© 2003 European Society of Cardiology
Endothelin receptor antagonists in heart failure—a refutation of a bold conjecture?
Cardiovascular Center, Division of Cardiology, University Hospital, Cardiovascular Research, Institute of Physiology and Clinical Research Center InterCorNet, CH-8091 Zurich, Switzerland
* E-mail address: cardiotfl{at}gmx.ch
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1. Introduction |
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The potent vasoconstrictor endothelin (ET)-1 essentially contributes to increased vascular resistance in heart failure [1]. Indeed, circulating ET-1 levels are substantially elevated and correlate both with the hemodynamic severity and NYHA class of the patients. Circulating levels of the ET-1 precursor, big ET-1, are strong independent predictors of death. ET receptor antagonists impressively improve hemodynamics without causing neurohormonal activation in patients with chronic heart failure. However, the recent ENABLE trial showed neutral effects in terms of mortality and symptoms.
Science is driven by conjectures and refutations [2]. Is this a refutation of the concept? Do we have to quit this promising class of drugs?
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2. Physiologic actions of endothelin-1 |
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Activation of specific ETA receptors on vascular smooth muscle cells causes vasoconstriction and cell proliferation [3]. Arterial smooth muscle cells also express ETB receptors mediating part of the vasoconstriction. In contrast, ETB receptors on endothelial cells cause vasodilation via release of nitric oxide (NO) and prostacyclin; the overall effect of ET-1 at the ETB receptor is vasodilation. Additionally, ETB receptors in the lung are a major pathway for the clearance of ET-1 from plasma. ETB receptors also contribute to the autocrine regulation of ET-1 synthesis. ET-1 generated in the vasculature is mostly secreted abluminally and determines basal vascular tone. Additionally, ET-1 influences myocardial contractility and renal sodium excretion.
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3. Clinical studies with ET antagonists in heart failure |
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ACE-inhibition and betablockade prove that neurohormonal blockade is a successful therapeutic principle in heart failure. In line with this assumption, both selective ETA as well as non-selective ETA/B receptor antagonists cause marked improvement of hemodynamics in patients with congestive heart failure [4–7]. In HEAT, selective ETA receptor blockade with darusentan was studied on top of standard therapy in 157 patients with moderate heart failure. While there was a pronounced decrease in systemic and pulmonary vascular resistance, cardiac output greatly improved without neurohormonal stimulation. Higher dosages were associated with a trend to more adverse events, particularly early exacerbation of heart failure.
The REACH-1 trial investigated the long-term effects of peroral bosentan on clinical events in patients with chronic heart failure and showed an improvement in symptoms in those patients who completed the study [8]. However, the trial had to be stopped prematurely because of elevation of liver enzymes. Bosentan dose-dependency inhibits hepatic bile acid transporters [9].
Lower dosages of bosentan have been evaluated in the ENABLE 1 and 2 trial including patients with NYHA IIIb and IV heart failure, ejection fraction <30%, and a hospitalization for heart failure in the previous year. One thousand six hundred and thirteen patients were randomized to receive either bosentan or matching placebo on top of standard therapy with diuretics, ACE-inhibitors, and betablockers. The initial dose of 62.5 mg was uptitrated to 125 mg twice daily. The primary endpoint was a composite of death and hospitalization for heart failure. During a mean follow-up of 18 months, no difference in the primary endpoint (odds ratio, 1.01; 95% CI, 0.86–1.18; P=0.90) or mortality (odds ratio, 0.94; 95% CI, 0.75–1.2; P=0.55) was observed. More patients reported worsening than improvement and fluid retention causing peripheral edema was a frequent problem. Again, elevation in liver transaminases was observed.
In the recently completed EARTH trial various dosages (10–300 mg/d) of the selective ETA receptor antagonist darusentan were evaluated in over 600 patients with NYHA II–IV heart failure and an ejection fraction of less than 35%. After 6 months of treatment the primary endpoint of end-systolic volume as assessed by cardiac MRI was unchanged compared to placebo treatment. These patients with advanced heart failure had severely dilated left ventricles, which may have limited the potential for beneficial effects (reported in the Hotline Session, Berlin, European Society of Cardiology, September 3, 2002) [10].
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4. What is the problem? |
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In view of the marked hemodynamic improvements shown in a series of studies with both selective ETA and non-selective ETA/B antagonists and the symptomatic benefit offered by bosentan in primary pulmonary hypertension, the results of the ENABLE trial are surprising [1,11]. ET antagonists—given on top of standard treatment with ACE-inhibitors and betablockers—failed to prove prognostic benefit in patients with heart failure. What is the problem then?
