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.     

Effects of a new calcium antagonist,mibefradil (Ro 40–5967), on silent ischemia in patients with stable chronic angina pectoris: A multicenter placebo-controlled study

Objectives. The purpose of this study was to evaluate the effects of mibefradil (Ro 40–5967) on the frequency and duration of episodes of asymptomatic ischemia in patients with stable angina pectoris and to determine the most efficient single therapeutic dose of this drug.Background. Mibefradil is a novel calcium channel antagonist that shows a high bioavailability, induces no reflex tachycardia and has no negative inotropic effects.Methods. In a multicenter, double-blind, placebo-controlled, parallel-design trial, 126 patients with chronic stable angina pectoris were studied. After 1 week of a placebo run-in period, patients were randomized to receive 25, 50, 100, 150 mg of mibefradil or placebo for 2 weeks. Ambulatory 48-h electrocardiographic (ECG) monitoring was performed at the end of both the placebo run-in period and the active treatment period.Results. Compared with placebo, mibefradil was associated with significantly less ischemia as manifested during ambulatory ECG monitoring. In the 150- and 100-mg groups, respectively, the drug resulted in a 73% and 63% reduction in the frequency of episodes of ST segment depression and a 78% and 58% reduction in the total duration of ST segment depression. Highly significant linear dose-response relations were present across all treatment groups for ischemic episodes and ischemia duration (p < 0.001). Electrocardiographic abnormalities related to treatment were first-degree atrioventricular block, sinus bradycardia and short Wenckebach episodes, observed during sleep on Holter monitoring. All ECG events were dose related.Conclusions. Mibefradil is a new, safe, well tolerated and very effective dose-dependent anti-ischemic calcium channel antagonist.     

Differences between male and female patients with regard to baseline demographics and clinical outcomes in the asymptomatic cardiac ischemia pilot (acip) trial

Background: Coronary artery disease (CAD) is a common problem in men and women; however, men and women with similar clinical presentations of myocardial ischemia may receive different revascularization treatments. Hypothesis: Using the data base of the Asymptomatic Cardiac Ischemia Pilot (ACIP) trial, this study was undertaken to compare by gender the baseline demographic data and the clinical outcome results in patients randomized to various treatments in the ACIP study. Methods: This randomized trial compared three treatment regimens [pharmacologic management of angina, pharmacologic management of angina and ambulatory electrocardiographic (ECG) evidence of ischemia, and revascularization—that is, angioplasty and coronary artery bypass surgery], in patients with known CAD, positive stress ECG tests, and ECG evidence of ischemia during 48 h ambulatory monitoring. In all, 558 patients were randomized, 79 of whom were women (mean age:men 61.6 years, women 60.6 years). Ambulatory ECG evidence of ischemia, clinical events, that is, death, myocardial infarction, hospital admission for coronary events, and exercise performance were monitored. Results: Although of the same age as men at baseline, women had a higher prevalence of hypertension and diabetes. Women had less severe CAD by angiography and higher left ventricular ejection fractions. Men had longer exercise tolerance times on the treadmill. However, men and women had similar numbers and duration of ambulatory ECG ischemic abnormalities. Regarding revascularization, men more commonly underwent coronary artery bypass surgery (p = 0.025) while women underwent percutaneous transluminal coronary angioplasty more frequently (p = 0.10). Clinical outcomes were comparable in men and women, although the numbers of events were relatively small. Conclusion: Men and women of comparable age manifest CAD with similar ischemic ECG abnormalities seen on both exercise tolerance and ambulatory ECG examinations. In ACIP, women tended to have more risk factors for CAD and less severity in anatomical disease, which may explain why women are less likely than men to have coronary bypass surgery.     

An initial strategy of intensive medical therapy is comparable to that of coronary revascularization for suppression of scintigraphic ischemia in high-risk but stable survivors of acute myocardial infarction.

