EUROPEAN HEART JOURNAL SUPPLEMENTS
Key lessons from morbidity/mortality trials: evidence for benefits of the perindopril/amlodipine combination ESC MUNICH 2008
1 Department of Cardiology, Università degli Studi di Ferrara, Italy
2 Cardiovascular Research Center IRCCS, Salvatore Maugeri Foundation, Gussago, Brescia, Italy
In the last 50 years, mean life span has increased by almost 8 years. Cardiology has played an important role in this achievement. It has been estimated that the contribution of cardiology to the extension of life accounts for almost 6 years!
This depends in part, of course, on the fact that cardiovascular disease itself contributes to more than 50% of total mortality of population, but also largely on the success of interventional cardiology and cardiovascular therapy.
The contribution of revascularization by any means, but particularly by primary angioplasty, has changed the natural history of acute myocardial infarction (MI) to the extent that, today, the need for intensive care units to treat acute MI is often questioned. Equally, there have been huge advances in heart surgery for revascularization of complex coronary, valvular, and congenital diseases, and transplantation.
Of similar, if not greater, relevance is the contribution of drug therapy to the improved prognosis of patients with cardiovascular disease. The key to this success, at least in my opinion, relates to the recognition by Dzau and Braunwald of a rather simple concept: the continuous progression of cardiovascular diseases leading to different, but related, clinical events. They called this pathophysiological and clinical concept the ‘cardiovascular continuum’. In this model, the progression of cardiovascular diseases starts from risk factors such as hypertension and diabetes, and leads through coronary artery disease (CAD) to myocardial ischaemia (in its own manifestation: angina, infarction, and sudden death), heart failure (HF), and end-stage heart disease. We do not know in detail the intimate cause of this continuum, although atherosclerosis and endothelial damage seem to play a major role.
However, we know from clinical trials targeting different portions of the continuum with different agents that it is possible to break this chain of events, and that this translates into prognostic benefits. What is remarkable is that the same class of drugs, namely angiotensin-converting enzyme (ACE) inhibitors, β-blockers, and lipid-lowering drugs, are essential to improve the prognosis in very different clinical diseases, such as angina, MI, hypertension, HF, diabetes, and so on. This should not be surprising as they are different clinical manifestations of the same underlying pathological condition. The modalities of each clinical manifestation relate to how each individual has progressed down the cardiovascular continuum, and at what rate.
The first article of this supplement reviews in detail the data obtained from clinical trials with ACE inhibitors across the continuum of cardiovascular disease, with particular emphasis on perindopril, the ACE inhibitor which has been most studied in the clinical arena, with more than 50 000 patients enrolled in major morbidity–mortality trials (e.g. ADVANCE, ASCOT, EUROPA, PREAMI, PEP CHF, and PROGRESS).
Importantly, these and many other trials have shown that the cardiovascular protective effect of ACE inhibition occurs beyond chronic blood pressure (BP) reduction. The other generally accepted mode of action for ACE inhibitors independently of BP lowering is endothelial protection with the effect of arresting or reducing the process of atherosclerosis. Chronic overexpression of tissue ACE in CAD disrupts the angiotensin II/bradykinin balance, the net result being endothelial dysfunction. ACE inhibitors reduce the 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 due to ACE inhibition raises the levels of this kinin, leading to vasodilation and to a powerful antiapoptotic action, as well as opposition to 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 endothelial nitric oxide synthase (eNOS), the rate of apoptosis, and the levels of von Willebrand factor (vWf). CAD patient serum was found to significantly downregulate eNOS protein expression and activity in comparison with serum of healthy controls, most likely due to upregulation of tissue ACE. One-year treatment with perindopril upregulated the eNOS protein expression and activity. Similarly, vWf was elevated at baseline, and significantly reduced after 1-year treatment with perindopril. PERTINENT also provides evidence showing that perindopril normalizes the angiotensin II/bradykinin balance, reduces inflammation, and prevents endothelial apoptosis. Interestingly, this is not necessarily a class effect. In fact, accumulating preclinical evidence for the absence of a class effect for ACE inhibitors includes significant differences in terms of endothelial apoptosis. These differences appear to be related to tissue affinity, penetration of atherosclerotic plaque, and affinity for the target enzyme.
These considerations are important when administering ACE inhibition to CAD patients as secondary prevention. In this context, the current European guidelines in stable angina recommend the prescription of agents and doses with proven efficacy in secondary prevention. All of these mechanisms are addressed in detail in the second article of this supplement.
However, the best strategy will be to prevent the occurrence of CAD, and this can, at least in part, be achieved by BP control. This is not always simple, and all randomized trials consistently show that the majority of patients with hypertension require at least two agents to reach the recommended targets. This is because different classes of drugs, with different mechanisms of action, are often complementary in achieving the reduction in BP. A recent meta-analysis suggests that some combinations produce more additive BP lowering effects than others, i.e. ACE inhibitors and dihydropyridine calcium channel blockers.
This is not surprising when we consider the intimate effects of each drug on the vessels. Calcium channel blockers reduce calcium influx through both the receptors and voltage-operating calcium channels of the smooth muscle. By doing so, they prevent contraction of myocardium. ACE inhibitors, however, induce dilation by two distinct mechanisms: the increase in bradykinin causes upregulation of expression and activity of eNOS, with enhanced production and release of NO from the endothelium, which promotes relaxation of vascular smooth muscle through guanosine monophosphate (GMP)-dependent calcium extrusion. It follows that calcium channel blockers prevent contraction whereas ACE inhibitors promote relaxation (Figure 1). Furthermore, inhibition of ACE reduces the production of angiotensin II, which also promotes the calcium entry.
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Given that the optimal combination is ACE inhibitor plus calcium channel blocker, the current question is whether these drugs should be given together at fixed doses or separately. In general, within the cardiological community, there is the incorrect belief that fixed-dose combinations are not ideal and that doctors should provide the correct dosage for each patient.
Although data are limited, the available evidence suggests that compliance with two drugs delivered in a fixed combination is greater than two agents provided separately. It follows that BP lowering is superior with the use of fixed combinations and hence cardiovascular events are further reduced. Remarkably, this helps reduce health care costs. Furthermore, uptitration and prescription costs are reduced when a fixed combination is used. It should be recalled that fixed combinations are an accepted standard in other fields of medicine such as pneumology, diabetes, and oncology. All of these issues are reviewed in depth in the third article of this supplement, with particular emphasis on perindopril/amlodipine combination, which the recent ASCOT trial has proved to be mechanistically logical, well tolerated, cost-effective, and prognostically beneficial. Thus, with the ageing of the population, there is likely to be a trend towards the use of combination therapy. This is likely to involve not just the combination of two antihypertensive agents, but also the combination of various products acting at different levels of the cardiovascular continuum.
Finally, the fourth article of this supplement addresses the important question of which patients should be given a fixed combination of perindopril and amlodipine. The combination is particularly beneficial in patients with CAD and either hypertension or anginal symptoms. In addition, both classes of medications have a favourable metabolic profile and have been shown to reduce the occurrence of new-onset diabetes mellitus in a variety of clinical situations. The impact of the amlodipine/perindopril combination on central aortic pressure suggests a particular relevance in situations of increased central pulse pressure, such as elderly populations or patients with chronic kidney disease.
It follows that this combination is an excellent choice to slow or stop the progression of hypertensive patients down the cardiovascular continuum.
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