© 2004 European Society of Cardiology
Clinical trials update from the European Society of Cardiology: SENIORS, ACES, PROVE-IT, ACTION, and the HF-ACTION trial
a Department of Cardiology, University of Hull, Castle Hill Hospital Cottingham, Kingston-upon-Hull, HU16 5JQ, UK
b Department of Primary Care and General Practice, University of Birmingham Edgbaston, Birmingham B15 2TT, 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. SENIORS: Study of...2. ACES (Azithromycin) and...3. ACTION: A Coronary...4. HF-ACTION Trial: Heart...References |
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This article provides information and a commentary on landmark trials presented at the European Society of Cardiology Congress in August 2004, relevant to the pathophysiology, prevention or treatment of heart failure. The SENIORS trial suggests that nebivolol is well tolerated and effective in older patients with heart failure, even if left ventricular systolic function is not markedly depressed. However, patients aged >75 years appeared to gain less benefit. Further data on the effects of nebivolol on symptoms and quality of life are awaited. Two new trials of long-term antibiotic prophylaxis after myocardial infarction (ACES and PROVE-IT) showed no benefit. The ACTION trial showed no reduction in serious cardiovascular events with nifedipine GITS in patients with chronic stable angina, despite a substantial reduction in blood pressure. The HF-ACTION trial announced that the first 700 patients of a projected 3000 had been randomised to either an exercise program or encouragement to exercise but without a formal program. The primary outcome measure is death or hospitalisation for any reason.
Key Words: SENIORS • ACES • PROVE-IT • ACTION • HF-ACTION trial
Received September 2, 2004; Accepted September 8, 2004
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1. SENIORS: Study of the Effects of Nebivolol Intervention on Outcomes and Rehospitalisation in Seniors with heart failure |
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TopAbstract1. SENIORS: Study of...2. ACES (Azithromycin) and...3. ACTION: A Coronary...4. HF-ACTION Trial: Heart...References |
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Over the last 5 years, beta-blockers have become one of the cornerstones of treatment for heart failure due to left ventricular systolic dysfunction (LVSD). However, most patients are not prescribed beta-blockers and even fewer are prescribed agents that are known to be effective at doses that have been shown to reduce mortality [1-5]. Data suggest that fewer than 10% of patients with heart failure and LVSD are receiving an appropriate beta-blocker at doses targeted in clinical trials [1-5].
There are many reasons for the underuse of beta-blockers. The most important reason is probably lack of a well-organised system of care for patients with heart failure [1,3,6], where this is provided, 85% or more of appropriate patients receive beta-blocker therapy [6]. Older patients are less likely to receive beta-blockers, which may reflect less access to expert care, a greater number of co-morbidities (such as pulmonary disease) or different treatment goals on the part of the physician (improving symptoms and avoiding side effects rather than improving prognosis) or, if they were consulted, the views of the patient [1]. Older patients with heart failure may also be less likely to receive a beta-blocker because a much higher proportion of these patients have preserved LV systolic function, for which there is less evidence of benefit with a beta-blocker.
The SENIORS trial was designed to assess the effects of nebivolol, a beta-blocker with vasodilator actions thought to be mediated by nitric oxide [7], in older patients with heart failure, whether or not LVSD was present.
1.1. Methods
The design and methods of the SENIORS trial have been reported previously [8]. Key inclusion criteria were age >70 years, a clinical diagnosis of heart failure and either a documented LV ejection fraction 
35% in the previous 6 months or a hospitalisation for heart failure within the previous year. Nebivolol was initiated at 1.25 mg/day and was titrated to a target dose of 10 mg/day at 2-4 week intervals. There was a 3-week down-titration period and a 1-month washout period at the end of the study. It is assumed, although it was unclear during the presentation, that the washout period was not included in the analysis. The primary outcome measure was time to death or cardiovascular hospitalisation.
1.2. Results
Altogether, 2128 patients were randomised and evaluated. Mean follow-up was about 20 months, longer than most other placebo-controlled trials of beta-blockers. The mean age of the patients was 76 years and about 37% were women, a higher proportion than in other studies reflecting the greater age of patients and the inclusion of some patients with preserved LV systolic function. The mean LV ejection fraction was 36%, about 60% of patients were in NYHA class I or II and ischaemic heart disease was present in 76%. Eighty-six percent were receiving diuretics, 83% ACE inhibitors, 26% aldosterone antagonists and 40% digoxin. Sixty-five percent of patients reached the top dose of nebivolol versus 76% of patients randomised to placebo. Seventy-six percent of patients randomised to nebivolol were receiving 
5 mg/day.