OBJECTIVES: The purpose of this study was to determine the relative benefit of intensive medical therapy compared with coronary revascularization for suppressing scintigraphic ischemia. BACKGROUND: Although medical therapies can reduce myocardial ischemia and improve patient survival after acute myocardial infarction, the relative benefit of medical therapy versus coronary revascularization for reducing ischemia is unknown. METHODS: A prospective randomized trial in 205 stable survivors of acute myocardial infarction was made to define the relative efficacy of an intensive medical therapy strategy versus coronary revascularization for suppressing scintigraphic ischemia as assessed by serial gated adenosine Tc-99m sestamibi myocardial perfusion tomography. All patients at baseline had large total (> or =20%) and ischemic (> or =10%) adenosine-induced left ventricular perfusion defects and an ejection fraction > or =35%. Imaging was performed during 1 to 10 days of hospital admission and repeated in an identical fashion after optimization of therapy. Patients randomized to either strategy had similar baseline demographic and scintigraphic characteristics. RESULTS: Both intensive medical therapy and coronary revascularization induced significant but comparable reductions in total (-16.2 +/- 10% vs. -17.8 +/- 12%; p = NS) and ischemic (-15 +/- 9% vs. -16.2 +/- 9%; p = NS) perfusion defect sizes. Likewise, a similar percentage of patients randomized to medical therapy versus coronary revascularization had suppression of adenosine-induced ischemia (80% vs. 81%; p = NS). CONCLUSIONS: Sequential adenosine sestamibi myocardial perfusion tomography can effectively monitor changes in scintigraphic ischemia after anti-ischemic medical or coronary revascularization therapy. A strategy of intensive medical therapy is comparable to coronary revascularization for suppressing ischemia in stable patients after acute infarction who have preserved LV function.     

The truth and consequences of the COURAGE trial

Percutaneous coronary intervention (PCI) has played an integral role in the therapeutic management strategies for patients who present with either acute coronary syndromes or stable angina pectoris. The COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation) trial enrolled patients with chronic stable angina and at least 1 significant (> or =70%) angiographic coronary stenosis who were randomly assigned to an initial treatment of either PCI in conjunction with optimal medical therapy or optimal medical therapy alone. Although the initial management strategy of PCI did not reduce the risk of death, myocardial infarction, or other major cardiovascular events, improvement in angina-free status and a reduction in the requirement for subsequent revascularization was observed. An in-depth analysis of the COURAGE trial design and execution is provided.     

The truth and consequences of the COURAGE trial.

Percutaneous coronary intervention (PCI) has played an integral role in the therapeutic management strategies for patients who present with either acute coronary syndromes or stable angina pectoris. The COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation) trial enrolled patients with chronic stable angina and at least 1 significant (> or =70%) angiographic coronary stenosis who were randomly assigned to an initial treatment of either PCI in conjunction with optimal medical therapy or optimal medical therapy alone. Although the initial management strategy of PCI did not reduce the risk of death, myocardial infarction, or other major cardiovascular events, improvement in angina-free status and a reduction in the requirement for subsequent revascularization was observed. An in-depth analysis of the COURAGE trial design and execution is provided.     

Therapeutic Strategies in Patients with Chronic Stable Coronary Artery Disease

In chronic stable angina of mild or moderate severity, there is an ongoing debate as to which treatment strategy should be offered to patients: intense medical drug therapy combined with revascularization if medical therapy fails, or direct coronary angiography in view of immediate revascularization in all patients if feasible, both combined with strict risk factor control and secondary prevention. Findings of two large randomized controlled trials, COURAGE and BARI 2D showed that in selected patients with mild to moderate angina and documented coronary disease by coronary angiography suitable for revascularization, there was no difference in death or myocardial infarction between the two strategies. It remains unclear, however, how these findings can be generalized to the broader spectrum of patients with unknown coronary anatomy. This review describes both treatment strategies, their strengths and limitations, and stresses the importance of the documentation of the extent of myocardial ischemia in risk stratifying such patients. Based on the available trial evidence, an algorithm is proposed how to tailor the management strategy to each patient's individual situation.     

The evolving role of medical therapy for chronic stable angina

The management of chronic stable angina has undergone considerable evolution over the past two decades. This article highlights the need for a comprehensive approach to management that includes carefully identifying cardiac risk factors, using therapeutic lifestyle interventions, aggressive, multifaceted medical therapy, and judiciously using myocardial revascularization. For patients whose ischemia cannot be optimally controlled with traditional anti-ischemic agents, a novel antianginal and anti-ischemic agent (ie, ranolazine) has promise in reducing refractory ischemia as add-on therapy. This article discusses the role of coronary artery bypass graft surgery and percutaneous coronary intervention (PCI) in managing chronic stable angina patients and the clinical implications of the COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive drug Evaluation) trial. The combined use of a “focal” approach (PCI to treat the culprit stenosis) and a “systemic” approach (lifestyle intervention and aggressive pharmacotherapy) may afford the best event-free survival and clinical outcomes in patients with stable angina.     

