© 2007 European Society of Cardiology
Clinical trials update from Heart Rhythm 2007 and Heart Failure 2007: CARISMA, PREPARE, DAVID II, SAVE-PACE, PROTECT and AREA-IN-CHF
a Department of Cardiology, University of Hull, Castle Hill Hospital Cottingham, Kingston-upon-Hull, HU16 5JQ, UK
b Leeds General Infirmary Great George Street, Leeds, LS1 3EX, 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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This article provides information and a commentary on trials relevant to the pathophysiology, prevention and treatment of heart failure, presented at Heart Rhythm 2007 organised by the Heart Rhythm Society which was held in Denver, USA and Heart Failure 2007 organised by the Heart Failure Association of the European Society of Cardiology which was held in Hamburg, Germany. Unpublished reports should be considered as preliminary data, as analyses may change in the final publication.
The CARISMA study suggests that non-invasive screening tests may help to identify post-MI patients who may benefit from ICD therapy. Data from the PREPARE study show that more conservative ICD programming can reduce morbidity at the cost of an increased risk of arrhythmic syncope. DAVID II indicates that atrial pacing may be a safe alternative to ventricular back-up pacing in patients with left ventricular dysfunction and standard indications for an ICD. The incidence of persistent atrial fibrillation in patients with sinus node disease in SAVE-PACE was reduced by dual chamber minimal ventricular pacing compared to conventional dual chamber pacing. The pilot phase of the PROTECT studies confirmed 30 mg as the dose of the selective A1 adenosine receptor antagonist KW-3902 to be used in pivotal studies. AREA-IN-CHF failed to show a beneficial effect of canrenone on LV volumes compared to placebo however some beneficial effects on secondary clinical endpoints were observed.
Key Words: Randomised controlled trials • Heart failure
Received July 2, 2007; Revised July 4, 2007; Accepted July 4, 2007
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1. Cardiac arrhythmias and risk stratification in patients with low ejection fraction after acute myocardial infarction (CARISMA) |
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Presented by Poul Erik Bloch Thomsen from Copenhagen, Denmark and Heikki Huikuri from Oulu, Finland.
The DEFINITE study [1] showed that implantation of an ICD within 40 days of a myocardial infarction reduced sudden death but not all-cause mortality. Longer-term studies, such as MADIT-II [2], showed that late implantation of an ICD in patients with an LVEF <30% reduced mortality, but the absolute magnitude of benefit was not large. Better early stratification of the risk of malignant arrhythmias and sudden death may improve the effective application of defibrillators.
The aim of the CARISMA study was to measure the incidence of cardiac arrhythmias occurring in patients with an acute myocardial infarction (MI) and with a left ventricular ejection fraction 
40%, using an implantable loop recorder (ILR). The study was also designed to assess the predictive value of electrophysiological and other non-invasive screening tests performed six weeks post-MI, for life threatening tachyarrhythmias.
Of 5869 patients screened, 312 were eligible to participate and 297 underwent successful ILR implantation. The mean age of patients was 65 years and 77% were male. At 6-weeks post-MI, all patients had a 12-lead ECG, a signal averaged electrocardiogram (SAECG), an exercise test with measurement of T-wave alternans, 24-hour ambulatory ECG monitoring and an electrophysiological (EP) study.
During a mean follow-up of 1.9 years, 183 patients (62%) had one or more arrhythmias recorded by the ILR; of these, 89% were reported to be asymptomatic. Atrial fibrillation was the most common rhythm disturbance, occurring in 32% of patients.
The primary endpoint, which was a composite of sudden cardiac death of arrhythmic origin, resuscitated arrhythmic death and spontaneous, symptomatic, sustained ventricular tachycardia, occurred in 25 patients (8.7%) over the 2 year follow-up. QRS duration of more than 120 ms on signal averaged ECG, several of the heart rate variability indices (including SDNN and VLF) on ambulatory monitoring and the EP study (inducibility of VT/VF) predicted the primary endpoint. A subsequent evaluation to determine the optimal combination found that the ratio of QRS duration on signal averaged ECG to SDNN may be the most useful predictor of the primary endpoint, suggesting that this measure might help to select patients most likely to benefit from ICD therapy.
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2. Aggressively programmed implantable defibrillator detection and therapy reduces shocks compared to physician tailored programming in primary prevention patients (PREPARE) |
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Presented by Bruce Wilkoff from Cleveland, Ohio, USA.
Implantable cardiac defibrillators (ICDs) improve survival in patients with an LVEF <35% [3] but the benefit is not large and the morbidity from both inappropriate (ie in the absence of a ventricular arrhythmia) or unnecessary (ie for a ventricular arrhythmia that would have self-terminated) shocks is considerable [4], which is of particular concern when considering lower-risk patients for a primary prevention defibrillator. The aim of the PREPARE trial was to evaluate different programming methods to reduce the incidence of inappropriate or unnecessary shocks in primary prevention patients implanted with an ICD.
