© 2008 European Society of Cardiology
Clinical trials update from the American College of Cardiology 2008: Carisma, Trends, meta-analysis of Cox-2 studies, Hat, on-Target, Hyvet, Accomplish, Momentum, Protect, Horizon-hf and Reverse
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
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Abstract |
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 Top Abstract 1. CARISMA: Cardiac Arrhythmias...2. TRENDS: is there...3. Meta-analysis of trials...4. HAT: Home Automatic...5. Studies related to...6. MOMENTUM: Multicentre trial...7. PROTECT: a Placebo-controlled...8. HORIZON-HF: Haemodynamic,...9. REVERSE: REsynchronisation...Conflict of InterestReferences |
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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 College of Cardiology. Unpublished reports should be considered as preliminary data, as analyses may change in the final publication.
CARISMA investigated the use of implantable loop recorders for detecting life-threatening arrhythmias in patients with LVSD after MI and found that brady- and ventricular tachy-arrhythmias predicted an adverse prognosis. The TRENDS study showed that the burden of atrial fibrillation detected by pacemakers or defibrillators predicted the risk of embolic events but not with sufficient precision to justify changes in anti-thrombotic management. A meta-analysis of six trials reported an increased cardiovascular risk associated with celecoxib, particularly for heart failure, which was related to dose and baseline cardiovascular risk. The HAT study failed to show a benefit of providing post-MI patients with a home defibrillator. MOMENTUM, a study of a device designed to augment aortic blood flow, was stopped early due to increased bleeding risk. Results from PROTECT support the use of rolofylline 30 mg/day in acute heart failure, a definitive study is now underway. Istaroxime, an agent that appears to have both inotropic and lusitropic effects, improved haemodynamics when added to standard therapy in patients stabilised after admission with heart failure in HORIZON-HF. The REVERSE study suggested that CRT improves ventricular function and reduces morbidity even in patients with few or no symptoms of heart failure and may delay or prevent worsening heart failure.
Key Words: Randomised controlled trials • Heart failure
Received May 6, 2008; Accepted May 7, 2008
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1. CARISMA: Cardiac Arrhythmias and RIsk Stratification after Myocardial infArction |
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TopAbstract1. CARISMA: Cardiac Arrhythmias...2. TRENDS: is there...3. Meta-analysis of trials...4. HAT: Home Automatic...5. Studies related to...6. MOMENTUM: Multicentre trial...7. PROTECT: a Placebo-controlled...8. HORIZON-HF: Haemodynamic,...9. REVERSE: REsynchronisation...Conflict of InterestReferences |
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Presented by Poul Erik Bloch Thomsen from Gentofte University Hospital, Copenhagen, Denmark
The mechanisms underlying sudden death remain elusive, probably reflecting its heterogeneous aetiology [1]. Some patients will die suddenly primarily due to occlusion of a cerebral, coronary or pulmonary artery. Others will die of a ruptured aortic aneurysm or cerebral haemorrhage. Many patients will die suddenly either from a primary cardiac arrhythmia or an arrhythmia provoked by myocardial ischaemia or neurological damage. Conventional wisdom suggests that ventricular tachycardia and fibrillation are the most common lethal arrhythmias but emergency services know that pulseless electrical activity is also common. Each potential cause of sudden death might be predicted by a different set of investigations, and be managed best by different interventions. Cardiologists are particularly interested in identifying asymptomatic arrhythmias that may portend a lethal one and most assume this will be a ventricular tachyarrhythmia for which an implantable cardioverter defibrillator (ICD) may be indicated. The problem so far has been the short-term nature of arrhythmia monitoring and the great day-to-day variability in arrhythmia density. One potential solution is the use of implantable loop recorders (ILRs) which can be used to record arrhythmias reliably over a period of months or years.
