Clinical trial NCT00006305
Conditions: Coronary Disease Cardiovascular Diseases Heart Diseases Insulin Resistance Diabetes Mellitus Diabetes Mellitus, Non-Insulin-Dependent
Sponsor: University of Pittsburgh
Start date: 2000-09-01; Completion date: 2009-03-01
Enrollment: 2368 participants; Allocation: RANDOMIZED; Intervention model: FACTORIAL

Brief summary:
The BARI 2D trial is a multicenter study that uses a 2x2 factorial design, with 2400 patients being assigned at random to initial elective revascularization with aggressive medical therapy or aggressive medical therapy alone with equal probability, and simultaneously being assigned at random to an insulin providing or insulin sensitizing strategy of glycemic control (with a target value for HbA1c of less than 7.0% for all patients).

SPECIFIC AIMS

A. Primary Aim

The primary aim of the BARI 2D trial is to test the following two hypotheses of treatment efficacy in 2400 patients with Type 2 diabetes mellitus and documented stable CAD, in the setting of uniform glycemic control and intensive management of all other risk factors including dyslipidemia, hypertension, smoking, and obesity:

1. Coronary Revascularization Hypothesis: a strategy of initial elective revascularization of choice (surgical or catheter-based) combined with aggressive medical therapy results in lower 5-year mortality compared to a strategy of aggressive medical therapy alone;
2. Method of Glycemic Control Hypothesis: with a target HbA1c level of less than 7.0%, a strategy of hyperglycemia management directed at insulin sensitization results in lower 5-year mortality compared to a strategy of insulin provision.

B. Secondary Aims

The secondary aims of the BARI 2D trial include: a) comparing the death, myocardial infarction or stroke combined endpoint event rate between the revascularization versus medical therapy groups and between the insulin sensitization versus insulin provision groups; b) comparing rates of myocardial infarction, other ischemic events, angina and quality of life associated with each revascularization and hyperglycemia management strategy; c) evaluating the relative economic costs associated with the trial treatment strategies, d) exploring the effect of glycemic control strategy on the progression and mechanism of vasculopathy including changes in PAI-1 gene expression.

Detailed description:
BACKGROUND:

Type 2 diabetes mellitus, which is becoming more prevalent in our society as the population ages, is one of the strongest risk factors for coronary artery disease (CAD) and consequent mortality. In addition to generating an enormous toll in human suffering, diabetes places an economic burden approaching 100 billion dollars annually on the U.S. health care system. Despite the well known dismal prognosis of diabetes complicated by angiographically documented CAD, the optimal treatment paradigm for this large group of patients has not been studied. Coronary revascularization, while increasingly used, has not been directly shown to be of additional benefit to simultaneous intensive medical management of CAD along with management of hyperglycemia, hypertension, dyslipidemia, and other risk factors. Moreover, while intensive efforts to lower HbA1c have been demonstrated to favorably affect the clinical course of Type 2 diabetes mellitus in terms of microvascular complications, the optimal hyperglycemia management strategy with regard to macrovascular outcome is not known.

These critical treatment dilemmas have motivated the development of BARI 2D, a multicenter randomized trial designed to determine in patients with Type 2 diabetes and stable CAD: 1) the efficacy of initial elective coronary revascularization combined with aggressive medical therapy, compared to an initial strategy of aggressive medical therapy alone; and 2) the efficacy of a strategy of providing more insulin (endogenous or exogenous), versus a strategy of increasing sensitivity to insulin (reducing insulin resistance), in the management of hyperglycemia, with a target HbA1c level of less than 7.0% for each strategy.

DESIGN NARRATIVE:

The BARI 2D trial is a multicenter study that uses a 2x2 factorial design, with 2400 patients being assigned at random to initial elective revascularization with aggressive medical therapy or aggressive medical therapy alone with equal probability, and simultaneously being assigned at random to an insulin providing or insulin sensitizing strategy of glycemic control (with a target value for HbA1c of less than 7.0% for all patients). Following confirmation of patient eligibility and provision of written consent, patients were randomized as shown below:

Number of Patients Per Treatment Assignment (N=2400 patients in total)

Stable Ischemic Heart Disease Treatment Strategy and Glycemic Control Strategy:

Revascularization and Insulin Providing (IP) N=600; Revascularization and Insulin Sensitizing (IS) N=600; Medical and Insulin Providing (IP) N=600; Medical and and Insulin Sensitizing (IS) N=600.

Arms: arm 1: Prompt revascularization with intensive medical therapy and insulin providing glycemic control strategy arm 2: Prompt revascularization with intensive medical therapy and insulin sensitizing glycemic control strategy arm 3: Intensive medical therapy with delayed revascularization if clinically indicated and insulin providing glycemic control strategy arm 4: Intensive medical therapy with delayed revascularization if clinically indicated and insulin sensitizing glycemic control strategy
Interventions: intervention 1: Angioplasty, Transluminal, Percutaneous Coronary, other catheter-based interventions intervention 2: Coronary Artery Bypass intervention 3: Biguanides, thiazolidinediones intervention 4: Insulin, sulfonylurea intervention 5: ACE Inhibitors, Angiotensin Receptor Blockers, Beta Blockers, Calcium Channel Blockers
Intervention descriptions: intervention 1: Angioplasty, Transluminal, Percutaneous Coronary, other catheter-based interventions intervention 2: Coronary Artery Bypass intervention 3: Biguanides, thiazolidinediones intervention 4: Insulin, sulfonylurea intervention 5: ACE Inhibitors, Angiotensin Receptor Blockers, Beta Blockers, Calcium Channel Blockers

Protocol documents: