Sustained-release diltiazem versus metoprolol in stable angina pectoris

The efficacy of sustained-release diltiazem (diltiazem-SR) 120 mg b.i.d. was compared with metoprolol 100 mg b.i.d. in 12 patients with stable angina. Following a 1-week placebo period, patients received diltiazem-SR or metoprolol in two 3-week treatment periods, in a randomized double-blind crossover design. Total exercise time was increased more with diltiazem-SR than with metoprolol (1.2 min vs 0.4 min, P = 0.02), although the reduction in frequency of weekly anginal attacks was equal with both drugs (5 +/- 3 with placebo to 1 +/- 1 with both drugs). The difference between diltiazem-SR and metoprolol may, in part, be due to the fact that the tests were performed 12 h after drug administration. The diltiazem plasma levels were in the therapeutic range; metoprolol plasma levels, in contrast, were all below the therapeutic range. In addition, the patients might be tired out earlier during beta-blockade therapy, because a greater increase in exercise time with diltiazem-SR compared with metoprolol was found in those patients in whom the exercise endpoint changed from angina to fatigue. Thus, diltiazem-SR effectively reduces the frequency of anginal attacks when given twice daily, and improves exercise capacity to a greater extent than metoprolol 12 h after last dose.     

Comparison of antianginal efficacies and exercise hemodynamic effects of nifedipine and diltiazem in stable angina pectoris

The antianginal efficacies of nifedipine (40 to 120 mg/day) and diltiazem (120 to 360 mg/day) were studied in 21 normotensive patients with chronic stable angina pectoris, using a randomized, double-blind, crossover design. Patients received each agent titrated to maximum tolerated doses for 6 weeks, after a 2-week placebo baseline period. The maximum tolerated dose for nifedipine was 72 +/- 8 (standard error) mg/day and for diltiazem 297 +/- 20 mg/day. Two patients discontinued nifedipine early because of side effects. Duration of symptom-limited treadmill exercise was longer during the nifedipine (556 +/- 43 seconds) and diltiazem periods (546 +/- 39 seconds) compared with placebo baseline (474 +/- 41 seconds, p less than 0.02). Compared with placebo, nifedipine caused a significant increase in heart rate both at rest standing and at peak exercise. Nifedipine decreased resting systolic blood pressure but had no effect at peak exercise. In contrast, diltiazem caused a significant decrease in heart rate at rest but had no effect on blood pressure at rest or at peak exercise. Thus, nifedipine and diltiazem have differential effects on heart rate and systolic blood pressure suggesting different modes of action. However, despite the increase in exercise duration, neither nifedipine nor diltiazem increased the heart rate-systolic pressure product during maximum exercise. This suggests that the antianginal effects of the 2 agents probably are mediated via reduction of myocardial oxygen demand at submaximal exercise. In addition, diltiazem appears to be better tolerated than nifedipine.     

Comparison of diltiazem and nifedipine for both angina pectoris and systemic hypertension

In a randomized, double-blind, placebo-controlled crossover trial, diltiazem and nifedipine were compared in 10 patients with stable angina pectoris and mild to moderate hypertension (supine diastolic blood pressure greater than or equal to 90 mm Hg). Patients received placebo for 2 weeks, then increasing doses of diltiazem (90 to 360 mg/day) or nifedipine (30 to 120 mg/day) in 3 daily divided doses over 2 weeks, followed by 1 week of therapy at the maximal dose, a 1-week placebo "washout," then crossover to the other drug. Heart rate and blood pressure at rest and during exercise, anginal frequency, nitroglycerin consumption and treadmill exercise tolerance were assessed. Compared with placebo, anginal frequency and nitroglycerin consumption were reduced with both diltiazem and nifedipine (p less than 0.01) and exercise tolerance was increased with both drugs (p less than 0.01). Standing blood pressure at rest was reduced by diltiazem and nifedipine (146.6 +/- 11.4/97.7 +/- 5.3 mm Hg at placebo, baseline reduced to 129.6 +/- 15.2/79.5 +/- 13.7 mm Hg with diltiazem, and to 122.2 +/- 9.9/82.0 +/- 7.1 with nifedipine, p less than 0.01 for both). Compared with placebo, diltiazem and nifedipine also reduced exercise diastolic blood pressure (p less than 0.01), but not systolic blood pressure. Diltiazem lowered the heart rate at rest from 88.5 +/- 14.4 beats/min at placebo baseline to 79.7 +/- 17.9 beats/min (p less than 0.01); the heart rate with diltiazem was 11 beats/min lower than that with nifedipine (p less than 0.05). Both diltiazem and nifedipine had similar effects on the heart rate-blood pressure product at rest and during exercise.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of diltiazem-induced calcium blockade upon exercise capacity in effort angina due to chronic coronary artery disease

