Clinical Outcomes Utilizing Revascularization And Aggressive Drug Evaluation Research Articles

Rates of Elective Percutaneous Coronary Intervention in England and Wales: Impact of COURAGE and ORBITA Trials.

Background There are limited data about how COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation) and ORBITA (Objective Randomized Blinded Investigation With Optimal Medical Therapy of Angioplasty in Stable Angina) trials have impacted percutaneous coronary intervention (PCI) practices at regional or national level. We evaluated temporal trends in elective PCI rates for stable angina and, specifically, examined the impact of the COURAGE and ORBITA trials on PCI practices in England and Wales. Methods and Results We used national PCI data comprising >1.2million patients undergoing PCI between January 2006 and December 2019. Patient demographics, procedural details, and clinical outcomes were analyzed, and temporal trends in PCI rates for stable angina were compared before and after the publication of the COURAGE and ORBITA trials. Of 1 245 802 PCI procedures, 430 248 (34.5%) were performed for stable angina. Over the study period, the number of elective PCI procedures per year (30 823 in 2006 to 34 103 in 2019) and per 100 000 population estimates (50.7 in 2006 to 58.4 in 2019) remained stable. The proportion of patients undergoing elective PCI without angina symptoms almost doubled from 5.1% to 9.7%. The incidence rate of elective PCI volume after the COURAGE trial, published in 2007, was not different from before the trial was published (incidence rate ratio, 1.06 [95% CI, 0.69-1.62]). It also remained stable after the publication of the ORBITA trial in 2017 (incidence rate ratio, 0.96 [95% CI, 0.74-1.23]). Conclusions In this nationwide analysis, rates of elective PCI for stable angina remained stable over 14 years. Publication of the COURAGE and ORBITA trials had no impact on elective PCI activity.

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 6.5years) had higher all-cause mortality (adjusted hazard ratio [aHR] 1.98 [1.61 to 2.43]) than participants from VA COURAGE (median follow-up: 4.6years). 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.

Clinical Implications and Debates on the International Study of Comparative Health Effectiveness with Medical and Invasive Approaches Trial.

The International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) was eagerly awaited study in the field of ischemic heart disease. Following the presentation and publication of ISCHEMIA, multiple opinions and viewpoints get complicated. The ongoing debates have been including the relevance of coronary revascularization, noninvasive diagnostic methods, and invasive ischemic testing in patients with stable ischemic heart disease (SIHD). Prior to ISCHEMIA, observational studies indicated the potential of coronary revascularization for improving clinical outcomes, while the randomized Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial did not support the plausible concept. Although the Fractional Flow Reserve Versus Angiography for Multivessel Evaluation (FAME) 2 trial implied the superiority of percutaneous coronary intervention over medical therapy alone, the clinical relevance of coronary revascularization to improve outcomes and quality of life has been questioned. As a consequence, the ISCHEMIA trial did not demonstrate clear benefits in reducing clinical events but showed antianginal effects of revascularization. This landmark trial also suggested the difficulties of noninvasive ischemia testing rather than computed tomography angiography. Despite the complex results, the ISCHEMIA trial may simplify the clinical indications of coronary revascularization in patients with SIHD. Future publications from the ISCHEMIA trial and debates on the results will sharpen our thinking and understanding.

An Application of the Cure Model to a Cardiovascular Clinical Trial

Intermediate events play an important role in determining the risk of a medical condition over time and should thus be accounted for in survival analysis. Myocardial infarction (MI) is one such condition whose hazard also depends upon the possible occurrence of an intermediate event—acute coronary syndrome (ACS). Accounting for the role that a possible ACS event plays in altering the hazard of MI becomes complicated when there is a cured fraction in the population. Data from the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial presents the scenario where the existence of a cured fraction is highly likely. In this article, we model the risk of developing an MI, while properly accounting for the effect/impact of a probable intermediate ACS event on that risk in the presence of a cured fraction. We adapt a maximum likelihood estimation approach to estimate the regression coefficients of this multi-part cure model. Simulation demonstrates satisfactory performance of the proposed estimator. We also utilize this dataset to explore the use of a proportionality constraint to help reduce the dimensionality of this multi-part model. The analysis yields novel findings that can be useful in guiding clinical practice.

