Intravenous nitroglycerin suppresses exercise-induced arrhythmias in patients with ischaemic heart disease: implications for long-term treatment

We studied 20 patients with ischaemic heart disease, who consistentlydeveloped complex ventricular arrhythmias during exercise testing.Treadmill exercise was performed twice, both during the placeboinfusion and then during intravenous administration of nitroglycerin,titrated to reduce systolic blood pressure by 10 mmHg. Exerciseduration in those administered placebo was 7·8 ±1·7 and 7·9 ± 1·5 min, respectively(ns): angina developed in five patients and ischaemic ST changesin 10. In those administered nitroglycerin, exercise durationincreased to 8·4 ± 2 mm (P<0·05). DiagnosticST segment depression was observed in only two patients andonly one had angina. Ventricular arrhythmias, consistently presentduring both tests on those administered placebo, were dramaticallyreduced by nitroglycerin in all 20 patients. There were 455(mean 35·8± 16·8) and 4l8 (mean 34·4±11·1)ventricular ectopic beats in the two exercise tests on thoseadministered placebo and 11 in those receiving the nitroglycerininfusion (mean 0·6 ± 0·1 (P<0·001).There were 28 and 29 couplets in those receiving placebo (ns)and none in those receiving nitroglycerin (P<0·001).Ventricular tachycardia was present in six and eight patientswho received placebo but in none in those administered nitroglycerin(P<0·001). Abolition of exercise-induced arrhythmiaswas maintained during chronic treatment with oral coronary vasodilators.Prevention of exercise-related arrhythmias by nitroglycerinappears a good indicator of their ischaemic origin and may providevaluable information for long-term prophylaxis with oral vasodilators,thus avoiding antiarrhythmic agents with their potential sideeffects.     

Intravenous nitroglycerin suppresses exercise-induced arrhythmias in patients with ischaemic heart disease: implications for long-term treatment

We studied 20 patients with ischaemic heart disease, who consistentlydeveloped complex ventricular arrhythmias during exercise testing.Treadmill exercise was performed twice, both during the placeboinfusion and then during intravenous administration of nitroglycerin,titrated to reduce systolic blood pressure by 10 mmHg. Exerciseduration in those administered placebo was 7·8 ±1·7 and 7·9 ± 1·5 min, respectively(ns): angina developed in five patients and ischaemic ST changesin 10. In those administered nitroglycerin, exercise durationincreased to 8·4 ± 2 mm (P<0·05). DiagnosticST segment depression was observed in only two patients andonly one had angina. Ventricular arrhythmias, consistently presentduring both tests on those administered placebo, were dramaticallyreduced by nitroglycerin in all 20 patients. There were 455(mean 35·8± 16·8) and 4l8 (mean 34·4±11·1)ventricular ectopic beats in the two exercise tests on thoseadministered placebo and 11 in those receiving the nitroglycerininfusion (mean 0·6 ± 0·1 (P<0·001).There were 28 and 29 couplets in those receiving placebo (ns)and none in those receiving nitroglycerin (P<0·001).Ventricular tachycardia was present in six and eight patientswho received placebo but in none in those administered nitroglycerin(P<0·001). Abolition of exercise-induced arrhythmiaswas maintained during chronic treatment with oral coronary vasodilators.Prevention of exercise-related arrhythmias by nitroglycerinappears a good indicator of their ischaemic origin and may providevaluable information for long-term prophylaxis with oral vasodilators,thus avoiding antiarrhythmic agents with their potential sideeffects.     

Exercise capacity with transdermal nitroglycerin in patients with stable angina pectoris

Transdermally delivered nitroglycerin (TTS-NTG) through a rate-controlling membrane yields stable blood levels for 24 h. We studied the effect of TTS-NTG (25 mg per 10 cm2) on exercise induced angina in 10 patients with stable angina pectoris, all in NYHA class III, who were not under treatment with other cardiac drugs. In a pre-study exercise test, all patients had angina pectoris and more than one mm ST depression. The study was placebo controlled and double blind with a randomized cross-over. Exercise tests were carried out on a treadmill according to the Bruce-protocol, 12 to 16 h after administration of TTS-NTG or of an identical placebo. After a 48 h wash-out period, the procedure was repeated after application of a plaster with the alternative content. A significant improvement was seen on TTS nitroglycerin compared with placebo in the total duration of exercise (7.2 +/- 3.6 min (mean +/- SD) vs 6.2 +/- 3.8 min; P less than 0.002). In 7 patients, the time to onset of angina was extended by TTS nitroglycerin. Maximal ST depression (lead V4 and V6) was significantly lower on TTS nitroglycerin (1.85 +/- 1 mm) compared with placebo (2.2 +/- 1 mm; P less than 0.05). It is concluded that 12 to 16 h after administration, transdermally delivered nitroglycerin improves exercise capacity and reduces maximal ST depression in patients with stable angina.     

