© 2006 European Society of Cardiology
Clinical trials update from the European Society of Cardiology heart failure meeting: TNT subgroup analysis, darbepoetin alfa, FERRIC-HF and KW-3902
Department of Cardiology, University of Hull, Castle Hill Hospital Cottingham, Kingston-upon-Hull, HU15 5JQ, UK
* Corresponding author. Tel.: +44 1482 624086; fax: +44 1482 624085. E-mail address: a.p.coletta{at}hull.ac.uk
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Abstract |
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 Top Abstract 1. TNT sub-study: effects...2. Darbepoetin alfa studies3. FERRIC-HF: effect of...4. Adenosine A1 receptor...References |
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This article provides information and a commentary on trials relevant to the pathophysiology, prevention and treatment of heart failure, presented at the European Society of Cardiology heart failure meeting held in June 2006. All reports should be considered as preliminary data, as analyses may change in the final publication.
In a sub-group analysis of the TNT study, intensive treatment with high-dose atorvastatin significantly reduced hospitalisations for heart failure in patients with stable coronary heart disease, compared with low-dose atorvastatin; this benefit was most evident in patients with a history of heart failure at baseline. In a combined analysis of two studies of darbepoetin alfa, which included 475 patients, treatment increased and maintained haemoglobin levels and produced non-significant improvements in symptoms and morbidity in anaemic heart failure patients compared to placebo. In the FERRIC-HF study (n=35), intravenous iron sucrose therapy improved exercise capacity and symptom status in iron-deficient heart failure patients. In a combined analysis of two studies (n=186), the adenosine A1 receptor antagonist KW-3902 showed diuretic properties and appeared to enhance response to loop diuretics in heart failure patients hospitalised with fluid overload.
Key Words: TNT sub-study • Darbepoetin alfa • FERRIC-HF • KW-3902
Received July 7, 2006; Accepted July 11, 2006
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1. TNT sub-study: effects of intensive lipid lowering with atorvastatin on congestive heart failure: subgroup analysis of the treating to new targets (TNT) study |
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TopAbstract1. TNT sub-study: effects...2. Darbepoetin alfa studies3. FERRIC-HF: effect of...4. Adenosine A1 receptor...References |
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Presented by David Waters from San Francisco, USA
The role of statins in the treatment of heart failure is uncertain. Although some studies have shown a beneficial effect, low serum cholesterol values have also been shown to predict a worse outcome in heart failure [1].
The TNT study was designed to assess the effect of intensive lipid lowering with atorvastatin 80 mg/day versus 10 mg/day on the incidence of major cardiovascular events in patients with stable coronary heart disease. The main results showed a 22% relative risk reduction in major cardiovascular events with high-dose atorvastatin over a median follow-up of 4.9 years [2]. Although patients with NYHA class IIIb-IV heart failure or an ejection fraction <30% were excluded, 8% of patients in the TNT study were reported to have heart failure at baseline. In addition, heart failure hospitalisation was a predefined secondary endpoint in the main study.
The results of a sub-group analysis looking at the incidence of heart failure in the TNT study were reported at this meeting. Overall, intensive treatment with high-dose atorvastatin significantly reduced hospitalisations for heart failure compared with low-dose atorvastatin (3.3% vs 2.4%, HR 0.74, p=0.01); this benefit was most evident in patients with a history of heart failure at baseline (17.3% vs 10.6%), and there was no effect on hospitalisations for heart failure in those patients with no heart failure at baseline. Patients with a history of heart failure at baseline were much more likely to be hospitalised with heart failure during the study period (Table 1). Univariate predictors of heart failure hospitalisation included a prior history of heart failure, LDL-cholesterol level, diabetes, cardiovascular disease, hypertension and age >65 years. The risk of an event was inversely related to on-treatment cholesterol level.
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Eighty-five percent of patients hospitalised for heart failure during the study did not have an ischaemic episode, which suggests that the benefit of high-dose atorvastatin may be via other mechanisms. Mortality rates were higher in patients with a history of heart failure than in patients with no history of heart failure (Table 1). Of the 286 patients hospitalised for heart failure during the study, 28% died.
The complex issues surrounding the use of stains in heart failure will hopefully be resolved by two ongoing large randomised trials, CORONA and GISSI-HF, [3,4]. However, previous studies have accumulated over 1000 deaths between them already and have not been stopped by their data safety monitoring committees. This suggests that the effects of statins may not be as powerful as suggested by observational studies or the above analysis. Indeed, it remains possible that treatment of patients who have heart failure with a statin is futile or worse.
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2. Darbepoetin alfa studies |
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TopAbstract1. TNT sub-study: effects...2. Darbepoetin alfa studies3. FERRIC-HF: effect of...4. Adenosine A1 receptor...References |
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Presented by Dirk van Veldhuisen from Groningen, The Netherlands
Anaemia is common in heart failure, with a reported prevalence of 20-30%, increasing up to 50% in severe heart failure. Anaemia has been shown to be associated with worse outcomes in patients with heart failure. Darbepoetin alfa is an erythropoiesis stimulating protein which has shown encouraging results in early studies [5].
Two double-blind randomised placebo-controlled studies of darbepoetin alfa were reported at this meeting. In one study 319 patients were randomised to treatment with either darbepoetin alfa 0.75 µg/kg or placebo for 1 year. In the second study, 165 patients were randomised to treatment with either darbepoetin alfa 50 µg, darbepoetin alfa 0.75 µg/kg or placebo for 26 weeks. Treatments were administered subcutaneously every 2 weeks. All patients had an ejection fraction 
40%, haemoglobin 9-12.5 g/dl and a history of heart failure for at least 3 months.
Data for both trials were pooled for the analysis; of the 475 patients, 266 received darbepoetin alfa and 209 received placebo. Baseline data were similar between the groups, the mean age of patients was 70 years and mean haemoglobin levels at baseline were 11.4 g/dl.
Over the treatment period, haemoglobin levels increased in the darbepoetin alfa group compared to placebo which had a minimal effect (Table 2). Overall, patients receiving darbepoetin alfa showed non-significant improvements in symptom-related endpoints (NYHA class, Patient Global Assessment and Minnesota Living With Heart Failure Questionnaire). In addition, although the studies were not powered to detect a mortality/morbidity difference, there was a suggestion of an effect in favour of darbepoetin alfa (p=0.064). There was no difference in the incidence of serious adverse events or deaths between the treatment groups (Table 2).
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In summary, darbepoetin alfa was well tolerated and produced a gradual and predictable increase in haemoglobin to target levels, which was maintained over the study period. However, the failure of symptoms to improve was disappointing. The lack of response may be due to
- the play of chance, although the studies are well powered to investigate the effect on symptoms
- insufficiently robust tools for the assessment of symptoms (a persistent problem in studies of heart failure)
- insufficient difference in haemoglobin between groups
- a lack of effect of erythropoietin and its analogues on symptoms.
One further possible explanation is that iron supplementation was insufficient leading to relative iron deficiency in the darbepoetin group, thereby attenuating its effects. Finally, an observational study presented at the meeting [6] suggested that haemoglobin was a poor predictor of red cell mass. Some patients with low haemoglobin have haemodilution and a normal red cell mass whilst others have normal haemoglobin, haemoconcentration and a low red cell mass. Darbepoetin may not work equally well for all anaemic patients. A large-scale randomised placebo-controlled trial to evaluate the effects of darbepoetin alfa on morbidity and mortality in 3400 heart failure patients (RED-HF) is now ongoing.
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3. FERRIC-HF: effect of intravenous iron sucrose on exercise tolerance in anaemic and non-anaemic iron-deficient patients with chronic heart failure |
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TopAbstract1. TNT sub-study: effects...2. Darbepoetin alfa studies3. FERRIC-HF: effect of...4. Adenosine A1 receptor...References |
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Presented by P Ponikowski from Wroclaw, Poland
Iron deficiency may be an underlying cause of anaemia in heart failure leading to exercise intolerance in these patients
The aim of the present study was to evaluate the effect of intravenous iron sucrose supplementation on exercise capacity, measured by peak VO2, in a cohort of heart failure patients with iron deficiency and exercise limitation (peak VO2 18 ml/kg/min). Patients were also stratified according to the presence or absence of anaemia. Iron deficiency was defined as serum ferritin <100 µg/l or 100-300 µg/l with a transferrin saturation <20%.
Following screening, patients were randomised in a ratio of 2:1 to open-label, observer-blinded treatment with either intravenous iron sucrose or control. Iron sucrose was administered as 200 mg/week during the 4-week correction phase and then every 4 weeks during a 12-week maintenance phase. Thirty-five patients were randomised, of these 18 were classified as anaemic and 17 non-anaemic. The majority of patients were male, the mean age was 63 years, and mean left ventricular ejection fraction was 29%. All patients were receiving optimal heart failure medication.
Ferritin levels increased significantly in the iron sucrose group compared with control; however, there was no difference in haemoglobin levels. There was an improvement in absolute peak VO2 from baseline to week 18 in the total study population (p=0.08) with a greater effect in anaemic patients (p=0.02), than in non-anaemic patients (ns). The change in transferrin iron saturation correlated with the change in exercise capacity. There was also a significant improvement in Patient Global Assessment and in NYHA class for iron sucrose compared to control. There was no difference in the incidence of adverse events between the treatment groups and no reported adverse effect on renal function.
The numbers of patients in the different subgroups were very small, but in light of these encouraging findings, larger studies of longer duration are now required to further evaluate the use of iron supplementation in heart failure patients with iron deficiency. Another similar study, showing comparable results, is currently in press and is due to be published shortly (R. Kaprielian, personal communication).
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4. Adenosine A1 receptor antagonist KW-3902 |
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TopAbstract1. TNT sub-study: effects...2. Darbepoetin alfa studies3. FERRIC-HF: effect of...4. Adenosine A1 receptor...References |
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Presented by Howard Dittrich from San Diego USA and Barry Massie from San Francisco, USA
Renal dysfunction is common in heart failure and is associated with poor outcomes [7,8]. Renal function can also deteriorate during treatment of decompensated heart failure. KW3902 is an adenosine A1 receptor antagonist which inhibits sodium reabsorption in the proximal tubule, thereby causing enhanced diuresis. It also blocks adenosine-mediated tubo-glomerular feedback, the process by which increased sodium in the distal convoluted tubule (due to loop diuretic use) causes afferent glomerular arteriolar constriction. This feedback loop reduces sodium loss and leads to "diuretic resistance".
The results of two early phase studies of KW-3902 were reported at this meeting. The aim of the first study was to establish an effective dose of KW-3902. One hundred and fifty patients with NYHA class II-IV heart failure and impaired renal function (creatinine clearance 20-80 ml/min), hospitalised with fluid overload, were randomised to treatment with KW-3902 (2.5 mg/15 mg/30 mg/60 mg) or placebo. Treatments were administered as a 2-h infusion for up to 3 days. A dose-dependent increase in urine volume was observed over the 6-h period following initiation of KW-3902 therapy. There was also a reduction in the dose of furosemide required. A greater proportion of patients receiving KW-3902 discontinued the trial prematurely since adequate diuresis was achieved.
The second study was designed to evaluate the effect of KW-3902 in 36 heart failure patients refractory to treatment with intravenous diuretics. Patients were randomised to treatment with either KW-3902 (10 mg, 30 mg, or 60 mg) or placebo. The primary endpoint was change in hourly urine output over 9 h. All doses of KW-3902 were associated with an increase in urine output particularly in the first 6 h; however, this did not reach significance.
There was no difference in the incidence of adverse events between the treatment groups. One seizure occurred in a patient receiving the highest dose of KW-3902, which may have been related to the modulatory effect of adenosine on seizure threshold.
Thus, KW-3902 has diuretic properties and appears to enhance response to loop diuretics. The optimal dose in these studies was 30 mg; however, lower doses may also be effective. In light of these encouraging data, a larger randomised, placebo-controlled study to evaluate the effect of KW-3902 on congestion and renal function in 1500 patients hospitalised with acute heart failure and volume overload (PROTECT-MC) is planned.
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References |
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TopAbstract1. TNT sub-study: effects...2. Darbepoetin alfa studies3. FERRIC-HF: effect of...4. Adenosine A1 receptor...References |
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- Rauchhaus M., Clark A.L., Doener W., et al. The relationship between cholesterol and survival in patients with chronic heart failure. J Am Coll Cardiol (2003) 42:1933–1944.
[Abstract/Free Full Text] - LaRosa J.C., Grundy S.M., Waters D.D., et al. Treating to New Targets (TNT) Investigators. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Eng J Med (2005) 352:1425–1435.
[Abstract/Free Full Text] - Kjekshus J., Duselman P., Blideskog M., et al. CORONA study group. A statin in the treatment of heart failure? Controlled rosuvastatin multinational study in heart failure (CORONA): study design and baseline characteristics. Eur J Heart Fail (2005) 7:1059–1069.
[Abstract/Free Full Text] - Tavazzi L., Tognoni G., Franzosi M.G., et al. GISSI-HF investigators. Rationale and design of the GISSI heart failure trial: a large trial to assess the effects of n–3 polyunsaturated fatty acids and rosuvastatin in symptomatic congestive heart failure. Eur J Heart Fail (2004) 6:635–641.
[Abstract/Free Full Text] - Cleland J.G.F., Coletta A.P., Nikitin N.P., Clark A.L. Clinical trials update from the American College of Cardiology: darbepoetin alfa, ASTEROID, UNIVERSE, paediatric carvedilol, UNLOAD and ICELAND. Eur J Heart Fail (2006) 8:326–329.
[Abstract/Free Full Text] - Tin L., Goode K., Tweddel A., et al. Haemodilution is the primary cause of mild anaemia in heart failure. Eur J Heart Fail (2006) 5:187. [Abstract 781].
- Smith G.L., Lichtman J.H., Bracken M.B., et al. Renal impairment and outcomes in heart failure: systematic review and meta-analysis. J Am Coll Cardiol (2006) 47:1987–1996.
[Abstract/Free Full Text] - de Silva R., Nikitin N.P., Witte K.K., et al. Incidence of renal dysfunction over 6 months in patients with chronic heart failure due to left ventricular systolic dysfunction: contributing factors and relationship to prognosis. Eur Heart J (2006) 27:569–581.
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