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Background: The extent to which recurrent events in patients with stable coronary artery disease is attributable to progression of an index lesion originally ≥50% diameter stenosis (DS) but not revascularized or originally <50% DS is unknown during optimal medical therapy (OMT)., Methods and Results: In the COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation) trial, 205 patients assigned to OMT plus percutaneous coronary intervention (PCI) and 284 patients assigned to OMT only had symptom-driven angiograms suitable for analysis. Percentages of patients in the OMT+PCI and OMT-only cohorts with index lesions originally <50% DS were 30% and 32%, respectively; 20% and 68% had index lesions originally ≥50% DS. In both groups, index lesions originally <50% or ≥50% DS represented <4% and <25% of all such lesions, respectively. The only angiographic predictor of myocardial infarction or acute coronary syndrome was the number of lesions originally ≥50% DS that had not been revascularized (odds ratio, 1.15; confidence limits, 1.01-1.31; P<0.04)., Conclusions: Lesions originally <50% DS were index lesions in one third of patients referred for symptom-driven repeat angiography, but represented <4% of all such lesions. Nonrevascularized lesions originally ≥50% DS were more often index lesions in OMT-only patients, but still represented a minority (<25%) of all such lesions. These findings underscore the need for improved therapies to arrest plaque progression and reliable strategies for selecting stenoses warranting PCI.

Background: In patients with stable coronary artery disease, it remains unclear whether an initial management strategy of percutaneous coronary intervention (PCI) with intensive pharmacologic therapy and lifestyle intervention (optimal medical therapy) is superior to optimal medical therapy alone in reducing the risk of cardiovascular events., Methods: We conducted a randomized trial involving 2287 patients who had objective evidence of myocardial ischemia and significant coronary artery disease at 50 U.S. and Canadian centers. Between 1999 and 2004, we assigned 1149 patients to undergo PCI with optimal medical therapy (PCI group) and 1138 to receive optimal medical therapy alone (medical-therapy group). The primary outcome was death from any cause and nonfatal myocardial infarction during a follow-up period of 2.5 to 7.0 years (median, 4.6)., Results: There were 211 primary events in the PCI group and 202 events in the medical-therapy group. The 4.6-year cumulative primary-event rates were 19.0% in the PCI group and 18.5% in the medical-therapy group (hazard ratio for the PCI group, 1.05; 95% confidence interval [CI], 0.87 to 1.27; P=0.62). There were no significant differences between the PCI group and the medical-therapy group in the composite of death, myocardial infarction, and stroke (20.0% vs. 19.5%; hazard ratio, 1.05; 95% CI, 0.87 to 1.27; P=0.62); hospitalization for acute coronary syndrome (12.4% vs. 11.8%; hazard ratio, 1.07; 95% CI, 0.84 to 1.37; P=0.56); or myocardial infarction (13.2% vs. 12.3%; hazard ratio, 1.13; 95% CI, 0.89 to 1.43; P=0.33)., Conclusions: As an initial management strategy in patients with stable coronary artery disease, PCI did not reduce the risk of death, myocardial infarction, or other major cardiovascular events when added to optimal medical therapy. (ClinicalTrials.gov number, NCT00007657 [ClinicalTrials.gov].)., (Copyright 2007 Massachusetts Medical Society.)

The main results of the Clinical Outcomes Utilizing Revascularization and Aggressive DruG Evaluation (COURAGE) trial revealed no significant differences in the primary end point of all-cause mortality or nonfatal myocardial infarction [MI] or major secondary end points (composites of death/MI/stroke; hospitalization for acute coronary syndromes [ACSs]) during a median 4.6-year follow-up in 2,287 patients with stable coronary artery disease randomized to optimal medical therapy (OMT) with or without percutaneous coronary intervention (PCI). We sought to assess the impact of PCI when added to OMT on major prespecified tertiary cardiovascular outcomes (time to first event), namely cardiac death and composites of cardiac death/MI, cardiac death/MI/hospitalization for ACS, cardiac death/MI/stroke, MI/stroke, or cardiac death/MI/ACS/stroke, during study follow-up. There were no significant differences between treatment arms for the composite of cardiac death or MI (15% in PCI + OMT group vs 14.2% in OMT group, hazard ratio 1.07, 95% confidence interval 0.86 to 1.33, p = 0.62) or in any of the major prespecified composite cardiovascular events during long-term follow-up, even after excluding periprocedural MI as an outcome of interest. Overall, cause-specific cardiovascular outcomes paralleled closely the primary and secondary composite outcomes of the trial as a whole. In conclusion, compared with an initial management strategy of OMT alone, addition of PCI did not decrease the incidence of major cardiovascular outcomes including cardiac death or the composite of cardiac death/MI/ACS/stroke in patients with stable coronary artery disease. [Copyright &y& Elsevier]