Effects of nicorandil on exercise tolerance in patients with stable effort angina: a double-blind study

Effects of nicorandil, a recently introduced 2-nicotinamidethyl nitrate, on exercise performance were studied in 11 patients with stable effort angina. The duration of exercise before the onset of angina and time to the onset of ischemic ST depression 30 minutes after 20 mg of oral nicorandil were compared with events 30 minutes after oral placebo and 5 minutes after 0.3 mg of sublingual nitroglycerin. Nicorandil and placebo were given according to the randomized double-blind method. Nicorandil prolonged the duration of exercise in all 11 patients by 2.3 +/- 2.2 minutes (mean +/- SD, p less than 0.01) and delayed the onset of ischemic ST depression by 2.3 +/- 1.7 minutes compared to placebo (p less than 0.01). The increment of the duration of exercise and the time to the onset of ischemic ST depression following 20 mg of oral nicorandil were almost equivalent to findings after sublingual nitroglycerin (by 2.0 +/- 1.8 and 2.5 +/- 1.7 minutes, respectively). Nicorandil also increased the pressure-rate product at the time of angina compared with placebo (20,420 +/- 480 vs 17,480 +/- 370, p less than 0.05). These results indicate that oral administration of nicorandil should be considered for the clinical treatment of effort angina.     

Comparison of nicardipine and propranolol for chronic stable angina pectoris

In a double-blind, randomized, crossover clinical trial, a new calcium antagonist, nicardipine (90 mg/day in 3 divided doses), was compared with propranolol (120 mg/day in 3 divided doses) in 25 patients with chronic stable angina. The mean weekly frequency of angina episodes decreased from 7.8 +/- 1.2 (+/- standard error of the mean) with placebo to 3.8 +/- 1.2 with nicardipine treatment and 3.5 +/- 1 with propranolol treatment (p less than 0.001). With exercise testing, 5 patients receiving nicardipine and 3 receiving propranolol had no angina or ST-segment changes. Comparing paired samples of both drugs with placebo, significant improvement occurred in exercise duration (nicardipine, 1.3 +/- 0.3 minutes, p less than 0.001; propranolol, 1.0 +/- 0.4 minutes, p less than 0.01), time to onset of angina (nicardipine, 1.5 +/- 0.4 minutes, p less than 0.001; propranolol, 1.5 +/- 0.5 minutes, p less than 0.001), maximal ST-segment changes (nicardipine, 0.7 +/- 0.1 mm, p less than 0.01; propranolol, 0.06 +/- 0.1 mm, p less than 0.01) and time to 1 mm of ST depression (nicardipine, 2.5 +/- 0.4 minutes, p less than 0.01; propranolol, 2.0 +/- 0.3 minutes, p less than 0.01). One patient receiving propranolol and 2 receiving nicardipine withdrew from the study because of transient side effects. Mild side effects occurred in 10 patients receiving propranolol and 5 receiving nicardipine. Nicardipine proved to be safe and effective for patients with chronic stable angina; it had fewer side effects than propranolol in the doses used.     

Ventricular arrhythmias during ergonovine-induced episodes of variant angina

Of 95 consecutive patients with active variant angina who underwent ergonovine testing in the coronary care unit while off treatment, 24 (25%) developed serious ventricular arrhythmias: ventricular tachycardia in eight, bigeminy in seven, pairs in five, and frequent ventricular extrasystoles in four. Ergonovine-induced arrhythmias were observed more often in patients with anterior than inferior ST segment elevation (p less than 0.05). ST segment elevation was significantly higher (10.3 +/- 8.1 vs 3.1 +/- 2.1 mm) in patients who developed arrhythmias. All ventricular arrhythmias began within 3 minutes after the onset of ST segment elevation. The intravenous administration of nitroglycerin eliminated arrhythmias in 22 of 24 cases; in only two patients did ventricular arrhythmias develop after the administration of nitroglycerin. Serious ventricular arrhythmias were found during spontaneous variant angina attacks in 14 of 24 patients with ergonovine-induced arrhythmias compared to 16 of 71 patients without ergonovine-induced arrhythmias (p less than 0.001). We conclude that arrhythmias during ergonovine testing are most often caused by ischemia and not reperfusion. Patients with arrhythmias during ergonovine-induced attacks are more likely to have arrhythmias during spontaneous attacks.     

Oral sustained-release nitroglycerin in chronic stable angina: a multicenter, double-blind, randomized crossover trial

Forty-six patients with stable angina pectoris were randomized to receive either oral sustained-release nitroglycerin (SRNG, 6.5 mg) or placebo (P) 3 times a day for a 2-week double-blind trial. They were investigated for the frequency of anginal episodes, for sublingual nitroglycerin consumption and for exercise tolerance. There was a slight but significant decrease in the number of anginal episodes (6.4 +/- 1.5 episodes/week with P, 4.9 +/- 1.7 with SRNG, p less than 0.005) and sublingual nitroglycerin consumption (3.9 +/- 1 tablets/week with P, 2.7 +/- 1 with SRNG, p less than 0.005). The patients performed 3 upright multistage (increments of 30 W every 3 minutes) exercise tests on a bicycle ergometer before the start of the study and 1 hour after the intake of SRNG or P, at the end of each double-blind phase. Exercise capacity, expressed as exercise duration, increased from 8.9 +/- 3.8 minutes with P to 10.2 +/- 3.8 minutes with SRNG (14.6%; p less than 0.001). At symptom-limited exercise, ST depression was significantly reduced (p less than 0.05) during the SRNG phase. Thirty-four patients (74%) reached a higher peak heart rate (139 beats/min with P, 145 beats/min with SRNG; p less than 0.001) and 35 patients (76%) a higher rate-pressure product (+6%; p less than 0.001). These changes in exercise tolerance are relatively modest and at least 11 patients would have benefited from larger doses of nitrates.(ABSTRACT TRUNCATED AT 250 WORDS)     

Evaluation of bepridil for the treatment of angina pectoris: evidence for preservation of left ventricular function

The efficacy of bepridil (400 mg once a day) was assessed in 15 patients with exertional angina pectoris. All 15 patients reported substantial clinical improvement during bepridil treatment compared with placebo treatment. Episodes of angina were 11.8 +/- 4.1 (mean +/- standard error of the mean)/week with placebo and 3.8 +/- 1.6 with bepridil (p less than 0.05); nitroglycerin use was 9.1 +/- 3.3 tablets/week with placebo and 3.5 +/- 1.7 with bepridil (p less than 0.05). Five of 15 patients receiving bepridil did not experience angina during treadmill exercise; in the remaining 10 patients, time to onset of angina during exercise was 5.7 +/- 0.9 minutes with bepridil as opposed to 4.5 +/- 0.8 minutes with placebo (p less than 0.05). Left ventricular (LV) performance at peak exercise as measured by first-pass radionuclide angiography revealed the ejection fraction to be 38 +/- 3% during placebo therapy and 47 +/- 4% during bepridil therapy (p less than 0.0025). End-diastolic LV volume was unchanged, but end-systolic volume was 136 +/- 11 and 117 +/- 13 ml (p less than 0.05) and stroke volume was 82 +/- 6 and 97 +/- 9 ml (p less than 0.05) during placebo and bepridil therapy, respectively. Heart rate at peak exercise was 136 +/- 3 beats/min with placebo and 128 +/- 3 beats/min with bepridil; however, blood pressure was unchanged. These studies demonstrate that bepridil results in significant clinical improvement and enhanced LV performance in patients with angina pectoris.     

