BARI 2D Research Articles

Appropriate Revascularization in Stable Angina: Lessons From the BARI 2D Trial

BackgroundThe 2012 Guidelines for Diagnosis and Management of Patients with Stable Ischemic Heart Disease recommend intensive antianginal and risk factor treatment (optimal medical management [OMT]) before considering revascularization to relieve symptoms. The Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial randomized patients with ischemic heart disease and anatomy suitable to revascularization to (1) initial OMT with revascularization if needed or (2) initial revascularization plus OMT and found no difference in major cardiovascular events. Ultimately, however, 37.9% of the OMT group was revascularized during the 5-year follow-up period. MethodsData from the 1192 patients randomized to OMT were analyzed to identify subgroups in which the incidence of revascularization was so high that direct revascularization without a trial period could be justified. Multivariate logistic analysis, Cox regression models of baseline data, and a landmark analysis of participants who did not undergo revascularization at 6 months were constructed. ResultsThe models that used only data available at the time of study entry had limited predictive value for revascularization by 6 months or by 5 years; however, the model incorporating severity of angina during the first 6 months could better predict revascularization (C statistic = 0.789). ConclusionsWith the possible exception of patients with severe angina and proximal left anterior descending artery disease, this analysis supports the recommendation of the 2012 guidelines for a trial of OMT before revascularization. Patients could not be identified at the time of catheterization, but a short period of close follow-up during OMT identified the nearly 40% of patients who underwent revascularization.

Re-evaluation of the cardiovascular safety of rosiglitazone

Rosiglitazone is one of thiazolidinediones (TZD),an antidiabetic agent which improves insulin sensitivity,but the cardiovascular safety of the drug remains controversial.The new re-evaluation of the RECORD trial has suggested that rosiglitazone-containing drugs do not show an increased risk of heart attack compared to the standard type 2 diabetes medicines,such as mefformin and sulfonylurea.The post hoc analysis of the BARI 2D also indicates that rosiglitazone may not relate with the increased risk of major ischemic cardiovascular events.According to these new results,there is no clear evidence that rosiglitazone may increase cardiovascular risk.The U.S.Food and Drug Administration announced in July 2013 that it is requiring the removal of some prescribing and dispensing restrictions for rosiglitazone-containing diabetes medicines. Key words: Rosiglitazone; Diabetes mellitus, type 2 ; Cardiovascular events; Safety

Risk Factors for Incident Peripheral Arterial Disease in Type 2 Diabetes: Results From the Bypass Angioplasty Revascularization Investigation in Type 2 Diabetes (BARI 2D) Trial

OBJECTIVEThe aim of this article was to define risk factors for incidence of peripheral arterial disease (PAD) in a large cohort of patients with type 2 diabetes mellitus (T2DM), overall and within the context of differing glycemic control strategies.RESEARCH DESIGN AND METHODSThe Bypass Angioplasty Revascularization Investigation in Type 2 Diabetes (BARI 2D) randomized controlled trial assigned participants to insulin-sensitizing (IS) therapy versus insulin-providing (IP) therapy. A total of 1,479 participants with normal ankle-brachial index (ABI) at study entry were eligible for analysis. PAD outcomes included new ABI ≤0.9 with decrease at least 0.1 from baseline, lower extremity revascularization, or lower extremity amputation. Baseline risk factors within the overall cohort and time-varying risk factors within each assigned glycemic control arm were assessed using Cox proportional hazards models.RESULTSDuring an average 4.6 years of follow-up, 303 participants (20.5%) experienced an incident case of PAD. Age, sex, race, and baseline smoking status were all significantly associated with incident PAD in the BARI 2D cohort. Additional baseline risk factors included pulse pressure, HbA1c, and albumin-to-creatinine ratio (P < 0.05 for each). In stratified analyses of time-varying covariates, changes in BMI, LDL, HDL, systolic blood pressure, and pulse pressure were most predictive among IS patients, while change in HbA1c was most predictive among IP patients.CONCLUSIONSAmong patients with T2DM, traditional cardiovascular risk factors were the main predictors of incident PAD cases. Stratified analyses showed different risk factors were predictive for patients treated with IS medications versus those treated with IP medications.