Seven hundred patients with a primary prevention indication for an ICD (with or without cardiac resynchronisation therapy) were recruited in 38 centres and followed-up for one year. A historical control cohort, which comprised 691 patients from the MIRACLE-ICD and EMPIRIC studies, was used as a comparator.
In the study cohort, ICDs were set to detect rhythms with a rate of more than 188 bpm for at least 30-40 ventricular beats, compared to a more conventional 16-18 beats. In addition, anti-tachycardia pacing was used before delivering a high-output first shock.
Patients in the PREPARE cohort were older (67 vs. 65 years), had a higher ejection fraction (27.6% vs. 24.7%) and a greater prevalence of ischaemic cardiomyopathy (70% vs. 57%) compared to the control group, for which analyses were adjusted.
The primary endpoint (a morbidity index comprising the total burden of shocks), was reduced in the PREPARE cohort compared to control (0.18 vs. 0.69 events per patient-year, p<0.0001). The time to first shock, time to first appropriate shock and time to first inappropriate shock were all delayed in the PREPARE cohort, compared to control. There were 9 episodes of arrhythmic syncope in 8 patients in the PREPARE cohort, which were not associated with adverse outcome. Mortality was similar in the two cohorts. These data show that more conservative ICD programming can reduce morbidity at a cost of an increased risk of arrhythmic syncope.
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3. Dual chamber and VVI implantable defibrillator trial (DAVID II) |
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Presented by Bruce Wilkoff from Cleveland, USA.
Results of the first DAVID study [5] showed an increased risk of worsening heart failure and a trend to excess mortality in patients with standard indications for ICD therapy and an ejection fraction 40% assigned to dual chamber rate responsive pacing at 70 bpm (DDDR-70) compared to ventricular back-up pacing at 40 bpm (VVI-40). This may have been due to the effects of right ventricular stimulation or higher heart rate [6]. In light of these findings, it has been suggested that atrial pacing may be a better strategy to manage bradycardia in this patient population.
The DAVID II study was therefore designed to compare the effects of atrial pacing and right ventricular back-up pacing in patients with left ventricular dysfunction who need an ICD, but who do not have disordered atrio-ventricular conduction. Six hundred patients were randomised to either atrial pacing at 70 bpm (AAI-70) or standby right ventricular pacing at 40 bpm (VVI-40). All patients were maintained on optimal heart failure medication and were followed-up for 24 months. There were no differences in baseline characteristics between the treatment groups; the mean age was 63 years, 85% of patients were men and the mean LVEF was 27%. The primary endpoint was the incidence of death or heart failure hospitalisation. Over a mean follow-up of 28 months, there was no reported difference in the incidence of the primary endpoint between the treatment groups. There was no difference in the incidence of atrial fibrillation or syncope, and no differences between treatments were observed in any patient subgroup.
It was concluded that atrial based pacing is not substantially worse and may be equivalent to ventricular back-up pacing. Atrial pacing may be a safe alternative to ventricular back-up pacing, but offers no clear advantages or disadvantages. Either strategy appears preferable to DDDR-70. A major potential flaw in the study design was the failure to appreciate that pacing rate as well as chamber paced may influence outcome. Perhaps back-up atrial pacing at 40 bpm would be best of all.
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4. Search AV extension and managed ventricular pacing for promoting atrioventricular conduction (SAVE PACe) trial |
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Presented by Michael Sweeney from Boston, USA.
Conventional dual chamber pacing has been shown to reduce the risk of atrial fibrillation compared with single chamber ventricular pacing in patients with AV node disease; however, the frequency of right ventricular paced beats has been reported to increase the risk of atrial fibrillation and heart failure in patients receiving a right ventricular pacemaker for sinus node disease. The SAVE PACE study was designed to evaluate whether dual chamber pacing incorporating a strategy to minimise right ventricular stimulation could reduce the risk of persistent atrial fibrillation compared to conventional dual chamber pacing in patients with sinus node disease.
One thousand and sixty five patients with symptomatic bradycardia due to sinus node disease were randomised to either dual chamber minimal ventricular pacing (n=530) or conventional dual chamber pacing (n=535). Only the patients were blinded to the identity of the treatment. The primary endpoint was persistent atrial fibrillation.
The mean age was 72 years and 50% of patients were women. The SAVE-PACE study was terminated prematurely for benefit following a planned interim analysis. The incidence of persistent atrial fibrillation was reduced by the ventricular pacing minimisation strategy (HR 0.60, CI 0.41-0.88, p=0.004). Mortality and stroke rates were similar with each strategy but patients without persistent AF had fewer HF hospitalisations (3.2% vs. 7.3%, p=0.03). This may reflect a reduction in the burden of iatrogenic ventricular dyssynchrony by minimising ventricular pacing.
