Angiotensin II type-I receptor antagonists in the treatment of heart failure

International Journal of Cardiology 62 Suppl. 1 (1997) S13–S17

Angiotensin II type-I receptor antagonists in the treatment of heart failure M. Gary Nicholls*, Ian G. Crozier, Hamid Ikram, A. Mark Richards Departments of Medicine and Cardiology, Christchurch Hospital, Christchurch, New Zealand

1. Introduction In Western countries, heart failure is a common disorder particularly in the later decades of life [1]. It presents serious problems. Firstly, the incidence is increasing [2,3]. Secondly, quality of life is severely impaired for sufferers [4]. Thirdly, established heart failure has a high short-term mortality rate [5]. Fourthly, heart failure accounts for 1–2% of total health care budgets in Western countries, with hospitalisation costs dominant [6–8]. Heart failure can be classified as being due primarily to diastolic left ventricular dysfunction or systolic left ventricular dysfunction. The former is relatively ill understood in so far as etiology is concerned, and also regards how best it should be treated [9,10]. By contrast, the etiology of heart failure due primarily to systolic dysfunction is known to be dominated by essential hypertension and coronary heart disease [11] and the principles of drug therapy are more clear. Central to the drug treatment of patients with left ventricular systolic dysfunction are the angiotensin converting enzyme (ACE) inhibitors and diuretics, whilst the place of digoxin, at least in those with sinus rhythm, remains open to discussion and dispute [12]. Given that the ACE inhibitors reduce symptoms, improve exercise performance, reduce manifestations of coronary artery disease and increase longevity in those with left ventricular systolic dysfunction, one might question whether there is a place for alternative *Corresponding author.

drugs which inhibit activity or actions of the renin– angiotensin system. Specifically, is there a place for a new group of drugs, the angiotensin II type-I receptor antagonists?

2. The theory As noted above, the ACE inhibitors have been shown, from well controlled studies, to alter favourably the wellbeing and longevity of patients with heart failure due to systolic left ventricular dysfunction [13–17]. In theory such benefits may relate either to a reduction in circulating angiotensin II levels or to alternative actions, particularly increased tissue bradykinin levels [18] and consequences thereof. Dissection of these two possibilities is difficult [19] if not impossible in man. Animal experiments have given conflicting information: some studies indicate that the benefits of ACE inhibition in experimental heart failure probably relate to decreased angiotensin II levels, whereas other evidence can be cited suggesting that increased tissue kinin levels are of central importance. If indeed augmented tissue kinin levels account totally or in part for the beneficial effects of ACE inhibitors, then these agents should prove theoretically superior to drugs which selectively block the angiotensin AT-I receptor since one would not expect the latter to increase kinin levels. On the other hand, there are theoretical reasons why angiotensin II type I receptor blockade could prove as effective, or even superior to ACE inhibi-

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tion. Routine treatment with ACE inhibitors appears to block angiotensin II formation incompletely, hence circulating levels of the octapeptide are reduced rather than obliterated [20]. Secondly, it is thought that, at least in some species, angiotensin II may be produced by pathways other than through ACE. In the heart, chymase is considered to be one such pathway which is not blocked by ACE inhibitors [21–23]. Thirdly, the angiotensin II type 2 receptor may subserve useful purposes. For example, there is some evidence that stimulation of AT-2 receptors inhibits growth effects of the AT-I receptor [24,25], restricts cell growth after vascular injury [24], and may reduce blood pressure [26]. With angiotensin AT-I blocking agents, renin release is accentuated hence circulating angiotensin II levels rise, and whereas the AT-I receptor is blocked, there will be considerable stimulation of the unblocked AT-2 receptor. As a result, growth of vascular tissues and lesions might be inhibited. Fourth, losartan or its active metabolites cross the blood–brain barrier when injected intravenously in rats, and blocks AT-I receptors in the brain [27]. Since blockade of ‘central’ AT-I receptors has been shown to improve haemodynamic functioning in sheep with heart failure induced by rapid ventricular pacing [28], there is potential for benefits from these receptor-blocking agents beyond partial inhibition of angiotensin II formation by ACE inhibitors in the peripheral circulation. From the point of view of side effects, the ACE inhibitors have proved relatively trouble-free. Nevertheless, they are associated with increased cough and angioneurotic oedema which are thought to relate directly or indirectly to increased tissue kinin levels. Drugs which selectively block the angiotensin II AT-I receptor should not increase tissue kinin levels and may not therefore be associated with these specific side effects. Evidence is that angiotensin AT-I blockade has a similar incidence of cough as diuretics in patients with essential hypertension [29] and presumably in heart failure: in other words, cough is not a side effect of this group of drugs.

