Four patients were withdrawn after 26 weeks of treatment; one patient underwent coronary artery bypass surgery and 3 patients required the addition of beta-adrenoreceptor blocking agents. In 1 patient an irritant rash developed on the torso, legs and arms after 39 weeks of diltiazem and disappeared after discontinuing the drug. One patient complained of swelling and stiffness of the fingers and 3 patients complained of shoulder and elbow pain. Another patient had a myocardial infarction after 8 weeks of diltiazem treatment and died. No other adverse effects were observed during this study.(ABSTRACT TRUNCATED AT 250 WORDS)

Changes of Q wave amplitude during exercise for the prediction of coronary artery disease

We have examined the changes of Q wave amplitude during exercise in 156 patients with chest pain with a view to improving the accuracy of stress testing for the diagnosis of coronary artery disease. Coronary arteriography showed significant disease in 127 patients and normal arteries or minimal disease in 29. The Q wave amplitude was measured in lead CM5 from the computer-derived average of 25 consecutive beats immediately before and at the peak of maximal treadmill exercise. The amplitude was greater in the normal subjects at rest and increased with exercise, but the reverse occurred in those with coronary disease. Using the criterion of decrease or no change of Q wave amplitude during exercise as indicating a positive test, the discriminative capacity of Q wave changes was equivalent to that of ST segment depression and was maintained when patients with myocardial infarction were excluded. Using either an abnormal Q wave or ST segment response to exercise improved the tests sensitivity with a loss of specificity but no change of predictive value. In 42% of patients with coronary disease when both the Q wave and ST segment exercise responses were abnormal coronary disease was predicted with an accuracy of 91%. Analysis of subgroups of patients with coronary artery disease suggested a possible explanation for the observed changes in Q wave amplitude, measurement of which can improve the stress tests accuracy for predicting obstructive coronary artery disease.

Usefulness of bevantolol for chronic, stable angina pectoris

An objective assessment of the efficacy of bevantolol was performed in 21 patients with chronic, stable angina using computer-assisted exercise testing and ambulatory ST-segment monitoring. Given once daily, 200 mg of bevantolol was compared with 200 mg of bevantolol given twice daily and with placebo, using a double-blind crossover technique. The mean exercise time with placebo was 7.4 +/- 0.6 minutes; this increased to 10.6 +/- 0.9 minutes (p less than 0.001) with once-daily bevantolol and to 9.4 +/- 0.9 minutes (p less than 0.001) with twice-daily bevantolol. The mean heart rate at rest was 80 +/- 3 beats/min with placebo; it decreased to 63 +/- 2 beats/min (p less than 0.001) with once-daily bevantolol and to 66 +/- 2 beats/min (p less than 0.001) with twice-daily bevantolol. The maximum exercise heart rate of 118 +/- 6 beats/min with placebo was reduced to 99 +/- 4 beats/min (p less than 0.001) on once-daily and 101 +/- 4 beats/min (p less than 0.001) on twice-daily bevantolol. There was a corresponding decrease in the rate-pressure product. The corrected maximum ST-segment depression was reduced from 0.3 +/- 0.06 mm min-1 with placebo to 0.2 +/- 0.03 mm min-1 (p less than 0.02) with once-daily and 0.2 +/- 0.04 mm min-1 (p less than 0.05) with twice-daily bevantolol. The mean hourly ambulatory heart rate was significantly reduced for 21 hours with once-daily and 22 hours with twice-daily bevantolol. The lowest mean minimum heart rate was 55 beats/min during twice-daily treatment. The mean number of episodes of ST depression over 24 hours in lead CM5 was decreased from 6.89 +/- 1.7 with placebo to 2.50 +/- 0.6 (p less than 0.001) with once-daily and to 3.72 +/- 1.3 (p less than 0.001) with twice-daily bevantolol. Three patients were withdrawn during the once-daily bevantolol regimen due to adverse experiences, and another patient was admitted for coronary artery bypass surgery after 25 days.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of diltiazem and propranolol on myocardial ischaemia during unrestricted daily life in patients with effort-induced chronic stable angina pectoris

SummaryTo examine the effect of diltiazem 60 mg thrice daily and propranolol 80 mg thrice daily on myocardial ischaemia during unrestricted daily life, we have studied 14 patients with established effort-induced chronic stable angina pectoris in a double-blind crossover study.Ambulatory electrocardiographic monitoring was performed using frequency modulated (FM) tape recorder after 2 weeks of placebo therapy and at the end of each 4 week treatment period for a minimum of 24 h.The mean (±SEM) number of episodes of ST-segment depression greater than 1 mm during placebo treatment were 97±28, and these fell to 54±27 during diltiazem treatment (p<0.05) and to 12±6 during propranolol treatment (p<0.02).The maximal depth of ST-segment depression in 24 h, which indicates the severity of the episode, was 3.3±0.4 mm during placebo, 2.5±0.2 mm during diltiazem (p<0.05), and 1.6±0.5 mm during propranolol (p<0.01). Both diltiazem and propranolol treatment produced significant reduction in the total area of ST-segment depression observed during 24 h.A uniform reduction in the mean heart rate during the 24 h was observed during propranolol therapy and not during diltiazem therapy.Both diltiazem and propranolol treatment improved indices of myocardial ischaemia during daily normal unrestricted life, as measured by ambulatory ST-segment monitoring in patients with established chronic stable angina pectoris. Their differing effects on heart rate suggest that they act by different mechanisms.

