© 2001 European Society of Cardiology
Clinical trials update: highlights of the scientific sessions of the American Heart Association year 2000: Val HeFT, COPERNICUS, MERIT, CIBIS-II, BEST, AMIOVIRT, V-MAC, BREATHE, HEAT, MIRACL, FLORIDA, VIVA and the first human cardiac skeletal muscle myoblast transfer for heart failure
Academic Cardiology, University of Hull, Castle Hill Hospital Castle Road, Kingston upon Hull, HU16 5JQ, UK
* Corresponding author. Tel.: +44-1482-624087; fax: +44-1482-624085. E-mail address: j.g.cleland{at}medschool.hull.ac.uk (J.G. Cleland).
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Abstract |
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 Top Abstract 1. Val-HeFT (valsartan in...2. Studies of beta-blockers...3. AMIOVIRT (amiodarone vs....4. VMAC: the vasodilation...5. Studies of endothelin-1...6. Post-infarction studies7. Gene therapyReferences |
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This article continues a series of reports summarising recent research developments pertinent to the topic of heart failure. This is a summary of presentations made at scientific sessions of the American Heart Association in November 2000. Clinical studies of particular interest to people caring for patients with heart failure include Val-HeFT, AMIOVIRT and V-MAC. New data from β-blockers trials are reviewed, highlights from some important developments in post-infarction care, including MIRACL and FLORIDA, discussed and results of some early studies of gene therapy reported.
Key Words: Val-HeFT • AMIOVIRT • V-MAC • Post-infarction care
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1. Val-HeFT (valsartan in heart failure trial) |
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TopAbstract1. Val-HeFT (valsartan in...2. Studies of beta-blockers...3. AMIOVIRT (amiodarone vs....4. VMAC: the vasodilation...5. Studies of endothelin-1...6. Post-infarction studies7. Gene therapyReferences |
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The protocol [1] and baseline patient information [2] for this study have already been published. The purpose of the study was to determine whether the addition of the angiotensin II receptor antagonist (ARA), valsartan, to an ACE inhibitor would confer additional benefits on mortality and morbidity in patients with heart failure and left ventricular systolic dysfunction. The rationale for the study was based on the concept that, despite ACE inhibition, angiotensin II production rises during long-term ACE inhibition and that the potential deleterious effects of angiotensin II could be blocked by an ARA [1].
In this study, 5010 patients with symptomatic [NYHA class II (62%), III (36%) or IV (2%)] left ventricular systolic dysfunction (ejection fraction <40%) and dilation (left ventricular end-diastolic dimension >2.9 cm/m2) were randomised to receive either Valsartan, initiated at a dose of 40 mg twice daily and force-titrated to a target dose of 160 mg twice daily or matching placebo. Patients with a systolic blood pressure <90 mmHg were excluded. Randomisation was stratified by beta-blocker use, to ensure equal distribution in each arm of the study.
The study had two primary outcome measures:
- All cause mortality; and
- Combined, all cause mortality and morbidity, defined as the time to the first of any of the following events: all cause mortality, sudden death with resuscitation, hospitalisation for heart failure and worsening heart failure requiring therapy with an inotropic or vasodilating agent for at least 4 h. Death and hospitalisation accounted for most of this composite.
Secondary end-points included hospitalisation for heart failure, NYHA status, symptoms, quality of life, echocardiographic indices of left ventricular function and coagulation markers. No pre-specified sub-group analyses were reported in the protocol paper [1], although analysis of outcome in patients with or without ACE inhibitors is intuitively obvious and randomisation was stratified by beta-blocker therapy.
1.1. Results
The mean follow-up was 1.89 years. Only seven patients were lost to follow-up. Most patients were male (80%) and Caucasian. At baseline, 85% of patients were taking diuretics, 67% digoxin, 93% ACE inhibitors but only 36% were taking beta-blockers [2]. Although the rate of use of beta-blockers would now be considered sub-optimal, it reflected the state of the art at the time of randomisation. Importantly for the interpretation of this study, it is likely that many patients started beta-blockers subsequent to randomisation. The dose of ACE inhibitor used was relatively high, equivalent to approximately 18 mg of enalapril per day. The mean baseline ejection fraction was 27%, left ventricular end-diastolic dimension 3.7 cm/m2 and blood pressure 124/76 mmHg.
