© 2006 European Society of Cardiology
Clinical trials update from the American Heart Association 2006: OAT, SALT 1 and 2, MAGIC, ABCD, PABA-CHF, IMPROVE-CHF, and percutaneous mitral annuloplasty
a Department of Cardiology, Postgraduate Medical Institute, Division of Cardiovascular and Respiratory Studies, University of Hull, Castle Hill Hospital Cottingham, Kingston-upon-Hull, HU16 5JQ, UK
b Department of Cardiology, Castle Hill Hospital Cottingham, Kingston-upon-Hull, HU16 5JQ, UK
c Department of Primary Care and General Practice, University of Birmingham Edgbaston, Birmingham, B15 2TT, UK
* Corresponding author. Tel.: +44 1482 624084; fax: +44 1482 624085. a.p.coletta{at}hull.ac.uk
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Abstract |
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 Top Abstract 1. Occluded artery trial...2. Study of ascending...3. First randomized placebo...4. The alternans before...5. Randomized controlled trial...6. N-terminal proBNP improves...7. Percutaneous mitral...References |
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This article provides information and a commentary on trials presented at the American Heart Association meeting held in November 2006, relevant to the pathophysiology, prevention and treatment of heart failure. All reports should be considered as preliminary data, as analyses may change in the final publication.
The OAT study failed to show a benefit of PCI over optimal medical therapy in patients with persistent total occlusion of the infarct related artery following a myocardial infarction. In SALT 1 and 2, tolvaptan was found to correct hyponatraemia of various aetiologies; however, whether this has an impact on heart failure prognosis requires further evaluation. A placebo controlled study of myocardial implantation of skeletal myoblasts in patients with moderate to severe LVSD (MAGIC) showed equivocal/uncertain effects, long term follow-up data are awaited. The ABCD study which compared the ability of an invasive and a non-invasive test to identify patients at risk of arrhythmic events prior to ICD implantation, suggested that the two strategies were comparable, although the practical value of either test remains uncertain and the study had many major flaws. The PABA-CHF study hinted that pulmonary vein antrum isolation might be more effective than AV node ablation with bi-ventricular pacing for the treatment of patients with heart failure in atrial fibrillation. In IMPROVE-CHF, an NT-pro BNP guided treatment strategy was found to reduce the cost of managing patients with acute breathlessness.
Key Words: OAT • SALT 1 and 2 • MAGIC • ABCD • PABA-CHF • IMPROVE-CHF
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1. Occluded artery trial (OAT) |
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TopAbstract1. Occluded artery trial...2. Study of ascending...3. First randomized placebo...4. The alternans before...5. Randomized controlled trial...6. N-terminal proBNP improves...7. Percutaneous mitral...References |
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Presented by Dr. Judith S. Hochman from New York University School of Medicine, USA.
Some hold the view that opening arteries even late after a myocardial infarction will reduce adverse left ventricular remodelling and thereby delay or prevent the development of heart failure and death [1-3]. The contrary view is that arteries that remain occluded generally do so either because the surviving myocardium subtended by the occluded artery already has a good collateral blood supply or because it is dead and/or scarred and therefore no longer requires a blood supply.
The aim of the OAT trial [4] was to determine whether a strategy of percutaneous coronary intervention (PCI) was superior to conservative medical management among stable, high-risk patients with persistent total occlusion of the infarct-related artery after a myocardial infarction (MI). High risk was defined as LVEF <50% or proximal occlusion of a major epicardial vessel. Exclusion criteria included shock, NYHA class III or IV heart failure, renal dysfunction, left main or three-vessel coronary artery disease or evidence of important ongoing ischaemia at rest or on stress testing.
Patients with total occlusion of the infarct-related artery were randomly assigned to PCI with stenting (n=1082) or no PCI (n=1084), 3-28 days after a MI. All patients also received optimal medical therapy. The primary endpoint was a composite of death, reinfarction, or New York Heart Association (NYHA) class IV heart failure, over a mean follow-up of 3 years. The mean age of patients was 59 years, 78% were men and mean baseline LVEF was 48%.
PCI was successful in 87% of patients, and only 3% of patients assigned to medical therapy received a stent within 30 days. Slightly more patients assigned to PCI received clopidogrel but medication use at discharge was otherwise similar. An angiographic sub-study which was performed in 381 patients (TOSCA) and which has also recently been published [5] showed that PCI with stenting effectively maintained long term patency of the persistently occluded infarct related artery, but had no effect on LVEF.
