Comparison of Characteristics and Outcomes of Veterans With Stable Ischemic Heart Disease Enrolled in the COURAGE Trial Versus the Veterans Affairs Clinical Assessment, Reporting, and Tracking Program.

Randomized clinical trials have not demonstrated a survival benefit with percutaneous coronary intervention in stable ischemic heart disease (SIHD). We evaluated the generalizability of the COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation) trial findings to the broader population of veterans with SIHD. Veterans who underwent coronary angiography between 2005 and 2013 for SIHD were identified from the Veterans Affairs Clinical Assessment, Reporting and Tracking Program (VA CART). Patient-level comparisons were made between patients from VA CART who met the eligibility criteria for COURAGE and veterans enrolled in COURAGE between 1999 and 2004. All-cause mortality over long-term follow-up was assessed using Cox proportional hazards models. COURAGE-eligible patients from VA CART (n = 59,758) were older, had a higher body mass index, a greater prevalence of co-morbidities, but fewer diseased vessels on index coronary angiography, and were less likely to be on optimal medical therapy at baseline and on 1-year follow-up compared with VA COURAGE participants (n = 968). Patients from VA CART (median follow-up 6.5 years) had higher all-cause mortality (adjusted hazard ratio [aHR] 1.98 [1.61 to 2.43]) than participants from VA COURAGE (median follow-up: 4.6 years). Risks of mortality were greater in the 56.4% patients from CART who were medically managed (aHR 1.94 [1.49 to 2.53]) and in the 43.6% who underwent percutaneous coronary intervention (aHR 1.99 [1.45 to 2.74]), compared with their respective VA COURAGE arms. In conclusion, in this noncontemporaneous patient-level analysis, veterans in the randomized COURAGE trial had more favorable outcomes than the population of veterans with SIHD at large.

Influence of LDL-Cholesterol Lowering on Cardiovascular Outcomes in Patients With Diabetes Mellitus Undergoing Coronary Revascularization.

BACKGROUND: Elevated low-density lipoprotein cholesterol (LDL-C) is associated with increased cardiovascular events, especially in high-risk populations. OBJECTIVES: This study sought to evaluate the influence of LDL-C on the incidence of cardiovascular events either following a coronary revascularization procedure (percutaneous coronary intervention [PCI] or coronary artery bypass grafting [CABG]) or optimal medical therapy alone in patients with established coronary heart disease and type 2 diabetes (T2DM). METHODS: Patient-level pooled analysis of 3 randomized clinical trials was undertaken. Patients with T2DM were categorized according to the levels of LDL-C at 1 year following randomization. The primary endpoint was major adverse cardiac or cerebrovascular events ([MACCE] the composite of all-cause mortality, nonfatal myocardial infarction, and nonfatal stroke). RESULTS: A total of 4,050 patients were followed for a median of 3.9 years after the index 1-year assessment. Patients whose 1-year LDL-C remained ≥100 mg/dl experienced higher 4-year cumulative risk of MACCE (17.2% vs. 13.3% vs. 13.1% for LDL-C between 70 and <100 mg/dl and LDL-C <70 mg/dl, respectively; p = 0.016). When compared with optimal medical therapy alone, patients with PCI experienced a MACCE reduction only if 1-year LDL-C was <70 mg/dl (hazard ratio: 0.61; 95% confidence interval: 0.40 to 0.91; p = 0.016), whereas CABG was associated with improved outcomes across all 1-year LDL-C strata. In patients with 1-year LDL-C ≥70 mg/dl, patients undergoing CABG had significantly lower MACCE rates as compared with PCI. CONCLUSIONS: In patients with coronary heart disease with T2DM, lower LDL-C at 1 year is associated with improved long-term MACCE outcome in those eligible for either PCI or CABG. When compared with optimal medical therapy alone, PCI was associated with MACCE reductions only in those who achieved an LDL-C <70 mg/dl.

Risk Prediction Tool for Assessing the Probability of Death or Myocardial Infarction in Patients With Stable Coronary Artery Disease.

