European Journal of Heart Failure

European Journal of Heart Failure 2007 9(10):1070-1073; doi:10.1016/j.ejheart.2007.09.005

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© 2007 European Society of Cardiology

Clinical trials update from the European Society of Cardiology Congress 2007: 3CPO, ALOFT, PROSPECT and statins for heart failure

John G.F. Cleland, Ahmed Tageldien Abdellah, Olga Khaleva, Alison P. Coletta^* and Andrew L. Clark

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).

	Abstract

Top Abstract 1. Efficacy of non-invasive... 2. Aliskiren observation of... 3. Predictors of response... 4. A pilot study... References

 
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 Congress 2007. Unpublished reports should be considered as preliminary data, as analyses may change in the final publication.

In the 3CPO study, non-invasive ventilation produced a more rapid resolution of symptoms in patients hospitalised with acute cardiogenic pulmonary oedema; but had no effect on survival, compared to standard oxygen therapy. The ALOFT study showed that the selective oral renin inhibitor aliskiren reduces plasma BNP levels and is well tolerated in patients with heart failure receiving ACE inhibitors or ARBs, although the study was not powered to show clinical benefit. In the PROSPECT study, no echocardiographic measure of mechanical dyssynchrony was identified that was useful for identifying patients more or less likely to respond to CRT. Low dose atorvastatin reduced the incidence of sudden cardiac death in a small placebo controlled study of patients with advanced chronic heart failure.

Key Words: Randomised controlled trials • heart failure

Received September 12, 2007; Accepted September 13, 2007

	1. Efficacy of non-invasive ventilation in patients with acute cardiogenic pulmonary oedema (3CPO)

Top Abstract 1. Efficacy of non-invasive... 2. Aliskiren observation of... 3. Predictors of response... 4. A pilot study... References

 
Presented by David E Newby from Edinburgh, UK

Acute cardiogenic pulmonary oedema is a common cause of hospitalisation and is associated with high in-hospital mortality. In severe cases that do not respond rapidly to conventional treatment, endotracheal intubation and mechanical ventilation may be required. One alternative is non-invasive ventilation, which is achieved by applying a tightly fitting face mask through which oxygen enriched air is administered, either at constant pressure (continuous positive airway pressure, CPAP) or at low pressure when breathing out and high pressure when breathing in (non-invasive intermittent positive pressure ventilation, NIPPV). A recent meta-analysis of small studies in patients with acute cardiogenic pulmonary oedema reported that non-invasive ventilation reduced the need for intubation and had a beneficial effect on mortality when compared to standard therapy [1].

In light of these findings, 3CPO, a large scale, open, randomised, controlled multicentre trial, was designed to evaluate the effect of non-invasive ventilation on mortality compared with standard therapy, and also to compare the effectiveness of CPAP vs. NIPPV. One thousand and sixty nine patients, hospitalised with acute cardiogenic pulmonary oedema, tachypnoea (>20 breaths/min) and acidosis were randomised to at least 2 h of 60% oxygen delivered either by standard face mask (n=367), CPAP (n=346) or NIPPV (n=356). The study was performed at 26 hospitals in the UK. The mean age of patients was 78 years and, unusually for a cardiovascular study, only 43% were men. The majority of patients were receiving diuretics (89%) and nitrates (90%).

Due to the nature of the treatments the study had an open design; however, adjudication of clinical endpoints was blinded to treatment allocation. Oxygen by standard facial mask was tolerated without the need to deviate from assigned therapy in 83% of cases, which was similar to CPAP (85%) and greater than NIPPV (78%; p=0.016); however, 12% of the standard facial mask failures crossed over to CPAP. Worsening respiratory distress occurred in 9%, 2% and 4% of patients respectively (p<0.001 for the difference). By intention to treat analysis, non-invasive ventilation reduced heart rate, respiratory rate and acidosis, but surprisingly, had a smaller effect on oxygen saturations. Oxygen delivered by standard facial mask, CPAP and NIPPV were all associated with similar and substantial mortality at 7 or 30 days (Table 1), consistent with the outcome observed in the EuroHeart Failure survey [2]. This study suggests that CPAP, and perhaps NIPPV, have a role in the management of cardiogenic pulmonary oedema that is failing to respond adequately to conventional treatment but the modest impact on symptoms and lack of effect on outcome suggests that it should not be routine initial treatment.

View this table: [in this window] [in a new window]   Table 1 Physiology data at one hour and mortality data at 7 and 30 days in the 3CPO study

 

	2. Aliskiren observation of heart failure treatment study (ALOFT)

Top Abstract 1. Efficacy of non-invasive... 2. Aliskiren observation of... 3. Predictors of response... 4. A pilot study... References

 
Presented by John JV McMurray from Glasgow, UK

Blockade of the renin-angiotensin-aldosterone system (RAAS) is beneficial in the treatment of heart failure. However, angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB s) can induce loss of the negative feedback system which inhibits renin secretion. The consequent compensatory increase in renin and other components of the RAAS may ultimately overwhelm the pharmacological blockade. Direct renin inhibitors block the RAAS higher up in the cascade and might therefore prevent this response. Aliskiren is the first selective oral renin inhibitor available for clinical evaluation [3,4].

The ALOFT study was designed to evaluate the safety and tolerability of aliskiren in patients with heart failure. Patients with stable New York Heart Association (NYHA) class II-IV heart failure, current or previous hypertension and an elevated BNP level (>100 pg/ml), were randomised to double blind treatment with either aliskiren 150 mg (n=156) or placebo (n=146) for three months, following a two week placebo run-in period. All patients were also optimally treated with an ACE inhibitor or ARB and a beta-blocker unless contraindicated or not tolerated.