Select Articles Published on the Topic of Coronary Heart Disease in 2013

Select Articles Published on the Topic of Coronary Heart Disease in 2013

Assessing Clinical Impact of Myocardial Perfusion Studies: Ischemia or Other Prognostic Indicators?

One of the major strengths of nuclear myocardial perfusion imaging (MPI) is the robust prognostic databases from observational studies demonstrating significantly different outcomes in patients with low-risk vs high-risk scans. The severity of the MPI defect can be semi-quantitated using the summed stress score (SSS) and summed difference score (SDS). SSS is more strongly associated with mortality, whereas SDS is the better predictor of subsequent coronary angiography and revascularization. The strength of MPI variables as prognostic indicators decreases when adjusted for prognostically important clinical and stress test variables. Nonetheless, most studies of general patient populations have demonstrated that MPI adds incremental prognostic value to clinical and stress test information. In contrast to these positive results from observational studies, the application of MPI ischemia as a treatment guide in several recent trials (DIAD, WOMEN, COURAGE, BARI 2D, STICH) has largely failed to identify patient subsets with improved outcome. This issue will continue to be investigated in the ongoing PROMISE and ISCHEMIA trials.

Coronary artery bypass in patients with type 2 diabetes: Experience from the Bypass Angioplasty Revascularization Investigation 2 Diabetes trial

Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) was a study of management strategies for diabetic patients with myocardial ischemia and coronary artery disease. In a 2×2 design, early revascularization versus medical management with or without late revascularization and insulin sensitization versus insulin provision were examined. No advantage for either strategy was seen, except in the group undergoing early coronary artery bypass grafting (CABG). In that group, a reduction in subsequent myocardial infarction was noted. The purpose of our report was to characterize the conduct and short-term outcomes for CABG that led to this result. Data from the BARI 2D CABG stratum were collected, including the baseline demographic and cardiovascular characteristics, technical details of the operation, and perioperative morbidity and mortality, and analyzed. A total of 347 patients were studied. The average cardiac function was normal, and most had multivessel disease. Almost all had undergone CABG by way of a median sternotomy using an internal mammary artery, and one third were off pump. The perioperative morbidity and mortality were low and compared well with larger outcomes databases. BARI 2D showed that early CABG in patients with type 2 diabetes and myocardial ischemia and multivessel disease reduced the subsequent myocardial infarction rates. The present results have demonstrated that this was achieved using off-pump surgery in certain cases, standard myocardial protection, and routine use of the internal mammary artery or other arterial grafts.

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The FREEDOM trial: a definitive answer to coronary artery bypass grafting or stents in patients with diabetes and multivessel coronary artery disease