Several risk scores in acute coronary syndromes are available, but few models exist for stable coronary artery disease to guide decision-making and prognosis. A multivariate model was developed using 23 baseline candidate variables from the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Therapy EvaluationTrial (n = 2,287 patients). Discrimination of the model was evaluated by the concordance c-index. The procedure was validated using 100 random half samples. We identified 9 independent predictors of death or myocardial infarction (MI) during a 5-year follow-up. The following predictors and points contributing to the risk score were: heart failure (3), number of diseased coronary arteries (1 for each vessel), diabetes (1), age (1 for each 15 years ≥ age 45), previous revascularization (1), current smoking (1), female (1), previous MI (1), and high-density lipoprotein cholesterol (1: 31 to 40 mg/dL; 2: <30 mg/dL). The risk tool had a potential range from 0 to 15, corresponding to 5-year event rates of 5.8% to 56%. C-indices ranged from 0.67 for the full data set to 0.62 for the validating subsamples. Respective observed versus predicted 5-year event rates for 3 predefined risk strata revealed: 30% had a low-risk score of 0 to 3 (9.3% vs 9.3%, or 1.9%/year); 59% had an intermediate-risk score of 4-6 (18.0% vs 18.1%, or 3.6%/year); and 11% had a high-risk score of 7-11 (36% vs 36.5%, or 7.2%/year). This stable coronary artery disease risk score permitted a prognostic assessment of 5-year probability of death or MI with an approximate 4-fold range in event rates from the lowest (9.3%) to the highest (36%) terciles, thus enabling better clinical practice decisions that allow physicians to tailor the intensity of treatment to the level of risk.

Lifestyle, Glycosylated Hemoglobin A1c, and Survival Among Patients With Stable Ischemic Heart Disease and Diabetes.

BACKGROUND: The importance of glycosylated hemoglobin A1c (A1c) control as part of comprehensive risk factor management in patients with stable ischemic heart disease (SIHD) and diabetes mellitus (DM) is controversial. OBJECTIVES: The purpose of this study was to determine whether a greater number of controlled risk factors at 1 year, including A1c, affects survival in patients with DM and SIHD. METHODS: Of 690 patients with DM followed in the COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation) trial, 592 (86%) had complete ascertainment of 7 pre-specified risk factors at baseline and after 1 year: systolic blood pressure, low-density lipoprotein cholesterol, nonsmoking, physical activity, diet adherence, body mass index, and A1c. The primary outcome measure was mortality beyond 1 year after randomization. RESULTS: During a mean follow-up of 7.0 ± 4.2 years beyond 1 year after randomization, 186 subjects died (31.4% overall, 4.5%/year). The greater the number of risk factors controlled at 1 year, the higher the probability of survival (unadjusted log rank p = 0.002). Compared with 0 to 1 controlled risk factors, attaining 3 to 7 goals predicted progressively lower mortality (hazard ratio for control of 6 or 7 risk factors was 0.13; 95% confidence interval: 0.05 to 0.40). Importantly, only 10.3% of subjects achieved control of 6 or 7 risk factors. In multivariate analysis, the strongest predictors of improved survival were no smoking, regular physical activity, dietary adherence, and A1c <7%. CONCLUSIONS: In this high-risk subset of SIHD patients with DM, the number of controlled risk factors, particularly lifestyle behaviors and A1c, were associated with improved survival. (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation; NCT00007657).

Effect of Coronary Anatomy and Myocardial Ischemia on Long-Term Survival in Patients with Stable Ischemic Heart Disease.

Background The severity of coronary artery disease (CAD) and of ischemia are evaluated to guide therapy, but their relative prognostic importance remains uncertain. Accordingly, we sought to clarify their association with long-term survival in the COURAGE trial (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation). Methods and Results Survival data from after the original trial period ended was obtained at 15 Veterans Affairs sites and 13 of 18 United States non-Veterans Affairs sites. Date of death was obtained from the Veterans Affairs system-wide Corporate Data Warehouse and the National Death Index. Of the original 2287 patients in COURAGE, 1370 (60%) had both stress perfusion imaging and quantitative coronary angiography available, with extended survival evaluated in 767 subjects. Survival was calculated by the Kaplan-Meier method, and a Cox proportional-hazards model adjusted for baseline differences. There were 369 all-cause deaths during a median follow-up of 7.9 years (range, 0-15 years). The number of coronary arteries diseased predicted survival (HR, 1.25; 95% CI, 1.09-1.43), whereas severity of ischemia did not (HR, 0.99; 95% CI, 0.80-1.22). Percutaneous coronary intervention did not offer a survival advantage over optimal medical therapy (HR, 0.95; 95% CI, 0.77-1.16) and there was no interaction between therapeutic strategy and number of coronary arteries diseased or severity of ischemia. In fully adjusted models, the number of coronary arteries diseased was not associated with increased mortality. Conclusions In univariate analysis, the number of coronary arteries diseased predicted long-term mortality, but severity of ischemia did not. Adjusted for baseline variables, neither assessment approach predicted mortality. Overall, there was no survival benefit from percutaneous coronary intervention in any subset defined by either angiographic or ischemic severity. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00007657.

