EDITORIAL
Europace (2015) 17, 339–342 doi:10.1093/europace/euu384
National Institute for Health and Care Excellence 2014 guidance on cardiac implantable electronic devices: health economics reloaded Francisco Leyva 1* and Christopher J. Plummer 1 1
Aston University and Queen Elizabeth Hospital, Metchley Drive, Birmingham B15 2TH, UK; and 2Freeman Hospital, Newcastle Upon Tyne, UK
Received 6 September 2014; accepted after revision 4 December 2014
Introduction The past decade has seen rapid progress in cardiac implantable electronic devices delivering implantable cardioverter defibrillator (ICD) and cardiac resynchronization therapy (CRT). Proof-of-principle studies and single-centre clinical studies led to large randomized controlled trials (RCTs). As evidence has accumulated, clinical guideline groups have extended CRT and ICD indications to an increasing number of patients. For a significant proportion of patients with left ventricular dysfunction and/or at risk of sudden cardiac death, device therapy is now part of standard management. Modern healthcare requires expensive treatments to be scrutinized for cost-effectiveness as well as clinical efficacy. This is the only fair approach to the distribution of finite financial resources. As clinicians, we will always strive for the best possible treatment for each individual patient, without directly taking into account financial cost, but the ultimate responsibility for choosing what is to be funded lies with commissioners and politicians. While we are not exempt from a responsibility to use resources efficiently, we are very fortunate in cardiology that our clinically effective treatments have also proven to be cost-effective. Clinical guideline groups, including those of the European Society of Cardiology, do comment on cost-effectiveness, but guidelines are not generally issued on the basis of cost.1,2 In contrast, the United Kingdom’s National Institute for Health and Care Excellence (NICE) does take into account health technology appraisals and cost-effectiveness analyses. In June 2014, new NICE guidance on ICD and CRT device implantation was published3 updating previous guidance from 2006 to 2007 (Table 1). This editorial discusses this process of guideline development and the new data on which it is based. A unique aspect of the 2014 NICE guidelines was its adoption of a new individual patient data network meta-analysis of all available clinical trial data. This included over 12 000 patients from all 13 major device RCTs sponsored by Boston Scientific, Medtronic, Inc. and St Jude Medical with a mean follow-up of 2.5 years. This analysis was performed to maximize the utility of the high-quality, rich data
available and allowed sub-analyses of efficacy as well as costeffectiveness.
The National Institute for Health and Care Excellence process The NICE was set up in 1999 to reduce variation in the availability and quality of National Health Service (NHS) treatments and care. It is accountable to the UK Department of Health, but operates independently of government. Its primary responsibilities fall in three areas: producing evidence-based guidance, developing quality standards and performance metrics, and providing information services. Technology appraisal guidance is developed from a review of clinical and economic evidence. The NHS is then legally obliged to fund and resource the recommended treatments, although treatments which have not been appraised should not have funding withheld simply because of an absence of NICE guidance. An independent academic group carries out a health technology assessment. Consultees, including representatives from patient groups, manufacturers, and professional bodies, then provide further information and selected clinical specialists, NHS commissioning experts, and patient experts also give evidence to the committee. The NICE uses the quality-adjusted life year (QALY) and incremental cost-effectiveness ratios (ICERs) in the cost-effectiveness analysis comparing the new treatment, to next-best, or ‘usual’ care. The stated willingness to pay threshold is usually between £20 000 and £30 000 (E25 000 and E37 500) per QALY although in practice, decisions are not based solely on ICERs and some treatments exceeding these limits are approved.4 The committee develops a scope for the guidance, and then issues an appraisal consultation document before issuing the final appraisal determination and publishing the guidance on the NICE website [http://www.nice.org.uk/]. Written consultation takes place at each stage and representatives of all groups are invited to attend the committee meetings, which are held in public.
The opinions expressed in this article are not necessarily those of the Editors of Europace or of the European Society of Cardiology.
* Corresponding author. Tel: (+44) 121 371 2000; fax: (+44) 121 3714621. E-mail address: [email protected] Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2015. For permissions please email: [email protected].
