Chaitman, Bernard

Background: Circulating cardiac troponin T concentrations are higher in men than in women, but the biological causes and clinical implications of this observation are poorly understood. Methods and Results: We measured cardiac troponin T with a high-sensitivity assay (hsTnT) in 684 women and 1601 men with type 2 diabetes (T2D) and stable ischemic heart disease (SIHD) who were enrolled in the BARI 2D trial. Median (IQR) hsTnT was higher in men [12.4 ng/L (8.7-20.8)] than in women [9.1 ng/L (6.4-15.6); P<0.0001] and a higher proportion of men (43.6%) than women (29.1%) were above the current established upper reference limit of 14 ng/L (P<0.0001). Sex remained a significant predictor of natural log normalized hsTnT after adjusting for a wide array of covariables, including age, race, insulin use, renal function, ejection fraction, and HbA1c. Within quintiles of hsTnT measured at baseline, the 5-year incidence of the composite cardiovascular outcome of myocardial infarction, stroke, heart failure, or death was consistently higher in women than in men (Figure 1). In sex-stratified Cox models adjusting for possible confounders, the increase in the relative risk of the composite endpoint across quintiles of hsTnT appeared similar in men and women (Figure 2). Conclusions: In the BARI 2D trial, women have lower baseline hsTnT concentrations, but higher absolute risk of myocardial infarction, stroke, heart failure, or death for a given concentration of hsTnT. These data raise the question of whether sex-specific cutoffs for cardiac troponin T should be considered.

Introduction: The benefits of optimal medical therapy (OMT) with or without percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) surgery have been evaluated in patients with Type 2 Diabetes Mellitus (T2DM) and stable coronary artery disease (CAD) but analyses have not been stratified by detailed angiographic CAD burden or left ventricular ejection fraction (LVEF). Methods: A patient-level meta-analysis was undertaken among T2DM patients enrolled in COURAGE, BARI 2D and FREEDOM to assess the impact of randomization to OMT, PCI + OMT, or CABG + OMT on a composite end-point of Death/MI/Stroke and stratified by LVEF (≥ 50%, < 50%), 1, 2 or 3 vessel disease (VD) (% diameter stenosis ≥ 50%) and presence or absence of proximal left anterior descending (pLAD) disease. Hazard ratios (HR) for treatment groups were calculated from Cox regression models including all patients adjusting for trial and revascularization stratum in BARI 2D. Multivariable adjustment for risk factors was performed as a sensitivity analysis. Results: There were 5,034 patients included in the analysis (BARI 2D: n=2,368, COURAGE: n=766, FREEDOM: n=1,900) of whom 17% had LVEF < 50%, 29% had pLAD, and 77% had 2 or 3 VD. A total of 1,591 patients were randomized to OMT alone, 2,118 to PCI + OMT, and 1,325 to CABG + OMT. There were 1,116 events during a median 4.5 year follow-up. There was no significant effect on outcomes with OMT vs PCI + OMT irrespective of LVEF, presence/absence of pLAD and number of VD. By contrast, CABG + OMT significantly reduced the risk of Death/MI/Stroke in patients with 2 or 3 VD, irrespective of LVEF and presence/absence of pLAD (see Table). Results were similar with multivariable adjustment. Conclusions: In patients with T2DM and stable CAD, OMT alone appears to be as effective as PCI + OMT while CABG + OMT significantly reduces cardiovascular events in those with multivessel CAD, irrespective of LVEF or presence of pLAD.