The mean age of the 302 patients who were enrolled from 73 centres was 68 years and 78% were men. Mean left ventricular ejection fraction (LVEF) was 31%. Aliskiren reduced plasma renin activity compared to placebo (5.71 vs. 0.97 ng/ml/h; p<0.0001). Aliskiren was well tolerated and there was no significant increase in the incidence of hypotension, renal dysfunction or hyperkalaemia. Aliskiren reduced plasma NT-proBNP (by 25%; 95% CI 6-39%; p=0.0106), plasma BNP (by 25%; 95% CI 5-41%; p=0.016) and urinary aldosterone (by 21%; 95% CI 4-34%; p=0.015) at 3 months. There was no significant effect on plasma aldosterone levels. Whether the reduction in plasma BNP levels translate into long term clinical benefit now needs to be evaluated in a large scale, phase III morbidity/mortality trial.

	3. Predictors of response to cardiac resynchronisation therapy (PROSPECT)

Top Abstract 1. Efficacy of non-invasive... 2. Aliskiren observation of... 3. Predictors of response... 4. A pilot study... References

 
Presented by Stefano Ghio from Pavia, Italy

Cardiac resynchronisation therapy improves ventricular function and symptoms and reduces morbidity and mortality in patients with heart failure due to left ventricular systolic dysfunction, and NYHA class III-IV symptoms despite optimal medical therapy, when the QRS duration is prolonged [6,7]. However, the response to CRT varies substantially between patients [5,8,9]. The PROSPECT study was a prospective, observational study to evaluate whether specific echocardiographic measures of dyssynchrony could be used to help predict CRT response [10].

The study was performed in 53 centres in 14 countries. All centres received training on image acquisition and the echo protocol. The echo assessments were performed at three core laboratories, one for each continent.

Four hundred and twenty six patients with heart failure and an indication for CRT including a QRS >130 ms were recruited. Response to CRT was assessed after 6 months using a composite clinical endpoint which included heart failure hospitalisation free survival, improvement in NYHA class and patient global assessment score. Patients also underwent an evaluation of changes in LVESV, as an indicator of reverse remodelling.

At six months, 69% of patients had improved according to the clinical criteria (76% of patients with non-ischaemic aetiology vs. 64% of ischaemic patients; p=0.01); and an improvement in LVESV was observed in 56% of patients overall (63% of patients without and 50% of patients with ischaemic heart disease; p=0.03).

Three of the echo measures (IVMD, LVFT/RR and LPEI) were predictors of a small but significant improvement in the clinical composite score and five echo measures (SPWMD, IVMD, LVFT/RR, LPEI and Tslat-sep) were predictors of reverse remodelling; however, all had low sensitivity and specificity. It was concluded that no echo measure of mechanical dyssynchrony used in the PROSPECT study could be used to improve the selection of patients for CRT according to current guidelines.

The inter-core lab variability was relatively high at 6.5-72%, indicating a need for refinement of the methodology.

A recent report from the CARE-HF study [11] suggests that patients with echocardiographic evidence of more severe dyssynchrony and low systolic blood pressure obtain greater benefit from CRT, but also found that these relationships were weak. The evidence that patients who fulfil the entry criteria for clinical trials should now be further selected on the basis of echocardiography is also weak. Some patients who did badly with CRT may have done much worse without, and some patients will have done just as well even if they had not received CRT. These issues can never be addressed by observational studies and require randomised controlled trials. It is likely that dyssynchrony is a dynamic problem and therefore that a single measurement, under one set of physiological circumstances, is not representative of the total disease burden [5]. Ultimately, careful consideration of the goals of therapy on an individual patient basis, taking into account co-morbid conditions such as respiratory or renal disease may be more useful in selecting patients than imaging data.

	4. A pilot study of low dose atorvastatin in advanced chronic heart failure

Top Abstract 1. Efficacy of non-invasive... 2. Aliskiren observation of... 3. Predictors of response... 4. A pilot study... References

 
Presented by Bojan Vrtovec from Ljubljana, Slovenia

Statins reduce morbidity and mortality in patients with coronary artery disease [12-14], a common cause of LVSD and heart failure. Although some observational studies and retrospective analyses have suggested that statin therapy may be associated with a reduction in mortality in patients with heart failure [15,16], as yet there are no data from prospective randomised controlled trials designed specifically to evaluate the effect of statins in patients with heart failure.

In a small single centre study, one hundred and ten patients with NYHA class III heart failure and LVEF <30%, were randomised to treatment with either low dose atorvastatin (10 mg/day) or placebo (n=55 per group). There was no difference in baseline characteristics between the groups. Approximately 60% of patients had ischaemic aetiology. The incidence of all cause mortality and sudden cardiac death at one year follow-up were lower on atorvastatin than on placebo (Table 2). However, this might reflect a spuriously high rate of events in the placebo group. Good medical treatment of stable NYHA class III heart failure should be associated with an annual mortality of around 10-15%.

View this table: [in this window] [in a new window]   Table 2 Effect of low dose atorvastatin on all cause mortality and sudden cardiac death

 
Although this study is underpowered to make any definitive claims about the effects of statins on sudden cardiac death in heart failure, these data are encouraging. The results of two large randomised controlled trials CORONA, which is due to report in November this year, and GISSI-HF [17,18] are awaited.

	References

Top Abstract 1. Efficacy of non-invasive... 2. Aliskiren observation of... 3. Predictors of response... 4. A pilot study... References

 

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