European Journal of Heart Failure 2000 2(3):237-240; doi:10.1016/S1388-9842(00)00084-2
© 2000 European Society of Cardiology
‘ACE inhibitors are better than AT1 receptor blockers (ARBs)’ — controversies in heart failure
Hazel L. White* and
Alistair S. Hall
Institute for Cardiovascular Research, Universtity of Leeds Leeds LS2 9JT, UK
* Corresponding author. Tel.: +44-113-233-4820; fax: +44-113-233-4803.
Received April 17, 2000; Accepted April 20, 2000
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1. Overview
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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 AT
1, angiotensin II receptor blockers (ARBs)
have yielded very disappointing results with a statistically
non-significant excess of deaths.
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2. Angiotensin II concentrations
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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 AT
1, 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 AT
1,
receptor is to be expected. The frequently prescribed ‘once
daily’ losartan has a half-life of 6–9 h
[3].
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3. AT2 receptor-mediated effects
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Elevated angiotensin II levels resulting from treatment with
an ARB also gives rise to unopposed stimulation of receptors
other than the AT
1 receptor, including the angiotensin AT
2 receptor.
Currently the role of the AT
2 receptors is ill defined with
experimental studies producing conflicting results. Animal studies
suggest that AT
2 receptors counteract the trophic and proliferative
effects of AT
1 receptors but these findings should be interpreted
with caution as there are significant cross-species differences
in the receptor. The rodent AT
1 receptor, in contrast to the
human AT
1 receptor, exists in two different isoforms each encoded
by a different gene on separate chromosomes
[4]. AT
2 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 AT
1 receptor
[7].
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4. Bradykinin potentiation
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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].
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5. Anti-thrombotic and anti-inflammatory effect
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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.
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6. ACE: survival studies
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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.
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7. ACE vs. ARB: survival studies
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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.
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8. Conclusion
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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’.
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1. Overview
2. Angiotensin II concentrations