European Journal of Heart Failure

European Journal of Heart Failure 2007 9(2):110-112; doi:10.1016/j.ejheart.2007.01.004

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© 2007 European Society of Cardiology

Are erythropoietin stimulating proteins safe and efficacious in heart failure? Why we need an adequately powered randomised outcome trial

Dirk J. van Veldhuisen, John J.V. McMurray RED-HF Executive Committee

Department of Cardiology, University Medical Center Groningen, University of Groningen PO Box 30.001, 9700RB Groningen, The Netherlands. E-maill address: d.j.van.veldhuisen{at}thorax.umcg.nl Tel.: +31 50 3612355; fax: +31 50 3614391.
Department of Cardiology, Western Infirmary Glasgow, UK

Received January 11, 2007;

	1. Introduction

Top 1. Introduction 2. CREATE and CHOIR 3. Prior evidence about... 4. Evidence from other... 5. Summary and implications... References

 
Following the development of recombinant erythropoietin in the 1980's, its use to treat anaemia in patients with chronic kidney disease (CKD) has increased markedly over the last two decades [1]. Subsequently, the prevalence of anaemia has been found to be high in patients with chronic heart failure (CHF), in whom it is an independent predictor of poor outcome [2]. Consequently, there has also been recent interest in erythropoiesis stimulating proteins (ESPs) as a treatment in CHF [3,4] One such agent, darbepoetin alfa, is currently being tested in a large-scale, phase III morbidity and mortality trial: the Reduction of Events with Darbepoetin alfa in Heart Failure (RED-HF) [5].

Recently, concerns about the cardiovascular safety of ESPs have been raised. On November 16, 2006, two separate studies, Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR) [6] and Cardiovascular Risk reduction by Early Anemia Treatment with Epoetin beta (CREATE) [7], were published in the New England Journal of Medicine, each comparing two different erythropoietin regimens, given in order to examine the optimal target level of haemoglobin (Hb) in patients with CKD [6,7]. We believe that these studies have limited relevance to patients with CHF, do not demonstrate convincing evidence of harm and emphasize the need to conduct a definitive trial like RED-HF.

	2. CREATE and CHOIR

Top 1. Introduction 2. CREATE and CHOIR 3. Prior evidence about... 4. Evidence from other... 5. Summary and implications... References

 
CHOIR and CREATE were both conducted in patients with CKD, as defined by a glomerular filtration rate (GFR) of 15-50 ml/min/1.73 m² [8] and 15-35 ml/min/1.73 m², respectively. (Table 1).

View this table: [in this window] [in a new window]   Table 1 Comparison of trials with erythropoietin

 
In CHOIR [6], the 1432 patients studied had a baseline Hb of 10.1±0.9 g/dl and an eGFR of 27.2 ml/min/1.73 m². Twenty three percent of patients had a history of CHF, although the proportion of patients with a low ejection fraction (EF) was not reported. Half of the patients were assigned to receive Epoetin alfa with the aim of achieving a target Hb of 13.5 g/dl and the other half a regimen aimed at a target of 11.3 g/dl. Patients in the higher Hb target group received more erythropoietin and iron and achieved a higher Hb. During a median follow-up of 16 months, the higher Hb target group had an increased incidence of the composite endpoint (death, myocardial infarction, hospitalization for CHF and stroke) with a hazard ratio of 1.34 (p=0.03). The excess of 28 events in the higher Hb target group was accounted for mainly by an increase in death (52 vs 36) and hospitalization for CHF (64 vs 47), although cardiovascular hospitalization for any cause was also increased. The aetiology of CHF and the EF in these patients were not reported. There was a trend to increased renal replacement therapy in the higher Hb group and no difference in quality of life between the two groups.

The findings of CHOIR have also been linked to an earlier trial in CKD by Besarab et al. [8] in which two regimens of Epoetin alfa were used to achieve a target haematocrit of either 42% or 30%. This study in 1233 patients, was terminated prematurely because there were trends towards an increased risk of the composite of death or nonfatal myocardial infarction (and in both its components) in the group assigned to the higher haematocrit, compared to the lower haematocrit concentration (risk ratio 1.3, 95% CI 0.9-1.9). There was no difference in blood pressure between the groups, but there was higher incidence of thrombosis of vascular access sites in the higher haematocrit group (39% vs 29%, p=0.001).

In CREATE [7], the 603 patients studied had a baseline Hb of 11.6±06 g/dl and eGFR of 24.5 ml/min/1.73 m². Thirty two percent of patients had a history of CHF, although what proportion of patients had a low EF is not known. During a mean follow-up of 3 years, correction of Hb with Epoetin beta to a target level of 13.0-15.0 g/dl, compared with partial correction (i.e. Epoetin beta was only given when Hb fell below 10.5 g/dl), was not associated with an increase in the incidence of cardiovascular events (sudden death, MI, acute heart failure, stroke, transient ischaemic attack, hospitalized angina pectoris, hospitalized arrhythmia or complication of peripheral arterial disease), in contrast to the results of CHOIR. Thirteen patients in the high Hb group developed acute heart failure compared to 23 in the lower Hb group, again in contrast to CHOIR. The cause of heart failure and the ejection fraction in these patients were not reported. More patients required haemodialysis in the high Hb treatment group (p=0.03), although quality of life was improved in that group (p<0.01).

In an accompanying editorial, Remuzzi and Ingelfinger discussed the potential explanations for the findings of CHOIR and CREATE [9]. They speculated that "complete" correction of anaemia might increase blood pressure, as well as the risk of thrombosis and accentuate vasoconstriction. In CREATE [7], blood pressure was slightly higher in the higher Hb group, and there was more uncontrolled hypertension; in CHOIR such data were not reported. In CREATE, 12 patients in the high Hb group vs 8 patients in the low Hb group had arteriovenous fistula thrombosis, but in CHOIR there was no difference in thrombotic events. The authors also speculated that relative iron overload could have increased overall renal and cardiovascular risks in the higher Hb group [9]. Paradoxically, iron alone has recently been suggested as a treatment option for CHF [10].

