European Journal of Heart Failure

European Journal of Heart Failure 1999 1(2):191-196; doi:10.1016/S1388-9842(99)00024-0

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© 1999 European Society of Cardiology

The Carvedilol Hibernation Reversible Ischaemia Trial; Marker of Success (CHRISTMAS)

The CHRISTMAS Study Steering Committee and Investigators, John G.F. Cleland^*, Dudley Pennel, Simon Ray, Gordon Murray, Peter MacFarlane, Allan Cowley, Andrew Coats and Avijit Lahiri

^* Corresponding author. Department of Cardiology University of Hull, Castle Hill Hospital, Kingston-upon-Hull, HU16 5JQ, UK

	Abstract

Top Notes Abstract 1. Introduction 2. Aims 3. Intervention 4. Study design 5. Conclusions References

 
Background: Carvedilol improves left ventricular (LV) function when heart failure is due to LV systolic dysfunction, but the magnitude of the response is heterogeneous among patients with coronary disease, possibly reflecting the presence or volume of hibernating myocardium. Aims: The primary objective of the study is to determine whether the presence of hibernating myocardium predicts the magnitude of improvement in LV ejection fraction in response to carvedilol among patients with heart failure and LV systolic dysfunction due to coronary disease.

Methods: The study is a prospective, randomised, parallel-group, double-blind, multi-centre study comparing carvedilol and placebo over a period of approximately 6 months in the above patient population. The primary end-point is the comparison of the mean change, from baseline to the final visit, in radionuclide-determined LV ejection fraction among patients on placebo with those on carvedilol stratified according to the presence of hibernating myocardium. Hibernating status will be determined by a combination of echocardiographic and myocardial perfusion (technetium-99m sestamibi) imaging.

Results: 255 patients have undergone screening tests of which 207 have been randomised so far. The study intends to randomise 400 patients and the first report of results is expected in 2000.

Conclusions: As far as we are aware this is the first randomised controlled trial to investigate the effects of treatment in patients stratified according to the presence of hibernating myocardium. The study will provide insights into the prevalence of myocardial hibernation, its natural history, and its influence on prognosis as well as the interaction between the presence of hibernating myocardium and the effects of treatment with carvedilol.

Key Words: Heart failure • Hibernating myocardium • Beta-blockers

Accepted April 7, 1999

	1. Introduction

Top Notes Abstract 1. Introduction 2. Aims 3. Intervention 4. Study design 5. Conclusions References

 
One of the most consistent findings in trials of beta-blockers for heart failure due to chronic left ventricular (LV) systolic dysfunction is that LV ejection fraction (EF) rises by 5–10% (absolute percentage points — equating to a 25–50% relative improvement in LV systolic function) [1–4]. This is associated with a reduction in cardiac volumes, providing powerful evidence for an effect of beta-blockers on LV remodelling [2–4]. The benefits of beta-blockers on LV function appear to be translated into clinical benefit as studies in heart failure have consistently shown reductions in hospitalisations, either for all causes or for heart failure [1]. Several meta-analyses [5–7], and several large individual studies [8–10], suggest that beta-blockers in general and carvedilol in particular may also reduce mortality in heart failure when added to ACE inhibitor therapy.

However, studies of carvedilol [2] and other beta-blockers [11–13] suggest that among patients with heart failure secondary to coronary artery disease the improvement in LVEF is heterogeneous compared to the response observed in patients with well-defined dilated cardiomyopathy. The relationship between dose of drug and increase in LVEF is also less obvious among patients with coronary artery disease [2,12]. The underlying mechanism by which beta-blockers improve LV function and retard the progression of heart failure is unknown. One plausible explanation for the observed heterogeneity is that beta-blockers prevent repetitive stunning and/or resuscitate hibernating myocardium. Patients who have large volumes of ischaemic or hibernating myocardium may respond in a similar fashion to patients with dilated cardiomyopathy while among patients who have predominantly infarct-related scar LV function may improve little during beta-blockade.

Beta-blockers could prove highly effective in resuscitating hibernating myocardium and protecting against recurrent stunning. Although the stimulus that induces hibernation is still disputed, repetitive stunning is likely to be important, while a reduction of blood flow below the threshold required to sustain normal cardiac myocyte function may also contribute [14–16]. Beta-blockers reduce myocardial metabolic requirements [17] by reducing heart rate and limiting its increase during exercise. Beta-blockers could also increase blood flow to areas of hibernation by reducing coronary steal to surrounding areas of ischaemia or the sub-endocardium, by prolonging diastolic coronary blood flow and by reducing the metabolic requirements of the surrounding myocardium.

