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.

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.).

The effect of compression socks worn during a marathon on hemostatic balance.

INTRODUCTION: Marathon running evokes parallel increases in markers of coagulation and fibrinolysis (i.e. hemostatic activation) immediately following strenuous, endurance exercise such that hemostatic balance is maintained. However, other factors incident to marathon running (i.e. dehydration, travel) may disproportionately activate the coagulatory system, increasing blood clot risk after an endurance event in otherwise healthy individuals. We investigated the effect of compression socks on exercise-induced hemostatic activation and balance in endurance athletes running the 2013 Hartford Marathon. METHODS: Adults (n = 20) were divided into compression sock (SOCK; n = 10) and control (CONTROL; n = 10) groups. Age, anthropometrics, vital signs, training mileage and finishing time were collected. Venous blood samples were collected 1 day before, immediately after and 1 day following the marathon for analysis of coagulatory (i.e. thrombin-antithrombin complex [TAT] and D-dimer) and fibrinolytic (i.e. tissue plasminogen activator [t-PA]) factors. RESULTS: Plasma D-dimer, TAT and t-PA did not differ between groups at baseline (p > 0.16). There were no significant group · time interactions (all p ≥ 0.17), however, average t-PA was lower in SOCK (8.9 ± 0.7 ng/mL) than CONTROL (11.2 ± 0.7 ng/mL) (p = 0.04). Average TAT also tended to be lower in SOCK (2.8 ± 0.2 µg/L) than CONTROL (3.4 ± 0.2 µg/L) (p = 0.07). CONCLUSIONS: Our results suggest that overall hemostatic activation (both coagulation and fibrinolysis) following a marathon tended to be lower with compression socks. Thus, compression socks do not adversely influence markers of hemostasis, appear safe for overall use in runners and may reduce exercise-associated hemostatic activation in individuals at risk for deep vein thrombosis.

Changes in muscle strength in individuals with statin-induced myopathy: A summary of 3 investigations.

BACKGROUND: There are inconsistent findings regarding muscular weakness in individuals with statin-induced myalgia. OBJECTIVE: We used rigorous muscle testing to compare findings from 3 investigations in 3 different study populations to determine if statin myalgia is associated with measurable weakness. METHODS: In all 3 studies, we measured maximal isometric handgrip strength, resting respiratory exchange ratio (RER), and knee extensor isometric and isokinetic force. In 2 of the 3 studies, elbow flexor isometric and isokinetic force and knee endurance fatigue index were also assessed. Knee extensor and elbow flexor measurements were obtained using an isokinetic dynamometer. Resting RER was measured using a metabolic breath-by-breath collection method. Measurement outcomes were compared on vs off drug. RESULTS: In study 1, 18 participants fit the criteria for statin myalgia. Participants taking atorvastatin 80 mg daily had significantly lower muscle strength in 5 (P < .05) of 14 measured variables. Participants on placebo (N = 10) with myalgia had significantly lower muscle strength in 4 (P < .05) of 14 measured variables. In study 2, 18 participants tested positive for statin-induced myalgia when receiving simvastatin 20 mg daily and displayed no significant muscle strength changes (all P > .05). In study 3, 11 patients with statin-induced myalgia completed the study and had a significant decrease in 2 (P < .05) of 10 leg muscle strength variables. In all 3 studies, no significant changes were shown for handgrip strength or RER (all P > .05). CONCLUSION: Our results indicate that after a short-term treatment with statin therapy, a rigorous muscle strength protocol does not show decrements of muscle strength in subjects with statin myalgia. Short-term treatment with statin therapy is not common in clinical practice. Thus, future studies should examine the effects of prolonged statin therapy on muscle strength.

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.

Influence of chronic exercise on carotid atherosclerosis in marathon runners.

OBJECTIVES: The effect of habitual, high-intensity exercise training on the progression of atherosclerosis is unclear. We assessed indices of vascular health (central systolic blood pressure (SBP) and arterial stiffness as well as carotid intima-medial thickness (cIMT)) in addition to cardiovascular risk factors of trained runners versus their untrained spouses or partners to evaluate the impact of exercise on the development of carotid atherosclerosis. SETTING: field study at Boston Marathon. PARTICIPANTS: 42 qualifiers (mean age±SD: 46±13 years, 21 women) for the 2012 Boston Marathon and their sedentary domestic controls (46±12 years, n=21 women). OUTCOMES: We measured medical and running history, vital signs, anthropometrics, blood lipids, C reactive protein (CRP), 10 years Framingham risk, central arterial stiffness and SBP and cIMT. RESULTS: Multiple cardiovascular risk factors, including CRP, non-high-density lipoprotein cholesterol, triglycerides, heart rate, body weight and body mass index (all p<0.05), were reduced in the runners. The left and right cIMT, as well as central SBP, were not different between the two groups (all p>0.31) and were associated with age (all r≥0.41; p<0.01) and Framingham risk score (all r≥0.44; p<0.01) independent of exercise group (all p>0.08 for interactions). The amplification of the central pressure waveform (augmentation pressure at heart rate 75 bpm) was also not different between the two groups (p=0.07) but was related to age (p<0.01) and group (p=0.02) in a multiple linear regression model. CONCLUSIONS: Habitual endurance exercise improves the cardiovascular risk profile, but does not reduce the magnitude of carotid atherosclerosis associated with age and cardiovascular risk factors.