Addition of valsartan did not affect overall mortality (Table 1) but reduced the co-primary, morbidity/mortality end-point by 13.3% (P=0.009). Re-hospitalisation for heart failure was markedly reduced by 27.5%. All-cause hospitalisation was not reported. All other secondary end-points, including ejection fraction, NYHA class, symptoms and Minnesota living with heart failure score, favoured adding valsartan. Although the statistical significance of these changes was high, the magnitude of improvement is more difficult to interpret. Placebo corrected NYHA scores suggested that approximately 1 in 20 patients would improve by one functional class on valsartan (P<0.001) with similar benefits for most other symptom assessments. The importance of this amount of benefit will depend on both the patient and carers’ expectations. The placebo-corrected improvement in ejection fraction was <1% (P=0.001).
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Valsartan was generally well tolerated. The mean achieved dose was 254 mg/day; 9.9% discontinued valsartan and 7.2% the placebo (P<0.05). Increase in dizziness (placebo corrected — 1.2%), hypotension (0.5%) and renal impairment (0.8%) accounted for most of the small difference in tolerability.
Several interesting sub-group analyses were presented. Three hundred and sixty-six patients were not taking an ACE inhibitor at baseline, mainly because they were ACE inhibitor intolerant. ACE intolerant patients tended more often to be women, more likely to have coronary disease and more likely to be taking a beta-blocker. Among these patients, valsartan reduced the morbidity/mortality end-point by 45% (P=0.0002). Among the 36% of patients taking a beta-blocker at baseline, there was a borderline interaction (relative risk 1.15; P<0.05) on the morbidity/mortality measure, suggesting that patients taking a beta-blocker at baseline did better when randomised to a placebo. Mortality data were not presented. It is premature to conclude too much based on these data. These interactions are for baseline therapy only. It is possible that a large increase in beta-blocker use occurred during the study among patients not on beta-blockers at baseline, although verbal reports indicate that this was not the case. If this were true, it would refute the idea of a real clinical interaction. It is possible that patients on ACE inhibitors and beta-blockers had lower blood pressures and that excessive blood pressure reduction caused harm in some patients. This would not preclude the use of triple therapy in patients with a well-sustained blood pressure. Also, triple therapy could have conferred a survival benefit but an increased risk of non-fatal events. Much more information is required before jumping to conclusions about treatment interactions.
Overall, Val-HeFT suggests that there may be an advantage to adding valsartan to an ACE inhibitor in patients with heart failure. Data on all-cause hospitalisation is required before a proper evaluation of the true clinical benefit and cost-effectiveness of this strategy can be judged. The next task will be to decide whether it is an increased dose of ACE inhibitors [3], spironolactone [4] or valsartan that should be added to standard therapy with ACE inhibitors and beta-blockers. Some patients will need all of these strategies, but tailoring treatment to the individual patient's needs is an important target for future research. Knowing when a patient is receiving too much therapy and which treatment to withdraw is of key importance.
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2. Studies of beta-blockers in heart failure |
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TopAbstract1. Val-HeFT (valsartan in...2. Studies of beta-blockers...3. AMIOVIRT (amiodarone vs....4. VMAC: the vasodilation...5. Studies of endothelin-1...6. Post-infarction studies7. Gene therapyReferences |
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New data from further analyses of the landmark trials on beta-blockers, published [5–7] or presented [8–11], are reported (Table 2).
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2.1. CIBIS-II (cardiac insufficiency bisoprolol study II)
An association between beta-blocker induced heart rate reduction and prognostic benefit in patients with heart failure is controversial. In CIBIS-II, the heart rate was measured with care at each clinic visit. The average heart rate reduction was 9.5 beats per min (bpm) in CIBIS-II, but the relative reduction in mortality was similar regardless of the reduction in heart rate. Indeed, 200 patients on bisoprolol with no reduction in heart rate appeared to have as great a benefit as those who did not. A better estimate of heart rate change may have been obtained by ambulatory monitoring. These data suggest that patients even with relatively low heart rates (>60 bpm) should receive a beta-blocker.
Sub-set analysis suggested that those patients with the worst ejection fractions, highest baseline heart rate and most limiting symptoms had a similar benefit to those with less severe clinical indices (Table 3). The investigators suggested that there was a direct relationship between placebo mortality and the magnitude of benefit across all beta-blocker trials and subgroups.
