Ravinder S. Kohli

Acute and sustained effects of isosorbide 5-mononitrate in stable angina pectoris

Isosorbide 5-mononitrate (IS 5-MN) is an active metabolite of isosorbide dinitrate and is widely used as an antianginal agent. The acute and subacute (2 weeks) effects of IS 5-MN, 40 mg twice daily, were evaluated in 18 patients with stable angina pectoris using computerized exercise testing and a placebo-controlled, double-blind, randomized trial protocol. There were 2 phases of 2 weeks each in which patients received placebo or active IS 5-MN. Acute testing (8 patients) was performed 2 hours after the first dose and subacute testing 2 hours after the morning dose on day 14. Acute testing showed an increase in exercise time from a mean (+/- standard error of mean) of 8.2 +/- 0.6 minutes to 11.1 +/- 0.5 minutes (p less than 0.001) after a single dose of IS 5-MN. Time to 1 mm of ST depression increased significantly and peak exercise ST-segment depression decreased significantly. Rest and peak exercise heart rate increased significantly during acute testing with IS 5-MN; blood pressure did not change significantly. After 2 weeks of therapy, exercise time had not changed (9.9 +/- 0.6 with placebo to 9.7 +/- 0.6 minutes). The beneficial effects on ST-segment variables were sustained at 2 weeks. The data suggest that there is an attenuation of effect with respect to exercise time and sustained beneficial effect on the ST-segment variables. This may be a result of development of partial tolerance to IS 5-MN after 2 weeks of therapy.

Coronary angioplasty in patients with severe left ventricular dysfunction

The applications for coronary angioplasty have greatly expanded and the procedure is now increasingly used in complex and potentially high risk conditions. This report describes the short- and long-term effects of coronary angioplasty in 61 patients with severely depressed left ventricular function (ejection fraction less than or equal to 35%) with unstable or refractory anginal symptoms, or both, in whom revascularization was necessary despite increased risk. In a retrospective analysis of 1,260 patients undergoing angioplasty between January 1985 through December 1987, 61 had an ejection fraction less than or equal to 35%. The common clinical presentation was unstable angina (70%) with or without recent myocardial infarction. Mean left ventricular ejection fraction was 27 +/- 6%. Forty-five patients (74%) had multivessel disease. Clinical success after angioplasty was achieved in 55 patients (90%). Major complications (death, infarction and emergency bypass surgery) occurred in five patients (8.2%), with death in two (3.2%). During long-term (mean 21 +/- 11 months) follow-up study of the 55 patients with successful angioplasty, 13 (23%) died, including 3 of noncardiac causes, and 11 (20%) had clinically symptomatic recurrence. Continued clinical success was present in 39 patients (71%), of whom 28 (51%) were event-free patients and 11 (20%) had clinical recurrence; a successful second angioplasty procedure was performed in 9 because of restenosis. Thus, in patients with depressed left ventricular function, coronary angioplasty can be performed with a short-term success rate comparable to that of routine angioplasty or surgical procedures. However, acute complications are more frequent and the late mortality rate is higher than in patients with less depressed function.

Antianginal efficacy of carvedilol, a beta-blocking drug with vasodilating activity

The efficacy of carvedilol, a new vasodilating beta-blocking drug, was evaluated in 20 patients with chronic angina using a single-blind, placebo-controlled protocol. A 2-week placebo phase was followed by therapy with carvedilol, 25 mg twice daily for 2 weeks, after which the dose was doubled. There was then a second placebo phase lasting 2 weeks. Treadmill exercise testing, 24-hour ambulatory electrocardiographic monitoring and drug blood level assays were performed at the end of each phase. Exercise time (mean +/- standard error of mean) increased from 7.4 +/- 0.5 minutes during placebo to 9.0 +/- 0.5 minutes carvedilol, 25 mg twice daily (p less than 0.001), and to 9.2 +/- 0.4 minutes with 50 mg twice daily (p less than 0.001). Mean time to 1 mm of ST depression in both bipolar leads CM5 and CC5 increased significantly, but peak ST depression did not change. Heart rate at rest was reduced at both dose levels, from 86 +/- 4 beats/min during placebo to 70 +/- 2 beats/min with 25 mg twice daily (p less than 0.001) and to 67 +/- 3 beats/min with 50 mg twice daily (p less than 0.001). Systolic blood pressure at rest was significantly reduced at both doses (p less than 0.05; p less than 0.01), but blood pressure during exercise was decreased only with the larger dose (p less than 0.001). The exercise rate-pressure product was 182 +/- 9 with placebo and decreased to 153 +/- 5 with 25 mg twice daily (p less than 0.001) and to 138 +/- 6 with 50 mg twice daily (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Does placebo improve indexes of effort-induced myocardial ischemia? An objective study in 150 patients with chronic stable angina pectoris

The effects of placebo were studied in 150 patients (135 men, 15 women) aged 42 to 75 years with stable exertional angina pectoris, using multistage graded exercise testing. Treadmill exercise, using on-line computer analysis of the electrocardiogram, was performed after a basal period, during which time the patients had no treatment for 2 weeks, and after 2 weeks of placebo therapy. Mean exercise time during no treatment was 6.0 +/- 0.2 minutes and during placebo was 6.1 +/- 0.2 minutes (difference not significant). Similarly, time to development of 1 mm of ST-segment depression of 4.0 +/- 0.2 minutes without treatment was 4.1 +/- 0.2 minutes after 2 weeks of placebo therapy (difference not significant). Placebo failed to show any effect on rest or maximal heart rate or on maximal ST-segment depression. It also failed to increase exercise tolerance or to improve other objective indexes of effort-induced myocardial ischemia in both single-and double-blind protocols in patients with stable exertional angina pectoris. Therefore, placebo control of antianginal drug trials that use exercise testing for evaluation of effect is unnecessary and can be omitted.