Few data are available regarding the effects of calcium blockade upon exercise tolerance in patients with stable effort angina due to coronary artery disease (CAD). Therefore we compared the effects of the calcium blocking agent, diltiazem (D), to placebo (P) in 12 patients with chronic effort angina and catheterization documented fixed CAD. The 8-week total protocol consisted of a 1-week baseline period followed by the double-blind randomized crossover alternate 1-week administration of P and D in doses of 120, 180, and 240 mg. Maximal exercise tests (MET) were performed at the end of each 1-week period, while rest radionuclide ventriculography (RVG) was obtained during 240 mg D and corresponding crossover P. Resting heart rate decreased from baseline and initial P at D doses of 60 and 240 mg, but not from P during crossover period. No changes were observed at any dose of D either at rest or during MET in systolic blood pressure or rate · pressure double product. D at 240 mg, but not lower doses, increased MET duration (437 vs 490 seconds, p < 0.01) and time to angina (383 vs 441 seconds, p < 0.01). Ejection fraction by RVG was greater with D than P (0.54 vs 0.50, p < 0.05). Thus these data indicate that calcium blockade with diltiazem provides antianginal efficacy by reducing myocardial oxygen demand, and increases exercise tolerance without depression of myocardial performance in effort angina patients with fixed chronic CAD.     

Comparative evaluation using an ergometric test of the efficacy of the 3 major calcium antagonists on exertion stable angina

Nifedipine, diltiazem and verapamil are three effective calcium-antagonists in the treatment of angina pectoris. We compared their effects on effort angina to evaluate whether one of them is more efficacious. The data were collected from 42 patients (37 males, 5 females; mean age 51 +/- 4) entering one of 3 different trials; the beginning of all trials comprised a two-week, single blind, placebo run-in phase. An exercise stress test was performed at the end of this period and it was considered as basal test for the statistical analysis. Then the 42 patients were divided in 3 groups of 14 and entered a double-blind, randomized phase of drug treatment. The 3 groups started 3 parallel trials: 1) placebo/nifedipine 60 mg/day; 2) placebo/verapamil 360 mg/day; 3) placebo/diltiazem 240 mg/day. The duration of each trial was of 6 weeks (3 weeks of treatment with placebo and 3 weeks with active substance). Exercise stress tests were performed at the end of each phase of the trials, and the resulting data were compared with the data of the test performed at the end of run-in period. Parameters evaluated were: heart rate, blood pressure and rate pressure product at basal conditions, at submaximal and peak exercise; moreover we considered workload, maximal ST segment depression, total exercise duration and frequency of exercise-induced angina. Verapamil reduced rate pressure product at basal condition; all three drugs reduced rate pressure product at submaximal exercise, but a significant statistical difference was found only for verapamil and diltiazem.(ABSTRACT TRUNCATED AT 250 WORDS)     

Long-term efficacy of high-dose diltiazem for chronic stable angina pectoris: 16-month serial studies with placebo controls

In order to assess the long-term efficacy of diltiazem for the treatment of angina pectoris, eight patients with chronic stable exertional angina who were previously entered into a 4-month randomized, double-blind placebo controlled study, were studied for an additional 12-months. The patients continued to take diltiazem, 360 mg/day, and underwent treadmill exercise testing after 10 and 16 months of therapy. A single-blind placebo week was introduced after 16 months and a treadmill test was performed at the end of this week. Diltiazem therapy continued to augment exercise duration until 0.1 mV of ECG ST depression at 10 and 16 months as compared to the final placebo period: 573 +/- 133 (SD) seconds at 10 months; 565 +/- 148 seconds at 16 months; vs 431 +/- 151 seconds at final placebo (both p less than 0.001). Also, the time to angina pectoris was prolonged on diltiazem by 181 seconds at 16 months (p less than 0.01) and the total duration of exercise was increased by 101 seconds (p less than 0.001) as compared to placebo. In addition, angina frequency decreased from 17 +/- 11 attacks/week on placebo to 0.6 +/- 0.6 attacks/week during diltiazem therapy at 16 months. Two of the eight patients noted mild pedal edema, but no other adverse effects were experienced. Thus diltiazem, 360 mg/day, can be an effective single agent for the long-term treatment of chronic stable angina pectoris.     

