© 2006 European Society of Cardiology
Clinical trials update from the joint European Society and World Congress of Cardiology meeting: PEP-CHF, ACCLAIM and the HHH study
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
 |
Abstract |
|---|
 Top Abstract 1. The perindopril in...2. Advanced chronic heart...3. A multi-country randomised...References |
|---|
This article provides information and a commentary on trials relevant to the pathophysiology, prevention and treatment of heart failure, presented at the joint European Society and World Congress of Cardiology meeting held in Barcelona in September 2006. All reports should be considered as preliminary data, as analyses may change in the final publication.
The PEP-CHF study suggests that perindopril improves symptoms and functional capacity and may reduce heart failure hospitalisations in patients with diastolic heart failure. Although immune modulation therapy failed to reduce the incidence of all-cause mortality and cardiovascular hospitalisations in the ACCLAIM study, the observed differences in outcome in some heart failure patients warrants further investigation. The HHH study failed to show a beneficial effect of telemonitoring over usual care in patients with heart failure but potentially important country interactions were observed.
Key Words: PEP-CHF • ACCLAIM • HHH study
Received September 21, 2006; Accepted September 21, 2006
|
1. The perindopril in elderly people with chronic heart failure (PEP-CHF) study |
|---|
|
TopAbstract1. The perindopril in...2. Advanced chronic heart...3. A multi-country randomised...References |
|---|
Presented by John Cleland from Kingston-upon-Hull, UK
The results of this study have recently been published (1). Many patients with clinical features suggesting heart failure have evidence neither of major systolic dysfunction nor valve disease. However, conceptually, a diagnosis of heart failure requires the patient to have important cardiac dysfunction as the cause of symptoms. Diastolic LV dysfunction has been invoked as a possible cause of heart failure, although no satisfactory, generally-accepted criteria exist for its diagnosis. (2,3) Patients with ‘diastolic’ heart failure or "heart failure with normal ejection fraction" (4,5) are usually older, more often women, more commonly have a history of hypertension and are less likely to have a history of myocardial infarction than patients with LVSD. Amongst patients who have recently been discharged from hospital with a diagnosis of heart failure about half have preserved LV systolic function. The prognosis of such patients subsequent to discharge is reported to be little better, in terms of morbidity or mortality, than those with LVSD.
PEP-CHF was a randomised, double-blind trial comparing perindopril (4 mg/day) and placebo in 850 patients with diastolic heart failure. Briefly, eligible patients were aged 
70 years, with a clinical diagnosis of heart failure, receiving diuretics, with a cardiovascular hospitalisation within the previous 6 months, and an echocardiogram which showed features of diastolic dysfunction but excluded valve disease or a low ejection fraction. The primary endpoint was a composite of all-cause mortality and heart failure related hospitalisation. Important secondary endpoints were the individual components of the primary composite, number of days in hospital and NYHA class at 1 year. The distance walked in 6 min was also measured at baseline and 1 year.
Median follow-up was 2.1 years. However, after 1 year a large proportion of patients withdrew from perindopril or placebo and started taking open-label ACE inhibitors. The event rates were substantially lower than predicted with only 15.3% of patients reaching the primary end-point at 1 year compared to a prediction of 50%. Overall, only slightly fewer patients assigned to receive perindopril reached the primary endpoint, but if the analysis was confined to the first year of follow-up when most patients were on assigned therapy, then a substantial reduction in events approaching statistical significance was observed (hazard ratio 0.69; 95% confidence intervals [0.47-1.01]; p=0.055). This was entirely driven by a reduction in heart failure related hospitalisations (hazard ratio: 0.63 [0.41-0.97]; p=0.033). There were few deaths. In the overall study, patients assigned to perindopril spent 3 days less in hospital. Symptoms and 6-min walk test were improved at 1 year. The latter finding corroborates a previous smaller trial (6).
The median plasma concentration of NT-proBNP, which was measured in 375 patients, was 400 pg/ml; suggesting that either the diagnosis of heart failure was wrong or heart failure was very well treated for many patients. Patients with NT-proBNP values below the median had few events. Patients with above median values had greater left atrial dimensions, were more likely to have regional wall motion abnormalities, but less likely to fulfil the Doppler criteria for diastolic dysfunction suggested by the ESC (7). They also had more advanced symptoms and worse exercise capacity.
