Efficacy of a single dose of slow-release isosorbide dinitrate in the treatment of silent or painful myocardial ischemia in stable angina pectoris.

A double-blind study was performed in 32 patients with stable angina pectoris to assess the effects of slow-release isosorbide dinitrate (ISDN) (a single dose of 120 mg/day) on the frequency and duration of painless and painful ischemic episodes, and on electrocardiographic changes and exercise tolerance. Forty-eight-hour electrocardiographic monitoring and treadmill exercise tests were performed before, and at 20 and 21 days of therapy. Holter monitoring showed a significant decrease in the frequency of painful and silent episodes (p less than 0.001), and in the duration of painful (1,623 +/- 664 seconds vs 323 +/- 161 seconds; p less than 0.001) and silent episodes (2,818 +/- 1,496 seconds vs 223 +/- 102 seconds; p less than 0.001). The magnitude of painful and silent ST-segment depression was significantly reduced (2.7 +/- 0.9 mm to 0.7 +/- 0.7 mm and 2.0 +/- 1.1 mm to 0.7 +/- 0.5 mm, respectively; p less than 0.001). Time of exercise testing to the onset of ST-segment depression (442 +/- 137 seconds vs 858 +/- 110 seconds; p less than 0.001) or anginal pain was doubled (461 +/- 128 seconds vs 830 +/- 130 seconds; p less than 0.001). The work load increased from 6 to 10 METs (p less than 0.001). ISDN in a single dose of 120 mg/day is a valuable drug for stable angina pectoris, decreasing the frequency of silent and painful ischemic episodes and the magnitude of ST-segment depressions, and increasing exercise tolerance. It particularly shortened the duration of silent episodes. For patients' compliance, a once-daily dose of ISDN could be advantageous.     

曲美他嗪对冠心病稳定性劳力型心绞痛患者心肌缺血的影响

目的探讨曲美他嗪对冠心病(CHD)稳定性劳力型心绞痛患者心肌缺血的影响.方法选择在1周内经2次运动试验结果为阳性,且运动持续时间变异低于10%的CHD稳定性劳力型心绞痛患者40例,在原有治疗不变的情况下,加用曲美他唪20mg每日3次,治疗12周.治疗前后均行平板运动试验,观察用药前后下述指标的变化(1)用药前后每周心绞痛发作的次数;(2)每周硝酸甘油片的用量;(3)心率及心率与收缩压的乘积;(4)运动诱发心绞痛发作所需的时间;(5)运动后ST段下降limn所需的时间;(6)运动持续时间;(7)总工作量.结果曲美他嗪应用12周后,患者每周心绞痛发作次数及硝酸甘油片的用量明显下降(P＜0.05),而对心率及心率与收缩压的乘积的影响无统计学显著意义(P＞0.05).与试验前相比,运动耐量和总工作量显著提高(P＜0.01),至心绞痛发作的时间及ST段下降1mm所需的时间均明显延长(P＜0.01).不良反应较少.结论曲美他嗪能增加CHD稳定性劳力型心绞痛患者的运动耐量,改善运动诱发心绞痛的心肌缺血,且安全有效,易于耐受.     

曲美他嗪对稳定型劳力性心绞痛患者 心肌缺血的影响

目的探讨曲美他嗪对冠心病(CHD)稳定型劳力性心绞痛患者心肌缺血的影响。方法选择经冠状动脉造影确诊的CHD稳定型劳力性心绞痛患者14例,在原有治疗不变的情况下,加用曲美他嗪治疗12周,治疗前后均行平板运动试验,观察用药前后下述指标的变化①用药前后每周心绞痛发作的次数;②每周硝酸甘油片的用量;③心率及心率和收缩压的乘积;④运动诱发心绞痛发作所需的时间;⑤运动后ST段下降0.1mV所需的时间;⑥运动持续时间。结果患者每周心绞痛发作的次数及硝酸甘油片的用量均明显下降(P＜0.05);心率及心率和收缩压乘积轻度变化(P＞0.05);明显延长运动诱发心绞痛所需的时间及运动后ST段下降≥0.1mV所需的时间(P＜0.05)。结论曲美他嗪能改善运动诱发的心肌缺血,对CHD劳力性心绞痛患者有一定的疗效。     