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.     

Randomized double-blind placebo-controlled comparison of nicardipine and nifedipine in patients with chronic stable angina pectoris

Forty-one patients were studied in a randomized double-blind placebo-controlled crossover trial to compare the antianginal actions of nicardipine 30 mg thrice daily and nifedipine 10 mg thrice daily. Efficacy was assessed using objective criteria from computer-assisted multistage graded exercise testing, performed after a two-week placebo run-in period and at the end of each four-week active treatment period. Thirty-seven patients completed both legs of the crossover trial. The mean (+/- standard error of the mean) baseline exercise time to development of angina was 6.7 +/- 0.4 min and this increased to 9.5 +/- 0.6 min on nicardipine (p less than 0.001) and 9.5 +/- 0.5 min on nifedipine (p less than 0.001 vs baseline; NS vs nicardipine). Both drugs significantly prolonged the time to the development of 1mm ST segment depression. The baseline resting heart rate of 83 +/- 2 beats/min increased to 87 +/- 3 beats/min during nicardipine (p less than 0.05) and remained unaltered at 83 +/- 2 beats/min during nifedipine therapy (p = NS vs baseline and p less than 0.02 vs nicardipine). Similarly, both drugs increased significantly the maximal heart rate at peak exercise. One patient was lost to follow-up during the placebo run-in period and four patients (two each on nicardipine and nifedipine) were withdrawn due to adverse effects. Our results indicate that nicardipine is comparable in efficacy to nifedipine and has a similar adverse effect profile and can also be considered a useful therapeutic agent for the treatment of chronic stable angina pectoris.     

Are anti-platelet drugs of value in the management of patients with chronic stable angina? A study with ticlopidine

Thirty patients (28 males and 2 females) aged 46-68 years with established chronic stable angina were studied in a placebo-controlled double-blind crossover trial to examine the efficacy of oral ticlopidine (an antiplatelet agent) 250 mg twice daily. The baseline mean +/- SEM exercise time of 7.5 +/- 0.5 min rose to 8.1 +/- 0.6 min after 2 weeks of placebo run-in, 8.8 +/- 0.7 min after 4 weeks of double-blind placebo, and to 9.2 +/- 0.6 min with ticlopidine therapy; none of these changes achieved statistical significance. Similarly, time to the development of 1 mm ST-segment depression, maximal ST-segment depression, heart rate, and rate-pressure product failed to show any statistically significant changes during ticlopidine therapy. Ambulatory electrocardiographic monitoring showed that the mean number of episodes of ST-segment depression greater than 1 mm remained unaltered during ticlopidine therapy. Four patients (3 during placebo, 1 during ticlopidine) stopped treatment prematurely because of unstable angina and two because of adverse effects. Our data suggest that ticlopidine has no significant effect on objective indices of myocardial ischemia in patients with chronic stable angina, that placebo has no effect on the objective indices of myocardial ischemia derived from exercise testing and ambulatory electrocardiographic monitoring, and that exercise testing and ambulatory electrocardiographic monitoring in patients with chronic stable angina pectoris are reproducible.     

Efficacy of the calcium antagonist isradipine in angina pectoris

Summary Thirty-six patients with chronic, stable angina pectoris were studied during 2-week treatment periods in which they received, in a randomized double-blind, crossover study, a new calcium entry blocking agent, isradipine, 7.5 mg three times daily or placebo. Antianginal efficacy was determined by treadmill exercise testing carried out 3 and 9 hours after drug administration on the final day of each treatment period. During placebo therapy, treadmill exercise time to the onset of angina (P₁) and to the development of moderate angina (P₂) was similar at 3 and 9 hours and similar to the placebo run-in period. During isradipine therapy, treadmill exercise time 3 hours after dosing was greater than with placebo therapy (P₁ 312±23.0 vs. 267±19.5 seconds,p<0.001; P₂ 410±20.2 vs. 355±18.8 seconds,p<0.002). Nine hours after drug administration, the results of exercise testing were similar to placebo.     

Usefulness of PY 108-068, a new calcium channel blocker, for angina pectoris

The efficacy of PY 108-068 (75 and 150 mg/day), a new dihydropyridine calcium antagonist, was compared with placebo for treatment of chronic stable angina. Twelve patients were studied in a placebo-controlled, double-blind, randomized, crossover trial of 2 weeks each. Antianginal efficacy was assessed by the number of episodes of angina and nitroglycerin tablets consumed during each 2-week period, as well as the number of episodes of ischemia during 48-hour ambulatory monitoring and the area and severity of ST-segment depression during 16-point precordial exercise mapping. Nitroglycerin consumption (mean +/- standard error of the mean) decreased from 6.1 +/- 2.9 with placebo to 1.8 +/- 1.5 with 75 mg/day of PY 108-068 (p less than or equal to 0.03) and to 3.6 +/- 2.3 with 150 mg/day of PY 108-068 (p less than or equal to 0.01 vs placebo, difference not significant vs 75 mg/day of PY 108-068), whereas episodes of angina were reduced significantly only by the high dose (p less than or equal to 0.03) (11.1 +/- 3.9 with placebo, 6.3 +/- 2.4 with 75 mg/day of PY 108-068 and 8.1 +/- 3.4 with 150 mg/day of PY 108-068). The low dose alone significantly reduced ST-segment depression during exercise testing (p less than or equal to 0.03) (29.6 +/- 3.6 with placebo, 23.1 +/- 5.6 with 75 mg/day of PY 108-068 and 24.4 +/- 5.0 with 150 mg/day of PY 108-068), whereas neither dose significantly altered the number of episodes of ischemia during ambulatory monitoring.(ABSTRACT TRUNCATED AT 250 WORDS)     

Diltiazem, nifedipine, and their combination in patients with stable angina pectoris: effects on angina, exercise tolerance, and the ambulatory electrocardiographic ST segment

The efficacy and safety of oral nifedipine and diltiazem were compared in 20 patients with stable angina pectoris with use of a placebo run-in, randomized, double-blind titration to maximal effect crossover protocol. The effects of treatment withdrawal were also analyzed. All patients received placebo for 2 weeks and were then randomly assigned to receive either diltiazem or nifedipine. A 2 week drug titration phase in which patients received either diltiazem (180 to 360 mg/day) or nifedipine (30 to 120 mg/day) in three divided doses was followed by a 1 week maintenance phase. Patients then received placebo for 1 to 2 weeks, followed by crossover to the other treatment regimen and a second placebo washout period of 1 week. Patients (n = 13) who remained symptomatic on both diltiazem and nifedipine during the monotherapy periods entered a 3 week combination treatment phase, followed by a final 1 week placebo washout period. Frequency of angina, nitroglycerin consumption, exercise tolerance (Naughton protocol), and frequency of daily episodes of ST segment deviations on the electrocardiogram (1 mm of ST segment depression persisting for at least 1 min with and without chest pain) on an ambulatory electrocardiographic monitor were assessed during the baseline placebo, active monotherapy, placebo withdrawal, and combination treatment phases. Plasma drug levels were also measured. Compared with initial placebo values, the frequency of angina and the amount of nitroglycerin treatment were reduced by both diltiazem (p less than .001) and nifedipine (p less than .02). Diltiazem was more effective than nifedipine in reducing angina (p less than .02). Exercise duration increased with both drugs (p less than .0001). Diltiazem was significantly better than nifedipine in reducing the episodes of ST segment depression on the ambulatory monitor (p less than .01). Diltiazem reduced the resting heart rate (p less than .01); both drugs reduced the resting blood pressure and rate-pressure product. Overall, combination therapy was more effective in patients who did not maximally respond to diltiazem or nifedipine alone with respect to anginal and exercise variables and in reducing blood pressure at rest and during exercise. Plasma drug levels could not predict an individual patient's treatment response. Diltiazem may increase nifedipine drug levels when the drugs are combined. Fewer side effects were observed with diltiazem than nifedipine; the most side effects were seen with combination treatment. There were no apparent withdrawal effects observed with either treatment regimen.(ABSTRACT TRUNCATED AT 400 WORDS)     

Combination therapy with diltiazem and nifedipine in patients with effort angina pectoris

The antianginal effects of diltiazem and nifedipine alone and in combination were evaluated in a double-blind, randomized, placebo-controlled trial in 11 patients (nine men and two women, 57 +/- 8 years old) with stable effort angina. Each patient received placebo, 30 mg of diltiazem, 10 mg of nifedipine, and 30 mg of diltiazem plus 10 mg of nifedipine four times daily for 1 week each. Antianginal efficacy was assessed by means of a treadmill exercise test. The exercise tolerance time was significantly prolonged from 235.1 +/- 52 (placebo period) to 342.2 +/- 101 sec by diltiazem (p less than .01) and to 325.6 +/- 73 sec by nifedipine (p less than .01). The drug combination further prolonged exercise time to 451.1 +/- 103 sec, which was significantly longer than the interval attained with either diltiazem (p less than .01) or nifedipine (p less than .01) alone. The plasma concentration of diltiazem was unaffected by the addition of nifedipine, whereas the plasma nifedipine concentration was significantly increased from 34.8 +/- 11 to 106.4 +/- 37 ng/ml (p less than .001) by the concomitant administration of diltiazem. These data suggest that exercise tolerance in patients with effort angina is increased by the concomitant administration of diltiazem and nifedipine associated with an increase in the nifedipine plasma concentration.     

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)     

Efficacy of diltiazem in variant angina. Results of a double-blind crossover study in CCU by Holter monitoring. The possible occurrence of a withdrawal syndrome

The short and long term efficacy of diltiazem, a calcium-entry blocker, has been evaluated in a group of ten patients with Prinzmetal's variant angina admitted to a CCU. In the short term part of the study, after a run-in period, diltiazem 60 mg tid and placebo were administered alternatively during 4 randomized 72 hour periods. Response was assessed using continuous Holter monitoring, measuring the frequency of transient ischemic attacks. During the run-in period the number of episodes/day/patient was 16.1. No episodes of transient ST segment elevation were recorded during both periods of diltiazem treatment in 3 patients and during one of the two periods in 4. For the group as a whole the number of episodes during the first placebo period was not statistically different from that during the run-in period (208 versus 161). No statistically significant difference was also found in 8 patients comparing the number of episodes during the second placebo period and the run-in period (166 versus 101). During each period of diltiazem treatment an highly significant reduction in the number of episodes was observed (43 and 5, p = .006 and p = .02). Two patients did not complete the study protocol. Both patients had a worsening of angina during the first placebo period following diltiazem treatment. One of them developed an acute myocardial infarction. The possible occurrence of a rebound phenomenon after withdrawal of diltiazem seems to be indicated, in 6 patients, by a significant increase in the number of ischemic episodes recorded during the placebo period following active treatment in respect to the number during the first placebo period (159 versus 73, p = .04).(ABSTRACT TRUNCATED AT 250 WORDS)     

Short- and long-term efficacy of high-dose oral diltiazem for angina due to coronary artery disease: a placebo-controlled, randomized, double-blind crossover study

The effects of oral diltiazem (360 mg/day) on exercise tolerance, left ventricular performance, and plasma lactate and catecholamine levels were studied in 13 patients with atherosclerotic coronary artery disease in a placebo-controlled, randomized, double-blind protocol. Exercise duration to the onset of ischemic ST segment depression, time to angina pectoris, and time to peak exercise improved by 120, 174, and 144 sec, respectively (p less than .0001). Left ventricular ejection fraction, as determined by radionuclide angiography, increased in patients at rest from 52 +/- 11% (mean +/- SD) during placebo therapy to 58 +/- 11% during diltiazem therapy (p less than .001); at peak exercise ejection fraction increased from 44 +/- 11% during placebo treatment to 52 +/- 15% during diltiazem therapy (p less than .01). The mean plasma norepinephrine level in patients at rest increased from 498 +/- 221 pg/ml during placebo treatment to 667 +/- 272 pg/ml during diltiazem therapy (p less than .05). Resting standing blood pressure and supine and standing diastolic blood pressures decreased significantly with diltiazem. In all 10 patients followed over a long term, oral diltiazem caused persistent improvement in exercise performance at 12 to 20 weeks, without evidence of placebo effects. Thus, diltiazem is highly effective in divided doses of 360 mg/day for the therapy of chronic angina pectoris due to coronary artery disease.     

Diltiazem in chronic stable angina

The safety and efficiency of the administration of diltiazem was evaluated in 10 patients with class II-III chronic stable angina. All the patients had ischemic heart disease documented by coronary angiography and/or an abnormal exercise test. A dose related improvement in both frequency of angina and exercise capacity were obtained by diltiazem administered in increased doses using a single blind protocol. The weekly frequency of angina was reduced from 7.5 +/- 9.8 with placebo to 3.8 +/- 5.5, 1.1 +/- (p less than 0.05) and 0.7 +/- 0.9 (p less than 0.01) with doses of 120, 240 and 360 mg/day respectively. The exercise duration on treadmill was significantly increased from 8.5 +/- 3.6 to 10.6 +/- 3.7 min (p less than 0.05) with the 360 mg/day dose. The mean exercise time required to develop 1 mm ST depression was 6.1 +/- 3 min on placebo and was significantly delayed to 9.0 +/- 3.8 min (p less than 0.05) with the 240 mg/day dose and to 10.7 +/- 4.0 min with 360 mg (p less than 0.01). In a double blind randomized crossover phase, the time to the onset of ischemia during exercise was increased from 8.5 +/- 3.8 min with placebo to 11.05 +/- 2.8 min with 360 mg/day of diltiazem (p less than 0.01). Diltiazem in doses ranging from 120 to 360 mg/day is an effective antianginal agent with no significant adverse effects.     

