Concomitant calcium antagonist plus isosorbide dinitrate therapy for markedly active variant angina

The present study was performed to assess the efficacy of concomitant calcium antagonist/isosorbide dinitrate therapy in patients with frequent episodes of variant angina and to compare such combination therapy with isosorbide dinitrate alone. We enrolled nine such patients (six men and three women, aged 47 ± 9 [mean ± standard deviation] years) in a long-term comparison of (1) oral isosorbide dinitrate (117 ± 63 mg per day) alone, (2) verapamil (453 ± 75 mg per day) + isosorbide dinitrate (given in the same dose as stated above), and (3) nifedipine (71 ± 14 mg per day) + isosorbide dinitrate (also given in the same dose as stated), each administered for 2 months. During isosorbide dinitrate therapy, these nine patients averaged 23.7 ± 37.3 chest pains per week, consumed 24.4 ± 47.4 sublingual nitroglycerin tablets per week, and demonstrated 46.5 ± 43.2 episodes per week of transient ST segment deviations on calibrated two-channel Holter monitoring. During therapy with verapamil/isosorbide dinitrate and nifedipine/isosorbide dinitrate, the frequency of angina and ST segment deviations was dramatically reduced (verapamil/isosorbide dinitrate, 3.9 ± 3.6 chest pains per week and 3.5 ± 2.6 ST segment deviations per week, p < 0.05; nifedipine/isosorbide dinitrate, 3.1 ± 4.0 chest pains per week and 5.5 ± 6.6 ST segment deviations per week, p < 0.05). In all respects, verapamil/isosorbide dinitrate and nifedipine/isosorbide dinitrate were similar to one another. Thus, in patients with very frequent episodes of variant angina, a calcium antagonist/isosorbide dinitrate combination is much more effective than isosorbide dinitrate alone in reducing the frequency of angina and ischemic ECG alterations.     

Double-blind randomised crossover trial comparing isosorbide dinitrate cream and oral sustained-release tablets in patients with angina pectoris

Percutaneous isosorbide dinitrate cream and sustained-release tablets were compared in a double-blind randomised crossover trial in 28 patients with coronary artery disease and chronic stable angina pectoris. Twenty-two patients completed the trial. Both preparations significantly increased the mean exercise time to the onset of angina (P less than 0.001) and to termination of exercise (P less than 0.001) compared to the pre-treatment period. There were no significant differences between the cream and tablets with respect to frequency of anginal attacks, glyceryl trinitrate consumption, heart rate and ST segment depression at the onset of angina, ST segment depression at maximal exercise and the double product of heart rate and systolic blood pressure at maximal exercise. Equal numbers of patients expressed preference for cream and tablets. We conclude that in this group of patients isosorbide dinitrate sustained-release tablets have no clinical advantage over isosorbide dinitrate cream which, may, therefore, be of particular value for those patients with angina pectoris who dislike taking tablets or who prefer this form of nitrate preparation.     

Medical treatment of myocardial ischemia in coronary artery disease: effect of drug regime and irregular dosing in the CAPE II trial

OBJECTIVES: The Circadian Anti-ischemia Program in Europe (CAPE II) compared the efficacy of amlodipine and diltiazem (Adizem XL) and the combination of amlodipine/atenolol and diltiazem (Adizem XL)/isosorbide 5-mononitrate on exercise and ambulatory myocardial ischemia during regular therapy and after omission of medication. BACKGROUND: The optimal medical therapy for ischemia suppression and the impact of irregular dosing using agents with different pharmacologic properties has not been established in patients with coronary disease. METHODS: Patients with > or = 4 ischemic episodes or > or = 20 min of ST segment depression on 72-h electrocardiogram were randomized to amlodipine 10 mg once daily or diltiazem (Adizem XL) 300 mg once daily in a 14-week double-blind randomized multicountry study. In the second phase, atenolol 100 mg was added to amlodipine and isosorbide 5-mononitrate 100 mg to diltiazem (Adizem XL). Ambulatory monitoring (72 h) and exercise testing were repeated after both phases, on treatment and after a 24-h drug-free interval. RESULTS: Both monotherapy with amlodipine and diltiazem (Adizem XL) were effective on symptoms and ambulatory and exercise ischemia. Combination therapy reduced ischemia further, with amlodipine/atenolol superior to diltiazem (Adizem XL)/isosorbide 5-mononitrate. Amlodipine/atenolol was significantly superior during the drug-free interval with maintenance of ischemia reduction. CONCLUSIONS: Amlodipine, with its intrinsically long half-life alone or together with beta-blocker, is likely to produce superior ischemia reduction in clinical practice when patients frequently forget to take medication or dose irregularly.     