Multiple clinical trials have demonstrated β-blockers improving survival after myocardial infarction (MI). Patients with “bradycardia-related” contraindications to β-blockers, such as those with asymptomatic bradycardia or AV conduction abnormalities, have been excluded from clinical trials of β-blockers and continue to be excluded from post-MI β-blocker therapy in routine clinical practice. These patients tend to be elderly and have a high 1-year mortality. If β-blockers provide benefit to the post-MI patient independent of their heart rate–lowering effect, then these patients could benefit substantially from initiation of β-blocker therapy. However, in this particular group of patients, β-blockers can be safely initiated only if more severe or significant bradycardia can be prevented by pacemaker implantation. It is unclear whether adverse effects related to pacemaker implantation could also negate some or all of the hypothesized benefit of β-blocker therapy. Although β-blockers are particularly effective in the elderly, the benefit of β-blocker therapy in patients with bradycardia-related contraindications to β-blockers has not been established. The PACE-MI trial is a randomized controlled trial that will address whether β-blocker therapy enabled by pacemaker implantation is superior to no β-blocker and no pacemaker therapy after MI in patients with rhythm contraindications to β-blockers or in those who have developed symptomatic bradycardia due to β-blockers. The trial will randomize 1124 patients to standard therapy (not to include β-blockers as patients must have a contraindication to be enrolled) or standard therapy plus pacemaker implantation and β-blocker. The primary end point is the composite end point of total mortality plus nonfatal reinfarction. [Copyright &y& Elsevier]

Major improvements in medical therapy and percutaneous coronary intervention for coronary artery disease (CAD) have emerged during the previous 2 decades, but no randomized trial in patients with stable CAD has been powered to compare these 2 strategies for the hard clinical end points of death or myocardial infarction (MI), and previous studies have not evaluated the effect of coronary stents and intensive medical therapy on cardiac events during long-term follow-up. Between 1999 and 2004, 2,287 patients with documented myocardial ischemia and angiographically confirmed CAD were randomized to the Clinical Outcomes Utilizing Revascularization and Aggressive DruG Evaluation (COURAGE) trial, with a principal hypothesis that a strategy of percutaneous coronary intervention plus intensive, guideline-driven medical therapy would be superior to a strategy of intensive medical therapy alone. The primary end point was a composite of all-cause mortality or acute MI (time to first event) during a 2.5- to 7-year (median 5) follow-up. Baseline characteristics were a mean age of 62 ± 5 years, 85% men, and 86% Caucasian. Mean duration of angina before randomization was 26 months (average 10 episodes/week), and 29% of patients were smokers, 67% had hypertension, 38% had previous MI, 71% had dyslipidemia, 34% had diabetes, 27% had previous revascularization, and 69% had multivessel CAD. Approximately 55% of patients met established criteria for the metabolic syndrome. In conclusion, baseline characteristics of the COURAGE trial study population indicate a highly symptomatic group of patients with CAD who have a significant duration and frequency of antecedent angina pectoris and a high prevalence of cardiac risk factors. [Copyright &y& Elsevier]

Background: Major improvements in medical therapy and percutaneous coronary intervention (PCI) for coronary heart disease have occurred during the past decade, but no randomized trial has compared these 2 strategies for the “hard” clinical end points of death or myocardial infarction nor have earlier studies incorporated the use of coronary stents and aggressive multifaceted medical therapy during long-term follow-up. Methods: The COURAGE trial is a multicenter study of patients with documented myocardial ischemia and angiographically confirmed single or multivessel coronary artery disease who are randomized to a strategy of PCI plus intensive medical therapy or intensive medical therapy alone. Medical therapy in both groups is guideline-driven and includes: aspirin, clopidogrel, simvastatin (low-density lipoprotein cholesterol target 60-85 mg/dL), long-acting metoprolol and/or amlodipine, lisinopril or losartan, and long-acting nitrates, as well as lifestyle interventions. The primary end point is a composite of all-cause mortality or acute myocardial infarction, and there will be 85% power to detect an absolute 4.6% (relative 22%) difference between strategies. The principal hypothesis is that PCI plus aggressive medical therapy (projected event rate 16.4%) will be superior to aggressive medical therapy alone (projected event rate 21%) during a 2.5- to 7-year (median of 5 years) follow-up. Conclusions: COURAGE is the largest prospective randomized trial of PCI versus intensive medical therapy to date and will define the incremental benefits of PCI in the setting of contemporary optimal medical therapy for chronic coronary heart disease. A total of 2287 patients have been enrolled, and follow-up will conclude in June 2006. [Copyright &y& Elsevier]

Discusses approaches in the diagnosis and management of unstable angina and non-stress-testing-segment elevation myocardial infarction. Patient identification and risk stratification; Improvement of balance between myocardial oxygen supply and demand; Benefits of aspirin and heparin; Platelet activation and thrombin generation after plaque disruption.