For the last two decades, there has been intense debate between cardiologists and surgeons regarding what the most effective mode is, of revascularization in patients with diabetes already receiving optimal medical therapy, who additionally require invasive coronary artery intervention on symptomatic and/or prognostic grounds. The debate began in earnest with the original interim analyses of the BARI trial, suggesting a survival advantage for the subset of patients with diabetes receiving coronary artery bypass grafting (CABG) rather than angioplasty [1], and was confirmed in the final 10-year follow-up with respective survival rates of 58 vs 46% (P=0.025) [2]. Since then, the recent publications of the 5-year outcomes of the SYNTAX Trial [3] and the ASCERT registry [4 ]h ave provided strong evidence that CABG, in comparison with percutaneous coronary intervention (PCI), offers a strong survival benefi ta s well as a marked reduction in myocardial infarction (MI) and repeat revascularization in patients with intermediate and more severe coronary artery disease (CAD) as judged by SYNTAX scores of >22. Because of the perception that patients with diabetes often have more severe and aggressive forms of CAD, intuitively there is an impression that they are also therefore likely to derive greater clinical benefit from CABG than from PCI. Others have argued, however, that significant advances in both medical therapy and stent technology would have eliminated the former—if any— benefit of CABG over PCI. Consequently, until the recent publication of the FREEDOM Trial [5], the relative merits of both interventions in patients with diabetes have also been fiercely debated. The main reason for the controversy was that, until the FREEDOM Trial, there was not a single trial in patients with diabetes, adequately powered, to give a definitive answer regarding whether CABG offered a survival or any other clinical benefit over PCI. It is therefore informative not only to examine the results of the FREEDOM trial, but also in the context of whether its findings are consistent with other evidence. The FREEDOM trial randomized 1900 patients with diabetes and multivessel CAD, already receiving aggressive medical therapy, to CABG or PCI with drug-eluting stents. This trial therefore included more patients with diabetes than the total from all the subgroups from the other randomized trials. The primary 5-year composite outcome of death from any cause, non-fatal MI or stroke, occurred in 26.6% of the PCI group and 18.7% of the CABG group (P=0.005). The benefit of CABG was driven by superior outcomes in both rates of death from any cause (10.6 vs 14.9%; P= 0.049) and MI (6.0 vs 13.9%; P< 0.001), but at the cost of a higher risk of stroke in the CABG group (5.2 vs 2.4%; P=0.03). And it is important to appreciate that this benefit of CABG over PCI was still evident although all patients were receiving aggressive medical therapy. It is alsoworth noting the relative risk of non-fatal stroke between CABG and PCI was 2.41 at 1 year, narrowing to 1.72 at 5 years [5]. The absolute clinical difference in stroke rates between CABG and PCI was actually small, being 2.1% (30 of 1444) and 0.82% (12 of 1471), respectively, at 1 year and 4.8% (65 of 1344) and 2.8% (42 of 1500) at 5 years. The early difference in stroke is almost certainly a consequence of the very well-recognized perioperative risk of stroke with CABG, with subsequent rates being more similar between the interventions. The same phenomenon was observed in the SYNTAX trial with CABG patients receiving less in the way of single and dual anti-platelet medication in the postoperative period [5]. Are the results of the FREEDOM trial consistent with other evidence? The answer is overwhelmingly, yes, from several other sources. Probably, the second-most definitive piece of evidence regarding the relative benefits of interventions in patients with diabetes is a subset analysis of the collaborative analysis of individual patient data from 7812 patients from 10 trials, of whom 1243 had diabetes, by Hlatky and co-workers. At a median follow-up of 5.9 years, mortality was substantially lower in the CABG group than in the PCI group (hazard ratio [HR]: 0.70, 95% confidence interval [CI]: 0.56–0.87) [6]. Since this analysis, several other pieces of data have emerged supporting the use of CABG rather than PCI in patients with diabetes. In the BARI 2D trial, 2368 patients with both type 2 diabetes and CAD were randomized to intensive medical therapy alone or to additionally undergo either prompt revascularization with PCI or CABG, according to the preference of the treating physician [7]. At 5 years, there was no significant difference in the composite primary end point between the PCI and medical therapy groups. In contrast, in the CABG group, the rate of major cardiovascular

Impact of Glycemic Control Strategies on the Progression of Diabetic Peripheral Neuropathy in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) Cohort