Indications for treatment of silent myocardial ischemia

Summary A rational approach to treatment of silent myocardial ischemia is based on an appreciation of those factors influencing prognosis in the three types of patients that clinicians see with this disorder: those who are totally asymptomatic (type 1), those who are asymptomatic following myocardial infarction (type 2), and those who have angina and silent myocardial ischemia (type 3). Prognosis in type 1 and type 2 patients is generally good, except when triple vessel or left main disease is present. Risk factor modification and anti-ischemic medication should be employed in these patients, with serious consideration given to revascularization procedures. The latter approach is less controversial in type 3 patients who have frequent episodes of silent myocardial ischemia, especially if high dose anti-ischemic agents fail.     

Prognostic significance of transient ischemic episodes: Response to treatment shows improved prognosis Results of the total ischemic burden bisoprolol study (TIBBS) follow-up

Objectives. The Total Ischemic Burden Bisoprolol Study (TIBBS) follow-up examined cardiac event rates in relation to translent ischemia and its treatment.Background. It is nuclear whether transient ischemia on the ambulatory electrocardiogram has prognostic implications in stable angina and whether medical treatment can improve the prognosis.Methods. The TIBBS trial was an 8-week, randomized, controlled comparison of the effects of bisoprolol and nifedipine on transient ischemic episodes in patients with stable angina pectoris. Of the 545 patients screened, 520 (95.4%) could be followed up. Rates of cardiac and noncardiac death, nonfatal acute myocardial infarction, hospital admission for unstable angina and need for coronary artery bypass graft surgery or percutaneous transluminal coronary angioplasty were recorded.Results. A total of 145 events occurred in 120 (23.1%) of 520 patients. Patients with more than six episodes had an event rate of 32.5% compared with 25.0% for patients with two to six episodes and 13.2% for patients with less than two episodes (p < 0.001). Hard events (death, acute myocardial infarction, hospital admission for unstable angina pectoris) were more frequent in patients with two or more ischemic episodes (12.1% vs. 4.7%, p = 0.0049). Patients with a 100% response rate of transient ischemic episodes during the TIBBS trial had a 17.5% event rate at 1 year compared with 32.3% for non-100% responders (p = 0.008). Patients receiving bisoprolol during the TIBBS trial had a lower event rate (22.1%) at 1 year than patients randomized to nifedipine (33.1%, p = 0.033).Conclusions. In patients with stable angina pectoris, frequent episodes of transient ischemia are a marker for an increased event rate. A 100% response to medical treatment reduces the event rate. The greater reduction of ischemia with bisoprolol than nifedipine during the TIBBS trial translated into animproved outcome at 1 year.     

ISCHEMIA trial:How to apply the results to clinical practice

During the last years two questions have been continuously asked in chronic coronary syndromes: (1) Do revascularization procedures (coronary artery bypass grafting or percutaneous coronary intervention) really improve symptoms of angina? and (2) Do these techniques improve outcomes, i.e. do they prevent new myocardial infarction events and cardiovascular death? Therefore, there was a need for a large definitive trial. This study was the ISCHEMIA trial, a large, multicentric trial sponsored by the National Heart, Lung, and Blood Institute. The main trial compared coronary revascularization and optimal medical treatment (OMT) vs OMT alone in 5179 patients enrolled after a stress test. During a median 3.2-year follow-up, 318 primary outcome events occurred; the adjusted hazard ratio for the invasive strategy as compared with the conservative strategy was 0.93 (95% confidence interval 0.80-1.08, P = 0.34). The ISCHEMIA trial deeply disrupted many of our prior attitudes regarding management strategies for patients with stable coronary artery disease. The findings underscore the benefits of disease-modifying OMT for stable coronary artery disease patients. The main purposes of ischemia assessment before this trial were: Diagnostic purposes, assessment of outcome, and adding to decision-making processes. Obviously, this changed after the trial results. The results of ISCHEMIA might challenge the current diagnostic approach for stable angina patients recommended in the last European Society of Cardiology guidelines on chronic coronary disease that were based on studies published before the ISCHEMIA trial. In this editorial we propose our approach based on the ISCHEMIA study and the pretest probability for a positive test in patients with chronic coronary syndromes.     