Nebivolol delayed the time to death or cardiovascular hospitalisation with a trend to a reduction in all-cause mortality (Table 1). Tests for heterogeneity in outcome were not significant but patients with LV ejection fraction >35% or age 75 years and women tended to fare better for the primary endpoint.
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1.3. Discussion
The small amount of information reported so far from the SENIORS trial suggests that nebivolol reduces a composite of mortality and morbidity in older patients with heart failure. The effect was rather modest and less than some might have expected. It is too early to judge what the final impact of this trial will be. The point-estimate of the effect of nebivolol was less than that observed with the beta-blockers used in USCT, the CIBIS trials, MERIT or COPERNICUS and rather closer to the effect of bucindolol in BEST [9-18]. However, meta-analysis of trials of beta-blockers with >40 deaths shows that the confidence intervals around their effects overlap, so we cannot be confident that the results are different (Fig. 1). The one powerful piece of evidence that the pharmacological differences between beta-blockers have an impact on clinical outcome is COMET, which showed that carvedilol reduced mortality compared to metoprolol tartrate [19].
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The mean age of patients in SENIORS was older than that in most other trials of beta-blockers and it does appear that patients aged >75 years tended to have less benefit. Previous trials have included several thousand patients aged >70 years. In the CIBIS trials, 25% of 3288 patients were aged 70 years or more [12]. Mortality was reduced by 37% in this group, an effect that tended to be greater than in younger patients [12]. In COPERNICUS, mortality was reduced significantly in the subgroup of patients aged
65 years when analysed on its own, an effect only slightly less than in younger patients [14]. In MERIT, one-third (about 1330) of patients were aged >70 years [16,20]. In this subgroup, all-cause mortality and death or hospitalisation for worsening heart failure were both reduced significantly with only a slight trend to less effect than in younger patients. Of note, the annual mortality in SENIORS was not higher than in other landmark trials of heart failure despite the greater age of the patients (Fig. 2). This may reflect the inclusion of patients with milder symptoms and less impaired LV systolic function.
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Prior to the SENIORS study, there was little evidence that beta-blockers were effective for patients with heart failure without LVSD. A study by Aronow et al. [9] did suggest a striking reduction in all-cause mortality with propranolol in patients aged
62 years who did not have LVSD but had developed persistent heart failure 6 months or more after a myocardial infarction. A smaller study of patients with rather mild heart failure suggested that carvedilol exerted little improvement on LV diastolic function [21]. The SENIORS study suggested that the benefits of nebivolol on the composite endpoint were slightly greater in patients with a LVEF >35%. However, the mean LVEF among this group of patients was 46%, suggesting that many did have mild LVSD. Data on mortality in this subgroup have not been presented. If it is accepted that patients with heart failure without LVSD obtain a morbidity/mortality benefit with nebivolol, then this is an important finding. The effect appears larger than that of candesartan in CHARM-preserved and could make nebivolol the first-line agent in these patients. As high arterial resistance and stiffness could be responsible for symptoms and other evidence of heart failure in patients without LVSD, the vasodilator properties of nebivolol could be its key to success in this group of patients. However, the problem of accurate diagnosis of heart failure in the absence of LVSD remains a barrier to the use of this agent [22]. |
2. ACES (Azithromycin) and PROVE-IT (Gatifloxacin): Pravastatin Or Atorvastatin Evaluation and Infection Therapy (PROVE IT-TIMI 22) trial and the Azithromycin and Coronary Events Study (ACES) |
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TopAbstract1. SENIORS: Study of...2. ACES (Azithromycin) and...3. ACTION: A Coronary...4. HF-ACTION Trial: Heart...References |
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Several infectious agents, including Coxsackie virus and Mycoplasma pneumoniae, have been implicated in the development of atherosclerosis and or plaque instability leading to myocardial infarction. The intestinal flora and altered gastrointestinal permeability have also been implicated in the absorption of endotoxin from the gut leading to cytokine activation and impaired myocardial contractility [23]. These hypotheses provide a possible rationale for the use of antimicrobial agents for the treatment of myocardial infarction and heart failure. Although early trials suggested that treatment directed at mycoplasma may reduce the risk of recurrent myocardial infarction, recent large well-designed studies have failed to show benefit [24]. Two further trials in which pulsed treatment with azithromycin (600 mg once per week) or gatifloxacin (400 mg for 10 days every month) was given for several years have failed to show benefit in terms of death or myocardial infarction. The effect on infections and progression of heart failure has not been reported. However, treatment seemed well tolerated. Let us hope that the trials have not contributed to the development of antibiotic resistant organisms.
