Laval, QC - When the Prevention of Events with Angiotensin Converting Enzyme Inhibition (PEACE) trial [1] was published and presented in 2004 at the American Heart Association Scientific Sessions, the results confused, rather than cleared up, the issue of whether or not to use ACE inhibitors in patients with atherosclerosis.

In PEACE, which included patients with stable coronary heart disease but without a history of heart failure or left ventricular systolic dysfunction, the addition of the ACE inhibitor trandolapril failed to provide any further benefit in terms of death from cardiovascular causes, MI, or coronary revascularization. These results differed from the Heart Outcomes Prevention Evaluation (HOPE) trial and European Trial on Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease (EUROPA) [2,3], which suggested that high-risk coronary patients could gain additional cardiovascular protection with the addition of an ACE inhibitor to therapy.

Now, a new meta-analysis combining the findings of HOPE, EUROPA, and, PEACE, published in the August 12, 2006 issue of the Lancet by Dr Gilles Dagenais (Laval University Heart and Lung Institute, Laval, QC) and colleagues, has shown that ACE inhibitors reduce the risk of serious vascular events in patients with atherosclerosis but without known heart failure or left ventricular dysfunction [4].

"I think that we should consider giving an ACE inhibitor to all patients who have atherosclerosis," Dagenais told heartwire. "However, they need to be able to tolerate it. As a clinician, I do believe that there is a benefit, even among low-risk patients. If you look only at the PEACE study and say that patients treated with statins or who had PCI should not receive an ACE inhibitor as proposed, I think that is going too far. I think there are patients who are very low risk and who probably don't need an ACE inhibitor, but the majority, as far as we're concerned, should be treated with the drugs."

Before the publication of PEACE, the American College of Physicians (ACP) published a recommendation in the Annals of Internal Medicine—based on HOPE and EUROPA—that all patients with coronary heart disease should be taking an ACE inhibitor. However, after the negative findings from PEACE, clinicians were left in a bind as to whether or not an ACE inhibitor was necessary in low-risk patients without heart failure or left ventricular dysfunction.

When presented and published, the PEACE investigators suggested the negative results could be explained by the fact that 70% of patients were taking lipid-lowering therapies and more than 90% were treated with aspirin. In addition, many patients in PEACE had undergone prior revascularization. In patients with well-controlled cholesterol levels and blood pressure, Dr Marc Pfeffer (Brigham and Women's Hospital, Boston, MA), who presented the PEACE findings, said, "We're getting to the point where some of our therapies are redundant when you really lower somebody's risk."

An editorial accompanying the meta-analysis, written by Drs Giuseppe Remuzzi and Piero Ruggenenti (Ospedali Riuniti, Bergamo, Italy), echoes these sentiments, noting that the reason for the negative findings is likely due to the fact that PEACE did not include patients with diabetes or high cardiovascular risk [5].

Dagenais told heartwire that he disagreed with this initial interpretation of the PEACE study. For this reason, the investigators conducted the meta-analysis of the three trials to assess the consistency with which ACE inhibitors reduce total mortality and fatal and nonfatal cardiovascular events. All three trials included more than 8000 stable patients and were followed for an average of 4.5 years.

Investigators report that when the three trials were combined, ACE inhibitors significantly reduced all-cause mortality, cardiovascular mortality, nonfatal myocardial infarction, all stroke, heart failure, and CABG surgery, but not PCI. There was a significant 18% reduction in the composite end point of cardiovascular mortality, nonfatal MI, or stroke in those treated with ACE inhibitors.

To examine the hypothesis that low-risk patients would not benefit from the addition of an ACE inhibitor, Dagenais and colleagues conducted a subgroup analysis looking only at low-risk patients in HOPE and EUROPA, as well as the entire low-risk PEACE cohort. They point out that even in these low-risk patients, there were still large reductions in the composite end point of cardiovascular death, nonfatal MI, or stroke in the HOPE and EUROPA trials.

"The point of the study is to address the interpretation of the PEACE trial," said Dagenais. "With an annualized rate in the placebo group of 2.13 (cardiovascular death, nonfatal MI, or stroke), the investigators suggest there is a threshold at which the ACE inhibitor is not working. What the subgroup analysis shows is that this is not the case. Even among the low-risk patients in EUROPA, where the annualized placebo rate is 1.40, there is still a clear benefit with the ACE inhibitor."

In addition, Dagenais noted there was a significant benefit observed in the combined HOPE and EUROPA subgroups of patients on lipid-lowering agents, beta blockers, and antiplatelet drugs, alone or combined, suggesting that even well-treated patients benefit from ACE-inhibitor therapy. The real reason for the negative findings in PEACE, said Dagenais, is due to the fact that study was underpowered and used revascularization, a soft end point, in assessing the benefit of ACE inhibitors in this low-risk patient population.

The editorialists, Remuzzi and Ruggenenti, disagree with these conclusions, noting that the conclusions reached by Dagenais could misdirect treatment decisions. They add that the power of statistical models to detect heterogeneity is small, especially in a meta-analysis that includes just three trials and not individual patient data. In contrast to the researchers' conclusions, they state that data still support the use of ACE inhibitors only for high-risk patients with diabetes or uncontrolled cholesterol levels and do "not offer added benefit to low-risk patients already on aspirin, beta blockers, and statins."