New England Journal of Medicine JUNE 11, 2009

A Randomized Trial of Therapies for Type 2 Diabetes and Coronary Artery Disease

The BARI 2D Study Group

Bottom Line

In patients with type 2 diabetes and stable ischemic heart disease, an initial strategy of elective coronary revascularization combined with intensive medical therapy did not significantly reduce the 5-year rate of all-cause mortality or major cardiovascular events compared to intensive medical therapy alone.

Key Findings

1. The 5-year rate of all-cause mortality was similar between the revascularization (REV) and intensive medical therapy (IMT) strategies (11.7% vs. 12.2%; p = 0.97).

2. The 5-year rate of major adverse cardiovascular events (death, myocardial infarction, or stroke) did not differ significantly between the REV and IMT groups (22.8% vs. 24.1%; p = 0.70).

3. In the coronary artery bypass grafting (CABG) stratum, revascularization was associated with a significant reduction in the composite of death, myocardial infarction, or stroke compared to medical therapy (15.3% vs. 30.3% among patients with mid/high SYNTAX scores).

4. No significant differences in mortality or cardiovascular outcomes were observed between the insulin-sensitization and insulin-provision glycemic control strategies.

5. Medical therapy alone was found to be a safe and effective initial strategy for many patients with stable ischemic heart disease and diabetes.

Study Design

Design

RCT

Open-Label

Sample

2,368

Patients

Duration

5.3 yr

Median

Setting

Multicenter, International

Population Patients with type 2 diabetes and angiographically defined stable coronary artery disease

Intervention Prompt coronary revascularization (PCI or CABG) plus intensive medical therapy vs. intensive medical therapy alone

Comparator Intensive medical therapy alone (with revascularization reserved for clinical progression)

Outcome All-cause mortality

Study Limitations

• The open-label design of the revascularization strategy may have introduced bias in clinical management decisions.

• The study was performed before current-generation drug-eluting stents and modern pharmacological therapies became the standard of care.

• Stratification by revascularization type (PCI or CABG) was based on physician preference before randomization, which may limit the generalizability of these findings to all patients.

• The factorial design, while robust, complicated the assessment of individual treatment interactions.

Clinical Significance

The trial challenged the paradigm that early revascularization is universally necessary for diabetic patients with stable coronary artery disease, supporting a shift toward optimal medical management as a primary initial strategy, especially for patients suitable for PCI.

Historical Context

The BARI 2D trial was a landmark study aimed at addressing the management of the 'diabetic paradox'—the significantly higher risk of cardiovascular events in patients with type 2 diabetes—by testing whether early aggressive intervention could improve long-term outcomes in an era when optimal medical therapy was rapidly evolving.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

How does the pathophysiology of type 2 diabetes contribute to the diffuse nature of coronary artery disease, and how does intensive medical therapy (IMT) mechanistically address these systemic risks compared to the focal approach of revascularization?

Key Response

Type 2 diabetes promotes a pro-inflammatory, pro-thrombotic state characterized by endothelial dysfunction and accelerated atherosclerosis. While PCI or CABG treats specific focal stenoses, IMT (statins, ACE inhibitors, and glucose management) stabilizes the entire coronary endothelium and reduces the risk of rupture in 'non-obstructive' plaques, which are often the source of future myocardial infarctions.

Resident

In a patient with stable ischemic heart disease (SIHD) and type 2 diabetes, what clinical 'red flags' or findings on non-invasive stress testing should prompt a shift from the BARI 2D-supported 'medical therapy first' strategy to early revascularization?

Key Response

BARI 2D demonstrated that IMT is a safe initial strategy; however, revascularization remains indicated for patients with refractory angina despite optimal medical therapy, evidence of high-risk anatomy (e.g., left main disease), or severe inducible ischemia (e.g., >10% myocardium) on imaging, as these high-risk subgroups were largely excluded or required intervention to prevent imminent events.

