Bypass Angioplasty Revascularization Investigation in Type 2 Diabetes
Condition: Coronary Disease; Cardiovascular Diseases; Heart Diseases; Insulin Resistance; Diabetes Mellitus; Diabetes Mellitus, Non-Insulin-Dependent
MeSH terms: Cardiovascular Diseases; Heart Diseases; Coronary Disease; Diabetes Mellitus; Insulin Resistance; Diabetes Mellitus, Type 2
Intervention: Angioplasty, Transluminal, Percutaneous Coronary, other catheter-based interventions; Coronary Artery Bypass; Biguanides, thiazolidinediones; Insulin, sulfonylurea; ACE Inhibitors, Angiotensin Receptor Blockers, Beta Blockers, Calcium Channel Blockers
Intervention description: Angioplasty, Transluminal, Percutaneous Coronary, other catheter-based interventions; Coronary Artery Bypass; Biguanides, thiazolidinediones; Insulin, sulfonylurea; ACE Inhibitors, Angiotensin Receptor Blockers, Beta Blockers, Calcium Channel Blockers
Intervention MeSH terms: Biguanides; 2,4-thiazolidinedione; Calcium Channel Blockers; Calcium; Adrenergic beta-Antagonists; Angiotensin-Converting Enzyme Inhibitors; Angiotensin Receptor Antagonists
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Factorial Assignment
Masking: None (Open Label)
Enrollment: 2368.0
Sex: All
Minimum age: 25 Years
Healthy volunteers: No

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.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Diagnosis of Type 2 diabetes mellitus

          -  Coronary arteriogram showing one or more vessels amenable to revascularization
             (greater than or equal to 50% stenosis)

          -  Objective documentation of ischemia OR subjectively documented typical angina with
             greater than or equal to 70% stenosis in at least one artery

          -  Suitability for coronary revascularization by at least one of the available methods
             (does not require the ability to achieve complete revascularization)

          -  Ability to perform all tasks related to glycemic control and risk factor management

        Exclusion Criteria:

          -  Definite need for invasive intervention as determined by the attending cardiologist

          -  Prior bypass surgery (CABG) or prior catheter-based intervention within the 12 months
             before study entry

          -  Planned intervention for disease in bypass graft(s) if the patient is randomly
             assigned to a strategy of initial revascularization

          -  Class III or IV CHF

          -  Creatinine greater than 2.0 mg/dL

          -  HbA1c greater than 13%

          -  Need for major vascular surgery concomitant with revascularization (e.g., carotid
             endarterectomy)

          -  Left main stenosis greater than or equal to 50%

          -  Non-cardiac illness expected to limit survival

          -  Hepatic disease (ALT greater than 2 times the ULN)

          -  Fasting triglycerides greater than 1000 mg/dL in the presence of moderate glycemic
             control (HbA1c less than 9.0%)

          -  Current alcohol abuse

          -  Chronic steroid use judged to interfere with the control of diabetes, exceeding 10 mg
             of Prednisone per day or the equivalent

          -  Pregnancy, known, suspected, or planned in 5 years after study entry

          -  Geographically inaccessible or unable to return for follow-up

          -  Enrolled in a competing randomized trial or clinical study

          -  Unable to understand or cooperate with protocol requirements

        Patients with Type 2 diabetes mellitus and CAD documented by coronary arteriography will be
        eligible for the trial if revascularization is not required for prompt control of severe or
        unstable angina. Diabetic patients who are being treated with insulin or oral hypoglycemic
        drugs will be eligible as well as diabetic patients treated with diet and exercise alone
        provided that a diagnosis of diabetes can be confirmed by record review or that a fasting
        plasma glucose (FPG) greater than 125/mg/dL (7.0 mmol/L) can be obtained. The determination
        of suitability for BARI 2D will be made by a physician-investigator at each participating
        institution on clinical grounds at the time of coronary angiography.

        Significant CAD will be defined as at least one stenosis greater than 50%. Angina and
        ischemia will be assessed by use of patient self-report, physician examination, and
        appropriate diagnostic measures including exercise myocardial perfusion imaging, exercise
        echocardiography, exercise electrocardiography, and IV dipyridamole or adenosine myocardial
        perfusion imaging or invasively by doppler or pressure wire. Objective documentation of
        myocardial ischemia includes any of the following:

          1. Exercise or pharmacologically-induced:

               1. Greater than or equal to 1 mm of horizontal or downsloping ST depression or
                  elevation for greater than or equal to 60-80 milliseconds after the end of the
                  QRS complex

               2. Myocardial perfusion defect

               3. Myocardial wall motion abnormality

          2. Stabilized, prior acute coronary syndrome with CK-MB or troponin elevation or with
             new, greater than or equal to 0.5 mm ST depression or elevation, or T wave inversion
             of greater than or equal to 3 mm in 2 contiguous ECG leads

          3. Doppler or pressure wire showing coronary flow reserve (CFR) less than 2.0 or
             fractional flow reserve (FFR) less than 0.75

        Among patients without documented ischemia, only patients with stenosis greater than or
        equal to 70% presenting with classic anginal symptoms will be eligible for randomization.