Atenolol reduced ischemia-related events in asymptomatic ischemia
ACP J Club. 1995 Mar-April;122:32. doi:10.7326/ACPJC-1995-122-2-032
Pepine CJ, Cohn PF, Deedwania PC, et al. Effects of treatment on outcome in mildly symptomatic patients with ischemia during daily life: the Atenolol Silent Ischemia Study (ASIST). Circulation. 1994 Aug;90: 762-8.
To study whether atenolol reduces adverse outcomes and daily-life ischemia in patients with coronary artery disease (CAD) and mild or no symptoms of ischemia.
Randomized, double-blind, placebo-controlled trial with 3 predesignated interim analyses.
Tertiary care and university hospitals.
Patients who were asymptomatic or minimally symptomatic (Canadian Cardiovascular Society class I or II), had transient ischemia detected by exercise electrocardiography (ECG), and evidence of CAD. Ischemic episodes were detected using ambulatory ECG. Exclusion criteria were unstable angina, myocardial infarction, or coronary revascularization within the previous 3 months; inability to exercise; other serious conditions; need for antianginal medications other than nitrates; heart failure; > first-degree atrioventricular block; asthma; or contraindications to β-blockers. 2037 patients were screened, and 306 were studied (mean age 64 y, 87% men).
After a 2-week lead-in period, patients were allocated to atenolol, 100 mg/d, which was lowered to 50 mg/d if side effects developed (n = 152), or to placebo (n = 154).
Main outcome measures
Event-free survival at 1 year (absence of death, resuscitation from ventricular tachycardia or fibrillation, nonfatal myocardial infarction, hospitalization for unstable angina, and need for revascularization) and amount and duration of ischemia.
At 1 year patients who received atenolol had a higher rate of event-free survival (log rank Kaplan-Meier P = 0.0066) (Table) and a longer time to first event than did patients in the placebo group (120 vs 79 d, P < 0.001). At 4 weeks, patients in the atenolol group had a reduction in number of episodes of ischemia (from 3.6 to 1.7/48 h, P < 0.001) and decreased duration of ischemia (from 30 to 16 min/48 h, P < 0.001). No changes in number or duration of ischemic episodes occurred in the placebo group. The groups did not differ for side effects.
Patients with coronary artery disease and mild or no ischemia who took atenolol had fewer adverse events and fewer episodes and shorter duration of ischemia.
Source of funding: ICI/Zeneca Pharmaceuticals.
For article reprint: Dr. C.J. Pepine, Division of Cardiology, Department of Medicine, University of Florida College of Medicine, Box 100277, Gainesville, FL 32610-0277, USA. FAX 904-371-037
Table. Atenolol vs placebo in patients with coronary artery disease and mild or no symptoms of ischemia*
|Outcome at 1 yr||Atenolol||Placebo||RBI (95% CI)||NNT (CI)|
|Event-free survival†||89%||75%||19% (7 to 33)||8 (5 to 18)|
*Abbreviations defined in Glossary; RBI, NNT, and CI calculated from data in article.
†Absence of death, resuscitation from ventricular tachycardia or fibrillation, hospitalization, and need for revascularization.
The study by Pepine and colleagues provides provocative new information about the role of β-blockers in the treatment of patients who have documented CAD with minimal or no symptoms. Although the study was not planned and was therefore underpowered for detecting differences in the "hard" end points of death, nonfatal myocardial infarction, or resuscitation from cardiac arrest, the most important finding is that the direction of the treatment effect was the same for every important end point: β-blockers were beneficial.
For the clinician, this information reinforces the concept that β-blockers along with aspirin should be mainstays of the treatment of CAD throughout its continuum. We already have definitive information about the benefit of these agents in acute and chronic phases of myocardial infarction, and this study provides support for extending the use of these agents to mildly symptomatic stable angina and, perhaps, to asymptomatic patients who have not had a myocardial infarction. The authors appropriately point out that the clinician should apply these findings with humility, realizing that ongoing studies with larger sample sizes will provide more definitive information.
These results also could be interpreted to support the concept that all ischemia (asymptomatic and symptomatic) should be treated, because β-blockers reduced both ischemia and symptomatic events. Whether the suppression of silent ischemia is the key finding or whether the use of β-blockers is simply beneficial in the setting of atherosclerotic CAD cannot be sorted out in this type of study. My current interpretation is that ischemia (most of which is silent) is a marker for CAD and that the benefit of the β-blocker is not caused by the suppression of ischemia itself but by the protective effects of β-blockers against ischemic triggers.
Robert M. Califf, MD
Duke University Medical CenterDurham, North Carolina, USA