Stable Exercise-induced Angina Research Articles

Acute dose-response, double-blind, placebo-controlled pilot study of lercanidipine in patients with angina pectoris

Abstract Objective The aim of this double-blind, placebo-controlled, parallel-group, dose-response, pilot study was to assess the acute hemodynamic and therapeutic effects of a single dose of lercanidipine in patients with angina pectoris. Background The calcium channel blocker lercanidipine is a new lipophilic, vasoselective dihydropyridine derivative with a slow onset and long duration of action that has been shown to be effective in hypertensive patients at a dosage of 10 to 20 mg/d. Methods Forty-five patients (42 males, 3 females) with chronic stable angina pectoris and angiographically documented coronary artery disease received a single oral dose of lercanidipine 5 mg (n = 7), 10 mg (n = 8), 20 mg (n = 7), 30 mg (n = 7), or 40 mg (n = 8) or of placebo (n = 8). Anti-ischemic and antianginal efficacy was assessed by a bicycle exercise test 3 and 8 hours after dosing. Systolic and diastolic blood pressures and heart rate were assessed both at rest and during exercise. Results Because of the small number of patients and high variability between the groups, no significant difference was seen compared with placebo. Nevertheless, a significant ( P Conclusions Our data indicated that the acute administration of lercanidipine 10 mg to 40 mg in patients with stable exercise-induced angina pectoris caused no unfavorable change in myocardial oxygen consumption and was well tolerated.

Carvedilol in Comparison and in Combination with Isosorbide Dinitrate Sustained Release in Patients with Chronic Stable Effort-Induced Angina Pectoris

In a double-blind randomised 6-month multicentre study the antianginal and anti-ischaemic effects of carvedilol 25mg twice daily were assessed in comparison and in combination with isosorbide dinitrate (ISDN) SR (sustained release) 40mg twice daily in patients with chronic stable exercise-induced angina pectoris. After a placebo phase of 14 days during which two symptom-limited seated bicycle exercise tests were performed, 187 patients were randomly allocated to one of the two parallel treatment groups. After 3 months of therapy a further exercise test was performed, and patients were then switched to combination therapy for a further 3 months, at the end of which another exercise test was carried out. The patients were issued diary cards to document the daily numbers of anginal attacks and nitroglycerin applications. For the three major variables from exercise testing (total symptom-limited exercise time, time to angina and time to ST-segment depression), the statistical analysis confirmed the hypothesis that the efficacy of carvedilol was at least as good as that of ISDN SR. Indeed, the risk ratios from the Cox proportional hazards model indicated a trend, although not statistically significant, towards a slight advantage of carvedilol over ISDN SR for total exercise time and time to angina. This was also supported based on a comparison of the individual improvements between the groups. In patients with angiographically proven coronary artery disease, only carvedilol appeared to be effective. The number of daily anginal attacks and applications of short-acting nitrates were reduced by the two drugs to the same extent. Additional improvements in all efficacy variables were obtained after patients had been switched to combination therapy. The two drugs given in monotherapy and in combination were shown to be well tolerated. There were no unexpected adverse events. As monotherapy, carvedilol appeared to be somewhat better tolerated with fewer patients experiencing adverse events (14 vs 25.5%, respectively) and fewer dropouts because of adverse events (3 vs 6, respectively). In conclusion, carvedilol was at least as effective as ISDN SR in the treatment of patients with chronic stable exercise-induced angina pectoris and it appeared to be somewhat better tolerated. Combination therapy with both agents led to increased efficacy without any relevant changes in the tolerability profile.

Effect of metoprolol and amlodipine on myocardial total ischaemic burden in patients with stable angina pectoris

