BARI 2D heralded a new era in National Heart, Lung, and Blood Institute–sponsored trials by exclusively studying patients with type 2 diabetes mellitus. BARI 2D demonstrated no difference in 5-year mortality between prompt revascularization and optimal medical therapy (OMT) alone (11.7% vs 12.2%; p = 0.97) as well as no difference in 5-year rates of the combined endpoint of death, MI, and stroke (22.8% vs 24.1%; p = 0.70).

Guidelines continue to recommend aggressive targets for key medical risk factors, including low-density lipoprotein (LDL) <100 mg/dL, blood pressure <130/80 mm Hg, and hemoglobin A1C <7.0%. The BARI 2D investigators followed subjects every 3 months for the duration of the trial. At 3-year follow-up, a majority of patients had achieved optimal goals for LDL cholesterol (83%) and blood pressure (71%).

Yes, but…

As with the earlier COURAGE trial, BARI 2D is said to demonstrate that OMT can be achieved in the setting of a clinical trial far more effectively than in routine clinical practice. Which raises the question: How to interpret the results for clinical practice where OMT is less likely? While BARI 2D and COURAGE are exemplary studies, Michael E. Farkouh, MD, FACC, turns that question around and considers the extent to which OMT is actually achieved in cardiovascular clinical trials. He is not impressed.

Indeed, he cites BARI 2D as an example of the large gap between what is optimal and what is achieved. While individual target levels of LDL and blood pressure were achieved in a high proportion of study participants, the level of OMT achieved is reduced considerably when looking at the percentage of patients who managed to hit target levels for the combination of three key cardiovascular risk factors.

Fewer than one-third of BARI 2D patients achieved target levels of LDL cholesterol (<100 mg/dl), glycated hemoglobin (<7.0%), and blood pressure (<130/80 mm Hg): 28.5% in the revascularization arm versus 28.3% in the medical therapy alone arm, p = 0.93.  It should be noted that the LDL target for BARI 2D is actually higher than the current guideline-recommended target for the patient population enrolled: <70 mg/dl. (The median LDL level at 3-year follow-up was 81±28 and 79±25 mg/dl respectively in BARI 2D.)

Overall, Michael E. Farkouh, MD, says the percentage of patients in contemporary clinical trials who achieve target levels of these individual risk factors is about 60%; only about 20% of patients get to target levels for all three.

Obstacles Abound

There are many reasons why even well-designed and conducted clinical trials are not achieving more optimal medical therapy. Dr. Farkouh, MD cites several:

• Community practitioners may be unaware of current guideline recommendations for specific high-risk populations.
• Physicians are reimbursed for procedures but not for following risk factors and adhering to current guidelines for risk reduction.
• Patient adherence continues to be a major challenge.
• Patient education is also a factor, with many patients still under the impression that once they have undergone revascularization they are “cured” and can go back to their poor diets and inactive lifestyles.

Is it worth the effort? Actually optimizing OMT takes a little more effort, but Dr. Farkouh said patients who achieve target levels for major risk factors will likely experience significantly better results with any intervention than those patients who fail to hit recommended goals.

While there is no answer, he also wonders: how should trial results be interpreted when one arm gets significantly better OMT?

The idea that background therapy can affect clinical trial results is a real phenomenon, he said. In the SYNTAX trial, for example, patients in the PCI arm were treated much more aggressively than the coronary artery bypass graft patients, who were less likely to receive statins, aspirin or other antiplatelet agents, and angiotensin-converting–enzyme inhibitors or angiotensin II–receptor antagonists (all <0.001). In looking at these cardiac-related medications given after the study procedure, there was typically at least a 10 percentage point spread between the study arms.

“Long-term follow-up studies have to track patient adherence,” said Dr. Farkouh. “We have to do a better job of that.”

References

1. BARI 2D Study Group, Frye RL, August P, Brooks MM, et al. A randomized trial of therapies for type 2 diabetes and coronary artery disease. N Engl J Med 2009;360:2503-15.
2. Shaw LJ, Berman DS, Maron DJ, et al.; COURAGE Investigators. Optimal medical therapy with or without percutaneous coronary intervention to reduce ischemic burden: results from the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial nuclear substudy. Circulation 2008;117:1283-91.
3. Serruys PW, Morice M-C, Kappetein AP, et al. Percutaneous coronary intervention versus coronary-artery bypass grafting for severe coronary artery disease. N Engl J Med 2009;360:961-72.

Keywords: Angiotensin Receptor Antagonists, Stroke, National Heart, Lung, and Blood Institute (U.S.), Follow-Up Studies, Platelet Aggregation Inhibitors, Cholesterol, LDL, Risk Reduction Behavior, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Diabetes Mellitus, Type 2, Blood Pressure, Glycated Hemoglobin A, Diet, Coronary Artery Bypass, Patient Compliance

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