Silent ischemia predicts infarction and death during 2 year follow-up of unstable angina

Silent myocardial ischemia as detected on Holter electrocardiographic (ECG) monitoring is present in greater than 50% of patients with unstable angina despite intensive medical therapy. The presence and the extent of silent ischemia have been correlated with an increased risk of early (1 month) unfavorable outcome including myocardial infarction and need for coronary revascularization for persistent symptoms. Seventy patients with unstable angina who had undergone continuous ECG monitoring for silent ischemia were followed up for 2 years; 37 patients (Group I) had Holter ECG evidence of silent ischemia at bed rest in the coronary care unit during medical treatment with nitrates, beta-receptor blockers and calcium channel antagonists; the other 33 patients (Group II) had no ischemic ST segment changes (symptomatic or silent) on Holter monitoring. Over a 2 year follow-up period, myocardial infarction occurred in 10 patients in Group I (in 2 it was fatal) compared with one nonfatal infarction in Group II (p less than 0.01 by Kaplan-Meier analysis); revascularization with either coronary bypass surgery or angioplasty for symptomatic ischemia was performed in 11 Group I and 5 Group II patients (p less than 0.05). Multivariate Cox's hazard analysis demonstrated that the presence of silent ischemia was the best predictor of 2 year outcome. Therefore, persistent silent myocardial ischemia despite medical therapy in patients with unstable angina carries adverse prognostic implications that persist over a 2 year period.     

Treatment of unstable angina pectoris.

Unstable angina pectoris may be manifested as new-onset angina, a change in the anginal pattern, pain at rest with associated electrocardiographic (ECG) changes, or postinfarction angina. Of these, pain at rest with ischemic ECG changes is known to be associated with the poorest prognosis. The pathogenesis of unstable angina pectoris involves a combination of a fixed atherosclerotic obstruction and a dynamic component related to coronary vasoconstriction, thrombus formation, or both. Long-acting nitrates, inhibitors of platelet aggregation, beta blockers, and calcium antagonists are among the agents that have been shown to be effective in the medical management of unstable angina. A study now in progress is evaluating the routine use of thrombolytic therapy for this indication. Although alleviation of symptoms and prevention of death and myocardial infarction are important therapeutic goals, the overall efficacy of a particular medical therapy can best be assessed by objective evaluation of its ability to control ischemia, using such techniques as exercise scintigraphy and ambulatory ECG monitoring. Cardiac catheterization and revascularization are indicated for patients with unstable angina who continue to experience symptoms or who show evidence of silent ischemia despite medical therapy. A study is under way to determine the advisability of routine revascularization of such patients. Revascularization will provide symptomatic relief in most patients with unstable angina and may prolong survival and improve left ventricular function in certain subsets.     

Effect of spinal cord stimulation on heart rate variability and myocardial ischemia in patients with chronic intractable angina pectoris—A prospective ambulatory electrocardiographic study

Background and hypothesis: Spinal cord stimulation is an effective treatment for chronic refractory angina pectoris. Its efficacy is related to an anti-ischemic action, possibly as a result of modulation of the autonomic nervous system. Therefore, the influence of spinal cord stimulation on the autonomic nervous system and myocardial ischemia was prospectively studied in 19 consecutive patients with intractable angina pectoris. Methods: Patients were included when demonstrating > 0.1 m V STsegment depression on the exercise electrocardiogram (ECG) during two separate treadmill tests. After enrollment, heart rate variability together with ischemic indices were studied with 48 h ambulatory ECG monitoring. Assessments were made at baseline and after 6 weeks of spinal cord stimulation therapy. Results: After 6 weeks, no significant changes in heart rate variability were detected. However, ischemic indices on the ambulatory ECG, as well as anginal attacks and consumption of sublingual nitrate tablets, were significantly decreased. Conclusion: Autonomic modulation assessable with heart rate variability analysis may not be the explanatory mechanism of action for the decrease of anginal attacks and ischemia, exerted by spinal cord stimulation used as an adjuvant therapy in patients with chronic intractable angina pectoris.     