340
Editorial
Table 1 Summary of 2014 NICE guidelines for CRT and ICD for patients with heart failure LVEF ≤ 35%
........................................................................................................................... NYHA functional class
........................................................................................................................... I
II
III
IV
............................................................................................................................................................................... QRS , 120 ms
ICD if there is a high risk of sudden cardiac death
ICD and CRT not clinically indicated
QRS 120–149 ms without LBBB QRS 120–149 ms with LBBB
ICD ICD
ICD CRT-D
ICD CRT-P or CRT-D
CRT-P CRT-P
QRS ≥ 150 ms
CRT-D
CRT-D
CRT-P or CRT-D
CRT-P
Treatment options for patients with heart failure, with a LVEF ≤ 35%, according to NYHA class, QRS duration and presence of LBBB. (Adapted from the 2014 NICE guidance TA314).3 ‘CRT’, cardiac resynchronisation therapy; ‘CRT-D’, cardiac resynchronization therapy-defibrillation; ‘CRT-P’, cardiac resynchronization therapy-pacing; ‘ICD’, implantable cardioverter-defibrillator; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association; LBBB, left bundle-branch block.
While the production of clinical guidelines by an independent UK agency separate from all other European professional organizations may have seemed incongruous at its inception, NICE has matured into a unique healthcare evaluation agency that commands international respect. It produces clinical guidance which assesses the cost-effectiveness, and affordability of healthcare. For innovative technologies, NICE also generates recommendations on further research. In addition, NICE’s transparent structure and processes, linking government, patients, clinicians and commissioners, adds to its influence, nationally and internationally.5
The 2014 National Institute for Health and Care Excellence guidelines In the absence of significant new clinical trial data, no significant changes have been made to the indications for ICD therapy for the secondary prevention of sudden cardiac arrest or for those with inherited cardiac conditions. The major changes in the 2014 NICE guidelines with respect to CRT and ICD indications for patients with heart failure are: † No distinction is made between ischaemic and non-ischaemic cardiomyopathy. † The left ventricular ejection fraction (LVEF) threshold for device therapy has been unified to ≤35% throughout. † There is no requirement for non-sustained ventricular tachycardia (VT) or VT-stimulation studies in risk stratification for ICD therapy. † The QRS duration threshold for CRT has remained at ≥120 ms. Further stratification between 120 and 149 ms is provided by symptoms [New York Heart Association (NYHA) class] and QRS morphology left bundle-brunch block (LBBB). † Measures of mechanical dyssynchrony have been abandoned. † No distinction is drawn between intrinsic and paced QRS durations. † Cardiac resynchronization therapy is indicated in asymptomatic (NYHA I) patients with QRS ≥ 150 ms and minimally symptomatic (NYHA II) patients with QRS 120– 149 ms with LBBB or QRS ≥ 150 ms.
† No distinction is made between patients in sinus rhythm or atrial fibrillation.
QRS duration In the 2006 NICE ICD guidance, patients with a LVEF ≤ 35%, NYHA class I –III, and a QRS , 120 ms were indicated for primary prevention ICD therapy only if they had ischaemic cardiomyopathy, nonsustained VT, and a positive VT-stimulation test. In the 2014 guidance, these are no longer requirements and ICD implantation is recommended for patients at ‘high risk of sudden cardiac death’, although this is not formally defined. As we do not currently have a test that can reliably identify those in this category who are not at high risk, clinicians are likely to interpret an LVEF ≤ 35% as ‘high risk’ per se in this context. The current European Society of Cardiology (ESC) and North American guidelines have used sub-analyses of RCTs to recommend device therapy according to QRS duration, while NICE has used the network meta-analysis. For patients with a QRS 120– 149 ms, the guideline recommends ICD therapy for those with a LVEF ≤ 35% and NYHA class I–III without LBBB, or NYHA class I with LBBB. For those in NYHA class I–II with QRS ≥ 150 ms or NYHA II with QRS 120–149 ms and LBBB, CRT-defibrillator (CRT-D) is indicated. For those in NYHA class III with QRS 120–149 ms and LBBB or QRS ≥ 150 ms, CRT-pacing (CRT-P) or CRT-D is recommended, while for those in NYHA class IV with QRS ≥ 120 ms, CRT-P is recommended. A post-hoc analysis of REVERSE (REsynchronization reVErses Remodeling in Systolic left vEntricular dysfunction)6 showed a linear relationship between clinical response and QRS duration, starting at 120 ms (Figure 1). A recently published meta-analysis of individual patient data from major CRT trials confirmed a mortality benefit from CRT in patients with QRS durations of approximately ≥126 ms.7 This study also concluded that LBBB morphology was not an independent predictor of mortality after CRT, although a significant effect of LBBB morphology was seen on the composite endpoint of all-cause mortality or heart failure hospitalization in univariable analysis. Importantly, the individual patient data network meta-analysis used in the development of NICE guidance was much larger (1430 deaths in 12 638 patients from 13 clinical trials, compared with 662 deaths in 3872 patients from five trials) and was
