Bypass Angioplasty Revascularization Investigation 2 Diabetes - BARI 2D

Description:

BARI 2D is a study of patients with type 2 diabetes with mild or stable cardiac symptoms designed to determine whether treatment targeted to attenuate insulin resistance can arrest or retard progression of coronary artery disease compared with treatment with an insulin-providing approach. It is also designed (2 x 2 factorial study design) to determine whether early revascularization compared with medical therapy in these patients reduces mortality and morbidity.

Hypothesis:

  1. Method of Glycemic Control Hypothesis: With a target glycated hemoglobin level of <7.0%, a strategy of hyperglycemia management directed at insulin sensitization would result in lower 5-year mortality compared with a strategy of insulin-providing approach. 
  2. Coronary Revascularization Hypothesis: A strategy of initial elective revascularization (surgical or percutaneous approach selected prior to randomization) combined with aggressive medical therapy would result in lower 5-year mortality compared with a strategy of aggressive medical therapy alone.

Study Design

  • Randomized
  • Parallel
  • Factorial
  • Stratified

Patients Screened: 4,623
Patients Enrolled: 2,368
Mean Follow Up: 5.3 years
Mean Patient Age: 62 years
Female: 30%

Patient Populations:

  • Patients of age 25 or more with the diagnosis of type 2 diabetes mellitus, with a coronary angiogram showing one or more vessels amenable to revascularization (≥50% stenosis) by at least one of the available methods
  • Objective documentation of ischemia or subjectively documented typical angina with >70% stenosis in at least one artery

Exclusions:

  • Definite need for invasive intervention
  • Prior CABG or prior PCI within the past 12 months
  • Planned intervention of bypass graft disease
  • Class III or IV congestive heart failure
  • Creatinine >2.0 mg/dl
  • Glycated hemoglobin >13%
  • Need for major vascular surgery concomitant with revascularization
  • Left main stenosis >50%
  • Noncardiac illness expected to limit survival
  • Hepatic disease (alanine aminotransferase >2 times the upper limit of normal)
  • Fasting triglycerides >1000 mg/dl in the presence of moderate glycemic control (glycated hemoglobin
  • Current alcohol abuse
  • Chronic steroid use judged to interfere with the control of diabetes
  • Pregnancy

Primary Endpoints:

  • All-cause mortality at 5 years

Secondary Endpoints:

  • Combination of death, myocardial infarction, or stroke at 5 years

Drug/Procedures Used:

2 x 2 factorial randomization to:

  1. Revascularization plus medical therapy (n = 953) versus medical therapy (n = 991)
  2. Insulin-sensitizing treatment of diabetes (n = 977) versus insulin-providing treatment (n = 967; both achieving a similar goal of glycemic control)

Concomitant Medications:

At baseline, the use of metformin was 54%, a thiazolidinedione 19%, rosiglitazone 10%, sulfonylurea 53%, insulin 28%, beta-blocker 73%, angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker 77%, aspirin 88%, thienopyridine 18%, and statin 75%.

Principal Findings:

Overall, 2,368 patients were randomized. The mean age was 62 years, 30% were women, mean glycated hemoglobin was 7.7%, low-density lipoprotein cholesterol was 96 mg/dl, systolic blood pressure was 132 mm Hg, body mass index was 32 kg/m2, symptomatic myocardial ischemia was present in 82%, and the mean duration of diabetes was 10.4 years. Among those who underwent revascularization, percutaneous coronary intervention (PCI) was performed on a mean of 1.5 lesions, whereas coronary artery bypass grafting (CABG) was performed on a mean of 3.0 distal anastomoses. By 5 years, 42% of the medical therapy group had undergone revascularization.

The occurrence of the primary outcome, 5-year mortality, was 11.7% in the revascularization group versus 12.2% in the medical therapy group (p = 0.97) and 11.8% in the insulin-sensitizing group versus 12.1% in the insulin-providing group (p = 0.89).

Major adverse cardiac events were 22.8% with revascularization versus 24.1% with medical therapy (p = 0.70) and 22.3% with insulin-sensitizing therapy versus 24.6% with insulin-providing therapy (p = 0.13).

In the PCI stratum, all-cause death was 10.8% with revascularization versus 10.2% with medical therapy (p = 0.48), cardiac death was 5.0% versus 4.2 (p = 0.16), myocardial infarction was 12.3% versus 12.6% (p = 0.42), and major adverse cardiac events were 23.0% versus 21.1% (p = 0.15), respectively.