Asymptomatic myocardial ischemia as a predictor of cardiac events after coronary artery bypass grafting for stable angina pectoris

Thirty-six patients with chronic stable angina were studied before and after coronary artery bypass grafting (CABG) to assess the prevalence and prognostic implications of asymptomatic myocardial ischemia obtained by ambulatory monitoring. Ambulatory monitoring performed during medical therapy before CABG detected 66 episodes of transient ischemia, 54 (82%) being asymptomatic. All patients were asymptomatic or with minimal symptoms 3 months after CABG. Additional ambulatory monitoring was performed for 36 hours. There were 39 episodes of silent ischemia detected in the 12 patients of group 1, whereas no episodes of ST-segment shift occurred in the 24 patients of group 2. Coronary artery bypass grafting reduced the frequency of transient ischemia by 41% (p less than 0.05) compared with medical therapy, whereas the number of ischemic episodes in group 1 increased from 23 during medical therapy to 39 episodes after CABG (41%, p less than 0.05). During a follow-up of 9 months, 8 cardiac events occurred: 6 in group 1 comprising sudden death (1), revascularization (2), and angina (3) and 2 in group 2, including revascularization (1) and angina (1) (p = 0.005). Kaplan-Meier analysis demonstrated that asymptomatic myocardial ischemia was correlated with a significant cumulative probability of cardiac events (p less than 0.025) and multivariate analysis of 11 variables showed that silent ischemia was the most powerful predictor of cardiac events (p less than 0.005). Silent ischemia was a forerunner for angina pectoris in some patients, whereas angina did not occur during the follow-up period in others. This study does not reveal whether or not these patients are at higher risk for cardiac events during long-term follow-up.     

Effects of asymptomatic ischemia on long-term prognosis in chronic stable coronary disease

BACKGROUND. Ischemia on ambulatory electrocardiographic monitoring has been shown to adversely affect short-term prognoses in patients with unstable angina, after myocardial infarction, and with chronic stable angina. METHODS AND RESULTS. In this long-term study, we followed 138 patients (mean age, 59 +/- 9 years) with chronic stable angina and positive exercise tests for cardiac events (e.g. death, myocardial infarction, percutaneous transluminal coronary angioplasty, or coronary artery bypass graft surgery). In 105 patients, ambulatory electrocardiographic monitoring was performed after all antianginal medication was withheld for 48 hours. In 26 patients, the diagnostic tests were repeated while on their usual medication. In addition to the 105 patients, 33 patients had their monitoring performed only while on their usual medication. During 37 +/- 17 months of follow-up, there were nine deaths, nine myocardial infarctions, and 35 revascularization procedures. In patients monitored off medication, Cox survival analysis showed that the occurrence of ischemia on electrocardiographic monitoring was the most significant predictor of death and myocardial infarction in the subsequent 2 years (p = 0.02) and all adverse events for 5 years (p = 0.009). Patients who were monitored on medication and did not have ischemia (n = 18) appeared to have more adverse events than patients who had no ischemia while being monitored off medication (n = 43). CONCLUSIONS. Asymptomatic ischemia on ambulatory electrocardiographic monitoring in patients with stable angina predicts death and myocardial infarction for 2 years and all adverse events for 5 years. Monitoring performed while on medication may show no ischemia; however, this may not indicate low risk of future coronary events.     

Ambulatory electrocardiography in the evaluation of anti-ischemic therapy

The role of ambulatory ECG monitoring (AEM) in the evaluation of anti-ischemic therapy is different in relation to the pathogenesis of myocardial ischemia. In spontaneous angina, caused by a primary reduction of coronary blood flow, the AEM represents the most efficient method to evaluate treatment results. In fact ECG monitoring permits the real evaluation of quantitative therapeutic effects, that is the reduction of the number of ischemic episodes or their abolition; besides it gives information about the treatment effects on the ischemic episodes duration, the ST dislocation entity, the incidence of asymptomatic episodes, the presence of ventricular arrhythmias and the possible different effect of treatment on the ischemic episodes characterized by ST elevation or depression. In patients undergoing anti-ischemic therapy AEM allows to study the temporal course of drug effect in order to achieve the best personal dosage schedule. While no doubt exists about Holter usefulness in the short-term control of the treatment, further data are needed to verify the role of AEM in predicting long-term efficacy of therapy. The role of Holter monitoring in the control of treatment efficacy in effort angina is more limited. However this method can be useful in those patients whose stress test shows only a partial protection in spite of anti-ischemic treatment: in these subjects the application of AEM permits to verify the presence of asymptomatic ischemic episodes that can occur either at rest or because of minimal activity.     