Sustained release verapamil, a once daily preparation: Objective evaluation using exercise testing, ambulatory monitoring and blood levels in patients with stable angina

The efficacy of a once daily, sustained release formulation of verapamil (Verapamil SR, 360 mg) was evaluated in 19 patients with chronic angina pectoris using a double-blind placebo-controlled crossover protocol. Evaluation by exercise testing, 24 hour electrocardiographic ambulatory monitoring and blood drug level assays was performed at the end of each 2 week phase, 21 to 23 hours after the last dose. After the crossover protocol, all patients were given sustained release verapamil for 4 weeks and the evaluation was repeated. Exercise time (mean +/- SEM) increased from 7.4 +/- 0.6 minutes with placebo to 9.6 +/- 0.8 minutes with verapamil (p less than 0.001) and to 9.5 +/- 0.7 minutes (p less than 0.001) after 4 weeks of therapy. The mean time to 1 mm ST depression also increased significantly, from 4.5 +/- 0.4 and 4.8 +/- 0.5 minutes in bipolar leads CM5 and CC5, respectively, with placebo, to 5.5 +/- 0.6 (p less than 0.05) and 6.2 +/- 0.5 minutes (p less than 0.01) with verapamil. Maximal ST depression and rest and peak heart rates were not altered significantly. The mean rate-pressure product was 208 +/- 9.9 with placebo and decreased to 189 +/- 7.7 (p less than 0.05) with verapamil but rose to 200.6 +/- 10.4 (p = NS) after 4 weeks of therapy. The mean hourly heart rates were lower with the drug than with placebo throughout the 24 hour period but there was no significant bradycardia, arrhythmia or heart block.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of nicardipine and verapamil in the management of chronic stable angina

Twenty-two patients with stable angina were studied in a randomised double-blind, placebo-controlled crossover trial to compare the antianginal effects of nicardipine (30 mg) and verapamil (120 mg), each given three times a day. Efficacy was assessed using treadmill exercise testing and 24-hour ambulatory electrocardiographic monitoring performed after an initial 2-week placebo phase and at the end of each 4-week active treatment period. Exercise time (mean +/- standard error of mean) increased from 7.4 +/- 0.5 min on placebo to 8.4 +/- 0.7 min on nicardipine (P less than 0.05) and to 9.9 +/- 0.7 min on verapamil (P less than 0.001). Resting heart rate was decreased by verapamil (P less than 0.002) and increased by nicardipine (P less than 0.02). Exercise heart rate was increased on nicardipine (P less than 0.005) but heart rate gain was higher on verapamil (P less than 0.01). Blood pressure and peak ST segment depression were unaltered by either drug but the time to 1 mm ST segment depression increased on both drugs. Ambulatory heart rates were lower on verapamil than on nicardipine and patient subjective preference was in favour of verapamil. This study confirms that both nicardipine and verapamil improve exercise capacity, but verapamil produces a greater improvement in exercise tolerance and indices of myocardial ischaemia whilst nicardipine is associated with an increase in the number of episodes of ST segment depression on ambulatory monitoring.

Oral nitroglycerin in angina pectoris—Evaluation of effect by computerized exercise testing using two different doses

SummaryThe antianginal effects of sustained-released oral nitroglycerin were evaluated in patients with chronic stable angina using a double-blind randomized protocol. Nineteen patients were inducted into the trial and 17 of these completed the study. Two doses of oral nitroglycerin were used; 2.6 mg and 6.5 mg given three times daily for a period of 2 weeks, the patients crossing over to the alternative dose at the end of each period. Evaluation of effect was carried out 2 hours after the morning dose using graded treadmill exercise testing with on-line computer analysis of the electrocardiogram (EKG) (CASE, Marquette Electronics, Inc.). Various exercise parameters were measured and the results compared to placebo values and between the two dosages. The aim was to demonstrate an antianginal effect and to look for a dose-response relationship and for attenuation of effect if any on continued administration. The mean±SEM exercise time on placebo was 6.7±0.6 min, increasing to 8.6±8 min (p<0.02) with 2.6 mg tds dosage and 8.4±0.7 min (p<0.01) with 6.5 mg tds of oral nitroglycerin. None of the other exercise-derived indices were altered significantly by oral nitroglycerin. Two patients were withdrawn because of severe headaches and both were receiving the higher dose. The data did not demonstrate and dose-response relationship but confirmed the anti-anginal efficacy of sustained action oral nitroglycerin. This efficacy did not show any significant attenuation of effect on continued administration, indicating a possible lack of development of tolerance.