© 2002 European Society of Cardiology
Clinical trials update from the American Heart Association meeting: PROSPER, DIAL, home care monitoring trials, immune modulation therapy, COMPANION and anaemia in heart failure
Department of Academic Cardiology, Castle Hill Hospital Cottingham, Kingston upon Hull HU16 5JQ, UK
* Corresponding author. Tel.: +44-1482-622613; 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. PROSPER: PROspective Study...2. Telemonitoring3. Immune modulation therapy4. COMPANION: the comparison...5. Anaemia in heart...References |
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This article continues a series of reports on research developments of particular interest to those involved in the management of patients with heart failure. Summaries of the following trials, reported at the 75th Scientific Sessions of the American Heart Association held in Chicago, Illinois between 17th and 20th November 2002 are included: PROSPER; DIAL; home care monitoring trials; immune modulation therapy; COMPANION; and anaemia in heart failure.
Key Words: PROSPER • DIAL • COMPANION • Heart failure • Telemonitoring • Anaemia
Received November 28, 2002; Accepted December 4, 2002
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1. PROSPER: PROspective Study of Pravastatin in the Elderly at Risk |
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TopAbstract1. PROSPER: PROspective Study...2. Telemonitoring3. Immune modulation therapy4. COMPANION: the comparison...5. Anaemia in heart...References |
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Heart failure is a common manifestation of coronary artery disease. Statins have been shown to reduce the risk of cardiovascular events, although the majority of data is from studies in middle-aged patients and there are few data on the use of statins in the elderly [1–3]. The PROSPER study was, therefore, designed to investigate whether pravastatin could reduce coronary and cerebral events in elderly patients who either had pre-existing vascular disease or who were considered to be at high risk for vascular disease. The design and main results of the PROSPER trial have been published [4,5].
A total of 5804 patients aged between 70 and 82 years (mean 75 years) of whom 52% were women, were randomised to double blind treatment with either pravastatin 40 mg per day (n=2891) or placebo (n=2913). Of these patients, 3239 had existing vascular disease and 2565 were considered to be at risk due to smoking, high blood pressure or diabetes. Patients were recruited in three centres in Scotland, Ireland and The Netherlands and were followed up for a mean of 3.2 years. This relatively short duration was selected due to the advanced age of the patients included in the study. The composite primary end-point was coronary death, non-fatal myocardial infarction and fatal or non-fatal stroke.
At baseline, the mean LDL-cholesterol was 3.8 mmol/l and total cholesterol was 5.7 mmol/l. After 3 months treatment, mean LDL-cholesterol was reduced by 34% in the pravastatin group, total cholesterol by 23%, triglycerides by 13% and HDL-cholesterol was increased by 5%, compared with the placebo group.
There were significantly fewer primary endpoints in the pravastatin group (n=408, 14.1%) compared with placebo (n=473, 16.2%) P=0.014. This difference was principally due to a 24% reduction in cardiac mortality, which was 3.3% in the pravastatin group compared with 4.2% in the placebo group (P=0.043). In addition, the risk of fatal or non-fatal myocardial infarction was reduced by 19% in the pravastatin group compared with placebo. There was no evidence of a decrease in cerebrovascular endpoints at 3 years. There was no reduction in the incidence of heart failure requiring hospitalisation or revascularisation procedures with pravastatin and no effect on cognitive function.
However, there was also no reduction in total mortality (n=306 for placebo vs. 298 for pravastatin) or disability from vascular events (stroke disability was measured and the fact that a reduction in myocardial infarction did not lead to a reduction in heart failure indicates that disability from myocardial infarction was also unaffected). Moreover, a significant increase in the incidence of cancers was observed in the pravastatin group (n=245) compared with placebo (n=199). A subsequent meta-analysis of statin trials including PROSPER suggested that this was a chance finding, although further close monitoring was recommended.
Overall, PROSPER appears to be a statistically positive but clinically neutral study. The apparent paradox of a reduction in cholesterol without an improvement in the overall outcome of patients requires confirmation and explanation. Perhaps pravastatin is simply ineffective in patients with advanced vascular disease in elderly patients in whom plaque pathology may differ from younger subjects. Alternatively, the potential benefits and risks of cholesterol reduction with statins may have cancelled each other out, resulting in the overall neutral outcome. Although the benefits of statin therapy are widely known, the biological rationale for harmful effects are rarely discussed. Statins impair the synthesis of coenzyme Q10 an endogenous anti-oxidant [6,7]. Cholesterol may be responsible for neutralising the endotoxins absorbed from the gut which are responsible for cytokine activation [6,8]. These effects may be especially harmful in patients with heart failure. Fortunately, large studies to address the SAFETY and efficacy of statins in patients with heart failure (predominantly patients known to have coronary artery disease) are now underway, which will determine whether statins are effective, futile or harmful in this population. PROSPER reinforces the need for these data.
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2. Telemonitoring |
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TopAbstract1. PROSPER: PROspective Study...2. Telemonitoring3. Immune modulation therapy4. COMPANION: the comparison...5. Anaemia in heart...References |
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2.1. DIAL: ranDomised trial of telephonic Intervention in chronic heArt faiLure
The DIAL trial was designed to evaluate the use of home based telephone monitoring on morbidity and mortality in patients with heart failure. The study, which was conducted in 51 medical centres in Argentina, recruited a total of 1518 patients with stable heart failure. Patients were included in the study if they had clinically stable heart failure of at least 3-months duration with stable medication for at least 2 months. Patients were randomised to receive either intensive telephone intervention from a trained nurse (n=760) or usual care (n=758). In the telephone intervention group, calls were made every 14 days for the first four calls and thereafter calls were made monthly or more frequently in individuals deemed at high risk of readmission. During the phone calls, nurses assessed symptoms, compliance with drug therapy, weight control, oedema, dietary compliance and physical activity. Following this evaluation, nurses could arrange a clinic visit, change the frequency of calls or change diuretic dosing, as considered appropriate for the patient. The average follow up was 439 days.
The mean age of patients was 64 years and 71% were male. More than 80% of patients were receiving diuretics, 80% ACE-inhibitors and 62% beta-blockers, it was therefore concluded that optimal medical therapy had generally been achieved in these patients.
The primary composite end-point of all-cause mortality and/or heart failure hospitalisation, showed a 20% relative risk reduction for patients in the intervention group compared with those in the usual care group (Table 1). This was principally due to a reduction in heart failure admissions in the intervention group. There was no difference between the groups for all-cause mortality.
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It was concluded that this low cost intervention was effective in reducing the number and duration of heart failure admissions both in patients with mild (NYHA class I–II) and more severe (NYHA class III–IV) symptoms of heart failure and in those with preserved ventricular function.
These findings contrast somewhat with the recently reported results of the TEN-HMS study, in which 427 patients were randomised to usual care, nurse management (usual care plus monthly telephone calls) or telemonitoring (twice daily monitoring of vital signs which were transmitted to the heart failure clinic). The TEN-HMS study showed a substantial reduction in mortality with either intervention compared to the usual care group [9].
2.2. Other home care monitoring trials
Abstracts of two other home care monitoring trials were presented at the meeting. In a study of 72 patients with moderate or severe heart failure, randomised to receive either nurse telemanagement or nurse visits, it was reported that after 3 months, patients in the telemanagement group had fewer symptoms, higher total heart failure self-efficacy and better global quality of life than patients who received home visits. It was concluded that nurse telemanagement was more effective than nurse visits in improving some biopsychosocial outcomes in patients with chronic heart failure.
In another study, 462 heart failure patients were randomised to usual care or nurse management which consisted of an initial visit plus monthly phone calls. Over a 1-year period, there was no difference between the groups for time to first rehospitalisation or the combined endpoint of hospitalisation, emergency room visit or death. It was suggested that this lack of benefit of telephone contact may have been due to the simultaneous implementation of a heart failure care programme in the centres involved, which may have improved the standard of usual care.
Overall, these studies provide further evidence that more attention should be paid to the adequate organisation of care in order to deliver the highly effective therapy that exists for patients with heart failure [10]. It is likely that several different systems of organisation will work. However, the system that provides adequate support to the largest number of patients with the fewest personnel (the main cost of delivering care) is likely to determine which model becomes most popular.