The incidence of death, reinfarction, or NYHA class IV heart failure was similar in the two groups (Table 1), with a trend to more re-infarctions (including late re-infarctions) in those assigned to PCI. If this outcome is also true in the setting of chronic LVSD and heart failure, it has important implications for studies such as STICH and HEART-UK [6] that are investigating the role of revascularisation in patients with heart failure. Even if there is extensive myocardial hibernation, pharmacological treatment alone may be the safest and most successful strategy [7].
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2. Study of ascending levels of tolvaptan in hyponatremia 1 and 2 trials (SALT 1 and 2) |
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TopAbstract1. Occluded artery trial...2. Study of ascending...3. First randomized placebo...4. The alternans before...5. Randomized controlled trial...6. N-terminal proBNP improves...7. Percutaneous mitral...References |
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Presented by Dr. Mihai Gheorghiade from Chicago, USA and Dr. Cesare Orlandi from Rockville, Maryland, USA.
Many patients with heart failure have hyponatraemia, which is a predictor of adverse outcome. Arginine vasopressin (AVP) antagonists such as tolvaptan correct hyponatraemia, reduce the required dose of conventional diuretics and may improve outcomes [8].
The design of the SALT 1 and 2 studies was identical and the data were combined in the analysis [9]. Patients with serum sodium <135 mmol/L (mean age 62 years, 42% women) were randomly assigned to double-blind treatment with either oral tolvaptan (15 mg/day, with adjustment to 30 mg or 60 mg if needed; n=225) or placebo (n=223) for up to 30 days. The primary endpoint was correction of hyponatraemia. The aetiology of hyponatraemia was heart failure in 31% of patients, liver cirrhosis in 27%, and inappropriate antidiuretic hormone secretion (SIADH) or other causes in 42%. Mean baseline serum sodium was 129 mmol/L. Sodium rose by about 4 mmol/L by day 4 and 6 mmol/L by day 30 in patients assigned to tolvaptan (compared to zero or 2 mmol/L with placebo) (p<0.001). By day 4, >40% of patients receiving tolvaptan had a normal serum sodium and by day 30, about 55% compared to about 10% at day 4 and 25% at day 30 with placebo (p<0.001). Dry mouth (13%) and thirst (14%) were the most common adverse effects. There were 14 deaths in the tolvaptan group and 13 in the placebo group during a mean follow-up of 37 days. These data indicate that AVP antagonists can correct hyponatraemia, but robust evidence that this intervention will improve outcomes is awaited. The cause of hyponatraemia may have an over-riding influence on the effect of treatment on morbidity and mortality.
The EVEREST study, which recently completed after at least 1065 deaths had occurred, should report on the effects of tolvaptan on morbidity and mortality at ACC 2007.
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3. First randomized placebo-controlled myoblast autologous grafting in ischemic cardiomyopathy trial (MAGIC) |
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TopAbstract1. Occluded artery trial...2. Study of ascending...3. First randomized placebo...4. The alternans before...5. Randomized controlled trial...6. N-terminal proBNP improves...7. Percutaneous mitral...References |
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Presented by Philippe Menasche, from Paris, France.
The use of stem cells to try and regenerate functioning myocardium has been reported in this [10,11] and other journals [12,13]. In the MAGIC study, a muscle biopsy was taken from the thigh of patients with moderate or severe LVSD, who had been referred for CABG surgery. The biopsy was sent to a core laboratory to isolate and grow skeletal muscle myoblasts. Patients were then randomised to double blind treatment with either a high or low dose of cells or cell-free medium, injected into areas of myocardial scar at the time of CABG surgery. Due to concerns about a possible arrhythmogenic effect of cell transplantation all patients also received a defibrillator (ICD).
The primary endpoint of the study was the improvement in echocardiographic LVEF at 6 months and ventricular volumes were also measured. A subgroup also had LV function assessed using gated nuclear scans. The principal safety outcome was a composite of death, myocardial infarction, resuscitated cardiac death and stroke. Therapy delivered by the ICD was also recorded.
The study was stopped early due to low enrolment. Overall, 120 patients were randomised but only 97 received treatment (Table 2). The average age of the patients was around 60 years. About 25% of the actively treated patients and 20% of the control patients experienced an adverse safety event and about 15% of each group received an ICD therapy over 6 months.
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Echocardiography suggested no improvement in the contraction of dysfunctional segments or increase in LVEF, but ventricular size decreased. Nuclear imaging showed an increase in LVEF with the high-dose myoblast transplant. Long-term follow-up is planned to investigate a possible effect on ventricular remodelling. However, the changes observed may just reflect the play of chance. Whether injection of cells into non-scarred but dysfunctional regions would be safe and provide greater benefit should also be considered. This study provides evidence that there is no dramatic short-term effect from this therapy but does not exclude the possibility of modest or longer-term effects. Cell transplantation for heart failure remains alive as a concept, although it may not be ‘kicking’.
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4. The alternans before cardioverter defibrillator trial (ABCD) |
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TopAbstract1. Occluded artery trial...2. Study of ascending...3. First randomized placebo...4. The alternans before...5. Randomized controlled trial...6. N-terminal proBNP improves...7. Percutaneous mitral...References |
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Presented by Ottorino Costantini from Cleveland, Ohio, USA.
Although implantable cardiac defibrillators (ICDs) reduce the risk of arrhythmic death by about 70% (and consequently all-cause mortality by about 25%) in patients with chronic heart failure, the annual absolute benefit on all-cause mortality is about 2%. ICD therapy should thus be directed at people who have a reasonably good life expectancy provided sudden death can be prevented, in other words younger patients with few co-morbidities and less severe heart failure [14]. The SCD-HeFT study suggested that patients with NYHA class III heart failure did not benefit from ICD implantation. Focussing on patients with a low to intermediate risk means that a high proportion of patients will never receive an appropriate ICD therapy, but will have the risk of inappropriate shocks and other device-related morbidity. A test that identifies patients in whom the risks of ICD therapy outweigh the potential benefit would be helpful.
ABCD included patients with coronary artery disease, a LVEF 
40% and non-sustained ventricular tachycardia (NSVT) on a 24 h tape. Patients with a history of sustained VT, those with atrial fibrillation or on an anti-arrhythmic drug and patients with NYHA class IV heart failure were excluded. The trial was an observational study designed to show that non-invasive testing using microvolt T-wave alternans assessment (MTWA) during a treadmill exercise test was not inferior to a conventional electrophysiological study (EPS) for predicting ventricular tachyarrhythmic events. MTWA is a normal phenomenon that occurs at high heart rates in normal people but at lower heart rates (105 bpm is the target) in patients with heart disease and is thought to reflect the potential for re-entry pathways [15].
ICD implantation was mandated in patients who were either EPS or MTWA positive and recommended even if both tests were negative. Overall, >85% of patients received an ICD. The primary outcome measure was sudden cardiac death or the delivery of appropriate ICD therapy.
The average age of the patients was 65 years, 84% were men, and the mean left ventricular ejection fraction was 28%. Medical therapy included beta-blockers (86%), ACEi or ARB (89%) and statins (81%). A positive EPS was observed in 39% of patients. For MTWA, 46% had a positive test, 29% had a negative test and 25% had an indeterminate result. Only 45% (255 patients) of tests were concordant while 43% (245 patients) had a positive MTWA but negative EPS (Table 3).
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The overall rate for the primary endpoint was 7.5% at one year and 65 patients (11.5% of those not excluded for protocol violation) reached a primary endpoint overall. Sudden cardiac death occurred in ten patients, four received anti-tachycardia pacing and 51 received an appropriate, although perhaps not a necessary, shock and 61 experienced an inappropriate shock. The number of deaths for other reasons was not reported.
Either a negative EPS or MTWA correctly predicted the absence of an event 95% of the time, but this is only a modest improvement since 88.5% of patients wouldn't have had an event anyway and of course some of these events were ‘unnecessary’. A positive test predicted an event correctly about 15% of the time over the 2 year observational period, only a modest improvement from no test at all (11.5%) However, MTWA only appeared to predict risk usefully for about 9 months, implying that if this strategy is used, patients will have to be assessed once or twice per year every year. The duration of prediction with EPS was longer but had also waned markedly by two years and presumably would have been lost with longer follow-up. These observations are important. It is highly likely that the ability of most tests to assess risk declines with time and that a strategy of repetitive testing will be necessary. Repetitive testing must be safe, relatively inexpensive and convenient. It is not yet clear whether this applies to either EPS or MTWA.