Healthy Behavior, Risk Factor Control, and Survival in the COURAGE Trial.

BACKGROUND: Individual risk factor control improves survival in patients with stable ischemic heart disease (SIHD). It is uncertain if multiple risk factor control further extends survival. OBJECTIVES: This study determined whether a greater number of risk factors at goal predicted improved survival in SIHD patients. METHODS: Of 2,287 participants in the COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation) trial, 2,102 (92%) had complete ascertainment of 6 pre-specified risk factors: systolic blood pressure, low-density lipoprotein cholesterol, smoking, physical activity, diet, and body mass index. Participants received interventions to control these risk factors. The outcome measure was mortality. RESULTS: During a mean follow-up of 6.8 years, 473 (22.5%) subjects died. In univariate analysis, the greater the number of risk factors controlled, the higher the probability of survival (unadjusted log rank: p < 0.001). In multivariate analysis, the strongest predictors at 1 year of improved survival were being a nonsmoker, regular physical activity, having a systolic blood pressure <130 mm Hg, and following the American Heart Association Step 2 diet. Baseline risk factor values and evidence-based medications did not independently predict survival once risk factor control at 1 year was included in the model. Having 4 to 6 risk factors compared with 0 to 1 risk factor at goal predicted lower mortality (hazard ratios for 4 and 6 controlled risk factors: 0.64; 95% confidence interval: 0.41 to 0.98, and 0.27; 95% confidence interval: 0.09 to 0.79, respectively). CONCLUSIONS: The greater the number of risk factors in control, the higher the probability of survival in patients with SIHD. More effective strategies are needed to achieve comprehensive risk factor control, including healthy behaviors. (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation [COURAGE]; NCT00007657).

Impact of treatment strategies on outcomes in patients with stable coronary artery disease and type 2 diabetes mellitus according to presenting angina severity: A pooled analysis of three federally-funded randomized trials.

BACKGROUND AND AIMS: The impact of treatment strategies on outcomes in patients with stable coronary artery disease (CAD) and type 2 diabetes mellitus (T2DM) according to presenting angina has not been rigorously assessed. METHODS: We performed a patient-level pooled-analysis (n = 5027) of patients with stable CAD and T2DM randomized to optimal medical therapy [OMT], percutaneous coronary intervention [PCI] + OMT, or coronary artery bypass grafting [CABG] + OMT. Endpoints were death/myocardial infarction (MI)/stroke, post-randomization revascularization (both over 5 years), and angina control at 1 year. RESULTS: Increasing severity of baseline angina was associated with higher rates of death/MI/stroke (p = 0.009) and increased need for post-randomization revascularization (p = 0.001); after multivariable adjustment, only association with post-randomization revascularization remained significant. Baseline angina severity did not influence the superiority of CABG + OMT to reduce the rate of death/MI/stroke and post-randomization revascularization compared to other strategies. CABG + OMT was superior for angina control at 1 year compared to both PCI + OMT and OMT alone but only in patients with ≥ Class II severity at baseline. Comparisons between PCI + OMT and OMT were neutral except that PCI + OMT was superior to OMT for reducing the rate of post-randomization revascularization irrespective of presenting angina severity. CONCLUSIONS: Presenting angina severity did not influence the superiority of CABG + OMT with respect to 5-year rates of death/MI/stroke and need for post-randomization revascularization. Presenting angina severity minimally influenced relative benefits for angina control at 1 year.

Medical Treatment and Revascularization Options in Patients With Type 2 Diabetes and Coronary Disease.