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

BackgroundThe 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. ObjectivesThe 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. MethodsOf 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. ResultsDuring 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%. ConclusionsIn 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)

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

BackgroundIndividual risk factor control improves survival in patients with stable ischemic heart disease (SIHD). It is uncertain if multiple risk factor control further extends survival. ObjectivesThis study determined whether a greater number of risk factors at goal predicted improved survival in SIHD patients. MethodsOf 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. ResultsDuring 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). ConclusionsThe 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)

CRT-100.77 Trends In National Hospitalization Rates With Abnormal Stress Tests - Impact of the COURAGE Trial

To assess trends in hospitalization rates among patients with an abnormal stress test in the eras before and after publication of the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial. Based on contemporary literature, trends in patients hospitalized for

Reexamining the Efficacy and Value of Percutaneous Coronary Intervention for Patients With Stable Ischemic Heart Disease

Percutaneous coronary intervention (PCI) continues to be performed frequently for patients with stable ischemic heart disease, despite uncertain efficacy. Individual randomized trial data and meta-analyses have not demonstrated that PCI in addition to optimal medical therapy reduces the incidence of death or myocardial infarction in patients with stable disease. The Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) Trial did not show benefit for cardiovascular outcomes or mortality but did find a modest improvement in quality of life that did not persist at 3 years. Long-term follow-up from COURAGE (up to 15 years) found no differences in mortality, consistent with other published literature. How PCI could reduce long-term mortality or prevent myocardial infarction is not clear because sites of future plaque rupture leading to myocardial infarction are unpredictable and PCI can only treat localized anatomic segments of obstructive atherosclerosis. In addition, PCI is expensive, and the value to society of PCI for stable disease has not been demonstrated. The ISCHEMIA trial will assess the role of PCI for stable ischemic heart disease using newer technology and in patients with greater ischemic burden than in COURAGE. After nearly a decade, the COURAGE trial and other studies have given us pause to critically reexamine the role of PCI for patients with stable ischemic heart disease. Until further research can show that PCI can reduce cardiovascular events in these patients, a first-line strategy of optimal medical therapy is known to be safe, effective, and noninferior to PCI, and our practice should more closely follow this strategy.

Intestinal Microbiota-Generated Metabolite Trimethylamine-N-Oxide and 5-Year Mortality Risk in Stable Coronary Artery Disease: The Contributory Role of Intestinal Microbiota in a COURAGE-Like Patient Cohort.

BackgroundTrimethylamine‐N‐oxide (TMAO), a metabolite derived from gut microbes and dietary phosphatidylcholine, is linked to both coronary artery disease pathogenesis and increased cardiovascular risks. The ability of plasma TMAO to predict 5‐year mortality risk in patients with stable coronary artery disease has not been reported. This study examined the clinical prognostic value of TMAO in patients with stable coronary artery disease who met eligibility criteria for a patient cohort similar to that of the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial.Methods and ResultsWe examined the relationship between fasting plasma TMAO and all‐cause mortality over 5‐year follow‐up in sequential patients with stable coronary artery disease (n=2235) who underwent elective coronary angiography. We identified the COURAGE‐like patient cohort as patients who had evidence of significant coronary artery stenosis and who were managed with optimal medical treatment. Higher plasma TMAO levels were associated with a 4‐fold increased mortality risk. Following adjustments for traditional risk factors, high‐sensitivity C‐reactive protein, and estimated glomerular filtration rate, elevated TMAO levels remained predictive of 5‐year all‐cause mortality risk (quartile 4 versus 1, adjusted hazard ratio 1.95, 95% CI 1.33–2.86; P=0.003). TMAO remained predictive of incident mortality risk following cardiorenal and inflammatory biomarker adjustments to the model (adjusted hazard ratio 1.71, 95% CI 1.11–2.61; P=0.0138) and provided significant incremental prognostic value for all‐cause mortality (net reclassification index 42.37%, P<0.001; improvement in area under receiver operator characteristic curve 70.6–73.76%, P<0.001).ConclusionsElevated plasma TMAO levels portended higher long‐term mortality risk among patients with stable coronary artery disease managed with optimal medical treatment.

Response to Zakkar et al.