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Patients with atrial fibrillation had no benefit from bisoprolol, despite having a similar reduction in heart rate to those in sinus rhythm and achieving the same doses of bisoprolol [12]. Within the placebo group, there was no difference in mortality between those with atrial fibrillation and sinus rhythm. Patients with atrial fibrillation are more likely to be taking digoxin. Is it possible that the worse outcome of patients with atrial fibrillation in CIBIS-II reflects an increased risk of digoxin withdrawal? Recent reports from the US carvedilol trial indicate similar benefits with carvedilol in patients with or without digoxin [13] and with or without atrial fibrillation [14], although carvedilol did not increase the rate of reversion to sinus rhythm. The CAFÉ study recently reported that carvedilol in combination with digoxin improved ventricular function in patients with atrial fibrillation and heart failure but that ventricular rate control and ventricular function deteriorated if digoxin was withdrawn [15].
2.2. MERIT-HF (metoprolol CR/XL randomised intervention trial in congestive heart failure)
The MERIT investigators reported that metoprolol could be used safely in patients with common co-morbidities such as diabetes and chronic (non-asthmatic) airways disease. Diabetics had no excess hypo- or hyperglycaemia. This contrasts with a significant hyperglycaemic effect observed with carvedilol in patients with heart failure. Patients with chronic airways disease had fewer exacerbations if they were in the active treatment arm.
The MERIT-HF trial demonstrated no significant reduction in mortality, all-cause hospitalisation or heart failure hospitalisation in the small group of patients with NYHA class IV heart failure randomised into the study. This probably reflects insufficient numbers in the subgroup. Statistical tests could show no heterogeneity in outcome in this subgroup compared to the rest of the study population. Data on a subset of patients similar to those in COPERNICUS were presented. Patients in NYHA III and IV with a left ventricular ejection fraction <25% on echocardiography had the greatest mortality benefit from metoprolol (risk reduction 39%; P=0.0086) with a 42% reduction in sudden death (Table 4). Overall, the number needed to treat to prevent one death over the course of the trial (1 year) was 27, but in the above-mentioned patient group, this was reduced to only 13. Overall, in CIBIS-II, MERIT high-risk subgroup and COPERNICUS there were 346 deaths on the placebo and 240 on the beta-blocker.
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2.3. BEST (bucindolol evaluation survival trial)
Controversy continues surrounding the BEST results [11]. Among 1354 patients randomised to placebo, there were 447 deaths, while among 1354 randomised to bucindolol, there were 409. The relative risk in Caucasian patients was 0.82 (95% CI 0.7–0.96). This 18% risk reduction did achieve statistical significance (P=0.012) but, nonetheless, the effect appeared less than in all the other beta-blocker studies. Among the 627 Afro–Americans there were trends to an excess mortality. Diabetes was present in 34% of Caucasians and 37% of Afro–Americans and did not explain the mortality difference. The investigators continue to deny any intrinsic sympathomimetic activity with bucindolol that could account for the difference, but did suggest that, uniquely among beta-blockers, bucindolol exerts a powerful sympatholytic effect. An interesting sub-study of BEST suggested a relationship between the extent of dysfunctional but viable (hibernating) myocardium on dobutamine stress, and the improvement in ejection fraction. The CHRISTMAS study, with carvedilol, should report on the outcome of a large randomised trial in patients stratified by the presence or absence of hibernating myocardium [16]. In summary, the BEST data lends further support to the possibility of clinically relevant differences between agents within the class.
2.4. COPERNICUS (carvedilol prospective randomised cumulative survival)
The mortality results of this study have been reported previously in this journal [10] (Fig. 1). The effects on hospitalisation are now reported. These showed a striking effect of carvedilol on all-cause hospitalisation, mainly due to a reduction in hospitalisations for heart failure (Table 5) over a mean follow-up of just less than 1 year. The MERIT study suggested that metoprolol had no effect on hospitalisation in patients with NYHA class IV heart failure.
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In contrast to the BEST study, there tended to be a greater reduction in mortality among the 5% of African–Americans with carvedilol in COPERNICUS, although, due to small numbers, this just failed to reach statistical significance when analysed in isolation. However, there was no racial heterogeneity in the observed benefit but a significant reduction in the combined outcome of death and all-cause hospitalisation was observed in each racial subgroup. Similar benefits were observed among the small number of Afro–Americans randomised in the earlier US Carvedilol trial.