BACKGROUND: There are scant outcomes data in patients with type 2 diabetes and stable coronary artery disease (CAD) stratified by detailed angiographic burden of CAD or left ventricular ejection fraction (LVEF). OBJECTIVES: This study determined the effect of optimal medical therapy (OMT), with or without percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG), on long-term outcomes with respect to LVEF and number of diseased vessels, including proximal left anterior descending artery involvement. METHODS: A patient-level pooled analysis was undertaken in 3 federally-funded trials. The primary endpoint was the composite of death, myocardial infarction (MI), or stroke, adjusted for trial and randomization strategy. RESULTS: Among 5,034 subjects, 15% had LVEF <50%, 77% had multivessel CAD, and 28% had proximal left anterior descending artery involvement. During a median 4.5-year follow-up, CABG + OMT was superior to PCI + OMT for the primary endpoint (hazard ratio [HR]: 0.71; 95% confidence interval [CI]: 0.59 to 0.85; p = 0.0002), death (HR: 0.76; 95% CI: 0.60 to 0.96; p = 0.024), and MI (HR: 0.50; 95% CI: 0.38 to 0.67; p = 0.0001), but not stroke (HR: 1.54; 95% CI: 0.96 to 2.48; p = 0.074). CABG + OMT was also superior to OMT alone for prevention of the primary endpoint (HR: 0.79; 95% CI: 0.64 to 0.97; p = 0.022) and MI (HR: 0.55; 95% CI: 0.41 to 0.74; p = 0.0001), and was superior to PCI + OMT for the primary endpoint in patients with 3-vessel CAD (HR: 0.72; 95% CI: 0.58 to 0.89; p = 0.002) and normal LVEF (HR: 0.71; 95% CI: 0.58 to 0.87; p = 0.0012). There were no significant differences in OMT versus PCI + OMT. CONCLUSIONS: CABG + OMT reduced the primary endpoint during long-term follow-up in patients with type 2 diabetes and stable CAD, supporting this as the preferred management strategy.

Optimal medical therapy with or without percutaneous coronary intervention in women with stable coronary disease: A pre-specified subset analysis of the Clinical Outcomes Utilizing Revascularization and Aggressive druG Evaluation (COURAGE) trial.

OBJECTIVES: To determine whether sex-based differences exist in clinical effectiveness of percutaneous coronary intervention (PCI) when added to optimal medical therapy (OMT) in patients with stable coronary artery disease. BACKGROUND: A prior pre-specified unadjusted analysis from COURAGE showed that women randomized to PCI had a lower rate of death or myocardial infarction during a median 4.6-year follow-up with a trend for interaction with respect to sex. METHODS: We analyzed outcomes in 338 women (15%) and 1949 men (85%) randomized to PCI plus OMT versus OMT alone after adjustment for relevant baseline characteristics. RESULTS: There was no difference in treatment effect by sex for the primary end point (death or myocardial infarction; HR, 0.89; 95% CI, 0.77-1.03 for women and HR, 1.02, 95% CI 0.96-1.10 for men; P for interaction = .07). Although the event rate was low, a trend for interaction by sex was nonetheless noted for hospitalization for heart failure, with only women, but not men, assigned to PCI experiencing significantly fewer events as compared to their counterparts receiving OMT alone (HR, 0.59; 95% CI, 0.40-0.84, P < .001 for women and HR, 0.86; 95% CI, 0.74-1.01, P = .47 for men; P for interaction = .02). Both sexes randomized to PCI experienced significantly reduced need for subsequent revascularization (HR, 0.72; 95% CI, 0.62-0.83, P < .001 for women; HR, 0.84; 95% CI, 0.79-0.89, P < .001 for men; P for interaction = .02) with evidence of a sex-based differential treatment effect. CONCLUSION: In this adjusted analysis of the COURAGE trial, there were no significant differences in treatment effect on major outcomes between men and women. However, women assigned to PCI demonstrated a greater benefit as compared to men, with a reduction in heart failure hospitalization and need for future revascularization. These exploratory observations require further prospective study.

Effect of PCI on Long-Term Survival in Patients with Stable Ischemic Heart Disease.

