NATIONAL INSTITUTE FOR HEALTH AND CLINICAL EXCELLENCE Health Technology Appraisal for the treatment of heart failure Final scope Appraisal objective To appraise the clinical and cost effectiveness of cardiac resynchronisation therapy (CRT) also known as biventricular pacing (BVP), with and without an implantable cardioverter-defibrillator (ICD), due to left ventricular systolic dysfunction (LVSD), and to provide guidance to the NHS in England and Wales 1. Background Heart failure most often occurs as the result of the loss of normal functioning of the ventricles of the heart. The ventricles should pump at the same time and in synchronisation with the heart's upper chambers (atria). If the contractions lack synchrony, either within or between the ventricles, or between the atria and ventricles, the heart becomes less efficient as a pump. The central problem is of delay in activation of the left ventricle, since this reduces the efficiency of an already damaged pump. This may lead to inefficient pumping of blood to the body and a number of symptoms including shortness of breath, swelling in the ankles or legs, weight gain, and fatigue ( heart failure ). The diagnosis of heart failure can be confirmed by a number of tests including chest x-ray, electrocardiogram (ECG), echocardiography, radionuclide ventriculography, angiography, as well as blood tests such as natriuretic peptides. Heart failure impacts on almost all aspects of the quality of life of patients, but particularly mobility. About 800,000 people in England and Wales have heart failure, of which at least half have LVSD. Patients with LVSD tend to be younger than the general population of people with heart failure. It is difficult to determine the death rate from heart failure, because of the way in which death is reported in the UK: the 4% of deaths recorded in the UK due to heart failure are an underestimate if heart failure is regarded as a cause of death rather than a mode of death. One-year survival rates in a survey in Hillingdon, London, in 1995 were 62% (comparable with colonic cancer but less favourable than current breast, prostate or bladder cancer survival rates), with a mortality rate after the first 1 The Department of Health and Welsh Assembly government remit to the Institute: To appraise the clinical and cost effectiveness of biventricular pacing (cardiac resynchronisation) to restore synchronous cardiac contraction in patients with advanced heart failure. Issue Date: February 2006 Page 1 of 5
year of around 8-10% per year. Heart failure costs an estimated 716 million in the UK each year, of which about 70% is due to hospitalisation. Hospital admissions are projected to rise by 50% in the next 25 years. The heart s performance can be described by left ventricular ejection fraction (LVEF), expressed as a percentage. Other analysis may include the width and shape of the QRS complex of an ECG waveform which gives an indication of the sequence of electrical activation of the ventricles, as well as the time it takes for depolarization. Patients with a broad QRS complex often have dyssynchronous (inefficient) contraction of the left ventricle (and dyssynchrony between the right and left ventricles). Cardiac resynchronisation therapy aims to ensure co-ordinated contraction of the left ventricle (that is, to correct intraventricular dyssynchrony), co-ordinated contraction of the right and left ventricles (that is, to correct interventricular dyssynchrony) and optimal atrio-ventricular synchronisation. There is evidence that the wider the QRS complex, the worse the prognosis. Symptoms of heart failure are classified by the New York Heart Association (NYHA) system from Class I (no limitations) to Class IV (inability to carry out any physical activity without discomfort). Patients with a risk of cardiac arrest due to ventricular tachycardia or ventricular fibrillation may be given an implantable cardioverter defibrillator (ICD) device to detect and treat such arrhythmia. The technology Traditional pacemakers use one or two leads to sense and pace the right atrium and right ventricle or both, thus keeping the right atrium and right ventricle working together (AV Synchrony). CRT uses a third lead to pace the left ventricle via the coronary sinus. After the atria contract, both ventricles are paced to contract at the same time, causing the heart to contract in a more efficient manner, resulting in improved cardiac function. CRT can be performed with or without a concomitant ICD. Two main types of CRT device are available in the EU from a variety of companies: St. Jude Medical, Medtronic, ELA Medical, Biotronik, Sorin and Guidant. CRT-P is biventricular pacing alone, alternatively termed low energy CRT ; CRT-D is biventricular pacing with an ICD, often termed high energy CRT. The risks and complications of CRT are similar to conventional pacing: implant plus coronary sinus dissection/perforation (approximately 1%), lead dislodgement (approximately 5%) and the risks associated with the use of intravenous contrast media. In all, there has been a device failure rate of between 5% and 10%. In the UK about 1200 CRT devices were implanted in 2005. Numbers are growing at about 40% per year. Issue Date: February 2006 Page 2 of 5
