‘ACE Inhibitors are Better than AT1 Receptor Blockers (ARBs)’ — Controversies in Heart Failure

Angiotensin-converting enzyme (kininase II) governs the equilibrium between the renin–angiotensin system and the kallakrein–kinin system. This in turn influences a wide variety of pathophysiological mechanisms including water and salt homeostasis, vascular tone, fibrinolysis, cell growth and inflammation, all of which are implicated in cardiac failure and two of the main underlying pathologies: coronary artery disease and systemic hypertension. ACE inhibitors, by adjusting this balance, play a pivotal role in the natural history of cardiac failure, a phenomenon reflected by the survival benefit observed in the numerous large-scale clinical trials of ACE inhibitors. In contrast, similar trials performed with the AT1, angiotensin II receptor blockers (ARBs) have yielded very disappointing results with a statistically non-significant excess of deaths. The deleterious effects of angiotensin II are well described. Systemically, it is a potent pressor agent also promoting salt and water retention. At a cellular level angiotensin II has been shown to produce endothelial dysfunction and to augment proliferation and hypertrophy of vascular smooth muscle cells [1]. Angiotensin II is a potent trophic stimulus to cardiomyocytes [2] resulting in cellular hypertrophy, fibrotic change and gross ventricular remodelling. These changes are all a common accompaniment to cardiac failure even in the absence of prior myocardial infarction. In patients with heart failure, ACE inhibitors reduce circulating angiotensin II levels whereas ARBs cause an increase, due to reduced negative feedback of angiotensin II on renin production. This may have no direct consequence via the AT1, receptor during times of complete blockade, though due to the competitive nature of the ligand–receptor interactions, effects may still be mediated during the times of the day when concentrations of the ARB are at their lowest. During these times and also following any non-compliance a rebound activation of the AT1, receptor is to be expected. The frequently prescribed ‘once daily’ losartan has a half-life of 6–9 h [3]. Elevated angiotensin II levels resulting from treatment with an ARB also gives rise to unopposed stimulation of receptors other than the AT1 receptor, including the angiotensin AT2 receptor. Currently the role of the AT2 receptors is ill defined with experimental studies producing conflicting results. Animal studies suggest that AT2 receptors counteract the trophic and proliferative effects of AT1 receptors but these findings should be interpreted with caution as there are significant cross-species differences in the receptor. The rodent AT1 receptor, in contrast to the human AT1 receptor, exists in two different isoforms each encoded by a different gene on separate chromosomes [4]. AT2 receptors have been shown to promote myocyte apoptosis [5], a phenomenon which may contribute to the progression of cardiac dysfunction [6]. Furthermore, angiotensin II is degraded to smaller peptides, angiotensin III and angiotensin IV, which may confer important pathophysiological effects not mediated via the AT1 receptor [7]. Chronic ACE inhibition does not produce sustained, complete inhibition of angiotensin II [8] despite continued clinical benefit. Angiotensin II can be generated by non-ACE-dependent pathways [9], so an additional biological mechanism must contribute to the beneficial effect of ACE inhibitors. Plasma bradykinin is inactivated by a number of peptidases of which ACE is the most potent [10]. Indeed the predominant biological effect underlying the beneficial role of ACE inhibitors may be its unique ability to inhibit the degradation of bradykinin. Experimental studies have demonstrated that at physiological concentrations, it is bradykinin that is the preferential substrate for the active binding sites of ACE, rather than angiotensin I [11]. Bradykinin stimulation of endothelial cells leads to nitric oxide and prostacyclin-mediated vasodilation and evidence suggests that ACE inhibitors sensitise vascular tissues to bradykinin thus augmenting its potency [12]. The TREND study demonstrated favourable effects of quinapril on endothelial dysfunction in diseased human coronary arteries indicating the potential clinical relevance of this level of action [13]. In addition to their favourable effects on vascular tone and cardiac remodelling ACE inhibitors have been implicated in the control of fibrinolytic balance, altering the equilibrium in favour of lysis. In the HEART study, ramipril therapy caused a significant reduction in the plasminogen activator inhibitor post myocardial infarction [14]. ACE has also been implicated in the modulation of inflammation in atherosclerotic lesions. Histological studies of atherosclerotic plaques have demonstrated increased ACE expression in lipid-laden macrophages and within the endothelial layer of the numerous microvessels, present throughout the more advanced lesions [15]. Therefore, ACE inhibition may directly prevent the development of unstable plaques as well as attenuating subsequent associated thrombosis. Over the last decade several large prospective randomised, placebo-controlled trials have demonstrated that ACE inhibitor therapy results in a substantial mortality reduction in patients with congestive heart failure [16,17]. A