© 2001 European Society of Cardiology
Clinical trials update: Highlights of the Scientific Sessions of Heart Failure 2001, a meeting of the Working Group on Heart Failure of the European Society of Cardiology. CONTAK-CD, CHRISTMAS, OPTIME-CHF
Department of Academic Cardiology, Castle Hill Hospital Cottingham Kingston-upon-Hull, Cottingham HU16 5JQ, UK
* Corresponding author. Tel.: +44-1482-624087; fax: +44-1482-624085. E-mail address: g.m.porter{at}hull.ac.uk (J.G. Cleland).
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Abstract |
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 Top Abstract 1. CONTAK-CD programme (not...2. CHRISTMAS: (Carvedilol...3. OPTIME-CHF: (Outcomes of...References |
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This article continues a series of reports summarising recent research developments pertinent to the topic of heart failure. This is a summary of presentations made at Scientific Sessions of Heart Failure 2001, a meeting of the Working Group on Heart Failure of the European Society of Cardiology. Clinical studies of particular interest to people caring for patients with heart failure include CONTAK-CD, CHRISTMAS and further updates on OPTIME-CHF. A brief review of the current status of cardiac resynchronisation therapy is included.
Key Words: Heart failure • Cardiology • CONTAK
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1. CONTAK-CD programme (not an acronym but the name of the device) |
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TopAbstract1. CONTAK-CD programme (not...2. CHRISTMAS: (Carvedilol...3. OPTIME-CHF: (Outcomes of...References |
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The CONTAK-CD trial evolved from a study called VENTAK-CHF, the design of which has already been published [1]. The VENTAK-CHF device was designed to provide an implantable defibrillator and cardiac resynchronisation but required a thoracotomy. The CONTAK-CD device provided similar therapies but could be delivered transvenously from a subcutaneously implanted device. The overall objective of VENTAK CHF/CONTAK CD programme was to determine if bi-ventricular pacing could reduce short-term morbidity and mortality in patients with heart failure. Secondary outcomes included the effects on symptoms and exercise capacity. Importantly, patients were randomly allocated to resynchronisation therapy and follow-up was double-blind. All patients had an indication for an implantable defibrillator and therefore this aspect of the device was activated in all patients.
The inclusion criteria for CONTAK CD were NYHA II–IV on contemporary drug therapy, left ventricular ejection fraction <35%, QRS duration >120 ms (a marker for ventricular dyssynchrony), normal sinus node function, an indication for an implantable cardiac defibrillator (ICD) (including the criteria used in the MADIT trial [2]) and ability to give informed consent. Patients were excluded if they had an indication for right ventricular pacing or chronic atrial arrhythmias or if they had a life expectancy <6 months.
The primary end-point of the study was a composite of all-cause mortality, hospitalisation for heart failure, worsening heart failure requiring intervention or appropriate ICD discharge. The study was powered to observe a 25% reduction in this composite endpoint.
Overall, 501 patients received the cardiac resynchronisation system, 490 of whom were randomised into the study, making it the largest randomised controlled trial of cardiac resynchronisation reported so far. Two hundred and fifteen patients received a system as part of the VENTAK CHF study, which had a cross-over design with 3-month treatment periods and 286 patients received a system as part of the CONTAK CD study which had a parallel-group design with 6-month treatment periods. Overall implant success rate was 87%, rising to >90% with experience.
The mean age of the patients was 66 years and 83% were male. The NYHA class was II in 33%, III in 58% and IV in 9%. Left ventricular ejection fraction was 21%, 57% had left bundle branch block, 13% right bundle branch block and 30% had had an intra-ventricular conduction defect and the mean QRS duration was 158 ms. Sixty-nine percent of the patients had ischaemic heart disease. Pharmacological therapy at baseline included diuretics (87%), digoxin (68%), ACE inhibitors or angiotensin receptor blockers (88%) and beta-blockers (47%). Beta-blocker use rose during the course of the study to reach 61% by the end of follow-up. No differences in therapy were reported between intervention and control.
Overall, the primary endpoint was reduced by 21%, which failed to achieve statistical significance. This was partly due to a lower than predicted event rate. The investigators had predicted a 15% mortality, which would have been one of the highest 6-month mortality rates observed in a trial of heart failure, similar to rates observed in the RALES [3] and worse than the placebo or active arms of COPERNICUS [4] but the mortality was only 5%. The proportion of patients with worsening heart failure was predicted to be 30% but was ‘only’ 21%. Appropriate ICD discharges were expected in 20% but occurred in only 13%. Thus, although the morbidity and mortality over an average of 4.5 months was large, with at least a quarter of patients experiencing a major adverse event, event rates were substantially lower than predicted. Resynchronisation therapy was associated with important trends to benefit including a 23% reduction in mortality, a 13% reduction in hospitalisation for heart failure, a 26% reduction in worsening heart failure events and a 9% reduction in appropriate ICD discharge.
Cardiac resynchronisation was associated with a significant reduction in echocardiographic left ventricular dimensions (4–5 mm, P<0.001), a control-group subtracted increase in peak oxygen of 1 ml kg–1 min–1 and improved NYHA class (33% of control group were in NYHA class I/II vs. 80% of patients on cardiac resynchronisation by the end of the study). Trends for improved quality of life and corridor walk distance were not significant.