CRT is of potential benefit to patients with moderate to severe heart failure and poor left ventricular systolic function and evidence of cardiac dyssynchrony. It is estimated that 20-30% of patients with NYHA Class III/IV chronic heart failure have sufficiently low LVEF and prolonged QRS duration to be potential candidates for CRT. Echocardiography in better diagnosing heart failure may improve the clinical and cost effectiveness of CRT. In England and Wales, it was estimated in the NICE Heart Failure Guideline (2003) that there are 4,200 8,400 people potentially eligible for CRT. The NICE Heart Failure Guideline recommends that resynchronisation therapy should be considered for selected patients with left ventricular dysfunction, drug refractory symptoms and QRS duration >120msecs. Given the shorter QRS in the guideline it is likely that the above estimated population size suitable for CRT will be conservative. Studies suggest an improved cardiac function and quality of life in patients treated with CRT devices. Recent data from the PAVE study has shown improved cardiac function (LVEF) and exercise tolerance (6-minute walk test) in CRT paced patients compared with right ventricular paced patients with class IV heart failure. A recent meta-analysis of trials using CRT without ICD has shown that in the selected heart failure patients when compared with optimal medical therapy alone, CRT without ICD reduces all-cause mortality and the risk of hospitalisation and improves patients health-related quality of life. More recently, the CARE-HF study (2005), a large RCT of CRT-P, also demonstrates that CRT without ICD produces a substantial absolute risk reduction of death and reduction in hospitalisations for heart failure, and improved quality of life. Intervention(s) Population(s) Standard comparators Cardiac resynchronisation therapy (biventricular pacing) devices. It is intended that CRT-P devices will be regarded as a class, as will CRT-D devices. People with heart failure (any NYHA classification class) with cardiac dyssynchrony and LVSD. Comparator intervention: optimal medical treatment For the consideration of cost effectiveness, further comparison of CRT-P, CRT-D and ICD (implantable cardioverter defibrillator) will be required for different subgroups of patients. Issue Date: February 2006 Page 3 of 5
Outcomes Economic analysis The outcome measures to be considered include: progressive heart-failure mortality non-heart-failure mortality all-cause mortality heart failure hospitalisations exercise capacity NYHA class before and after treatment adverse effects of treatment health-related quality of life. Ideally, the cost effectiveness of treatments should be expressed in terms of incremental cost per qualityadjusted life year. Comparisons between CRT-P and medical treatment, CRT-D and medical treatment, CRT-D and ICD, and CRT-D and CRT-P should be made. Indirect comparisons between alternatives may be necessary. The time horizon should be patient lifetime. Different age and risk groups should be analysed separately. Costs will be considered from an NHS and Personal Social Services perspective. Issue Date: February 2006 Page 4 of 5
Other considerations Related NICE recommendations Guidance will only be issued for devices that have obtained a CE marking 4 weeks before the date that NICE is due to have received the Assessment Report. A separate analysis should be carried out for patients who are likely to require a CRT-P and those likely to require a CRT-D, in order to inform guidance on which patients should be considered for which intervention. The evidence base may be limited to some extent by excluding data from a time when CRT performance and price were sufficiently different from the present. Relatedly, qualitative differences between devices within each class of CRT being appraised may need to be considered. Potential subgroups may include age groups, atrial fibrillation, NHYA class, LVEF fraction and QRS duration. The role of echocardiography in assessing LVSD and therefore affecting the cost effectiveness of interventions. Epidemiological estimates of numbers of patients in each subgroup and of the number already treated may be required. Who may implant, staffing and technical support levels and other facilities in secondary care may need to be considered. Related Technology Appraisals: Technology Appraisal number 95: Implantable cardioverter defibrillators (ICDs) for the treatment of arrhythmias - review of guidance no 11 (Jan 2006) Related Guidelines: CG5: Chronic heart failure (July 2003) Atrial fibrillation (expected completion June 2006) MI: secondary prevention (expected completion May 2007) Issue Date: February 2006 Page 5 of 5