© 2004 European Society of Cardiology
Clinical trials update from the Heart Failure Society of America: EMOTE, HERB-CHF, BEST genetic sub-study and RHYTHM-ICD
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
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Abstract |
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 Top Abstract 1. EMOTE: (EnoxiMone in...2. HERB-CHF (Hawthorn Extract...3. BEST genetic sub-study:...4. RHYTHM-ICD:...References |
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This article summarises key presentations relevant to the pathophysiology, prevention or treatment of heart failure, from the Heart Failure Society of America annual meeting held in Toronto, Canada. Data from the EnoxiMone in intravenous inOTropE-dependent subjects (EMOTE) study suggest that the oral PDE-3 inhibitor enoximone may be effective for weaning severe heart failure patients from intravenous inotropic therapy. Hawthorn Extract Randomised Blinded Trial in CHF (HERB-CHF) failed to show a benefit of hawthorn extract added to conventional heart failure therapy. A genetic sub-group analysis of the Blocker Evaluation of Survival Trial (BEST) study showed that bucindolol reduced mortality and hospitalisations in patients who were homozygous for the Arg389 variant of the β1 adrenoceptor. In the Resynchronisation Hemodynamic Treatment for Heart Failure Management (RHYTHM-ICD) study, patients randomised to cardiac resynchronisation therapy (CRT) showed an improvement in symptoms and functional capacity compared to the control group.
Key Words: EMOTE • HERB-CHF • BEST genetic sub-study • RHYTHM-ICD
Received September 30, 2004; Accepted October 3, 2004
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1. EMOTE: (EnoxiMone in intravenous inOTropE-dependent subjects) |
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TopAbstract1. EMOTE: (EnoxiMone in...2. HERB-CHF (Hawthorn Extract...3. BEST genetic sub-study:...4. RHYTHM-ICD:...References |
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Some patients with severe heart failure respond to intravenous inotropic therapy and exhibit deterioration in symptoms, arterial pressure and/or renal function when withdrawal is attempted. Strategies to wean such patients from intravenous therapy, temporarily or permanently would be a useful advance in therapy. Trials of oral enoximone, a phosphodiesterase-3 (PDE-3) inhibitor [1-3], in doses of up to 150 mg tid have shown temporary improvement in symptoms but were accompanied by an increase in mortality. The EMOTE study investigated whether short-term use of lower doses in patients with very severe heart failure could produce short-term benefit.
Two hundred and one patients with persistent NYHA III/IV symptoms and LVEF 
25% who were intermittently or permanently dependent on intravenous dobutamine were randomised to placebo or low-dose oral enoximone (either 25 mg ( 75 kg) or 50 mg (>75 kg) tid or, if requiring continuous dobutamine, 50 or 75 mg tid for 1 week followed by the lower dose regimen). Inotrope-dependent was defined as requiring continuous dobutamine or milrinone for at least 5 days or intermittent >6 h at least once per week over at least 4 weeks with dobutamine or milrinone. Weaning had to have been attempted and failed.
The primary end-point was alive and free of the need for i.v. inotropic therapy at 30 days. Secondary end-points were time to death or resumption of i.v. inotropic therapy and number of days of i.v. inotropic therapy over 60 days. Survival at 26 weeks was also recorded.
There was a non-significant trend to benefit on the primary end-point and a 43% (p<0.05) reduction in days on i.v. inotropic therapy. The reduction in the need for i.v. therapy was associated with less sepsis and anaemia. However, mortality was high, with slightly more deaths in the enoximone group. The results of two large trials, ESSENTIAL 1 and 2, investigating the effects of oral enoximone in patients with severe heart failure (but not i.v. inotrope dependent) in addition to ACE inhibitors and β-blockers are awaited (Table 1).
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2. HERB-CHF (Hawthorn Extract Randomised Blinded Trial in CHF) |
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TopAbstract1. EMOTE: (EnoxiMone in...2. HERB-CHF (Hawthorn Extract...3. BEST genetic sub-study:...4. RHYTHM-ICD:...References |
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Many patients consult physicians who practice ‘alternative’ medicine. It is important to establish whether such interventions are effective in the setting of randomised controlled trials (RCT) [4,5]. Other trial designs have been heavily criticised [6-9].
Hawthorn extract (the brand used was WS1442 450) is widely used in Germany and some other countries for treating heart failure but no RCT data exist. Hawthorn extract contains flavanoids and organic acids that inhibit ACE, PDE and sodium/potassium ATPase (although it contains no glycosides). It also appears to have anti-inflammatory actions.
This was a conventional double-blind RCT of 6 weeks duration in patients with NYHA II-III heart failure, LVEF<40%, treated with ACE inhibitors and β-blockers unless contraindicated. Patients had to have a 6-min walk test distance of 150-450 m. This was also the primary endpoint measure. LVEF fell slightly on placebo but was stable on Hawthorn extract (p=0.04). No other difference was observed (Table 2). There were a few more deaths and morbid events in those randomised to Hawthorn extract. In conclusion, this study provides little evidence of benefit with Hawthorn extract added to conventional therapy for heart failure. However, the study was inadequately powered and of insufficient duration to provide robust evidence of lack of benefit. The results of a large outcome study should be reported soon.
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3. BEST genetic sub-study: (β-Blocker Evaluation of Survival Trial) |
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TopAbstract1. EMOTE: (EnoxiMone in...2. HERB-CHF (Hawthorn Extract...3. BEST genetic sub-study:...4. RHYTHM-ICD:...References |
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The BEST study [10] failed to show that the non-selective β-blocker, bucindolol, was superior to placebo for the management of patients with severe heart failure. This may have been due partly to reduced efficacy in African-Americans or, controversially, a β-1-partial agonist effect.
A genetic sub-study was performed on 1,040 patients who had a median follow-up of 765 days to investigate the significance of the Arg/Gly389 polymorphism that, in vitro, appeared to determine the magnitude of the response to β-1-receptor stimulation. Arg389 is associated with a greater response to norepinephrine and a greater reduction in contractility when propranolol is administered. Arg389 is the more common polymorphism, especially in the Caucasian population. About 500 patients were homozygous for the Arg389 variant. In these patients, mortality was reduced by 38% (p<0.02) and death or hospitalisation by 34% (p=0.004) with bucindolol compared to placebo.
A similar analysis of the MERIT study showed no effect of this polymorphism [10a].
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4. RHYTHM-ICD: (Resynchronisation Hemodynamic Treatment for Heart Failure Management) |
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TopAbstract1. EMOTE: (EnoxiMone in...2. HERB-CHF (Hawthorn Extract...3. BEST genetic sub-study:...4. RHYTHM-ICD:...References |
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This is the fourth double-blind study of cardiac resynchronisation therapy (CRT) to report [11]. Two of these studies also focused on patients requiring an implantable defibrillator (ICD).
RHYTHM-ICD included patients with an approved ICD indication, symptomatic New York Heart Association (NYHA) class III/IV heart failure, LV ejection fraction (LVEF) 35% and QRS duration 
150 ms. Patients with a standard bradycardia pacing indication, history of chronic atrial fibrillation or who could walk more than 450 meters on the 6-min hall walk test were excluded.
Follow-up was for 6 months. Patients randomised to CRT switched on (n=83) were more likely to report improved symptoms and had a greater increase in exercise distance than those who were not (n=43). The primary efficacy endpoint, peak VO2, improved by 0.52 ml/kg/min in patients randomized to CRT-on compared to a decline of 1.41 ml/kg/min in the CRT-off group (p=0.001 for the difference). Forty-five percent of patients randomised to CRT-on improved their peak VO2 values at 6 months, vs. only 28% of patients in the CRT-off group. Exercise duration increased in the CRT-on group by 58 s and declined by 50 s in the CRT-off group (p=0.002 for the difference). NYHA class (net mean change –0.2 of a class; p=0.048) and quality of life scores (net mean change of 11 points from a baseline score of 48 on Minnesota; p=0.009) improved, whilst there was a strong trend for the 6-min hall walk test to improve (net difference of 28 m from a baseline of 284 m; p=0.07). Morbidity and mortality in the run-in phase were not reported; there were no deaths after randomisation.
Thus, of four double-blind studies [11], the three most recent have all shown an improvement in symptoms and functional capacity. The open-label COMPANION trial [12] has suggested that CRT delays hospitalisation with a trend to reduced mortality. These data will be confirmed or refuted by the CARE-HF trial [13].
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TopAbstract1. EMOTE: (EnoxiMone in...2. HERB-CHF (Hawthorn Extract...3. BEST genetic sub-study:...4. RHYTHM-ICD:...References |
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