Vascular Protection After the PEACE Trial

Has PEACE ever before caused such havoc?

The Prevention of Events With Angiotensin Converting Enzyme Inhibition trial has been widely misinterpreted, to the detriment of patient care.

PEACE involved the double-blind randomization of patients with stable coronary artery disease (CAD) and normal left ventricular systolic function to the ACE inhibitor trandolapril or placebo on top of modern conventional therapy with other drugs of proven effectiveness. Surprisingly, the trandolapril group experienced no reduction in clinical atherosclerotic events, compared with placebo. Many physicians have concluded as a result that the study casts doubt upon the overall vasculoprotective effects of ACE inhibition.

So what effect, then, has PEACE had on my own clinical practice? None whatsoever. I continue to place essentially all my patients with CAD or any other form of vascular disease and normal left ventricular systolic function on an ACE inhibitor, giving preference to those agents that have demonstrated compelling evidence of benefit in this setting—namely, ramipril and perindopril. And in talking with cardiology opinion leaders, I find most of them are doing the same.

Why are many of us not more willing to give PEACE a chance? Because the persuasive bulk of the randomized clinical trial data, including the nearly 10,000-patient Heart Outcomes Prevention Evaluation (HOPE) trial as well as the 12,218-patient European Trial on Reduction of Cardiac Events With Perindopril in Stable Coronary Artery Disease (EUROPA), has shown that ACE inhibitor therapy results in a highly significant 20%-22% reduction in atherosclerotic events in patients with CAD or other vascular disease but no history of heart failure or depressed left ventricular systolic function.

This demonstrated clinical efficacy has a compelling mechanistic basis. ACE inhibitors not only lower blood pressure, they also have antithrombotic properties, have antioxidant effects, potentiate bradykinin, reduce vascular inflammation, promote atherosclerotic plaque stabilization, reduce endothelial dysfunction, and curb deleterious vascular and cardiac remodeling. It's a very potent package of beneficial effects.

PEACE involved 8,290 patients with stable CAD and preserved left ventricular systolic function randomized at 187 U.S., Canadian, and Italian sites to trandolapril at a target dose of 4 mg/day or placebo. After a median 4.8-year follow-up, the incidence of the primary study end point—a composite of cardiovascular death, acute myocardial infarction, or coronary revascularization—was 21.9% in the trandolapril arm and 22.5% with placebo. Nearly identical. There were no identifiable patient subgroups that benefited from the ACE inhibitor.

Why did the outcome of PEACE differ so from those of HOPE and EUROPA? One possibility is that not all ACE inhibitors are equally effective in patients like those included in these three studies. Perhaps trandolapril, unlike ramipril and perindopril, simply doesn't cut the mustard in this setting. Maybe a more lipophilic ACE inhibitor is required. This, in my view, is an unlikely explanation.

It is much more likely that the difference in PEACE was due to the markedly higher background utilization rates of other drugs of proven effectiveness in vasculopathic patients. To put it plainly, because of changing practice patterns, the patients were much better treated in terms of guideline-recommended therapies for their coexisting risk factors. The use of statins, for example, was significantly more common in PEACE than in the earlier HOPE and EUROPA trials. The PEACE participants on statin therapy were also treated to lower target LDL-cholesterol values.

Similarly, PEACE participants had higher rates of antiplatelet therapy than those in HOPE and EUROPA. They also had better blood pressure control, greater utilization of β-blocker therapy, and a higher rate of coronary revascularization procedures prior to study enrollment.

PEACE has raised an important question in my mind and in those of other observers: If we treat our patients in exemplary fashion with all of the other guideline-recommended risk-reduction therapies, do we still obtain added value from ACE inhibitor therapy, or does it become redundant? The verdict is still out on that. But because the weight of the evidence to date still supports the vasculoprotective role of ACE inhibitors, I'm not planning to change my own practice unless a future randomized trial replicates the PEACE findings.

I don't expect that to happen. In fact, that kind of a trial will be virtually impossible to conduct. It would be a no-win situation for a sponsoring pharmaceutical company, and the National Institutes of Health usually does not conduct comparative trials.