HomeCirculationVol. 133, No. 18Response to Zakkar et al Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBResponse to Zakkar et al William S. Weintraub, MD and Kirk N. Garratt, MD William S. WeintraubWilliam S. Weintraub Search for more papers by this author and Kirk N. GarrattKirk N. Garratt Search for more papers by this author Originally published3 May 2016https://doi.org/10.1161/CIR.0000000000000422Circulation. 2016;133:1817IntroductionDo we have sufficient information to guide our choice of therapy for chronic total occlusions (CTOs)? The articles by Weintraub and Garratt (“we” in this rebuttal) and Zakker et al are complementary. Zakker et al are highly critical of technical limitations and outcomes of percutaneous coronary intervention for CTOs, stressing the technical advantages of coronary artery bypass graft (CABG) for CTOs, covering a number of the same studies as Weintraub and Garratt. We placed less emphasis on technical ability to perform CABG for CTOs and more on case selection, the importance of viable myocardium, and clinical outcomes. We stressed that the literature concerning outcomes of CABG for CTOs is limited and that additional studies are needed. Overall comparisons of CABG to percutaneous coronary intervention, such as the Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery (SYNTAX) trial, or of percutaneous coronary intervention to medical therapy, such as the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial, cannot directly address the issue of whether to perform CABG for CTOs. The only randomized comparison of CABG to percutaneous coronary intervention was in a subset of the SYNTAX trial that included 543 CTOs, which found more complete revascularization with CABG. Complete revascularization is a surrogate; presumably, this SYXTAX subset was too small to compare clinical outcomes. We also learned little from nonrandomized comparative effectiveness studies of CABG for CTOs. Even excellent uncontrolled observational studies, such as the one by Holzhey et al, can only tell us that CABG for total occlusions can be performed; it cannot tell us whether CABG improved outcomes. We think it can be agreed that our data are inadequate and that randomized trials would offer considerably better information to guide clinical decisions. In the meantime, careful case selection, preferably with assessment of viability, is appropriate. Previous Back to top Next FiguresReferencesRelatedDetails May 3, 2016Vol 133, Issue 18 Advertisement Article InformationMetrics © 2016 American Heart Association, Inc.https://doi.org/10.1161/CIR.0000000000000422PMID: 27143548 Originally publishedMay 3, 2016 PDF download Advertisement

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.

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

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. 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. 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. 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. 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.

Does ischemia burden in stable coronary artery disease effectively identify revascularization candidates? Ischemia burden in stable coronary artery disease does not effectively identify revascularization candidates.

Over 30 years ago, a benefit of surgical revascularization was demonstrated in patients with stable ischemic heart disease (SIHD) but this was before most of our current disease-modifying medical therapies for coronary artery disease (CAD) were available.1 Analysis of these trials indicated that patients who derived the most benefit from surgery were those with more extensive CAD, particularly those with significant left main CAD or multivessel CAD, including proximal left anterior descending stenosis. After the introduction of percutaneous coronary intervention (PCI), studies were performed in the 1990s comparing PCI with contemporary medical therapy and found no benefit on death, myocardial infarction, or revascularization.2 It was at the time unclear whether this was because of the different revascularization technique or advances in medical therapy. See Response by Hachamovitch Subsequently, 2 large, randomized, multicenter trials were undertaken to determine whether revascularization offered an advantage over intensive medical therapy (optimal medical therapy). The Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) and Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI-2D) trials randomized patients with SIHD to a strategy of routine revascularization in addition to optimal medical therapy or to a strategy of optimal medical therapy alone.3,4 The optimal medical therapy approach included statin-based lipid-lowering therapy with a target low-density lipoprotein 60 to 85 mg/dL, anti-ischemic medications alone or in combination, and angiotensin-converting enzyme inhibition or angiotensin receptor blockade. The COURAGE trial included 2287 patients and used PCI as the revascularization technique. There was no benefit on the primary end point of death or myocardial infarction (MI) for the routine PCI strategy over a median 4.6 years of follow-up and there was also no difference between groups in survival. The BARI-2D trial included 2368 patients with diabetes mellitus and both PCI and surgery were used for revascularization. Randomization was …

Patient selection for elective revascularization to reduce myocardial infarction and mortality: new lessons from randomized trials, coronary physiology, and statistics.

As stated in American College of Cardiology/American Heart Association Guidelines, randomized trials have not demonstrated that elective percutaneous coronary intervention (PCI) reduces myocardial infarction (MI) or mortality over medical treatment. Even the Fractional Flow Reserve Guided PCI Versus Medical Therapy in Stable Coronary Disease (FAME 2) trial showed no statistically significant benefit of PCI over the deferred group by traditional intention-to-treat, nonbenchmark analysis starting at randomization that includes procedure-related events. Benchmark analysis in FAME 2 beginning 1 week after PCI removed procedure-related events that counterbalanced subsequent reduced MI and mortality compared with the deferred group. Meta-analysis of the literature on risk of events related to fractional flow reserve (FFR), including FFR Versus Angiography in Multivessel Evaluation (FAME), and other physiological measures of severity reveal an underappreciated, powerful interdependence among physiological severity of stenosis, diffuse coronary artery disease (CAD), event rates, sample size, and statistical certainty of differences. This analytic review synthesizes an evidenced-based, quantitative hypothesis and potential solution to this issue based on hard data from the literature by coauthors of diverse cardiovascular disciplines in trial design, biostatistics, invasive procedures, coronary physiology, fluid dynamics, coronary pathology, and quantitative imaging. Our synthesis elucidates a dual hypothesis for failure of elective PCI in stable CAD to reduce MI or mortality and novel trial design for selecting patients for whom PCI will likely reduce these events. First, a large burden of global diffuse CAD carries a high risk of coronary events unmitigated by PCI of a focal stenosis. Second, focal stenosis severity in previous randomized revascularization trials has been too modest without objectively quantified sufficient severity to observe benefit of PCI. In previous trials, mixture of diffuse coronary disease and intermediate stenosis may not incur high enough risk for potential benefit by PCI for sample size of reported trials. Greater quantitative severity with …