Carvedilol may prove clinically superior to other beta-blockers, a hypothesis that is currently being tested [18]. Carvedilol is a relatively non-selective beta-blocker that also has pharmacological properties not generally shared by other beta-blockers such as the ability to block alpha-1 receptors and anti-oxidant activity [19]. Alpha-1 and beta-2-receptor blockade may be advantageous by protecting a wider array of adrenoceptors from catecholamine excess. Coronary vasodilatation mediated by alpha-adrenoceptor blockade could further improve myocardial blood flow while peripheral venous and arterial dilatation could reduce pre- and after-load. Protection of the ischaemic myocardium from free radical damage provides an additional mechanism by which carvedilol may reverse stunning and hibernation [19,20] and protect the failing heart.

	2. Aims

Top Notes Abstract 1. Introduction 2. Aims 3. Intervention 4. Study design 5. Conclusions References

 
The primary objective of the study is to determine whether the presence of hibernating (or stunned) myocardium, predicts the degree of improvement in LVEF with carvedilol among patients with chronic LV systolic dysfunction and heart failure due to coronary artery disease. There are a number of secondary aims outlined below.

	3. Intervention

Top Notes Abstract 1. Introduction 2. Aims 3. Intervention 4. Study design 5. Conclusions References

 
Carvedilol titrated to a target dose of 25 mg b.d. if patients weigh <85 kg or 50 mg b.d. if patients' body weight is >85 kg. The comparison is with matching placebo.

	4. Study design

Top Notes Abstract 1. Introduction 2. Aims 3. Intervention 4. Study design 5. Conclusions References

 
This study is a multi-centre, double-blind, randomised, parallel-group study comparing carvedilol and placebo among patients with chronic LV systolic dysfunction and heart failure due to ischaemic heart disease.

Patients who satisfy the inclusion and exclusion criteria at the ‘Pre-Screening visit’ are classified according to whether they have hibernating myocardium or not at the ‘Screening visit’. Diagnosis of hibernation is based on a mismatch between echocardiographic wall motion abnormalities and radioisotopic myocardial perfusion imaging at rest using technetium-99m sestamibi (see below). To guarantee a high level of diagnostic quality and consistency core laboratories are used to analyse echocardiography and nuclear imaging data. Patients considered for randomisation on the basis of these tests are further characterised by exercise myocardial perfusion imaging, equilibrium radionuclide ventriculography, ambulatory ECG monitoring and blood tests, for neuro-endocrine activation and cytokines, before receiving their assigned treatment determined by a central telephone randomisation procedure (Clinphone). Patients with hibernating myocardium are matched with patients without hibernating myocardium over the study as a whole to allow comparability between these two groups. (See Fig. 1; for assumptions on patient numbers see section on sample size and power calculations.) An adaptive allocation procedure is used such that patient groups will be balanced for age, sex, wall motion index (WMI) and presence or absence of active angina.

View larger version (13K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 1 Study design and sample size. Isch LVD: ischaemic left ventricular dysfunction; N-HIB: patients without hibernating myocardium; HIB: patients without hibernating myocardium; numbers: patients needed per protocol in the respective group.

 
Randomised patients will undergo ‘Up-titration Visits’ until the target dose or maximally tolerated dose of carvedilol or matching placebo is reached. Patients will then be maintained on the maximally tolerated dose of study medication for 4 months. should side effects become a problem, patients can be down-titrated if necessary, but only if adjustment of concomitant cardiovascular medication did not resolve the problem. At the ‘end of study’, patients undergo repeat echocardiography, rest and stress myocardial perfusion imaging, radionuclide ventriculography, ambulatory ECG monitoring and blood tests.

4.1. Inclusion criteria

• All patients must have given written informed consent.
  
• Patients have to have chronic stable heart failure in New York Heart Association (NYHA) functional class severity I–III with no acute event or deterioration within the last 3 months.
  
• Patients must be receiving treatment for heart failure, including an ACE inhibitor unless the latter is contra-indicated or not tolerated, in stable doses for at least 2 weeks.
  
• LV systolic dysfunction must be present as evidenced by an echocardiographic WMI, determined by the investigator, of 1.3 (equating to a LVEF of approximately 39%) [21,22].
  
• LV dysfunction must be secondary to coronary artery disease. A prior history of myocardial infarction, with documented pain, ECG and enzyme changes, prior coronary bypass surgery or angioplasty or coronary disease documented by angiography are required to substantiate this diagnosis.
  

The study entails administration of a higher dose of radiation than is usual in clinical practice. Although the prognosis of patients with heart failure is generally poor and even though it was felt that the radiation dose administered did not constitute an appreciable risk to this patient population, additional precautionary measures were felt advisable. Accordingly only patients >40 years of age can be entered and, in addition, women must be post-menopausal or sterilised.