OBJECTIVEThe Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial demonstrated similar long-term clinical effectiveness of insulin-sensitizing (IS) versus insulin-providing (IP) treatments for type 2 diabetes on cardiovascular outcomes in a cohort with documented coronary artery disease. We evaluated the effects of randomized glycemic control strategy (IS vs. IP) on the prevalence and incidence of diabetic peripheral neuropathy (DPN).RESEARCH DESIGN AND METHODSDPN (defined as Michigan Neuropathy Screening Instrument [MNSI] clinical examination score >2) was assessed at baseline and yearly for 4 years. DPN prevalence and incidence were compared by intention-to-treat modeling by logistic generalized estimating equation models for prevalence and Kaplan-Meier estimates and Cox regression models for incidence rates.RESULTSResults are reported for 2,159 BARI 2D participants (70% males) with valid baseline and at least one follow-up MNSI score (mean age 62 ± 9 years, mean HbA1c 7.7 ± 1.6%, diabetes duration 10 ± 9 years). There were no differences in the prevalence of DPN between the IS and the IP groups throughout the 4 years of follow-up. In 1,075 BARI 2D participants with no DPN at baseline, the 4-year cumulative incidence rate of DPN was significantly lower in the IS (66%) than in the IP (72%) strategy group (P = 0.02), which remained significant after adjusting for the in-trial HbA1c (P = 0.04). In subgroup analyses, IS strategy had a greater benefit in men (hazard ratio 0.75 [99% CI 0.58–0.99], P < 0.01).CONCLUSIONSAmong patients with type 2 diabetes followed for up to 4 years during BARI 2D, a glycemic control therapy with IS significantly reduced the incidence of DPN compared with IP therapy and may add further benefit for men.

Favorable Effects of Insulin Sensitizers Pertinent to Peripheral Arterial Disease in Type 2 Diabetes

OBJECTIVEThe aim of this manuscript was to report the risk of incident peripheral arterial disease (PAD) in a large randomized clinical trial that enrolled participants with stable coronary artery disease and type 2 diabetes and compare the risk between assigned treatment arms.RESEARCH DESIGN AND METHODSThe Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial randomly assigned participants to insulin sensitization (IS) therapy versus insulin-providing (IP) therapy for glycemic control. Results showed similar 5-year mortality in the two glycemic treatment arms. In secondary analyses reported here, we examine the effects of treatment assignment on the incidence of PAD. A total of 1,479 BARI 2D participants with normal ankle-brachial index (ABI) (0.91–1.30) were eligible for analysis. The following PAD-related outcomes are evaluated in this article: new low ABI ≤0.9, a lower-extremity revascularization, lower-extremity amputation, and a composite of the three outcomes.RESULTSDuring an average 4.6 years of follow-up, 303 participants experienced one or more of the outcomes listed above. Incidence of the composite outcome was significantly lower among participants assigned to IS therapy than those assigned to IP therapy (16.9 vs. 24.1%; P < 0.001). The difference was significant in time-to-event analysis (hazard ratio 0.66 [95% CI 0.51–0.83], P < 0.001) and remained significant after adjustment for in-trial HbA1c (0.76 [0.59–0.96], P = 0.02).CONCLUSIONSIn participants with type 2 diabetes who are free from PAD, a glycemic control strategy of insulin sensitization may be the preferred therapeutic strategy to reduce the incidence of PAD and subsequent outcomes.

Change in enrollment patterns, patient selection, and clinical outcomes with the availability of drug-eluting stents in the Bypass Angioplasty Revascularization Investigation 2 Diabetes trial

In the BARI 2D trial, patients with type 2 diabetes and stable coronary artery disease were randomized to prompt revascularization versus intensive medical therapy (IMT). This analysis sought to evaluate how the availability of drug-eluting stents (DESs) has changed practice and outcomes. In BARI 2D, 1,605 patients were in the percutaneous coronary intervention (PCI)-intended stratum. As DES became available midway through recruitment, we report clinical outcomes among patients who underwent IMT versus prompt PCI with bare-metal stents (BMSs) or DES up to 4 years. In North America, after DES became available, selection for the PCI-intended stratum increased from 73% to 79% (P = .003). Fewer BMS than DES patients had total occlusions treated or underwent rotational atherectomy (5.6% vs 9.7%, P = .02, and 1.2% vs 3.7%, P < .01, respectively). Subsequent revascularization (IMT 39%, BMS 29%, DES 21%, P < .01) and target vessel revascularization (BMS 16.1% vs DES 9.6%, P = .03) were lower with DES. Angina at 2 years tended to be less common with DES (IMT 39%, BMS 37%, DES 29%, P = .04, for 3 groups, P = .07 for DES vs BMS). The composite of death, myocardial infarction, or stroke was IMT 16.0%, BMS 20.5%, DES 17.5%; P = .80. When DES became available in North America, patients were more likely to be selected into the PCI-intended stratum. Compared with patients receiving BMS, those receiving DES tended to have less target vessel revascularization and angina.