Long-term efficacy of continuous and intermittent use of transdermal nitroglycerin in stable angina pectoris

To assess efficacy of transdermal nitrate use, a randomized, placebo-controlled trial of continuous and intermittent use of nitroglycerin patches (10 mg/24 hours) was conducted in 127 patients with stable angina pectoris who discontinued exercise testing within 9 minutes because of angina. After a placebo run-in week, baseline (day 0) symptom-limited exercise testing was performed and repeated on day 1 and 14 before and after the administration of 0.5 mg of sublingual nitroglycerin. On day 0, total exercise duration was the same (within narrow limits) in all 3 groups and remained unchanged in the placebo group. On day 1, total exercise duration increased from 406 +/- 115 to 469 +/- 158 seconds (p less than 0.001) in the continuously treated group and from 396 +/- 105 to 475 +/- 171 seconds (p less than 0.001) in the intermittently treated group. In the intermittent group, exercise duration increased slightly to 483 +/- 140 seconds on day 14, and in the continuous group exercise duration decreased to 447 +/- 144 seconds. However, this decrease was not statistically significant. Similar treatment effects were seen for time to 1-mm ST depression. Sublingual nitroglycerin remained effective in all 3 groups and on all days. Eleven actively treated patients and 1 patient taking placebo discontinued the study because of headache. It is concluded that continuous use of transdermal nitroglycerin remains partially effective and intermittent therapy remains fully effective in improving long-term exercise capacity with acceptable adverse effects in patients with stable angina pectoris.     

Felodipine in chronic stable angina: a randomized, double-blind, placebo-controlled, crossover study

To investigate the antianginal efficacy and tolerability of felodipine, a new dihydropyridine calcium antagonist, 20 patients with stable exertional angina, not completely controlled by beta-blocker monotherapy, entered a randomized, double-blind, placebo-controlled, crossover study. Patients on standard beta-blocker therapy, who had at least 3 weekly anginal episodes and a reproducible exercise test (stopped for angina and ECG signs of ischaemia) at the end of 2 weeks placebo treatment, were eligible for the study. They were randomized to one sequence of treatment: felodipine 5 mg twice daily for 2 weeks followed by placebo for a further 2 weeks, or vice versa. Beta-blocker treatment was unchanged throughout the study. A treadmill test was carried out at the end of each crossover period, 2-4 h after drug administration. The number of anginal attacks and nitroglycerin consumption was recorded on a diary card. At rest, felodipine significantly (P less than 0.05) reduced standing systolic but not diastolic blood pressure. Heart rate was not modified by the active treatment. At ischaemic threshold and at peak exercise, heart rate, systolic blood pressure and rate-pressure product remained unchanged. Exercise duration was increased by felodipine (P less than 0.01) and maximal ST change was reduced (P less than 0.01). Time to 1 mm ST depression was prolonged non-significantly by felodipine (basal 5.7 +/- 1.5, felodipine 7.4 +/- 2.0, placebo 6.6 +/- 1.5 min). The number of patients who stopped exercise due to angina and ST change was 20/20 at baseline, 16/20 with placebo and 10/20 with felodipine. Felodipine significantly reduced weekly anginal episodes (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Stress testing predischarge and six weeks after myocardial infarction to compare submaximal and maximal exercise predischarge and to assess the reproducibility of induced abnormalities

Submaximal and maximal treadmill exercise tests were performed predischarge in 64 patients after acute myocardial infarction to assess the relative yield of residual ischaemic abnormalities. The reproducibility of individual abnormalities resulting from maximal stress tests performed predischarge and 6 weeks after infarction was also assessed in 55 of these patients. Compared with predischarge submaximal exercise testing, a maximal exercise test identified a significantly greater number of patients with residual myocardial ischaemia (26 vs. 15, P less than 0.05) and this was associated with a significantly longer average maximal exercise duration (P less than 0.001), and a higher rate-pressure product (P less than 0.001). Among the 55 patients who had maximal stress tests both predischarge and 6 weeks after infarction, there was a significant lack of reproducibility in the occurrence of exercise induced angina (P less than 0.01) and an abnormal blood pressure response (P less than 0.02). In contrast, exercise induced ST segment depression and elevation and ventricular arrhythmias were relatively reproducible. More patients had an ischaemic test result (ST depression or angina) at the later test compared to the predischarge test (33 vs. 25 patients) but this increase was not statistically significant. There were, however, significant increases at the later test in mean maximal exercise duration (P less than 0.001). mean maximal heart rate (P less than 0.001) and heart rate-systolic blood pressure double product (P less than 0.001). The majority of patients who had a cardiac event in the period between the two tests had a predischarge test abnormality. We conclude that a significantly greater number of patients with residual reversible myocardial ischaemia after infarction will be identified by symptom limited exercise testing compared with a submaximal predischarge test. Because ST depression and elevation appear reproducible, patients who develop these abnormalities during a predischarge test do not, for prognostic reasons, need retesting 6 weeks after infarction. Exercise induced angina pectoris and an abnormal blood pressure response, however, are highly variable and in these patients a repeat test may be useful.     

