ASYMPTOMATIC CARDIAC ISCHEMIA PILOT - Europe PMC

ASYMPTOMATIC CARDIAC ISCHEMIA PILOT (ACIP) C. RICHARD CONTI and (by invitation), MARTLAL G. BOURASSA, BERNARD R. CHAITMAN, NANCY L. GELLER, GENELL L. KNATTERUD, CARL J. PEPINE, CRAIG PRATT AND GEORGE SOPKO. GAINESVILLE, FLORIDA

INTRODUCTION Although adverse outcomes have been associated with cardiac ischemia in patients with all forms of coronary heart disease, treatment to suppress cardiac ischemia has not been formally tested in a prospective randomized trial. This is because most cardiac ischemia is asymptomatic. The Asymptomatic Cardiac Ischemia Pilot trial (ACIP) was initiated by the NHLBI to determine whether or not a prognosis trial is feasible.(1, 2). Three treatment strategies were considered. First, revascularization of all important stenoses in major coronary arteries; second, angina-guided medical therapy with titration of anti-ischemic medication to relieve angina; and third, angina-guided plus ambulatory ECG ischemia-guided medical therapy with titration of anti-ischemic medication to eliminate both angina and AECG ischemia. Treatment of AECG ischemia was placebo-controlled and administered in a double blind manner.

STUDY PARTICIPANTS Eleven clinical units participated in this study. These include University of Alabama, Brigham and Women's Hospital, University of Florida, St. Louis University, St. Bartholomew's Hospital (London U.K.), Montreal Heart Institute and University of Ottawa (Canada), Johns Hopkins University, Baylor College of Medicine, Albert Einstein College of Medicine, and Henry Ford Hospital. There was a core laboratory for interpretation of ambulatory ECG's, exercise ECG's and coronary angiography. ENTRY CRITERIA Three major criteria for entry were required. 1. Coronary angiography: angiographic evidence of coronary artery stenoses suitable for revascularization, i.e. 2 50% diameter stenosis in Department of Medicine, University of Florida College of Medicine, Gainesville, Florida, Requests for reprints should be addressed to: C. Richard Conti, M.D., Division of Cardiology, PO Box 100277, Gainesville, FL 32610 77

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one or more vessells. 24%,37%,and 39% had 1, 2, and 3 vessel disease respectively; Angiography had to be performed within 2 years of randomization. 2. Stress test; Evidence of exercise-induced myocardial ischemia on ACIP protocol (modified Balke) treadmill testing (n MIT=600) or reversible myocardial perfusion defect on IV dipyridimole scintigraphic imaging (n MIT= 16) or an abnormal arm exercise ECG (n MIT= 2). 3. Ambulatory ECG:At least one episode of asymptomatic ischemic ST segment depression on a 48 hour ambulatory ECG. A positive ischemic response was defined as 1 mm ST segment depression for at least one minute. Evidence for ischemia with stress testing and ambulatory ECG was obtained with the patient off medical therapy for at least 5 half lives in most instances.

RANDOMIZATION Patients were randomized to one of three strategies: (1) angina guided therapy, (2) Ischemia-guided therapy (3) Revascularization. Medication was titrated to relieve symptoms in all patient groups. Angina-guided therapy. The goal of angina-guided strategy was to achieve control of angina with either Atenolol combined with nifedipine or diltiazem combined with isosorbide dinitrate during the first four weeks of the study. Whenever possible the choice between this drug combination therapy was made by randomization. Adequate angina control was defined as less than 3 episodes of angina per week which were easily controlled with sublingual nitroglycerin and did not interfere with usual daily activities. Ambulatory ECG ischemia-guided strategy. The goal of the AECG guided strategy was to eliminate ST segment abnormalities after angina had been controlled. Therapy was based on the Core AECG laboratory reading of a 48 hour ambulatory ECG performed at 4 and 8 weeks. If ambulatory ECG ischemic episodes were present, the clinical coordinating center notified the clinical unit that blinded Atenolol! Nifedipine or Diltizem/Isosorbide Dinitrate or matching placebo medication should be started or increased. Revascularization. The goal of revascularization was to achieve complete revascularization when possible by either coronary angioplasty or bypass surgery within 4 weeks of the randomization visit. The choice of revascularization was determined by the clinical unit staff.

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STUDY END POINTS The primary endpoint of the study was the absence of cardiac ischemia at 12 weeks as measured by a 48 hour ambulatory ECG and clinical outcomes, i.e. death, myocardial infarction or non protocol revascularization. ECG parameters of exercise testing were also evaluated at 12 weeks. STUDY RESULTS A total of 618 patients (32% of patients screened) were enrolled into this randomized trial from December 1, 1991 through February 1, 1993. Mean age was 62 ± 8 years. Eighty five percent were male and 87% white. Twenty two percent had prior PTCA and/or Coronary bypass surgery. Table 1 summarizes drug requirements of patients in the three therapeutic strategies.

DRUG REQUIREMENTS Angina-guided strategy- 24% of the 204 randomized patients did not require any medications to control angina at 12 weeks, 51% were taking only 1 drug of the regimen, e.g. nitrates in patients randomized to nitrate/diltiazem therapy, and 25% were taking both drugs of the

assigned regimen. Angina-guided plus AECG-guided strategy- the study medication includes the medication given to control angina in an unblinded fashion as well as the blinded active medication given to control AECG ischemia. Twenty two percent of the 202 randomized patients were receiving no therapy at 12 weeks, 54% one drug and 24% both drugs. Revascularization- the majority of the 212 patients randomized to revascularization (65%) did not require any medication to control angina. Twenty eight received one drug and 7% received both drugs of the assigned regimen. ISCHEMIA DURING DAILY LIFE ACTIVITIES Table 2 summarizes the percentage of patients who had no evidence of ischemia during daily life activities as determined by a 48 hour

Strategies Angina Guided Angina Guided Plus AECG Guided Revascularization

TABLE 1 Drug Requirements at 12 Weeks Drug Requirements None One 24% 51% 22% 54%

65%

28%

Two 25%

24% 7%

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TABLE 2 Ischemia on AECG During Daily Life Activity Present Strategies 61.1% Angina-Guided 58.7% Angina-Guided Plus AECG-Guided 45.3% Revascularization

Absent 38.9% 41.3%

54.7%*

*p