© 2008 European Society of Cardiology
Clinical trials update from the American Heart Association 2007: CORONA, RethinQ, MASCOT, AF-CHF, HART, MASTER, POISE and stem cell therapy
Department of Cardiology, University of Hull, Castle Hill Hospital Cottingham, Kingston-upon-Hull, HU16 5JQ, UK
* Corresponding author. Tel.: +44 1482 624086; fax: +44 1482 624085. E-mail address: a.p.coletta{at}hull.ac.uk (A.P. Coletta).
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Abstract |
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 Top Abstract 1. CORONA: controlled...2. RethinQ: resynchronisation...3. MASCOT: management of...4. AF-CHF: atrial fibrillation...5. HART: heart failure...6. MASTER: microvolt T-wave...7. POISE: perioperative ischemic...8. Stem cell therapyConflict of interest statementReferences |
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This article provides information and a commentary on trials relevant to the pathophysiology, prevention and treatment of heart failure, presented at the American Heart Association 2007. These should be considered as preliminary data, as analyses may change in the final publication.
Rosuvastatin did not reduce mortality compared to placebo in patients with heart failure and left ventricular systolic dysfunction due to ischaemic heart disease in the CORONA study. Results of RethinQ provide equivocal evidence of benefit from CRT in patients with heart failure, echocardiographic dyssynchrony and QRS interval <130 ms. In the MASCOT study, the addition of atrial overdrive pacing did not reduce the incidence of permanent atrial fibrillation in patients receiving CRT. The AF-CHF study failed to show a benefit of rhythm control over rate control in patients with heart failure and atrial fibrillation. Self-management skills training and education had no benefit on the combined outcome of death or heart failure hospitalisation, compared with education alone in heart failure patients in the HART study. Microvolt T-wave alternans testing failed to identify patients at increased risk of life-threatening ventricular arrhythmias in the MASTER study. POISE suggests that initiating metoprolol therapy shortly prior to non-cardiac surgery increases the risk of hypotension, stroke and death, despite reducing the risk of myocardial infarction. Three trials of stem cell therapy in post-MI patients gave conflicting results.
Key Words: Randomised controlled trials • Heart failure
Received December 6, 2007; Accepted December 12, 2007
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1. CORONA: controlled rosuvastatin multinational trial in heart failure |
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TopAbstract1. CORONA: controlled...2. RethinQ: resynchronisation...3. MASCOT: management of...4. AF-CHF: atrial fibrillation...5. HART: heart failure...6. MASTER: microvolt T-wave...7. POISE: perioperative ischemic...8. Stem cell therapyConflict of interest statementReferences |
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Presented by Ake Hjalmarson from Goteborg, Sweden
Statins reduce morbidity and mortality in younger patients with coronary artery disease without heart failure, including a reduction in new-onset heart failure [1-4]. However, patients with heart failure are generally older and were excluded from previous statin trials by design. Observational data provide conflicting evidence of harm and benefit with the use of statins in patients with heart failure [5-8]. Patients with heart failure and higher cholesterol have a better survival, which has been attributed to protection against endotoxin-induced cytokine activation [9]. Supplements of co-enzyme Q10, an endogenous anti-oxidant that may be reduced by statins, have been beneficial in some trials of heart failure. On the other hand, statins could reduce the progression of atherosclerosis to occlusive events, thereby reducing the risk of stroke or myocardial infarction as suggested in a series of observational studies [5]. Reduction in such events should reduce mortality. This might be mediated predominantly by reducing sudden vascular death. CORONA is the first adequately powered randomised placebo-controlled trial specifically designed to evaluate the effects of statins in patients with heart failure [10,11].
Five thousand and eleven patients aged 
60 years, with systolic heart failure, evidence of ischaemic heart disease and an ejection fraction 
40%, were randomised to treatment with either rosuvastatin (10 mg) or placebo. The median age of patients was 73 years and the oldest was 103 years of age! All patients were on optimal heart failure therapy and were followed for an average of 2.7 years. Adherence to assigned therapy appeared good with 12.1% of patients assigned to placebo and 9.6% assigned to rosuvastatin discontinued for adverse events (p=0.004). Few patients from either group subsequently received open-label statin. The safety profile in terms of side effects on muscle metabolism or renal function was excellent.
As expected, LDL-cholesterol levels were reduced by about 40% on rosuvastatin compared to placebo. However, there was no difference in the incidence of the primary composite endpoint (cardiovascular death, non-fatal MI and non-fatal stroke) between the treatment groups. This result was driven by a lack of effect on mortality. Patients assigned to rosuvastatin had fewer non-fatal vascular events and cardiovascular or heart failure hospitalisations (Table 1).
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CORONA provides no compelling reason to use a statin in older patients with heart failure. No heterogeneity in effect was observed in patients above and below 77 years (the upper tercile), although trends favoured younger patients, which deserves further exploration. Patients with an LDL cholesterol greater than 3.12 mmol/L had a lower mortality than those with lower levels and did not obtain any greater benefit with rosuvastatin. Why cholesterol [9] and other traditional cardiovascular risk markers [7] are operating in this paradoxical fashion is uncertain but, whatever the reason, these paradoxes argue for caution in extrapolating information from other populations to heart failure and of course the reason for the paradox, when discovered, could be a target for therapy. Nor was heterogeneity in effect observed in any other pre-specified analysis, but, patients with body mass index
28 and in the lower two terciles of NT-proBNP (<277.6 pmol/l or 2349 pg/ml; median value in CARE-HF for reference was about 1800 pg/ml [12]), suggesting that patients with less severe heart failure may have benefited. The Heart Protection Study (HPS) did not record whether patients had heart failure at baseline but did measure NT-proBNP using a non-commercial assay in 20,536 patients [13]. In about 50% of patients, values were >1000 pg/ml suggesting the presence of major cardiac or renal dysfunction or both, a likely high prevalence of heart failure and a high risk of events. Amongst this patient group in HPS, 923 patients (18.4%) assigned to simvastatin died compared to 1030 (20.6%) assigned to placebo (p=0.229 on a chi-square test) over 5 years. Mortality rates were lower than observed in CORONA (29.1% with median follow-up of 2.7 years), perhaps reflecting an additional adverse prognostic factor, such as a clinical diagnosis of heart failure in CORONA, or differences in the assay for NT-proBNP used. The HPS suggested that the relative effects of simvastatin in reducing coronary events declined dramatically from >40% in those with NT-proBNP values <386 pg/ml to <15% in those with values >2618 pg/ml, which was accompanied by a similar trend for mortality. Interestingly, the absolute reduction was similar across all NT-proBNP groups, suggesting that some factor resistant to the effects of statins was contributing to a large proportion of events in patients with increased NT-proBNP levels but that processes that could be modified by statins were still at play. Use of simvastatin was also associated with a reduction in heart failure events and a reduction in NT-proBNP in the long-term, suggesting a reduction in the progression to or of heart failure. This was not explained solely by fewer clinically overt vascular events.
Do the results of CORONA reflect a class-effect? The answer is probably yes. The PROSPER study investigating the effects of pravastatin in patients with, or at risk of, vascular disease and aged >70 years observed no effect on mortality [14]. The 4D study of atorvastatin in high-risk patients with diabetes on haemodialysis also failed to show an effect on death or vascular events [15]. Considerable uncertainty exists about the benefits of statins in older people, those at very high risk of cardiovascular events and for how long statins should be continued [16]. For the moment, CORONA provides useful support for the withdrawal of statins in older patients and those in the terminal stages of the disease. For younger patients with less advanced disease for whom prognosis is the key therapeutic goal, statins are safe and may be effective. As rosuvastatin also reduces the rate of hospitalisation and days in hospital it is most likely cost-effective. More detailed analyses are awaited.
The results of another large, randomised, placebo-controlled trial, GISSI-HF, to evaluate the effects of n-3 polyunsaturated fatty acids and rosuvastatin in patients with symptomatic heart failure, may shed further light on the issue [17]. The confidence intervals around the CORONA result include the target for the therapeutic effect in GISSI-HF.
However, perhaps the most important legacy of CORONA will be to change the current fashion of not having an upper age limit to studies of the effects of CV therapy on prognosis. Medicine does not offer immortality. Younger people with few comorbidities should not be denied effective therapy just because treatment does not work in elderly multi-morbid patients. Equally, treatment should not be inflicted on elderly multi-morbid patients just because it works in younger people. The goals of treatment may differ, with a greater emphasis on prognosis in younger patients with reasonable quality of life and lower co-morbidity while improving well-being may be the main goal of treating older, sicker and multi-morbid patients. It is time to take stock. Perhaps trials of new treatments designed to improve prognosis should initially exclude elderly patients (with an upper chronological age limit of 75-85 years unless someone can come up with a way of measuring biological age). Alternatively, older patients could be included but the primary endpoint could be survival until age 80 years. This does not exclude older people from trials but does emphasise that immortality is not on offer. Adhering to political correctness by not having an age limit should not override the need to serve patients well.
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2. RethinQ: resynchronisation therapy in normal QRS trial |
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TopAbstract1. CORONA: controlled...2. RethinQ: resynchronisation...3. MASCOT: management of...4. AF-CHF: atrial fibrillation...5. HART: heart failure...6. MASTER: microvolt T-wave...7. POISE: perioperative ischemic...8. Stem cell therapyConflict of interest statementReferences |
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Presented by John Beshai from Chicago, Illinois, USA
The current indications for CRT therapy in patients with heart failure include a prolonged QRS interval (
120 ms) on the surface ECG, LVEF 35% and recent or persistent NYHA class III-IV symptoms. Many patients with shorter QRS duration have intraventricular dyssynchrony as assessed by echocardiography and so might be thought to benefit from CRT. The RethinQ trial [18] investigated whether CRT was effective in improving exercise capacity and symptoms in patients with a standard indication for ICD and CRT, except that their QRS duration was <130 ms. They did, however, have evidence of dyssynchrony by echo. All 172 patients had a CRT-D device implanted. Patients were randomly assigned to CRT-on or CRT-off with double-blind follow-up. By 6 months, exercise capacity (peak VO2 was the primary endpoint), quality of life scores and ventricular function (assessed by echocardiography) were similar in both groups, but symptoms had improved to a greater extent in those with CRT-on. Few patients died or had worsening heart failure in either group.
Despite the small size of the study, the investigators nonetheless did a subgroup analysis of those patients with QRS 120 ms (i.e. who already fulfilled all indications for CRT-D) and those with lesser values. Symptoms improved in both CRT-on groups. Exercise capacity increased significantly only in those with QRS >120 ms although the confidence intervals around the effect are wide and it is not clear that a real difference between subgroups exists. In summary, the RethinQ study enrolled too few patients and failed to follow them long enough to properly investigate the effects of CRT on morbidity. The most important endpoint, the patients' symptoms, (although not the primary one) suggested benefit with CRT. Overall, this result is encouraging. We may hope for better designed and resourced trials. On the other hand, this study provides no evidence that echocardiographic dyssynchrony is a useful method to select patients for CRT [19].
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3. MASCOT: management of atrial fibrillation in AF-HF co-morbidity therapy study |
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TopAbstract1. CORONA: controlled...2. RethinQ: resynchronisation...3. MASCOT: management of...4. AF-CHF: atrial fibrillation...5. HART: heart failure...6. MASTER: microvolt T-wave...7. POISE: perioperative ischemic...8. Stem cell therapyConflict of interest statementReferences |
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Presented by Luigi Padeletti from Florence, Italy
Patients with heart failure who also have atrial fibrillation (AF), have a worse prognosis [20]. The CARE-HF study showed that the AF burden was unchanged by CRT with 15% of patients developing a clinically overt episode during a median follow-up of 29.6 months — an annual event rate of about 5% [21]. The aim of the MASCOT study was to evaluate whether the addition of atrial overdrive pacing (AOP) to CRT (bi-ventricular pacing) could reduce the incidence of permanent AF in patients with heart failure. This AOP algorithm has been shown to reduce symptomatic AF in patients with sick sinus syndrome [22].
MASCOT was a single blind, multi-centre study in which 394 patients with NYHA class III-IV heart failure, LVEF 35% and a QRS 130 ms, were randomised to either "AOP ON" or "AOP OFF" following CRT implantation. Patients with permanent AF were excluded. The primary endpoint was the incidence of permanent AF at 12 and 24 months.
The mean age of patients was 68 years and 79% were male. The incidence of permanent AF was only 3.3% at 12 months, which is lower than the investigators had anticipated. The incidence of permanent AF was similar between the two treatment groups (n=6 for "AOP OFF" and n=7 for "AOP ON"). Results at 2 years are awaited. In addition, it was suggested that the selection of permanent AF as the primary endpoint may have affected the ability to show a difference between treatments. If paroxysmal and persistent AF, which may have similar clinical and prognostic implications, had been included the outcome of the study might have been different.
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4. AF-CHF: atrial fibrillation and congestive heart failure trial |
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TopAbstract1. CORONA: controlled...2. RethinQ: resynchronisation...3. MASCOT: management of...4. AF-CHF: atrial fibrillation...5. HART: heart failure...6. MASTER: microvolt T-wave...7. POISE: perioperative ischemic...8. Stem cell therapyConflict of interest statementReferences |
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Presented by Denis Roy from Montreal, Canada
Atrial fibrillation (AF) is common in patients with heart failure and is associated with an adverse outcome [20,21]. Previous studies have suggested that there is little benefit from attempting to cardiovert patients with AF to sinus rhythm [23-25]. This could reflect the fact that in many patients, AF is well tolerated, associated with little excess risk and no worsening in symptoms. In contrast, patients with AF and HF, might have more to gain from a return to sinus rhythm, but attaining and maintaining sinus rhythm (SR) may be more difficult than in patients without HF. The aim of the AF-CHF study was to determine whether restoring and maintaining sinus rhythm in patients with heart failure and AF reduced cardiovascular mortality compared to a strategy of ventricular rate control.
One thousand three hundred and seventy six patients with NYHA class II-IV heart failure and a LVEF35% and a history of significant AF were randomly assigned to either a rate or rhythm control strategy in addition to optimal medical therapy. In the rate control group, patients were treated with beta-blockers and digoxin, with pacemaker therapy and AV node ablation where necessary to control ventricular rate. Rhythm control was achieved using electrical cardioversion combined with antiarrhythmic drug therapy, which was amiodarone in 82% of patients. All patients also received optimal heart failure therapy and anticoagulation, and were followed-up for a minimum of two years.
The mean age of patients was 67 years, 82% were male and 31% of patients were in NYHA class III-IV at baseline. The mean LVEF at baseline was 27%. Over the mean follow-up period of 37 months, 79% of patients in the rhythm control group were maintained in SR, a remarkably good effort! Of the patients in the rate control group, 10% were cardioverted, mainly to try and control worsening symptoms.
There was no difference in cardiovascular deaths, the primary endpoint, between the rate control and rhythm control groups (25.2% vs. 26.7%, p=0.59). Similarly there was no difference between the treatments for the predefined secondary endpoints (Table 2). Thus a routine strategy of rhythm control cannot be advocated for patients with heart failure and atrial fibrillation. However, the greater use of amiodarone in the rhythm control strategy might have negated the potential benefits of this strategy [26,27]. A rate control strategy that could avoid the use of amiodarone might achieve better results. Randomised controlled trials of pulmonary vein ablation for AF are underway [28].
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5. HART: heart failure adherence and retention trial |
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TopAbstract1. CORONA: controlled...2. RethinQ: resynchronisation...3. MASCOT: management of...4. AF-CHF: atrial fibrillation...5. HART: heart failure...6. MASTER: microvolt T-wave...7. POISE: perioperative ischemic...8. Stem cell therapyConflict of interest statementReferences |
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Presented by Lynda Powell from Chicago, Illinois, USA
There is little evidence that patient-education improves outcomes in HF [29]. Few behavioural trials in patients with heart failure have shown a sustained benefit in terms of morbidity, mortality and costs. The aim of the HART study was to evaluate the impact of self-management skills training on outcome in patients with mild to moderate heart failure.
Nine hundred and two patients with systolic or diastolic heart failure, who expressed a willingness to comply with suggested behavioural changes, were randomised to either [1] self-management skills training plus education or [2] education alone. There was no control group without intervention. Self-management training was delivered by 18 small-group counselling sessions over one year. Outcome was evaluated for up to three years. The co-primary endpoints were death or heart failure hospitalisation and death or all-cause hospitalisation.
The mean age of patients was 64 years and 47% were women. There was no effect of either intervention on drug adherence levels over the study period; with the reportedly high baseline levels being maintained. There was an improvement in depression in each intervention group, but no difference between groups. There was no difference between interventions for time to death or heart failure hospitalisation or for death or all-cause hospitalisation. Subgroup analysis suggested that there might be benefit from self-management skills training in sicker patients on lower incomes and in those with poor functional capacity. This hypothesis needs to be tested in a new study. Another important issue is that education and training content needs to be defined more precisely in these patients [30].
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6. MASTER: microvolt T-wave alternans testing for risk stratification of post-MI patients |
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TopAbstract1. CORONA: controlled...2. RethinQ: resynchronisation...3. MASCOT: management of...4. AF-CHF: atrial fibrillation...5. HART: heart failure...6. MASTER: microvolt T-wave...7. POISE: perioperative ischemic...8. Stem cell therapyConflict of interest statementReferences |
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Presented by Theodore Chow from Cincinnati, Ohio, USA
Implantable cardiac defibrillators (ICDs) reduce the incidence of arrhythmic death in patients with chronic heart failure and a reduced ejection fraction; however, the annual absolute reduction in all-cause mortality is only about 2% [28]. A test to improve patient selection for ICD therapy could improve cost effectiveness and help to reduce morbidity from inappropriate shocks and other device related effects. Microvolt T-Wave Alternans (MTWA) is a marker of electrophysiological abnormalities that predispose to ventricular arrhythmias. Previous studies have suggested that absence of T-wave alternans, detected non-invasively during an exercise test, may help to identify patients at low risk of arrhythmias, whilst an abnormal test may identify patients at increased risk of spontaneous ventricular arrhythmias who may benefit from ICD therapy [28,29].
The aim of the MASTER study was to determine whether an abnormal T-wave alternans test result is associated with subsequent life-threatening ventricular tachyarrhythmias in patients for whom an ICD was indicated on MADIT II criteria. In this open, non-randomised study, 575 patients with a prior MI and a LVEF 30% underwent MTWA testing prior to ICD implantation. All patients had follow-up evaluations performed every 6 months for a minimum of 2 years. MTWA testing was repeated annually, using the spectral method, and results were interpreted at a core laboratory. All test results classified as "indeterminate" were repeated unless considered medically inappropriate. Tests classified as "positive or "indeterminate" were combined as "non-negative" for the primary outcome analysis. The primary endpoint was a life-threatening left ventricular tachyarrhythmic event, which was defined as a composite of arrhythmic death or an appropriate ICD discharge, although there is a wealth of evidence that only about half of ‘appropriate’ shocks are also ‘necessary’ shocks — many arrhythmias would self terminate if not interrupted by a shock and may therefore be termed ‘appropriate but unnecessary’.
The mean age of patients was 65 years, mean ejection fraction at baseline was 24% and most patients had a prior history of heart failure. Indeterminate tests were reported in 107 patients, of whom 69 were retested with a definitive result obtained in 59%. Baseline MTWA test was negative in 214 patients and "non-negative" in 361 patients. A primary endpoint event occurred in 22 MTWA negative patients (10%) and 48 "non-negative" patients (13%), with no difference between the groups (HR 1.26 CI 0.76-2.09, p=0.37). Subgroup analysis suggested that patients with a QRS interval <120 ms were at low risk regardless of MTWA status. Total mortality was lower in patients with a negative MTWA test (6% vs. 13%, p=0.02) but testing using NT-proBNP would probably have been much more effective at risk stratification.
The results of the MASTER study cast further doubt on the use of MTWA testing for the selection of patients for an ICD. It may be time to abandon the approach in favour of other more promising ones; such as in the CARISMA trial [31].
The recent REFINE study [32] reported the utility of serial assessment of arrhythmia risk in patients after myocardial infarction. It showed that a combination of tests (TWA, baroreflex sensitivity and LVEF <50%) identified 10% of the population with a 32% risk of cardiac death or resuscitated cardiac arrest (10 of the 29 events that occurred) over a 4 year period. On the other hand, the probability of no event was 90% without information from the tests which rose to only 94% with the tests. These tests might therefore be used to identify patients who might benefit from an ICD. However, the study predicted only 10 events in a population that initially comprised 5699 patients. Most of the high-risk patients had been excluded on clinical grounds alone. An annual event rate of only 2% is not representative of routine clinical practice.
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7. POISE: perioperative ischemic evaluation trial |
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TopAbstract1. CORONA: controlled...2. RethinQ: resynchronisation...3. MASCOT: management of...4. AF-CHF: atrial fibrillation...5. HART: heart failure...6. MASTER: microvolt T-wave...7. POISE: perioperative ischemic...8. Stem cell therapyConflict of interest statementReferences |
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Presented by Philip Devereaux from the University of Hamilton, Ontario, Canada
About 100 million patients undergo non-cardiac surgery each year and of these approximately 1 million have a major cardiovascular event in the perioperative period. Non-cardiac surgery increases catecholamine levels which can have adverse cardiac effects. Theoretically, since beta-blockers attenuate these effects, perioperative administration of beta-blocker therapy might reduce the risk of major cardiovascular complications in the immediate post-operative period. However, results from previous small scale studies have been inconclusive.
Patients undergoing non-cardiac surgery who were aged 45 years or more and who had a history of coronary heart disease, peripheral vascular disease, stroke, heart failure hospitalisation or major vascular surgery were eligible to participate in the POISE study. Patients were randomised to receive either controlled release metoprolol (n=4174) or placebo (n=4177), administered as 100 mg 2-4 h prior to surgery and 0-6 h post-operatively and then 200 mg/day for 30 days. The primary endpoint was a 30 day composite of cardiovascular death, non-fatal myocardial infarction or non-fatal cardiac arrest.
The mean age of the 8351 patients was 69 years and 36% were female. There was a reduction in the incidence of the primary composite outcome with metoprolol, principally due to a reduction in the incidence of non-fatal myocardial infarction (Table 3). However, in stark contrast to the beneficial effect on the primary endpoint, the incidence of stroke and total mortality was higher in the metoprolol group.
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The study is by far the largest of its kind and demonstrates that metoprolol should not be initiated routinely just prior to surgery in patients undergoing non-cardiac surgery. It is uncertain whether these results should be extended to non-selective agents. The study does not address what to do in patients receiving long-term beta-blockers. The authors believe that treatment should usually be continued perioperatively until evidence is presented to the contrary. The recent ACC/AHA Guidelines on perioperative cardiovascular evaluation and care for non-cardiac surgery cite evidence from two small studies, but large scale randomised controlled trials are lacking [33]. Further, clinical trials to address these issues are appropriate. This is a very curious but definitive result. It is rare for a study to achieve its primary endpoint but definitively show that the ‘winning’ strategy should not be implemented.
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8. Stem cell therapy |
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TopAbstract1. CORONA: controlled...2. RethinQ: resynchronisation...3. MASCOT: management of...4. AF-CHF: atrial fibrillation...5. HART: heart failure...6. MASTER: microvolt T-wave...7. POISE: perioperative ischemic...8. Stem cell therapyConflict of interest statementReferences |
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Myocardial regeneration via implantation of stem cells could play an important role in the treatment of myocardial infarction and heart failure. Three studies to evaluate the use of stem cells in post-MI patients were reported at the meeting, one study used skeletal myoblasts and two studies used bone marrow derived cells (BMCs).
8.1. CAUSMIC: first United States randomised controlled trial utilising 3D catheter based delivery of autologous skeletal myoblasts for ischaemic cardiomyopathy
Presented by Nabil Dib, from California, USA
Previous studies have demonstrated the safety and feasibility of transplantation of skeletal myoblasts into infarcted myocardium; however, studies on clinical efficacy have reported mixed results [28,34].
CAUSMIC was a phase I open study, in which 23 patients with a previous myocardial infarction, LVEF 40% and in NYHA class II-IV, were randomised to either transplantation of autologous skeletal myoblasts administered at four dose levels or control (no transplant). All patients also received optimal medical therapy. Stem cells (myoblasts) were isolated from a biopsy of the patient's thigh muscle. Cells were grown in-vitro and then transplanted percutaneously using three dimensional electromechanical mapping.
The primary endpoint was the safety and feasibility of skeletal myoblast transplantation. Efficacy, in terms of quality of life, myocardial viability and heart function was measured as a secondary endpoint.
All transplantation procedures were successful. There were no deaths, myocardial infarctions or cerebrovascular events in either of the study groups. One patient in each group was hospitalised due to heart failure. Improvements in myocardial viability assessed by electromechanical mapping, NYHA class and quality of life, and indications of an improvement in heart function assessed by echocardiography were reported for patients in the transplanted group. In light of these positive findings, a larger scale phase II study in 165 patients is planned.
8.2. FINCELL: efficacy and safety of intracoronary injection of mononuclear bone marrow cells after thrombolytic therapy of acute myocardial infarction
Presented by Heikki Huikuri from Oulu, Finland
Recent studies have suggested that intracoronary injection of bone marrow derived cells may improve left ventricular ejection fraction in patients with acute ST elevation myocardial infarction treated initially with percutaneous coronary intervention. However, the effect of bone marrow cells on the risk of arrhythmias and restenosis in these patients is not known. In addition the efficacy and safety of treatment in patients undergoing thrombolytic therapy remains to be established.
FINCELL, a double-blind, placebo-controlled study, was conducted in two centres in Finland. Seventy eight patients were randomised to treatment with either bone marrow (iliac crest biopsy) derived cells (BMCs) or placebo, administered by intracoronary injection within two to six days of an acute myocardial infarction.
The mean age of patients was 60 years, and most were men. At six months follow-up, there was an increase in ejection fraction in the BMC group compared with placebo (Table 4). No adverse effects on arrhythmogenesis, restenosis or excess in other major adverse events were reported.
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8.3. Intramuscular or intracoronary administration of autologous bone marrow cells in scarred myocardium
Presented by Keng-Leong Ang from Leicester UK
Although several studies have investigated the administration of BMCs in the acute phase following myocardial ischaemia [35-37], few randomised trials exist in the chronic phase. This study was designed to evaluate the effect on systolic function of transplanting autologous BMCs into the myocardial scar.
Sixty three patients undergoing elective CABG surgery, with chronic irreversible myocardial scar, were randomised to receive either intracoronary (IC) or intramuscular (IM) injection of autologous (per-operative iliac crest biopsy) BMCs or no injection (control). Cardiac function was assessed by dobutamine stress echocardiography and MRI before and six months after surgery. The primary endpoint was improvement in systolic function in the scar tissue assessed from wall motion and systolic fractional thickening.
There were similar improvements in wall motion assessment at rest and at low dose dobutamine stress echocardiography in both BMC treatment groups and control. There was no improvement in systolic fractional thickening in any of the three groups. There were no complications directly related to BMC administration.
Although these data show that administration of BMCs was safe, there was no evidence of an improvement in systolic function.
The first large randomised multi-centre trial infusing BMC in the post-infarction phase is now well under way. We are only a few years away from the first study that is large enough to begin to determine the clinical effects and safety of stem cell therapy for ischaemic LV dysfunction.
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Conflict of interest statement |
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TopAbstract1. CORONA: controlled...2. RethinQ: resynchronisation...3. MASCOT: management of...4. AF-CHF: atrial fibrillation...5. HART: heart failure...6. MASTER: microvolt T-wave...7. POISE: perioperative ischemic...8. Stem cell therapyConflict of interest statementReferences |
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JGF Cleland is a member of the CORONA Steering Committee and has received research support from Medtronic.