Background— The Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial assigned patients with type 2 diabetes mellitus to prompt coronary revascularization plus intensive medical therapy versus intensive medical therapy alone and reported no significant difference in mortality. Among patients selected for coronary artery bypass graft surgery, prompt coronary revascularization was associated with a significant reduction in death/myocardial infarction/stroke compared with intensive medical therapy. We hypothesized that clinical and angiographic risk stratification would affect the effectiveness of the treatments overall and within revascularization strata. Methods and Results— An angiographic risk score was developed from variables assessed at randomization; independent prognostic factors were myocardial jeopardy index, total number of coronary lesions, prior coronary revascularization, and left ventricular ejection fraction. The Framingham Risk Score for patients with coronary disease was used to summarize clinical risk. Cardiovascular event rates were compared by assigned treatment within high-risk and low-risk subgroups. Overall, no outcome differences between the intensive medical therapy and prompt coronary revascularization groups were seen in any risk stratum. The 5-year risk of death/myocardial infarction/stroke was 36.8% for intensive medical therapy compared with 24.8% for prompt coronary revascularization among the 381 coronary artery bypass graft surgery–selected patients in the highest angiographic risk tertile ( P =0.005); this treatment effect was amplified in patients with both high angiographic and high Framingham risk (47.3% intensive medical therapy versus 27.1% prompt coronary revascularization; P =0.010; hazard ratio=2.10; P =0.009). Treatment group differences were not significant in other clinical-angiographic risk groups within the coronary artery bypass graft surgery stratum, or in any subgroups within the percutaneous coronary intervention stratum. Conclusion— Among patients with diabetes mellitus and stable ischemic heart disease, a strategy of prompt coronary artery bypass graft surgery significantly reduces the rate of death/myocardial infarction MI/stroke in those with extensive coronary artery disease or impaired left ventricular function. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00006305.

Background —The impact of percutaneous transluminal coronary angioplasty (PTCA) and coronary artery bypass grafting (CABG) on long-term mortality rates in the presence of various demographic, clinical, and angiographic factors is uncertain in the population of patients suitable for both procedures. Methods and Results —In the Bypass Angioplasty Revascularization Investigation (BARI) randomized trial and registry, 3610 patients who were eligible to receive PTCA and CABG were revascularized between 1989 and 1992. Multivariate Cox models were used to identify factors associated with 5-year mortality and cardiac mortality, with particular attention to factors that interact with treatment. Diabetic patients receiving insulin had higher mortality and cardiac mortality rates with PTCA compared with CABG (relative risk [RR] 1.78 and 2.63, respectively, P <0.001), and patients with ST elevation had higher cardiac mortality rates with CABG than with PTCA (RR 4.08, P <0.001). Factors most strongly associated with high overall mortality rates were insulin-treated diabetes, congestive heart failure, kidney failure, and older age. Black race was also associated with higher mortality rates (RR 1.49, P =0.019). Conclusions —A set of variables was identified that could be used to help select a revascularization procedure and to evaluate risk of long-term mortality in the population of patients considering revascularization.

Background —Numerous studies have shown that women undergoing coronary revascularization procedures do so at a higher risk for an adverse outcome compared with men. However, the impact of advances in technology and improvements in techniques on in-hospital and long-term outcome after revascularization in women is unclear. Methods and Results —We evaluated 1829 patients with symptomatic multivessel coronary disease randomized to CABG or PTCA in the Bypass Angioplasty Revascularization Investigation (BARI), of whom 27% were women. As expected, women were older (64.0 versus 60.5 years), with more congestive heart failure (14% versus 7%), hypertension (68% versus 42%), treated diabetes mellitus (31% versus 15%), and unstable angina (67% versus 61%) than men but had similar preservation of left ventricular function and extent of multivessel disease. Women assigned to surgery received the same number of total grafts but fewer internal mammary artery grafts (72% versus 85%, P <0.01), and those assigned to angioplasty had more intended lesions (76% versus 71%, P <0.01) successfully dilated than men. At an average of 5.4 years’ follow-up, crude mortality rates were similar in women (12.8%) and men (12.0%). The Cox regression model adjusting for baseline differences revealed that women had a significantly lower risk of death (relative risk, 0.60; 95% CI, 0.43 to 0.84; P =0.003) but not a significantly lower risk of death plus myocardial infarction (relative risk, 0.84; 95% CI, 0.66 to 1.07; P =0.16) than men. Conclusions —Although the unadjusted mortality rate suggests that women and men undergoing CABG and PTCA have a similar 5-year mortality, women have higher risk profiles; consequently, contrary to previous reports, female sex is an independent predictor of improved 5-year survival after we control for multiple risk factors.