Asymptomatic myocardial ischemia in patients with stable and typical angina pectoris

The existence of transient myocardial ischemia (TMI) and the value of the serial dynamic electrocardiogram (DCG) in patients with variant or unstable angina pectoris are known. However, less information is available on the frequency and characteristics of TMI in patients with stable angina pectoris. For this study, we selected 40 patients with stable and typical angina pectoris. The presence of coronary artery disease and the ejection fraction were evaluated by means of angiocardiography. The DCG monitoring was performed with bichannel portable recorders for three 24-h periods at 7-day intervals. The patients were on optimal doses of beta blockers and isosorbidilate throughout the study. We detected 788 episodes of TMI in 22 of the 40 patients. The ejection fraction was poorer in the 22 patients with ST-T changes than in the 18 without such changes. The repolarization changes were: (1) ST elevation (55 symptomatic and 87 asymptomatic episodes, (2) ST depression (138 symptomatic and 236 asymptomatic episodes, and (3) T-wave changes (83 symptomatic and 164 asymptomatic episodes). All 22 patients with TMI presented a combination of the above changes. It appears, therefore, that ST-T changes are more frequent in patients with stable angina pectoris than was hitherto suspected. The DCG is valuable in assessing these changes, especially when one considers that the asymptomatic episodes are almost twice as frequent as the symptomatic ones. The asymptomatic episodes lasted a mean of 1.8±1.3 min (mean±SD), while the symptomatic episodes lasted 3.8±2.7 min (p <0.02, by sign test). Heart rate was unchanged during the episodes of TMI, and did not show any significant difference between asymptomatic and symptomatic episodes. Additional investigation is necessary, however, to determine the clinical implications of these findings.     

The ability of captopril to enhance the anti-anginal effect of isosorbide dinitrate in patients with stable exercise-induced angina pectoris]

The interaction between isosorbide dinitrate (ISDN) and the angiotensin-converting enzyme inhibitor captopril was investigated in 14 patients with coronary heart disease concurrent with stable exercise-induced angina pectoris. The efficacy of placebo, ISDN, 10 mg, captopril, 50-100 mg, and ISDN + captopril was evaluated in each patient by pharmacodynamic treadmill studies. The single-blind, randomized technique was applied. Captopril alone produced a weak antianginal effect. The concomitant use of ISDN and captopril showed significantly more marked and prolonged effects than ISDN alone. The highest effect was exhibited by ISDN supplemented with captopril in 6 patients who had been refractory to ISDN alone. Thus, captopril may potentiate the antianginal effect of ISDN.     

Sustained effect of orally administered isosorbide dinitrate on exercise performance of patients with angina pectoris.

The efficacy of oral isosorbide dinitrate was evaluated in nine hospitalized patients with chronic angina pectoris and positive maximal bicycle exercise tests. Patients were randomized double-blind to receive either 20 mg of isosorbide dinitrate or placebo on successive days after a control maximal upright bicycle exercise test. On each day hourly exercise tests were performed for 4 hours after drug administration to an end point of fatigue or angina pectoris. Mean systolic blood pressure 4 hours after the administration of isosorbide dinitrate was 25 mm Hg less than the control value (P less than 0.001). The values for resting heart rate and exercise-attained heart rate-blood pressure product were not significantly different from the values after placebo. The duration of exercise was prolonged (P less than 0.025) for at least 3 hours, and less ST depression (P less than 0.01) was observed up to 3 hours after the administration of isosorbide dinitrate compared with control values. The demonstration of sustained imporved exercise performance and previously described hemodynamic effects with the use of higher doses suggests that adequate blood levels of isosorbide dinitrate or mononitrate metabolites may be important for the efficacy of oral organic nitrates.     