341
Editorial
Percentage of patients improved
Hazard ratio for CRT
2.5 2.0 1.5 1.0 0.5 0.0
100
100 80 60 40 20 0 –20 –40 –60 –80 –100 –120 –140
CRT off CRT on
80 60 40 20 0
80
100
120
140
160
180
200
220
QRS duration (ms)
80
100
120
140
160
180
200
LVESVi change at 12 months
Clinical response and left ventricular reverse remodeling
Total mortality
220
QRS duration (ms)
Figure 1 Response to and outcome of CRT according to QRS duration. The left panel is taken from a meta-analysis of individual patient data from landmark CRT trials, with hazard ratios (Y-axis and solid black line) and 95% CI (green shading) for the effects on total mortality of CRT vs. controls (QRS duration is plotted on the X-axis, using spline smoothing). The intersection of the 95% CI and the line indicating a hazard ratio of 1 (no effect) indicates the cut-off of QRS duration above which there is likelihood of response. Adapted from Cleland et al.7 The right-hand panel shows data from a sub-analysis of REVERSE, showing the proportion of patients with an improved clinical response (CRT in solid black line and control in interrupted black line) and the absolute change in left ventricular end-systolic volume index (LVESVi) at 12 months (CRT in solid red line and controls in interrupted red line). The curves use spline smoothing (adapted from Gold et al. 6). Figure reproduced with permission from Leyva et al. 8
able to analyse data from each treatment modality separately, whereas the meta-analysis by Cleland et al. pooled the results from CRT-P with CRT-D, and ICD with medical therapy.
New York Heart Association class IV The recommendation of CRT-P for patients in NYHA class IV with QRS ≥ 120 ms is justified on the grounds that such patients are unlikely to benefit from defibrillation. This is supported by the findings from COMPANION (COmparison of Medical therapy, PAcing, aNd defibrillatION in heart failure) in which neither CRT-P nor CRT-D reduced all-cause mortality in NYHA class IV patients.9
NYHA class III with QRS 120 –149 ms and left bundle-branch block or ≥150 ms In these groups, a choice is offered between CRT-P and CRT-D, although no guidance is offered on which treatment is preferred. The network meta-analysis used by NICE shows CRT-D to be the most clinically effective treatment in a wide range of patient groups. Using a constant mortality treatment effect for 5 years followed by tapering over 20 years, the ICERs were £14 489 for CRT-P and £26 192 for CRT-D in those in NYHA III with QRS 120 –149 ms, £14 203 for CRT-P and £26 586 for CRT-D in those with ≥150 ms without LBBB, and £10 769 for CRT-P and £30 548 for CRT-D in those with ≥150 ms with LBBB. In practice, clinicians are likely to offer CRT-D implantation to these patients, except where specific patient wishes or characteristics make CRT-P more appropriate.
Other considerations Not all aspects of device therapy can be included in the clear and concise guidance which NICE have produced. However, it must be remembered that all patients should undergo appropriate diagnostic tests to establish the aetiology and optimal management of their heart condition and that they should receive optimal pharmacological therapy, revascularization, and corrective valve surgery when indicated. All patients should have their condition and its management options discussed with them to make a fully informed decision. If a decision is made not to implant a device, this should be reviewed at least annually or when there is a significant change in the patient’s condition. The current ESC and North American guidance do not advocate primary prevention ICD implantation within 40 days of acute myocardial infarction. This was not included in NICE guidance, although it is likely that clinicians will observe this restriction in view of the clinical trial data showing no benefit. It is also clear that heart failure is a progressive condition with worsening symptoms and QRS prolongation over time. Upgrading a device from ICD to CRT-D carries a significant complication rate and is expensive. Implanters would clearly want to choose the most appropriate device for their patient’s lifetime based on the likely progression of the disease, but these aspects of personalized care were not considered in the NICE guidelines because of the lack of clinical trial data to support these decisions.
Conclusions The 2014 NICE guidance on ICDs and CRT for arrhythmias and heart failure is the most up-to-date available. It is unique, in that it has
342 systematically evaluated clinical and cost-effectiveness through a transparent, formal, and independent health technology appraisal. It has recommended simplified selection criteria, which should reduce the time taken and costs of identifying patients for device therapy. We expect the guidance to further contribute to the organization’s goal of reducing variation in the availability and quality of treatments and care, by increasing the number of patients receiving evidence-based device treatment. This is likely to influence the further development of guidelines and the delivery of device therapy worldwide. Conflict of interest: F.L. is a consultant and has received research sponsorship from Medtronic, Inc., St Jude Medical, Boston Scientific and Sorin. He has previously been a medical advisor to NICE health technology appraisals on CRT and ICD.