BACKGROUND: Percutaneous coronary intervention (PCI) relieves angina in patients with stable ischemic heart disease, but clinical trials have not shown that it improves survival. Between June 1999 and January 2004, we randomly assigned 2287 patients with stable ischemic heart disease to an initial management strategy of optimal medical therapy alone (medical-therapy group) or optimal medical therapy plus PCI (PCI group) and did not find a significant difference in the rate of survival during a median follow-up of 4.6 years. We now report the rate of survival among the patients who were followed for up to 15 years. METHODS: We obtained permission from the patients at the Department of Veterans Affairs (VA) sites and some non-VA sites in the United States to use their Social Security numbers to track their survival after the original trial period ended. We searched the VA national Corporate Data Warehouse and the National Death Index for survival information and the dates of death from any cause. We calculated survival according to the Kaplan-Meier method and used a Cox proportional-hazards model to adjust for significant between-group differences in baseline characteristics. RESULTS: Extended survival information was available for 1211 patients (53% of the original population). The median duration of follow-up for all patients was 6.2 years (range, 0 to 15); the median duration of follow-up for patients at the sites that permitted survival tracking was 11.9 years (range, 0 to 15). A total of 561 deaths (180 during the follow-up period in the original trial and 381 during the extended follow-up period) occurred: 284 deaths (25%) in the PCI group and 277 (24%) in the medical-therapy group (adjusted hazard ratio, 1.03; 95% confidence interval, 0.83 to 1.21; P=0.76). CONCLUSIONS: During an extended-follow-up of up to 15 years, we did not find a difference in survival between an initial strategy of PCI plus medical therapy and medical therapy alone in patients with stable ischemic heart disease. (Funded by the VA Cooperative Studies Program and others; COURAGE ClinicalTrials.gov number, NCT00007657.).

Effect of baseline exercise capacity on outcomes in patients with stable coronary heart disease (a post hoc analysis of the clinical outcomes utilizing revascularization and aggressive drug evaluation trial).

The impact of baseline exercise capacity on clinical outcomes in patients with stable ischemic heart disease randomized to an initial strategy of optimal medical therapy (OMT) with or without percutaneous coronary intervention (PCI) in the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial has not been studied. A post hoc analysis was performed in 1,052 patients of COURAGE (PCI + OMT: n = 527, OMT: n = 525) who underwent exercise treadmill testing at baseline. Patients were categorized into 2 exercise capacity groups based on metabolic equivalents (METs) achieved during baseline exercise treadmill testing (<7 METs: n = 464, ≥7 METs: n = 588) and were followed for a median of 4.6 years. The primary composite end point of death or myocardial infarction was similar in the PCI + OMT group and the OMT group for patients with exercise capacity <7 METs (19.1% vs 16.1%, p = 0.31) and ≥7 METs (13.3% vs 10.3%, p = 0.27). After adjusting for baseline covariates, the hazard ratio (99% confidence interval) for the primary end point for the PCI + OMT group versus the OMT group was 1.42 (0.90 to 2.23, p = 0.05) and for the exercise capacity subgroups of ≥7 METs and <7 METs was 0.75 (0.46 to 1.22, p = 0.13). There was no statistically significant interaction between the original treatment arm allocation (PCI + OMT vs OMT) and baseline exercise capacity. In conclusion, there was no difference in the long-term clinical outcomes in patients with exercise capacity <7 METs compared with ≥7 METs, irrespective of whether they were assigned to initial PCI. Patients with exercise capacity <7 METs did not derive a proportionately greater clinical benefit from PCI + OMT compared with those patients who received OMT alone.

Validation of the appropriate use criteria for percutaneous coronary intervention in patients with stable coronary artery disease (from the COURAGE trial).

Establishing the validity of appropriate use criteria (AUC) for percutaneous coronary intervention (PCI) in the setting of stable ischemic heart disease can support their adoption for quality improvement. We conducted a post hoc analysis of 2,287 Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation trial patients with stable ischemic heart disease randomized to PCI with optimal medical therapy (OMT) or OMT alone. Within appropriateness categories, we compared rates of death, myocardial infarction, revascularization subsequent to initial therapy, and angina-specific health status as determined by the Seattle Angina Questionnaire in patients randomized to PCI + OMT to those randomized to OMT alone. A total of 1,987 patients (87.9%) were mapped to the 2012 publication of the AUC, with 1,334 (67.1%) classified as appropriate, 551 (27.7%) uncertain, and 102 (5.1%) as inappropriate. There were no significant differences between PCI and OMT alone in the rate of mortality and myocardial infarction by appropriateness classification. Rates of revascularization were significantly lower in patients initially receiving PCI + OMT who were classified as appropriate (hazard ratio 0.65; 95% confidence interval 0.53 to 0.80; p <0.001) or uncertain (hazard ratio 0.49; 95% confidence interval 0.32 to 0.76; p = 0.001). Furthermore, among patients classified as appropriate by the AUC, Seattle Angina Questionnaire scores at 1 month were better in the PCI-treated group compared with the medical therapy group (80 ± 23 vs 75 ± 24 for angina frequency, 73 ± 24 vs 68 ± 24 for physical limitations, and 68 ± 23 vs 60 ± 24 for quality of life; all p <0.01), with differences generally persisting through 12 months. In contrast, health status scores were similar throughout the first year of follow-up in PCI + OMT patients compared with OMT alone in patients classified as uncertain or inappropriate. In conclusion, these findings support the validity of the AUC in efforts to improve health care quality through optimal use of PCI.