Presents a study that evaluated patients with predischarge and six-week post myocardial infarction treadmill exercise tests to determine the importance of repeat tests to identify abnormalities of known prognostic value. Background on the safety and feasibility of modified treadmill exercise testing before hospital discharge after myocardial infarction; Analysis of individual variability of treadmill abnormality responses; Results and implications.

BACKGROUND Controversy surrounds optimum treatment during the subacute phase after myocardial infarction (MI) in stable patients presenting with occlusion of the infarct-related artery. Percutaneous coronary intervention (PCI) is a favored procedure in these circumstances, but its efficacy has not been established. OBJECTIVE To determine whether PCI 3-28 days after MI, plus optimum medical therapy, improves long-term arterial patency and left ventricular (LV) size and function at 1 year when compared with medical therapy alone. DESIGN The Total Occlusion Study of Canada (TOSCA)-2 trial was an ancillary study of the international, randomized Occluded Artery Trial (OAT), and included patients already enrolled in OAT from 33 of 217 participating centers. Enrollment into the ancillary study took place between May 2000 and July 2005. All patients underwent cardiac catheterization 3-28 days after a documented MI, and had either proximal coronary occlusion of the artery supplying at least 25% of the left ventricle, or LV ejection fraction (LVEF) of less than 50%. Exclusion criteria included clinical instability, severe inducible ischemia, or left-main or three-vessel disease. INTERVENTION Patients were randomly assigned to receive PCI with optimum medical therapy (PCI+M; including aspirin, angiotensin-converting-enzyme inhibitors, β-blockers, lipid-lowering therapy, and anticoagulants), or medical therapy alone. PCI using one or more coronary stents was performed within 24 h of randomization. All patients undergoing PCI also received thienopyridine therapy before and 2-4 weeks after the procedure, with a recommendation for medication to be continued up to 1 year. Follow-up angiography took place 12±3 months after randomization. OUTCOME MEASURES There were two primary end points: IRA patency and change in LVEF. Changes in LV end-systolic and end-diastolic volume index were also assessed as secondary end points. RESULTS The TOSCA-2 trial enrolled 381 patients (PCI+M n=195; medical therapy n=186), representing 67% of the OAT study population. Crossover from the medical therapy group to the PCI+M group was 17.5%. Late arterial patency was observed in significantly more patients who underwent PCI+M than in those who received medical therapy alone (83% versus 25%, respectively; P<0.0001). Although both treatments resulted in an improvement in LVEF at 1-year follow-up, there was no significant difference between the groups (mean change in LVEF 4.2±8.9% versus 3.5±8.2%, respectively; P=0.47). Neither was there a significant difference between PCI+M and medical therapy in the two secondary end points of LV endsystolic volume index (P=0.10) and LV end-diastolic volume index (P = 0.07). CONCLUSION PCI and stenting of an occluded IRA 3-28 days following MI, plus optimum medical therapy, significantly improves long-term arterial patency, but not LVEF, when compared with medical therapy alone. [ABSTRACT FROM AUTHOR]

A response by William E. Boden, Robert A. O'Rourke, and Michael H. Crawford to a letter to the editor about their article "Management of NonWave Myocardial Infarction," which was published in the July 18, 1998 issue, is presented.