3. The practice A number of studies in animals with experimen-

tally-induced heart failure have been performed looking at the effects of selective angiotensin II AT-I receptor blockade alone or in combination with ACE inhibition. No uniform outcome has been evident. Some reports are of a clear beneficial effect from selective angiotensin II AT-I receptor blockade. For example, Raya and colleagues showed that angiotensin AT-I receptor blockade produced similar beneficial haemodynamic effects to captopril in rats with heart failure after myocardial infarction [30]. Likewise, Nishikimi and colleagues reported that both an angiotensin II AT-I receptor antagonist and an ACE inhibitor attenuated left ventricular dilatation after myocardial infarction in hypertensive rats [31]. Qing and Garcia concluded that losartan (like captopril) improved haemodynamic functioning and water balance, and reversed cardiac hypertrophy in rats with highoutput cardiac failure due to an aortocaval shunt [32]. Yoshiyama and colleagues and Schieffer and colleagues demonstrated similar protective effects of angiotensin II AT-I receptor blockade and ACE inhibition in rats during or after acute myocardial ischaemia or infarction [33,34]. Losartan and captopril evoked similar acute haemodynamic responses in sheep with pacing-induced cardiac failure [35]. By contrast, other authors have been unable to show convincingly a protective effect of AT-I receptor blockade in various models of myocardial ischaemia, infarction or heart failure. For example, Murakami et al. noted that whereas acute intravenous captopril improved cardiac output in conscious dogs with heart failure, losartan did not [36]. Kanda and colleagues showed that captopril inhibited cardiac fibrosis in a murine model of dilated cardiomyopathy, but losartan did not although both agents showed other beneficial cardiac effects [37]. McDonald and colleagues reported that whereas high dose ACE inhibitor treatment prevented progressive structural changes resulting from localised myocardial damage induced by DC shock, angiotensin II AT-I receptor blockade did not [38]. Ford et al. demonstrated that AT-I receptor antagonism was not cardioprotective in ischaemia reperfusion injury in left atrium-perfused isolated working rat hearts [39]. There are limited data regarding the effects of angiotensin II AT-I receptor blockade on survival in heart failure models in animals. Milavetz et al. showed no difference in survival for animals receiving the angiotensin II type I receptor blocker, losartan

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and animals randomized to the ACE inhibitor captopril in rats after myocardial infarction [40]. Human studies are thus far limited but do give some cause for optimism. Short-term investigations indicate that AT-I selective receptor blockade has beneficial haemodynamic effects with maintenance of clinical benefit over weeks and months [41–44]. The expected hormone changes are seen, that is a rise in circulating renin and angiotensin II levels and a decline in aldosterone concentrations [41,44]. As for comparisons between these agents and ACE inhibitors, Dickstein et al. reported that losartan and enalapril were of comparable efficacy and tolerability in 166 patients with stable heart failure (NYHA functional class 3 or 4) over an eight week period of study [43]. Most interesting and provocative is the ELITE study [45] which compared captopril and losartan in elderly patients with heart failure (NYHA functional class 2–4 and left ventricular ejection fraction of 40% or less). Although the trial directed its attention primarily to changes in renal function, death and / or hospital admission for heart failure was lower in losartan than in captopril treated patients. In fact, all cause mortality was lower in the losartan group and this might have related to an effect of the drug to reduce sudden cardiac death. Numbers of patients with hard end-points however, were quite small [45] and this trial cannot therefore be seen as definitive. However, a combined analysis of two exercise studies showed a significant reduction in death and hospitalisation for heart failure with losartan, compared with placebo, to levels observed in ELITE, and below levels earlier documented with SOLVD [45]. Another study, ELITE-2 is now being launched to determine whether indeed angiotensin AT-I receptor blockers are more effective than ACE inhibitors with regards reduction in mortality and specifically sudden cardiac death. As to the side effect profile, the adverse event rate in the ELITE study was higher with captopril than with losartan, and in particular cough was not a problem with the latter, whereas it affected 3.8% of those taking captopril [45].