Background Cardiac mortality and myocardial infarction (MI) rates are used to evaluate the efficacy of coronary artery bypass grafting (CABG) and percutaneous transluminal coronary angioplasty (PTCA). We compared 5-year cardiac mortality and MI rates in 1829 patients with multivessel disease randomized to CABG or PTCA. Methods and Results The 5-year cardiac mortality rate was 8.0% in patients assigned to PTCA compared with 4.9% in those assigned to CABG (relative risk [RR] of 1.55 with a 95% confidence interval [CI] of 1.07 to 2.23; P =.022). In a subgroup of 1476 nondiabetic patients, there were no significant differences between treatment groups in cardiac mortality either overall (4.6% versus 4.2%; RR=1.04, 95% CI, 0.65 to 1.66; P =.908) or in subgroups based on symptoms, left ventricular function, number of diseased vessels, or stenotic proximal left anterior descending artery. The two treatment groups had similar event rates for the combined end point of cardiac death or MI. The RR for cardiac mortality in 264 patients who sustained an MI compared with those who did not was 5.9 ( P <.001). MIs were more common after CABG during index hospitalization ( P =.004), but in the PTCA group, they were more common after discharge ( P <.001). Conclusions The Bypass Angioplasty Revascularization Investigation (BARI) trial indicates 5-year cardiac mortality in patients with multivessel disease was significantly greater after initial treatment with PTCA than with CABG. The difference was manifest in diabetic patients on drug therapy. There were no significant differences overall for the composite end point of cardiac mortality or MI between treatment groups or for cardiac mortality in nondiabetic patients regardless of symptoms, left ventricular function, number of diseased vessels, or stenotic proximal left anterior descending artery.

Background Combined severe proximal left anterior descending and proximal left circumflex coronary artery disease, or left main equivalent (LMEQ) disease, defines a prognostic high-risk angiographic subset of patients with chronic ischemic heart disease. While numerous observational and randomized clinical trials showed prolonged survival in surgically compared with medically treated patients with left main coronary artery disease, relatively few observational studies compared surgical and medical therapies in patients with LMEQ disease. The present report of 912 patients with LMEQ disease in the Coronary Artery Surgery Study (CASS) Registry extends the originally published 5-year surgical and medical group survival analysis to more than 16 years of follow-up and permits analysis of LMEQ patient subgroups. Methods and Results The CASS Registry contains 912 patients with LMEQ disease, defined as combined stenoses of ≥70% in the proximal left anterior descending coronary artery before the first septal perforator and proximal circumflex coronary artery before the first obtuse marginal branch, initially treated with either surgical or nonsurgical therapy. The 15-year cumulative survival estimates were 44% for the 630 patients in the surgical group and 31% for the 282 patients in the medical group. Median survival in the surgical group was 13.1 years (12.7 to 14.1 years, 95% confidence limits) compared with only 6.2 years (4.8 to 7.9 years) in the medical group (difference, 6.9 years; P <.0001). Median survival was also significantly longer in the surgical group stratified by age, sex, anginal class, left ventricular (LV) function, and coronary anatomy. However, coronary artery bypass graft (CABG) surgery did not significantly prolong median survival in patient subgroups with (1) normal LV systolic function, even if a significant right coronary artery stenosis (≥70%) also was present, and (2) mildly abnormal (LV score, 6 to 10) LV systolic function. The 15-year cumulative survival in patients with normal LV systolic function in the surgical and medical groups was 63% and 54%, respectively. Median survival was >15 years in both the surgical and medical groups ( P =NS). In patients with normal LV systolic function and right coronary artery stenosis ≥70%, the 15-year cumulative survival was also similar in the surgical and medical groups (63% and 53%, respectively). Median survival was >15 years in both the surgical and medical groups ( P =NS). The 15-year cumulative survival estimates in all subgroups were affected by convergence of the surgical and medical group survival curves caused by a disproportionate increase in late surgical group mortality. Overall, 26% of patients in the medical group ultimately underwent CABG surgery. If all medical group patients had survived long enough, about 65% would be estimated to have had surgery by 15 years. When the CASS Registry patients with LMEQ disease who participated in the randomized trial or who were randomizable were analyzed, CABG surgery did not prolong the 15-year cumulative survival estimates compared with nonsurgical therapy for randomized (71% versus 67%, respectively) and for randomizable patients (62% versus 92%, respectively) with an LV ejection fraction ≥50%. Conclusions This report, which extends follow-up of more than 16 years in CASS Registry patients with LMEQ disease, shows that CABG surgery prolongs life in most clinical and angiographic subgroups. However, median survival was not prolonged by CABG surgery in patients with normal LV systolic function, even if a significant right coronary artery stenosis (≥70%) also was present or in patients with an LV ejection fraction ≥50% who participated in the CASS randomized trial or who were randomizable. These results extend our understanding of the natural history of LMEQ disease and permit a more accurate estimate of long-term surgical and medical group survival. These long-term results should allow clinicians to make more informed decisions about the best choice of treatment available for patients with similar clinical and angiographic features.