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3. AMIOVIRT (amiodarone vs. implantable defibrillator in patients with non-ischaemic cardiomyopathy and asymptomatic non-sustained ventricular tachycardia) |
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TopAbstract1. Val-HeFT (valsartan in...2. Studies of beta-blockers...3. AMIOVIRT (amiodarone vs....4. VMAC: the vasodilation...5. Studies of endothelin-1...6. Post-infarction studies7. Gene therapyReferences |
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The precise role of implantable defibrillators for the management of patients with heart failure who have not had a near sudden death experience remains controversial. Many sudden deaths in heart failure may not be primarily arrhythmic [17].
The AMIOVIRT study compared amiodarone with an implantable defibrillator in 103 patients with non-ischaemic dilated cardiomyopathy (DCM), ejection fraction <35% (mean 22–23%) and NYHA class I–III, to determine whether there were differences in survival. Follow-up was over 21 months. The amiodarone dosing regimen was: 400 mg twice daily for a week, 400 mg once daily for 51 weeks and 300 mg/day thereafter. The trial was stopped early because of futility (Table 6).
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These data suggest that implantable defibrillators should be reserved for patients with heart failure who have already suffered a haemodynamically unstable ventricular arrhythmia. Electrophysiological testing remains a controversial means of stratification for the risk of sudden death in heart failure. Along with the CABG-PATCH study [18], this report suggests that patients at lower risk of arrhythmias may be best managed medically with ACE inhibitors and beta-blockers, rather than an ICD. It is not clear that amiodarone adds to the protection of this regimen [19]. However, the current study is too small to give a definitive result, considering the relatively benign prognosis of the patients randomised. The ongoing SCD-HeFT trial should provide a more definitive answer to whether implantable defibrillators are effective among patients with heart failure in patients without other markers of increased arrhythmic risk [20] (Fig. 2).
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4. VMAC: the vasodilation in the management of acute CHF (VMAC) |
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TopAbstract1. Val-HeFT (valsartan in...2. Studies of beta-blockers...3. AMIOVIRT (amiodarone vs....4. VMAC: the vasodilation...5. Studies of endothelin-1...6. Post-infarction studies7. Gene therapyReferences |
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The management of acute heart failure remains unsatisfactory in terms of rapid symptom relief, acute complications and longer-term prognosis. Nesiritide is a genetically engineered stable analogue of brain natriuretic peptide (BNP) being considered for use in acute CHF. It has been found effective in decreasing preload and afterload [21].
The VMAC trial compared the haemodynamic and clinical effects of nesiritide and intravenous nitro-glycerine, when added to standard therapy, in 498 patients (mean age 62) hospitalised with decompensated CHF. Patients were randomised to fixed or adjustable dose intravenous nesiritide, IV nitro-glycerine or placebo, in addition to standard care, including diuretics, dobutamine, and dopamine.
The trial was divided into a 3-h placebo-controlled period, followed by a 6-month follow-up. The primary analysis compared the effects of nesiritide (n=204), nitro-glycerine (n=143), and placebo (n=142) at 3 h, with primary end points of change in pulmonary capillary wedge pressure (PCWP) and dyspnoea. Other analyses included a 24-h PCWP assessment and an overall safety profile of nesiritide. Two hundred and eleven patients received a 2-mcg/kg bolus and 0.01-mcg/min infusion of nesiritide, and 62 received a 2-mcg/kg bolus and 0.01-mcg/min infusion nesiritide for the first 3 h, followed by an adjustable dose that could be increased up to 0.03 mcg/kg/min.
Within 15 min, compared to placebo, PCWP was reduced by nesiritide. The effect was more rapid than nitro-glycerine. Breathlessness had improved significantly more by 3 h in patients receiving nesiritide compared to nitro-glycerine and placebo. A 0.01-mcg/kg/min infusion dose of nesiritide was sufficient in 56% of the patients in the adjustable dose arm. Nesiritide was associated with a rate of headache between placebo and nitro-glycerine. No significant difference in mortality was noticed between the four treatment groups.