CONTAK CD reinforces data from other randomised trials, suggesting that cardiac resynchronisation improves patients symptoms and exercise capacity over periods of 3–6 months. However, there is a paucity of evidence that cardiac resynchronisation can reduce the risk of recurrent hospitalisation and mortality (Table 1). Although MIRACLE [5] and CONTAK CD were conducted double-blind, it is difficult to guarantee blinding in a device study. Accordingly, before cardiac resynchronisation can be widely endorsed as a therapy for heart failure and ventricular dyssynchrony, the results of long-term outcome studies such as CARE-HF and COMPANION are required [6].
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CONTAK CD included many patients with NYHA II heart failure and patients with less marked QRS prolongation (other studies have had entry criteria ranging from 130 to 200 ms). Had such patients been followed long-term it might have indicated whether cardiac resynchronisation was a useful prophylactic therapy for patients with mild heart failure and/or ventricular dyssynchrony, given that heart failure tends to worsen and QRS duration to increase over time.
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2. CHRISTMAS: (Carvedilol Hibernation Reversible ISchaemia Trial; MArker of Success) |
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TopAbstract1. CONTAK-CD programme (not...2. CHRISTMAS: (Carvedilol...3. OPTIME-CHF: (Outcomes of...References |
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The design and purpose of this trial have been published [11]. CHRISTMAS is designed to investigate how the underlying myocardial substrate affects the response to carvedilol. On average, patients with heart failure due to ischaemic heart disease have less of an increase in left ventricular ejection fraction with a beta-blocker than do patients with dilated cardiomyopathy. This reflects a much more heterogeneous response, with some patients responding like patients with dilated cardiomyopathy and others having a markedly diminished response. This could reflect the underlying myocardial substrate, with myocardial scar being unresponsive but hibernating myocardium responding like patients with dilated cardiomyopathy. According to this hypothesis, dilated cardiomyopathy may fundamentally be a disease of global myocardial ischaemic dysfunction due to microvascular disease [12].
To be included, patients had to have mild to moderate (NYHA I–III), chronic, stable heart failure on treatment with an ACE inhibitor unless contra-indicated or not tolerated. Patients had to have coronary artery disease as evidenced by a previous myocardial infarction, previous revascularisation or coronary arteriography. Patients had to have evidence of left ventricular systolic dysfunction with an echocardiographic wall motion index <1.3 (equivalent to LVEF <40%). Patients were excluded if they had more than mild angina, atrial fibrillation, bradycardia, blood pressure <85 mmHg, asthma, NYHA class IV heart failure, major renal dysfunction or ‘unstable’ diabetes.
Hibernation was assessed by looking for a mismatch between echocardiographic wall motion abnormalities and technetium sestamibi uptake at rest. Reversible ischaemia was assessed by comparing technetium sestamibi injection at peak exercise with the resting injection scan. A nine-segment model was used.
Patients were stratified at baseline for the presence or absence of myocardial hibernation and then randomised to placebo or carvedilol. The primary outcome measure of the randomised trial is based on the change in ejection fraction with carvedilol in patients with and without hibernation.
Baseline results only were presented at this meeting. Four hundred and six patients underwent baseline assessment of hibernating status, of whom 58% had one or more hibernating segments. Three hundred and sixty-eight of these patients also underwent stress testing and 54% had reversible ischaemia. Altogether 79% of patients exhibited either hibernation or ischaemia and 34% exhibited both. On average 2.6 segments were affected or almost 30% of the myocardium.
These data suggest that viable but dysfunctional myocardium is very common in patients with heart failure. However, before investigation for such abnormalities is adopted as a routine for patients with heart failure we must first be sure that the test will influence therapy. It is possible that modern medical therapy is as or more effective than revascularisation for the management of these phenomena. Two large trials, HEART in the UK and STITCH in the US, are currently addressing this issue [13].
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3. OPTIME-CHF: (Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure) |
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TopAbstract1. CONTAK-CD programme (not...2. CHRISTMAS: (Carvedilol...3. OPTIME-CHF: (Outcomes of...References |
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This study has been reported previously in this journal [14]. Precise mortality data were presented that are reported here. OPTIME-CHF was a randomised placebo-controlled trial to assess the effects of a 48-h infusion of milrinone in addition to standard therapy for patients within 48 h of an admission for an acute exacerbation of heart failure. Nine hundred and fifty-one patients were randomised over a 2-year period. Of the patients, 43% were diabetics, 70% were receiving an angiotensin converting enzyme inhibitor, 25% were on a beta-blocker and 34% had atrial fibrillation.
There was no significant difference between the two groups in length of hospital stay during the index admission, subsequent readmissions and days in hospital over the following 60 days. Subjective clinical assessment scores were also no different. There was a significant increase in the incidence of sustained hypotension in the Milrinone group, which accounted for all of the increased adverse event rates for the active therapy. There were trends to an excess mortality in in-hospital (2.3 vs. 3.8%, ns) and 60-day mortality (8.9 vs. 10.3%, ns) with milrinone.
These data suggest that treatment with phosphodiesterase inhibitors, like beta-agonists, should not be part of the routine for the management of patients with heart failure. Levosimendan, a new type of calcium sensistiser, may be the agent of choice in this setting as controlled trials against placebo and dobutamine have suggested that it can reduce mortality and days in hospital [15,16].
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