Bypass Angioplasty Revascularization Investigation in Type 2 Diabetes - Full Text View

Sponsor:	University of Pittsburgh
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
ClinicalTrials.gov Identifier:	NCT00006305

Sponsor:

University of Pittsburgh

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

ClinicalTrials.gov Identifier:

NCT00006305

Purpose

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:

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;
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.

Condition	Intervention	Phase
Coronary Disease Cardiovascular Diseases Heart Diseases Insulin Resistance Diabetes Mellitus Diabetes Mellitus, Non-Insulin-Dependent	Procedure: Angioplasty, Transluminal, Percutaneous Coronary, other catheter-based interventions Procedure: Coronary Artery Bypass Drug: Biguanides, thiazolidinediones Drug: Insulin, sulfonylurea Drug: ACE Inhibitors, Angiotensin Receptor Blockers, Beta Blockers, Calcium Channel Blockers	Phase III

Study Type:	Interventional
Study Design:	Allocation: Randomized Intervention Model: Factorial Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	Bypass Angioplasty Revascularization Investigation in Type 2 Diabetes

Resource links provided by NLM:

Genetics Home Reference related topics: 6q24-related transient neonatal diabetes mellitus

MedlinePlus related topics: Angioplasty Calcium Coronary Artery Bypass Surgery Coronary Artery Disease Diabetes Diabetes Medicines Diabetes Type 2 Heart Attack Heart Diseases

Drug Information available for: Insulin Insulin beef Calcium gluconate

U.S. FDA Resources

Further study details as provided by University of Pittsburgh:

Primary Outcome Measures:

Number of Participants With All-Cause Mortality [ Time Frame: five years ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Number of Participants With Death, Myocardial Infarction, or Stroke [ Time Frame: five years ] [ Designated as safety issue: No ]

Enrollment:	2368
Study Start Date:	September 2000
Study Completion Date:	March 2009
Primary Completion Date:	November 2008 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Active Comparator: Revascularization and Insulin Providing (IP) Prompt revascularization with intensive medical therapy and insulin providing glycemic control strategy	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: 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
Active Comparator: Revascularization and Insulin Sensitizing (IS) Prompt revascularization with intensive medical therapy and insulin sensitizing glycemic control strategy	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: ACE Inhibitors, Angiotensin Receptor Blockers, Beta Blockers, Calcium Channel Blockers 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	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
Active Comparator: Medical Therapy and Insulin Sensitizing (IS) Intensive medical therapy with delayed revascularization if clinically indicated and insulin sensitizing glycemic control strategy	Drug: Biguanides, thiazolidinediones Biguanides, thiazolidinediones Drug: ACE Inhibitors, Angiotensin Receptor Blockers, Beta Blockers, Calcium Channel Blockers ACE Inhibitors, Angiotensin Receptor Blockers, Beta Blockers, Calcium Channel Blockers

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:

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.

Eligibility

Ages Eligible for Study:	25 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

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:

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
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
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.

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

Responsible Party:	Maria Mori Brooks, Associate Professor of Epidemiology, University of Pittsburgh
ClinicalTrials.gov Identifier:	NCT00006305 History of Changes
Other Study ID Numbers:	133, U01HL061744, U01HL061746, U01HL061748, U01HL063804
Study First Received:	September 28, 2000
Results First Received:	January 27, 2011
Last Updated:	January 24, 2012
Health Authority:	United States: Federal Government