Editorial
3.
4.
5.
6.
7.
References 1. Daubert JC, Saxon L, Adamson PB, Auricchio A, Berger RD, Beshai JF et al. 2012 EHRA/HRS expert consensus statement on cardiac resynchronization therapy in heart failure: implant and follow-up recommendations and management. Europace 2012;14:1236 –86. 2. Brignole M, Auricchio A, Baron-Esquivias G, Bordachar P, Boriani G, Breithardt OA et al. 2013 ESC guidelines on cardiac pacing and cardiac resynchronization therapy: the task force on cardiac pacing and resynchronization therapy of the European
8. 9.
Society of Cardiology (ESC). Developed in collaboration with the European Heart Rhythm Association (EHRA). Europace 2013;15:1070 – 118. National Institute of Health and Care Excellence. NICE technology appraisal [TA 314]: implantable cardioverter defibrillators and cardiac resynchronisation therapy for arrhythmias and heart failure (review of TA95 and TA120). http://www.nice.org. uk/Guidance/TA314. Devlin N, Parkin D. Does NICE have a cost effectiveness threshold and what other factors influence its decisions? A discrete choice analysis. http://www.city.ac.uk/ arts-social-sciences/economics/research/discussion-papers (last accessed 9th September 2014). Sorenson C, Drummond M, Kanavos P, McGuire A. National Institute for Health and Clinical Excellence (NICE): how does it work and what are the implications for the US? (executive summary). http://www.scribd.com/doc/8737637 (last accessed 6th September 2014). Gold MR, Thebault C, Linde C, Abraham WT, Gerritse B, Ghio S et al. Effect of QRS duration and morphology on cardiac resynchronization therapy outcomes in mild heart failure: results from the resynchronization reverses remodeling in systolic left ventricular dysfunction (REVERSE) study. Circulation 2012;126:822–9. Cleland JG, Abraham WT, Linde C, Gold MR, Young JB, Claude Daubert J et al. An individual patient meta-analysis of five randomized trials assessing the effects of cardiac resynchronization therapy on morbidity and mortality in patients with symptomatic heart failure. Eur Heart J 2013;34:3547 –56. Leyva F, Nisam S, Auricchio A. 20 years of cardiac resynchronization therapy. J Am Coll Cardiol 2014;64:1047 –58. Lindenfeld J, Feldman AM, Saxon L, Boehmer J, Carson P, Ghali JK et al. Effects of cardiac resynchronization therapy with or without a defibrillator on survival and hospitalizations in patients with New York Heart Association class IV heart failure. Circulation 2007;115:204 –12.
Europace (2015) 17, 339–342 doi:10.1093/europace/euu384
National Institute for Health and Care Excellence 2014 guidance on cardiac implantable electronic devices: health economics reloaded Francisco Leyva 1* and Christopher J. Plummer 1 1
Aston University and Queen Elizabeth Hospital, Metchley Drive, Birmingham B15 2TH, UK; and 2Freeman Hospital, Newcastle Upon Tyne, UK
Received 6 September 2014; accepted after revision 4 December 2014
Introduction The past decade has seen rapid progress in cardiac implantable electronic devices delivering implantable cardioverter defibrillator (ICD) and cardiac resynchronization therapy (CRT). Proof-of-principle studies and single-centre clinical studies led to large randomized controlled trials (RCTs). As evidence has accumulated, clinical guideline groups have extended CRT and ICD indications to an increasing number of patients. For a significant proportion of patients with left ventricular dysfunction and/or at risk of sudden cardiac death, device therapy is now part of standard management. Modern healthcare requires expensive treatments to be scrutinized for cost-effectiveness as well as clinical efficacy. This is the only fair approach to the distribution of finite financial resources. As clinicians, we will always strive for the best possible treatment for each individual patient, without directly taking into account financial cost, but the ultimate responsibility for choosing what is to be funded lies with commissioners and politicians. While we are not exempt from a responsibility to use resources efficiently, we are very fortunate in cardiology that our clinically effective treatments have also proven to be cost-effective. Clinical guideline groups, including those of the European Society of Cardiology, do comment on cost-effectiveness, but guidelines are not generally issued on the basis of cost.1,2 In contrast, the United Kingdom’s National Institute for Health and Care Excellence (NICE) does take into account health technology appraisals and cost-effectiveness analyses. In June 2014, new NICE guidance on ICD and CRT device implantation was published3 updating previous guidance from 2006 to 2007 (Table 1). This editorial discusses this process of guideline development and the new data on which it is based. A unique aspect of the 2014 NICE guidelines was its adoption of a new individual patient data network meta-analysis of all available clinical trial data. This included over 12 000 patients from all 13 major device RCTs sponsored by Boston Scientific, Medtronic, Inc. and St Jude Medical with a mean follow-up of 2.5 years. This analysis was performed to maximize the utility of the high-quality, rich data
available and allowed sub-analyses of efficacy as well as costeffectiveness.
