Steven P. Sedlis

Percutaneous Coronary Intervention Versus Coronary Artery Bypass Graft Surgery for Patients With Medically Refractory Myocardial Ischemia and Risk Factors for Adverse Outcomes With Bypass: A Multicenter, Randomized Trial

Abstract BACKGROUND Percutaneous coronary intervention (PCI) and coronary artery bypass graft surgery (CABG) are being applied to high-risk populations, but previous randomized trials comparing revascularization methods have excluded a number of important high-risk groups. OBJECTIVES This five-year, multicenter, randomized clinical trial was designed to compare long-term survival among patients with medically refractory myocardial ischemia and a high risk of adverse outcomes assigned to either a CABG or a PCI strategy, which could include stents. METHODS Patients from 16 Veterans Affairs Medical Centers were screened to identify myocardial ischemia refractory to medical management and the presence of one or more risk factors for adverse outcome with CABG, including prior open-heart surgery, age >70 years, left ventricular ejection fraction RESULTS A total of 232 patients was randomized to CABG and 222 to PCI. The 30-day survivals for CABG and PCI were 95% and 97%, respectively. Survival rates for CABG and PCI were 90% versus 94% at six months and 79% versus 80% at 36 months (log-rank test, p = 0.46). CONCLUSIONS Percutaneous coronary intervention is an alternative to CABG for patients with medically refractory myocardial ischemia and a high risk of adverse outcomes with CABG.

Prognostic Value of Fractional Flow Reserve: Linking Physiologic Severity to Clinical Outcomes

BACKGROUND Fractional flow reserve (FFR) has become an established tool for guiding treatment, but its graded relationship to clinical outcomes as modulated by medical therapy versus revascularization remains unclear. OBJECTIVES The study hypothesized that FFR displays a continuous relationship between its numeric value and prognosis, such that lower FFR values confer a higher risk and therefore receive larger absolute benefits from revascularization. METHODS Meta-analysis of study- and patient-level data investigated prognosis after FFR measurement. An interaction term between FFR and revascularization status allowed for an outcomes-based threshold. RESULTS A total of 9,173 (study-level) and 6,961 (patient-level) lesions were included with a median follow-up of 16 and 14 months, respectively. Clinical events increased as FFR decreased, and revascularization showed larger net benefit for lower baseline FFR values. Outcomes-derived FFR thresholds generally occurred around the range 0.75 to 0.80, although limited due to confounding by indication. FFR measured immediately after stenting also showed an inverse relationship with prognosis (hazard ratio: 0.86, 95% confidence interval: 0.80 to 0.93; p < 0.001). An FFR-assisted strategy led to revascularization roughly half as often as an anatomy-based strategy, but with 20% fewer adverse events and 10% better angina relief. CONCLUSIONS FFR demonstrates a continuous and independent relationship with subsequent outcomes, modulated by medical therapy versus revascularization. Lesions with lower FFR values receive larger absolute benefits from revascularization. Measurement of FFR immediately after stenting also shows an inverse gradient of risk, likely from residual diffuse disease. An FFR-guided revascularization strategy significantly reduces events and increases freedom from angina with fewer procedures than an anatomy-based strategy.

Racial differences in performance of invasive cardiac procedures in a Department of Veterans Affairs Medical Center

Racial differences have recently been described in hospital practice, most notably with regard to cardiac procedure utilization. To evaluate the possible reasons behind these differences, we analyzed statistics generated from a surgical referral conference at a large, tertiary care Veterans Affairs hospital between the years 1988 and 1996. In this setting, there is no financial incentive for physicians to recommend or perform invasive procedures, as all physicians are salaried employees of the Veterans Administration. Furthermore, all patients presented at conference have already had cardiac catheterization and are felt to be potential candidates for surgery or angioplasty. Cardiac therapeutic procedures (surgery or percutaneous transluminal coronary angioplasty) were recommended for 1075 of 1474 (72.9%) Caucasian patients and 207 of 322 (64.3%) African-American patients (odds ratio 1.497, 95% confidence interval 1.160 to 1.932, p = 0.0022). Of those patients presented with the option of an invasive procedure, 32 of 207 (15.4%) African-American patients and 89 of 1075 (8.3%) Caucasian patients refused any invasive procedure (odds ratio 2.026, 95% confidence interval 1.311 to 3.130, p = 0.0025). We conclude that reluctance by African-American patients to undergo invasive cardiac procedures may help explain observed disparities in race-related cardiac care.

Percutaneous coronary intervention versus repeat bypass surgery for patients with medically refractory myocardial ischemia: AWESOME randomized trial and registry experience with post-CABG patients

OBJECTIVES This report compares long-term percutaneous coronary intervention (PCI) and coronary artery bypass graft (CABG) survival among post-CABG patients included in the Angina With Extremely Serious Operative Mortality Evaluation (AWESOME) randomized trial and prospective registry. BACKGROUND Repeat CABG surgery is associated with a higher risk of mortality than first-time CABG. The AWESOME is the first randomized trial comparing CABG with PCI to include post-CABG patients. METHODS Over a five-year period (1995 to 2000), patients at 16 hospitals were screened to identify a cohort of 2,431 individuals who had medically refractory myocardial ischemia and at least one of five high-risk factors. There were 454 patients in the randomized trial, of whom 142 had prior CABG. In the physician-directed registry of 1,650 patients, 719 had prior CABG. Of the 327 patient-choice registry patients, 119 had at least one prior CABG. The CABG and PCI survivals for the three groups were compared using Kaplan-Meier curves and log-rank tests. RESULTS The CABG and PCI three-year survival rates were 73% and 76% respectively for the 142 randomized patients (75 and 67 patients) (log-rank = NS). In the physician-directed registry, 155 patients were assigned to reoperation and 357 to PCI (207 received medical therapy); 36-month survivals were 71% and 77% respectively (log-rank = NS). In the patient-choice registry, 32 patients chose reoperation and 74 chose PCI (13 received medical therapy); 36-month survivals were 65% and 86% respectively (log-rank test p = 0.01). CONCLUSIONS Percutaneous coronary intervention is preferable to CABG for many post-CABG patients.