Efficacy of calcium channel blocker therapy for angina pectoris resulting from small-vessel coronary artery disease and abnormal vasodilator reserve

Abnormal vasodilator reserve of the coronary microcirculation is a frequent mechanism of angina pectoris in patients with angiographically normal coronary arteries. To assess the effect of calcium channel blocking agents on symptoms and exercise capacity, 26 patients shown to have angina pectoris because of abnormally small coronary arteries and limited vasodilator reserve underwent randomized, double-blind, placebo-controlled outpatient study, with 1 month for each period. An unblinded lead-in phase determined the best dose of verapamil (17 patients) or nifedipine (9 patients). Exercise testing using bicycle ergometry was performed at the end of each period. Four patients interrupted the placebo period and 1 patient interrupted both placebo and drug period because of frequent and severe chest pain. While receiving calcium channel blocker drugs, patients who completed both phases of the study recorded fewer episodes of angina (21 +/- 21 vs 35 +/- 27, p less than 0.001) and consumed fewer nitroglycerin tablets (23 +/- 27 vs 41 +/- 50, p less than 0.001) than during the placebo period. Exercise duration was slightly but significantly prolonged (278 +/- 129 vs 231 +/- 136 seconds, p less than 0.025) during drug treatment compared with placebo, and significantly fewer patients terminated exercise with chest pain while receiving drug treatment. Subjectively, 22 of 26 patients felt better on the calcium channel blocker than on placebo. Thus, calcium channel blocker therapy appears to be beneficial in controlling angina and improving exercise tolerance in patients with angina pectoris resulting from abnormally small coronary arteries and limited vasodilator reserve.(ABSTRACT TRUNCATED AT 250 WORDS)     

Long-lasting effect of oral molsydomine on exercise performance: a new antianginal agent.

This study examines whether the beneficial effects of molsydomine, a recently introduced antianginal agent, on exercise performance of patients with angina pectoris are long lasting. The hemodynamic effects are known to persist for several hours. The effects of molsydomine on the duration of exercise and the time to the onset of ST depression were compared to those of placebo during two hours after oral administration. Molsydomine prolonged the duration of exercise in all eight patients (average 2.8 min, P less than 0.001) and delayed the onset of ST depression (average 2.2 min, P less than 0.001), while the placebo failed to alter these measurements. The increment of the duration of exercise produced by 2 mg of molsydomine in two hours following oral administration was comparable to the increment produced in a few minutes after 0.3 mg of nitroglycerin given sublingually. The results indicate that molsydomine offers prophylasis for angina pectoris that lasts at least two hours after oral administration.     

Verapamil therapy for stable exertional angina pectoris

Clinical and exercise responses to therapy with the calcium-channel blocking agent verapamil were assessed in 26 patients with stable exertional angina pectoris using a double-blind, placebo-controlled, randomized crossover study design. Verapamil, 480 mg daily, reduced the frequency of angina attacks (5.6 +/- 7.3 to 2.2 +/- 3.0 attacks per week, p less than 0.001) and number of nitroglycerin tablets consumed (3.4 +/- 4.9 to 1.2 +/- 2.5 tablets per week, p less than 0.05), and increased exercise duration (6.4 +/- 2.1 to 7.5 to 1.8 minutes, p less than 0.001) (all data are mean +/- standard deviation). These changes were significantly better than those seen with placebo. These beneficial effects of verapamil were related to significant reduction in the heart rate-systolic blood pressure product during submaximal exercise. Adverse effects from verapamil were few and consisted primarily of constipation in 6 patients. A total of 193 patients had been entered in 6 independent clinical trials, which have compared verapamil with placebo for the treatment of stable exertional angina pectoris, using a similar study design. The combined evidence from all these studies indicates that verapamil is a highly effective and safe drug for the treatment of stable effort-related angina pectoris.     