An Insight into the Recent Diabetes Trials: What is the Best Approach to Prevent Macrovascular and Microvascular Complications?

Type 2 diabetes mellitus (T2DM) accounts for 90%-95% of all diabetes cases. The overarching goal in caring for patients with T2DM is to prevent microvascular and macrovascular complications with glycemic control. Several studies such as UKPDS, DCCT, and EDIC have been performed to evaluate the effects of glucose control on tissue complications in patients with diabetes. In recent diabetes trials including ACCORD, ADVANCE, VADT, BARI 2D, and ORIGIN, intensive glucose control did not prevent macrovascular complications in older patients with long-standing diabetes with either cardiovascular disease or risk factors for cardiovascular disease. In fact, intensive therapy was associated with increased mortality in the ACCORD trial. Although no clear macrovascular benefit was seen in these trials, analyses of earlier studies in younger patients with type 1 and type 2 diabetes have suggested a significant benefit of intensive glycemic control in patients with a shorter duration of diabetes and less vasculopathy. In the UKPDS, the incidence of microvascular disease, particularly retinopathy, was reduced significantly with intensive glucose control, but in the more recent trials (ACCORD, ADVANCE, VADT, ORIGIN) the benefit was relatively modest and limited to reduced proteinuria. Perhaps the most important message from the above trials is to optimize control of cardiovascular risk factors. Although the goal HbA1c to prevent microvascular and macrovascular complications, per the American Diabetes Association, is less than 7%, hypoglycemia should be avoided as it can increase the risk for severe cardiovascular events.

Race/Ethnic Disparities in Risk Factor Control and Survival in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) Trial

This study sought to evaluate the impact of race/ethnicity on cardiovascular risk factor control and on clinical outcomes in a setting of comparable access to medical care. The BARI 2D trial enrolled 1,750 participants from the United States and Canada that self-reported either White non-Hispanic (n = 1,189), Black non-Hispanic (n = 349), or Hispanic (n = 212) race/ethnicity. Participants had type 2 diabetes and coronary artery disease and were randomized to cardiac and glycemic treatment strategies. All patients received intensive target-based medical treatment for cardiac risk factors. Average follow-up was 5.3 years. Kaplan-Meier survival curves and Cox proportional hazards regression models were constructed to assess potential differences in mortality and cardiovascular outcomes across racial/ethnic groups. Long-term risk of death and death/myocardial infarction/stroke did not vary significantly by race/ethnicity (5-year death: 11.0% Whites, 13.7% Blacks, 8.7% Hispanics, p = 0.19; adjusted hazard ratio 1.18 Black versus White, 95% confidence interval 0.84 to 1.67, p = 0.33 and 0.82 Hispanic versus White, 95% confidence interval 0.51 to 1.34, p = 0.43). Among the 1,168 patients with suboptimal risk factor control at baseline, the ability to attain better risk factor control during the trial was associated with higher 5-year survival (71%, 86% and 95% for patients with 0 or 1, 2, and 3 factors in control, respectively, p <0.001); this pattern was observed within each race/ethnic group. In conclusion, significant race/ethnic differences in cardiac risk profiles that persisted during follow-up did not translate into significant differences in 5-year death or death/MI/stroke.

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Rosiglitazone and outcomes for patients with diabetes mellitus and coronary artery disease in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial.

