No mortality, CV-event differences between revascularization and medical therapy in diabetics: BARI 2D

Martha Kerr and Shelley Wood

June 08, 2009

New Orleans, LA - Mortality risk is the same for patients with type 2 diabetes and stable ischemic heart disease whether they are managed with optimal medical therapy, CABG surgery, or PCI, results of the Bypass Angioplasty Revascularization Investigation in Type 2 Diabetes (BARI 2D) show[1].

However, CABG was associated with a reduction in risk of cardiovascular events, primarily nonfatal MI, compared with intensive medical management. No such difference was seen for PCI vs optical medical therapy.

Results were presented by coinvestigators Drs Trevor Orchard (University of Pittsburgh, PA) and Robert L Frye (Mayo Clinic, Rochester, MN) at the American Diabetes Association (ADA) 2009 Scientific Sessions and simultaneously published online in the New England Journal of Medicine.

These findings are "consistent with the [Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation] COURAGE findings" and unlikely to alter clinical practice, Frye said in an interview.

"Our findings suggest that patients who have diabetes, evidence of myocardial ischemia, and extensive multivessel disease would benefit from prompt surgical revascularization, mainly because of a lower rate of nonfatal myocardial infarction," Orchard, Frye, and their coinvestigators conclude in the published paper. "However, for the many patients with type 2 diabetes who have less extensive coronary disease and for whom PCI is judged to be more appropriate, prompt revascularization did not reduce the risk of cardiovascular events, as compared with medical therapy."

BARI 2D findings

BARI 2D involved 2368 patients with type 2 diabetes and stable ischemic heart disease who were randomly assigned to early revascularization (either PCI or CABG, at the discretion of the treating physician) plus intensive medical therapy or intensive medical therapy alone. In a second randomization strategy, patients were assigned to either insulin-provision therapy—an insulin secretagogue or insulin—or insulin-sensitization therapy.

For the first of the two treatment comparisons, survival rates at five years were 88.3% in the revascularization group and 87.8% in the medical-therapy group, a statistically nonsignificant difference (p=0.97). For the second, the five-year survival rate was 88.2% in the insulin-sensitization group and 87.9% among patients who received insulin-provision therapy (p=0.89).

Major cardiovascular event rates were similar in all four patient groups. Five-year event rates were 77.2% with revascularization and 75.9% with medical therapy (p=0.70) and 77.7% with insulin sensitization and 75.4% with those taking insulin (p=0.13).

However, the event rate was significantly lower in one subgroup. Patients randomized to both CABG and insulin-sensitization therapy had "a significantly lower rate of major cardiovascular events [primarily nonfatal myocardial infarction] than any of the other three treatment combination groups," the BARI 2D investigators report.

Rates were 22.4% with revascularization and 30.5% with medical therapy at five years among those receiving insulin-sensitization therapy (p=0.01).

Severe hypoglycemia was significantly more frequent in the group that received insulin-provision therapy (9.2%) compared with those who received insulin-sensitization therapy (5.9%; p=0.003).

Interpreting the results

"From the diabetes perspective, we can be assured that insulin-sensitization drugs are not harmful and there is in fact a suggestion of benefit," Orchard said. "The insulin-sensitizing agents were associated with less weight gain and with fewer episodes of hypoglycemia than insulin-provision therapy."

"From the cardiologist's point of view, we have identified a group of high-risk patients with extensive cardiovascular disease who benefit from early revascularization," Frye said. "For lower-risk patients, they can be maintained safely on medical therapy until their condition changes.

"But nothing stays fixed for five years in patients with diabetes and heart disease," Frye added. "As they develop more angina or more episodes of ischemia on stress testing or if the features change, physicians will have to use their clinical judgment on when to perform revascularization."

"Diabetes is not static. Things will change as beta cells die and the disease progresses," Orchard commented.

In BARI 2D, patients in the intervention group were assigned to either CABG or PCI, according to whichever was most appropriate, Orchard noted, with patients assigned to CABG typically being higher risk at baseline. "It would not have been appropriate to compare these two groups," Orchard noted. "They were very different populations."