Changes in myocardial ischaemia during isosorbide dinitrate or indoramin therapy in patients with stable angina using relations between the ST segment and heart rate

The effect of isosorbide dinitrate or indoramin on myocardial ischaemia was examined in patients with stable angina pectoris. In a prospective trial, randomization resulted in 8 and 9 patients, respectively, given isosorbide dinitrate in a dose of 30–90 mg daily, and indoramin in a dose of 75–225 mg daily; 2 of these patients were serially examined during the two types of therapy. Changes in myocardial ischaemia were assessed by exercise testing using 12 standard electrocardiographic leads and a bipolar lead CM₅. Individual and group comparisons showed that isosorbide dinitrate resulted in an increase in ST segment depression, the maximal ST/heart rate slope and the ratio of net ST segment depression to increases in heart rate (at least P < 0.01). In contrast, with indoramin therapy there were no significant changes in these indices. The results in these patients suggest that isosorbide dinitrate leads more consistently to increases in the severity of myocardial ischaemia than indoramin, although this effect on ischaemia is apparently less than the benefit of these agents on exercise performance.     

Comparison of controlled-onset, extended-release verapamil with amlodipine and amlodipine plus atenolol on exercise performance and ambulatory ischemia in patients with chronic stable angina pectoris

This multicenter, randomized, double-blind, parallel group, placebo lead-in, placebo-controlled study compared the antianginal and anti-ischemic effects of once-daily bedtime dosing of controlled-onset extended-release (COER-24) verapamil to a once-daily morning dosing of amlodipine +/- atenolol in patients with chronic stable angina. A total of 551 patients with exercise-induced myocardial ischemia and evidence of coronary artery disease were randomized to a 4-week, forced-dose titration treatment period with (1) COER-24 verapamil 240 mg titrated to 480 mg at bedtime (n = 173), (2) amlodipine 5 mg titrated to 10 mg/day (n = 149), (3) amlodipine 5 mg (titrated to 10 mg) plus atenolol 50 mg/day in the A.M. (n = 154), or (4) placebo (n = 75). Treadmill exercise tolerance testing (standard Bruce protocol), and 48-hour ambulatory electrocardiographic (Holter) monitoring were performed at the end of placebo lead-in and double-blind treatment. Each active treatment significantly improved symptom-limited exercise duration and time to moderate angina (p < or = 0.01 vs placebo). For patients with baseline ischemia, amlodipine resulted in a statistically significant increase in total duration of ischemic episodes compared with placebo, whereas COER-24 verapamil and amlodipine plus atenolol resulted in statistically significant decreases compared with placebo and amlodipine. Heart rate at onset of ischemic episodes and ST product were also significantly increased with amlodipine (p < 0.05) compared with either COER-24 or amlodipine plus atenolol. COER-24 and amlodipine alone or in combination with atenolol improved exercise capacity in patients with angina pectoris. COER-24 verapamil monotherapy or amlodipine plus atenolol combination therapy were more effective than amlodipine monotherapy in decreasing ambulatory myocardial ischemia, especially during the hours of 6 A.M. to 12 noon.     

Amlodipine reduces transient myocardial ischemia in patients with coronary artery disease: Double-blind circadian anti-ischemia program in Europe (CAPE trial)

Objectives. This study was carried out to determine the effect of the once-daily calcium channel blocking agent amlodipine (halflife 35 to 50 h) on the circadian pattern of myocardial ischemia in patients with chronic stable angina.Background. Myocardial ischemia during normal daily life, both symptomatic and asymptomatic, has been associated with increased risk of cardiovascular morbidity and mortality, and the circadian pattern parallels that for myocardial infarction and sudden death.Methods. The Circadian Anti-Ischemia Program in Europe (CAPE) was a large, 10-week international (63 sites), doubleblind, parallel study. After a 2-week, single-Mind placebo phase, during which stable doses of antianginal treatment were maintained (beta-adrenergic blocking agents in 65% of patients), patients with chronic stable angina with at least three attacks of angina per week, with at least four ischemic episodes or ≥ 20 min of ST segment depression in 48 h of Holter monitoring, were randomized to receive treatment with either 5 mg/day of amlodipine or placebo (2:1 randomization). The dose was increased to 10 mg/day after 4 weeks. During week 7 of treatment, 48-h ambulatory ECG monitoring was repeated.Results. Three hundred fifteen of 1,160 patients screened were eligible, and 250 had complete evaluable data. Compared with placebo, amlodipine significantly reduced both the frequency of ST segment depression episodes (60% for amlodipine vs. 44% for placebo, p = 0.025) and total integrated ST ischemic area (62% mm-min vs. 50% mm-min, p = 0.042). Amlodipine reduced ischemia over the 24 h with the intrinsic circadian pattern maintained. In addition, diary data showed a significant reduction in angina (70% for amlodipine vs. 44% for placebo, p = 0.0001) and in nitroglycerin consumption (67% vs. 22%, respectively, p = 0.0006). Amlodipine and placebo demonstrated similar safety profiles (adverse events 17.3% for amlodipine and 13.3% for placebo; discontinuation rates due to adverse events were 2% vs. 4.4%, respectively).Conclusions. Once-daily amlodipiae, when added to background treatment, significantly reduced both symptomatic and asymptomatic ischemic events over 24 h in patients with chronic stable angina.     

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.     

T-Wave Alternans During Ambulatory Ischemia in Patients with Stable Coronary Disease

Background: T-wave alternans is a marker of vulnerability to ventricular tachyarrhythmias and has been documented during myocardial ischemia associated with angioplasty, bypass graft occlusion, and episodes of Prinzmetal's variant angina. We examined whether this phenomenon was present during ambulatory ischemia in ten patients randomly selected from the placebo phase of the Angina and Silent Ischemia Study [ASIS]. Methods: The eligibility criteria for participation in the ASIS study were stable coronary disease, a positive exercise stress test, and verified ischemic episodes during ambulatory ECG (AECG) monitoring. For each patient, one ischemic episode was analyzed which met the criteria of > 2-mm ST segment depression for > 3 minutes with a relatively stable ST segment baseline of > 1 hour preceding the index episode. T-wave alternans was measured using the spectral analytical technique of complex demodulation. Results: In the stable coronary patients of the ASIS trial, we found that T-wave alternans magnitude nearly tripled from 0.27 ± 0.02 mV × ms before ischemia onset to 0.77 ± 0.08 mV × ms (P < 0.01) during ischemic episodes. Heart rates ranged from 83 ± 2.9 beats/min prior to ischemia to 116 ± 2.5 beats/min during ischemia (P < 0.01). There was no statistical correlation between the magnitude of the ST segment depression > 2 mm and the ischemia-induced increase in T-wave alternans. Conclusions: We conclude that T-wave alternans often occurs in association with ambulatory ischemia. Thus, risk assessment in stable coronary patients may be enhanced by monitoring both ST segment deviation and T-wave alternans as they measure relevant but fundamentally different electrophysiological properties.     

Evaluation using serial exercise tests of verapamil alone and combined with isosorbide dinitrate in exertional angina

The response to verapamil alone and combined with isosorbide dinitrate in a group of 12 patients with severe ischemic heart disease and stable effort angina was assessed by means of serial treadmill testing. The study was randomized, of a square latin design and double-blind. The tested drugs and dosages were 120 mg of verapamil, 120 mg of verapamil plus 20 mg of isosorbide dinitrate and placebo. Patients were serially tested (Bruce protocol) over three consecutive days at 8-9-12 and 16 hours. A significative improvement was observed in several ischemic parameters both with verapamil alone and combined with isosorbide dinitrate, but this improvement was remarkably enhanced with the combination of drugs. The mean exercise time to produce angina improved from 268 +/- 18 sec (basal) to 379 +/- 19 sec (verapamil plus isosorbide dinitrate) and the time for 1 mm ST segment depression from 163 +/- 22 sec (basal) to 257 +/- 19 sec (verapamil plus isosorbide dinitrate) when measured at the last daily test (8 hours after drug administration). It is concluded that both verapamil alone and combined with isosorbide dinitrate at the chosen doses are clinically efficient, significantly improving the ischemic parameters. The combination of verapamil and isosorbide dinitrate resulted in a remarkably better improvement in this group of patients with stable effort angina.     