Rosiglitazone improves glycemic control for patients with type 2 diabetes mellitus, but there remains controversy regarding an observed association with cardiovascular hazard. The cardiovascular effects of rosiglitazone for patients with coronary artery disease remain unknown. To examine any association between rosiglitazone use and cardiovascular events among patients with diabetes mellitus and coronary artery disease, we analyzed events among 2368 patients with type 2 diabetes mellitus and coronary artery disease in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial. Total mortality, composite death, myocardial infarction, and stroke, and the individual incidence of death, myocardial infarction, stroke, congestive heart failure, and fractures, were compared during 4.5 years of follow-up among patients treated with rosiglitazone versus patients not receiving a thiazolidinedione by use of Cox proportional hazards and Kaplan-Meier analyses that included propensity matching. After multivariable adjustment, among patients treated with rosiglitazone, mortality was similar (hazard ratio [HR], 0.83; 95% confidence interval [CI], 0.58-1.18), whereas there was a lower incidence of composite death, myocardial infarction, and stroke (HR, 0.72; 95% CI, 0.55-0.93) and stroke (HR, 0.36; 95% CI, 0.16-0.86) and a higher incidence of fractures (HR, 1.62; 95% CI, 1.05-2.51); the incidence of myocardial infarction (HR, 0.77; 95% CI, 0.54-1.10) and congestive heart failure (HR, 1.22; 95% CI, 0.84-1.82) did not differ significantly. Among propensity-matched patients, rates of major ischemic cardiovascular events and congestive heart failure were not significantly different. Among patients with type 2 diabetes mellitus and coronary artery disease in the BARI 2D trial, neither on-treatment nor propensity-matched analysis supported an association of rosiglitazone treatment with an increase in major ischemic cardiovascular events. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00006305.

Potential modification of the UKPDS risk engine and evaluation of macrovascular event rates in controlled clinical trials

BackgroundThe aim of this study was to evaluate a modified UKPDS risk engine in order to establish a risk prediction benchmark for the general diabetes population.MethodsData sources were summary demographic and risk factor data from the major type 2 diabetes mellitus outcomes studies, including ACCORD, ADVANCE, VADT, RECORD, PROactive, ADOPT, and BARI 2D. Patients in these studies spanned a wide spectrum of disease, from drug-naïve to insulin-dependent. Cardiovascular events/major adverse coronary events (CVE/MACE) were primary or safety end points. Overall observed rates for cardiovascular events/MACE were summarized, and the observed annualized event rates were calculated using linear approximation. Simulation studies were then conducted using original (cardiovascular history excluded) and modified (cardiovascular history included) United Kingdom Prospective Diabetes Study (UKPDS) models; the predicted event rates were then compared with the observed event rates for all studies. The consistency of the predicted rates derived from each model was then evaluated using descriptive statistics and linear regression.ResultsThe original UKPDS model tended to overestimate event rates across studies. The ratio of predicted events versus observed MACE ranged from 0.9 to 2.0, with mean of 1.5 ± 0.4 and a coefficient of variation of 26% (R2 = 0.80). However, cardiovascular risk predictions were more precise using a modified UKPDS model; the ratio of predicted versus observed MACE events ranged from 1.8 to 2.4, with a mean of 2.1 ± 0.25 and a coefficient of variation of 13% (R2 = 0.94).ConclusionA modified UKPDS model which includes adjustments for prior cardiovascular history has the potential for use as a tool for benchmarking and may be useful for predicting cardiovascular rates in clinical studies. This modification could be further evaluated, recalibrated, and validated using patient-level information derived from prospective clinical studies to yield greater predictability.

Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D)

