Bypass Angioplasty Revascularization Investigation in Type 2 Diabetes

Cardiovascular Diseases Clinical Trial

— BARI2D  

Official title:

Bypass Angioplasty Revascularization Investigation in Type 2 Diabetes

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00006305
• Other study ID #: 133
• Secondary ID: U01HL061744U01HL
• Status: Completed
• Phase: Phase 3
• First received: September 28, 2000
• Last updated: January 12, 2016
• Start date: September 2000
• Est. completion date: March 2009

Study information

• Verified date: January 2016
• Source: University of Pittsburgh
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Federal Government
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 2368
• Est. completion date: March 2009
• Est. primary completion date: November 2008
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 25 Years and older

Eligibility

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.

Study Design

Allocation: Randomized, Intervention Model: Factorial Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Cardiovascular Diseases
• Coronary Artery Disease
• Coronary Disease
• Diabetes Mellitus
• Diabetes Mellitus, Non-Insulin-Dependent
• Diabetes Mellitus, Type 2
• Heart Diseases
• Insulin Resistance

Intervention

Procedure:
• Angioplasty, Transluminal, Percutaneous Coronary, other catheter-based interventions
Angioplasty, Transluminal, Percutaneous Coronary, other catheter-based interventions
• Coronary Artery Bypass
Coronary Artery Bypass

Drug:
• Biguanides, thiazolidinediones
Biguanides, thiazolidinediones
• Insulin, sulfonylurea
Insulin, sulfonylurea
• ACE Inhibitors, Angiotensin Receptor Blockers, Beta Blockers, Calcium Channel Blockers
ACE Inhibitors, Angiotensin Receptor Blockers, Beta Blockers, Calcium Channel Blockers

Locations

Country	Name	City	State
n/a

Sponsors (3)

Lead Sponsor	Collaborator
University of Pittsburgh	National Heart, Lung, and Blood Institute (NHLBI), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

References & Publications (29)

Albu J, Gottlieb SH, August P, Nesto RW, Orchard TJ; Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) Trial Investigators. Modifications of coronary risk factors. Am J Cardiol. 2006 Jun 19;97(12A):41G-52G. Epub 2006 Apr 19. — View Citation

Albu JB, Lu J, Mooradian AD, Krone RJ, Nesto RW, Porter MH, Rana JS, Rogers WJ, Sobel BE, Gottlieb SH; BARI 2D Study Group. Relationships of obesity and fat distribution with atherothrombotic risk factors: baseline results from the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial. Obesity (Silver Spring). 2010 May;18(5):1046-54. doi: 10.1038/oby.2009.339. Epub 2009 Oct 29. — View Citation

BARI 2D Study Group, Frye RL, August P, Brooks MM, Hardison RM, Kelsey SF, MacGregor JM, Orchard TJ, Chaitman BR, Genuth SM, Goldberg SH, Hlatky MA, Jones TL, Molitch ME, Nesto RW, Sako EY, Sobel BE. A randomized trial of therapies for type 2 diabetes and coronary artery disease. N Engl J Med. 2009 Jun 11;360(24):2503-15. doi: 10.1056/NEJMoa0805796. Epub 2009 Jun 7. — View Citation

Barsness GW, Gersh BJ, Brooks MM, Frye RL; BARI 2D Trial Investigators. Rationale for the revascularization arm of the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) Trial. Am J Cardiol. 2006 Jun 19;97(12A):31G-40G. Epub 2006 Apr 17. — View Citation

Brooks MM, Chung SC, Helmy T, Hillegass WB, Escobedo J, Melsop KA, Massaro EM, McBane RD, Hyde P, Hlatky MA; Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) Study Group. Health status after treatment for coronary artery disease and type 2 diabetes mellitus in the Bypass Angioplasty Revascularization Investigation 2 Diabetes trial. Circulation. 2010 Oct 26;122(17):1690-9. doi: 10.1161/CIRCULATIONAHA.109.912642. Epub 2010 Oct 11. — View Citation

Brooks MM, Frye RL, Genuth S, Detre KM, Nesto R, Sobel BE, Kelsey SF, Orchard TJ; Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) Trial Investigators. Hypotheses, design, and methods for the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) Trial. Am J Cardiol. 2006 Jun 19;97(12A):9G-19G. Epub 2006 Apr 17. — View Citation

Bypass Angioplasty Revascularization Investigation 2 Diabetes Study Group. Baseline characteristics of patients with diabetes and coronary artery disease enrolled in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial. Am Heart J. 2008 Sep;156(3):528-536, 536.e1-5. doi: 10.1016/j.ahj.2008.05.015. Epub 2008 Jul 31. — View Citation