Monotherapy with amlodipine or atenolol versus their combination in stable angina pectoris

BACKGROUND: The basic cause of angina pectoris is imbalance between the metabolic needs of the myocardium and the capacity of the coronary circulation to deliver sufficient oxygenated blood to satisfy these needs. HYPOTHESIS: The study was undertaken to evaluate whether the effect of combined amlodipine and atenolol therapy on patients with stable angina pectoris and with ST-depression during exercise testing and 48-h ambulatory electrocardiographic monitoring is superior to that of either agent given alone. METHODS: Patients with stable angina pectoris and ST depression during exercise and ambulatory monitoring were randomized to receive amlodipine (n = 116) or atenolol (n = 116), or both (n = 119). All patients were also treated with short- and long-acting nitrates. The design was a double-blind, randomized, triple-arm parallel group study with 10 weeks of administration of the test medication. RESULTS: In terms of time to onset of ST depression > 1 mm, time to onset of angina, total exercise time, maximum achieved workload, and peak intensity of angina, amlodipine and atenolol alone were as effective as their combination. During ambulatory monitoring, atenolol was more effective than amlodipine regarding total time and number of ST-depression episodes, and as effective as the combined drugs. CONCLUSION: For individual patients with stable angina pectoris, combination of a beta blocker with a calcium antagonist is not necessarily more effective than either drug given alone.     

Relation of antianginal efficacy of nifedipine to degree of coronary arterial narrowing and to presence of coronary collateral vessels

Thirty-six patients with chronic stable angina pectoris or with stable and vasospastic components of angina pectoris were classified by coronary arteriographic findings into 4 groups. Patients in group A had a single stenotic coronary artery; patients in groups B, C and D had occluded arteries, but these arteries had been collateralized to varying degrees, and an epicardial coronary steal phenomenon was possible. All patients underwent multiple exercise tests before and after randomized, double-blind, crossover treatment with 20 mg of nifedipine, 20 mg of isosorbide dinitrate, a combination of both, and placebo. Maximal and mean ST-segment depression, occurrence of angina pectoris and heart rate were evaluated. After nifedipine treatment, mean ischemic ST-segment depression was reduced 21% in group A (p less than 0.05), but was not significantly altered in the other groups (group B, 2% decrease; group C, 10% increase; group D, 3% decrease). However, isosorbide dinitrate reduced ST-segment depression significantly in all groups (group A, 29%, p less than 0.001; group B, 18%, p less than 0.01; group C, 19%, p less than 0.05; group D, 33%, p less than 0.05). The combination with nifedipine did not further improve the effect of isosorbide dinitrate. Maximal ST-segment depression and angina pectoris paralleled the changes in mean ST depression during the different medications. Heart rate at rest was not significantly changed after nifedipine treatment in any group, but increased significantly after isosorbide dinitrate treatment in groups B and C (group B, 12%, p less than 0.01; group C, 9%, p less than 0.05); heart rate during exercise did not differ significantly in any group or after any form of medication from placebo.     

Cardiorespiratory effects of isosorbide dinitrate and nifedipine in combination with nadolol: A double-blind comparative study of beneficial and adverse antianginal drug interactions

Combinations of 2 or 3 drugs are often used to treat angina pectoris, but their combined cardiorespiratory effects have not been investigated. Using a randomized, double-blind, placebo-controlled protocol, the effects of nadolol alone and nadolol in combination with isosorbide dinitrate and nifedipine were compared, in low and high doses, on antianginal efficacy, respiratory functions and arterial blood oxygen saturation (SaO₂) in 19 patients with stable angina pectoris. A complete assessment including a bicycle exercise test with the measurement of the sum of ST-segment depression in all leads (2ST) was carried out every 2 weeks. The frequency of anginal attacks and nitroglycerin consumption was reduced significantly (p < 0.001) by nadolol alone and in combination with the other drugs. Nadolol caused a slight reduction in the forced expiratory volume in 1 second, which was improved by isosorbide dinitrate and nifedipine. The ∑ST profile (basal, at peak exercise and 2 and 5 minutes after exercise) was decreased by nadolol alone and in combination with the other drugs, although the greatest reduction was achieved with large doses of nifedipine and nadolol. The rest and postexercise SaO₂ decreased after nadolol alone and in combination with isosorbide dinitrate, but recovered to pretrial values after nifedipine and nadolol. With all drug combinations, ∑ST depression was greater when the postexercise SaO₂ was < 92%, and decreased (p < 0.05) in the same patients when their postexercise SaO₂ was > 92%. Thus, isosorbide dinitrate improved antianginal efficacy of nadolol but decreased SaO₂, which was associated with an increased ∑ST depression. Nifedipine in combination with nadolol increased SaO₂ and significantly decreased ∑ST depression.     