	3. Prior evidence about the effects of ESPs in chronic heart failure

Top 1. Introduction 2. CREATE and CHOIR 3. Prior evidence about... 4. Evidence from other... 5. Summary and implications... References

 
Early small-scale studies showed a remarkable improvement in clinical status with erythropoietin in CHF although no study was placebo-controlled and double-blind [3]. More recently, three double-blind, placebo-controlled randomised studies were conducted with darbepoetin alfa in patients with mild to moderate CHF and anaemia, although none is published in full yet. In the first study [11], lasting six months, 19 of 41 patients were treated with darbepoetin alfa, which improved quality of life and showed a trend towards improvement in exercise capacity. In the second study [12] 162 of 319 patients were treated with active drug for 12 months, which led to a Hb-dependent increase in exercise duration and a non-significant trend towards a reduction in the composite of first hospitalization for CHF or death. The third study [13] examined 165 patients, of whom 110 were treated with darbepoetin alfa in two different dosing regimens for 6 months. This study showed a favourable effect on some quality of life measurements and a non-significant trend towards improvement in exercise tolerance. Clearly, none of the studies was powered to evaluate the effect of darbepoetin alfa on clinical outcome. However, when the two largest studies [12,13] were combined in a prespecified, pooled analysis, there was a trend to a decrease in the risk (39 of 266 [15%] patients on darbepoetin alfa vs 46 of 209 [22%] patients on placebo; HR 0.67, 95% CI 0.44-1.03, p=0.06) of the composite outcome of death or hospitalization for CHF (and for death alone, HR 0.76) in the darbepoetin treated patients [6]. Obviously, these data must be interpreted with caution, as the duration of follow-up was short and the number of events small. Nevertheless, in these trials more than 250 patients with well characterized low EF CHF were exposed to 6-12 months treatment with darbepoetin alfa without any evidence of harm. These data are therefore more directly relevant to the RED-HF trial than the data from either CHOIR or CREATE in terms of both patients and active drug studied.

	4. Evidence from other trials

Top 1. Introduction 2. CREATE and CHOIR 3. Prior evidence about... 4. Evidence from other... 5. Summary and implications... References

 
The Trial to Reduce cardiovascular Events with Aranesp® Therapy (TREAT) [14] is a placebo-controlled morbidity-mortality trial which to date has recruited approximately 4000 patients with type 2 diabetes, CKD and a Hb 11 g/dl. Patients are randomised to darbepoetin alfa (with a target Hb of 13 g/dl) or to placebo (unless Hb drops below 9 g/dl). At the last interim analysis, >2000 patients, many with CHF, had been enrolled and the Data Monitoring Committee (DMC) recommended continuation of the study, having taken account of the results of CHOIR, CREATE and prior studies with ESPs.

	5. Summary and implications of CHOIR and CREATE for RED-HF

Top 1. Introduction 2. CREATE and CHOIR 3. Prior evidence about... 4. Evidence from other... 5. Summary and implications... References

 
In summary, CHOIR [6] and CREATE [7] gave inconsistent findings about cardiovascular events and do not, we believe, raise concerns about randomising patients to treatment with darbepoetin alfa, but instead, reinforce the need for an adequately powered clinical outcome trial in patients with CHF and anaemia. Specifically:

1. The patients in CREATE and CHOIR were fundamentally different to the target population of RED-HF [15,16]. This is critical, since these populations have different co-morbidities, baseline renal function, aetiology of anaemia and concomitant medications (Table 1). Indeed, potential side effects of ESP therapy in CKD (discussed above) may not necessarily have the same untoward effects in CHF [15], but studies on this issue are needed.
   
2. The erythropoietic agent used in RED-HF (and TREAT) is different to the compounds used in CHOIR and CREATE. The largest difference is that darbepoetin alfa has a longer plasma half life, but it also has a stronger affinity for the erythropoietin receptor than the conventional compounds [15]. Although we have no indication that this will affect its adverse effect profile at the present time, this cannot be excluded. Important differences between drugs in the same class have been noted in cardiovascular medicine (like bucindolol and cerivastatin).
   
3. The design of RED-HF is different to that of CHOIR and CREATE. While the latter two were open-label studies, in which both treatment groups received active drug, RED-HF has a placebo-controlled design. In addition, in CHOIR, one third of all patients dropped out without experiencing a primary endpoint event.
   
4. Although the number of cardiovascular endpoints in both CHOIR and CREATE was substantial, the numbers were still relatively small compared to those (anticipated) in RED-HF (and also in TREAT). It should be noted, that there are several examples in cardiovascular medicine where the early unexpected findings of medium-size studies were subsequently reversed by larger, adequately powered trials [17].
   

In the light of these important differences between CHOIR and CREATE on the one hand, and RED-HF on the other, both the Executive Committee (EC) and the DMC of RED-HF are of the opinion that the data in CKD cannot be extrapolated to the RED-HF trial. In addition, both extensive epidemiological data and the results of the phase II trials (in over 500 patients) in CHF strongly support a trial in this condition. To ensure safety for all subjects, the DMC will review the accumulating data during the course of the study, four times a year. In considering the evidence to date, the EC firmly believes that the impact of anaemia treatment on morbidity and mortality remains an important and unanswered question. It remains confident that the RED-HF Trial will allow us to definitely answer this question.

	References

Top 1. Introduction 2. CREATE and CHOIR 3. Prior evidence about... 4. Evidence from other... 5. Summary and implications... References

 

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