Objectives: The purpose of this analysis was to assess in patients with type 2 diabetes and stable coronary artery disease, (CAD) whether the risk of all-cause mortality and cardiovascular events varied according to the presence or absence, of angina and angina equivalent symptoms. Background: Data on the prognostic value of symptoms in these patients are limited. Methods Post-hoc analysis was performed in 2,364 patients with type 2 diabetes and documented CAD enrolled in the, BARI 2D (Bypass Angioplasty Revascularization Investigation 2 Diabetes) trial to determine the occurrence of, death and composite of death, myocardial infarction, and stroke during a 5-year follow-up according to cardiac symptoms at baseline. Results: There were 1,434 patients with angina (A), 506 with angina equivalents (E), and 424 with neither of these (N). The cumulative death rates (total 316) were 12% in A, 14% in E, and 10% in N (p 0.3), and cardiovascular composite rates (total 548) were 24% in A, 24% in E, and 21% in N (p 0.5). Compared with N, the hazard ratios adjusted for confounders were not different for death in A (1.11; 99% CI: 0.81 to 1.53) and E (1.17; 99% CI: 0.81 to 1.68) or for cardiovascular events in A (1.17; 99% CI: 0.92 to 1.50) and E (1.11; 99% CI: 0.84 to 1.48). Conclusions: Whatever their symptom status, patients with type 2 diabetes and stable CAD were at similar risk of cardiovascular events and death. These findings suggest that these patients may be similarly managed in terms of risk stratification and preventive therapies. (Bypass Angioplasty Revascularization Investigation 2 Diabetes [BARI 2D]; {type:clinical-trial,attrs:{text:NC6305,term_id:NC6305}}NC6305) (J Am Coll Cardiol 2013;61:702–11) © 2013 by the American College of Cardiology Foundation Diabetes mellitus (DM) is a global epidemic. Accelerated atherosclerosis in DM leads to high incidence of Cardiovascular Disease (CVD). Coronary Artery Disease (CAD) accounts for large fraction of morbidity, mortality and cost of DM. In Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial, it was analyzed whether symptoms affect prognosis or not in Type 2 DM and CAD with documented ischemia. A total of 2368 patients with Type 2DM and stable CAD with documented ischemia were followed up for 5.3 years. Patients were divided into those with angina, angina equivalent (dyspnea, palpitation or diaphoresis on exertion) or no cardiac symptom. Stable CAD and Type 2DM had similar long term prognosis across a variety of cardiovascular outcome irrespective of their symptomatic status. Five-year death rate was 12% with angina, 14% with angina equivalent, and 10% in asymptomatic patient. Cumulative 5-year composite outcome rate were 24%, 24% and 21%, respectively. Asymptomatic patients were at the same relative high risk for all cause mortality, the composite outcome, CVD death, nonfatal myocardial infarction (MI) and nonfatal stroke, compared to patients with angina or angina equivalent. These were independent of baseline characteristics, severity of CAD and coronary revascularization. In separate analysis of optimized medical therapy and revascularization, the outcome remained unchanged. Left ventricular systolic function was normal in all three groups. Exercise induced ischemia causing diastolic dysfunction could be responsible for exertional dyspnea qualifying angina equivalent. Summarizing, the take home message of this study is that Type 2DM, stable CAD with documented ischemia and no symptoms are at the same high risk for all cause mortality and major cardiovascular outcomes compared to those with angina or angina equivalent. These patients should be similarly managed in terms of risk stratification and preventive therapy.

Impact of ischemia and scar on therapeutic benefit of myocardial revascularization

The question of how to optimally manage coronary artery disease (CAD) has been a challenge for the cardiology community. The results of early, large randomized clinical trials (RCTs) comparing strategies of medical therapy alone versus revascularization plus medical therapy in patients with stable CAD suggested a survival advantage for a revascularization strategy in the setting of more advanced, higher-risk CAD (left main, three-vessel CAD), but a superiority of medical therapy in patients with more limited, relatively lower-risk CAD (one vessel, limited two-vessel CAD). The results of the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) and Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trials redefined the management of CAD, supporting the concept that the impact of aggressively applied modern "medical therapy" on patient survival and patient-reported outcomes is not further improved by the addition of percutaneous intervention. On the other hand, RCTs incorporating fractional flow reserve have shown that this physiologic metric can help identify which patients will benefit from a revascularization strategy. This paradigm has been extended to the use of myocardial perfusion imaging-identified ischemia to determine which patients may have enhanced survival with early revascularization versus medical therapy. Although data from a series of observational studies suggest that inducible ischemia on myocardial perfusion scintigraphy can identify revascularization candidates, several studies, including substudies from major RCTs, do not support this idea. Until RCTs comparing revascularization with medical therapy strategies are performed, many questions remain open. The correct thresholds for treatment, the metric to guide treatment, and how revascularization should be performed are as yet undefined.