Effects of coenzyme Q10 on exercise tolerance in chronic stable angina pectoris

The effects of coenzyme Q10(CoQ10) on exercise performance were studied in 12 patients, average age 56 years, with stable angina pectoris. The study involved a double-blind, placebo-controlled, randomized, crossover protocol, using multistage treadmill exercise tests. CoQ10(150 mg/day in 3 daily doses) was administered orally for 4 weeks, tended to reduce anginal frequency from 5.3 +/- 4.9 to 2.5 +/- 3.3 attacks for 2 weeks and nitroglycerin consumption from 2.6 +/- 2.8 to 1.3 +/- 1.7 tablets for 2 weeks compared with patients receiving the placebo, but the reduction was not statistically significant. Exercise time increased from 345 +/- 102 seconds with placebo to 406 +/- 114 seconds during CoQ10 treatment (p less than 0.05). The time until 1 mm of ST-segment depression occurred increased from 196 +/- 76 seconds with placebo to 284 +/- 104 seconds during CoQ10 treatment (p less than 0.01). During the exercise test, ST-segment depression, heart rate and pressure-rate product at the same and at the maximal workload showed no significant difference between patients after placebo and CoQ10 administration. The average CoQ10 plasma concentration increased from 0.95 +/- 0.48 microgram/ml to 2.20 +/- 0.98 microgram/ml after CoQ10 treatment. This increase was significantly related to the increase in exercise duration (r = 0.68, p less than 0.001). Only 1 patient had a loss of appetite, but continued therapy. This study suggests that CoQ10 is a safe and promising treatment for angina pectoris.     

Limited usefulness of intermittent nitroglycerin patches in stable angina

The efficacy of continuous and intermittent nitroglycerin patches (10 mg/day) was compared in a randomized, placebo-controlled trial in 36 patients with stable angina and reproducible, exercise-induced ST depression. Intermittent treatment was administered either 18 or 14 h/day with an intermission of 6 h or 10 h, respectively. Exercise tests were performed during the last 2 h of patch application. Compared with placebo, neither continuous nitroglycerin nor the two intermittent regimens prolonged total treadmill time or time to 1 mm ST depression. No treatment eliminated exercise-induced ST depression in greater than 1 of the 36 patients. Time to angina was prolonged (by 40 +/- 66 s) only during the "10 h off" treatment (p = 0.001); time to angina increased by greater than or equal to 20% in 13 patients. Responders to treatment could be predicted by a short history of angina (p less than 0.05) and a time to angina less than or equal to 250 s during the placebo test. For each treatment, greater than or equal to 25 of the patients reported headache; 4 additional patients dropped out because of severe headache and 2 others because of a coronary event in a washout period. Thus, in most patients with stable angina, side effects outweight any benefit demonstrable with this therapy.     

The effect of lidoflazine on exercise tolerance in patients with angina pectoris.

The effect of therapy with lidoflazine on maximal exercise in the upright position was evaluated in 21 patients with angina pectoris. The study consisted of the following three consecutive periods: (1) a three-month period of receving placebo; (2) six months of therapy with lidoflazine; and (3) a six-month period in which patients were randomized to either therapy with lidoflazine or placebo. Functional status was monitored by multistage tests of exercise capacity and the amount of nitroglycerin consumed. From period 1 to period 2, the mean maxial exercise time increased from 4.4 to 6.5 minutes (48 percent; P less than 0.001), and the external workload increased by 68 percent (P less than 0.001). the mean heart rate at two minutes of exercise decreased from 114 to 101 beats per minute (P less than 0.001) but was unchanged at symptom-tolerated maximal exercise. During period 3, the patients receiving therapy with liodflazine maintained their improved exercise tolerance, and the reduction in mean heart rate at two minutes of exercise persisted. Patients receiving placebo during period 3 had a decrease in exercise tolerance, and the mean heart rate at two minutes of exercise increased to control values. Lidoflazine in effective as an antianginal medication, in part due to suppression of the heart rate during exercise.     