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References |
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TopAbstract1. CORONA: controlled...2. RethinQ: resynchronisation...3. MASCOT: management of...4. AF-CHF: atrial fibrillation...5. HART: heart failure...6. MASTER: microvolt T-wave...7. POISE: perioperative ischemic...8. Stem cell therapyConflict of interest statementReferences |
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- Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet (1994) 344:1383–1389.[CrossRef][Web of Science][Medline]
- Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. The long term intervention with pravastatin in ischemic heart disease (LIPID) study group. N Eng J Med (1998) 339:1349–1357.
[Abstract/Free Full Text] - Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo controlled trial. Lancet (2002) 360:7–22.[CrossRef][Web of Science][Medline]
- Khush K.K., Waters D.D., Bittner V., et al. Effect of high-dose atorvastatin on hospitalizations for heart failure. Subgroup analysis of the treating to new targets (TNT) study. Circulation (2007) 115:576–583.
[Abstract/Free Full Text] - Loh P.H., Windram J.D., Tin L., et al. The effects of initiation or continuation of statin therapy on cholesterol level and all-cause mortality after the diagnosis of left ventricular systolic dysfunction. Am Heart J (2007) 153:537–544.[CrossRef][Web of Science][Medline]
- Kjekshus J., Pedersen T.R., Olsson A.G., et al. The effects of simvastatin on the incidence of heart failure in patients with coronary heart disease. J Card Fail (1997) 3:249–254.[CrossRef][Medline]
- Cleland J.G., Loh H., Windram J., Goode K., Clark A.L. Threats, opportunities and statins in the modern management of heart failure. Eur Heart J (2006) 27:641–643.
[Free Full Text] - Cleland J.G.F., Abdellah A.T., Khaleva O., et al. Clinical trials update from the European Society of Cardiology Congress 2007: 3CPO, ALOFT, SEARCH-MI, PROSPECT and Statins for Heart Failure. Eur J Heart Fail (2007) 9:1070–1073.
[Abstract/Free Full Text] - Rauchhaus M., Clark A.L., Doehner W., et al. The relationship between cholesterol and survival in patients with chronic heart failure. J Am Coll Cardiol (2003) 42:1933–1944.
[Abstract/Free Full Text] - Kjekshus J., Dunselman P., Blideskog M., et al. A statin in the treatment of heart failure? Controlled rosuvastatin multinational study in heart failure (CORONA): study design and baseline characteristics. Eur J Heart Fail (2005) 7:1059–1069.
[Abstract/Free Full Text] - Kjekshus J., Apetrei E., Barrios V., et al. Rosuvastatin in older patients with systolic heart failure. N Eng J Med (2007) 357:2248–2261.
[Abstract/Free Full Text] - Cleland J.G., Daubert J.G., Erdmann E., et al. The effect of cardiac resynchronisation therapy on morbidity and mortality in heart failure. N Eng J Med (2005) 352:1539–1549.
[Abstract/Free Full Text] - Heart Protection Study Collaborative Group. N-terminal pro-B-Type natriuretic peptide, vascular disease risk, and cholesterol reduction among 20,536 patients in the MRC/BHF Heart Protection Study. J Am Coll Cardiol (2007) 49:311–319.
[Abstract/Free Full Text] - Shepherd J., Blauw G.J., Murphy M.B., et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet (2002) 360:1192–1197.
- Wanner C., Krane V., Marz W., et al. Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N Eng J Med (2005) 353:238–248.
[Abstract/Free Full Text] - Cleland J.G. Is aspirin the "weakest link" in cardiovascular prophylaxis? The surprising lack of evidence supporting the use of aspirin for cardiovascular disease. Prog Cardiovasc Dis (2002) 44:275–292.[CrossRef][Web of Science][Medline]
- Tavazzi L., Tognoni G., Franzosi M.G., et al. Rationale and design of the GISSI heart failure trial: a large trial to assess the effects of n-3 polyunsaturated fatty acids and rosuvastatin in symptomatic congestive heart failure. Eur J Heart Fail (2004) 6:635–641.
[Abstract/Free Full Text] - Beshai J.F., Grimm R.A., Nagueh S.F., et al. Cardiac-resynchronisation therapy in heart failure with narrow QRS complexes. N Eng J Med (2007) 357:2461–2471.
[Abstract/Free Full Text] - Cleland J.G.F., Abdellah A.T., Khaleva O., et al. Clinical trials update from the European Society of Cardiology Congress 2007: 3CPO, ALOFT, PROSPECT, and statins in heart failure. Eur J Heart Fail (2007) 9:1070–1073.