The CARISMA trial was designed to assess the value of ILRs in detecting life-threatening tachyarrhythmias, in patients within 3-21 days of an acute myocardial infarction (AMI) who had an echocardiographic LVEF
40%. Of 5869 patients screened, 1393 had an LVEF40%; of these 297 patients agreed to participate and had an ILR implanted. Of patients enrolled, 77% were men, the mean age was 65 years, LVEF was 31%, QRS was >120 ms in 15%, 9% were in AF and 11% had heart failure. Two thirds had received primary PCI or thrombolysis and 90% or more were discharged on aspirin, beta blockers and either an ACE inhibitor or ARB. During a mean follow-up of 1.9 years, 46% of patients developed a significant brady- or tachy-arrhythmia of which 86% were asymptomatic. Atrial fibrillation with a rapid ventricular response was the commonest arrhythmia (duration not specified but presumably lasting 
30 s). On univariate analysis, brady — rather than tachy-arrhythmias were more closely associated with death (Table 1). The poor relationship between VT and VF and prognosis may reflect the relative rarity of these events and the fact that many patients died of causes other than a primary lethal arrhythmia.
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This very interesting study should be interpreted cautiously. Observation and association cannot be equated with causation and therapeutic benefit, which require randomised controlled trials for proof. However, the results help interpret some existing trials, such as DINAMIT [2], which failed to show a benefit from ICD implantation within 40 days of AMI possibly because, as CARISMA shows, sustained VT and VF are uncommon phenomena. CARISMA suggests that some of the benefits of ICDs might be due to the prevention of lethal brady-arrhythmias, although back-up pacing by ICDs in DINAMIT did not improve overall outcome. Other studies suggest that the risk associated with brady-arrhythmias are under-appreciated in patients with heart failure [3,4] and perhaps some of the benefits of ICD and CRT in reducing sudden death reflect their ability to prevent lethal bradycardia [5,6]. Should ILRs be used routinely to detect serious arrhythmias in patients with post-infarction LV dysfunction? The answer is probably not, for two reasons. Firstly, serious arrhythmias that would have resulted in a major change in therapy were rare. This might be resolved by a better screening test, such as NT-proBNP, prior to ILR implantation. Secondly, we need to be sure that treating the observed abnormality is beneficial for patients. The next step should surely be a randomised study of ILR implantation, with ILR-guided therapy or not in high-risk patients selected by a better screening test than LVEF.
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2. TRENDS: is there a critical value of daily atrial tachyarrhythmia burden from device diagnostics that raises stroke risk? |
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TopAbstract1. CARISMA: Cardiac Arrhythmias...2. TRENDS: is there...3. Meta-analysis of trials...4. HAT: Home Automatic...5. Studies related to...6. MOMENTUM: Multicentre trial...7. PROTECT: a Placebo-controlled...8. HORIZON-HF: Haemodynamic,...9. REVERSE: REsynchronisation...Conflict of InterestReferences |
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Presented by Taya Glotzer from Hackensack University Medical Centre, New Jersey, USA
This retrospective study used diagnostic algorithms of dual-chamber pacemakers (50%), implantable defibrillators (31%) or cardiac resynchronisation (19%) devices to investigate the relationship between the burden of paroxysmal atrial fibrillation (AF) and the risk of a thrombo-embolic events (TEE) in 2486 patients with high rates of morbidity including heart failure (60%), age >65 years (mean 71 years), diabetes (32%), hypertension (76%) or previous neurological event (13%). The defined threshold rate for atrial fibrillation was >175 bpm, which seems extraordinarily high given that many patients must have been on beta blockers, lasting at least 20 s. The burden of AF was quantified using a 30-day moving average over a mean duration of 1.4 years. Anti-thrombotic treatment was warfarin in 21% of cases and aspirin in 62%. 76% of patients had no AF by the above criteria. In patients who had an episode of AF, the median duration of the longest episode in any 30-day period was 5.5 h. The annual rate of TEE was 1.2%, which is in line with expectations in a well-managed population with heart failure, and included 20 strokes, 17 transient ischaemic attacks (TIAs) and 3 systemic emboli. Patients without episodes of AF had an annual rate of events of 1.1% (0.5% if TIA excluded), patients with a low AF burden 1.1% (1.1% if TIA excluded) and those with a high AF burden 2.4% (1.8% if TIA excluded). These differences were of borderline statistical significance.