Fellow

The BARI 2D trial utilized a non-randomized assignment to the PCI or CABG strata before randomization to revascularization vs. medical therapy. How do the divergent outcomes in the CABG stratum (lower MACE) versus the PCI stratum (no benefit) inform the selection of revascularization modality in diabetic multivessel disease?

Key Response

The trial suggested that in patients with more complex disease (those selected for the CABG stratum), revascularization provided a significant reduction in MACE (primarily driven by lower MI rates) compared to IMT alone. This aligns with the FREEDOM trial and the belief that CABG offers superior protection against new proximal lesions in the diabetic population, whereas PCI only treats the specific target lesion.

Attending

How should the findings of BARI 2D shape the shared decision-making process with a diabetic patient who is found to have significant but stable multivessel CAD during an elective catheterization?

Key Response

The attending should use BARI 2D to emphasize that 'opening the artery' does not necessarily prevent death or MI more effectively than aggressive lifestyle and pharmacological management. The discussion should pivot from survival benefit to quality-of-life and symptom control, helping the patient understand that starting with intensive medical therapy is a validated, safe approach.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

BARI 2D employed a 2x2 factorial design to simultaneously study revascularization and glycemic control strategies. What are the methodological risks of 'interaction effects' in this design, and how might they complicate the interpretation of the revascularization primary endpoint?

Key Response

A 2x2 factorial design assumes that the effect of revascularization is independent of the glycemic control strategy (insulin-sensitizing vs. insulin-providing). If a specific glucose-lowering medication (like metformin or TZDs) significantly altered the restenosis rate or endothelial function, an interaction effect would exist, potentially masking the true benefit of one intervention or requiring a much larger sample size to detect a synergistic effect.

Journal Editor

Given that 42% of the medical-therapy group in BARI 2D eventually underwent revascularization during the 5-year follow-up, how does this high 'crossover' rate affect the internal validity and the 'intention-to-treat' analysis of the study?

Key Response

High crossover rates from medical therapy to revascularization bias the results toward the null, potentially obscuring a true difference between the strategies. A tough reviewer would question whether the study was a comparison of 'revascularization vs. no revascularization' or merely 'early vs. delayed revascularization,' which limits the ability to claim revascularization has no long-term benefit.

Guideline Committee

How does the evidence from BARI 2D, in conjunction with the ISCHEMIA trial, influence the strength of recommendation for revascularization in diabetic patients with stable multivessel disease in current ACC/AHA guidelines?

Key Response

BARI 2D and ISCHEMIA collectively support a Class 1 recommendation for Intensive Medical Therapy as the initial management for stable CAD. However, the BARI 2D sub-analysis favoring CABG in complex disease supports the current guideline recommendation (Class 1, LOE A) that CABG is preferred over PCI for diabetic patients with multivessel disease (Syntax Score >22) to improve long-term survival and reduce non-fatal MI.

Clinical Landscape

Noteworthy Related Trials

2008

ACCORD Trial

n = 10,251 · NEJM

Tested

Intensive glycemic control (HbA1c < 6.0%)

Population

Patients with T2DM at high risk for CV events

Comparator

Standard glycemic control (HbA1c 7.0-7.9%)

Endpoint

Composite of nonfatal MI, nonfatal stroke, or death from CV causes

Key result: Intensive glucose lowering did not reduce major cardiovascular events and was associated with increased mortality.

2008

ADVANCE Trial

n = 11,140 · NEJM

Tested

Intensive glucose control

Population

Patients with T2DM at high risk of macrovascular or microvascular disease

Comparator

Standard glucose control

Endpoint

Composite of major macrovascular and microvascular events

Key result: Intensive glucose control reduced the incidence of major microvascular events, but had no significant effect on major macrovascular events.

2009

VADT Trial

n = 1,791 · NEJM

Tested

Intensive glycemic control

Population

Veterans with poorly controlled T2DM

Comparator

Standard glycemic control

Endpoint

Composite of CV death, MI, stroke, new or worsening CHF, amputation, or surgery for vascular disease

Key result: Intensive glucose control did not significantly reduce the rate of major cardiovascular events or cardiovascular mortality compared to standard therapy.

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