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5. Was the concept tested appropriately? |
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Unselective ETA/B receptor antagonists such as bosentan block the endothelial ETB receptor mediating vasodilation and clearance of ET-1. The fact that the EARTH trial, with the selective ETA antagonist darusentan, did not alter remodeling, also suggests that selective ETA receptor blockade per se is unlikely to be advantageous in this context.
Dosage is certainly crucial in drug development. Most commonly, in the initial phase of development, dosages are used, which are too high—with REACH being an excellent example. Unfortunately, the lower dosages of bosentan used in the ENABLE trial did not achieve more in this patient population. Also, in the development of darusentan, very careful acute and chronic hemodynamic studies with various dosages of the ETA antagonist were performed [6] and in the EARTH trial an up-titration protocol was used with the higher dosages to avoid negative effects. Nevertheless, overall neither remodeling nor clinical symptoms improved. Thus, although in certain trials dosage might be an issue, the results of the trials with bosentan and darusentan make such an explanation unlikely.
5.1. Did we reach the ceiling with neurohumoral blockade in chronic heart failure?
Is it possible that ETA or ETA/B antagonists could have been extremely successful drugs in heart failure, if they had been introduced before ACE inhibitors, betablockers and spironolactone? Obviously, the current concept of testing new drugs in heart failure on top of standard therapy does create problems. In the Val-HeFT trial, angiotensin II receptor antagonists did not fulfill the promise given in the ELITE study when added on top of ACE-inhibitors and betablockers [12]. Indeed, there was a trend towards a harmful effect when angiotensin II receptor antagonists were given in combination with ACE-inhibitors and betablockers. Similarly, omapatrilat, a neutral endopeptidase inhibitor showing impressive reduction of mortality in the small IMPRESS trial [13], disappointed with a negative result in the OVERTURE study [14]. A further trial investigating moxonidine, a promising novel substance for neurohumoral blockade, failed to show any beneficial effect in patients with heart failure and raised concerns about the safety of the compound [15]. Moxonidine causes profound inhibition of sympathetic nervous activity [16].
Furthermore, not all patients entering trials have the same ‘standard therapy’. Thus, it might well be that in those with almost complete neurohumoral blockade, an additional blocker might be harmful, while it may provide some benefit in those with less appropriate standard therapy. Indeed, in experimental models with chronic angiotensin infusion, both AT1 blockade and ETA blockade exert similar protective effects [17–19]. Thus, it might be that ET blockade is less efficacious on the background of ACE- or AT1-inhibition. If so, then the concept could only be tested in a direct comparison with ACE-inhibitors or betablockers as in the CARMEN study. Preliminary data from EARTH however, suggest that the overall effects were neutral both in patients with or without betablockers, while no data are available on the role of concomitant ACE-inhibitor therapy.
5.2. Different effects in different patients?
Finally, is there reason to believe that the drugs might cause both favourable and unfavourable effects in the disease process? In a rat model of myocardial infarction, the early use of ETA receptor antagonists led to impaired scar healing and left ventricular dilatation [20]. There might thus be a detrimental effect of ET antagonism on left ventricular function during postischemic remodeling [20,21]. Moreover, volume retention caused by ET antagonists may counteract the hemodynamic improvement in patients with heart failure. There was indeed a trend towards more frequent hospitalizations for heart failure in the ENABLE trials. Also in EARTH, a statistically non-significant trend towards more frequent adverse effects related to volume retention was observed with the higher dosages of the drug.
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6. Where do we go from here? |
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Will ET antagonists find a way into clinical usage in patients with heart failure? Large randomized clinical trials comparing ET antagonist to standard treatment in patients with heart failure are needed to decide the fate of ET antagonists. In view of the financial risks for the sponsor associated with such large trials, it is doubtful whether these studies will be performed. Strictly, we cannot refute the concept without such studies. Practically, it is a dead-end for ET antagonists in heart failure.
A further promising field for ET antagonism is the prevention of atherosclerotic vascular disease [3]. The drugs interfere with many factors involved in the atherosclerotic process such as stress-induced vascular dysfunction, high blood pressure and vascular remodeling as well as the atherosclerotic process itself [18,22,23]. This may be where the future lies for ET antagonists.
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Acknowledgements |
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Original research of the authors was supported by grants of the Swiss National Research Foundation (No. 32-51069.97 and 32-52690.97), the Stanley Thomas Johnson Foundation and the Swiss Heart Foundation.
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References |
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