Effect of atorvastatin on exercise-induced myocardial ischemia in patients with stable angina pectoris

To investigate whether marked and sustained lipid-lowering in subjects with stable angina pectoris and dyslipidemia reduces exercise-induced myocardial ischemia, 17 subjects were treated with dose-adjusted atorvastatin over 1 year and underwent serial evaluation of exercise electrocardiographic ischemic parameters, serum biomarkers, and brachial artery endothelial function. Endothelial function improved progressively and C-reactive protein, P-selectin, and tissue plasminogen activator inhibitor levels decreased, but there was no decrease in exercise electrocardiographic ischemia.     

Enhancement of the efficacy of isosorbide dinitrate by captopril in stable angina pectoris.

This study was designed to assess whether the angiotensin-converting enzyme inhibitor captopril could potentiate the efficacy of a single dose of oral isosorbide dinitrate (ISDN) in patients with coronary artery disease. Fourteen men (mean age 53 years) with stable angina pectoris were studied. In each patient the efficacy of placebo, captopril (50 to 100 mg), ISDN (10 mg), and a combination of captopril (50 to 100 mg) and ISDN (10 mg) was assessed by repeated exercise treadmill tests performed before and 1, 2, 3 and 6 hours after administration of a single dose. A single-blind, randomized technique was applied. According to the mean data in the whole group of 14 patients, captopril alone produced no improvement in exercise duration to the onset of angina and to angina of moderate severity compared with placebo. The magnitude of ST-segment depression did not significantly change after captopril administration. ISDN alone significantly increased exercise duration to onset of angina and to angina of moderate severity (antianginal effect) and decreased the magnitude of ST-segment depression (antiischemic effect) 1 to 3 hours after administration. Combined administration of ISDN and captopril resulted in more expressed antianginal and antiischemic effects; at 2, 3 and 6 hours these effects with ISDN plus captopril were significantly more pronounced than those with ISDN alone. According to individual data, the most marked potentiation of ISDN efficacy was observed in patients who had poor response to ISDN alone. In all 6 patients in whom ISDN alone was ineffective, after the addition of captopril the desired antianginal effect was obtained.(ABSTRACT TRUNCATED AT 250 WORDS)     

Preventive administration of intravenous N-acetylcysteine and development of tolerance to isosorbide dinitrate in patients with angina pectoris.

BACKGROUND. Development of tolerance to organic nitrates may be related to depletion of sulfhydryl groups in vascular smooth muscle. N-Acetylcysteine (NAC), a sulfhydryl donor, has been reported to potentiate the effect of nitroglycerin and reverse tolerance in humans. However, its ability to prevent or delay the development of nitrate tolerance in patients with angina pectoris has not been established. METHODS AND RESULTS. Ten patients with stable angina pectoris were treated with intravenous isosorbide dinitrate (ISDN; 5 mg/hr) combined with NAC (2 g i.v. over 15 minutes followed by 5 mg/kg/hr) or matching placebo for 30 hours in a double-blind, randomized, crossover study with a washout interval of 8 days. Bicycle exercise tests were performed before and at 1 1/2, 8, 20, 24, and 30 hours after start of treatment. After 24 hours of infusion, exercise parameters were not significantly different from pretreatment values (p greater than 0.05) during ISDN plus placebo, indicating development of tolerance to ISDN. In contrast, time to onset of angina, time to 1-mm ST segment depression, and total amount of ST segment depression were still significantly improved after 24-hour infusion of ISDN plus NAC (p less than 0.05). In addition, compared with placebo, a significant difference (p less than 0.05) in favor of NAC was observed regarding time to angina (507 +/- 63 versus 445 +/- 69 seconds, mean +/- SEM), time to 1-mm ST segment depression (435 +/- 43 versus 407 +/- 45 seconds), and total ST segment depression (1.8 +/- 0.9 versus 3.1 +/- 0.4 mm). CONCLUSIONS. These results suggest that infusion of high doses of NAC in combination with ISDN for 30 hours affects and partially prevents the development of tolerance to antianginal effects normally observed during infusion with ISDN.     