Beneficial effects of high-dose diltiazem in patients with persistent effort angina on beta-blockers and nitrates: a randomized, double-blind, placebo-controlled cross-over study

The effects of orally administered diltiazem combined with maximally tolerated doses of beta-blockers and nitrates were assessed in 12 patients, who during stress testing exhibited persistent effort angina and continued objective evidence for inducible myocardial ischemia. Patients performed multistage semisupine exercise on a bicycle ergometer during equilibrium-gated radionuclide angiography after consecutive 2 week treatment periods of placebo or diltiazem 90 mg qid (mean dose 340 mg/day) combined with maximally tolerated propranolol (mean dose 178 mg/day) and isosorbide dinitrate (mean dose 137 mg/day). All medications (including diltiazem or placebo) were administered four times daily for the duration of the study. Diltiazem or placebo was administered according to a double-blind design, with randomized cross-over at the end of each 2 week treatment period. The average number of angina attacks decreased during the double-blind cross-over phase of the trial (7 +/- 7 episodes/week at baseline vs 4 +/- 3 on placebo vs 2 +/- 2 on diltiazem; p = .08). Angina pectoris was abolished during peak exercise in eight of 12 patients on diltiazem (p less than .05 vs placebo). Diltiazem increased total exercise duration from 276 +/- 92 to 310 +/- 78 sec (p less than .005 vs baseline). Diltiazem likewise increased the time to onset of angina from 231 +/- 84 sec at baseline to 305 +/- 77 sec (p less than .005), as well as the time to the onset of 1 mm ischemic ST segment depression (p = .01). Diltiazem decreased heart rate at rest, during submaximal workload, and at peak exercise (p less than .05), and decreased systolic blood pressure at peak exercise only (p less than .05). A significant decline in rate-pressure product at submaximal and peak exercise was noted (p less than .05). At any given workload there was significantly less ST segment depression during submaximal (p = .05) and peak exercise (p less than .025).(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparison of the anti-anginal efficacy of nicardipine and nifedipine in patients receiving atenolol: a randomized, double-blind, crossover study

The effects of oral nicardipine (40 mg) and nifedipine (20 mg) in combination with atenolol (100 mg) were compared with those of placebo, oral nitroglycerin (0.4 mg) and atenolol alone (100 mg) in 17 patients with stable effort angina. Patients performed symptom-limited, multistage, upright bicycle ergometric exercises with computer-assisted ECG analysis in bipolar lead CM5. Nicardipine and nifedipine were given double blind and in randomized order. In comparison with placebo (4818 +/- 2021 kpm), patients exercised longer and with a greater work load with nitroglycerin (5748 +/- 1711 kpm, P less than 0.001), the combinations of atenolol and nifedipine (6120 +/- 2274 kpm, P less than 0.05), and atenolol and nicardipine (6671 +/- 2339 kpm, P less than 0.01), but not with atenolol alone (5305 +/- 1524 kpm, P = NS). The magnitude of ST-segment depression at peak exercise with placebo (3.22 +/- 1.72 mm) was dramatically reduced with nitroglycerin (1.39 +/- 1.87 mm) but less with atenolol alone (2.95 +/- 1.83 mm, P less than 0.05) or the combinations of atenolol and nicardipine (3.05 +/- 1.51 mm, P = NS), and atenolol and nifedipine (2.45 +/- 1.25 mm, P less than 0.001). Compared to the combination of atenolol and nifedipine, that of atenolol and nicardipine produced a significantly (P less than 0.05) greater exercise tolerance (6671 +/- 2339 versus 6120 +/- 2274 kpm) but with a greater ST-segment depression at peak exercise (3.05 +/- 1.51 versus 2.45 +/- 1.29 mm, P less than 0.01).     

Transdermal nitroglycerin patches in angina pectoris. Dose titration, duration of effect, and rapid tolerance

The duration of effect of transdermal nitroglycerin patches was studied in 14 patients with angina pectoris. By titrating the dose to achieve specific circulatory effects, we chose a patch size that produced a consistent fall in systolic blood pressure of 10 mm Hg or greater for each patient (10 cm2 in 7 patients, 20 cm2 in 5, and 40 cm2 in 2; releasing 5, 10, and 20 mg of nitroglycerin per 24 hours, respectively). The effects of these individualized patches were compared with those of placebo patches. Compared with placebo, nitroglycerin patches increased exercise duration to the onset of angina (257 +/- 72 compared with 383 +/- 130 seconds, p less than 0.0001) and total exercise time (338 +/- 89 compared with 456 +/- 119 seconds, p less than 0.0001) and decreased ST segment depression (1.0 +/- 0.5 compared with 0.6 +/- 0.4 mm, p less than 0.05) at 4 hours but not at 24 and 48 hours. We conclude that nitroglycerin patches do not show objective evidence of antianginal or antiischemic effects for 24 hours. Tolerance to the circulatory and antianginal effects probably develops within 24 hours of patch application.