Transient myocardial ischemia during daily life in patients with syndrome X

Nineteen patients with syndrome X (typical exertional angina, positive exercise test response [at least 0.1 mV of ST-segment depression], no evidence of coronary spasm and angiographically normal coronary arteries) underwent continuous 48-hour electrocardiographic (ECG) monitoring during unrestricted daily life. Fifty-eight ischemic episodes of at least 0.1 mV of ST-segment depression were observed in the same ECG leads that showed ST depression during stress testing: 28 (48%) were accompanied by anginal pain and 30 (52%) were asymptomatic. No significant differences were found between painful and silent ST-segment depression with regard to the number of episodes, their temporal distribution, magnitude, duration or heart rate (HR) at onset of ST-segment depression. In the minute preceding ischemic ST shifts, HR did not change in 33% of episodes or increased by less than 10 beats/min in 28%. HR at onset of ST depression was significantly lower during ambulatory ECG monitoring than during exercise testing (98 ± 18 vs 117 ± 18 beats/min, p < 0.01). During ambulatory monitoring, 85 episodes of sinus tachycardia (exceeding by 10 to 80 beats/min the HR that triggered ischemia during exercise testing) occurred in the absence of angina or ST-segment shifts. The results of this study suggest that in patients with syndrome X, (1) myocardial ischemia frequently develops during daily life; (2) silent ischemia is an important component of this syndrome; and (3) increased oxygen demand in the presence of impaired coronary vasodilatory capacity is not the only cause of myocardial ischemia. Active mechanisms that transiently reduce coronary flow may act and explain occurrence of angina at rest and with minimal exertion.     

Nifedipine and isosorbide dinitrate alone and in combination for patients with chronic stable angina: a double-blind crossover study

Since not all patients tolerate beta-blockers, the efficacy of nifedipine and isosorbide dinitrate was evaluated alone and in combination in patients with stable angina pectoris. The study was a randomized double-blind crossover design with patients titrated to maximally tolerated doses of both drugs. Phases included isosorbide dinitrate alone, nifedipine alone, and isosorbide dinitrate plus nifedipine in combination, with efficacy determined by stress testing. Eleven men and one woman patient with a mean age of 60 years and a mean of five anginal episodes/week completed the study. Patients were in New York Heart Association (NYHA) classes I, II, and III. With nifedipine alone compared with isosorbide dinitrate alone, patients had fewer angina attacks/week (p less than 0.02), exercised longer before experiencing angina (p less than 0.03), and had less ST segment depression during (p less than 0.03) or after (p less than 0.05) exercise. When patients received isosorbide dinitrate plus nifedipine, only time to onset of angina during exercise (p less than 0.05) was significantly different from the response with isosorbide dinitrate alone. Analysis of variance between nifedipine and isosorbide dinitrate plus nifedipine was not significant. Diastolic blood pressure with isosorbide dinitrate plus nifedipine (p less than 0.04) was lower than with isosorbide dinitrate alone. No significant differences in systolic blood pressure were noted between the treatment groups. The drugs alone and in combination were relatively well tolerated. Nifedipine alone may be superior to isosorbide dinitrate alone. The combination of isosorbide dinitrate plus nifedipine demonstrated no advantage over nifedipine alone compared with isosorbide dinitrate alone.     