TRENDS is important because it quantifies the burden of atrial fibrillation with a very rapid ventricular response in a population with, or at high risk of, heart failure. The results do not suggest that there is great value in changing patients' management on the basis of these findings. Interesting questions include:
did the burden of AF predict patients likely to have worsening heart failure or cardiac function, creating a rationale for suppressing AF by drugs or ablation?
was an interaction with anti-thrombotic therapy observed? Removing patients on warfarin from the analysis might have identified patients with a higher rate of TEE.
can clinical profiles (eg:— heart failure and poor left ventricular function) be developed that identify higher risk populations that might benefit from such diagnostic algorithms?
are the criteria developed to express AF burden correct, in particular the heart rate criterion for patients with heart failure on beta blockers?
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3. Meta-analysis of trials of the cyclooxygenase-2 inhibitor celecoxib |
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TopAbstract1. CARISMA: Cardiac Arrhythmias...2. TRENDS: is there...3. Meta-analysis of trials...4. HAT: Home Automatic...5. Studies related to...6. MOMENTUM: Multicentre trial...7. PROTECT: a Placebo-controlled...8. HORIZON-HF: Haemodynamic,...9. REVERSE: REsynchronisation...Conflict of InterestReferences |
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Presented by Scott Solomon from Brigham and Women's Hospital, Boston, Massachusetts, USA
These data have been published in full in Circulation [7]. Briefly, the meta-analysis of six placebo controlled trials reported that the use of celecoxib, the most widely used cycloxygenase-2 (COX-2) inhibitor, was associated with an increased risk of cardiovascular events including death, myocardial infarction, stroke and heart failure. The effects were dose related, with 400 mg once per day associated with a modest increase, 200 mg bd an approximate doubling and 400 mg bd a tripling of risk. The effects were more or less confined to patients at medium or high cardiovascular risk. Of course, all NSAIDs inhibit COX-2, including low-dose aspirin, and an increased cardiovascular risk with chronic use may be common to all agents of this class [8-10].
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4. HAT: Home Automatic external defibrillator Trial |
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TopAbstract1. CARISMA: Cardiac Arrhythmias...2. TRENDS: is there...3. Meta-analysis of trials...4. HAT: Home Automatic...5. Studies related to...6. MOMENTUM: Multicentre trial...7. PROTECT: a Placebo-controlled...8. HORIZON-HF: Haemodynamic,...9. REVERSE: REsynchronisation...Conflict of InterestReferences |
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Presented by Gust Bardy from the Seattle Institute for Cardiac Research, Seattle, Washington, USA
This study has been reported in full [11]. Briefly, providing patients who have had a myocardial infarction and who were educated on how to deal with an out of hospital cardiac arrest with, in addition, a home defibrillator, did not increase survival from out of hospital cardiac arrest or reduce mortality. The HAT study enrolled over 7000 patients, 60% from North America and 40% from the UK, Australia and New Zealand. The median age of patients was 62 years; making this a relatively young and low risk population, who were about 2 years after their index myocardial infarction. About one third of patients had heart failure, one quarter were on diuretics and one quarter had an LVEF <35%. Less than 5% of patients received an ICD during the study. About 90% of patients received beta blockers, ACE inhibitors or ARBs, statins and aspirin. The mortality was about 2% per year, with only 60% of deaths being cardiac, half of them sudden and mostly unwitnessed but presumed to be due to an arrhythmia, and an additional 8% vascular. Only 0.5% had a resuscitated cardiac arrest (19 patients in the defibrillator group) and fewer than half of these occurred at home (8 patients). Of these patients, only 4 survived to be discharged from hospital. Four people not included in the study were resuscitated while visiting study patients' homes and two survived to discharge. Subgroup analysis did not reveal a benefit in high-risk groups such as patients with LVEF <35% or in those with heart failure. Home defibrillators are not a successful strategy to reduce the risk of sudden death in patients at relatively low risk of events.
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5. Studies related to hypertension |
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TopAbstract1. CARISMA: Cardiac Arrhythmias...2. TRENDS: is there...3. Meta-analysis of trials...4. HAT: Home Automatic...5. Studies related to...6. MOMENTUM: Multicentre trial...7. PROTECT: a Placebo-controlled...8. HORIZON-HF: Haemodynamic,...9. REVERSE: REsynchronisation...Conflict of InterestReferences |
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Three large studies, two already published in full [12,13], relevant to the treatment of hypertension, were reported at the meeting: these were ON-TARGET, HYVET and ACCOMPLISH.
5.1. ON-TARGET: Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial
Presented by Salim Yusuf from McMaster University, Hamilton, Ontario, Canada
The ON-TARGET study investigated the effects of ramipril, telmisartan and their combination in 25,620 patients with vascular disease or diabetes at increased risk of vascular events. Such large studies are by their nature designed to demonstrate that different treatments are the same rather than showing that one treatment is superior to another, since such large studies would inevitably be stopped early if one treatment was superior to another in any way that was clinically relevant. The ON-TARGET study showed that ramipril 10 mg per day was equivalent to telmisartan 80 mg/day in terms of its ability to reduce the composite primary outcome of cardiovascular death, myocardial infarction, stroke or heart failure. These results should not be extrapolated to lower doses, since there is more evidence of a dose-related response to ARBs [14] than ACE inhibitors [15]. The combination was no more effective than either agent alone but caused more side effects. Telmisartan was associated with a lower rate of cough as a side effect. As women are more prone to cough, there is some argument to use an ARB in preference to an ACE inhibitor in women, although this is not a strong argument since treatment may be switched when and if the side-effect appears. However, the approach could have convenience value and the cost-differential is not huge in absolute terms (generic ramipril 10 mg £6.56 per month and telmisartan £14.18 per month in the UK (BNF 2007).
These data need to be placed in the context of other large studies that have investigated the combination of ACE inhibitors and ARBs such as VALIANT (neutral) [16] and CHARM (a benefit) [17]. Perhaps the institution of ACE inhibitors and ARBs simultaneously in lower risk populations, such as patients with hypertension and uncomplicated myocardial infarction, cannot be extrapolated to the sequential use of combination therapy in patients with LVSD who have persistently moderate or severe heart failure despite target doses of ACE inhibitors. In such patients, neurohormonal activation is more pronounced, which might explain the different results. Doubtless the debate on the utility of combining ACE inhibitors and ARBs will continue.
5.2. HYVET: HYpertension in the Very Elderly Trial
Presented by Nigel Beckett from Imperial College, London, UK
The HYVET study was a placebo controlled study to investigate the effects of an indapamide (1.5 mg), administered with or without perindopril, on cardiovascular morbidity and mortality in older people (mean age 84 years; 61% women) with hypertension. Indapamide is a thiazide-like agent that has anti-hypertensive efficacy via both a diuretic effect on the distal tubule and a direct vascular effect. About one third of patients had systolic hypertension only and >70% were treated with both indapamide and perindopril. Mean blood pressure at baseline was 173/91 mm Hg. Enrolled patients had few co-morbidities (only 6% were smokers, 7% were diabetic and mean serum creatinine was only 89 µmol/L). Treatment reduced mean blood pressures by 15/6 mm Hg. By an intention to treat analysis, mortality was reduced by 21%, stroke by 30% and heart failure by 64%. Over four years of follow-up in the control group, the rate of death was 24%, of death due to cardiovascular causes 12%, the rate of stroke 8% and of heart failure 6.5% and hence the greatest absolute benefit of therapy was in delaying the development of heart failure or death. A per-protocol analysis suggested even more striking benefits. Patients in the active treatment group reported fewer adverse events. These data suggest that chronological age should not deter active treatment. However, the results should be extrapolated to older people with multiple co-morbidities with caution, since treatment may be more or may be less effective in such patients.