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).

Frequency, predictors, and consequences of crossing over to revascularization within 12 months of randomization to optimal medical therapy in the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial.

BACKGROUND: In the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial, some patients with stable ischemic heart disease randomized to optimal medical therapy (OMT) crossed over to early revascularization. The predictors and outcomes of patients who crossed over from OMT to revascularization are unknown. METHODS AND RESULTS: We compared characteristics of OMT patients who did and did not undergo revascularization within 12 months and created a Cox regression model to identify predictors of early revascularization. Patients' health status was measured with the Seattle Angina Questionnaire. To quantify the potential consequences of initiating OMT without percutaneous coronary intervention, we compared the outcomes of crossover patients with a matched cohort randomized to immediate percutaneous coronary intervention. Among 1148 patients randomized to OMT, 185 (16.1%) underwent early revascularization. Patient characteristics independently associated with early revascularization were worse baseline Seattle Angina Questionnaire scores and healthcare system. Among 156 OMT patients undergoing early revascularization matched to 156 patients randomized to percutaneous coronary intervention, rates of mortality (hazard ratio=0.51 [0.13-2.1]) and nonfatal myocardial infarction (hazard ratio=1.9 [0.75-4.6]) were similar, as were 1-year Seattle Angina Questionnaire scores. OMT patients, however, experienced worse health status over the initial year of treatment and more unstable angina admissions (hazard ratio=2.8 [1.1-7.5]). CONCLUSION: Among COURAGE patients assigned to OMT alone, patients' angina, dissatisfaction with their current treatment, and, to a lesser extent, their health system were associated with early revascularization. Because early crossover was not associated with an increase in irreversible ischemic events or impaired 12-month health status, these findings support an initial trial of OMT in stable ischemic heart disease with close follow-up of the most symptomatic patients. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00007657.

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.

All-cause readmission and repeat revascularization after percutaneous coronary intervention.

BACKGROUND: Percutaneous coronary intervention (PCI) is one of the most frequently performed cardiac interventions. However, there is limited data regarding the cause of recurrent hospitalization and repeat revascularization. The aim of this study was to assess re-hospitalization and repeat revascularization within 30 days of the initial hospitalization for PCI, using data from Opolskie Voivodeship, National Health Fund (NHF) Registry. METHODS: The study population consisted of all PCI patients treated in three interventional cardiology laboratories in Opolskie Voivodeship in Poland between 1 July 2008 and 30 June 2009. All PCI patients who died during the initial hospitalization or who were transferred to other units were excluded from the analysis. The study end-point comprised 30 day all-cause readmission and repeat revascularization. RESULTS: A total of 2,039 PCI patients were included in the analysis. The all-cause 30-day readmission rate was 14.6%. The 30-day readmission rate of acute coronary syndrome (ACS) patients was significantly higher compared to the stable coronary disease patients (ACS 15.8%, non-ACS 10.7%, p = 0.008). The 30-day readmission rate did not differ between the three cardiac laboratories. Approximately half (46.2%) of all readmitted patients underwent a repeat revascularization procedure, mainly in the form of PCI. The overall all-cause 30-day mortality rate was 0.8%. Compared to the PCI patients who did not require readmission, the readmitted patients had a significantly higher all-cause 30-day mortality rate (3.6% vs 0.3%, p < 0.001). CONCLUSIONS: Almost one in seven PCI patients requires readmission within 30 days of hospital discharge. Approximately 50% of all readmitted PCI patients resulted in a repeat revascularization procedure. PCI patients who were readmitted within 30 days of an index PCI procedure had a significantly higher all-cause 30-day mortality rate.

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.

Impact of metabolic syndrome and diabetes on prognosis and outcomes with early percutaneous coronary intervention in the COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation) trial.

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).

The cost-effectiveness of percutaneous coronary intervention as a function of angina severity in patients with stable angina.