Background There are few data comparing clinical outcome and potential indications for routine post–myocardial infarction cardiac catheterization and revascularization of patients who sustain a non–Q-wave versus Q-wave infarct after thrombolytic therapy. Methods and Results A secondary analysis of 2634 patients enrolled in the TIMI II trial with a first myocardial infarction was performed to determine 6-week and 1-year cardiac event rates and identify clinical and angiographic differences between the 1867 patients (70.9%) who evolved a Q-wave infarct and the 767 patients (29.1%) who sustained a non–Q-wave infarct after treatment with intravenous thrombolytic therapy. Male sex (85.3% versus 75.6%; P <.001) and anterior wall infarcts (53.8% versus 43.7%; P <.001) were more frequent in the Q-wave versus the non–Q-wave group. During recombinant tissue-type plasminogen activator (rTPA) infusion, a greater percentage of non–Q-wave patients (37.3% versus 23.5%; P =.001) had normalization of initial ST-segment elevation. Infarct-related artery patency (TIMI flow grade 2 or 3) ( P =.02), complete infarct-related artery reperfusion (TIMI 3 flow grade) ( P <.001), and the percentage of patients with a predischarge resting left ventricular ejection fraction >55% ( P <.001) were greater in the non–Q-wave group. New congestive heart failure during hospitalization developed more frequently in Q-wave patients (18.9% versus 11.6%; P <.001). After 42 days, the occurrences of reinfarction ( P =.76), death ( P =.76), and combined death or reinfarction ( P =.43) were similar in patients assigned to the invasive or conservative postlytic management strategy, regardless of infarct type. One-year mortality was 3.4% versus 4.4% for non–Q-wave versus Q-wave infarct type, respectively ( P =.25). Conclusions Angiographic and clinical differences were observed between patients who present with initial ST-segment elevation and evolve early non–Q-wave versus Q-wave myocardial infarcts after treatment with rTPA, heparin, and aspirin. Early mortality and adverse clinical cardiac events in these patients are not significantly different after a conservative compared with an invasive treatment strategy, regardless of whether the infarct type is non–Q wave or Q wave.

Background Observational and randomized studies designed to compare surgical and medical therapies in patients with left main coronary artery disease (LMCD) have shown that coronary artery bypass graft (CABG) surgery prolongs life in most patients with LMCD. The present report of 1484 patients with LMCD in the Coronary Artery Surgery Study (CASS) Registry extends the originally published 5-year surgical and medical group survival analysis to more than 16 years of follow-up and permits analysis of LMCD patient subgroups. Methods and Results The CASS Registry contains 1484 patients with ≥50% left main coronary artery stenosis initially treated with either surgical or nonsurgical therapy. The 15-year cumulative survival estimates were 37% for the 1153 patients in the surgical group compared with 27% for the 331 patients in the medical group. Median survival in the surgical group was 13.3 years (12.8 to 13.8 years, 95% confidence limits) compared with only 6.6 years (5.4 to 7.9 years) in the medical group (difference, 6.7 years; P <.0001). Median survival was also significantly longer in the surgical group stratified by age, sex, anginal class, left ventricular (LV) function, coronary anatomy, and the extent of LMCD. However, CABG surgery did not significantly prolong median survival in patient subgroups with (1) left main coronary stenosis of 50% to 59%; (2) normal LV systolic function; (3) normal or mildly abnormal LV systolic function and a right coronary artery stenosis ≥70%; and (4) a nonstenotic (≤70%) right coronary artery. The 15-year cumulative survival for patients with normal LV systolic function in the surgical and medical groups was 42% and 51%, respectively. Median survival was 14.7 years in the surgical group and >15 years in the medical group ( P =NS). In patients with normal LV systolic function and a right coronary artery stenosis ≥70%, the 15-year cumulative survival rates were also similar in the surgical and medical groups (40% and 48%, respectively). Median survival was 14.3 years in the surgical group and 14.2 years in the medical group ( P =NS). The 15-year cumulative survival estimates for all subgroups were affected by convergence of the surgical and medical survival group curves owing to a disproportionate increase in the late surgical group mortality. Overall, 25% of patients in the medical group ultimately underwent CABG surgery. If all medical group patients had survived long enough, about 47% would be estimated to have had surgery by 15 years. Conclusions This report, which extends follow-up of more than 16 years in CASS Registry patients with LMCD, shows that CABG surgery prolongs life in most clinical and angiographic subgroups. However, median survival was not prolonged by CABG surgery in patients with normal LV systolic function, even if a significant right coronary artery stenosis (≥70%) also was present. These results extend our understanding of the natural history of LMCD and permit a more accurate estimate of long-term surgical and medical group survival.

Background — Data are absent that compare midterm angiographic outcome between patients with and without diabetes after initial percutaneous transluminal coronary angioplasty (PTCA) and coronary artery bypass graft surgery (CABG). Importantly, diabetes mellitus may differentially influence long-term survival after PTCA or CABG. Methods and Results — Patients with multivessel coronary disease who were previously enrolled in the Bypass Angiopathy Revascularization Investigation to compare initial PTCA versus CABG (n=1829) and who had a reduction in jeopardized myocardium after initial revascularization and at least 1 angiogram during 5-year follow-up were analyzed (n=897). This included 369 CABG-treated patients (16% with diabetes) and 528 PTCA-treated patients (18% with diabetes). The influence of diabetes on angiographic increase in percentage of jeopardized myocardium after initial revascularization with either PTCA or CABG was investigated. Among PTCA patients, the mean percentage increase in total jeopardized myocardium was significantly greater in those with diabetes than in those without at 1-year protocol-directed angiography (42% versus 24%, P =0.05) and on the first clinically performed (unscheduled) angiogram within 30 months (63% versus 50%, P =0.01) but not at 5-year protocol-directed angiography (34% versus 26%, P =0.33). This excess midterm risk associated with diabetes persisted after statistical adjustment. In contrast, among CABG patients, diabetes was not associated with percentage increase in jeopardized myocardium at any angiographic follow-up interval. Conclusions — Presence of diabetes differentially influences worsening of jeopardized myocardium after initial PTCA compared with CABG. This differential effect occurs irrespective of whether follow-up angiography is undertaken for clinical or nonclinical purposes.