State of the art in stress testing and ischaemia monitoring

Electrocardiography remains the most widely used method for detecting myocardial ischemia. ST segmentabnormalities in the resting 12-lead electrocardiogram in subjects with angina and coronary risk factors seem todefinitely indicate ischemic heart disease and an adverse prognosis. ST depression during exercise testing is thefirst line provocative test for ischemic heart disease although it has a mean sensitivity of only 68% anda slightly higher specificity (77%). The presence or absence of chest pain in patients with anischemic ST response to exercise testing does not change the risk of future ischemic events. However, STdepression during the recovery period is associated with increased risk both for acute coronary events andcoronary death, whereas silent ischemia during recovery is an even stronger predictor than during exercise. Theamplitude of ST depression has not been documented to reflect the magnitude of ischemia. Therefore, new methodsare under investigation such as adding R and Q wave amplitude criteria, maximal ST/heart rate slope, linearregression analysis of the heart rate related change in ST depression and a score integrating ST segment amplitudeand slope changes. The demonstration of episodic ST segment depressions in the ambulatory setting, even withoutaccompanying chest pain, are an expression of transient ischemia and such episodes seem to represent a poorprognosis. In the hospital setting, ST depression detected by continuous monitoring is related to the clinicaloutcome. ST segment monitoring during the first 6–9 hours after coronary care unit admission providesimportant prognostic information on-line and considerably improves early risk stratification. Such continuous STmonitoring overcomes some of the limitations of static monitoring, as it improves the likelihood of capturing themaximal point of ST deviation, as well as early episodes of reocclusion that are manifest as recurrent STelevation.     

Oral Isosorbide dinitrate in angina pectoris: Comparison of duration of action and dose-response relation during acute and sustained therapy

The effects of different oral doses of isosorbide dinitrate administered acutely and four times daily during sustained therapy were studied in 12 patients with angina pectoris. After administration of 30, 60 and 120 mg of isosorbide dinitrate, the average plasma concentrations were higher and the area under the plasma concentration time curve was greater during sustained than during acute therapy (p < 0.01). Reduction in standing systolic blood pressure was greater during acute than during sustained therapy (p < 0.001). This reduction in systolic blood pressure was dose-related and persisted for 8 hours during acute therapy, but was not dose-related and was demonstrable for only 4 hours during sustained therapy. Compared with placebo therapy, exercise duration to the onset of angina and to the development of moderate angina increased significantly after each dose of isosorbide dinitrate for 8 hours during acute therapy but for only 2 hours during sustained therapy. During acute therapy, administration of a single dose of 15 or 30 mg of isosorbide dinitrate produced similar improvement in exercise tolerance as did a dose of 60 or 120 mg. During sustained therapy (15 mg four times daily), exercise tolerance increased to the same magnitude as with doses of 30, 60 or 120 mg four times daily. In most patients, near maximal improvement in exercise tolerance occurred after a dose of 15 or 30 mg four times daily.It is concluded that during sustained therapy with isosorbide dinitrate, partial tolerance to the antianginal and circulatory effects develops rapidly.     

Transient ST-segment depression as a marker of myocardial ischemia during daily life

Patients with angina and coronary artery disease (CAD) have many episodes of transient ST-segment depression during ordinary daily life, and these are often asymptomatic. To investigate this signal as a marker of myocardial ischemia, 30 patients with chronic stable angina and CAD underwent positron tomography, recording the regional myocardial uptake of rubidium-82, pain and ST-segment changes before, during and after 59 technically satisfactory exercise tests, 35 cold pressor tests and 22 episodes of unprovoked ST depression. Exercise resulted in 53 episodes of ST depression with angina and in 5 episodes without pain. After cold pressor tests, there were 3 episodes of ST depression and pain and 12 of painless ST depression. Only 9 episodes of unprovoked ST depression were accompanied by pain. Tomography showed independent evidence of ischemia in 63 (97%) of the total 65 episodes of ST depression with angina and in all 30 episodes of painless ST depression. In each patient perfusion defects occurred in the same myocardial segment during painful and painless ST depression and responses were significantly different from those in 16 normal subjects studied in the same way. These findings support the use of transient ST depression in continuous monitoring to assess the activity of CAD, but only in patients with typical angina pectoris, ST depression during exercise and proved CAD. They strengthen the evidence derived from ambulatory monitoring for a wider picture of the disease than is generally appreciated, with more frequent episodes of silent myocardial ischemia than of angina pectoris.     