Comparison of buccal nitroglycerin and oral isosorbide dinitrate for nitrate tolerance in stable angina pectoris

Sixteen patients with chronic stable angina pectoris were studied to compare the hemodynamic and antianginal effects of buccal nitroglycerin (GTN) in a dose of 3 mg administered 3 times daily and oral isosorbide dinitrate (ISDN) in a dose of 30 mg administered 4 times daily. Compared with placebo, both oral ISDN and buccal GTN treatment induced a decrease in systolic blood pressure at rest over a 5-hour period during acute but not during sustained therapy. Neither buccal GTN nor oral ISDN modified the changes in systolic blood pressure during exercise. Both treatment programs were associated with a higher exercise heart rate during acute therapy. During sustained treatment with buccal GTN, the heart rate during exercise remained greater than that during placebo throughout the 5-hour test period, but during treatment with oral ISDN, only the exercise heart rate at 1 hour was greater than that seen with placebo. Treadmill walking time to the onset of angina and to the development of moderate angina increased significantly during acute therapy with both buccal GTN and oral ISDN. The clinical efficacy of buccal GTN was maintained after 2 weeks of 3-times-daily therapy. In contrast, during 4-times-daily therapy with oral ISDN, treadmill walking time was prolonged for only 1 hour after drug administration. This investigation indicates that tolerance develops during 4-times-daily therapy with oral ISDN, but 3 times daily therapy with buccal GTN is not associated with diminished antianginal effects.     

Abrupt cessation of short-term continuous treatment with isosorbide dinitrate may cause a rebound increase in silent myocardial ischaemia in patients with stable angina pectoris.

OBJECTIVE: To examine by Holter electrocardiographic monitoring the effect of abruptly stopping nitrate treatment in patients with stable angina pectoris. PATIENTS: 12 men with confirmed ischaemic heart disease and stable exertional class 3 angina (Canadian). All had episodes of horizontal or down sloping ST segment depression during 24 hour electrocardiographic monitoring. All were nitrate responders. DESIGN: Each patient was given isosorbide dinitrate (10-30 mg four times a day) and placebo (four times a day) for three days in a randomised crossover trial. There was a washout period of 3-5 days between the two treatment periods. Holter monitoring was performed on the third day of isosorbide dinitrate and placebo administration and on the first day of their withdrawal. RESULTS: When treatment with isosorbide dinitrate was stopped there was a significant increase in the total number and duration of painless episodes of myocardial ischaemia. During placebo and isosorbide dinitrate administration 8 patients had episodes of painless myocardial ischaemia whereas after isosorbide dinitrate cessation they were recorded in all 12 patients. Episodes of silent myocardial ischaemia at rest appeared in 4 patients after isosorbide dinitrate withdrawal. CONCLUSION: Abrupt cessation of short-term continuous nitrate treatment in patients with severe angina may cause a rebound increase in myocardial ischaemia which is predominantly silent.     

Double-blind randomized multicenter study on the efficacy of trapidil versus isosorbide dinitrate in stable angina pectoris

Background: Trapidil is an inhibitor of phosphodiesterase I-IV with resulting positive lusitropic, vasodilating, and antiplatelet effects. Hypothesis: This study was undertaken to compare the antianginal efficacy of trapidil with that of isosorbide dinitrate (ISDN) in patients with stable angina pectoris. Methods: We studied 95 patients with stable angina pectoris who were randomized into a double-blind parallel group study with either oral trapidil or ISDN. After a 1-week run-in period and a 2-week wash-out phase, the patients received either trapidil 200 mg t.i.d. (n = 48) or ISDN 20 mg t.i.d. (n = 47) for 12 weeks. All antianginal medication, except sublingual glyceryl trinitrate (GTN), was discontinued during the study. Patients underwent an exercise electrocardiogram on an ergometer bicycle according to a modified Bruce protocol before and at 6 and 12 weeks during treatment. Results: The workload capacity increased from 583 ± 281 W-min before treatment to 833 ± 444 W-min after 12 weeks of treatment in the trapidil group (p<0.01) and from 555 ± 276 W-min to 827 ± 361 W-min in the ISDN group (p<0.01). The anginal attacks per week as well as the use of GTN decreased significantly in both groups. After 12 weeks of therapy, the cumulative ST-segment depression during exercise decreased by 67% in the trapidil patients and by 23% in the ISDN patients. Compared with baseline, the double product at the 75 W level was reduced in both groups after 12 weeks of treatment. Blood pressure and heart rate at rest remained nearly unchanged. Overall, no statistical difference was found between the two study groups. The tolerability was good. Conclusion: Oral trapidil therapy is safe and effective in stable angina pectoris and is equivalent to standard therapy with ISDN.     