The National Institute for Health and Care Excellence process The NICE was set up in 1999 to reduce variation in the availability and quality of National Health Service (NHS) treatments and care. It is accountable to the UK Department of Health, but operates independently of government. Its primary responsibilities fall in three areas: producing evidence-based guidance, developing quality standards and performance metrics, and providing information services. Technology appraisal guidance is developed from a review of clinical and economic evidence. The NHS is then legally obliged to fund and resource the recommended treatments, although treatments which have not been appraised should not have funding withheld simply because of an absence of NICE guidance. An independent academic group carries out a health technology assessment. Consultees, including representatives from patient groups, manufacturers, and professional bodies, then provide further information and selected clinical specialists, NHS commissioning experts, and patient experts also give evidence to the committee. The NICE uses the quality-adjusted life year (QALY) and incremental cost-effectiveness ratios (ICERs) in the cost-effectiveness analysis comparing the new treatment, to next-best, or ‘usual’ care. The stated willingness to pay threshold is usually between £20 000 and £30 000 (E25 000 and E37 500) per QALY although in practice, decisions are not based solely on ICERs and some treatments exceeding these limits are approved.4 The committee develops a scope for the guidance, and then issues an appraisal consultation document before issuing the final appraisal determination and publishing the guidance on the NICE website [http://www.nice.org.uk/]. Written consultation takes place at each stage and representatives of all groups are invited to attend the committee meetings, which are held in public.
The opinions expressed in this article are not necessarily those of the Editors of Europace or of the European Society of Cardiology.
* Corresponding author. Tel: (+44) 121 371 2000; fax: (+44) 121 3714621. E-mail address: [email protected] Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2015. For permissions please email: [email protected].
340
Editorial
Table 1 Summary of 2014 NICE guidelines for CRT and ICD for patients with heart failure LVEF ≤ 35%
........................................................................................................................... NYHA functional class
........................................................................................................................... I
II
III
IV
............................................................................................................................................................................... QRS , 120 ms
ICD if there is a high risk of sudden cardiac death
ICD and CRT not clinically indicated
QRS 120–149 ms without LBBB QRS 120–149 ms with LBBB
ICD ICD
ICD CRT-D
ICD CRT-P or CRT-D
CRT-P CRT-P
QRS ≥ 150 ms
CRT-D
CRT-D
CRT-P or CRT-D
CRT-P
Treatment options for patients with heart failure, with a LVEF ≤ 35%, according to NYHA class, QRS duration and presence of LBBB. (Adapted from the 2014 NICE guidance TA314).3 ‘CRT’, cardiac resynchronisation therapy; ‘CRT-D’, cardiac resynchronization therapy-defibrillation; ‘CRT-P’, cardiac resynchronization therapy-pacing; ‘ICD’, implantable cardioverter-defibrillator; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association; LBBB, left bundle-branch block.
While the production of clinical guidelines by an independent UK agency separate from all other European professional organizations may have seemed incongruous at its inception, NICE has matured into a unique healthcare evaluation agency that commands international respect. It produces clinical guidance which assesses the cost-effectiveness, and affordability of healthcare. For innovative technologies, NICE also generates recommendations on further research. In addition, NICE’s transparent structure and processes, linking government, patients, clinicians and commissioners, adds to its influence, nationally and internationally.5
The 2014 National Institute for Health and Care Excellence guidelines In the absence of significant new clinical trial data, no significant changes have been made to the indications for ICD therapy for the secondary prevention of sudden cardiac arrest or for those with inherited cardiac conditions. The major changes in the 2014 NICE guidelines with respect to CRT and ICD indications for patients with heart failure are: † No distinction is made between ischaemic and non-ischaemic cardiomyopathy. † The left ventricular ejection fraction (LVEF) threshold for device therapy has been unified to ≤35% throughout. † There is no requirement for non-sustained ventricular tachycardia (VT) or VT-stimulation studies in risk stratification for ICD therapy. † The QRS duration threshold for CRT has remained at ≥120 ms. Further stratification between 120 and 149 ms is provided by symptoms [New York Heart Association (NYHA) class] and QRS morphology left bundle-brunch block (LBBB). † Measures of mechanical dyssynchrony have been abandoned. † No distinction is drawn between intrinsic and paced QRS durations. † Cardiac resynchronization therapy is indicated in asymptomatic (NYHA I) patients with QRS ≥ 150 ms and minimally symptomatic (NYHA II) patients with QRS 120– 149 ms with LBBB or QRS ≥ 150 ms.
