A. David Goldberg

Asymptomatic Cardiac Ischemia Pilot (ACIP) Study Two-Year Follow-up Outcomes of Patients Randomized to Initial Strategies of Medical Therapy Versus Revascularization

BACKGROUND Patients with ischemia during stress testing and ambulatory ECG monitoring have an increased risk of cardiac events, but it is not known whether their prognosis is improved by more aggressive treatment with anti-ischemic drugs or revascularization. METHODS AND RESULTS The Asymptomatic Cardiac Ischemia Pilot study randomized 558 such patients who had coronary anatomy suitable for revascularization to three treatment strategies: angina-guided drug therapy (n=183), angina plus ischemia-guided drug therapy (n=183), or revascularization by angioplasty or bypass surgery (n=192). Two years after randomization, the total mortality was 6.6% in the angina-guided strategy, 4.4% in the ischemia-guided strategy, and 1.1% in the revascularization strategy (P<.02). The rate of death or myocardial infarction was 12.1% in the angina-guided strategy, 8.8% in the ischemia-guided strategy, and 4.7% in the revascularization strategy (P<.04). The rate of death, myocardial infarction, or recurrent cardiac hospitalization was 41.8% in the angina-guided strategy, 38.5% in the ischemia-guided strategy, and 23.1% in the revascularization strategy (P<.001). Pairwise testing revealed significant differences between the revascularization and angina-guided strategies for each comparison. CONCLUSIONS A strategy of initial revascularization appears to improve the prognosis of this population compared with angina-guided medical therapy. A larger long-term study is needed to confirm this benefit and to adequately test the potential of more aggressive drug therapy.

Ischemic, Hemodynamic, and Neurohormonal Responses to Mental and Exercise Stress Experience From the Psychophysiological Investigations of Myocardial Ischemia Study (PIMI)

BACKGROUND The pathophysiology of mental stress-induced myocardial ischemia, which occurs at lower heart rates than during physical stress, is not well understood. METHODS AND RESULTS The Psychophysiological Investigations of Myocardial Ischemia Study (PIMI) evaluated the physiological and neuroendocrine functioning in unmedicated patients with stable coronary artery disease and exercise-induced ischemia. Hemodynamic and neurohormonal responses to bicycle exercise, public speaking, and the Stroop test were measured by radionuclide ventriculography, ECG, and blood pressure and catecholamine monitoring. With mental stress, there were increases in heart rate, systolic blood pressure, cardiac output, and systemic vascular resistance that were correlated with increases in plasma epinephrine. During exercise, systemic vascular resistance fell, and there was no relationship between the hemodynamic changes and epinephrine levels. The fall in ejection fraction was greater with mental stress than exercise. During mental stress, the changes in ejection fraction were inversely correlated with the changes in systemic vascular resistance. Evidence for myocardial ischemia was present in 92% of patients during bicycle exercise and in 58% of patients during mental stress. Greater increases in plasma epinephrine and norepinephrine occurred with ischemia during exercise, and greater increases in systemic vascular resistance occurred with ischemia during mental stress. CONCLUSIONS Mental stress-induced myocardial ischemia is associated with a significant increase in systemic vascular resistance and a relatively minor increase in heart rate and rate-pressure product compared with ischemia induced by exercise. These hemodynamic responses to mental stress can be mediated by the adrenal secretion of epinephrine. The pathophysiological mechanism involved are important in the understanding of the etiology of myocardial ischemia and perhaps in the selection of appropriate anti-ischemic therapy.