Predicting outcome in the COURAGE trial (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation): coronary anatomy versus ischemia.

OBJECTIVES: The aim of this study was to determine the relative utility of anatomic and ischemic burden of coronary artery disease for predicting outcomes. BACKGROUND: Both anatomic burden and ischemic burden of coronary artery disease determine patient prognosis and influence myocardial revascularization decisions. When both measures are available, their relative utility for prognostication and management choice is controversial. METHODS: A total of 621 patients enrolled in the COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation) trial with baseline quantitative nuclear single-photon emission computed tomography (SPECT) and quantitative coronary angiography were studied. Several multiple regression models were constructed to determine independent predictors of the endpoint of death, myocardial infarction (MI) (excluding periprocedural MI) and non-ST-segment elevation acute coronary syndromes (NSTE-ACS). Ischemic burden during stress SPECT, anatomic burden derived from angiography, left ventricular ejection fraction, and assignment to either optimal medical therapy (OMT) + percutaneous coronary intervention (PCI) or OMT alone were analyzed. RESULTS: In nonadjusted and adjusted regression models, anatomic burden and left ventricular ejection fraction were consistent predictors of death, MI, and NSTE-ACS, whereas ischemic burden and treatment assignment were not. There was a marginal (p = 0.03) effect of the interaction term of anatomic and ischemic burden for the prediction of clinical outcome, but separately or in combination, neither anatomy nor ischemia interacted with therapeutic strategy to predict outcome. CONCLUSIONS: In a cohort of patients treated with OMT, anatomic burden was a consistent predictor of death, MI, and NSTE-ACS, whereas ischemic burden was not. Importantly, neither determination, even in combination, identified a patient profile benefiting preferentially from an invasive therapeutic strategy. (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation [COURAGE]; NCT00007657).

Prognostic importance of coronary anatomy and left ventricular ejection fraction despite optimal therapy: assessment of residual risk in the Clinical Outcomes Utilizing Revascularization and Aggressive DruG Evaluation Trial.

BACKGROUND: It is unknown if baseline angiographic findings can be used to estimate residual risk of patients with chronic stable angina treated with both optimal medical therapy (OMT) and protocol-assigned or symptom-driven percutaneous coronary intervention (PCI). METHODS: Death, myocardial infarction (MI), and hospitalization for non-ST-segment elevation acute coronary syndrome were adjudicated in 2,275 COURAGE patients. The number of vessels diseased (VD) was defined as the number of major coronary arteries with ≥50% diameter stenosis. Proximal left anterior descending, either isolated or in combination with other disease, was also evaluated. Depressed left ventricular ejection fraction (LVEF) was defined as ≤50%. Cox regression analyses included these anatomical factors as well as interaction terms for initial treatment assignment (OMT or OMT + PCI). RESULTS: Percutaneous coronary intervention and proximal left anterior descending did not influence any outcome. Death was predicted by low LVEF (hazard ratio [HR] 1.86, CI 1.34-2.59, P < .001) and VD (HR 1.45, CI 1.20-1.75, P < .001). Myocardial infarction and non-ST-segment elevation acute coronary syndrome were predicted only by VD (HR 1.53, CI 1.30-1.81 and HR 1.24, CI 1.06-1.44, P = .007, respectively). CONCLUSIONS: In spite of OMT and irrespective of protocol-assigned or clinically driven PCI, LVEF and angiographic burden of disease at baseline retain prognostic power and reflect residual risk for secondary ischemic events.

