Angina and Silent Ischemia Study - ASIS

Description:

Propranolol, diltiazem, and nifedipine for ambulatory ischemia in stable angina.

Hypothesis:

A significant difference would exist among propranolol, diltiazem and nifedipine as monotherapy for the treatment of episodes of asymptomatic ischemia and stable angina.

Study Design

Study Design:

Patients Screened: 194
Patients Enrolled: 62
Mean Follow Up: 9-10 weeks

Patient Populations:

Stable angina pectoris without a major change in anginal pattern for the preceding 2 months.
Positive exercise test characterized by both angina and > 1 mm of reversible ST segment depression.
Ability to complete stage 1 of the standard Bruce exercise protocol with a positive ischemic response by stage 3 or less.
Coronary disease documented by either prior angiography showing at least 1 major coronary artery or its branches with > 50% reduction in lumen diameter, prior myocardial infarction, or a reversible defect evident on stress-reperfusion thallium imaging.
At least 6 episodes of ambulatory ischemia in a 48-h period, of which at least 2 were asymptomatic.

Exclusions:

Myocardial infarction or cardiac surgery within 3 months.
Congestive heart failure of New York Heart Association class III or more, or uncontrolled hypertension (blood pressure > 180/105 mm Hg).
ST segment deviation > 1 mm at rest or in response to hyperventilation or positional changes.
Presence of conditions known to preclude accurate interpretation of ST segment deviation (conduction delay, left ventricular hypertrophy and digitalis administration, for example).
Atrioventricular block, sick sinus syndrome, ventricular pre-excitation or electronic pacemaker.
Contraindication to any study medications.
Presence of marked coronary artery vasospasm (Prinzmetal's angina).
Significant major systemic diseases.
Child-bearing potential.

Primary Endpoints:

Anginal episodes, quantified as the number of episodes/week and the number of nitroglycerin tablets consumed/ week based on patient diaries.
Exercise performance, measured as total duration of exercise and the time to 1-mm ST segment depression.
Ischemic episodes derived from ambulatory ECG data, including the number of ischemic episodes/24 h. and the total duration of ischemia 24/h

Drug/Procedures Used:

Propranolol - LA (mean daily dose, 293 mg)
Diltiazem-SR (mean daily dose, 350 mg)
Nifedipine (mean daily dose, 79 mg)
Study drugs and placebo were randomly assigned to each patient for a 2-week period; dose was titrated at end of first week. Each 2-week treatment was followed by a 48-hour ambulatory
ECG and exercise test. Patients were then randomly crossed over to each of the other treatments; ambulatory ECG and exercise test were repeated after each 2-week period.

Principal Findings:

There was no correlation among the different methods of assessing the presence or severity of ischemia.

Compared with placebo, only propranolol was associated with a marked reduction in all manifestations of asymptomatic ischemia during ambulatory ECG monitoring (2.3 vs 1.0 episodes/24 hr.; mean duration of ischemia/ 24 hours, 43.6 vs 5.7 minutes; both p < 0.0001).

Diltiazem's reduction of the frequency of episodes compared to placebo (2.3 vs 1.9 episodes/24 hours) was associated with a trend (p = 0.08) in the protocol-completed analysis and with a significant reduction in the intent-to-treat analysis (p = 0.03).

Nifedipine had no significant effect on any measured variable of ambulatory ischemia.

In contrast to the marked effect of the active agents on ambulatory asymptomatic ischemia, the effects on exercise performance were slight.

Anginal frequency was significantly decreased by both propranolol and diltiazem.

Interpretation:

No single testing approach for the presence or severity of ischemia is clearly comprehensive or definitive. Treatment response with respect to anginal symptoms or exercise performance cannot be used to infer efficacy of treatment aimed at ambulatory ischemia.

References:

1. Circulation 1990;82:1962-72. Design and baseline results
2. Circulation 1993;88:92-100. Subset analysis
3. J Am Coll Cardiol 1993;21:1605-11. Final results

Clinical Topics: Arrhythmias and Clinical EP, Stable Ischemic Heart Disease, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias, Chronic Angina

Keywords: Diltiazem, Depression, Myocardial Infarction, Angina, Stable, Propranolol, Thallium, Electrocardiography, Ambulatory, Nifedipine, Calcium Channel Blockers, Exercise Test


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