Mental Stress-Induced Ischemia and All-Cause Mortality in Patients With Coronary Artery Disease Results From the Psychophysiological Investigations of Myocardial Ischemia Study

Background—Ischemia during laboratory mental stress tests has been linked to significantly higher rates of adverse cardiac events. Previous studies have not been designed to detect differences in mortality rates. Methods and Results—To determine whether mental stress–induced ischemia predicts death, we evaluated 196 patients from the Psychophysiological Investigations of Myocardial Ischemia (PIMI) study who had documented coronary artery disease and exercise-induced ischemia. Participants underwent bicycle exercise and psychological stress testing with radionuclide imaging. Cardiac function data and psychological test results were collected. Vital status was ascertained by telephone and by querying Social Security records 3.5±0.4 years and 5.2±0.4 years later. Of the 17 participants who had died, new or worsened wall motion abnormalities during the speech test were present in 40% compared with 19% of survivors (P =0.04) and significantly predicted death (rate ratio=3.0; 95% CI, 1.04 to 8.36;P =0.04). Ejection fraction changes during the speech test were similar in patients who died and in survivors (P =0.9) and did not predict death even after adjusting for resting ejection fraction (P =0.63), which was similar in both groups (mean, 56.4 versus 59.7;P =0.24). Other indicators of ischemia during the speech test (ST-segment depression, chest pain) did not predict death, nor did psychological traits, hemodynamic responses to the speech test, or markers of the presence and severity of ischemia during daily life and exercise. Conclusions—In patients with coronary artery disease and exercise-induced ischemia, the presence of mental stress–induced ischemia predicts subsequent death.

Asymptomatic Cardiac Ischemia Pilot (ACIP) study : outcome at 1 year for patients with asymptomatic cardiac ischemia randomized to medical therapy or revascularization

OBJECTIVES This report discusses the outcome at 1 year in patients in the Asymptomatic Cardiac Ischemia Pilot (ACIP) study. BACKGROUND Comparative efficacy of medical therapy versus revascularization in treatment of asymptomatic ischemia is unknown. The ACIP study assessed the ability of three treatment strategies to suppress ambulatory electrocardiographic (ECG) ischemia to determine whether a large-scale trial studying the impact of these strategies on clinical outcomes was feasible. METHODS Five hundred fifty-eight patients with coronary anatomy amenable to revascularization, at least one episode of asymptomatic ischemia on the 48-h ambulatory ECG and ischemia on treadmill exercise testing were randomized to one of three treatment strategies: 1) medication to suppress angina (angina-guided strategy, n = 183); 2) medication to suppress both angina and ambulatory ECG ischemia (ischemia-guided strategy, n = 183); or 3) revascularization strategy (angioplasty or bypass surgery, n = 192). Medication was titrated atenolol-nifedipine or diltiazem-isosorbide dinitrate. RESULTS The revascularization group received less medication and had less ischemia on serial ambulatory ECG recordings and exercise testing than those assigned to the medical strategies. The ischemia-guided group received more medication but had suppression of ischemia similar to the angina-guided group. At 1 year, the mortality rate was 4.4% in the angina-guided group (8 of 183), 1.6% in the ischemia-guided group (3 of 183) and 0% in the revascularization group (overall, p = 0.004; angina-guided vs. revascularization, p = 0.003; other pairwise comparisons, p = NS). Frequency of myocardial infarction, unstable angina, stroke and congestive heart failure was not significantly different among the three strategies. The revascularization group had significantly fewer hospital admissions and nonprotocol revascularizations at 1 year. The incidence of death, myocardial infarction, nonprotocol revascularization or hospital admissions at 1 year was 32% with the angina-guided medical strategy, 31% with the ischemia-guided medical strategy and 18% with the revascularization strategy (p = 0.003). CONCLUSIONS After 1 year, revascularization was superior to both angina-guided and ischemia-guided medical strategies in suppressing asymptomatic ischemia and was associated with better outcome. These findings require confirmation by a larger scale trial.