A randomized double-blind cross-over study to assess the effect on myocardial total ischaemic burden and the anti-anginal efficacy of the beta-1-blocker metoprolol given as metoprolol CR/Zok versus the calcium channel blocker amlodipine, both given in the recommended and commonly used doses of 100 mg o.d. and 5 mg o.d., respectively. Fifty-two patients with a history of stable exercise-induced angina pectoris and at least six episodes of significant ST-segment depression during 24-h ambulatory electrocardiographic monitoring after 9 days of placebo were included in the study. The patients first completed a 9-day placebo run-in phase with additional administration of a long-acting nitrate during the first 7 days. They then received in a randomized sequence metoprolol CR/Zok and amlodipine each for 4 weeks. During placebo treatment and at the end of each phase of active treatment the patients' clinical progress was assessed and a 24-h ECG monitor performed. Forty-seven patients completed the two 4-week treatment periods. Five patients withdrew from the study. The number of ischaemic episodes during 24 h was 30.4 at baseline with placebo, which was reduced significantly by both treatments (P<0.005) to 6.8 episodes after metoprolol and 15.8 episodes after amlodipine treatment (P<0.001 for the difference between the treatment groups). Metoprolol and amlodipine reduced the total duration of ischaemic episodes from 86.0 min to 15-1 and 48.3 min with a mean episode duration of 1.1 and 2.6 min, respectively. Twenty patients on metoprolol (42.6%) and four on amlodipine (8.4%) showed no ST-segment depression at the end of treatment. Baseline heart rate of 80 b.p.m. decreased by 11.1 b.p.m. after metoprolol and increased by 4b.p.m. after amlodipine. Anginal attacks were reduced from 14.8 attacks per week at baseline to 2.4 attacks on metoprolol and 4.4 attacks on amlodipine treatment. For all variables the observed changes from baseline were significant after either treatment (P<0.005) with a significantly more pronounced effect in favour of metoprolol (P<0.0001). Ten patients reported nine different adverse events during metoprolol treatment. On amlodipine, 12 patients were affected by 11 different symptoms leading to three treatment withdrawals. On metoprolol one patient withdrew due to adverse events. Both drugs reduce total ischaemic burden by reducing ischaemic episodes and antianginal attacks, with a significantly greater effect from metoprolol 100 mg o.d. as compared to amlodipine 5 mg o.d.

Usefulness of amlodipine for angina pectoris

Calcium antagonists are effective antianginal agents in the treatment of patients with stable exercise-induced angina pectoris. A series of randomized, double-blind, placebo-controlled studies with the novel, once-daily calcium antagonist amlodipine have been completed in a large number of patients with stable exercise-induced angina pectoris. Compared with placebo, once-daily amlodipine demonstrated a significant dose-related extension in exercise duration and workload accomplished, and reduction in number of anginal attacks and associated glyceryl trinitrate consumption. The clinical antianginal attributes of amlodipine were accompanied by significant reductions in electrocardiographic evidence of myocardial ischemia. In comparison with other antianginal drugs, once-daily amlodipine at a dosage range of 5–10 mg demonstrated antianginal activity comparable to thrice-daily diltiazem and once-daily nadolol. Amlodipine administered once daily achieves symptomatic and electrocardiographic amelioration of myocardial ischemic episodes induced by exercise in the majority of patients with stable angina pectoris. Amlodipine does not depress left ventricular pumping activity, and its side-effect profile does not differ substantially from that of placebo.

Randomised Double-Blind Comparison of Isosorbide-5-Mononitrate and Sustained Release Nifedipine in Patients with Stable Exercise-Induced Angina

The therapeutic effects of isosorbide-5-mononitrate (IS-5-MN) and sustained release (SR) nifedipine for 2 weeks were, investigated in this double-blind randomised comparative multicentre study in 252 patients with well documented coronary artery disease and stable reproducible exercise-induced angina. After 1 week’s treatment with IS-5-MN 20mg twice daily, 50% of the patients were responders, showing an increase in total exercise time (to onset of moderately severe angina) of ⩾ 20% in comparison with the placebo run-in phase. The corresponding rate after SR nifedipine 20mg twice daily was 45%. By increasing the dose in the nonresponders to 20mg 3 times daily for IS-5-MN and 40mg twice daily for SR nifedipine (double-dummy technique), and continuing lower dose treatment in responders for an additional week, the responder rate increased to 61 and 53%, respectively. Both IS-5-MN and SR nifedipine significantly increased total exercise time, time to angina onset and ⩾ 1 mm ST-segment depression, and significantly reduced the rate-pressure product and ST-segment depression at peak exercise compared with the placebo run-in. However, differences between treatments were not significant. The improvement in quality of life, indicated by the reduction in angina episodes and intake of short-acting nitrates, was similar for the 2 drugs. During IS-5-MN treatment, 8 patients were withdrawn prematurely because of adverse events (7 for headache, 1 for tachycardia, vertigo and dizziness). In the SR nifedipine group, 1 patient withdrew because of headache and tachycardia, and another because of a lack of increase in diastolic blood pressure during exercise. Adverse events were reported more frequently in the IS-5-MN group than in the SR nifedipine group (17 and 3.9%, respectively, for transient headache). The pattern and incidence of all adverse effects were as expected in the 2 active treatment groups. Daily treatment costs for a 20mg twice daily dosing regimen for both drugs in the Federal Republic of Germany was 64% higher for SR nifedipine than for IS-5-MN.