Health status and quality of life in patients with stable coronary artery disease and chronic kidney disease treated with optimal medical therapy or percutaneous coronary intervention (post hoc findings from the COURAGE trial).

Chronic kidney disease (CKD) is an important clinical co-morbidity that increases the risk of death and myocardial infarction in patients with coronary artery disease (CAD) even when treated with guideline-directed therapies. It is unknown, however, whether CKD influences the effects of CAD treatments on patients' health status, their symptoms, function, and quality of life. We performed a post hoc analysis of the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) study to compare health status in patients with stable CAD with and without CKD defined as a glomerular filtration rate of <60 ml/min/1.73 m(2) randomized to either percutaneous coronary intervention (PCI) and optimal medical therapy (OMT) or OMT alone. Health status was measured at baseline, 1, 3, 6, 12, 24, and 36 months of follow-up with the Seattle Angina Questionnaire in 310 patients with CKD and 1,719 patients without CKD. Linear mixed-effects models were used to analyze Seattle Angina Questionnaire scores longitudinally. Mean scores for angina-related quality of life, angina frequency, and physical limitation domains improved from baseline values in both patients with and without CKD and plateaued. Early improvement (1 to 6 months) was more common in patients treated with PCI plus OMT than with OMT alone in both patients with and without CKD. Treatment satisfaction scores were high at baseline in all groups and did not change significantly over time. In conclusion, although CKD is an important determinant of event-free survival in patients with stable CAD, it neither precludes satisfactory treatment of angina with PCI plus OMT or OMT alone nor is it associated with an unsatisfactory quality of life.

Low levels of high-density lipoprotein cholesterol and increased risk of cardiovascular events in stable ischemic heart disease patients: A post-hoc analysis from the COURAGE Trial (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation).

OBJECTIVES: This study sought to assess the independent effect of high-density lipoprotein-cholesterol (HDL-C) level on cardiovascular risk in patients with stable ischemic heart disease (SIHD) who were receiving optimal medical therapy (OMT). BACKGROUND: Although low HDL-C level is a powerful and independent predictor of cardiovascular risk, recent data suggest that this may not apply when low-density lipoprotein-cholesterol (LDL-C) is reduced to optimal levels using intensive statin therapy. METHODS: We performed a post-hoc analysis in 2,193 men and women with SIHD from the COURAGE trial. The primary outcome measure was the composite of death from any cause or nonfatal myocardial infarction (MI). The independent association between HDL-C levels measured after 6 months on OMT and the rate of cardiovascular events after 4 years was assessed. Similar analyses were performed separately in subjects with LDL-C levels below 70 mg/dl (1.8 mmol/l). RESULTS: In the overall population, the rate of death/MI was 33% lower in the highest HDL-C quartile as compared with the lowest quartile, with quartile of HDL-C being a significant, independent predictor of death/MI (p = 0.05), but with no interaction for LDL-C category (p = 0.40). Among subjects with LDL-C levels <70 mg/dl, those in the highest quintile of HDL-C had a 65% relative risk reduction in death or MI as compared with the lowest quintile, with HDL-C quintile demonstrating a significant, inverse predictive effect (p = 0.02). CONCLUSIONS: In this post-hoc analysis, patients with SIHD continued to experience incremental cardiovascular risk associated with low HDL-C levels despite OMT during long-term follow-up. This relationship persisted and appeared more prominent even when LDL-C was reduced to optimal levels with intensive dyslipidemic therapy. (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation; NCT00007657).

Impact of adding ezetimibe to statin to achieve low-density lipoprotein cholesterol goal (from the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation [COURAGE] trial).

In the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) study, a revascularization strategy trial with optimal medical therapy in both arms, the low-density lipoprotein (LDL) cholesterol goal was 60 to 85 mg/dl; this was revised to <70 mg/dl in 2004. COURAGE patients (n = 2,287) were titrated with increasing statin doses to achieve the initial LDL cholesterol goal using a prespecified protocol. Ezetimibe was not available when study enrollment began in 1999 but became available after approval in 2003. After maximizing statin dose, ezetimibe was added to reach the LDL cholesterol goal in 34% of patients (n = 734). Median baseline LDL cholesterol was higher in patients who received ezetimibe than in those who did not (109 vs 96 mg/dl). At baseline, 18% of patients who would later receive ezetimibe had LDL cholesterol <85 mg/dl, and 8% had LDL cholesterol <70 mg/dl. On maximum tolerated statin (with or without other lipid-lowering drugs), 40% had LDL cholesterol <85 mg/dl and 23% had LDL cholesterol <70 mg/dl before starting ezetimibe. At the final study visit, 68% of ezetimibe patients achieved LDL cholesterol <85 mg/dl, and 46% achieved LDL cholesterol <70 mg/dl. Using Cox regression analysis, the most significant factors associated with achieving LDL cholesterol goals were lower baseline LDL cholesterol, average statin dose, and ezetimibe use. In conclusion, after maximizing statin dose, the addition of ezetimibe results in a substantial increase in the percentage of patients who reach LDL cholesterol goal, a key component of optimal medical therapy.