Of note, however, 10-year follow-up analysis, published in 2007, of the original BARI study comparing balloon angioplasty with CABG showed that the initial mortality difference between these two groups, favoring CABG, persisted at 10 years[2].

In the wake of COURAGE

In an editorial accompanying the BARI 2D results[3], Drs William E Boden (State University of New York, Buffalo) and David P Taggart (Oxford University, UK) write that the BARI 2D results "replicate" the principal finding of the COURAGE trial—namely, "that an initial strategy of PCI provides no incremental clinical benefit over intensive medical therapy, including in patients with both diabetes and coronary disease. Among patients who remain symptomatic despite intensive medical therapy or who have substantial ischemia or extensive coronary artery disease, revascularization is appropriate, and either PCI or CABG is a reasonable choice, depending on the anatomical complexity of disease."

Moreover, secondary findings from the study also support other recent evidence suggesting a benefit of CABG over PCI in patients with diabetes and those with multivessel coronary artery disease, Boden and Taggart observe. "The cardioprotective superiority of CABG is postulated to result from bypass grafts to the mid-coronary vessels that not only treat culprit lesions (even anatomically complex ones) but also afford prophylaxis against new proximal disease, whereas stents treat only suitable stenotic segments with no benefit against native coronary disease progression."

Given the upward "spiral" of healthcare costs in the US and the heavy usage of PCI and drug-eluting stents in the US, the BARI 2D results should have an impact on clinical practice, Boden and Taggart argue.

"BARI 2D shows that for many patients with both diabetes and coronary disease, optimal medical therapy rather than any intervention is an excellent first-line strategy, particularly for those with less severe disease. When revascularization is indicated, both BARI 2D and other studies support the use of CABG as the preferred approach, unless or until future studies indicate otherwise."

But in a statement issued by the Society for Cardiovascular Angiography and Interventions (SCAI), interventional cardiologists counter that while BARI 2D is a "useful and focused" trial, its results are important only for the kinds of patients enrolled in the study. "BARI 2D specifically applies to those with carefully controlled diabetes, multivessel but stable coronary artery disease, and few heart-disease symptoms," the statement reads. "This trial does not answer the question of whether all patients with diabetes and multivessel CAD might be better treated with optimal medical therapy plus either PCI or CABG."

"It's important to note that in a real-world setting, patients' blood sugar levels are not so closely monitored to maintain optimal levels as in this study," Dr Robert Chilton (South Texas VA Medical Center, San Antonio, TX) notes in the SCAI statement. "The patients I see with diabetes and heart disease frequently have difficulty complying with a drug regimen that includes upward of 10 pills per day, often coupled with insulin injection. Not surprisingly, noncompliance can quickly lead to deteriorating health and should be carefully considered for patients who may be candidates for revascularization."

Also quoted in the SCAI statement, SCAI president Dr Steven R Bailey (University of Texas Health Sciences Center, San Antonio) observed: "No one questions that for patients with stable angina, optimal medical therapy is important as one of the first steps to manage disease. But for many patients, medical therapy is not enough, and revascularization may be a safe and effective option for improving their quality of life."

Benefits of risk factor reductions across the board

During the ADA meeting, investigators and others stressed yet another important message from BARI 2D—the need for intensive risk-factor modification with weight loss, dietary intervention, lipid-lowering therapy, etc, in all patients with type 2 diabetes. "That's why the event rates were so low, and they were low in all of the groups," Orchard pointed out. "We don't think of it as a lack of benefit. It's not the procedure, it's the risks," he asserted.

Commenting on the results, ADA spokeswoman Susan McLaughlin said that BARI 2D "reinforces the importance of diet and exercise in maintaining quality of life and from keeping patients from having to undergo revascularization in the first place."

BARI 2D was supported by funding from the National Institutes of Health . Frye reports serving on advisory boards for Sanofi-Aventis and Schering-Plough; Orchard discloses receiving consulting fees from AstraZeneca, Eli Lilly, and Takeda and grant support from VeraLight and having an equity interest in Bristol-Myers Squibb. Disclosures for other investigators are listed in the paper. Boden reports receiving lecture fees from Abbott Laboratories and Sanofi-Aventis.

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