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5. Studies of endothelin-1 receptor antagonists in heart failure and pulmonary hypertension |
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TopAbstract1. Val-HeFT (valsartan in...2. Studies of beta-blockers...3. AMIOVIRT (amiodarone vs....4. VMAC: the vasodilation...5. Studies of endothelin-1...6. Post-infarction studies7. Gene therapyReferences |
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Bosentan is a non-selective endothelin antagonist that causes peripheral and systemic vasodilatation and has shown controversial evidence of benefit in patients with chronic heart failure [22]. Bosentan was recently granted a license for the treatment of pulmonary hypertension in the United States of America.
5.1. BREATHE-1 in pulmonary hypertension (primary and secondary to connective tissue disease)
A pilot trial randomised 32 patients with pulmonary hypertension and in NYHA class III to receive either 62.5 mg twice daily of bosentan (increased to 125 mg after 4 weeks) or placebo. At 12 weeks, the 21 patients receiving bosentan demonstrated a significant increase in baseline 6-min walk distance, compared to the 11 patients on placebo. In addition, patients in the bosentan group had a decreased pulmonary artery pressure and increased cardiac index. Nine of the bosentan patients also experienced improvements in NYHA functional class compared to only one patient on placebo. No persistent disturbance in liver function with bosentan was noted at these doses. The full BREATHE-1 trial has already randomised 112 out of an intended 150 patients. A 4-month follow-up period is planned. The results should be available by late next year. It is not yet clear whether bosentan is effective in patients who are symptomatic at rest, or whether it should be used in combination with or instead of prostacyclin infusion for these patients.
5.2. HEAT study (Heart failure endothelin-A antagonist trial)
This study randomised 157 patients to placebo or one of three doses of darusentan (30, 100 and 300 mg/day), a relatively selective ETA receptor antagonist. Acute haemodynamic studies were conducted 3 weeks apart. A dose dependent reduction in vascular resistances and blood pressure was noted with a rise in cardiac index, but no fall in filling pressures. There was a small increase in endothelin-1 with higher doses, suggesting some loss of receptor selectivity. Worryingly, four deaths were noted on the two higher doses vs. none on placebo or low dose. This is reminiscent of the REACH-1 results, which also showed early harm with high doses of an endothelin antagonist followed by possible long-term benefits. An outcome study is underway. Fortunately, patients start with low doses and are titrated up to a maximum of 100 mg/day.
5.3. Tezosentan in acute heart failure
Tezosentan is a non-selective endothelin antagonist for parenteral use. A cumulative dose ranging study in patients of this non-selective antagonist for intravenous use in acute heart failure demonstrated the expected haemodynamic effects including increased cardiac index and decreased blood pressure, systemic and pulmonary vascular resistance.
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6. Post-infarction studies |
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TopAbstract1. Val-HeFT (valsartan in...2. Studies of beta-blockers...3. AMIOVIRT (amiodarone vs....4. VMAC: the vasodilation...5. Studies of endothelin-1...6. Post-infarction studies7. Gene therapyReferences |
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Trials of statins have established that late initiation (>3 months at least and generally >1 year) after myocardial infarction confers benefit. Neither the safety nor the efficacy of early introduction of statins in patients with unstable coronary disease has been established. This is also true of their use in patients with heart failure.
6.1. MIRACL (myocardial ischaemia reduction with aggressive cholesterol lowering trial)
In this trial [23], 3086 patients with unstable angina or non-Q-wave infarctions were randomised to receive either Atorvastatin 80 mg/day or placebo within 4 days of onset of symptoms. Patients scheduled for revascularisation were excluded. Patients were followed for 16 weeks. Average LDL at baseline was only 123 mg/dl. At the end of 16 weeks, the average LDL in the Atorvastatin group was 72 mg/dl, while LDL had increased slightly in the placebo group.
The primary endpoint was the time to the occurrence of an ischaemic event, defined as death, non-fatal acute myocardial infarction, cardiac arrest with resuscitation, or recurrent symptomatic myocardial ischaemia requiring emergency re-hospitalisation. The incidence of events at 16 weeks was 17.4% in the placebo group and 14.8% (risk reduction 16%) in the atorvastatin group, a result that achieved borderline significance (P=0.048) There was no effect on death or recurrent myocardial infarction, most of the effect being on symptomatic myocardial ischaemia, which was reduced by 26% (P=0.02). There was an unexpected 50% reduction in stroke in those treated with atorvastatin (P=0.045). The overall event rate in this study was low, perhaps reflecting the inclusion criteria. The incidence of adverse effect on liver function was 2.5% and was reversible with discontinuation of the drug.