Prognosis in stable angina pectoris and silent myocardial ischemia

The results of current investigation suggest that a former clinical standby, namely, the presence or absence of angina, is no longer the principal prognostic factor for determining a patient's risk of cardiac events, including myocardial infarction. In a retrospective analysis, patients with chronic stable angina were compared on the basis of presence or absence of angina during ischemia detected by thallium imaging. Patients were similar in terms of risk factors, clinical characteristics and catheterization data. At 30 months of follow-up, the myocardial infarction rate was 22% in the silent group compared with 4% in the group with angina. Transient asymptomatic ischemia has prognostic value independent of other variables such as exercise stress testing or cardiac catheterization data. Future prognostic studies should be careful to include patient populations with similar characteristics; they also will need to provide protracted follow-up and utilize sensitive and reproducible diagnostic techniques.     

Enhanced effectiveness of combined sustained-release forms of isosorbide dinitrate and diltiazem for stable angina pectoris

In 14 patients with documented coronary artery disease, the extent and duration of acute anti-ischemic, antianginal and hemodynamic effects of monotherapies with 120 mg of sustained-release isosorbide dinitrate and diltiazem were compared; their combined therapy administered once daily in the morning with diltiazem given again in the evening were also compared according to a randomized, double-blind, crossover, placebo-controlled protocol including exercise testing for assessment of ST-segment depression (ST decreases) at an identical work load, exercise capacity and determination of plasma concentrations of both substances. Comparison of individual substances revealed more marked and sustained effects of isosorbide dinitrate (ST decreases at 2 hours, -66%; at 6 hours, -50%; p less than or equal to 0.05 for both), remaining statistically significant up to 12 hours (-24%) than of diltiazem (2 hours, -30%; 6 hours, -16%; p less than 0.05). Combined therapy resulted in increased effects (ST decreases at 2 hours, -80%; 6 hours, -76%; 12 hours, -30%; p less than or equal to 0.05) as opposed to individual substances for a period of up to 12 hours. However, therapeutic coverage over 24 hours could not be demonstrated, even with renewed administration of sustained-release diltiazem in the evening. Plasma concentrations of isosorbide-5-mononitrate were greater than 250 ng/ml for 12 hours on days when isosorbide dinitrate was given, decreasing to less than 100 ng/ml at 24 hours. On days when diltiazem was given, plasma levels greater than 50 ng/ml were detected only at 2 and at 6 hours, and at 24 hours only after a second tablet was given.     

Comparison of nifedipine and isosorbide dinitrate when added to maximal propranolol therapy in stable angina pectoris

A study was performed to compare isosorbide dinitrate and nifedipine as adjunctive therapy in 14 patients with coronary artery disease and stable angina pectoris taking maximal beta-blocking drugs. Drug titration phases ensured maximal therapy of propranolol, isosorbide or nifedipine. The combination of nifedipine and propranolol was more effective than the combination of isosorbide and propranolol in reducing angina and increasing exercise capacity (323 vs 416 seconds, p less than 0.005) during exercise treadmill testing. Nifedipine produced a greater reduction in systolic blood pressure at submaximal exercise than isosorbide. Global and regional ejection fraction at rest and exercise was assessed with radionuclide ventriculography. The substitution of nifedipine for isosorbide depressed the global ejection fraction at rest (0.61 to 0.56 p less than 0.05) and produced a slight improvement in exercise ejection fraction (0.47 to 0.51, difference not significant). The decrease in ejection fraction from rest to exercise was 0.14 to 0.04 with nifedipine (p less than 0.005). The benefit of nifedipine compared with isosorbide occurred in regions with marked exercise-induced ischemia. In patients treated with maximal beta-blocking therapy, nifedipine is an effective alternative to isosorbide as a combination agent with propranolol. The salutary effects of nifedipine included afterload reduction with exercise and possible improvements in coronary blood supply.     