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5. Effects of the selective A1 adenosine receptor antagonist KW-3902 in the treatment of patients with acute heart failure, congestion and renal impairment (PROTECT) |
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Presented by Marco Metra from Bresica Italy and Gad Cotter from Durham, North Carolina, USA.
Renal dysfunction commonly complicates and may cause worsening heart failure, and is associated with poor prognosis [7,8]. Treatment for worsening heart failure may exacerbate renal dysfunction. KW-3902 is an adenosine A1 receptor antagonist, which exerts its effect by inhibiting sodium reabsorption in the proximal tubule, enhancing natriuresis induced by conventional diuretics, and by blocking adenosine mediated constriction of the afferent glomerular arteriole, preserving glomerular filtration rate [9].
The PROTECT I and II studies are identical randomised, double-blind, placebo controlled trials designed to evaluate the effects of intravenous KW3902 in patients hospitalised with acute heart failure. Two trials are being conducted in order to show that the observed result can be replicated. A pilot phase was devised to determine the most effective dose of KW3902, followed by a pivotal programme in which 1200 patients will receive treatment with the chosen dose of KW3902 or placebo.
In the pilot phase, 304 patients with acute decompensated heart failure requiring intravenous diuretic therapy were randomised to treatment with either KW-3902 (10 mg, 20 mg or 30 mg per day) or placebo, administered intravenously for up to 3 days.
Outcome data from 276 patients at 14 days were presented. The mean age of patients was 70 years. The primary endpoint was a categorical outcome defined as treatment success, unchanged or treatment failure. No p values were quoted in the presentation of results. There were more reports of treatment success for KW-3902 in the 30 mg treatment group and fewer reports of treatment failure, compared to placebo. This was principally due to an improvement in patient-reported dyspnoea at days 2 and 3. There was also a suggestion of a renal protective effect in the active treatment group. There was no evidence of a greater incidence of adverse events in the active treatment groups.
Based on these data, the pivotal phases of the PROTECT I and II studies are currently ongoing to further evaluate the 30 mg dose of KW-3902.
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6. Anti-remodelling effect of aldosterone receptor blockade with canrenone in mild chronic heart failure (AREA-IN-CHF) |
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Presented by Alessandro Boccanelli from Rome, Italy.
Aldosterone antagonists such as spironolactone and eplerenone reduce morbidity and mortality in patients with heart failure [10,11]. These beneficial effects may be due to improvements in electrolyte balance or volume status, a reduction in arrhythmias or due to effects on cardiac and vascular remodelling. Recently reported studies have shown conflicting effects of aldosterone antagonists on LV remodelling. One study reported a beneficial effect on LV remodelling following the addition of spironolactone to an angiotensin receptor blocker in patients with chronic heart failure [12]; however, the REMODEL trial failed to show a beneficial effect of eplerenone on ventricular remodelling in patients with mild to moderate heart failure [13]. Another recent study suggested that spironolactone reduced arrhythmias substantially [14]. Canrenone is the principal unconjugated metabolite of spironolactone and has a long half life of around 16.5 h.
AREA-IN-CHF was a randomised, double-blind, placebo controlled study to investigate the effect of aldosterone blockade with canrenone (25-50 mg per day) on left ventricular remodelling in patients with NYHA class II heart failure and LVEF 45%, receiving optimal pharmacological therapy. The primary endpoint was change in left ventricular diastolic volume assessed by echocardiography. Echocardiograms were performed at baseline, 6 and 12 months and BNP was measured at baseline and 6 months. Of the 505 patients randomised, 465 patients had data verified and 382 patients (188 canrenone and 194 placebo) had echo data available for evaluation of the primary endpoint. The mean age of patients was 62 years and more than 50% of patients had ischaemic heart disease. Heart failure therapy included beta blockers in approximately 80% of patients and ACEI or ARBs in 96%.
The percentage of patients who permanently discontinued study therapy was greater for canrenone than placebo (11.7% vs. 6.5%, p=0.052), due mainly to increased potassium levels.
End diastolic volume decreased by around 18% in both treatment groups over the duration of the study, but there was no difference between the treatment groups. A number of secondary endpoints, including ejection fraction, LV mass and NYHA class improved more with canrenone than with placebo. In addition, there was a greater reduction in BNP levels at 6 months in the canrenone group compared to placebo (p<0.0001). There was no difference in cardiovascular mortality between the treatments; however, fewer patients on canrenone reached the combined endpoint of cardiac death or hospitalisation for cardiac causes (Table 1).
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The EMPHASIS-HF study, which is currently ongoing, will further investigate the effects of aldosterone blockade, on cardiovascular mortality and heart failure hospitalisation in patients with NYHA class II heart failure.
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