4.2. Exclusion criteria
Major exclusion criteria include heart rate <60 bpm, atrial fibrillation, uncontrolled symptomatic ventricular arrhythmias, sick sinus syndrome with known bradycardic episodes, second or third degree heart block with or without the presence of a pacemaker, sitting systolic blood pressure<85 mmHg, uncontrolled hypertension (i.e. systolic >180 mmHg or diastolic >110 mmHg), NYHA IV heart failure or recent exacerbation of heart failure, unstable angina, chronic obstructive pulmonary disease requiring steroids or bronchodilator therapy, serum creatinine >221 µmol/l, clinically significant hepatic disease, brittle insulin dependent diabetes and any condition likely to interfere with compliance with medication. MAO-inhibitors, verapamil, diltiazem, class 1 anti-arrhythmic agents or current beta-blocker therapy are specifically excluded.

4.3. Definition of hibernation
Hibernation is defined to be present when there is a significant regional mismatch between resting contraction defined by echocardiography and resting, nitrate-enhanced myocardial MIBI uptake [23–25]. Only segments with contractile dysfunction graded as severe hypokinesia, akinesia or dyskinesia are eligible to be considered as potentially hibernating. For each such dysfunctional segment, the mean segmental ^99mTc-MIBI uptake compared with the maximum in the heart is calculated, and categorised into three groups:

• Type a: Segment with <51% uptake;
  
• Type b: Segment with 51–60% uptake; and
  
• Type c: Segment with >60% uptake.
  

Using a nine-segment model of the heart, a hibernating patient is defined as:

• presence of two or more Type c segments; or
  
• presence of one Type c segment if, and only if, it is immediately adjacent to two Type b.
  

All other patients have been designated, prospectively, as non-hibernating.

4.4. Endpoints
4.4.1. Primary treatment-related end-point
Comparison of the mean change, from baseline to the final visit, in radionuclide-determined LVEF in response to placebo or carvedilol, between the groups designated as hibernating and non-hibernating.

4.4.2. Secondary treatment-related end-points
1. Comparison of the mean change, from baseline to the final visit, in radionuclide-determined left ventricular ejection fraction on carvedilol versus placebo regardless of hibernation status.

2. Comparison of the mean change from baseline to the final visit in patients on carvedilol vs. placebo regardless of hibernation status and, further, in hibernators vs. non-hibernators:

• in regional, echocardiographically-determined, contractile dysfunction;
  
• of the mean number of segments per patient with 50% uptake, 51–60% uptake and >60% ^99mTc-MIBI uptake;
  
• of the mean number of segments per patient with reversible exercise-induced myocardial perfusion defects; and
  
• for the composite clinical end-point of all cause mortality or worsening of heart failure.
  

3. The relationship between the volume of hibernating myocardium and the mean change, from baseline to the final visit, in radionuclide-determined left ventricular ejection fraction in the two treatment groups separately.

4. Comparison of the mean change from baseline to the final visit of circulating BNP and total plasma anti-oxidants (TPAA) in patients on placebo with those on carvedilol.

4.5. Primary non-treatment related analysis
Determination of the prevalence of hibernating myocardium and reversible exercise-induced myocardial perfusion defects among patients with heart failure due to coronary artery disease.

4.6. Exploratory analyses
A multivariate analysis to determine those baseline variables that predict best the improvement in resting LVEF will be conducted. Variables will include age, gender, symptoms, concomitant disease, baseline ECG, measures of LV function and myocardial perfusion, heart rate variability, plasma concentrations of neuroendocrine and cytokine markers and oxidative stress. Sub-studies on the effects of carvedilol on right ventricular EF, LVEF during exercise, dobutamine stress echocardiography and magnetic resonance imaging are being conducted.

4.7. Sample size and power calculations
The intention is to randomise 400 patients (200 per treatment arm). It is anticipated that up to 1000 patients may need to be pre-screened in order to enrol 200 patients with evidence of a substantial volume of hibernating myocardium assuming, conservatively, that only 20% of patients with chronic LV dysfunction exhibit this phenomenon.

Previous studies of carvedilol suggest that the standard error of the difference between the two groups in the mean change from baseline of LVEF will be approximately 1.6%, so that the standard error of the comparison of this difference between hibernators and non-hibernators will be approximately 2.3% [2]. This means that the study has approximately 80% power to detect at the 5% significance level a difference in the effect of carvedilol on mean LVEF between the hibernators and the non-hibernators of 6% (absolute), and approximately 90% power to detect at the 5% significance level a difference in the effect of carvedilol on mean LVEF between the hibernators and the non-hibernators of 7% (absolute). The above calculation is conservative and the study has a high probability of detecting much smaller differences between the hibernators and the non-hibernators in practice.