significant survival benefit is also observed in patients with asymptomatic LV dysfunction following myocardial infarction [18]. This is attributable not only to a slowing of the progression to congestive heart failure but also to reduction in sudden death and myocardial infarction. Following myocardial infarction, ACE inhibitors also confer a survival benefit even in those patients with preserved LV function [19,20]. This expanse of clinically meaningful data is not available for the ARBs. The results of the HOPE study suggest additional mechanisms of ACE inhibitors other than an impact on haemodynamics and cardiac remodelling [21]. Indeed the haemodynamic effects of ARBs and ACE inhibitors are said to be comparable, but additional anti-ischaemic effects can to date only be attributed to ACE inhibition. This was eloquently demonstrated in the HOPE study which demonstrated a 22% reduction in cardiovascular events following randomised ramipril therapy amongst a wide range of patients who either had, or were at risk of developing vascular disease, namely myocardial infarction, stroke or cardiovascular death. Comparative studies of the two therapeutic classes gives further strong support in favour of ACE inhibitors. Despite not being designed for this purpose the ELITE I study [22] was the first study (722 individuals; 10 months mean follow-up) to explore the possibility of an equivalent survival benefit in patients with LV impairment randomised to either the ARB losartan or the ACE-inhibitor captopril. It appeared that patients given losartan were more likely to survive, specifically due to a reduction in sudden death. The difference in absolute numbers was very small (14 vs. 5 deaths) emphasising that the study was not powered to be in any way conclusive regarding mortality differences. The RESOLVD pilot study [23] involved a similar number of patients with symptomatic heart failure and observed a statistically non-significant (P=0.15) higher mortality with the ARB candesartan as compared to the ACE inhibitor enalapril. Very importantly the study had to be stopped early after the External Safety and Efficacy Monitoring Committee ‘voiced concerns about the number of events in the patients treated with candesartan’. Based upon the observed trend it is possible that completion of the study would have resulted in the mortality excess achieving statistical significance. The recently completed ELITE II [24] study confirmed that ACE inhibitors should remain first-line therapy in the treatment of heart failure and once again raised important questions about the safety of using ARBs in patients with heart failure. This study was specifically designed to compare effects on mortality of the ACE-inhibitor captopril or the ARB losartan. This was a much larger trial than ELITE I recruiting 3152 patients, again showing a strong trend towards greater mortality with losartan. Of particular interest was the more marked trend towards harm when considering the occurrence of sudden death. This achieved conventional levels of statistical significance in patients receiving beta-blocker therapy (Hazard Ratio 1.79; P<0.05). Based on the results of the CIBIS II [25] and MERIT-HF [26] beta-blocker trials the majority of heart failure patients should be prescribed beta-blocker therapy. The ELITE II Trial was designed to demonstrate the superiority of losartan (which it failed to do) and was not powered to establish equal efficacy of the two drug classes. Therefore, to conclude that the two therapies are equivalent and can be freely interchanged is inappropriate. It is also noteworthy that the ELITE II study chose to compare against the first-generation sulfydryl ACE-inhibitor captopril, which has less favourable pharmacokinetics than do the newer carboxyl ACE-inhibitor subclass. Had a newer ACE inhibitor been selected for comparison, then the relative harm seen with losartan may have been even more apparent. Of some concern is the fact that the OPTIMAAL study [27] comparing captopril with losartan in patients with heart failure after myocardial infarction is still on-going despite the adverse trends seen in RESOLVD and ELITE II. Even if losartan were to have no statistically significant different effect on survival as compared to captopril the conclusion that ARBs as a class are as good as ACE-inhibitors as a class would be unsound. Certainly it has been the view of the US Food and Drug Administration (FDA) that losartan's licence for treating heart failure should be withdrawn. There are some theoretical reasons supporting the combined use of an ARB with an ACE inhibitor, although the outcome of two large clinical trials testing this strategy, are awaited, Val HeFT and CHARM [28,29]. However, the RESOLVD Pilot Study demonstrated a trend towards an even higher coronary event rate when an ARB and ACE inhibitor were combined, as compared to the use of an ACE inhibitor alone. This represents an additional cause for concern. ACE inhibitors are undoubtedly the ‘better’ class of drug for the treatment of heart failure and for the prevention of serious cardiovascular events in other patient groups. The thought that this is an issue for debate or controversy ignores the wealth of robust data describing the benefits resulting from treatment with an ACE inhibitor and the total absence of a comparable evidence base for the fashionable ARB ‘pretenders to the throne’.