© 2008 European Society of Cardiology
Clinical trials update from Heart Rhythm 2008 and Heart Failure 2008: ATHENA, URGENT, INH study, HEART and CK-1827452
Department of Cardiology, University of Hull, Castle Hill Hospital Cottingham, Kingston-upon-Hull, HU16 5JQ, UK
* Corresponding author. Tel.: +44 1482 624086; fax: +44 1482 624085. E-mail address: a.p.coletta{at}hull.ac.uk (A.P. Coletta).
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Abstract |
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 Top Abstract 1. ATHENA: effects of...2. URGENT: the early...3. INH: interdisciplinary...4. HEART: the heart...5. A study of...6. Conflict of interest...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 Heart Rhythm Society meeting in San Francisco, USA and the Heart Failure Association meeting of the European Society of Cardiology which was held in Milan, Italy in June 2008. Unpublished reports should be considered as preliminary data, as analyses may change in the final publication.
The ATHENA study showed that dronedarone reduced the incidence of the composite outcome of cardiovascular hospitalisation or death, in patients with atrial fibrillation or flutter, 29% of whom had a history of heart failure, compared with placebo. The URGENT study demonstrated that treatment of acute heart failure with standard therapy, including intravenous diuretics and nitrates, leads to a rapid resolution of breathlessness in the sitting position but that orthopnoea often persists. The INH study showed that a disease management programme could reduce mortality compared to usual care but not hospitalisation rates. The HEART study failed to recruit its planned number of patients, although it is the largest randomised trial of revascularisation in heart failure reported to date. At a median follow-up of 5 years no difference in mortality was observed but the study lacked power to provide a conclusive result. The selective myosin activator CK-1827452 produced a concentration dependent increase in systolic ejection time, stroke volume and fractional shortening in patients with heart failure compared to placebo.
Key Words: Randomised controlled trials • Heart failure
Received July 2, 2008; Accepted July 3, 2008
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1. ATHENA: effects of dronedarone on cardiovascular outcomes in high-risk patients with atrial fibrillation or atrial flutter |
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TopAbstract1. ATHENA: effects of...2. URGENT: the early...3. INH: interdisciplinary...4. HEART: the heart...5. A study of...6. Conflict of interest...References |
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Presented by Stefan Hohnloser from Frankfurt, Germany
There is little evidence, as yet, that cardioversion of atrial fibrillation improves symptoms and well designed studies suggest no improvement in prognosis [1]. However, many cardiologists still believe that restoring sinus rhythm should be attempted. Amiodarone and dofetilide are the only agents shown to restore and maintain sinus rhythm in patients with left ventricular systolic dysfunction (LVSD) heart failure. Their effects are modest and, overall, their use was not associated with a reduction in morbidity and mortality, although patients converted to sinus rhythm may have benefited [2,3]. Dronedarone is an oral, class III, antiarrhythmic agent, which is structurally similar to amiodarone, but non-iodinated. It is claimed to have an improved safety and tolerability profile. Dronedarone has a much shorter elimination half life than amiodarone.
Previous studies of dronedarone have shown conflicting results. The ANDROMEDA study, which was a placebo controlled evaluation in patients with moderate or severe chronic heart failure and a low ejection fraction, was discontinued early as interim results suggested a higher mortality with dronedarone [4]. This could reflect a similar adverse effect to amiodarone but dronedarone was considered to interfere with the assay for creatinine. The apparent worsening in renal function led to patients being treated with lower doses of ACE inhibitors or even having ACE inhibitor withdrawn, which may have accounted for the observed difference in outcome.
In the combined EURIDIS and ADONIS studies of patients with paroxysmal or recently cardioverted AF, dronedarone was more effective at maintaining sinus rhythm and reducing ventricular rate during recurrence of arrhythmia than placebo. Only 17% of these patients had heart failure and those with moderate or severe symptoms were excluded. There was also a reduction in the secondary composite outcome of hospitalisation or death. The incidence of adverse events was similar in each group [5].
ATHENA was a randomised, double blind, placebo controlled study to evaluate the efficacy of dronedarone (400 mg bd) for preventing cardiovascular hospitalisation and all-cause mortality in 4628 patients with atrial fibrillation or flutter, 29% of whom had a history of heart failure. However, only about 12% of patients had evidence of systolic dysfunction and patients with severe heart failure were excluded. Over a mean follow-up of 21 months, patients receiving dronedarone were less likely to reach the primary endpoint (cardiovascular hospitalisation or death) compared with placebo (Table 1). This was due predominantly to a reduction in cardiovascular hospitalisation and arrhythmic deaths. The incidence of adverse events was similar in each group.
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These results are encouraging and are reinforced by the similar findings of two previous, smaller studies. However, uncertainties persist over its safety in patients with heart failure due to LVSD, reinforced by concerns about amiodarone. It is not yet clear that dronedarone and amiodarone differ in terms of effects or side effects on lung or liver.
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2. URGENT: the early assessment of dyspnoea in patients with acute heart failure syndromes: the Ularatide global evaluation in acute decompensated heart failure |
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TopAbstract1. ATHENA: effects of...2. URGENT: the early...3. INH: interdisciplinary...4. HEART: the heart...5. A study of...6. Conflict of interest...References |
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Presented by Peter Pang from Chicago, USA
Dyspnoea is the characteristic presenting symptom in patients with acute heart failure. However, although most large trials in acute heart failure have evaluated dyspnoea, only a minority have reported a greater improvement with treatment compared to placebo [6,7]. The failure to show a beneficial effect on dyspnoea may reflect the rapid relief of symptoms with intravenous diuretics and delays in enrolling patients until many hours after admission, by which time the most severe symptoms may have already resolved. Alternatively, the complete lack of standardisation in studies of the assessment of breathlessness could confound assessment. The aim of the URGENT study was to evaluate a new method for assessing changes in breathlessness of patients with acute heart failure in response to usual therapy [8].
The study inclusion criteria were intentionally broad and only excluded patients whose dyspnoea was not due to heart failure and those who could not be enrolled within 1 h of admission. All patients underwent a medical evaluation within 15 min of admission and the baseline assessment of dyspnoea was performed within 1 h. Breathlessness was re-evaluated sitting up and lying down 6 h later.
Five hundred and twenty four patients were included in the study. The mean age was 68 years and median BNP was grossly elevated at 867 pg/ml; 83% of patients received intravenous loop diuretic therapy within the first 6 h. Overall, 81% of patients reported an improvement in dyspnoea at 6 h. The number of patients with very severe breathlessness was reduced from 81 patients at baseline to only 4 patients at 6 h, severe breathlessness was reduced from 109 patients at baseline to only 30 patients at 6 h. More patients reported that symptoms were worse in the supine position than when seated. Assessment of the severity of breathlessness on an absolute scale appeared superior to measuring changes from baseline, perhaps because patients tend to report change from their most severe state rather than from the actual measured baseline. The URGENT study suggests that postural ‘stress’ could be a method to improve the assessment of breathlessness in clinical trials.
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3. INH: interdisciplinary network for heart failure study |
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TopAbstract1. ATHENA: effects of...2. URGENT: the early...3. INH: interdisciplinary...4. HEART: the heart...5. A study of...6. Conflict of interest...References |
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Presented by Christine Angermann from Wurzburg, Germany
Multidisciplinary management programmes have been shown to be effective in patients with heart failure but the effects are inconsistent [9-12]. One of the main problems is in trying to determine which components of a management programme determine its success. The aim of the INH study was to develop and document a management programme consisting of telephone based monitoring and a modular education programme administered by specialist heart failure nurses; and to evaluate efficacy versus usual care.
Patients recovering from a hospitalisation for heart failure with an ejection fraction 
40% were eligible to participate. Of 1010 patients screened, 715 were randomised to the management programme or to usual care. The primary endpoint was a composite of the time to first event of either all-cause mortality or all-cause hospitalisation.
The mean age of patients was relatively young at 69 years and only 29% were women, probably reflecting the exclusion of patients with higher LVEF. Patients had many co-morbid conditions, with a particularly high prevalence of anaemia and depression. Treatment with guideline recommended therapies was high, with around 88% of patients receiving an ACE inhibitor and 80% a beta-blocker.
Over a follow-up period of 180 days, there was a reduction in all-cause mortality in the intervention arm versus usual care (HR 0.57; p=0.018); however, due to a higher incidence of all-cause hospitalisation in the intervention arm, there was no difference in the primary endpoint. Patients in the intervention arm had a reduced severity of heart failure symptoms (p=0.05), shorter hospitalisations, improved quality of life and improved adherence to guideline recommended doses of heart failure therapy, compared to usual care.