4. The future Considerable interest has been awakened by the results of the ELITE study. Taking an optimistic

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approach, it does seem conceivable that selective angiotensin II type I receptor blockers may prove more effective than ACE inhibitors in patients with heart failure. Perhaps through antiproliferative effects from stimulation of AT-2 receptors and effective blockade of angiotensin II AT-I receptors in the heart, sudden arrhythmic death will be less with these drugs than with ACE inhibitors. Likewise, the side effect profile in the absence of increased tissue kinin levels may be superior with these new agents than with the ACE inhibitors. Results of ELITE-2 and similar studies are therefore keenly awaited. A less buoyant view is that the ACE inhibitors have already been shown to increase longevity and otherwise to improve the lot of patients with heart failure, and at least some of these benefits relate to increased tissue kinin levels which seem unlikely to occur with the selective angiotensin II type-I receptor blockers. Whereas the ACE inhibitors appear particularly effective in reversing left ventricular hypertrophy, at least in patients with essential hypertension [46,47] evidence that the angiotensin II type I receptor blockers are similarly effective, is lacking. In fact, one preliminary report is that losartan might actually increase left ventricular wall thickness in patients with essential hypertension [48]. Whether these new agents are as effective as ACE inhibitors in preventing remodelling after acute myocardial infarction in man, a common precursor of frank heart failure, remains to be seen. A question for the future is whether combined ACE inhibition and angiotensin II type I receptor antagonism may be superior to either drug alone in heart failure. If stimulation of angiotensin II type II receptors is beneficial, if increased tissue levels of kinins and its consequences is beneficial, and if blockade of angiotensin II type I receptors is likewise beneficial, then combined ACE inhibition and angiotensin II type I receptor blockade may be more useful than either agent alone. Certainly the fall in arterial pressure with such combined treatment in healthy volunteers is greater than with either agent alone [49,50]. Studies are in progress to address this question in heart failure [51–53]. Another recent development in the treatment of heart failure is synthesis of compounds with inhibitory actions against both ACE and neutral endopeptidase (NEP; E.C.3.4.24.11), the latter being responsible for enzymic inactivation of the bioactivity

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of cardiac natriuretic peptides, ANP and BNP [54]. Preliminary data suggest that these combined NEP– ACE inhibitors may be therapeutically superior to NEP- or ACE-inhibitors alone-at least in some animal models of heart failure or hypertension [55,56]. Studies in patients with heart failure are underway. Whether a compound which inhibits NEP whilst also blocking the angiotensin II type I receptor, has therapeutic potential beyond that of its individual components, remains to be seen if, indeed, such a compound can be synthesized. Other innovative approaches might be feasible. For example, Wong and colleagues described a compound with combined angiotensin II type I and beta-adrenergic blocking activity [57]. Such an agent could be of benefit after acute myocardial infarction and, perhaps, in established heart failure.

5. Overview There are theoretical reasons why blockade of angiotensin II type I receptors may be therapeutically desirable in heart failure. The data from studies in animals with heart failure are inconsistent as to whether ACE inhibition or AT-I receptor blockade is superior. In this regard, the ELITE study raises the possibility that mortality is reduced more by AT-I receptor blockade than by ACE inhibition, and at lesser cost in side effects. Additional information on this issue is needed, however, as is information on the therapeutic role of combined angiotensin II type-I receptor antagonism with ACE inhibition, NEP inhibition and beta-adrenergic blockade.

Acknowledgements We thank Barbara Griffin for secretarial assistance.

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