Ambulatory monitoring and exercise testing in the evaluation of a new long-acting calcium ion antagonist KB-944 (Fostedil) for the treatment of exertional angina pectoris

The anti-anginal effects of KB-944 (Fostedil), a new calcium ion antagonist with a half life of approximately 23-28 hr, were evaluated in 20 patients with exertional angina pectoris in a placebo-controlled single-blind dose titration trial. Ambulatory monitoring and multistage treadmill exercise with computer-assisted electrocardiographic analysis was performed after 2 weeks of placebo therapy and after two 2-weekly periods of KB-944 therapy. The mean (+/- SEM) exercise time to the development of angina on treadmill walking increased from 6.9 +/- 0.4 min on placebo to 9.4 +/- 0.5 min on KB-944 100 mg/day (P less than 0.001) and 9.7 +/- 0.8 min on KB-944 200 mg/day (P less than 0.001 vs placebo and not significant vs KB-944 100 mg/day). The time to the development of 1 mm ST-segment depression of 5.3 +/- 0.4 min on placebo increased to 6.5 +/- 0.5 and 6.6 +/- 0.5 min on KB-944 100 and 200 mg/day, respectively (P less than 0.01 vs placebo). The heart rate at rest of 77 +/- 3 beats/min on placebo was reduced to 68 +/- 3 beats/min on KB-944 100 mg/day (P less than 0.001) and 71 +/- 2 beats/min on KB-944 200 mg/day (P less than 0.01). The maximal heart rate and the rate-pressure product were not altered by KB-944 therapy. One patient developed unstable angina during the treatment phase of KB-944 200 mg/day and was withdrawn. Five patients complained of dyspepsia and one of headache and lethargy during KB-944 200 mg/day. One patient developed ventricular tachycardia during treadmill testing while on KB-944 200 mg/day. The 24-hr ambulatory monitoring data confirmed the findings of exercise testing. KB-944 (Fostedil) in a dose of 100 mg once daily was well tolerated as compared to KB-944 200 mg once daily and both the doses were equally effective. The drug merits further evaluation for the treatment of exertional angina pectoris.

Tiapamil, a new calcium channel blocking agent for the treatment of effort induced chronic stable angina pectoris

SummaryThe anti-anginal efficacy of tiapamil, a new calcium channel blocking agent was studied in 24 patients with established effort induced chronic stable angina pectoris. The patients were allocated randomly in a double-blind fashion to tiapamil 300 mg thrice daily or placebo for 2 weeks and thereafter all the patients received tiapamil 300 mg thrice daily in a single-blind fashion for a further 2 weeks. All patients performed symptom limited multistage graded exercise testing with computer-assisted analysis of the electrocardiogram before entering the study and at the end of the double-blind and single-blind phases. The mean exercise time to develop angina during the control test in the group which received placebo during the double-blind phase was 7.1 min; this increased to 8.5 min after 2 weeks of placebo and 9.7 min after 2 weeks of subsequent tiapamil therapy. Similarly in the group which received tiapamil during the double-blind phase the mean exercise time on control test was 6.4 min, increasing to 9.7 min and 9.7 min after 2 and 4 weeks of tiapamil therapy respectively. There were no statistical significant differences between the changes from control, seen with tiapamil and placebo during the double-blind phase. However, the changes observed between control and active therapy in the tiapamil group did reach statistical significance (p=0.003). Similarly, 1 mm ST-segment depression time was prolonged by tiapamil therapy. The heart rate at rest and maximal exercise remained unaltered with tiapamil therapy. Two patients were withdrawn during tiapamil therapy; one developed unstable angina and the other a skin rash which resolved completely after withdrawing the drug. Another patient showed raised liver enzymes after 4 weeks of tiapamil therapy. These results indicate that tiapamil merits further evaluation for the treatment of effort induced chronic stable angina pectoris.

Evaluation of oxprenolol slow release and osmotic release by exercise testing and ambulatory electrocardiographic monitoring in patients with chronic stable angina pectoris

SummaryWe have treated eleven patients with chronic stable angina pectoris with slow-release oxprenolol (160 mg and 320 mg) in a double-blind crossover study and evaluated its efficacy objectively by exercise testing between 180 and 240 min after dosing.The mean exercise time increased significantly from 6.2 min on placebo to 7.2 min and 7.3 min on oxprenolol 160 mg and 320 mg respectively. No overall beneficial effects could be demonstrated for the higher dose.A further 20 patients received slow release oxprenolol 160 mg and 10/170 mg “Oros” (osmotic release) oxprenolol in a double-blind crossover study using exercise testing and ambulatory electrocardiographic monitoring at 21–23 h after dosing.The mean exercise time increased significantly from 7.0 min on placebo to 8.3 min on slow-release oxprenolol and to 8.1 min on “Oros” oxprenolol. The effects of the 2 treatments on exercise and ambulatory heart rates were comparable.Two patients were withdrawn during the doubleblind treatment period while receiving oxprenolol slow-release, one because of unstable angina and another becaues of throbbing headache.These findings confirm that slow-release oxprenolol is effective in treating chronic stable angina pectoris at the 160-mg dose. “Oros” oxprenolol 10/170 mg has a profile of action closely similar to but without any additional benefit over slow-release oxprenolol 160 mg.