Percutaneous coronary intervention versus coronary bypass graft surgery for diabetic patients with unstable angina and risk factors for adverse outcomes with bypass: Outcome of diabetic patients in the AWESOME randomized trial and registry

OBJECTIVES This study compared survival after percutaneous coronary intervention (PCI) with survival after coronary artery bypass graft surgery (CABG) among diabetics in the Veterans Affairs AWESOME (Angina With Extremely Serious Operative Mortality Evaluation) study randomized trial and registry of high-risk patients. BACKGROUND Previous studies indicate that CABG may be superior to PCI for diabetics, but no comparisons have been made for diabetics at high risk for surgery. METHODS Over five years (1995 to 2000), 2,431 patients with medically refractory myocardial ischemia and at least one of five risk factors (prior CABG, myocardial infarction within seven days, left ventricular ejection fraction <0.35, age >70 years, or an intra-aortic balloon being required to stabilize) were identified. A total of 781 were acceptable for CABG and PCI, and 454 consented to be randomized. The 1,650 patients not acceptable for both CABG and PCI constitute the physician-directed registry, and the 327 who were acceptable but refused to be randomized constitute the patient-choice registry. Diabetes prevalence was 32% (144) among randomized patients, 27% (89) in the patient-choice registry, and 32% (525) in the physician-directed registry. The CABG and PCI survival rates were compared using Kaplan-Meier curves and log-rank tests. RESULTS The respective CABG and PCI 36-month survival rates for diabetic patients were 72% and 81% for randomized patients, 85% and 89% for patient-choice registry patients, and 73% and 71% for the physician-directed registry patients. None of the differences was statistically significant. CONCLUSIONS We conclude that PCI is a relatively safe alternative to CABG for diabetic patients with medically refractory unstable angina who are at high risk for CABG.

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).

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.).

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).

Optimal medical therapy with or without percutaneous coronary intervention for patients with stable coronary artery disease and chronic kidney disease.

Chronic kidney disease (CKD) is a risk factor for poor outcomes in patients with coronary artery disease (CAD), but it is unknown whether CKD influences the efficacy of alternative CAD treatment strategies. Thus, we compared outcomes in stable CAD patients with and without CKD randomized to percutaneous coronary intervention (PCI) and optimal medical therapy (OMT) or OMT alone in a post hoc analysis of the 2,287 patient COURAGE study. At baseline, 320 patients (14%) had CKD defined as a glomerular filtration rate of <60 mL/min/1.73 m(2), as estimated by the abbreviated 4-variable Modification of Diet in Renal Disease equation. The patients with CKD were older (68 +/- 9 vs 61 +/- 10 years; p <0.001) and more often had diabetes mellitus (42% vs 33%; p = 0.002), hypertension (81% vs 65%; p <0.03), heart failure (13% vs 3.4%; p <001), and three-vessel CAD (37% vs 29%, p = 0.01). After adjustment for these differences, CKD remained an independent predictor of death or nonfatal myocardial infarction (hazard ratio 1.48, 95% confidence interval 1.15 to 1.90). PCI had no effect on these outcomes. Furthermore, at 36 months, a similar percentage of patients with CKD treated with OMT (70%) and PCI plus OMT (76%) were angina free compared to patients without CKD. In conclusion, CKD is an important determinant of clinical outcomes in patients with stable CAD, regardless of the treatment strategy. Although PCI did not reduce the risk of death or myocardial infarction when added to OMT for patients with CKD, it also was not associated with worse outcomes in this high-risk group.

Long-Term Prognostic Significance of Dobutamine Echocardiography in Patients With Suspected Coronary Artery Disease: Results of a 5-Year Follow-Up Study

OBJECTIVES This study sought to assess the long-term prognostic utility of dobutamine stress echocardiography in predicting fatal and nonfatal cardiac events. BACKGROUND Although dobutamine stress echocardiography has improved sensitivity and specificity for detection of coronary artery disease, little is known of its predictive value for long-term cardiac events. Therefore, we followed up 120 consecutive patients who underwent dobutamine echocardiography for suspected coronary disease from March 1989 to August 1991. METHODS All patients presenting for coronary angiography for chest pain were eligible for recruitment. Follow-up was 100% complete at 5 years (range 3.0 to 6.1). Cardiac events were defined as cardiac death or nonfatal myocardial infarction or the need for coronary revascularization (coronary angioplasty or bypass surgery). RESULTS Positive (n = 78) and negative (n = 42) dobutamine test groups differed in their rates of coronary artery bypass graft surgery (37.2% vs. 9.5%, p < 0.001, respectively) and mortality. Of 26 total deaths, 22 occurred in the group with positive dobutamine test results (28% vs. 9.5%, p < 0.018); all 7 cardiac deaths occurred in this group as well (9% vs. 0%, p < 0.045). By multivariate regression analysis, positive results on dobutamine echocardiography remained independently predictive of future cardiac death after left ventricular ejection fraction and other clinical variables were accounted for. CONCLUSIONS A positive finding on dobutamine echocardiography is an independent predictor of long-term cardiac mortality, whereas a negative finding confers a significantly reduced likelihood of cardiac death as much as 5 years from initial testing. We conclude that dobutamine stress echocardiography can be used to predict which patients with suspected coronary artery disease are at low risk for cardiac death and do not require concurrent nuclear or invasive testing.