Anti-ischaemic efficacy of L-propionylcarnitine -- a promising novel metabolic approach to ischaemia?

L-propionylcarnitine, a naturally occurring derivative of L-Carnitine,essential for mitochondrial fatty acid transport and high-energyphosphate exchange, acutely reduces myocardial ischaemia andimproves ischaemia-induced cardiac dysfunction following intravenousadministration. This randomized, crossover study was designedto compare the long-term anti-ischaemic effects of oral L-propionylcarnitinewith diltiazem in patients with stable, exercise-induced angina.After a 2-week washout phase of anti-anginal medication anda 2-week single-blind placebo period, 46 patients were includedin the study, 23 of whom received 1500 mg L-propionylcarnitinedaily for 6 weeks, and 23 diltiazem (180 mg daily for 3 weeks,followed by 360 mg daily for 3 weeks), crossing over to theother treatment after a 1-week washout period. Three patientson L-propionylcarnitine and two on diltiazem discontinued. Bothtreatments resulted in comparable exercise duration (582 ±35 s and 588 ± 33s, x ± SEM), time to 0·1mV ST depression (436 ± 38 s and 465 ± 36 s),and increase in time to 0·1 mV ST depression from baseline(20% and 28%), L-propionylcarnitine and diltiazem, respectively. Diltiazem decreased the rate-pressure product at rest and exercise,L-prOpionylcarnitine did not. Both compounds significantly reducedST depression at maximal exercise [23% (L-propionylcarnitine)vs 35% (diltiazem), P<0·05 diltiazem vs L-propionylcarnitine].Diltiazem increased the time to onset of angina by 22%. In contrast,no significant changes occurred with L-propionylcarnitine. Duringthe study, anginal attacks were reduced by 70% and 57%, andnitroglycerin consumption decreased by 57% and 70%, L-proplonylcarnitineand diltiazem, respectively. Thus, both L-propionylcarnitineand (high-dose) diltiazem result in anti-ischaemic effects anddecrease angina attacks in daily life. Although the effect ofdiltiazem on exerciseinduced ischaemia appears more pronouncedthan that of L-propionylcarnitine, this novel metabolic approachto ischaemia warrants further development. (Eur Heart J 1996; 17: 414–420)     

Opposing effects of propranolol and diltiazem on the angina threshold during an exercise test in patients with syndrome X

Patients with angina pectoris, exercise induced myocardial ischemia, normal coronary arteries and no evidence of epicardial spasm, i.e. patients with syndrome x, have been suggested to haven inadequate increase in coronary blood flow during tachycardia, possibly due to a functional disorder of small coronary vessels. To evaluate the best medical management of this syndrome we studied 13 patients who showed the above set of findings. Patients were given propranolol (160 mg daily), diltiazem (360 mg daily) and placebo for 2 weeks, using a randomized single blind protocol. Upright bicycle ergometer testing was performed at the end of each period of treatment. Compared to placebo, diltiazem significantly (p less than 0.001) prolonged exercise duration (x +/- SD: 365 +/- 86 vs 303 +/- 89 sec) and time to onset of angina (358 +/- 88 vs 276 +/- 90 sec). Angina appeared in 7 patients with diltiazem vs 13 patients with placebo and occurred at a higher rate pressure product (26.3 +/- 3.5 vs 24.1 +/- 2.8 X 10(-3); p less than 0.02). Conversely, following propranolol exercise duration and time to onset of angina were unchanged and angina appeared in all patients at a lower rate pressure product (18.3 +/- 2.9 vs 24.4 +/- 3.6 X 10(-3); p less than 0.001). The most likely explanations for these findings are: propranolol counteracts beta 2-adrenergic receptors, thus further reducing coronary reserve. This may lower the anginal threshold; Diltiazem reduces smooth muscle tone in small coronary vessels. This may result in increased coronary reserve and exercise duration.     

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)