6.2. FLORIDA (fluvastatin on risk diminishing after acute myocardial infarction trial)
This trial randomised 550 patients with acute myocardial infarction to receive 80 mg/day of fluvastatin or placebo within 8 days. The follow up was for 12 months. The reduction in LDL was less than in the MIRACL trial. No significant difference was seen between the groups either for recurrent ischaemia or major adverse events (death, readmission, recurrent infarction), although a trend to reduced mortality with fluvastatin at 1 year was noted (4.0% reduced to 2.6%).
The above studies suggest that the early use of statins after myocardial infarction is probably safe, but provides little evidence of efficacy. The results of more definitive studies, such as the A to Z study — Aggrastat (tirofiban) to Zocor (simvastatin), are required before an firm recommendation about early statin use can be made. Unlike MIRACL, the A to Z study includes patients undergoing interventions. Data on the safety and efficacy of statins in heart failure are still awaited.
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7. Gene therapy |
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TopAbstract1. Val-HeFT (valsartan in...2. Studies of beta-blockers...3. AMIOVIRT (amiodarone vs....4. VMAC: the vasodilation...5. Studies of endothelin-1...6. Post-infarction studies7. Gene therapyReferences |
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7.1. VIVA (VEGF in ischaemia for vascular angiogenesis)
Vascular endothelial growth factor (VEGF) is a potentially important stimulus to neo-vascularisation and could form the basis of a medical revascularisation strategy [24].
The VIVA trial randomised 178 patients with severe myocardial ischaemia not amenable to conventional revascularisation to receive intracoronary plus intravenous placebo or low or high dose recombinant VEGF. All groups had improved after 60 days, but no difference in symptoms or exercise capacity was noted between groups. Favourable trends in favour of VEGF were noted at 120 days. A subgroup of 107 patients was followed for 1 year. The placebo group had deteriorated back to baseline, but the VEGF groups had lost less of the early benefit. 40% of patients in the high-dose VEGF group remained markedly improved with little or no angina. Patients randomised to high-dose VEGF in this subgroup analysis had a lower risk of major cardiovascular events and of cancer (Table 7).
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The analysis is open to a number of criticisms. The follow-up was only on a sub-group of patients. The major impact on cardiovascular events was a reduction in the need for revascularisation in a group of patients who had already been considered inoperable. The rate of myocardial infarction was highest in the high-dose VEGF group. The differences in cancer rate probably reflect the play of chance and are not reliable evidence to refute concerns about a tumour enhancing effect. This is an interesting study, but too small to confirm safety. Safety in other groups, such as patients with diabetic retinopathy also needs to be studied. However, the improvement in symptoms, if confirmed in other studies is impressive. Further trials are certainly to be encouraged.
7.2. Case reports and animal experiments on myocyte cell implantation to the heart
Dr Philippe Ménasché (France) reported the results of the first autologous skeletal muscle myoblast transfer in a 72-year-old patient with heart failure after an anterior myocardial infarction. Skeletal myoblasts, cultured from biopsies taken from the patient's leg, were injected into infarcted tissue during coronary bypass surgery. Echocardiography and PET scanning prior to the implant had shown the area to be metabolically non-viable. After 5 months of follow-up, repeat studies showed a limited recovery of contractile function in the area of the transplant, the magnitude of which was enhanced by dobutamine. The patient had also experienced symptomatic improvement.
Dr Ray Chiu (Canada) suggested that adult bone marrow stem cells could be induced to differentiate into cardiac myocytes. He demonstrated the feasibility of this approach in a rat experimental model. Within 6 weeks, the implanted stem cells expressed proteins typical of cardiomyocytes and developed gap junctions with the host's native cells. Neither occurs with implanted skeletal muscle cells. However, stem cells differentiated into scar tissue if implanted into scars. It may be necessary to differentiate the cells into cardiac myocytes before implantation. Cells may also be modified prior to implantation to increase their production of substances such as VEGF to improve myocardial vascularisation. It is not clear whether these therapies increases the risk of arrhythmias.
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