In the CABG stratum, all-cause death was 13.6% with revascularization versus 16.4% with medical therapy (p = 0.33), cardiac death was 8.0% versus 9.0% (p = 0.79), myocardial infarction was 10.0% versus 17.6% (p = 0.003), and major adverse cardiac events were 22.4% versus 30.5% (p = 0.01), respectively.

Insulin-providing therapy resulted in more hypoglycemia than insulin-sensitizing therapy (9.2% vs. 5.9%, p = 0.003). Compared with medical therapy, revascularization improved the Duke Activity Status Index (DASI) (p = 0.002), self-rated health score (p = 0.017), energy score (p = 0.018), but not health distress score (p = 0.40).

Cost-effectiveness was performed in a subgroup of 2,005 patients. In the PCI stratum, 4-year costs were $73,400 for revascularization versus $67,000 for medical therapy (p < 0.02) and in the CABG stratum, 4-year costs were $80,900 for revascularization versus $60,600 for medical therapy (p < 0.0001).

Among patients exposed to rosiglitazone, the 5-year mortality incidence was 10.4% compared with 9.3% among those not exposed to rosiglitazone (p = 0.70). Death, myocardial infarction, or stroke: 18.2% versus 18.3% (p = 0.66), respectively.

Interpretation:

Among patients with diabetes and stable coronary artery disease, a strategy of revascularization by PCI or CABG failed to demonstrate superiority to medical therapy over a mean of 5.3 years. There was also no notable benefit from insulin-sensitizing therapy versus insulin-providing therapy. There was no association of exposure to rosiglitazone and adverse events.

Examining outcomes by the prerandomization intended revascularization strategy (PCI or CABG), there was no mortality or myocardial infarction benefit from PCI compared with medical therapy. In the CABG stratum, mortality was similar versus medical therapy; however, MI was less with CABG versus medical therapy.

This study builds upon the COURAGE trial (tested PCI vs. medical therapy) which showed that many diabetic patients with less extensive coronary disease and stable controlled angina can be safely managed with an initial treatment strategy of optimal medical therapy. However, in the present study among patients with more severe and diffuse atherosclerotic coronary disease, CABG was associated with reduced adverse outcomes (MI).

Cost-effectiveness favors initial medical management among patients suitable for PCI. Revascularization results in small improvements for DASI functional capacity and self-rated health and energy.

There was no association of exposure to rosiglitazone and adverse events.

References:

Bach RG, Brooks MM, Lombardero M, et al., on behalf of the BARI 2D Investigators. Rosiglitazone and Outcomes for Patients With Diabetes and Coronary Artery Disease in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) Trial. Circulation 2013;Jul 15:[Epub ahead of print].

Presented by Drs. Bernard Chaitman, Maria Brooks, and Mark Hlatky at the American Heart Association Scientific Sessions, Orlando, FL, November 17, 2009.

Chaitman BR, Hardison RM, Adler D, et al. The Bypass Angioplasty Revascularization Investigation 2 Diabetes randomized trial of different treatment strategies in type 2 diabetes mellitus with stable ischemic heart disease. Impact of treatment strategy on cardiac mortality and myocardial infarction. Circulation 2009;Nov 17:[Epub ahead of print].

Hlatky MA, Boothroyd DB, Melsop KA, et al. Economic outcomes of treatment strategies for type 2 diabetes mellitus and coronary artery disease in the Bypass Angioplasty Revascularization Investigation 2 Diabetes trial. Circulation 2009;Nov 17:[Epub ahead of print].

The BARI 2D Study Group. A randomized trial of therapies for type 2 diabetes and coronary artery disease. N Engl J Med 2009;360:2503-15.

Sobel BE, Frye R, Detre KM. Burgeoning Dilemmas in the Management of Diabetes and Cardiovascular Disease: Rationale for the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) Trial. Circulation 2003;107:636-42.

Clinical Topics: Cardiac Surgery, Dyslipidemia, Invasive Cardiovascular Angiography and Intervention, Aortic Surgery, Lipid Metabolism, Nonstatins

Keywords: Myocardial Infarction, Stroke, Hyperglycemia, Self Report, Diabetes Mellitus, Type 2, Blood Pressure, Constriction, Pathologic, Insulin Resistance, Angioplasty, Balloon, Coronary, Hypoglycemia, Lipoproteins, LDL, Hemoglobin A, Glycosylated, Cholesterol, Body Mass Index, Coronary Artery Bypass


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