Left Ventricular, Peripheral Vascular, and Neurohumoral Responses to Mental Stress in Normal Middle-Aged Men and Women Reference Group for the Psychophysiological Investigations of Myocardial Ischemia (PIMI) Study

BACKGROUND The normal cardiovascular response to mental stress in middle-aged and older people has not been well characterized. METHODS AND RESULTS We studied 29 individuals 45 to 73 years old (15 women, 14 men) who had no coronary risk factors, no history of coronary artery disease, and a negative exercise test. Left ventricular (LV) volumes and global and regional function were assessed by radionuclide ventriculography at rest and during two 5-minute standardized mental stress tasks (simulated public speaking and the Stroop Color-Word Test), administered in random order. A substantial sympathetic response occurred with both mental stress tests, characterized by increases in blood pressure, heart rate, rate-pressure product, cardiac index, and stroke work index and rises in plasma levels of epinephrine and norepinephrine but not beta-endorphin or cortisol. Despite this sympathetic response, LV volume increased and ejection fraction (EF) decreased secondary to an increase in afterload. The change in EF during mental stress-varied among individuals but was associated positively with changes in LV contractility and negatively with baseline EF and changes in afterload. EF decreased > 5% during mental stress in 12 individuals and > 8% in 5; 3 developed regional wall motion abnormalities. CONCLUSIONS Mental stress in the laboratory results in a substantial sympathetic response in normal middle-aged and older men and women, but EF commonly falls because of a concomitant rise in afterload. These results provide essential age- and sex-matched reference data for studies of mental stress-induced ischemia in patients with coronary artery disease.

Effects of treatment strategies to suppress ischemia in patients with coronary artery disease: 12-Week results of the Asymptomatic Cardiac Ischemia Pilot (ACIP) study

OBJECTIVES The Asymptomatic Cardiac Ischemia Pilot (ACIP) study was initiated to determine the feasibility of a large trial in evaluating the effects of treatment of ischemia on outcome (mortality and myocardial infarction). The study was designed to examine the effects of medical treatment to control angina compared with treatment strategies guided by ambulatory electrocardiographic (ECG) ischemia or coronary anatomy. BACKGROUND Treatments to suppress ischemia (asymptomatic and symptomatic) have not been evaluated in a large prospective, randomized trial. Before undertaking such a trial, issues about recruitment and treatment strategies must be addressed. METHODS The 618 enrolled patients had coronary artery disease suitable for revascularization, ischemia on stress test and asymptomatic ischemia on ambulatory ECG. Patients were assigned randomly to one of three treatment strategies: 1) angina-guided medical strategy with titration of anti-ischemic medication to relieve angina (angina-guided strategy); 2) angina-guided plus ambulatory ECG ischemia-guided medical strategy with titration of anti-ischemic medication to eliminate both angina and ambulatory ECG ischemia (ischemia-guided strategy); and 3) revascularization by angioplasty or bypass surgery (revascularization strategy). RESULTS Ambulatory ECG ischemia was no longer present at the week 12 visit in 39% of patients assigned to the angina-guided strategy, 41% of patients assigned to the ischemia-guided strategy and 55% of patients assigned to the revascularization strategy. All strategies reduced the median number of episodes and total duration of ST segment depression during follow-up ambulatory ECG monitoring. Revascularization was the most effective strategy. Treadmill test results were concordant with those of ambulatory ECG monitoring. For most patients in the two medical strategies, angina was controlled with low to moderate doses of anti-ischemic medication, and the majority of patients (65%) in the revascularization strategy did not require medication for angina. CONCLUSIONS This pilot study demonstrated that cardiac ischemia can be suppressed in 40% to 55% of patients with either low or moderate doses of medication or revascularization and that a large trial is feasible.

The Asymptomatic Cardiac Ischemia Pilot (ACIP) study: Design of a randomized clinical trial, baseline data and implications for a long-term outcome trial