5.3. ACCOMPLISH: Avoiding Cardiovascular events through COMbination therapy in Patients LIving with Systolic Hypertension
Presented by Kenneth Jamerson from the University of Michigan, Ann Arbor, Michigan, USA
The ACCOMPLISH study investigated the effects of the ACE inhibitor benazepril (20-40 mg/day) combined either with hydrochlorothiazide (12.5-25 mg/day) or amlodipine (5-10 mg/day) in over 11,000 patients with largely inadequately controlled blood pressure on their existing regimen (most patients were on two agents). About 40% of patients were aged >70 years. Each treatment regimen reduced blood pressure by a similar amount to about 130 mm Hg systolic (79% and 82% achieved the target of <140/90 mm Hg or <130/80 mm Hg in patients with diabetes or renal insufficiency). About half of patients were controlled by study medication alone and others by the addition of 1-2 open-label agents. The study was stopped early because of a difference in outcomes favouring amlodipine. Only 95% of the available data had been analysed. There was a 20% reduction in the primary endpoint (CV death, stroke, MI, revascularisation, hospitalisation for unstable angina or resuscitated cardiac arrest) in the amlodipine/benazapril arm compared with the hydrochlorothiazide/benazapril arm (p=0.0002). Cardiovascular death, stroke or MI was also reduced by 20% (p=0.007). These data suggest that ACE inhibitor plus amlodipine is a good anti-hypertensive combination and are consistent with the ASCOT result [18]. This is one of very few studies to suggest that treatments that are similarly effective in reducing blood pressure have different effects on outcome. The final analysis may not be available for some time.
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6. MOMENTUM: Multicentre trial of the Orquis® Medical cancion system for the ENhanced Treatment of CHF Unresponsive to Medical therapy |
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TopAbstract1. CARISMA: Cardiac Arrhythmias...2. TRENDS: is there...3. Meta-analysis of trials...4. HAT: Home Automatic...5. Studies related to...6. MOMENTUM: Multicentre trial...7. PROTECT: a Placebo-controlled...8. HORIZON-HF: Haemodynamic,...9. REVERSE: REsynchronisation...Conflict of InterestReferences |
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Presented by Barry Greenberg from the University of California, San Diego, USA
The MOMENTUM study investigated the use of continuous aortic flow augmentation (CAFA) for 4 days using an external pump. CAFA has been shown to increase cardiac index by 15-20% and reduce left ventricular filling pressure in patients with severe heart failure (mean NT-proBNP 7684 pg/ml — median not reported) who had shown an inadequate response to intravenous inotropic agents. The primary outcome was treatment success defined as:
- a minimum of 24 h of treatment
a fall in pulmonary capillary wedge pressure (PCWP) 5 mm Hg after 3 days of therapy
survival and discharge from hospital for at least 10 days without readmission within 35 days of randomisation.
The study was stopped after 168 patients had been enrolled due to an increased bleeding risk, without evidence of clinical benefit, with CAFA. About 35% of patients died within 60 days in each group, which is similar to the REMATCH study [19]. Patients assigned to CAFA tended to have more deterioration in renal function. Haemodynamically, the device improved cardiac index by about 0.2 L/min/m2 (p<0.0001) and reduced PCWP by 2 mm Hg (p=0.074) and systemic vascular resistance by about 100 dyn/s/cm5 (p<0.0002). Further studies are planned in lower risk populations with a lower risk of bleeding.
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7. PROTECT: a Placebo-controlled Randomised study of the selective a1 adenosine receptor antagonist rolofylline for patients hospitalized hospitalised with acute heart failure and volume Overload to assess Treatment Effect on Congestion and renal funcTion |
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TopAbstract1. CARISMA: Cardiac Arrhythmias...2. TRENDS: is there...3. Meta-analysis of trials...4. HAT: Home Automatic...5. Studies related to...6. MOMENTUM: Multicentre trial...7. PROTECT: a Placebo-controlled...8. HORIZON-HF: Haemodynamic,...9. REVERSE: REsynchronisation...Conflict of InterestReferences |
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Presented by Barry Massie from the University of California, San Francisco, California, USA
Stimulation of adenosine A1 receptors causes afferent arteriolar constriction and therefore a decline in renal blood flow and, potentially, a decline in glomerular filtration rate and an increase in proximal renal tubular sodium reabsorption, the site at which >90% of all sodium filtered at the glomerulus is reabsorbed. Preliminary studies of adenosine antagonists have been encouraging [20,21] confirming that they lead to diuresis and improve renal function. An unwanted side potential side effect is that they may lower the seizure threshold; this is a dose-related effect. Identifying that effective doses are safe is clearly an important issue.
PROTECT was a randomised, controlled, dose-ranging study comparing placebo and the selective adenosine A1 receptor antagonist, rolofylline (10 mg. 20 mg and 30 mg), administered intravenously over 4 h on three consecutive days. Three hundred and one patients admitted to hospital with acute decompensation of chronic (at least 14 days) heart failure, requiring intravenous diuretic therapy and with mild to moderate renal impairment (GFR 20-80 ml/min), were enrolled. Patients with systolic BP<95 mm Hg, severe valve stenosis, BNP<250 pg/ml or NT-proBNP <1000 pg/ml or who had had a seizure, stroke or brain surgery within the previous 2 years, and therefore were at high risk of seizures, were excluded. Patients were included regardless of LVEF. Patients with an intermediate risk of seizures were given lorazepam 1 mg each day prior to the infusion. The study was not powered to show statistically significant differences, but was done to provide an impression of the best and safest dose. Treatment success was defined as moderate or marked improvement on days two and three. Failure was worsening of heart failure symptoms, death or readmission within 7 days or worsening renal function (increase in creatinine of >26.5 µmol/L).
The mean age of patients was about 70 years, most were men (even though LVEF was not an inclusion criterion), 70% had IHD, 50% had diabetes, and mean GFR was 50 ml/min. About 70% of patients were treated with an ACEi or ARB, 70% with a beta blocker and 35% with an aldosterone receptor antagonist. Treatment success increased and failure decreased in a dose-related fashion with 30 mg rolofylline per day appearing most effective. Worsening renal function in patients assigned to rolofylline was also reduced in a dose-related manner, with no deterioration in renal function by day 14 in patients assigned to the highest dose. By 60 days, patients who had received the highest dose of rolofylline were less likely to be dead or to have been re-admitted for cardiovascular or renal reasons (Table 2). Data on all-cause hospitalisation or length of stay were not provided. No patient had a seizure. A definitive outcome trial is now underway comparing placebo and 30 mg/day.
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8. HORIZON-HF: Haemodynamic, echocardiographic and neurohormonal effects of istaroxime, a novel intravenous inotropic and lusitropic agent: a randomised controlled trial in patients hospitalised with heart failure |
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TopAbstract1. CARISMA: Cardiac Arrhythmias...2. TRENDS: is there...3. Meta-analysis of trials...4. HAT: Home Automatic...5. Studies related to...6. MOMENTUM: Multicentre trial...7. PROTECT: a Placebo-controlled...8. HORIZON-HF: Haemodynamic,...9. REVERSE: REsynchronisation...Conflict of InterestReferences |
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Presented by Mihai Gheorghiade from Northwestern University, Chicago, Illinois, USA
Istaroxime is an agent that inhibits sodium/potassium ATPase, which is the classical mechanism of digoxin's inotropic effect. Istaroxime is chemically unrelated to digoxin and, unlike digoxin, also inhibits SERCA-2, enhancing relaxation (a lusitropic effect). The principal aim of this haemodynamic study was to investigate the effect on pulmonary capillary wedge pressure (PCWP) of three doses of istaroxime (0.5, 1.0 and 1.5 µg/kg/min) and placebo, given over 6 h. There were about 30 patients per treatment group. Patients with LVEF35%, PCWP>20 mm Hg and a blood pressure of less than 150/90 mm Hg were enrolled. Patients receiving intravenous inotropic or diuretic agents and those with serum digoxin levels >0.5 ng/ml were excluded. All doses of istaroxime reduced PCWP by 4-5 mm Hg, heart rate by 4-8 bpm and QTc by 26-49 ms. The highest dose also reduced right atrial pressure and increased cardiac output and may have improved measures of diastolic function. Two of the 90 patients assigned to istaroxime died. There were no deaths in the placebo group.
