Effects of nicorandil on rest and effort angina unresponsive to combination therapy with a calcium antagonist and oral nitrate.

The efficacy of nicorandil, a new anti-anginal agent, was evaluated in 11 patients with rest and effort angina not inhibited by combination therapy with a calcium antagonist and an oral nitrate. Electrocardiographic findings during an attack demonstrated ST depression in seven patients, ST elevation in three, and either elevation or depression in two. Coronary angiography in nine patients revealed significant stenosis (greater than or equal to 75%) in eight. Angina persisted in all 11 patients in spite of treatment with 120 to 360 mg/day of diltiazem or 80 mg/day of nifedipine plus 20 to 160 mg/day of isosorbide dinitrate. Three patients were receiving beta-blocker as well; seven were receiving antiplatelet therapy. During combination therapy, patients had between 3.7 and 25 anginal attacks per week (mean +/- SD, 12.2 +/- 6.9). When nicorandil in a dosage of 20 to 40 mg/day was added to the regimen, the mean number of attacks dropped significantly (P less than 0.01) to 1.4 +/- 1.8 times/week. Two patients did not respond to nicorandil. When placebo was substituted for nicorandil in eight of nine responders, the frequency of attacks increased significantly (P less than 0.05) from 0.6 +/- 0.7 to 6.7 +/- 4.8 times/week. Nicorandil did not affect heart rate or blood pressure. These results suggest that nicorandil inhibits rest and effort angina unresponsive to usual doses of calcium antagonist and oral nitrate.

Effects of nipradilol, a new beta-blocking agent with vasodilating properties, on exercise tolerance in patients with stable effort angina: a double-blind study.

The effects of nipradilol, a new beta-blocking agent with vasodilating properties, on exercise tolerance were examined in eight patients with stable effort angina. Symptom-limited treadmill tests were performed two hours after administration of oral nipradilol (9 mg) or placebo in a double-blind manner. Exercise time to the onset of angina was significantly longer after nipradilol than after placebo (6.8 +/- 2.5 min versus 5.0 +/- 1.2 min, P less than 0.05). Exercise duration after nipradilol was not statistically different from that after 0.3 mg of sublingual nitroglycerin (7.2 +/- 1.9 min). Nipradilol significantly decreased heart rate both at rest and during exercise (P less than 0.01). Systolic blood pressure at rest did not change after nipradilol. However, an increase in systolic blood pressure during exercise was inhibited by nipradilol. The pressure rate product was significantly lower after nipradilol than after placebo. It is concluded that nipradilol improves exercise tolerance in patients with stable effort angina by decreasing the myocardial oxygen consumption during exercise.

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.

Diagnosis of important fixed coronary stenosis in patients with variant angina by exercise tests after treatment with calcium antagonists.

A 12 lead electrocardiogram was recorded during treadmill exercise in 57 patients with variant angina in whom coronary angiography was performed. Thirty six patients performed exercise tests with and without calcium antagonists, and 21 performed them only with calcium antagonists. In 55 patients calcium antagonists had prevented spontaneous attacks of variant angina for more than two days before the test. The other two patients were given a single dose of diltiazem (90 mg) two hours before the test. Exercise testing without calcium antagonists induced ST segment elevation with chest pain in nine patients, ST segment depression in 10 (nine with chest pain), and no important shift of the ST segment in 17. Five patients had severe coronary stenosis (greater than or equal to 75%) and all of them showed positive response. Thirty one patients had no important coronary stenosis and 14 of them showed positive response. The sensitivity of the exercise test in detecting a coronary stenosis greater than or equal to 75% was 100% without calcium antagonists but the specificity was low (55%). When the exercise test was done in patients taking calcium antagonists, only two (specificity 96%) of 48 patients without severe coronary stenosis showed positive response (elevation of ST segment in one and depression in another) whereas all nine patients with severe coronary stenosis had a positive response (depression of ST segment in six and elevation in three (sensitivity 100%). It is concluded that exercise testing with calcium antagonists may be a useful method for detecting severe coronary stenosis in patients with variant angina.

Clinical evidence suggesting vasospastic cause of myocardial infarction.

To examine the vasospastic cause of myocardial infarction (MI) we studied 1) the incidence of rest angina before MI, 2) clinical features of postinfarction angina and 3) the occurrence of MI in variant angina. 1) Of 178 patients with MI, 60 (34%) experienced rest angina for 1 day to 10 years before the onset of MI. The incidence of rest angina was significantly higher in patients having milder coronary stenosis of 75% or less (15/30, 50%) than in others having severe stenosis of 90% or more (45/148, 30%), p less than 0.05. 2) Postinfarction angina with ST elevation was observed in 16 patients (9%) and ST elevation developed in leads with pathological Q waves in all patients. The incidence of postinfarction angina was significantly higher in those having milder coronary stenosis than in others having severe stenosis, (27% versus 5%, p less than 0.005). Patients with postinfarction angina experienced rest angina before MI more frequently (81%) than others (29%, p less than 0.005). Sublingual nitroglycerin was effective in relieving postinfarction angina attacks and oral calcium antagonist prevented attacks in all patients. 3) MI developed in 9 of 97 patients with variant angina. Six patients had transmural and 3, non-transmural MI. Pathological Q waves and/or coronary T waves appeared in leads where ST elevation was observed during anginal attack. In 7 patients MI developed when antispastic agents were not used and in 2, when angina persisted even under treatment with calcium antagonist. These data strongly suggest that the coronary spasm can be a cause of MI in some patients.

Provocation of variant angina by alcohol ingestion.

The effect of alcohol on variant angina was studied in six patients who had a history of chest pain occurring with alcohol ingestion. On alcohol testing, Holter ECG monitoring was performed and a 12-lead ECG was recorded at the time of chest pain. In five, chest pain with ST elevation occurred 5.5 to 17.5 h after the ingestion of alcohol (100 to 150 ml as ethanol). These showed recurrent ST elevation on Holter ECG, most episodes being asymptomatic. Results of provocation testing were reproducible in all four patients in whom tests were repeated and ST elevation occurred in the same leads. No complications were observed. The Holter ECG revealed a higher heart rate after alcohol ingestion. The plasma level of alcohol was zero when angina occurred and plasma epinephrine, norepinephrine and serotonin were unchanged following alcohol ingestion. Alcohol ingestion may be a useful method of provoking variant angina, particularly in those who have a history of angina related to alcohol ingestion.