This study can be considered a useful pilot with major limitations requiring confirmation by other studies. An analysis of 490 patients from SCD-HeFT also presented at this meeting showed a much higher rate of indeterminate tests (41%) and low predictive accuracy with MTWA, highlighting its rather short-term predictive value and the need for repeat testing [16].
The data from ABCD need to be fully disclosed, including the outcome in protocol violators and the individual components of the composite primary endpoint. The study enrolled 629 patients, but unspecified protocol violations were used to exclude 63 patients, so this report did not use the intention to treat principle, another serious limitation. The endpoint definition includes ICD treatment delivered for a prolonged but not necessarily lethal NSVT. A careful review of ICD trials suggests that perhaps two out of three appropriate shocks are ‘unnecessary’ (i.e.: — the device correctly gave a shock for a ventricular arrhythmia according to programming but the arrhythmia would not have been fatal had the patient not had a device) and this is a major limitation to the interpretation of this trial. It is unclear from the data presented so far whether the primary endpoint was to be counted at 1year or for the whole duration of observation. Two year follow-up was reported, which also has serious limitations since only 3–6% of patients would be expected to die suddenly in this relatively short time-period.
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5. Randomized controlled trial of pulmonary vein antrum isolation vs. AV node ablation with bi-ventricular pacing for treatment of atrial fibrillation in patients with congestive heart failure (PABA-CHF) |
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TopAbstract1. Occluded artery trial...2. Study of ascending...3. First randomized placebo...4. The alternans before...5. Randomized controlled trial...6. N-terminal proBNP improves...7. Percutaneous mitral...References |
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Presented by Andrea Natale from Cleveland, Ohio, USA.
More than 25% of patients with heart failure have chronic atrial fibrillation (AF) and 40% or more may have experienced an episode [17,18]. Patients with heart failure who develop AF are prone to further deterioration in LV function, worsening heart failure, thrombo-embolic events and death [19]. The AFFIRM study [20] and others [21] suggest that a policy of ventricular rate control was possibly superior to one of rhythm control, since those assigned to rate control had a significantly lower rate of adverse events and hospitalisation and a trend to lower mortality. However, only 73% of patients assigned to rhythm control were maintained in sinus rhythm at 3 years and those who were maintained in sinus rhythm appeared to do better. Thus, the failure of the rhythm control strategy may reflect the limited ability of existing techniques to achieve the desired goal rather than failure of the concept. The results of other ongoing studies in patients with heart failure and AF, including AF-CHF and several other smaller studies are awaited.
Since the AFFIRM study, new and potentially more effective methods of maintaining or controlling sinus rhythm have been developed that might be applied in patients with heart failure, including pulmonary vein ablation (or isolation) (PVI) and atrio-ventricular node ablation (AVN) with bi-ventricular pacing (BiVP).
PABA-CHF was a randomised, un-blinded study comparing PVI and AVN-BiVP (devices with a defibrillator function were used) in patients with NYHA class II/III heart failure and a LVEF <40% despite treatment with a beta-blocker, ACEi/ARB and spironolactone (if NYHA III) and adequate ventricular rate control. Patients were anti-coagulated to achieve an INR of 2-3 even if restored to sinus rhythm. Follow-up was 6 months. The primary endpoints were 6MWT, echocardiographic LVEF and QoL using the MLWHF questionnaire. The study required all three outcomes to be significant at p<0.05 or two at p<0.025 or at least one at p<0.017.
Eighty one patients were randomised and outcome reported on 39 assigned to PVI and 38 to AVN-BiVP. The mean age was 60 years, 95% were men, 73% had CAD, mean LVEF was 28%, left atrial diameter 48 mm, 6MWT about 270 m and about 55% of patients had paroxysmal AF. MLWHF scores were improved in the PVI group but not in the AVN-BiVP group. (However, scores appeared to have been calculated wrongly in the presentation as they were reported as 88 which would imply NYHA class IV heart failure). PVI alone restored sinus rhythm at 6 months in 72% of patients; and in combination with anti-arrhythmic drugs this was increased to >90%.