OBJECTIVES The primary objectives of the Asymptomatic Cardiac Ischemia Pilot were 1) to compare the 12-week efficacy of three treatment strategies to suppress cardiac ischemia, and 2) to assess the feasibility of a prognosis trial in patients with asymptomatic cardiac ischemia. BACKGROUND Cardiac ischemia has been associated with increased morbidity and mortality. However, most cardiac ischemia is asymptomatic, and although therapeutic strategies ranging from no medication to revascularization are being used to treat ischemia, no prospective study evaluating different treatment strategies has been reported. METHODS Patients with angiographically documented coronary artery disease and ischemia on exercise and ambulatory electrocardiogram (ECG) in 11 clinical units were randomized to receive angina-guided medical therapy, angina-guided plus ambulatory ECG ischemia-guided medical therapy or revascularization (coronary angioplasty or bypass surgery). Patients were also randomized to receive either diltiazem plus isosorbide dinitrate or atenolol plus nifedipine when possible. After anti-ischemic medication adjustment to control angina, blinded medication was adjusted in the medical therapy groups to eliminate ischemia in the ischemia-guided group. The primary outcome was the absence of ischemia at 12 weeks. Follow-up was scheduled for 1 year. RESULTS A total of 1,959 patients were screened by ambulatory ECG monitoring; 982 (49%) had asymptomatic ischemia, and 618 (65%) were enrolled in the study. Most patients were men, were > 60 years old and had two or more ischemic episodes, early positive exercise tests and multivessel disease. CONCLUSIONS Design and baseline data for a pilot study of ischemia treatment strategies are described.

A randomized, double-blind comparison of intravenous diltiazem and digoxin for atrial fibrillation after coronary artery bypass surgery

BACKGROUND Atrial fibrillation (AF) after coronary bypass graft surgery may result in hypotension, heart failure symptoms, embolic complications, and prolongation in length of hospital stay (LOHS). The purpose of this study was to determine whether intravenous diltiazem is more effective than digoxin for ventricular rate control in AF after coronary artery bypass graft surgery. A secondary end point was to determine whether ventricular rate control with diltiazem reduces postoperative LOHS compared with digoxin. METHODS AND RESULTS Patients with AF and ventricular rate > 100 beats/min within 7 days after coronary artery bypass graft surgery were randomly assigned to receive intravenous therapy with diltiazem (n = 20) or digoxin (n = 20). Efficacy was measured with ambulatory electrocardiography (Holter monitoring). Safety was assessed by clinical monitoring and electrocardiographic recording. LOHS was measured from the day of surgery. Data were analyzed with the intention-to-treat principle in all randomly assigned patients. In addition, a separate intention-to-treat analysis was performed excluding patients who spontaneously converted to sinus rhythm. In the analysis of all randomly assigned patients, those who received diltiazem achieved ventricular rate control (> or = 20% decrease in pretreatment ventricular rate) in a mean of 10 +/- 20 (median 2) minutes compared with 352 +/- 312 (median 228) minutes for patients who received digoxin (p < 0.0001). At 2 hours, the proportion of patients who achieved rate control was significantly higher in patients treated with diltiazem (75% vs 35%, p = 0.03). Similarly, at 6 hours, the response rate associated with diltiazem was higher than that in the digoxin group (85% vs 45%, p = 0.02). However, response rates associated with diltiazem and digoxin at 12 and 24 hours were not significantly different. At 24 hours, conversion to sinus rhythm had occurred in 11 of 20 (55%) patients receiving diltiazem and 13 of 20 (65%) patients receiving digoxin (p = 0.75). Results of the analysis of only those patients who remained in AF were similar to those presented above. There was no difference between the diltiazem-treated and digoxin-treated groups in postoperative LOHS (8.6 +/- 2.2 vs 7.7 +/- 2.0 days, respectively, p = 0.43). CONCLUSIONS Ventricular rate control occurs more rapidly with intravenous diltiazem than digoxin in AF after coronary artery bypass graft surgery. However, 12- and 24-hour response rates and duration of postoperative hospital stay associated with the two drugs are similar.