Chaitman BR, Hardison RM, Adler D, Gebhart S, Grogan M, Ocampo S, Sopko G, Ramires JA, Schneider D, Frye RL; Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) Study Group. 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 Dec 22;120(25):2529-40. doi: 10.1161/CIRCULATIONAHA.109.913111. Epub 2009 Nov 17. Erratum in: Circulation. 2010 Mar 30;121(12):e254. — View Citation

Detre KM, Frye RL, Genuth S, guest editors. A Symposium: Treatment of Coronary Artery Disease and Type 2 Diabetes: The Rationale for the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) Trial. American Journal of Cardiology 2006; 97(suppl 12A): 1G-65G.

Escobedo J, Rana JS, Lombardero MS, Albert SG, Davis AM, Kennedy FP, Mooradian AD, Robertson DG, Srinivas VS, Gebhart SS; BARI 2D Study Group. Association between albuminuria and duration of diabetes and myocardial dysfunction and peripheral arterial disease among patients with stable coronary artery disease in the BARI 2D study. Mayo Clin Proc. 2010 Jan;85(1):41-6. doi: 10.4065/mcp.2009.0265. — View Citation

Grogan M, Jenkins M, Sansing VV, MacGregor J, Brooks MM, Julien-Williams P, Amendola A, Abbott JD; BARI 2D Study Group. Health insurance status and control of diabetes and coronary artery disease risk factors on enrollment into the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial. Diabetes Educ. 2010 Sep-Oct;36(5):774-83. doi: 10.1177/0145721710374653. Epub 2010 Jun 28. — View Citation

Hlatky MA, Boothroyd DB, Melsop KA, Kennedy L, Rihal C, Rogers WJ, Venkitachalam L, Brooks MM; Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) Study Group. 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 Dec 22;120(25):2550-8. doi: 10.1161/CIRCULATIONAHA.109.912709. Epub 2009 Nov 17. — View Citation

Hlatky MA, Chung SC, Escobedo J, Hillegass WB, Melsop K, Rogers W, Brooks MM; BARI 2D Study Group. The effect of obesity on quality of life in patients with diabetes and coronary artery disease. Am Heart J. 2010 Feb;159(2):292-300. doi: 10.1016/j.ahj.2009.11.004. — View Citation

Hlatky MA, Melsop KA, Boothroyd DB; Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) Trial Investigators. Economic evaluation of alternative strategies to treat patients with diabetes mellitus and coronary artery disease. Am J Cardiol. 2006 Jun 19;97(12A):59G-65G. Epub 2006 Apr 7. — View Citation

Iskandrian AE, Heo J, Mehta D, Tauxe EL, Yester M, Hall MB, MacGregor JM. Gated SPECT perfusion imaging for the simultaneous assessment of myocardial perfusion and ventricular function in the BARI 2D trial: an initial report from the Nuclear Core Laboratory. J Nucl Cardiol. 2006 Jan-Feb;13(1):83-90. — View Citation

Kim LJ, King SB 3rd, Kent K, Brooks MM, Kip KE, Abbott JD, Jacobs AK, Rihal C, Hueb WA, Alderman E, Sing IR, Attubato MJ, Feit F; BARI 2D (Bypass Angioplasty Revascularization Investigation Type 2 Diabetes) Study Group. Factors related to the selection of surgical versus percutaneous revascularization in diabetic patients with multivessel coronary artery disease in the BARI 2D (Bypass Angioplasty Revascularization Investigation in Type 2 Diabetes) trial. JACC Cardiovasc Interv. 2009 May;2(5):384-92. doi: 10.1016/j.jcin.2009.01.009. — View Citation

Magee MF, Isley WL; BARI 2D Trial Investigators. Rationale, design, and methods for glycemic control in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) Trial. Am J Cardiol. 2006 Jun 19;97(12A):20G-30G. Epub 2006 Apr 19. — View Citation

McBane RD 2nd, Hardison RM, Sobel BE; BARI 2D Study Group. Comparison of plasminogen activator inhibitor-1, tissue type plasminogen activator antigen, fibrinogen, and D-dimer levels in various age decades in patients with type 2 diabetes mellitus and stable coronary artery disease (from the BARI 2D trial). Am J Cardiol. 2010 Jan 1;105(1):17-24. doi: 10.1016/j.amjcard.2009.08.643. Epub 2009 Nov 14. — View Citation