Risk Factor Control for Coronary Artery Disease Secondary Prevention in Large Randomized Trials

This study evaluated data from 3 federally funded trials that focused on optimal medical therapy to determine if formalized attempts at risk factor control within clinical trials are effective in achieving guideline-driven treatment goals for diabetic patients with coronary artery disease (CAD). Despite clear evidence of benefit for CAD secondary prevention, the level of risk factor control in clinical practice has been disappointing. We obtained data from the COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation) diabetes subgroup, (n = 766 of 2,287), the BARI 2D (Bypass Angioplasty Revascularization Investigation 2 Diabetes) trial (n = 2,368), and the FREEDOM (Comparison of Two Treatments for Multivessel Coronary Artery Disease in Individuals With Diabetes) trial (n = 1,900) to evaluate the proportion of patients achieving guideline-based, protocol-driven treatment targets for systolic blood pressure, low-density lipoprotein cholesterol, smoking cessation, and hemoglobin A1c. The primary outcome measure was the proportion of diabetic CAD patients meeting all 4 pre-specified targets at 1 year after enrollment. The pooled data include 5,034 diabetic patients. The percentages of patients achieving the 1-year low-density lipoprotein cholesterol targets compared with baseline increased from 55% to 77% in COURAGE, from 59% to 75% in BARI 2D, and from 34% to 42% in FREEDOM. Although similar improved trends were seen for systolic blood pressure, glycemic control, and smoking cessation, only 18% of the COURAGE diabetes subgroup, 23% of BARI 2D patients, and 8% of FREEDOM patients met all 4 pre-specified treatment targets at 1 year of follow-up. A significant proportion of diabetic CAD patients fail to achieve pre-specified targets for 4 major modifiable cardiovascular risk factors in clinical trials. We conclude that fundamentally new thinking is needed to explore approaches to achieve optimal secondary prevention treatment goals. (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation; NCT00007657) (Bypass Angioplasty Revascularization Investigation 2 Diabetes [BARI 2D]; NCT00006305) (Comparison of Two Treatments for Multivessel Coronary Artery Disease in Individuals With Diabetes [FREEDOM]; NCT00086450).

Determinants of successful glycemic control among participants in the BARI 2D Trial: A Post-hoc Analysis

ObjectiveThe BARI 2D trial compared insulin provision (IP) versus insulin sensitization (IS) for the primary outcome of total mortality in participants with T2DM and cardiovascular disease (CVD). In this analysis we examine baseline characteristics that are associated with successful long-term glycemic control. Research design and methodsIn a 2×2 factorial design, 2368 participants were randomized to either IP or IS therapy, and to either prompt revascularization with medical therapy or medical therapy alone. Successful long-term glycemic control (success) was defined by simultaneously meeting 1) a mean HbA1c level of <7.0% after each participant's third year of follow-up period, and 2) adherence with medications only from the assigned glycemic treatment arm during >80% of the BARI 2D follow-up. The association between baseline variables and success was determined using unadjusted and adjusted logistic regression models. Results1917 participants (962 IP and 955 IS participants) had sufficiently long follow-up and data for this analysis. Among these IP and IS participants, 235 and 335 participants met both criteria of success, respectively (p<0.001). Those not on insulin at entry had higher odds of success (OR 2.25; CI 1.79–2.82) when treated with IS versus IP medications, irrespective of baseline HbA1c levels. Younger age, shorter duration of T2DM, and lower HbA1c at baseline were also each independently associated with higher success when treated with IS versus IP medications. ConclusionPatients similar to those in the BARI 2D trial may have a higher chance of achieving success with IS versus IP medications if they are younger, have shorter duration of T2DM, have lower HbA1c levels, have moderate or strenuous physically activity, and are not on insulin. In contrast, increasing age, longer duration of T2DM, higher HbA1c, and insulin therapy are associated with increased chance of success if treated with IP medications.