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3. ACTION: A Coronary disease Trial Investigating Outcome with Nifedipine gastrointestinal therapeutic system |
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TopAbstract1. SENIORS: Study of...2. ACES (Azithromycin) and...3. ACTION: A Coronary...4. HF-ACTION Trial: Heart...References |
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The ACTION study was designed to find out whether nifedipine gastrointestinal therapeutic system (GITS; target dose 60 mg/day) could reduce the risk of death or nonfatal cardiovascular events in patients with chronic stable angina. It has been fully reported in The Lancet [25]. A total of 7665 patients with heart failure or LV ejection fraction <40% were excluded at baseline due to the perceived risk of giving such patients nifedipine. The primary endpoint was a composite of all-cause mortality, myocardial infarction, refractory angina, new overt heart failure, debilitating stroke or peripheral revascularisation. Follow-up was for a mean of 4.9 years.
A similar number of patients reached the primary endpoint in each group but patients randomised to nifedipine were less likely to undergo revascularisation, probably reflecting the anti-anginal effect of nifedipine rather than an effect on the progression of atheroma, as nifedipine did not reduce the need for peripheral vascular surgery. It is unlikely that the slightly higher rate of revascularisation improved the prognosis in the placebo group since few patients were affected and the impact of revascularisation for angina on survival is small. It is surprising that, despite a substantial reduction in blood pressure with nifedipine, there was no reduction in stroke or myocardial infarction. This suggests that perhaps there is some concealed disadvantage to the use of a dihydropyridine calcium channel blocker in this setting, which means that the results of ACTION are not as reassuring as they appear at first sight.
The ACTION study provides some valuable insights into the prognosis of medically managed angina and the incidence of and mechanisms leading to heart failure. Nifedipine appeared to reduce the number of patients developing overt heart failure although many more patients were withdrawn from nifedipine for ankle oedema and in some of these patients this may have been a manifestation of heart failure (Table 2). Heart failure was one of the most common serious events in this population. In about half of the cases, heart failure occurred without another antecedent vascular event, suggesting that either hypertension or the development of ischaemic or hibernating myocardium led to the development of heart failure ‘silently’. The incidence of heart failure at around six per thousand per year is about double that reported in epidemiological studies of the general population. The exclusion of patients with LV dysfunction and the relatively young population may account for a lower than expected incidence of heart failure in this study [26].
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4. HF-ACTION Trial: Heart Failure: A Controlled Trial Investigating Outcomes of exercise traiNing |
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TopAbstract1. SENIORS: Study of...2. ACES (Azithromycin) and...3. ACTION: A Coronary...4. HF-ACTION Trial: Heart...References |
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Evidence that exercise reduces the morbidity or mortality of heart failure is lacking although a recent meta-analysis has suggested that such benefits may occur [27]. Many trials may have failed to show long-term effects due to their small size and the reluctance of patients to continue with long-term exercise programs. The HF-ACTION trial attempts to overcome these problems and provide a definitive answer on this issue. Key inclusion criteria are heart failure due to LV systolic dysfunction with ejection fraction
35%, NYHA II, on stable optimal medical therapy (for at least 6 weeks), and able to undergo an exercise training program. Patients who exercise regularly (more than once per week) are excluded. Patients in the control group are told to stay active and an activity log is recorded. Patients randomised to exercise are given a prescription to exercise to 60% of heart rate reserve, defined as the difference between peak heart rate at exercise testing and the individual's baseline heart rate. This is increased to 70-80% as and when the patient is willing and able. Based on the patients enrolled so far, this target was usually reached by the end of the second or third week of exercise training. For the first 3 months, the exercise program is conducted three times a week at the participating institution, using either a treadmill or stationary bicycle. After this initial period, participants continue their customized exercise regimen at home. The trial supplies home exercise equipment and research team members maintain frequent telephone contact with participants to monitor their health and ensure that they are continuing to exercise.
The study has enrolled 784 patients so far (3000 is the target over the next 2 years) in the USA and Canada and is shortly to commence recruitment in Europe. The mean age of patients is 58 years, so the results may not be applicable to older patients. Currently, 90% of the enrolled patients are on beta-blocker therapy.
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