Increased exercise tolerance and reduced duration of ischemia after isosorbide dinitrate oral spray in angina pectoris

The prophylactic and therapeutic anti-ischemic efficacy of isosorbide dinitrate (ISDN) oral spray was assessed in 10 patients with coronary artery disease and stable angina pectoris. The patients entered a randomized crossover study of ISDN spray and placebo, involving bicycle exercise testing. Each patient underwent 2 exercise tests at least 4 hours apart. Immediately before initiation of exercise they received either ISDN spray or placebo and crossed over during the other test. ISDN spray delayed the onset of anginal pain by about 40%, from a mean of 5.1 +/- 1.4 minutes with placebo to 7.2 +/- 1.3 minutes with the active drug (p less than 0.001). Time of onset of ST-segment depression was also significantly prolonged, from 7.1 +/- 1.5 minutes with placebo to 10.2 +/- 1.2 minutes with ISDN (p less than 0.001). The patients achieved a higher double product at onset of pain with ISDN than with placebo. The drug also reduced the time of disappearance of pain after discontinuation of exercise from 3.2 +/- 0.7 to 2.1 +/- 0.8 minutes (p less than 0.001), and the time of disappearance of electrocardiographic changes from 4.2 +/- 0.6 to 2.5 +/- 0.8 minutes (p less than 0.005). These findings indicate that oral ISDN spray is an effective prophylactic for exercise-induced angina. Its rapid onset of action makes it especially suitable for usage immediately before exercise.     

Transdermal isosorbide dinitrate in angina pectoris: Effect of acute and sustained therapy

Twelve patients with chronic, stable angina pectoris underwent hemodynamic investigations and treadmill exercise testing before and during a 24-hour period after the application of 100 mg of transdermal isosorbide dinitrate (ISDN) and matching placebo. Compared with placebo, there were no changes in systolic blood pressure or heart rate at rest or during exercise; but treadmill walking time to the onset of angina and to the development of moderate angina was significantly prolonged at 2,4 and 8 hours, but not at 24 hours, after drug application. Patients subsequently received these same treatment regimens for 7 to 10 days and underwent repeat exercise testing. During this sustained phase of the investigation, treadmill walking time to the onset of angina and to the development of moderate angina was similar 4, 8 and 24 hours after application of ISDN and placebo. Thus, transdermal ISDN in a dose of 100 mg is effective for 8 hours during acute therapy, but during sustained therapy tolerance developed and no antianginal effects of ISDN persisted.     

Differences in the antiischaemic effects of molsidomine and isosorbide dinitrate (ISDN) during acute and short-term administration in stable angina pectoris

The acute and short-term effects of treatment with 10 consecutive doses of isosorbide dinitrate 40 mg t.i.d. and molsidomine 8 mg t.i.d. in slow release formulations were investigated in 10 patients with angiographically documented coronary artery disease and stable angina pectoris according to a randomized, double-blind, double-dummy, cross-over study design using conventional symptom-limited exercise testing. Acute exercise testing 3 h following the first dose of ISDN and molsidomine showed a significant reduction of maximal ST segment depression and of the area above the ST segments. Time to occurrence of 0.1 mV ST segment depression, exercise duration, time to onset of angina and exercise tolerance increased significantly. On the fourth treatment day with ISDN and molsidomine an attenuation of these antiischaemic effects was seen. The mean effects on ST segment depression, area above ST segments, time to occurrence of 0.1 mV ST segment depression, exercise duration, time to onset of angina and exercise tolerance were reduced by 40%, 44%, 47%, 58%, 54% and 65%, respectively, in patients administered ISDN and by 33%, 48%, 58%, 59%, 45% and 60% in those given molsidomine. Thus, following sustained short-term therapy the antiischaemic effects of both drugs seem to be attenuated. In this report no marked differences were found between ISDN and molsidomine.