Secondary prevention of coronary artery disease and the choice of the ACE inhibitor why EUROPA and not PEACE

Cardiovascular Drugs and Therapy (Impact Factor: 3.19). 01/2008; 21(6):405-7. DOI: 10.1007/s10557-007-6071-x
Source: PubMed
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  • Kim Fox ·
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    ABSTRACT: Cardiovascular risk factors such as hypertension and diabetes are understood to trigger a sequence of pathological events starting from hypertension and atherosclerosis, which if left unmanaged can ultimately progress to end-stage cardiovascular disease. This chain of events is termed the cardiovascular continuum. The angiotensin-converting enzyme inhibitor, perindopril, has marked restorative effects on endothelial dysfunction and this translates into clinical benefits for patients at all stages of the continuum, making it a highly effective treatment in cardiovascular disease. In hypertensive patients, large-scale clinical trials have shown that perindopril-based treatments reduce morbidity and mortality and reduce the onset of stroke, renal failure, and diabetes when compared with other anti-hypertensive therapies. In patients at more advanced stages of the cardiovascular continuum, the use of perindopril on top of other standard management practices further improves long-term prognosis in coronary artery disease. Perindopril also reduces cardiac remodelling following myocardial infarction and improves patient symptoms and prognosis in diastolic heart failure. Current trial evidence confirms the clinical benefits of perindopril throughout the cardiovascular continuum, thus slowing the progression of cardiovascular disease and improving patient prognosis.
    European Heart Journal Supplements 09/2008; 10. DOI:10.1093/eurheartj/sun026 · 15.80 Impact Factor
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    ABSTRACT: ACE inhibition is now recognized as superior to placebo on outcomes in stable coronary artery disease (CAD), including total and cardiovascular mortality, fatal and nonfatal myocardial infarction, heart failure, revascularization and stroke. This review examines clinical evidence for the mode of action of ACE inhibitors in CAD, which is dominated by the results of a single trial, EUROPA, and its substudies. The generally accepted mode of action for ACE inhibitors in CAD is blood pressure reduction. However, the EUROPA data demonstrate that endothelial protection, with the effect of arresting or reducing the processes of atherosclerosis is also important. Chronic overexpression of tissue ACE in CAD disrupts the angiotensin II/bradykinin balance with a net result of endothelial dysfunction. ACE inhibitors reduce production of angiotensin II, which prevents vasoconstriction, reduces adhesion molecules and growth factors, decreases oxidative stress and prevents apoptosis. A concomitant decrease in the degradation of bradykinin as a result of ACE inhibition raises levels of this kinin, leading to vasodilation and an antiapoptotic action, as well as opposition of the negative actions of angiotensin II. We now have clinical trial evidence of these processes in CAD patients participating in the EUROPA study by measurement of markers of endothelial function, including nitric oxide synthase (eNOS), the rate of apoptosis and levels of von Willebrand factor (vWf). Serum from CAD patients was found to significantly downregulate eNOS protein expression and activity versus that of healthy controls (p < 0.01), most probably as a result of upregulation of tissue ACE. One year of treatment with perindopril upregulated eNOS protein expression and activity (19% and 27% vs placebo; p < 0.05). Similarly, vWf was elevated at baseline and significantly reduced after 1 year of treatment with perindopril (p < 0.001). Increased endothelial apoptosis by serum of CAD patients was accompanied by excess angiotensin II and tumour necrosis factor-alpha and a reduction in bradykinin; all of these parameters were reversed by treatment. We therefore have clinical results showing that perindopril normalizes the angiotensin II/bradykinin balance, reduces inflammation and prevents endothelial apoptosis. Accumulating preclinical evidence for the absence of a class effect for ACE inhibitors includes differences in terms of effect on eNOS and rate of endothelial apoptosis. These differences appear to be related to tissue affinity, penetration of atherosclerotic plaque and affinity for the target enzyme. Consideration of these features is important when administering ACE inhibition as secondary prevention in CAD patients. In this context, current European guidelines for stable angina pectoris recommend prescription of agents and doses with proven efficacy in secondary prevention.
    Drugs 01/2009; 69(3):265-77. DOI:10.2165/00003495-200969030-00003 · 4.34 Impact Factor
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    ABSTRACT: AimsWe determined whether blood pressure (BP) lowering by perindopril was related to its benefit in the EUROPA study. Methods and resultsTwelve thousand two hundred eighteen patients with documented coronary artery disease received perindopril 8mg once daily or matching placebo after a 4-week run-in period in which all patients received perindopril. Patients were excluded if systolic (S) BP was >180 or <100mmHg. Mean age was 60years (range 26ā€“89). 27% had a history of hypertension. After 4.2years of follow-up, the primary endpoint (cardiovascular death, nonfatal myocardial infarction, or resuscitated cardiac arrest) was observed in 603 (9.9%) placebo versus 488 (8.0%) perindopril patients [20% relative risk reduction (RRR), CI 9ā€“29%, Pā€‰=ā€‰0.003]. There was no interaction between baseline SBP levels (using JNC-7 cutoff values) and treatment effect. If anything, the greatest RRR of the primary endpoint (32%) occurred in patients with the lowest SBP (<120mmHg) in whom perindopril did not reduce SBP. Also, RRR during blinded treatment was comparable, irrespective of whether BP decreased or not or of the extent of BP reduction during perindopril treatment. ConclusionThe treatment benefit in EUROPA cannot be fully explained by baseline BP or BP reduction with perindopril. Other mechanisms including direct anti-atherosclerotic effects of ACE inhibition may play a role.
    Cardiovascular Drugs and Therapy 04/2009; 23(2):161-170. DOI:10.1007/s10557-008-6143-6 · 3.19 Impact Factor
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