Pambianco G, Lombardero M, Bittner V, Forker A, Kennedy F, Krishnaswami A, Mooradian AD, Pop-Busui R, Rana JS, Rodriguez A, Steffes M, Orchard TJ. Control of lipids at baseline in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial. Prev Cardiol. 2009 Winter;12(1):9-18. — View Citation

Pop-Busui R, Lombardero M, Lavis V, Forker A, Green J, Korytkowski M, Sobel BE, Jones TL; BARI 2D Study Group. Relation of severe coronary artery narrowing to insulin or thiazolidinedione use in patients with type 2 diabetes mellitus (from the Bypass Angioplasty Revascularization Investigation 2 Diabetes Study). Am J Cardiol. 2009 Jul 1;104(1):52-8. doi: 10.1016/j.amjcard.2009.02.046. Epub 2009 May 13. — View Citation

Pop-Busui R, Lu J, Lopes N, Jones TL; BARI 2D Investigators. Prevalence of diabetic peripheral neuropathy and relation to glycemic control therapies at baseline in the BARI 2D cohort. J Peripher Nerv Syst. 2009 Mar;14(1):1-13. doi: 10.1111/j.1529-8027.2009.00200.x. — View Citation

Rana JS, Hardison RM, Pop-Busui R, Brooks MM, Jones TL, Nesto RW, Bourassa MG; BARI 2D Investigators. Resting heart rate and metabolic syndrome in patients with diabetes and coronary artery disease in bypass angioplasty revascularization investigation 2 diabetes (BARI 2D) trial. Prev Cardiol. 2010 Summer;13(3):112-6. doi: 10.1111/j.1751-7141.2010.00067.x. — View Citation

Schneider DJ, Hardison RM, Lopes N, Sobel BE, Brooks MM; Pro-Thrombosis Ancillary Study Group. Association between increased platelet P-selectin expression and obesity in patients with type 2 diabetes: a BARI 2D (Bypass Angioplasty Revascularization Investigation 2 Diabetes) substudy. Diabetes Care. 2009 May;32(5):944-9. doi: 10.2337/dc08-1308. Epub 2009 Feb 19. — View Citation

Schwartz L, Kip KE, Alderman E, Lu J, Bates ER, Srinivas V, Bach RG, Mighton LD, Feit F, King S 3rd, Frye RL; BARI 2D Study Group. Baseline coronary angiographic findings in the Bypass Angioplasty Revascularization Investigation 2 Diabetes trial (BARI 2D). Am J Cardiol. 2009 Mar 1;103(5):632-8. doi: 10.1016/j.amjcard.2008.11.024. Epub 2009 Jan 12. — View Citation

Sobel BE, Frye R, Detre KM; Bypass Angioplasty Revascularization Investigation 2 Diabetes Trial. Burgeoning dilemmas in the management of diabetes and cardiovascular disease: rationale for the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) Trial. Circulation. 2003 Feb 4;107(4):636-42. Review. Erratum in: Circulation. 2003 Jul 29;108(4):500. — View Citation

Sobel BE; BARI 2D Trial Investigators. Ancillary studies in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) Trial: Synergies and opportunities. Am J Cardiol. 2006 Jun 19;97(12A):53G-58G. Epub 2006 Apr 17. — View Citation

Steiner G; Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) Trial Investigators. Statement of the problem. Am J Cardiol. 2006 Jun 19;97(12A):3G-8G. Epub 2006 Apr 7. — View Citation

Thomas SB, Sansing VV, Davis A, Magee M, Massaro E, Srinivas VS, Helmy T, Desvigne-Nickens P, Brooks MM; BARI 2D Study Group. Racial differences in the association between self-rated health status and objective clinical measures among participants in the BARI 2D trial. Am J Public Health. 2010 Apr 1;100 Suppl 1:S269-76. doi: 10.2105/AJPH.2009.176180. Epub 2010 Feb 10. — View Citation

Wall BM, Hardison RM, Molitch ME, Marroquin OC, McGill JB, August PA; BARI 2D Study Group. High prevalence and diversity of kidney dysfunction in patients with type 2 diabetes mellitus and coronary artery disease: the BARI 2D baseline data. Am J Med Sci. 2010 May;339(5):401-10. doi: 10.1097/MAJ.0b013e3181d430ad. — View Citation

* Note: There are 29 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants With All-Cause Mortality		five years	No
Secondary	Number of Participants With Death, Myocardial Infarction, or Stroke		five years	No

External Links

•   Click here for the BARI 2D Study Web site