Efficacy of continuous and intermittent transdermal treatment with nitroglycerin in effort angina pectoris: a multicentric study

Eighty-eight patients (84 men and 4 women; mean age 59.3 years) with stable exercise-induced angina pectoris were enrolled in this within-patient, placebo-controlled study aimed at comparing the efficacy of the continuous and intermittent (12 hour on, 12 hour off) application of transdermal nitroglycerin. Eighty-one patients completed the study. After a 1-week placebo run-in period, during which the stability of angina was assessed on a bicycle ergometer, the patients received continuous treatment (two 10 mg 24 hour patches twice daily, at 8 a.m. and 8 p.m.), intermittent treatment (two 10 mg 24 hour patches at 8 a.m. and two placebo patches at 8 p.m.) and placebo (two placebo patches twice daily, at 8 a.m. and 8 p.m.), each given for one week in a double-blind randomised sequence, according to a 3 × 3 latin-square design. A cycloergometric exercise test was performed at the end of each period of treatment, 4 and 10 hours after the application of the morning patch. In comparison with placebo, both schedules of the active treatment induced a significant increase in both the ischemic (duration of exercise to 1 mm ST segment depression) and the angina threshold (duration of exercise to mild angina) at the 4th and at the 10th hours after-dosing. A significant difference was also found between continuous and intermittent treatment at the same times of observation, in favour of the intermittent schedule. The limited number of anginal attacks recorded during placebo prevented any clinical evaluation of the treatments. This study shows that the efficacy of transdermal nitroglycerin is more pronounced when it is given following an intermittent schedule. The overnight nitrate-free interval does not lead to increased cardiovascular risk in patients with stable exercise-induced angina.

Comparison of the effects of a controlled-release formulation of isosorbide-5-mononitratt and conventional isosorbide dinitrate on exercise performance in men with stable angina pectoris

Thirty-three men with stable exercise-induced angina pectoris entered a randomized, doubleblind, crossover study in which controlled-release isosorbide-5-mononitrate 60 mg once daily was compared with conventional isosorbide dinitrate 20 mg 3 times daily. Each drug was given for 2 weeks. Twenty-eight patients completed the study and data on exercise variables are available in 23 patients. Treatment with either drug resulted in significant antianginal effects, when measured 6 hours after a single dose and after 2 weeks of therapy compared with baseline placebo; however, there were significantly fewer signs of myocardial ischemia during treatment with Isosorbide-5-mononitrate. There was no evidence of tolerance to either drug treatment but a significant attenuation of resting blood pressure (but not of exercise blood pressure) was observed with both drugs. Headache was the only clinically significant adverse event during therapy and it occurred more frequently in the isosorbide dinitrate treatment group (p <0.05 vs placebo); 3 such patients had to withdraw from the study because of headache. Thus, once-daily, controlled-release Isosorbide-5-mononitrate appears as effective as conventional Isosorbide dinitrate 3 times daily in patients with stable angina pectoris. The once-daily administration is convenient and improves patient compliance.

Safety and Efficacy of β-Blockers in the Treatment of Stable Angina Pectoris

In stable exercise-induced angina pectoris. β-blockers exert their beneficial effects mainly through a reduction in heart rate. blood pressure. and contractility. Additional beneficial effects are an improvement in myocardial oxygen supply through a redistribution of coronary flow, a lengthening of diastole, a facilitation of aerobic metabolism. and a rightward shift of the oxygen-hemoglobin dissociation curve. Cardioselective β-blockers can be expected to have fewer side effects than the nonselective drugs. Apart from a reduction in anginal attack rate and an improvement in exercise capacity, a reduction in silent ischemia may be desirable when treating patients with stable effort angina. β-blockers effectively reduce asymptomatic ischemia. Bisoprolol is a new β1-selective β-blocker with a clear 24-h duration of action regarding symptoms and improvement of exercise capacity in patients with stable exercise-induced angina pectoris. Bisoprolol 10 mg and atenolol 100 mg are equipotent in achieving these effects.