4.8. Planned subgroups
The study is specifically designed around testing the hypothesis of whether carvedilol improves LVEF equally or not in subgroups with and without stunning/hibernation.

4.9. Analysis plan and stopping rules
The statistical analysis will focus on testing for an interaction between the effect of carvedilol and the hibernator/non-hibernator status of the patient. The primary end-point is the change from baseline in LVEF, and this will be analysed using analysis of covariance. The covariates will be the patient characteristics used in the matching process (age, gender, WMI and the presence of angina), together with the study treatment, hibernation status and their interaction. The analysis will be performed on an intention-to-treat basis, and will be supported by exploratory analyses based on a quantification of the degree of hibernation. There are no plans for an interim analysis. No stopping rules exist. The study would only be stopped if it failed to enrol patients at the required rate.

4.10. Centres
Patients are being recruited from 17 centres in the UK, three centres in Hungary and one centre in the US.

4.11. Data monitoring
The raw data for the primary and most secondary outcomes are gathered at the core nuclear, echocardiographic and ECG laboratories and analysed blind to treatment allocation. Clinical events are subject to rigid definitions and an end-points committee is thought unnecessary. The steering committee will monitor the situation and may appoint an end-points committee if required.

4.12. Ethical and indemnity issues
The study has been approved by a UK national multi-centre ethics committee and the local hospital ethics committee at each centre. Written informed consent is required from each patient. The study is also ‘ARSAC’ approved in the UK as required for research procedures involving the administration of radioactive substances. The conduct and compensation arrangements for the study are in accordance with the Association of British Pharmaceutical Industry (APBI) Guidelines.

4.13. Current status of the study
The first patient was recruited in April 1997. Enrolment is expected to be complete by the fourth quarter of 1999 and follow-up completed by the summer 2000. The study is expected to report in the year 2000. As of February 1999, 207 patients have been randomised.

	5. Conclusions

Top Notes Abstract 1. Introduction 2. Aims 3. Intervention 4. Study design 5. Conclusions References

 
The CHRISTMAS study is unique in several respects. We are not aware of any previous randomised multi-centre study investigating the effects of treatment among patients stratified according to the presence of hibernating myocardium or, indeed, of any study that has deliberately randomised patients with hibernating myocardium to an intervention. The CHRISTMAS study could help identify hibernating myocardium as a specific target for medical treatment among patients with heart failure. This could have major implications for the diagnostic work-up of patients with heart failure and for future studies in heart failure.

Few data exist on the prevalence of hibernating myocardium or of exercise induced myocardial ischaemia among patients with heart failure. The few data that do exist come from highly specialised centres that may not be representative of the general population of heart failure in cardiology practice. If such syndromes prove common in a representative population with chronic LV systolic dysfunction due to coronary artery disease this will have much wider implications for how heart failure should be investigated [26] and treated [27]. The CHRISTMAS study will also help elucidate the natural history and prognosis of heart failure with and without hibernation. This could help determine if revascularisation is really necessary for patients with myocardial hibernation. The use of core laboratories will also allow comparisons between centres and methods for the evaluation of LV function and myocardial hibernation.

Medical treatment for stunning/hibernation appears an attractive proposition whether as a complement or alternative to revascularisation or when revascularisation is not possible or not advisable. Although revascularisation is recommended by some elite cardiovascular centres for patients with evidence of a large volume of myocardium affected by stunning/hibernation, supported by reports of benefit in observational series [28,29], this recommendation has never been subjected to a randomised trial. Operative mortality even in published reports is high among such patients and is likely to be still higher in routine practice [30–32]. Moreover, as the severity of LV dysfunction is a determinant of operative mortality, improving it with beta-blockers prior to surgery could reduce operative risk. Many patients will have an insufficient volume of hibernating myocardium to warrant the risks of surgery, but treatment could potentially still produce worthwhile benefit.

Detection of ischaemia, hibernation and stunning among patients with heart failure may identify a group of patients who obtain particular benefit from treatment with a beta-blocker. However, it should be pointed out that even patients whose LV function does not improve with carvedilol may be protected from lethal arrhythmias and recurrent infarction by its beta-blocking properties and therefore still obtain clinical benefit.

	Acknowledgements

 
We wish to acknowledge the support of Roche, SmithKline Beecham and DuPont for their support of this study.

	Notes

Top Notes Abstract 1. Introduction 2. Aims 3. Intervention 4. Study design 5. Conclusions References

 
A double-blind, randomised, multi-centre study of oral carvedilol versus placebo in patients with chronic stable heart failure due to left ventricular systolic dysfunction, with or without hibernating myocardium

	References

Top Notes Abstract 1. Introduction 2. Aims 3. Intervention 4. Study design 5. Conclusions References

 

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