Other trials in similar populations have also reported much lower event rates than suggested by epidemiological studies. The Digitalis Investigation Group (DIG) ancillary study in patients with preserved LV systolic function reported a mortality rate of only 7% and heart failure hospitalisation of <20% in the first year of follow-up. The Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM) preserved study, which enrolled 3023 patients, of whom 20% were receiving ACE inhibitors, reported an annual rate of cardiovascular death or heart failure hospitalisation of 9.1% in patients assigned to placebo compared to 8.1% in those assigned to candesartan, a difference that approached statistical significance (p=0.118). Patients in PEP-CHF thus had higher event rates than in previous studies.
PEP-CHF suggests that treating patients who have a diagnosis of diastolic heart failure with perindopril will improve symptoms and functional capacity and may reduce hospitalisations for heart failure. The study also suggests that NT-proBNP, or possibly other natriuretic peptides, should become part of the definition of heart failure, especially diastolic heart failure.
|
2. Advanced chronic heart failure Clinical Assessment of Immune Modulation therapy (ACCLAIM) |
|---|
|
TopAbstract1. The perindopril in...2. Advanced chronic heart...3. A multi-country randomised...References |
|---|
Presented by Guillermo Torre-Amione from Houston, 112 Texas, USA
There is evidence that the immune system is disturbed in patients with heart failure and that activation is associated with more advanced disease. Increases in plasma markers of inflammation, such as CRP (8,9) predict a worse outcome. However, it is not clear whether the increase in inflammatory markers is a marker or mediator of worsening cardiac function or heart failure. Randomised trials of interventions designed to block the effects of some inflammatory pathways, such as TNF, have not shown benefit so far (10). A different approach is to try to reduce immune activation by exposing a small sample of autologous whole blood to oxidative stress and then injecting the cells back into skeletal muscle in the same patient where they undergo apoptotic cell death. This process is designed to reduce the chronic inflammation associated with heart failure, by activating the physiological response of the recipients immune system to apoptotic cells, causing an increase in anti-inflammatory cytokines and a decrease in inflammatory cytokines. Preliminary studies of immune modulation therapy in patients with heart failure due to LVSD with and without coronary artery disease have been encouraging. (11)
The ACCLAIM study enrolled patients with a LVEF 
30% and NYHA class II-IV heart failure and randomly assigned them to placebo or immune modulation therapy (IMT), administered on days 1, 2 and 14 and then every 28 days thereafter. Treatment was administered for a minimum of 22 weeks (8 injections). The primary outcome was all-cause mortality or CV hospitalisation and the mean duration of follow-up was 12-15 months.
At baseline, the mean age of patients was 64 years, 20% were women and 68% had an ischaemic aetiology. Overall, patients were well treated for heart failure, 94% were receiving an ACE-inhibitor or ARB and 87% were receiving a beta blocker. In addition 26% of patients had an implantable cardiac defibrillator and 10% were receiving cardiac resynchronisation therapy.
The study failed to show an effect on the primary outcome and there were slightly more deaths in the IMT group (Table 1). However, in two pre-specified subgroups; patients in NYHA class II (n=689) and patients with no prior myocardial infarction (n=919) more striking effects were seen (Table 1). Statistical tests suggested that these differences were unlikely to have arisen by chance alone but that does not mean to say that the investigational treatment was responsible. Differences in baseline characteristics or management as a consequence of therapy might have resulted in differences in outcome.
|
This study shows a neutral overall effect of immune modulation therapy on outcome. The rate of serious adverse events was similar between placebo and IMT. The differences in outcome in the subgroup analysis are intriguing. The subgroup with no prior myocardial infarction deserve further investigation, since the disease substrate (and thus mechanism of progression) might be different in this group. It is difficult to come up with a convincing reason for the difference in outcome in those with milder symptoms. These patients had lower event rates, as did those without ischaemic heart disease. One of the failings of clinical trials is to enrol patients at high risk rather than modifiable risk. Perhaps the outcome of less sick patients without ischaemic heart disease is more amenable to IMT. However, the lack of any clear trend for an effect on mortality, even in subgroups where treatment appeared to influence the primary endpoint favourably, is not encouraging.