Intermittent transdermal nitroglycerin monotherapy in stable exercise-induced angina: A comparison with a continuous schedule

The aim of this study was to investigate nitrate tolerance during continuous treatment with nitroglycerin patches (NTG) as monotherapy, and to assess whether tolerance might be prevented by an overnight nitrate-free interval. Ten male patients, of mean age 53.2 years (range 41-62 years), with pathological coronary angiography and stable exercise-induced angina pectoris took part in a double-blind crossover study (two 15-day periods), during which the continuous and intermittent (12-h nitrate-free interval) application of NTG 20 mg (24 h)-1 patches were compared. Single-blind placebo was given acutely before and at the end of the crossover. Exercise testing was performed on a treadmill according to the Bruce protocol 4 and 12 h after dosing, both during placebo and at the end of the two active treatment periods. In comparison with continuous treatment, the intermittent administration of 20 mg (24 h)-1 NTG patches significantly increased ischaemic threshold and total work time at the 4th and the 12th hour. Night-time withdrawal of NTG transdermal delivery systems determined during the 15-day period a total of 11 night anginal attacks in six out of 10 patients (0.07 attacks per patient per nitrate-free interval).

Antianginal efficacy of a new nitroglycerin patch

Sixteen patients with chronic, stable exercise-induced angina pectoris were studied during acute and sustained therapy with a new nitroglycerin (GTN) patch*. This patch provides a biphasic GTN release profile with therapeutic GTN plasma concentrations developing soon after application and persisting for 12h, but with low plasma concentrations during the remainder of the 24h period. This profile of GTN release was designed to avoid nitrate tolerance by providing a low nitrate period for substantial periods during each 24-h application period. In a placebo-controlled double-blind study, two GTN patches each releasing 7.5 mg GTN were applied. The active patches induced a significant decrease in systolic blood pressure and an increase in heart rate during initial application. Exercise duration to the end-point of moderate angina (P2) was increased at 4 and 8h during acute therapy and the changes during sustained therapy were similar. Thus, the Biophase GTN patch has been shown to improve exercise performance during acute therapy and, more importantly, to maintain this effect during sustained once-daily therapy.

Acute effects of felodipine in exertional angina pectoris

To investigate the antianginal efficacy, duration of action and tolerability of 2 doses of the new calcium antagonist felodipine, 15 patients (14 men and 1 woman, mean age 62 years) with stable exertional angina pectoris and angiographically demonstrated coronary artery disease were randomly given felodipine, 5 and 10 mg, and placebo on 3 different days. A bicycle ergometer exercise test was performed 3 and 10 hours after dosing. In comparison with placebo, felodipine 5 and 10 mg significantly increased resting heart rate and decreased resting systolic and diastolic blood pressure 3 hours after administration (p < 0.001). Ten hours after administration, only supine systolic blood pressure was still significantly lower (p < 0.001). Anginal (time to mild chest pain) and ischemie (time to 1 mm ST depression) thresholds, as well as duration of exercise and total work at peak exercise, were higher in comparison with placebo at 3 and 10 hours (p < 0.001). In comparison with the lower dose, 10 mg felodipine induced a decrease in supine (p < 0.05) and sitting (p < 0.01) systolic blood pressure at rest and an increase in total work to anginal threshold (p < 0.01), as well as in total work and duration of exercise at peak exercise (p < 0.05). These results suggest that a single administration of felodipine, 5 and 10 mg, may improve exercise capacity over a 10-hour period in patients with stable exercise-induced angina due to atherosclerotic heart disease.