Improved uptake of treatment, shorter hospitalisations and reduced mortality but with a tendency for an increase in the number of hospitalisations appears to be a fairly consistent finding of management programmes and telemonitoring studies [9,10,13]. This suggests that the rate of hospitalisation may not be the best choice of endpoint in such trials. Quality-adjusted days-alive and out of hospital might be more appropriate [14].
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4. HEART: the heart failure revascularisation trial |
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TopAbstract1. ATHENA: effects of...2. URGENT: the early...3. INH: interdisciplinary...4. HEART: the heart...5. A study of...6. Conflict of interest...References |
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Presented by John Cleland from Kingston-upon-Hull, UK
Many patients with heart failure and left ventricular systolic dysfunction due to coronary artery disease appear to have extensive amounts of viable myocardium affected either by reversible dysfunction, thought to be due to ischaemia, or by chronic contractile dysfunction, otherwise known as myocardial stunning or hibernation. The aim of the HEART study was to evaluate whether revascularisation could improve prognosis in such patients [15].
Patients with heart failure, an ejection fraction 35%, requiring chronic diuretic therapy and with evidence of at least 5 of 17 left ventricular segments affected by ischaemia and/or hibernation, were included. All imaging tests, predominantly stress echocardiography, were verified in a core laboratory prior to enrolment. Patients were randomised either to a strategy of pharmacological management alone or with the addition of revascularisation, either by surgery or angioplasty.
The study aimed to enrol 800 patients, but due to problems with recruitment and funding, the study was stopped early. Of the 139 patients recruited, 69 were randomised to a strategy of angiography and revascularisation. Their median age was about 67 years. However, there were deaths related to the diagnostic procedure, some patients had coronary arteries unsuitable for revascularisation and some patients changed their mind. Ultimately, only 45 patients were revascularised, predominantly by CABG. Few patients crossed-over from the conservative management strategy to revascularisation. There was no difference in the incidence of all-cause mortality, quality of life or, in a sub-study, ventricular function assessed by MRI. Mortality by intention to treat was 36% with the conservative strategy versus 38% with the revascularisation strategy. Although HEART is underpowered, it suggests that revascularisation does not have striking benefits in this population and therefore should be subject to further randomised controlled trials. Also, these results may not apply to patients aged <60 years who were poorly represented in the trial.
The results of the ongoing STICH study [16], which is a large randomised controlled trial designed to evaluate the efficacy of revascularisation and/or LV reconstructive surgery versus standard medical therapy in 2800 patients with ischaemic heart failure, may yet resolve the issue of whether heart failure patients can benefit from revascularisation.
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5. A study of the selective myosin activator CK-1827452 |
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TopAbstract1. ATHENA: effects of...2. URGENT: the early...3. INH: interdisciplinary...4. HEART: the heart...5. A study of...6. Conflict of interest...References |
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Presented by John Cleland from the University of Hull, UK
An inotropic agent that does not increase energy demands or cytosolic calcium could be useful in the treatment of heart failure. Cardiac myosin activators such as CK-1827452 are a novel class of agents that increase myofibril ATPase activity, thereby altering the function of myosin so that the sarcomere can increase force generation without consuming more energy in the form of ATP. Unlike conventional inotropic agents, selective myosin activators increase the duration of systole rather than the rate of increase in systolic pressure (Fig. 1) [17-19].
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At plasma concentrations of 300-900 ng/ml, CK-1827452 led to dose-related increases in left ventricular ejection time and stroke volume and was well tolerated. One patient received an unintended high dose of this agent, achieving a calculated plasma concentration in excess of 1700 ng/ml. This appeared to cause myocardial ischaemia with sweating, tachycardia and hypotension. There was a minor troponin leak but the patient recovered rapidly within 45 min. The novelty of the mechanism of action of CK-1827452 provides hope that it may become a valuable new therapy but, at the same time, makes predicting its future more difficult. It is well absorbed when taken orally and studies of the oral formulation will start shortly.
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6. Conflict of interest statement |
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TopAbstract1. ATHENA: effects of...2. URGENT: the early...3. INH: interdisciplinary...4. HEART: the heart...5. A study of...6. Conflict of interest...References |
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John Cleland was the Principal Investigator for the HEART study and the CK-1827452 study.
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References |
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