The reported outcome greatly favoured PVI, suggesting either that it is very effective or that the un-blinded nature of the study had given great bias to PVI. Benefit was particularly marked in those with chronic AF. The lack of improvement in LV function and 6MWT (Table 4) with BiV pacing is very different from that reported in other studies [22,23]. Some degree of LV dyssynchrony would be expected in this population. Nonetheless, this study shows the feasibility and technical success of PVI in this population in skilled hands. Maybe the best approach for many will be PVI with CRT (or CRT-D).
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At least two and potentially all three of the primary endpoints may have been heavily influenced by knowledge of treatment received and this is a major limitation to this study. It would be very difficult to blind both patient and investigator for this study. Accordingly, more robust endpoints will be needed for definitive studies.
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6. N-terminal proBNP improves the management of patients with suspected acute decompensated heart failure: primary results of the Canadian multicentre study (IMPROVE-CHF) |
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TopAbstract1. Occluded artery trial...2. Study of ascending...3. First randomized placebo...4. The alternans before...5. Randomized controlled trial...6. N-terminal proBNP improves...7. Percutaneous mitral...References |
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Presented by Gordon Moe, from Toronto, Canada.
Natriuretic peptides are the best prognostic marker in heart failure [23], one of the best epidemiological markers [24] and potentially a useful aid to diagnosis [25-27]. The purpose of this study was to assess the value of NT-proBNP (Roche) in assisting the diagnosis and management of patients presenting with acute breathlessness and suspected HF to the emergency departments of seven Canadian hospitals between December 2004 and February 2006 (15 months). The study was randomised and double-blind. The primary outcome was calculated cost of care over the first 60 days.
534 patients were screened; of these 33 were excluded leaving 254 randomised to usual care and 247 to the NT-proBNP strategy, which included measurements at baseline and 72 h. The mean age was 71 years and 52% were men. There was a prior history of heart failure or ventricular dysfunction (37%), myocardial infarction (32%), stroke (16%), diabetes (27%) or chronic lung disease (36%) in many patients. Presentation included acute breathlessness in 55%, lung crepitations in 48% and raised JVP in 26%. Median NT-proBNP was 1299 pg/ml (95% CI 213-4204 pg/ml).
Receiver operator curve analysis suggested an AUC for clinical diagnosis of 0.834, for NT-proBNP of 0.855 and for the combination 0.904. Since, clinical judgement at the time might bias subsequent objective assessment these data should be treated cautiously. NT-proBNP was a powerful predictor of prognosis. The NT-proBNP guided strategy reduced costs slightly, probably mainly by reducing the risk of re-admission, which presumably reflects institution of a better care pathway (Table 5). These data are supported by the results of the PRIDE (9.4% reduction in cost [28]) and BASEL (25% reduction in in-patient costs and 24% reduction in costs at 180 days [29]) studies. Although the IMPROVE-CHF study is substantial, its completeness is doubtful. Each emergency department enrolled only 5 patients per month per centre and only 6% of screened patients were excluded, compared to almost 60 patients per centre per month in the EuroHeart Failure study [30]. Possibly, the centres involved were not serving large communities but it is likely that case pre-selection, reflected in the relatively young age of the patients, was at work. It is possible that NT-proBNP would have proved more useful had it been used less selectively.
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7. Percutaneous mitral annuloplasty |
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Mitral regurgitation is common in patients with heart failure and is linked to poor prognosis. Current surgical methods to replace or repair the mitral valve are associated with high levels of morbidity and mortality. A novel, minimally invasive technique using percutaneous delivery of an implantable mitral annuloplasty device has recently been developed and the feasibility demonstrated in patients [31]. Two further experimental studies to evaluate the feasibility of these devices, which exploit the anatomical proximity of the coronary sinus and the mitral annulus, were presented at the meeting [32,33]. There have been concerns that the coronary sinus may not be appropriately related to the mitral valve annulus to allow successful use of the devices in humans. One study reported on the anatomical relationship between the mitral annulus, the coronary sinus and the circumflex artery, in ten explanted human hearts; information which is essential for further development of this technology [32].
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J. G.F. Cleland, A. P. Coletta, and A. L. Clark Clinical trials update from the American College of Cardiology 2007: ALPHA, EVEREST, FUSION II, VALIDD, PARR-2, REMODEL, SPICE, COURAGE, COACH, REMADHE, pro-BNP for the evaluation of dyspnoea and THIS-diet Eur J Heart Fail, June 1, 2007; 9(6-7): 740 - 745. [Abstract] [Full Text] [PDF]
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