Achievement of Optimal Medical Therapy Goals for U.S. Adults With Coronary Artery Disease: Results From the REGARDS Study (REasons for Geographic And Racial Differences in Stroke)

In a nonclinical trial setting, we sought to determine the proportion of individuals with coronary artery disease (CAD) with optimal risk factor levels based on the COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive DruG Evaluation) trial. In the COURAGE trial, the addition of percutaneous coronary intervention (PCI) to optimal medical therapy did not reduce the risk of death or myocardial infarction in stable CAD patients but resulted in more revascularization procedures. The REGARDS (REasons for Geographic And Racial Differences in Stroke) study is a national prospective cohort study of 30,239 African-American and white community-dwelling individuals older than 45 years of age who enrolled in 2003 through 2007. We calculated the proportion of 3,167 participants with self-reported CAD meeting 7 risk factor goals based on the COURAGE trial: 1) aspirin use; 2) systolic blood pressure <130 mm Hg and diastolic blood pressure <85 mm Hg (<80 mm Hg if diabetic); 3) low-density lipoprotein cholesterol <85 mg/dl, high-density lipoprotein cholesterol >40 mg/dl, and triglycerides <150 mg/dl; 4) fasting glucose <126 mg/dl; 5) nonsmoking status; 6) body mass index <25 kg/m 2 ; and 7) exercise ≥4 days per week. The mean age of participants was 69 ± 9 years; 33% were African American and 35% were female. Overall, the median number of goals met was 4. Less than one-fourth met ≥5 of the 7 goals, and 16% met all 3 goals for aspirin, blood pressure, and low-density lipoprotein cholesterol. Older age, white race, higher income, more education, and higher physical functioning were independently associated with meeting more goals. There is substantial room for improvement in risk factor reduction among U.S. individuals with CAD.

Predicting Outcome in the COURAGE Trial (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation): Coronary Anatomy Versus Ischemia

The aim of this study was to determine the relative utility of anatomic and ischemic burden of coronary artery disease for predicting outcomes. 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. 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. 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. 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).

Changes in Geographic Variation in the Use of Percutaneous Coronary Intervention for Stable Ischemic Heart Disease After Publication of the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) Trial

Clinical uncertainty is cited as a cause of geographic variation. However, little is known about the effect of comparative effectiveness research on variation. We examined whether geographic variation in the use of percutaneous coronary intervention (PCI) for stable ischemic heart disease (SIHD) declined after publication of the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial. We examined changes in utilization and geographic variation in 67 hospital referral regions using the State Inpatient Databases. We compared age- and sex-adjusted rates of PCI for SIHD before (2006) and after (2008) publication of the COURAGE trial and compared those with contemporaneous changes in PCI volume for acute coronary syndrome. A total of 272,659 PCIs for SIHD from 526 hospitals were included in the analysis. After the publication of the COURAGE trial, PCI volume for SIHD declined by 25% (P<0.001) and decreased by 12% for acute coronary syndrome (P<0.001). This was predominantly attributable to changes in hospital referral regions with the highest levels of utilization pre-COURAGE trial (35% decline in the highest tertile versus 18% in the lowest). As measured by the systematic component of variation, there was substantial geographic variation in the use of PCI for SIHD preceding the publication of the COURAGE trial. Variation declined by 28% (0.53 versus 0.40) after publication, but geographic variation remained higher for SIHD than acute coronary syndrome (0.40 versus 0.17). There was a substantial decline in the use of and geographic variation in PCI for SIHD after the publication of the COURAGE trial. However, geographic variation in the use of PCI for SIHD remained high.

The reversal of cardiology practices: interventions that were tried in vain.

Medical reversal happens when new trials-better powered, designed or controlled than predecessors--contradict current standard of care. The Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial and CAST study are notable examples of investigations that overturned current practice by demonstrating that these interventions offered no survival benefits. In this mini-review, we summarize our experience reviewing a decade of original articles in the New England Journal of Medicine with an eye towards investigations that reversed cardiology practice. From the management of arrhythmias to lipids to percutaneous coronary intervention (PCI) and finally, hemodynamics, reversals in the cardiology literature cover a broad set of practices. These reversals are instructive in that many of the therapies overturned were widely adopted and based on either sound physiologic reasoning or observational trials.

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 <60ml/min/1.73m(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 36months 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.

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

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. 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]). 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. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00007657.