Background: Non–Q-wave myocardial infarction is usually managed according to an “invasive” strategy (i.e., one of routine coronary angiography followed by myocardial revascularization). Methods: We randomly assigned 920 patients to either “invasive” management (462 patients) or “conservative” management, defined as medical therapy and noninvasive testing, with subsequent invasive management if indicated by the development of spontaneous or inducible ischemia (458 patients), within 72 hours of the onset of a non–Q-wave infarction. Death or nonfatal infarction made up the combined primary end point. Results: During an average follow-up of 23 months, 152 events (80 deaths and 72 nonfatal infarctions) occurred in 138 patients who had been randomly assigned to the invasive strategy, and 139 events (59 deaths and 80 nonfatal infarctions) in 123 patients assigned to the conservative strategy (P=0.35). Patients assigned to the invasive strategy had worse clinical outcomes during the first year of follow-up. The number of patients with one of the components of the primary end point (death or nonfatal myocardial infarction) and the number who died were significantly higher in the invasive-strategy group at hospital discharge (36 vs. 15 patients, P=0.004, for the primary end point; 21 vs. 6, P=0.007, for death), at one month (48 vs. 26, P=0.012; 23 vs. 9, P=0.021), and at one year (111 vs. 85, P=0.05; 58 vs. 36, P=0.025). Overall mortality during follow-up did not differ significantly between patients assigned to the conservative-strategy group and those assigned to the invasive-strategy group (hazard ratio, 0.72; 95 percent confidence interval, 0.51 to 1.01). Conclusions: Most patients with non–Q-wave myocardial infarction do not benefit from routine, early invasive management consisting of coronary angiography and revascularization. A conservative, ischemia-guided initial approach is both safe and effective. (N Engl J Med 1998;338:1785-92.) [ABSTRACT FROM AUTHOR]

Objectives: Our purpose was to clarify the clinical utility of identifying metabolic syndrome (MetS) in patients with coronary artery disease (CAD). Background: It is uncertain whether MetS influences prognosis in patients with CAD and whether the risk associated with MetS exceeds the risk associated with the sum of its individual components. Methods: In a post hoc analysis, we compared the incidence of death or myocardial infarction (MI) in stable CAD patients in the COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation) trial according to the presence (+) or absence (−) of MetS and diabetes: Group A, −MetS/−diabetes; Group B, +MetS/−diabetes; Group C, −MetS/+diabetes; and Group D, +MetS/+diabetes. We explored which MetS components best predicted adverse outcomes and whether MetS had independent prognostic significance beyond its individual components. Results: Of 2,248 patients, 61% had MetS and 34% diabetes. Risk for death or MI increased from Group A (14%) to Group D (25%, p < 0.001). Hypertension (hazard ratio [HR]: 1.30; 95% confidence interval [CI]: 0.98 to 1.71; p = 0.07), low high-density lipoprotein cholesterol (HR: 1.26; 95% CI: 1.03 to 1.55; p = 0.03), and elevated glucose (HR: 1.17; 95% CI: 0.96 to 1.47; p = 0.11) most strongly predicted death or MI. MetS was associated with an increased risk of death or MI (unadjusted HR: 1.41; 95% CI: 1.15 to 1.73; p = 0.001). However, after adjusting for its individual components, MetS was no longer significantly associated with outcome (HR: 1.15; 95% CI: 0.79 to 1.68; p = 0.46). Allocation to initial percutaneous coronary intervention did not affect the incidence of death or MI within any group. Conclusions: Among stable CAD patients in the COURAGE trial, the presence of MetS identified increased risk for death or MI, but MetS did not have independent prognostic significance after adjusting for its constituent components. The addition of early percutaneous coronary intervention to optimal medical therapy did not significantly reduce the risk of death or MI regardless of MetS or diabetes status. (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation [COURAGE]; NCT00007657) [Copyright &y& Elsevier]

We explored the safety and quality-of-life consequences of treating patients with stable coronary disease and high-risk features initially with optimal medical therapy (OMT) alone compared to OMT plus percutaneous coronary intervention. This was a post hoc analysis of Clinical Outcomes Utilizing Revascularization and Aggressive DruG Evaluation (COURAGE) trial patients. We defined high risk as the onset of Canadian Cardiovascular Society class III angina within 2 months or stabilized acute coronary syndrome within 2 weeks of enrollment. The primary end point was death or myocardial infarction after 4.6 years. Of the 2,287 patients enrolled in the COURAGE trial, 264 (12%) were high risk and had a relative risk of 1.56 for death or myocardial infarction (p = 0.0008) compared to those with non–high-risk features. A total of 35 primary events occurred in the OMT group and 32 in the percutaneous coronary intervention plus OMT group (hazard ratio 1.11, 95% confidence interval 0.69 to 1.79; p = 0.68). No significant difference was found in the prevalence of angina between the 2 groups at 1 year. During the first year of follow-up, 30% of the OMT patients crossed over to the revascularization group. In conclusion, an initial strategy of OMT alone for high-risk patients in the COURAGE trial did not result in increased death or myocardial infarction at 4.6 years or worse angina at 1 year, but it was associated with a high rate of crossover to revascularization. [Copyright &y& Elsevier]