Abstract and Introduction
The renin-angiotensin-aldosterone system (RAAS) is now known to play a key role in the pathogenesis of hypertension and a range of other cardiovascular diseases. Two groups of drugs, the ACE inhibitors and angiotensin II type 1 receptor antagonists (angiotensin receptor blockers [ARBs]) have been developed with the aim of improving clinical outcomes by regulating the RAAS in patients with cardiovascular disease.
Initial assumptions were that these two drug types might be interchangeable, but ongoing research has revealed differences between them in terms of pharmacology and outcomes in clinical trials. Although both groups of drugs lower blood pressure, studies of the ACE inhibitor perindopril have revealed preservation of beneficial vascular and endothelial effects mediated by bradykinin and nitric oxide. The selective blockade exerted by ARBs is not associated with these effects. Furthermore, examination of clinical endpoints in major clinical trials has provoked discussion about outcomes comparing ACE inhibitors and ARBs, with recent debate focusing on the incidence of myocardial infarction (MI) in patients receiving these agents. Whether there is an actual difference in protection from MI remains unresolved, although available data confirm the benefit and safety of ACE inhibitors, in particular perindopril, for myocardial protection.
The renin-angiotensin-aldosterone system (RAAS) is essential for the regulation of blood pressure (BP) and cardiovascular and renal function. Disordered functioning of the RAAS plays a key role in the pathophysiology of hypertension, coronary artery disease (CAD) and chronic heart failure. Of particular interest is the vasoactive peptide angio-tensin II, a potent vasoconstrictor and growth promoter, which is formed by the action of angiotensin-converting enzyme (ACE) on angiotensin I. ACE is a metalloprotease found mainly in tissues that regulates the balance between angiotensin II-induced vasoconstriction/salt retention and the vasodilatory and natriuretic properties of bradykinin. Increased expression of this enzyme is seen in nearly all models of cardiac injury and has a major influence on the development of hypertension. Blockade of the RAAS has therefore become universally accepted as a target in cardiovascular disease.
The physiological effects of angiotensin II are mediated principally via two types of receptor: these are known as AT1 and AT2. Both belong to the family of G protein-coupled receptors, but have different functions. AT1 essentially transactivates growth pathways and is responsible for most of the well known physiological effects of angiotensin II; these include vasoconstriction, increased contractility, tubular sodium reabsorption, cell proliferation, vascular and cardiac hypertrophy, inflammatory responses and oxidative stress. The function of AT2 has until relatively recently been unknown, possibly because this receptor is expressed to a lower extent than the AT1 subtype, but accumulating evidence suggests that AT2 induces effects that generally oppose those of AT1. These include vasodilation, growth inhibition and antihypertrophic effects.[4,5,6] Both AT1 and AT2 receptors are important in BP regulation.[7,8] Animal experiments have shown that AT2 is expressed in the kidney, mesenteric blood vessels and the heart, and that stimulation of this receptor subtype results in a vasodilator signalling cascade response involving bradykinin, nitric oxide (NO) and cyclic guanosine-3',5'-monophosphate.
Uncertainty has also been expressed over the effects of long-term overstimulation of AT2 receptors.[9,10] Overall, it appears that AT2 receptor stimulation may have more complex physiological consequences than previously realised and, in addition to a beneficial role in cardiovascular and renal diseases, overstimulation of the AT2 receptor may have potentially detrimental effects, such as increases in proliferation and mitosis. An association between the angiotensin II receptor allele and the presence of left ventricular hypertrophy in hypertensive subjects has also been demonstrated. In addition, the overall beneficial effects of ACE inhibition on cardiovascular outcomes are becoming more apparent as our understanding of the mechanisms involved increases and data from large clinical trials accumulate.[12,13]
The role of angiotensin II in cardiovascular, renal and cerebrovascular disease is well documented. Because a variety of signalling pathways and compounds are involved, the question of optimal pharmacological intervention in cardiology has been the subject of considerable debate for some years and has led to the development of a wide range of therapeutic agents. However, improved understanding of the mechanisms underlying the pathological changes involved in cardiovascular disease has led to the development of two major inhibitors of the RAAS: the ACE inhibitors and, more recently, the angiotensin II type 1 receptor antagonists (angiotensin receptor blockers [ARBs]).
Although the desired end result in terms of effects on BP in patients with hypertension is the same, ACE inhibitors and ARBs have modes of action that are, while related, nevertheless quite distinct. ACE inhibitors competitively inhibit circulating and local formation of angiotensin II, which decreases stimulation of both AT1 and AT2 receptors, may inhibit kininase II, and increases levels of bradykinin, especially at tissue level. This in turn stimulates NO and vasoactive prostaglandin release. Other actions include the reduction of aldosterone and vasopressin secretion, suppression of sympathetic nerve activity and reduction of the trophic effects of angiotensin II. ARBs work by blocking AT1 receptors, which leaves the AT2 subtype unopposed. The first consequence is an increase in circulating angiotensin II, which provokes marked stimulation and multiplication of AT2 receptors.
While both classes of drugs act on the RAAS, the premise that they should both have the same beneficial effect on cardiovascular protection still remains to be proven. Early comparative trials showed similarity between captopril (the first-generation ACE inhibitor) and losartan: in the ELITE (Evaluation of Losartan in the Elderly)-II Losartan Heart Failure Survival Study of 3152 patients, there were no significant differences between losartan 50 mg/day and captopril 50mg three times daily in all-cause mortality (280 vs 250 deaths; +13% with losartan), rates of sudden death or resuscitated arrest. The results of the OPTIMAAL (Optimal Trial in Myocardial Infarction with Angiotensin II Antagonist Losartan) study are also of special interest in this respect. This trial, which evaluated 5477 high-risk patients aged =50 years with acute myocardial infarction (MI) and heart failure, found no significant difference in total mortality between patients receiving losartan or captopril at the same dosages as were used in ELITE II.
However, recent correspondence and meta-analyses[10,18,19] have indicated that most trials performed with ARBs show either a neutral effect on or an increase in MI; of note, the increase in incidence of MI in CHARM (Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity)-Alternative was 52% (p = 0.025) in the ARB group relative to placebo. This detrimental effect was not seen when an ARB was taken in addition to an ACE inhibitor as in the CHARM-Added or CHARM-Preserved trials.
Such examination of clinical endpoints in major trials has stimulated discussion about the relative clinical benefits of ACE inhibitors and ARBs, both as drug classes and as individual agents. While ACE inhibitors all share the same mechanism of action, significant differences in the pharmacodynamic and pharmacokinetic properties of individual ACE inhibitors have been documented, and these may influence clinical effects. This review compares the documented evidence from clinical trials of the ACE inhibitor perindopril with that reported in trials of ARBs, with particular emphasis on cardiovascular outcomes.
Clin Drug Invest. 2007;27(3):149-161. © 2007 Adis Data Information BV
Cite this: Perindopril versus Angiotensin II Receptor Blockade in Hypertension and Coronary Artery Disease - Medscape - Mar 01, 2007.