Treatment of stable angina.

Severe atherosclerotic narrowing of one or more coronary arteries is responsible for myocardial ischemia and angina pectoris in most patients with stable angina pectoris. The coronary arteries of patients with stable angina also contain many nonobstructive plaques, which are prone to fissures or rupture resulting in presentation of acute coronary syndromes (unstable angina, myocardial infarction, sudden ischemic death). In addition to symptomatic relief of symptoms and an increase in angina-free walking time with antianginal drugs or revascularization procedures, the recent emphasis of treatment has been to reduce adverse clinical outcomes (coronary death and myocardial infarction). The role of smoking cessation, aspirin, treatment of elevated lipids, and treatment of high blood pressure in all patients and of beta-blockers and angiotensin-converting enzyme inhibitors in patients with diminished systolic left ventricular systolic function in reducing adverse outcomes has been well established. What is unknown, however, is whether any anti-anginal drugs (beta-blockers, long-acting nitrates, calcium channel blockers) effect adverse outcomes in patients with stable angina pectoris. Recent trials evaluated the usefulness of suppression of ambulatory ischemia in patients with stable angina pectoris, but it remains to be established whether suppression of ambulatory myocardial ischemia with antianginal agents or revascularization therapy is superior to pharmacologic therapy targeting symptom relief. Patients who have refractory angina despite optimal medical treatment and are not candidates for revascularization procedures may be candidates for newer techniques of transmyocardial revascularization, enhanced external counterpulsation, spinal cord stimulation, or sympathectomy. The usefulness of these techniques, however, needs to be confirmed in large randomized clinical trials.     

Suppression of inducible painless myocardial ischemia by conventional medical therapy: Effect on short-term outcome and left ventricular systolic function

To test the hypothesis that abolition of exercise-induced painless myocardial ischemia by antiischemic medication improves prognosis in patients with medically treated coronary artery disease, we studied such patients with painless ischemia during exercise radionuclide ventriculography performed after temporary discontinuation of medication. The test was repeated while patients received conventional medical therapy that rendered angina no worse than New York Heart Association class I. The relative risk of adverse cardiac events was reduced by >5-fold when painless ischemia was abolished by symptom-dictated therapy. Thus, the abolition of exercise-induced painless ischemia by conventional medical therapy carries a better short-term prognosis in medically treated coronary artery disease, suggesting that therapeutic efficacy may need to be assessed by titration against ischemia and not angina. In patients without overt cardiac events, there were no significant differences between baseline and 12-month measurements of ejection fraction at rest, peak exercise, and the change in ejection fraction from rest to exercise. Thus, in those who remain asymptomatic and event-free, painless ischemia that is easily inducible at baseline despite medication does not lead per se to deterioration of left ventricular systolic function at rest or during exercise over 12 months. Such an effect, if evident as early as at 12 months, would favor a strategy of early revascularization over medical treatment in asymptomatic patients who have inducible painless ischemia despite medication.     

Cost-effective management of chronic stable angina

In certain patients with stable angina who are at moderate to high risk, coronary bypass surgery or coronary angioplasty are the therapeutic options of choice. However, in selected other patients the use of anti-ischemic drug therapy and secondary prevention reduce episodes of myocardial ischemia and result in a good long-term prognosis. Factors affecting management include the extent of coronary disease, the magnitude of cardiac symptoms, the severity of myocardial ischemia and of left ventricular function. Based upon these and other clinical characteristics, patients can be divided into low-, moderate-, or high-risk categories for morbidity and mortality. Patients at high risk are more likely to be selected for myocardial revascularization and patients at low risk are often treated with medical therapy, at least initially. Based on the available cost-effectiveness data, medical therapy or coronary angioplasty are the preferred initial strategies for low-risk coronary disease, whereas coronary bypass surgery (CABG) is recommended for many high-risk patients, particularly for those with triple-vessel disease and impaired left ventricular function or ischemia at a low workload. CABG is cost-effective for patients with severe angina and left main coronary artery disease and also for patients with mild angina and triple-vessel disease. Coronary angioplasty is cost-effective for patients with severe angina, and single- or multivessel disease. In patients with lesser symptoms and mild coronary disease, the cost effectiveness of myocardial revascularization therapy is less likely to be as good as it is in patients with more extensive disease and severe symptoms.