Should Erythropoietin Treatment in Chronic Heart Failure Be Haemoglobin Targeted?

This editorial refers to the paper entitled ‘A meta-analysis of erythropoiesis-stimulating agents in anaemic patients with chronic heart failure’ by B. Jin et al., on page 249. Erythropoietin (EPO) is traditionally known for its haematopoietic effect on the bone marrow, through salvaging erythroid precursors from apoptosis. Blunted EPO production can cause anaemia. In chronic heart failure (CHF), anaemia is prevalent and associated with poor prognosis.1 Therefore, erythropoiesis-stimulating agents (ESAs) have extensively been investigated in a large number of experimental studies, and have been shown to possess cardioprotective effects as well. In addition, several studies have been performed to evaluate the safety, feasibility, and clinical outcome of ESA treatment in patients with heart failure. In the present issue of the European Journal of Heart Failure, Jin et al. present a meta-analysis on the effects of ESA on clinical outcome in patients with CHF.2 Seven clinical trials are included, of which four evaluated darbepoietin alfa and three investigated other ESAs. Erythropoiesis-stimulating agent treatment was associated with a mean increase in left ventricular ejection fraction of 7.55%. NYHA class improved by 1.2 and KCCQ scores improved by 4.61 points. The authors conclude that the treatment of anaemia with ESAs in patients with symptomatic CHF can improve cardiac function, exercise capacity, and quality of life. The current study did not include an analysis of hospitalization due to heart failure. In an earlier meta-analysis, the risk for hospitalization due to heart failure was proved to be decreased (risk ratio 0.59) in the ESA treated group.3 Similar to that study, Jin et al. were also unable to establish a significant protective effect of ESA treatment on overall mortality, although a strong trend was observed. The study by Jin et al. is particularly interesting because it strongly suggests that ESA treatment may also improve the quality of life. But how can these potentially beneficial effects of ESA on cardiac function and clinical outcome in heart failure patients be explained? With the discovery of a functional EPO receptor in tissue other than bone marrow, it was hypothesized that EPO elicits extra-haematopoietic effects as well.4 This was supported when a functional EPO receptor was discovered in heart tissue.5 Exogenous stimulation of these receptors in animal models with human recombinant EPO was shown to decrease infarct size and ameliorate left ventricular function.6 These results might be explained by the finding that stimulation of the EPO receptor in the heart increases neovascularization through increasing vascular endothelial growth factor and endothelial progenitor cell homing to the myocardium.7 In CHF patients, myocardial cells grow (hypertrophy) without a concomitant increase in the number of capillaries; this subsequently leads to a demand–supply mismatch of oxygen and nutrients.8 Therefore, especially in CHF, ESAs might be an attractive approach to improve this demand–supply mismatch. In addition to increasing neovascularization after ischaemia, EPO also exerts anti-apoptotic effects. Following myocardial infarction, EPO prevents apoptosis of cardiomyocytes and this in turn might reduce permanent damage and loss of function. These findings led to the design of a randomized multicentre study to evaluate whether EPO can attenuate post-myocardial infarction loss of cardiac function. The results of this study are expected soon.9 Interestingly, the beneficial effects of ESAs on myocardial function have been described with doses that did not influence haemoglobin and/or haematocrit.10 In addition, similar cardiac effects have been demonstrated with carbamylated erythropoietin (CEPO), a non-erythropoietic derivative of erythropoietin.10 Therefore, the observed beneficial cardiac effects of ESAs may not just originate from increased haemoglobin levels, but may also be due to the previously described non-haematopoietic effects of EPO. The definite mechanisms still remain elusive. The Trial to Reduce Cardiovascular Events With Aranesp® Therapy (TREAT), performed to evaluate cardiovascular events in chronic kidney disease, showed that treatment with darbepoietin alfa was associated with an increased risk of stroke and more hospitalizations.11 In a study in patients with stroke, ESAs were associated with an increased incidence of stroke recurrence.12 These findings have raised concerns about the safety of ESAs. It is unclear, however, whether the safety issues are similar in patients with heart failure.13 Jin et al. did not draw any conclusions about safety; however, they did see a non-significant decrease in mortality in favour of the ESA-treated group. In addition, in the studies of patients with a renal aetiology of anaemia, the major aim was to improve clinical outcome with ESAs through increasing haemoglobin. In heart failure, however, the beneficial effects of ESAs are probably due to non-haematopoietic effects.14 Therefore, new agents like CEPO are being developed that could elicit the beneficial protective of effects of EPO, without its undesirable erythropoietic side effects.15 In conclusion, the study by Jin et al. confirms that EPO has a large therapeutic potential in patients with heart failure and indicates that there is a growing need for larger studies to be performed. The ongoing Reduction of Events With Darbepoetin Alfa in Heart Failure (RED-HF) trial is a large multicentre, double-blind, randomized, placebo-controlled trial, which will hopefully provide a definitive answer to the question whether erythropoietin can decrease mortality and morbidity in anaemic CHF.16 It should, however, be noted that in RED-HF erythropoietin treatment is titrated to achieve specific haemoglobin levels. So far about two-thirds of the patients have been recruited and the expected date of completion is in 2012. With the development of novel agents that have similar cardioprotective effects, without increasing of haemoglobin levels, the applications for these agents could even be extended to non-anaemic heart failure patients as well. Conflict of interest: none declared.