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Bypass Angioplasty Revascularization Investigation in Type 2 Diabetes (BARI2D)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00006305
Recruitment Status : Completed
First Posted : September 29, 2000
Results First Posted : May 12, 2011
Last Update Posted : February 8, 2016
Sponsor:
Collaborators:
National Heart, Lung, and Blood Institute (NHLBI)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Information provided by (Responsible Party):
Maria Mori Brooks, University of Pittsburgh

Tracking Information
First Submitted Date  ICMJE September 28, 2000
First Posted Date  ICMJE September 29, 2000
Results First Submitted Date  ICMJE January 27, 2011
Results First Posted Date  ICMJE May 12, 2011
Last Update Posted Date February 8, 2016
Study Start Date  ICMJE September 2000
Actual Primary Completion Date November 2008   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 11, 2011)		 Number of Participants With All-Cause Mortality [ Time Frame: five years ]
Original Primary Outcome Measures  ICMJE Not Provided
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 11, 2011)		 Number of Participants With Death, Myocardial Infarction, or Stroke [ Time Frame: five years ]
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Bypass Angioplasty Revascularization Investigation in Type 2 Diabetes
Official Title  ICMJE Bypass Angioplasty Revascularization Investigation in Type 2 Diabetes
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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Coronary Disease
  • Cardiovascular Diseases
  • Heart Diseases
  • Insulin Resistance
  • Diabetes Mellitus
  • Diabetes Mellitus, Non-Insulin-Dependent
Intervention  ICMJE
  • Procedure: Angioplasty, Transluminal, Percutaneous Coronary, other catheter-based interventions
    Angioplasty, Transluminal, Percutaneous Coronary, other catheter-based interventions
  • Procedure: Coronary Artery Bypass
    Coronary Artery Bypass
  • Drug: Biguanides, thiazolidinediones
    Biguanides, thiazolidinediones
  • Drug: Insulin, sulfonylurea
    Insulin, sulfonylurea
  • Drug: ACE Inhibitors, Angiotensin Receptor Blockers, Beta Blockers, Calcium Channel Blockers
    ACE Inhibitors, Angiotensin Receptor Blockers, Beta Blockers, Calcium Channel Blockers
Study Arms  ICMJE
  • Active Comparator: Revascularization and Insulin Providing (IP)
    Prompt revascularization with intensive medical therapy and insulin providing glycemic control strategy
    Interventions:
    • Procedure: Angioplasty, Transluminal, Percutaneous Coronary, other catheter-based interventions
    • Procedure: Coronary Artery Bypass
    • Drug: Insulin, sulfonylurea
    • Drug: ACE Inhibitors, Angiotensin Receptor Blockers, Beta Blockers, Calcium Channel Blockers
  • Active Comparator: Revascularization and Insulin Sensitizing (IS)
    Prompt revascularization with intensive medical therapy and insulin sensitizing glycemic control strategy
    Interventions:
    • Procedure: Angioplasty, Transluminal, Percutaneous Coronary, other catheter-based interventions
    • Procedure: Coronary Artery Bypass
    • Drug: Biguanides, thiazolidinediones
    • Drug: ACE Inhibitors, Angiotensin Receptor Blockers, Beta Blockers, Calcium Channel Blockers
  • Active Comparator: Medical Therapy and Insulin Providing (IP)
    Intensive medical therapy with delayed revascularization if clinically indicated and insulin providing glycemic control strategy
    Interventions:
    • Drug: Insulin, sulfonylurea
    • Drug: ACE Inhibitors, Angiotensin Receptor Blockers, Beta Blockers, Calcium Channel Blockers
  • Active Comparator: Medical Therapy and Insulin Sensitizing (IS)
    Intensive medical therapy with delayed revascularization if clinically indicated and insulin sensitizing glycemic control strategy
    Interventions:
    • Drug: Biguanides, thiazolidinediones
    • Drug: ACE Inhibitors, Angiotensin Receptor Blockers, Beta Blockers, Calcium Channel Blockers
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: February 26, 2008)		 2368
Original Enrollment  ICMJE Not Provided
Actual Study Completion Date  ICMJE March 2009
Actual Primary Completion Date November 2008   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 25 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Not Provided
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00006305
Other Study ID Numbers  ICMJE 133
U01HL061744 ( U.S. NIH Grant/Contract )
U01HL061746 ( U.S. NIH Grant/Contract )
U01HL061748 ( U.S. NIH Grant/Contract )
U01HL063804 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Current Responsible Party Maria Mori Brooks, University of Pittsburgh
Original Responsible Party Not Provided
Current Study Sponsor  ICMJE University of Pittsburgh
Original Study Sponsor  ICMJE National Heart, Lung, and Blood Institute (NHLBI)
Collaborators  ICMJE
  • National Heart, Lung, and Blood Institute (NHLBI)
  • National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Investigators  ICMJE
Principal Investigator: Bernard Chaitman, MD St. Louis University
Study Chair: Robert L Frye, MD Mayo Clinic
Principal Investigator: Mark Hlatky Stanford University
Principal Investigator: Burton Sobel University of Vermont & State Agricultural College
Principal Investigator: Sheryl F. Kelsey, PhD University of Pittsburgh
PRS Account University of Pittsburgh
Verification Date January 2016

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP