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Congress Report |
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the 70th Scientific Session |
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Joint Symposiums |
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Secondary Prevention of Coronary Artery Disease: the Role of ACE Inhibitors Established by the EUROPA and PREAMI Studies
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Willem J. Remme
Sticares Cardiovascular Research Foundation
The Netherlands |
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ACE inhibitors have the capacity to significantly affect coronary artery disease through direct anti-atherogenic properties, improvement in endothelial function, enhanced fibrinolysis, reduction of plaque rupture, and inhibition of neurohormonal activation during ischemia and subsequent coronary vasoconstriction.
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EUROPA study of secondary prevention with perindopril
Secondary prevention with an ACE inhibitor in heart failure was demonstrated in the SAVE and SOLVD studies. The HOPE study showed that ramipril significantly improved morbidity and mortality in selected patients at high cardiovascular (CV) risk. Thus, the EUROPA study sought to determine the secondary preventive effects of perindopril in a broad unselected coronary disease population with low, medium, and high CV risk profiles. The patients had stable coronary artery disease (CAD), and heart failure was the only exclusion criterion.
A total of 12,218 patients were randomized to perindopril 8 mg or placebo and followed for five years. The primary outcome was the composite of CV death, non-fatal myocardial infarction (MI), and cardiac arrest. At baseline, 27% of the EUROPA patients had hypertension, compared to >40% of the HOPE population, and only 12% of EUROPA patients had diabetes.
The composite primary endpoint was reduced with perindopril by 10% at one year and by a significant nearly 40% after 3 years, and a very significant 20% reduction at 4.2 years when the study was stopped. Perindopril significantly reduced the primary outcome and its effect was progressive over time.
The secondary endpoint of fatal and non-fatal MI was reduced by a significant 34% with perindopril compared to placebo. Again, a progressive effect of the drug was seen over time. A 39% reduction in the risk of new onset heart failure was seen with perindopril,
Perindopril was equally effective in all of the subgroups. Further, the treatment effects of perindopril was independent of concomitant drugs. |
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EUROPA substudy results
The PERSUADE substudy of patients with diabetes showed a risk reduction for the primary and secondary endpoints. The absolute risk reduction was 2.9% in the diabetic patients with perindopril in PERSUADE, and 1.9% in the overall EUROPA population.
The CV benefits observed in EUROPA were independent of baseline blood pressure and blood pressure reduction during the trial, which was 5/2 mm Hg. Although there was no interaction, the greatest effect of perindopril was seen in the low baseline systolic blood pressure group, although blood pressure was not reduced.
Thus, other mechanisms, including a direct vascular atherosclerotic effect, must play a role in the risk reduction seen with perindopril. The PERTINENT (PERindopril Thrombosis INflammation ENndothelial dysfunction and neurohormonal activation Trial) and PERFECT (PERindopril and Function of the Endothelium in Coronary disease Trial) were substudies to evaluate the possible vascular effects of perindopril.
The PERTINENT sought to evaluate the effects of perindopril on endothelial function and markers of inflammation and thrombosis. In studies of the endothelial cells, in which serum was incubated at baseline and at one year, they found that perindopril reduced the rate of apoptosis compared to controls. Perindopril also significantly increased bradykinin levels, which were reduced at baseline, and reduced angiotensin II.
This effect on bradykinin is not seen with all ACE inhibitors. Dog studies also have shown a reduction in bradykinin with perindopril but not with enalapril. The lipophilicity of perindopril allows it to enter the vascular wall.
The PERTINENT trial showed in patients with CAD that perindopril increases bradykinin, reduces angiotensin, and reduces apoptosis, and thereby improves endothelial dysfunction. The PERFECT study also demonstrated significant improvement in flow-mediated dilation, compared to placebo, using B-mode ultrasound of the brachial artery. |
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Risk reduction in low CV risk population
The secondary prevention PEACE study surprisingly reported that enalapril, compared to placebo, did not reduce the primary outcome. The investigators stated this was because of the low CV risk study population.
Thus, the EUROPA investigators analyzed the effect of perindopril in their patients at low, medium, and high CV risk. Notably, they found the greatest risk reduction in the medium risk patients compared to the high risk patients, and that the lower risk patients had a better and significant risk reduction compared to the high risk patients. In EUROPA, the effect of perindopril is found irrespective of the risk profile.
EUROPA quantified LV function at baseline in 7,096 patients, and showed that perindopril, compared to placebo, significantly reduced the primary and secondary endpoints in patients with compromised and normal LV function. The significant reduction in outcomes with perindopril in the normal LV function is in contrast to the finding in PEACE, and Remme stated the lack of effect in PEACE was because of number of patients lost to follow-up (134 versus 3 in EUROPA) and a very low rate of receiving a titer dose (68% versus 93% in EUROPA).
The EUROPA study showed significant reductions with perindopril in an unselected broad coronary disease population. The effect was consistent at all risks levels, even low risk, and the effect was independent of blood pressure. Patients with normal LV function also had benefit with perindopril. |
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The PREAMI study
The PREAMI study was designed to investigate the prevention of remodeling post-MI in elderly patients with normal LV function. Previous studies showed that long-term ACE inhibition prevents LV remodeling in younger patients post-MI with LV dysfunction.
PREAMI studied the effect of one-year of ACE inhibition with perindopril in patients over 65 years old with document MI, and an LV ejection fraction >40%. The primary composite endpoint was all-cause mortality, heart failure, and LV remodeling.
At baseline, patients were 72 years of age on average, and had a normal heart rate and blood pressure. The patients were usually asymptomatic post-MI; some had class II heart failure. The infarcts were relatively small (LV asymmetry only 12%) and the LV ejection fraction a low 59% on average.
A significant 38% reduction in the primary outcome with perindopril compared to placebo was found. A 46% reduction in remodeling was the driver for the primary outcome reduction, A 27% reduction in heart failure was also seen. About 50% of placebo patients had an increase of ≥8% of LV and diastolic volume. Perindopril significantly reduced this increase, from 51% to 27.7%. This effect was consistent in all pre-specified groups. |
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Conclusion
The PREAMI trial provided significant information to the known therapeutic profile of ACE inhibition in different types of coronary disease. The results from the EUROPA and PREAMI trials indicate that perindopril is mandatory treatment in a large population, including the large unselected stable CAD patients and elderly patients with preserved cardiac function post-MI. |
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