|
3. A multi-country randomised trial on the role of a new telemonitoring system in CHF: The HHH Study (Home or Hospital Heart Failure) |
|---|
|
TopAbstract1. The perindopril in...2. Advanced chronic heart...3. A multi-country randomised...References |
|---|
Presented by Andrea Mortara from Monza, Italy
Disease management programmes have been shown to improve outcome in heart failure patients; however, the optimal design and strategy remain to be established. (12)
There is growing interest in telemonitoring as a means of helping deliver care to patients with chronic disease, including heart failure. This is driven by the increasing number of people requiring care, the increasing complexity of care, the expected decline in the number of qualified carers (since a declining proportion of the population is of working age) and the results of clinical trials. (13,14) Telemonitoring can help with drug titration and maintenance, monitoring for deterioration or complications and can be used to educate patients about their illnesses. Ultimately, telemonitoring helps empower patients, the largest and, from a health-service point of view, least expensive human resource available for fighting disease (15).
The design paper for the HHH study has been published (16) The study enrolled 461 patients in NYHA class II-IV, with one or more hospitalisation for heart failure within the previous 12 months and a LVEF<40%. There was no requirement for the use of diuretics unlike previous studies. All patients were on optimised medical therapy. Patients were randomly assigned to usual care (n=160) or one of three telemonitoring strategies (n=301); 1) nurse telephone support; 2) home telemonitoring, which included symptom assessment, weight, heart rate and blood pressure measurement or 3) home telemonitoring with additional monthly assessment for sleep apnoea and 24-h heart rate. The primary endpoint was days in hospital for heart failure. The study was conducted in Poland, Italy and the UK. The mean age of the patients was 60 years, 57% had ischaemic heart disease and >80% were on ACE inhibitors and beta-blockers. The study identified a high prevalence of sleep apnoea (>20%). Over a 12-month follow-up period, mortality (6.9%) and rate of first hospitalisation for heart failure (10.4%) were remarkably low. Any intervention would have difficulty in showing a benefit on outcome in this patient group and indeed, there was no difference between telemonitoring and usual care in this study (Table 2). However, there were strong country interactions. Telemonitoring increased the rate of hospitalisation in Poland but reduced it in Italy.
|
The study highlights some of the difficulties of conducting studies using telemetry technology. Of previous large trials, only the DIAL trial showed a reduction in hospitalisations (17). In the TEN-HMS and WHARF studies (13 14 18), telemonitoring reduced mortality only in patients at considerably higher risk of events, which leads to the suggestion that appropriate timely hospitalisation may be a good thing that improves the management of complications and survival. The recruitment of patients with such a low risk in the control group in HHH made it unlikely that any benefit could have been shown. The divergent results from previous studies, identifies a need for a precise definition of the content of telemonitoring. HHH also highlights the need to integrate telemonitoring into existing services. This is no small challenge.
|
References |
|---|
|
TopAbstract1. The perindopril in...2. Advanced chronic heart...3. A multi-country randomised...References |
|---|
- Cleland J.G.F., Tendera M., Adamus J., Freemantle N., Polonski L., Taylor J. The perindopril in elderly people with chronic heart failure (PEP-CHF) study. Eur Heart J (2006 (Sep 8)) [Electronic publication ahead of print].
- Dahlstom U. Can natriuretic peptides be used for the diagnosis of diastolic heart failure? Eur J Heart Fail (2004) 281–287.
- van Kraj D.J., van Pol P.E., Ruiters A.W., et al. Diagnosing diastolic heart failure. Eur J Heart Fail (2002) 4:419–430.
[Abstract/Free Full Text] - Banerjee P., Clark A.L., Cleland J.G. Diastolic heart failure: a difficult problem in the elderly. Am J Geriatr Cardiol (2004) 13:16–21.[CrossRef][Medline]
- Banerjee P., Banerjee T., Khand A., Clark A.L., Cleland J.G. Diastolic heart failure: neglected or misdiagnosed? J Am Coll Cardiol (2002) 39:138–141.
[Abstract/Free Full Text] - Hutcheon S.D., Gillespie N.D., Crombie I.K., Struthers A.D., McMurdo M.E.T. Perindopril improves six minute walking distance in older patients with left ventricular systolic dysfunction: a randomised, double-blind placebo controlled trial. Heart (2002) 88:373–377.
[Abstract/Free Full Text] - Swedberg K., Cleland J., Dargie H., et al. Task force for the diagnosis and treatment of chronic heart failure of the European Society of Cardiology. Guidelines for the diagnosis and treatment of chronic heart failure: executive summary (update 2005): the task force for the diagnosis and treatment of chronic heart failure of the European Society of Cardiology. Eur Heart J (2005) 26:1115–1140.
[Free Full Text] - Windram J., Loh P.H., Tin L., Clark A.L., Cleland J.G.F. The increased inflammatory response seen in heart failure is related to the severity of tricuspid regurgitation rather than the severity of LV impairment. Eur J Heart Fail (2006) 5(Suppl_1). [Abstract 726].
- Alonso-Martinez J.L., Llorente-Diez B., Echegaray-Agara M., et al. C-reactive protein as a predictor of improvement and readmission in heart failure. Eur J Heart Fail (2002) 4:331–336.
[Abstract/Free Full Text] - Mann D. Targeted anticytokine therapy and the failing heart. Am J Cardiol (2005) 95(Suppl 1):9–16.[CrossRef]
- Torre-Amione G., Sestier F., Radoavancevic B., Young J. Effects of a novel immune modulation therapy in patients with advanced chronic heart failure: results of a randomized, controlled, phase II trial. J Am Coll Cardiol (2004) 44:1181–1186.
[Abstract/Free Full Text] - Roccaforte R., Demers C., Baldassarre F., Teo K.K., Yusuf S. Effectiveness of comprehensive disease, management programmes in improving clinical outcomes in heart failure patients. A meta-analysis. Eur J Heart Fail (2005) 7:1133–1144.
[Abstract/Free Full Text] - Goldberg L.R., Piette J.D., Walsh M.N., et al. WHARF Investigators. Randomized trial of a daily electronic home monitoring system in patients with advanced heart failure: the weight monitoring in heart failure (WHARF) trial. Am Heart J (2003) 146:705–712.[CrossRef][Web of Science][Medline]
- Cleland J.G., Louis A.A., Rigby A.S., Janssens U., Balk A.H. TEN-HMS Investigators. Non-invasive home telemonitoring for patients with heart failure at high risk of recurrent admission and death: the Trans-European Network-Home-Care Management System (TEN_HMS) study. J Am Coll Cardiol (2005) 45:1654–1664.
[Abstract/Free Full Text] - Cleland J.G.F. The Trans-European Network-Home care Management System (TEN-HMS) study: an investigation of the effect of telemedicine on outcomes in Europe. Dis Manag Health Outcomes (2006) 14:1–6.[CrossRef]
- Mortara A., Pinna G.D., Johnson P., et alon behalf of HHH Investigators. A multi-country randomised trial of the role of a new telemonitoring system in chronic heart failures: the HHH study (Home or Hospital in Heart failure). Rationale, study design and protocol. Eur Heart J (2004) 6:F99–F102.[CrossRef]
- GESICA Investigators. Randomised trial of telephone intervention in chronic heart failure: DIAL trial. BMJ (2005) 331:425.
[Abstract/Free Full Text] - Louis A.A., Turner T., Gretton M., Baksh A., Cleland J.G.F. A systematic review of telemonitoring for the management of heart failure. Eur J Heart Fail (2003) 5:583–590.
[Abstract/Free Full Text]
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  B. Maric, A. Kaan, A. Ignaszewski, and S. A. Lear A systematic review of telemonitoring technologies in heart failure Eur J Heart Fail, May 1, 2009; 11(5): 506 - 517. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. P. Coletta, D. Cullington, A. L. Clark, and J. G.F. Cleland Clinical trials update from European Society of Cardiology meeting 2008: TIME-CHF, BACH, BEAUTIFUL, GISSI-HF, and HOME-HF Eur J Heart Fail, December 1, 2008; 10(12): 1264 - 1267. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||