Has PEACE ever before caused such havoc?

The Prevention of Events With Angiotensin Converting Enzyme Inhibition trial has been widely misinterpreted, to the detriment of patient care.

PEACE involved the double-blind randomization of patients with stable coronary artery disease (CAD) and normal left ventricular systolic function to the ACE inhibitor trandolapril or placebo on top of modern conventional therapy with other drugs of proven effectiveness. Surprisingly, the trandolapril group experienced no reduction in clinical atherosclerotic events, compared with placebo. Many physicians have concluded as a result that the study casts doubt upon the overall vasculoprotective effects of ACE inhibition.

So what effect, then, has PEACE had on my own clinical practice? None whatsoever. I continue to place essentially all my patients with CAD or any other form of vascular disease and normal left ventricular systolic function on an ACE inhibitor, giving preference to those agents that have demonstrated compelling evidence of benefit in this setting—namely, ramipril and perindopril. And in talking with cardiology opinion leaders, I find most of them are doing the same.

Why are many of us not more willing to give PEACE a chance? Because the persuasive bulk of the randomized clinical trial data, including the nearly 10,000-patient Heart Outcomes Prevention Evaluation (HOPE) trial as well as the 12,218-patient European Trial on Reduction of Cardiac Events With Perindopril in Stable Coronary Artery Disease (EUROPA), has shown that ACE inhibitor therapy results in a highly significant 20%-22% reduction in atherosclerotic events in patients with CAD or other vascular disease but no history of heart failure or depressed left ventricular systolic function.

This demonstrated clinical efficacy has a compelling mechanistic basis. ACE inhibitors not only lower blood pressure, they also have antithrombotic properties, have antioxidant effects, potentiate bradykinin, reduce vascular inflammation, promote atherosclerotic plaque stabilization, reduce endothelial dysfunction, and curb deleterious vascular and cardiac remodeling. It's a very potent package of beneficial effects.

PEACE involved 8,290 patients with stable CAD and preserved left ventricular systolic function randomized at 187 U.S., Canadian, and Italian sites to trandolapril at a target dose of 4 mg/day or placebo. After a median 4.8-year follow-up, the incidence of the primary study end point—a composite of cardiovascular death, acute myocardial infarction, or coronary revascularization—was 21.9% in the trandolapril arm and 22.5% with placebo. Nearly identical. There were no identifiable patient subgroups that benefited from the ACE inhibitor.

Why did the outcome of PEACE differ so from those of HOPE and EUROPA? One possibility is that not all ACE inhibitors are equally effective in patients like those included in these three studies. Perhaps trandolapril, unlike ramipril and perindopril, simply doesn't cut the mustard in this setting. Maybe a more lipophilic ACE inhibitor is required. This, in my view, is an unlikely explanation.

It is much more likely that the difference in PEACE was due to the markedly higher background utilization rates of other drugs of proven effectiveness in vasculopathic patients. To put it plainly, because of changing practice patterns, the patients were much better treated in terms of guideline-recommended therapies for their coexisting risk factors. The use of statins, for example, was significantly more common in PEACE than in the earlier HOPE and EUROPA trials. The PEACE participants on statin therapy were also treated to lower target LDL-cholesterol values.

Similarly, PEACE participants had higher rates of antiplatelet therapy than those in HOPE and EUROPA. They also had better blood pressure control, greater utilization of β-blocker therapy, and a higher rate of coronary revascularization procedures prior to study enrollment.

PEACE has raised an important question in my mind and in those of other observers: If we treat our patients in exemplary fashion with all of the other guideline-recommended risk-reduction therapies, do we still obtain added value from ACE inhibitor therapy, or does it become redundant? The verdict is still out on that. But because the weight of the evidence to date still supports the vasculoprotective role of ACE inhibitors, I'm not planning to change my own practice unless a future randomized trial replicates the PEACE findings.

I don't expect that to happen. In fact, that kind of a trial will be virtually impossible to conduct. It would be a no-win situation for a sponsoring pharmaceutical company, and the National Institutes of Health usually does not conduct comparative trials.

Has PEACE ever before caused such havoc?

The Prevention of Events With Angiotensin Converting Enzyme Inhibition trial has been widely misinterpreted, to the detriment of patient care.

PEACE involved the double-blind randomization of patients with stable coronary artery disease (CAD) and normal left ventricular systolic function to the ACE inhibitor trandolapril or placebo on top of modern conventional therapy with other drugs of proven effectiveness. Surprisingly, the trandolapril group experienced no reduction in clinical atherosclerotic events, compared with placebo. Many physicians have concluded as a result that the study casts doubt upon the overall vasculoprotective effects of ACE inhibition.

So what effect, then, has PEACE had on my own clinical practice? None whatsoever. I continue to place essentially all my patients with CAD or any other form of vascular disease and normal left ventricular systolic function on an ACE inhibitor, giving preference to those agents that have demonstrated compelling evidence of benefit in this setting—namely, ramipril and perindopril. And in talking with cardiology opinion leaders, I find most of them are doing the same.

Why are many of us not more willing to give PEACE a chance? Because the persuasive bulk of the randomized clinical trial data, including the nearly 10,000-patient Heart Outcomes Prevention Evaluation (HOPE) trial as well as the 12,218-patient European Trial on Reduction of Cardiac Events With Perindopril in Stable Coronary Artery Disease (EUROPA), has shown that ACE inhibitor therapy results in a highly significant 20%-22% reduction in atherosclerotic events in patients with CAD or other vascular disease but no history of heart failure or depressed left ventricular systolic function.

This demonstrated clinical efficacy has a compelling mechanistic basis. ACE inhibitors not only lower blood pressure, they also have antithrombotic properties, have antioxidant effects, potentiate bradykinin, reduce vascular inflammation, promote atherosclerotic plaque stabilization, reduce endothelial dysfunction, and curb deleterious vascular and cardiac remodeling. It's a very potent package of beneficial effects.

PEACE involved 8,290 patients with stable CAD and preserved left ventricular systolic function randomized at 187 U.S., Canadian, and Italian sites to trandolapril at a target dose of 4 mg/day or placebo. After a median 4.8-year follow-up, the incidence of the primary study end point—a composite of cardiovascular death, acute myocardial infarction, or coronary revascularization—was 21.9% in the trandolapril arm and 22.5% with placebo. Nearly identical. There were no identifiable patient subgroups that benefited from the ACE inhibitor.

Why did the outcome of PEACE differ so from those of HOPE and EUROPA? One possibility is that not all ACE inhibitors are equally effective in patients like those included in these three studies. Perhaps trandolapril, unlike ramipril and perindopril, simply doesn't cut the mustard in this setting. Maybe a more lipophilic ACE inhibitor is required. This, in my view, is an unlikely explanation.

It is much more likely that the difference in PEACE was due to the markedly higher background utilization rates of other drugs of proven effectiveness in vasculopathic patients. To put it plainly, because of changing practice patterns, the patients were much better treated in terms of guideline-recommended therapies for their coexisting risk factors. The use of statins, for example, was significantly more common in PEACE than in the earlier HOPE and EUROPA trials. The PEACE participants on statin therapy were also treated to lower target LDL-cholesterol values.

Similarly, PEACE participants had higher rates of antiplatelet therapy than those in HOPE and EUROPA. They also had better blood pressure control, greater utilization of β-blocker therapy, and a higher rate of coronary revascularization procedures prior to study enrollment.

PEACE has raised an important question in my mind and in those of other observers: If we treat our patients in exemplary fashion with all of the other guideline-recommended risk-reduction therapies, do we still obtain added value from ACE inhibitor therapy, or does it become redundant? The verdict is still out on that. But because the weight of the evidence to date still supports the vasculoprotective role of ACE inhibitors, I'm not planning to change my own practice unless a future randomized trial replicates the PEACE findings.

I don't expect that to happen. In fact, that kind of a trial will be virtually impossible to conduct. It would be a no-win situation for a sponsoring pharmaceutical company, and the National Institutes of Health usually does not conduct comparative trials.