BACKGROUND: The COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation) trial compared percutaneous coronary intervention (PCI) plus optimal medical therapy (OMT) to OMT alone in reducing the risk of cardiovascular events in 2287 patients with stable coronary disease. We examined the cost-effectiveness of PCI as a function of angina severity at the time of randomization. METHODS AND RESULTS: Angina severity was assessed with the Seattle Angina Questionnaire (SAQ). Patients were grouped into tertiles based on the distribution of baseline scores such that higher tertiles represented better health status. Clinically significant improvement from baseline within individual patients was defined as score increases of >8 for physical limitation, >20 for angina frequency, and >16 for quality-of-life domains. The incremental cost-effectiveness ratio for PCI was calculated as the difference in costs divided by the difference in proportion of patients with clinically significant improvement. Improvement in angina severity was significantly greater for PCI patients in the lowest and middle tertiles. The number of patients needed to treat was much larger for the highest tertile. The added in-trial cost of PCI ranged from $7300 to $13 000. Incremental cost-effectiveness ratios ranged from $80 000 to $330 000 for the lowest and middle tertiles and from $520 000 to >$3 million for the highest tertile for 1 additional patient to achieve significant clinical improvement in health status. CONCLUSIONS: The incremental cost of PCI to provide meaningful clinical benefit above that achieved by OMT alone was lower for patients with severe angina than for those with mild or no angina. However, it is uncertain that at any level of angina severity that PCI as an initial strategy would achieve a socially acceptable cost threshold. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00007657.

Do major cardiovascular outcomes in patients with stable ischemic heart disease in the clinical outcomes utilizing revascularization and aggressive drug evaluation trial differ by healthcare system?

BACKGROUND: The Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial enrolled patients from 3 distinct healthcare systems (HCSs) in North America. The primary aim of this study was to determine whether there is a treatment difference in cardiovascular outcomes by HCS. METHODS AND RESULTS: The study population included 968 patients from the US Department of Veterans Affairs (VA), 386 from the US non-VA, and 931 from Canada with different comorbidities and prognoses. The primary outcome was all-cause mortality or nonfatal myocardial infarction (MI) during the median 4.6-year follow-up. Baseline demographics were similar between percutaneous coronary intervention and optimal medical therapy treatment groups within each HCS. After follow-up, the primary end point of total mortality and nonfatal MI was not statistically significant between percutaneous coronary intervention and optimal medical therapy, regardless of HCS: VA, 22.3% versus 21.9% (hazard ratio, 1.05; 95% CI, 0.80-1.38; P=0.95); US non-VA, 15.8% versus 21.8% (hazard ratio, 0.70; 95% CI, 0.43-1.12; P=0.24); Canadian HCS, 17.3% versus 13.5% (hazard ratio, 1.30; 95% CI, 0.93-1.83; P=0.17). The interaction between HCSs and treatment was not statistically significant. Long-term mortality was significantly higher in the VA system as a result of significantly greater comorbidity and worse left ventricular function. CONCLUSIONS: In the COURAGE trial, addition of percutaneous coronary intervention to optimal medical therapy did not improve 5-year survival or reduce MI or other major adverse cardiovascular events regardless of whether patients were Canadian or American or US veterans or non-veterans. Outcome differences were largely explained by differences in baseline characteristics known to affect long-term prognosis.

Intensive multifactorial intervention for stable coronary artery disease: optimal medical therapy in the COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation) trial.

OBJECTIVES: This paper describes the medical therapy used in the COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation) trial and its effect on risk factors. BACKGROUND: Most cardiovascular clinical trials test a single intervention. The COURAGE trial tested multiple lifestyle and pharmacologic interventions (optimal medical therapy) with or without percutaneous coronary intervention in patients with stable coronary disease. METHODS: All patients, regardless of treatment assignment, received equivalent lifestyle and pharmacologic interventions for secondary prevention. Most medications were provided at no cost. Therapy was administered by nurse case managers according to protocols designed to achieve predefined lifestyle and risk factor goals. RESULTS: The patients (n = 2,287) were followed for 4.6 years. There were no significant differences between treatment groups in proportion of patients achieving therapeutic goals. The proportion of smokers decreased from 23% to 19% (p = 0.025), those who reported <7% of calories from saturated fat increased from 46% to 80% (p < 0.001), and those who walked >or=150 min/week increased from 58% to 66% (p < 0.001). Body mass index increased from 28.8 +/- 0.13 kg/m(2) to 29.3 +/- 0.23 kg/m(2) (p < 0.001). Appropriate medication use increased from pre-randomization to 5 years as follows: antiplatelets 87% to 96%; beta-blockers 69% to 85%; renin-angiotensin-aldosterone system inhibitors 46% to 72%; and statins 64% to 93%. Systolic blood pressure decreased from a median of 131 +/- 0.49 mm Hg to 123 +/- 0.88 mm Hg. Low-density lipoprotein cholesterol decreased from a median of 101 +/- 0.83 mg/dl to 72 +/- 0.88 mg/dl. CONCLUSIONS: Secondary prevention was applied equally and intensively to both treatment groups in the COURAGE trial by nurse case managers with treatment protocols and resulted in significant improvement in risk factors. Optimal medical therapy in the COURAGE trial provides an effective model for secondary prevention among patients with chronic coronary disease. (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation; NCT00007657).