Efficacy of a new transdermal nitroglycerin patch (deponit 10) for stable angina pectoris

In this double-blind randomized placebo-controlled crossover study, the antianginal and anti-ischemic effect of a new transdermal system, releasing 10 mg of nitroglycerin (NTG) over 24 hours, was assessed in 19 outpatients with stable exercise-induced angina pectoris. The trial consisted of a 3-day washout: a 1-week period with verum or placebo patch followed by a second 1-week period with the other patch. During the study only sublingual NTG was allowed, and its consumption and the number of attacks recorded. Treadmill exercise tests were performed at the end of washout before patch application (baseline test) and 3 and 24 hours, respectively, after each period of 7 days of application of 1 patch daily. Systolic blood pressure and heart rate did not vary significantly at rest in the 17 patients who completed the trial. Angina was reduced 31.3% and NTG consumption 34.3% (p < 0.01) during the week with Deponit ® 10 as compared with placebo. Exercise duration increased 29 and 16.1% (p < 0.001 and p < 0.1, respectively) at 3 and 24 hours with a verum patch as compared with placebo. ST-segment depression at comparable loads decreased 69 and 40.5% (p < 0.01) at 3 and 24 hours, respectively, after application of Deponit. Onset of angina was delayed and maximal heart rateblood pressure product significantly increased at 3 and 24 hours of treatment. It is concluded that Deponit 10 patch is effective in reducing anginal attacks and in increasing exercise capacity up to 24 hours after application.

Nicardipine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy, in the treatment of angina pectoris, hypertension and related cardiovascular disorders.

Nicardipine is an antagonist of calcium influx through the slow channel of the cell membrane and has been shown to be an effective and relatively well-tolerated treatment for stable effort angina and rest angina due to coronary artery spasm, and mild to moderate hypertension. Although its exact mechanism of action in these disease states has not been precisely defined, the potent coronary and peripheral arterial dilator properties of nicardipine, with concomitant improvements in oxygen supply/demand and reductions in systemic vascular resistance, are of major importance. Clinical studies have shown that nicardipine appears to be effective in the treatment of chronic stable exercise-induced angina pectoris and possibly in angina at rest due to coronary artery spasm. In the treatment of stable angina, nicardipine has proved to be equally as effective as nifedipine. However, haemodynamic and clinical studies indicate that nicardipine may have a further advantage of not depressing cardiac conduction or left ventricular function, even in patients with compromised cardiac pumping ability. Nicardipine also appears to be useful as initial monotherapy or in combination with other antihypertensive drugs when used in the treatment of mild to moderate hypertension, and may have some advantages over other vasodilators in this regard in that it may not be as frequently associated with fluid retention or weight gain as other similar drugs. In the treatment of hypertension nicardipine has been shown to be as effective as drugs such as hydrochlorothiazide, cyclopenthiazide, propranolol and verapamil in short term studies although confirmation of its long term usefulness in well-designed clinical trials is still required. Similarly, although the use of nicardipine in other disorders such as congestive heart failure and cerebrovascular disease has provided encouraging preliminary results, more studies are needed to clarify its place in their treatment. Side effects appear to be dose related and more frequent within the first few weeks of therapy. Most of these effects are minor and transient in nature and include headache, flushing and peripheral oedema. Thus, there is no doubt that nicardipine provides a suitable alternative to other drugs available for the treatment of angina and hypertension. However, further well-designed comparative clinical trials are needed to clarify its relative place in the long term management of these disorders.

Effect of a new transdermal therapeutic system containing nitroglycerin on exercise capacity in patients with angina pectoris

In a double-blind, within-patient, randomized, placebo-controlled, acute study, the effects at rest and on exercise capacity of two doses of a new transdermal therapeutic system (TTS), releasing respectively 10 and 20 mg of nitroglycerin (NTG) over 24 hours, were assessed in 15 outpatients with stable exercise-induced angina pectoris. A symptom-limited exercise test was performed 4 and 24 hours after the application of each system. In comparison with placebo, both TTS-NTG doses induced a statistically significant ( p < 0.01) increase in total duration of exercise, in exercise duration to 1 mm ST segment depression, in maximal workload and in total work performed, at both 4 and 24 hours after dosing. Furthermore, both TTS-NTG doses induced a significant rise in the pressure-rate product, both 4 and 24 hours after dosing ( p < 0.01 and p < 0.05, respectively). No statistical difference was found between the two doses of active drug in any of the above-mentioned evaluation parameters. The only unpleasant side effect was the typical nitrate headache, which occurred in 11 of 15 patients. In conclusion, a single application of TTS-NTG, 20 cm 2 or 40 cm 2, may improve exercise capacity over a 24-hour period in patients with stable exercise angina due to atherosclerotic heart disease.