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3. Immune modulation therapy |
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TopAbstract1. PROSPER: PROspective Study...2. Telemonitoring3. Immune modulation therapy4. COMPANION: the comparison...5. Anaemia in heart...References |
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Immune activation and inflammation appear to contribute to the progression of heart failure [11,12]. However, anti-cytokine strategies such as infliximab and etanercept have not been shown to be successful in the treatment of heart failure [13]. This may be because they are highly selective. It is possible that broad-spectrum anti-inflammatory therapy may be effective in the treatment of heart failure. Immune modulation is a novel non-pharmacological therapy, in which a sample of the patients’ blood is exposed to oxidative stress and then readministered intramuscularly to stimulate the immune system.
In a double-blind, multicentre, phase II study, 73 patients with NYHA class III–IV heart failure were randomised to treatment with either immune modulation therapy (n=36) or placebo (n=37) administered on days 1, 2, 14 and then monthly, for a period of 6 months.
The mean age of patients in the study was 62 years, the majority were men and all patients were receiving treatment with ACE inhibitors, beta blockers and/or diuretics.
The primary end points, which were change in 6-min walk test and NYHA class showed no significant differences between the treatment groups. However, there was a significant reduction in death and the composite end-point of all-cause mortality or hospitalisation for patients receiving immune modulation therapy compared to placebo (Table 2). The clinical composite score showed that more patients were improved on active therapy (P=0.046) and more patients were worse in the placebo group (P=0.010).
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There were no changes in serum markers and the incidence of adverse events was similar between the groups, although there was a greater incidence of worsening heart failure in the placebo group.
It was concluded that these results have established the basis for a larger phase III trial of immune modulation therapy in heart failure. The ACCLAIM study (Advanced Chronic Heart Failure Clinical Assessment of Immune Modulation Therapy) has been approved and will commence shortly.
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4. COMPANION: the comparison of medical therapy, pacing and defibrillation in chronic heart failure trial |
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TopAbstract1. PROSPER: PROspective Study...2. Telemonitoring3. Immune modulation therapy4. COMPANION: the comparison...5. Anaemia in heart...References |
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The aim of the COMPANION study was to assess whether optimal medical therapy combined with either ventricular resynchronisation therapy alone (CRT) or ventricular resynchronisation therapy combined with cardioverter–defibrillator capability (CRT/ICD) is superior to optimal medical therapy alone in the treatment of chronic heart failure.
To be eligible for entry, patients were required to be in NYHA class III–IV, with an ejection fraction 
35% and a QRS duration of 120 ms or less. The aim was to recruit 2200 patients over 2 years with a follow up of 3 years from study initiation. The randomisation ratio was 1:2:2, with half of the number of patients in the medical therapy group compared with the resynchronisation therapy groups. The primary outcome measure was the composite of all-cause hospitalisation or all-cause mortality. The primary analyses of interest were of each intervention against control but not one intervention vs. the other. The design of the COMPANION study has been published [14].
The study was terminated prematurely in November 2002 by the study Data and Safety Monitoring Board as it had achieved its primary endpoint, although it is not yet clear that this was the sole reason for stopping the trial. Approximately 1630 patients had been recruited, of which approximately 330 were randomised to the control group. A >20% relative reduction in the primary outcome measure was noted with intervention, although it has not yet been stated explicitly whether this was a combined analysis of intervention groups against control group or the pre-planned analysis. It appears that the control group may have had a much higher than expected mortality. A 40% relative reduction in mortality was noted in the CRT/ICD group vs. control, which was significant. A smaller, non-significant reduction in mortality was reported with CRT. The effect of CRT alone vs. CRT and ICD on mortality was reported not to be different. The full results of the study will be presented at the American College of Cardiology meeting in Chicago in March 2003. Meanwhile, the CARE-HF study, which compares best medical therapy alone vs. best medical therapy plus CRT, continues, having randomised more patients to the control group than has COMPANION [15]. The results of both trials should be presented before drawing conclusions on the efficacy of CRT in patients with heart failure. The apparent efficacy of the ICD in reducing mortality supports the findings of the MADIT-II study amongst patients with a broad QRS [16]. If COMPANION, CARE-HF and SCD-HeFT [17] deliver consistent and favourable results then the management of heart failure may undergo its biggest revolution in care yet.
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5. Anaemia in heart failure |
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TopAbstract1. PROSPER: PROspective Study...2. Telemonitoring3. Immune modulation therapy4. COMPANION: the comparison...5. Anaemia in heart...References |
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The growing interest in the relationship between heart failure and anaemia is reflected in the large number of abstracts on this topic presented at the meeting. Anaemia commonly complicates heart failure (14–28% of patients depending on the threshold used) [18] and is a potential exacerbating factor. Observational studies and small randomised trials have shown that treatment may improve symptoms and delay death [19].
Two studies reported on the relationship between anaemia and survival in heart failure. In a retrospective analysis of the ELITE II (evaluation of losartan in the elderly) study (n=3044; baseline haemoglobin 14.0±1.6 g/dl), haemoglobin was not found to be a significant prognostic marker of survival. However, by classifying patients according to 1 g/dl increments in haemoglobin levels showed, a U-shaped relationship between haemoglobin levels and survival was identified. The worst survival rates were found in those patients with the lowest and the highest haemoglobin levels, (i.e. <12.5 and >15.4 g/dl). The presence of chronic obstructive pulmonary disease (n=260), a potential confounding factor, did not substantially affect haemoglobin concentrations.
In another study of 29 302 unselected heart failure patients, it was reported that 16.4% of patients had anaemia and for 59% of these there was no identifiable cause. It was found that patients with anaemia had a lower survival at 1 year (63.2%) compared with non-anaemic patients (71.6%, P<0.001). This effect on survival was apparent irrespective of whether the cause of anaemia had been identified.
The relationship between haemoglobin levels and exercise capacity was reported in a study of 113 male patients with chronic heart failure. Cardio-pulmonary exercise testing was performed on a treadmill and patients were classified according to their baseline haemoglobin levels. It was found that patients with the lowest haemoglobin levels (10–11.7 g/dl) had the lowest peak VO2, highest VE/VCO2 slope and highest NYHA class. It was concluded that heart failure patients with low haemoglobin concentrations have the poorest exercise capacity and that the two variables are closely related. It was suggested that reduced exercise capacity and fatigue observed in these patients, may be exacerbated by the reduced oxygen carrying capacity of the blood.
The relationship between inflammatory cytokines and haemoglobin levels was reported in a study of 157 patients with stable heart failure. Blood levels of haemoglobin TNF, sTNFR1, sTNFR2 and soluble CD14 were measured in these patients and compared with 56 healthy controls. Of the heart failure patients 29% were found to have haemoglobin levels <12.1 g/dl. Haemoglobin levels and haematocrit were significantly less in patients with NYHA class IV heart failure compared with the controls (P<0.0001). Results showed that all four immune variables were inversely related to both haemoglobin and haematocrit. Over a mean follow up of 31 months, 56 patients died. Haemoglobin was found to predict mortality with a relative risk of 1.38 for every g/dl decrease in blood level (P=0.001). It was concluded that both anaemia and inflammatory immune activation should be considered as important therapeutic targets in patients with heart failure.
The predictive value of white blood cells as indicators of mortality in patients with heart failure was evaluated in a retrospective study of 995 patients. Over a mean follow-up period of 37 months, 247 patients died. It was found that absolute neutrophil and lymphocyte counts were both independent prognostic indicators of mortality in patients with heart failure. It was concluded that further research was now required to establish whether this was related to disease progression. The study also confirmed the prognostic importance of haematocrit.
These reports suggest that anaemia confers an adverse outcome in patients with heart failure but cannot determine whether it is a marker or mediator of a worse outcome. Anaemia may merely reflect the severity of heart failure or of renal dysfunction or the presence of other co-morbidities. Properly designed randomised controlled trials are now required to determine if treatment of low haemoglobin levels with agents such as erythropoeitin might improve the symptoms and the prognosis of patients with heart failure.
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