[Abstract/Free Full Text] - Swedberg K., Olsson L.G., Charlesworth A., et al. Prognostic relevance of atrial fibrillation in patients with chronic heart failure on long-term treatment with beta-blockers: results from COMET. Eur Heart J (2005) 26:1303–1308.
[Abstract/Free Full Text] - Hoppe U.C., Casares J.M., Eiskjaer H., et al. Effect of cardiac resynchronization on the incidence of atrial fibrillation in patients with severe heart failure. Circulation (2006) 114:18–25.
[Abstract/Free Full Text] - Carlson M.D., Ip J., Messenger J., et al. A new pacemaker algorithm for the treatment of atrial fibrillation: results of the Atrial Dynamic Overdrive Pacing Trial (ADOPT). J Am Coll Cardiol (2003) 42:627–633.
[Abstract/Free Full Text] - Wyse D.G., Waldo A.L., DiMarco J.P., et al. A comparison of rate control versus rhythm control in patients with atrial fibrillation. N Eng J Med (2002) 347:1825–1833.
[Abstract/Free Full Text] - VanGelder I.C., Hagens V.E., Bosker H.A., et al. A comparison of rate control and rhythm control in patients with recurrent persistent atrial fibrillation. N Eng J Med (2002) 347:1834–1840.
[Abstract/Free Full Text] - Coletta A., Thackray S., Nikitin N., Cleland J.G.F. Clinical trials update: highlights of the scientific sessions of the American College of Cardiology 2002: LIFE, DANAMI 2, MADIT-2, MIRACLE-ICD, OVERTURE, OCTAVE, ENABLE 1 & 2, CHRISTMAS, AFFIRM, RACE, WIZARD, AZACS, REMATCH, BNP trial, and HARDBALL. Eur J Heart Fail (2002) 4:381–388.
[Abstract/Free Full Text] - Torp-Pedersen C., Metra M., Spark P., et al. The safety of amiodarone in patients with heart failure. J Card Fail (2007) 13:340–345.[CrossRef][Medline]
- Bardy G.H., Lee K.L., Mark D.B., et al. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Eng J Med (2005) 352:225–237.
[Abstract/Free Full Text] - Cleland J.G.F., Coletta A.P., Abdellah A.T., et al. Clinical trials update from the American Heart Association 2006: OAT, SALT 1 and 2, MAGIC, PABA-CHF, IMPROVE-CHF, and percutaneous mitral annuloplasty. Eur J Heart Fail (2007) 9:92–97.
[Abstract/Free Full Text] - Cleland J.G.F., Coletta A.P., Clark A.L. 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 (2007) 9:740–745.
[Abstract/Free Full Text] - Eldh A.C., Ehnfors M., Ekman I. The meaning of patient participation for patients and nurses at a nurse led clinic for chronic heart failure. Eur J Cardiovasc Nurs (2006) 5:45–53.[CrossRef][Medline]
- Cleland J.G.F., Coletta A.P., Abdellah A.T., et al. Clinical trials update from Heart Rhythm 2007 and Heart Failure 2007: CARISMA, PREPARE, DAVID II, SAVE-PACE, PROTECT and AREA-IN-CHF. Eur J Heart Fail (2007) 9:850–853.
[Abstract/Free Full Text] - Exner D.V., Kavanagh K.M., Slawnytch M.P., et al. Non-invasive risk assessment early after a myocardial infarction. The REFINE study. J Am Coll Cardiol (2007) 50:2275–2284.
[Abstract/Free Full Text] - Fleisher L.A., Beckman J.A., Brown K.A., et al. ACC/AHA 2007 Guidelines on perioperative cardiovascular evaluation and care for non-cardiac surgery; executive summary. Circulation (2007) 116:1971–1996.
[Free Full Text] - Dib N., Michler R.E., Pagani F.D., et al. Safety and feasibility of autologous skeletal myoblast transplantation in patients with ischemic cardiomyopathy: four year follow-up. Circulation (2005) 112:1748–1755.
[Abstract/Free Full Text] - Cleland J.G.F., Freemantle N., Coletta A.P., Clark A.L. Clinical trials update from the American Heart Association: REPAIR-AMI, ASTAMI, JELIS, MEGA, REVIVE II, SURVIVE and PROACTIVE. Eur J Heart Fail (2006) 8:105–110.
[Abstract/Free Full Text] - Lunde K., Solheim S., Aakhus S., et al. Intracoronary injection of mononuclear bone marrow cells in acute myocardial infarction. N Eng J Med (2006) 355:1199–1209.
[Abstract/Free Full Text] - Meyer G.P., Wlooert K.C., Lotz J., et al. Intracoronary bone marrow cell transfer after myocardial infarction: eighteen months follow-up data from the randomized, controlled BOOST trial. Circulation (2006) 113:1287–1294.
[Abstract/Free Full Text]
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