Nitrate tolerance: influence of isosorbide dinitrate on the hemodynamic and antianginal effects of nitroglycerin

In a randomized, double blind, crossover study, 10 patients with stable exercise-induced angina pectoris were studied during acute and sustained therapy with oral isosorbide dinitrate. Circulatory changes and exercise performance were evaluated before and 2 and 6 hours after medication. Sublingual nitroglycerin was administered 30 minutes after the 2 and 6 hour exercise tests and the exercise test was repeated after another 5 minutes. Systolic blood pressure at rest 2 hours after isosorbide dinitrate decreased by 25% during the acute phase, but by only 11% during the sustained phase (probability [p] < 0.05). Systolic blood pressure was not decreased further by nitroglycerin during acute therapy, but was decreased during sustained therapy (p < 0.05). Six hours after isosorbide dinitrate administration, systolic blood pressure remained significantly below the control value during sustained therapy. Treadmill walking time to moderate angina was significantly prolonged 2 hours after isosorbide dinitrate administration during both the acute and sustained phases. During the sustained phase, there was no difference from control values after 6 hours. Nitroglycerin did not increase walking time 2 1/2 hours after isosorbide dinitrate during either acute (567 ± 122 versus 560 ± 119 seconds) or sustained (582 ± 115 versus 567 ± 129 seconds) therapy, but at 6 1/2 hours, nitroglycerin increased walking time from 473 ± 125 to 547 ± 107 seconds (p < 0.05) during sustained therapy. This study demonstrates that 1) tolerance to the hemodynamic and antianginal effects of isosorbide dinitrate develops rapidly, 2) nitroglycerin does not further prolong exercise duration 2 1/2 hours after isosorbide dinitrate administration, 3) nitroglycerin prolongs exercise duration when isosorbide dinitrate is no longer exerting a beneficial effect, and 4) there is possible cross-tolerance between isosorbide dinitrate and nitroglycerin.

Comparison of metoprolol and verapamil in the treatment of angina pectoris

The cardioselective beta adrenoceptor blocking agent metoprolol was compared with the calcium antagonist verapamil in relation to effects on angina pectoris. Twenty patients with stable, exercise-induced angina pectoris took part in a 14 week study that began with a 4 week single blind placebo period. In the succeeding 4 weeks, verapamil in a daily dose of 360 mg or metoprolol, 200 mg twice daily, was administered in double-blind fashion. After 2 weeks the patients were transferred to a second 4 week period of treatment with the other drug. The number of anginal attacks and the consumption of nitroglycerin tablets were reported. At the end of each treatment period a symptom-limited maximal exercise test was performed. The mean daily rate of anginal attacks and nitroglycerin consumption decreased significantly (p < 0.01) and to a similar extent with both drugs. Exercise capacity increased from 103 ± 7 to 113 ± 7 watts (p < 0.01) with metoprolol and to 119 ± 6 watts (p < 0.01) with verapamil. The increase with verapamil was significantly higher (p < 0.05) than with metoprolol. Metoprolol caused a substantial reduction in the rate-pressure product both at rest and during exercise (p < 0.001); this variable was not influenced by verapamil. Adverse effects were only mild to moderate and did not cause the cessation of treatment in any case. In conclusion, metoprolol and verapamil are two effective drugs for treatment of stable exercise-induced angina pectoris. Which drug is preferable as a first choice may depend on possible contraindications to one of these agents rather than on the belief that one is much more effective than the other.

Comparison of Clinical Effects of Propranolol (Inderal ®) with Once Daily Slow-Release Oxprenolol (Slow Trasicor®) in Angina Pectoris

In a double-blind, crossover, randomized study, the therapeutic effectiveness of a single daily dose of slow-release oxprenolol (160 mg/day) was compared with a conventional dosage schedule of propranolol (40 mg three times daily) in eighteen patients with uncomplicated, stable exercise-induced angina pectoris. Compared to control values both drugs produced equipotent reduction in the frequency and severity of anginal attacks accompanied by a significant increase in exercise tolerance, a significant suppression of exercising heart rate and an appreciable reduction in the electrocardiographic evidence of myocardial ischaemia when tested on a treadmill. The possible advantages offered by a single dose treatment with slow-release oxprenolol are discussed.