A Detailed Angiographic Analysis of Patients With Ambulatory Electrocardiographic Ischemia: Results From the Asymptomatic Cardiac Ischemia Pilot (ACIP) Study Angiographic Core Laboratory

OBJECTIVES The purpose of this Asymptomatic Cardiac Ischemia Pilot (ACIP) data bank study was to characterize angiographic features of coronary pathology of patients enrolled in the ACIP study. BACKGROUND Ischemia during ambulatory electrocardiographic (AECG) monitoring is associated with increased morbidity and mortality. Reports relating AECG ischemia to severity or complexity of coronary artery disease are few in number and small in size and have produced conflicting results. METHODS Coronary angiograms from patients with asymptomatic AECG ischemia enrolled in the ACIP study were reviewed at a central core laboratory. Quantitative measurement of percent stenosis and Thrombolysis in Myocardial Infarction flow grades were used to assess the severity of coronary artery disease. Lesions were also evaluated for the presence of intracoronary thrombus, ulceration and lumen contour as indicators of stenosis complexity. In addition, comparisons were made with 27 patients screened for the ACIP study, but who were found ineligible because they did not have AECG ischemia on 48-h Holter monitoring. RESULTS A total of 329 (75%) of 439 patients with AECG ischemia had multivessel coronary artery disease. Proximal stenoses > or = 50% diameter reduction were common in patients with AECG ischemia (62.2%), as were proximal stenoses > or = 70% (38.7%). Features suggesting complex plaque were found in 50.1% of patients with AECG ischemia. CONCLUSIONS Multivessel coronary artery disease, severe proximal stenoses and features of complex plaque were observed frequently in patients who exhibited AECG ischemia. The presence of severe and complex coronary artery disease may explain, in part, the increased risk for adverse outcome associated with ischemia during activities of daily life.

Relationship among mental stress-induced ischemia and ischemia during daily life and during exercise: the Psychophysiologic Investigations of Myocardial Ischemia (PIMI) study.

OBJECTIVES The purposes of this database study were to determine: 1) the relationship between mental stress-induced ischemia and ischemia during daily life and during exercise; 2) whether patients who exhibited daily life ischemia experienced greater hemodynamic and catecholamine responses to mental or physical stress than patients who did not exhibit daily life ischemia, and 3) whether patients who experienced daily life ischemia could be identified on the basis of laboratory-induced ischemia using mental or exercise stress testing. BACKGROUND The relationships between mental stress-induced ischemia in the laboratory and ischemia during daily life and during exercise are unclear. METHODS One hundred ninety-six stable patients with documented coronary disease and a positive exercise test underwent mental stress testing and bicycle exercise testing. Radionuclide ventriculography and electrocardiographic (ECG) monitoring were performed during the mental stress and bicycle tests. Patients underwent 48 h of ambulatory ECG monitoring. Hemodynamic and catecholamine responses were obtained during mental stress and bicycle tests. RESULTS Ischemia (reversible left ventricular dysfunction or ST segment depression > or = 1 mm) developed in 106 of 183 patients (58%) during the mental stress test. There were no significant differences in clinical characteristics of patients with, compared with those without, mental stress-induced ischemia. Patients with mental stress ischemia more often had daily life ischemia than patients without mental stress ischemia, but their exercise tests were similar. Patients with daily life ischemia had higher ejection fraction and cardiac output, and lower systemic vascular resistance during mental stress than patients without daily life ischemia. Blood pressure and catecholamine levels at rest and during the mental stress tests were not different in patients with, compared with those without, daily life ischemia. Patients with daily life ischemia had a higher ejection fraction at rest and at peak bicycle exercise compared with patients without daily life ischemia, but there were no other differences in peak hemodynamic or catecholamine responses to exercise. The presence of ST segment depression during routine daily activities was best predicted by ST segment depression during mental or bicycle exercise stress, although ST segment depression was rare during mental stress. CONCLUSIONS Patients with daily life ischemia exhibit a heightened generalized response to mental stress. ST segment depression in response to mental or exercise stress is more predictive of ST segment depression during routine daily activities than other laboratory-based ischemic markers. Therapeutic management strategies might therefore focus on patients with these physiologic responses to stress and on whether lessening such responses reduces ischemia.