Baseline stress myocardial perfusion imaging results and outcomes in patients with stable ischemic heart disease randomized to optimal medical therapy with or without percutaneous coronary intervention.

BACKGROUND: The COURAGE trial reported similar clinical outcomes for patients with stable ischemic heart disease (SIHD) receiving optimal medical therapy (OMT) with or without percutaneous coronary intervention (PCI). The current post hoc substudy analysis examined the relationship between baseline stress myocardial ischemia and clinical outcomes based on randomized treatment assignment. METHODS: A total of 1,381 randomized patients (OMT n = 699, PCI + OMT n = 682) underwent baseline stress myocardial perfusion single-photon emission computed tomographic imaging. Site investigators interpreted the extent of ischemia by the number of ischemic segments using a 6-segment myocardial model. Patients were divided into those with no to mild (<3 ischemic segments) and moderate to severe ischemia (≥ 3 ischemic segments). Cox proportional hazards models were calculated to assess time to the primary end point of death or myocardial infarction. RESULTS: At baseline, moderate to severe ischemia occurred in more than one-quarter of patients (n = 468), and the incidence was comparable in both treatment groups (P = .36). The primary end point, death or myocardial infarction, was similar in the OMT and PCI + OMT treatment groups for no to mild (18% and 19%, P = .92) and moderate to severe ischemia (19% and 22%, P = .53, interaction P value = .65). There was no gradient increase in events for the overall cohort with the extent of ischemia. CONCLUSIONS: From the COURAGE trial post hoc substudy, the extent of site-defined ischemia did not predict adverse events and did not alter treatment effectiveness. Currently, evidence supports equipoise as to whether the extent and severity of ischemia impact on therapeutic effectiveness.

Effectiveness of percutaneous coronary intervention in patients with silent myocardial ischemia (post hoc analysis of the COURAGE trial).

Previous studies have suggested that percutaneous coronary intervention (PCI) decreases long-term mortality in patients with silent myocardial ischemia (SMI), but whether PCI specifically decreases mortality when added to intensive medical therapy is unknown. We performed a post hoc analysis of clinical outcomes in patients in the COURAGE trial based on the presence or absence of anginal symptoms at baseline. Asymptomatic patients were classified as having SMI by electrocardiographic ischemia at rest or reversible stress perfusion imaging (exercise-induced or pharmacologic). Study end points included the composite primary end point (death or myocardial infarction [MI]); individual end points of death, MI, and hospitalization for acute coronary syndrome; and need for revascularization. Of 2,280 patients 12% (n = 283) had SMI and 88% were symptomatic (n = 1,997). There were no between-group differences in age, gender, cardiac risk factors, previous MI or revascularization, extent of angiographic disease, or ischemia by electrocardiogram or imaging. Compared to symptomatic patients, those with SMI had fewer subsequent revascularizations (16% vs 27%, p <0.001) regardless of treatment assignment and fewer hospitalizations for acute coronary syndrome (7% vs 12%, p <0.04). No significant differences in outcomes were observed between the 2 treatment groups, although there was a trend toward fewer deaths in the PCI group (n = 7, 5%) compared to the optimal medical therapy (OMT) group (n = 16, 11%, p = 0.12). In conclusion, addition of PCI to OMT did not decrease nonfatal cardiac events in patients with SMI but showed a trend toward fewer deaths. Although underpowered, given similar outcomes in other small studies, these findings suggest the need for an adequately powered trial of revascularization versus OMT in SMI patients.

Angiographic disease progression and residual risk of cardiovascular events while on optimal medical therapy: observations from the COURAGE Trial.

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.