Prognostic significance of transient myocardial ischaemia after first acute myocardial infarction: five year follow up study.

OBJECTIVE--To assess the five year prognostic significance of transient myocardial ischaemia on ambulatory monitoring after a first acute myocardial infarction, and to compare the diagnostic and long term prognostic value of ambulatory ST segment monitoring, maximal exercise testing, and echocardiography in patients with documented ischaemic heart disease. DESIGN--Prospective study. SETTING--Cardiology department of a teaching hospital. PATIENTS--123 consecutive men aged under 70 who were able to perform predischarge maximal exercise testing. INTERVENTIONS--Echocardiography two days before discharge (left ventricular ejection fraction), maximal bicycle ergometric testing one day before discharge (ST segment depression, angina, blood pressure, heart rate), and ambulatory ST segment monitoring (transient myocardial ischaemia) started at hospital discharge a mean of 11 (SD 5) days after infarction. MAIN OUTCOME MEASURES--Relation of ambulatory ST segment depression, exercise test variables, and left ventricular ejection fraction to subsequent objective (cardiac death or myocardial infarction) or subjective (need for coronary revascularisation) events. RESULTS--23 of the 123 patients had episodes of transient ST segment depression, of which 98% were silent. Over a mean of 5 (range 4 to 6) years of follow up, patients with ambulatory ischaemia were no more likely to have objective end points than patients without ischaemic episodes. If, however, subjective events were included an association between transient ST segment depression and an adverse long term outcome was found (Kaplan-Meier analysis; P = 0.004). The presence of exercise induced angina identified a similar proportion of patients with a poor prognosis (Kaplan-Meier analysis; P < 0.004). Both exertional angina and ambulatory ST segment depression had high specificity but poor sensitivity. The presence of exercise induced ST segment depression was of no value in predicting combined cardiac events. Indeed, patients without exertional ST segment depression were at increased risk of future objective end points (Kaplan-Meier analysis; P < 0.0045). These findings may be explained in part by a higher prevalence of left ventricular dysfunction in patients without ischaemic changes in the exercise electrocardiogram (P < 0.05). CONCLUSION--There seem to be limited reasons to perform ambulatory ST segment monitoring in survivors of a first myocardial infarction who can perform exercise tests before discharge. Patients at high risk of future myocardial infarction or death from cardiac causes are not identified. Ambulatory monitoring and exertional angina distinguish a small subset of patients who will develop severe angina pectoris demanding coronary revascularisation during follow up. Patients without exercise induced ST segment depression comprise a high risk subgroup in terms of subsequent objective end points. The role of ambulatory ST segment monitoring performed in unselected patients immediately after infarction when risk is maximal remains to be clarified.     

Ischemia in the ambulatory setting--the total ischemic burden: relation to exercise testing and investigative and therapeutic implications

To establish the relation between treadmill exercise testing and ambulatory St segment monitoring in the detection of ischemia in patients with coronary artery disease, and to assess whether standard medical therapy affects any such relation, 277 patients with stable angina and angiographically documented coronary artery disease were studied with treadmill exercise testing and 48 h ambulatory ST segment monitoring. One hundred forty-six patients (52%) were studied while receiving no routine antianginal therapy, and 131 (48%) while receiving standard medical therapy. In 187 patients (67%) the exercise test was positive for ischemia. During 11,964 h of ambulatory monitoring, 881 episodes of ischemia (645 [73%] silent) were recorded, of which 809 (92%) occurred in patients with a positive exercise test. The mean heart rate at the onset of ischemic episodes during ambulatory monitoring was significantly less than that at the onset of 1 mm ST segment depression during exercise testing (94.5 versus 105.9 beats/min, p less than 0.0001). However, the frequency of ambulatory ischemic episodes was strongly related to a positive exercise test (p less than 0.001), and this relation was similar for both silent and painful ischemia (p less than 0.0001 for both) and in patients who were and were not receiving therapy (p less than 0.0001 for both). The total duration of ischemia was similarly related to a positive exercise test (p less than 0.0001). Only one patient with a negative exercise test had frequent (greater than 5/day) episodes of ischemia on ambulatory monitoring and had documented coronary artery spasm. Thus, exercise testing identifies the majority of patients likely to have significant ischemia during their daily activities.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.