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9. REVERSE: REsynchronisation reVErses Remodelling in Systolic left vEntricular dysfunction |
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TopAbstract1. CARISMA: Cardiac Arrhythmias...2. TRENDS: is there...3. Meta-analysis of trials...4. HAT: Home Automatic...5. Studies related to...6. MOMENTUM: Multicentre trial...7. PROTECT: a Placebo-controlled...8. HORIZON-HF: Haemodynamic,...9. REVERSE: REsynchronisation...Conflict of InterestReferences |
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Presented by Cecilia Linde from Karolinska University Hospital, Stockholm, Sweden
Previous studies [22,23] have shown that CRT improves cardiac function and symptoms and reduces morbidity and mortality in patients in sinus rhythm with LVEF35%, NYHA class III/IV symptoms and QRS>120 ms. Some short-term studies have suggested benefits on cardiac function in patients with NYHA class II symptoms [24,25]. A subset analysis of 175 patients from CARE-HF who had improved to NYHA class I/II during the run-in period prior to randomisation in CARE-HF suggested that CRT was beneficial even in patients whose symptoms had resolved [26].
The entry criteria for the REVERSE study were LVEF40%, LVEDD>55 mm, NYHA class I/II symptoms on optimal medical therapy and QRS>120 ms. All patients received best medical therapy and a CRT device. They were then randomised 2:1 to either CRT-on or CRT-off. Patients with or without an indication for ICD could be enrolled. The effects over one year are described in this report but patients enrolled in Europe will be followed for two years. The primary outcome was the proportion of patients who worsened during follow-up, defined as death, cross-over or hospitalisation for worsening heart failure, worse NYHA class or worse patient global assessment.
Of 642 eligible patients, 621 had a successful implant and 610 (262 in Europe) were randomised, 191 to CRT-off and 419 to CRT-on. Of patients assigned to CRT-on, the mean age was 63 years, 56% had ischaemic heart disease, mean QRS duration was 153 ms and LVEF was 27%. Patients in REVERSE were less symptomatic, were less likely to be on diuretics and had much lower rates of hospitalisation for heart failure and of death than in CARE-HF and COMPANION but were rather similar in terms of QRS duration and LVEF (Table 3) and had only slightly smaller LV end-systolic volumes (
100 v 121 ml/m2).
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CRT had a favourable effect on symptoms (54% improved and 30% stable in the CRT-on group versus 40% and 39%, respectively, in the control group) and reduced the rate of hospitalisation for worsening heart failure from about 7% to about 3% (hazard ratio 0.47; p=0.03) but there were only 12 deaths which were distributed similarly between CRT and control groups. This compares with a one year mortality of 12.6% and 9.7% in CARE-HF patients assigned to control or CRT.
LV end-systolic volume was reduced by 17 ml/m2 (BSA) (p<0.0001), and end-diastolic volume by 19 ml/m2 and increased LVEF by about 3% in patients assigned to CRT-on in the REVERSE study, all remarkably similar to the effects of CRT observed in CARE-HF. Baseline Quality of Life score was similar to that of patients in NYHA I/II in the CARE-HF study but improved to a similar extent in each group in REVERSE. The 6-minute walk test improved similarly in each group. 9.5% of patients had LV lead related complications.
REVERSE together with the subgroup analysis of CARE-HF and other smaller studies of CRT [24-26] provides sufficient information to suggest that patients who have recovered from an episode of moderate to severe heart failure but have persistently and substantially reduced LVEF should be considered for CRT in order to prevent relapse and improve long-term outcome. Two large studies comparing ICD with CRT-D [27] are ongoing, these will provide further data within the next few years.
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Conflict of Interest |
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TopAbstract1. CARISMA: Cardiac Arrhythmias...2. TRENDS: is there...3. Meta-analysis of trials...4. HAT: Home Automatic...5. Studies related to...6. MOMENTUM: Multicentre trial...7. PROTECT: a Placebo-controlled...8. HORIZON-HF: Haemodynamic,...9. REVERSE: REsynchronisation...Conflict of InterestReferences |
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Prof JGF Cleland has received research grants from Medtronic, Servier and NovaCardia.
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References |
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TopAbstract1. CARISMA: Cardiac Arrhythmias...2. TRENDS: is there...3. Meta-analysis of trials...4. HAT: Home Automatic...5. Studies related to...6. MOMENTUM: Multicentre trial...7. PROTECT: a Placebo-controlled...8. HORIZON-HF: Haemodynamic,...9. REVERSE: REsynchronisation...Conflict of InterestReferences |
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