† No distinction is made between patients in sinus rhythm or atrial fibrillation.
QRS duration In the 2006 NICE ICD guidance, patients with a LVEF ≤ 35%, NYHA class I –III, and a QRS , 120 ms were indicated for primary prevention ICD therapy only if they had ischaemic cardiomyopathy, nonsustained VT, and a positive VT-stimulation test. In the 2014 guidance, these are no longer requirements and ICD implantation is recommended for patients at ‘high risk of sudden cardiac death’, although this is not formally defined. As we do not currently have a test that can reliably identify those in this category who are not at high risk, clinicians are likely to interpret an LVEF ≤ 35% as ‘high risk’ per se in this context. The current European Society of Cardiology (ESC) and North American guidelines have used sub-analyses of RCTs to recommend device therapy according to QRS duration, while NICE has used the network meta-analysis. For patients with a QRS 120– 149 ms, the guideline recommends ICD therapy for those with a LVEF ≤ 35% and NYHA class I–III without LBBB, or NYHA class I with LBBB. For those in NYHA class I–II with QRS ≥ 150 ms or NYHA II with QRS 120–149 ms and LBBB, CRT-defibrillator (CRT-D) is indicated. For those in NYHA class III with QRS 120–149 ms and LBBB or QRS ≥ 150 ms, CRT-pacing (CRT-P) or CRT-D is recommended, while for those in NYHA class IV with QRS ≥ 120 ms, CRT-P is recommended. A post-hoc analysis of REVERSE (REsynchronization reVErses Remodeling in Systolic left vEntricular dysfunction)6 showed a linear relationship between clinical response and QRS duration, starting at 120 ms (Figure 1). A recently published meta-analysis of individual patient data from major CRT trials confirmed a mortality benefit from CRT in patients with QRS durations of approximately ≥126 ms.7 This study also concluded that LBBB morphology was not an independent predictor of mortality after CRT, although a significant effect of LBBB morphology was seen on the composite endpoint of all-cause mortality or heart failure hospitalization in univariable analysis. Importantly, the individual patient data network meta-analysis used in the development of NICE guidance was much larger (1430 deaths in 12 638 patients from 13 clinical trials, compared with 662 deaths in 3872 patients from five trials) and was
341
Editorial
Percentage of patients improved
Hazard ratio for CRT
2.5 2.0 1.5 1.0 0.5 0.0
100
100 80 60 40 20 0 –20 –40 –60 –80 –100 –120 –140
CRT off CRT on
80 60 40 20 0
80
100
120
140
160
180
200
220
QRS duration (ms)
80
100
120
140
160
180
200
LVESVi change at 12 months
Clinical response and left ventricular reverse remodeling
Total mortality
220
QRS duration (ms)
Figure 1 Response to and outcome of CRT according to QRS duration. The left panel is taken from a meta-analysis of individual patient data from landmark CRT trials, with hazard ratios (Y-axis and solid black line) and 95% CI (green shading) for the effects on total mortality of CRT vs. controls (QRS duration is plotted on the X-axis, using spline smoothing). The intersection of the 95% CI and the line indicating a hazard ratio of 1 (no effect) indicates the cut-off of QRS duration above which there is likelihood of response. Adapted from Cleland et al.7 The right-hand panel shows data from a sub-analysis of REVERSE, showing the proportion of patients with an improved clinical response (CRT in solid black line and control in interrupted black line) and the absolute change in left ventricular end-systolic volume index (LVESVi) at 12 months (CRT in solid red line and controls in interrupted red line). The curves use spline smoothing (adapted from Gold et al. 6). Figure reproduced with permission from Leyva et al. 8
able to analyse data from each treatment modality separately, whereas the meta-analysis by Cleland et al. pooled the results from CRT-P with CRT-D, and ICD with medical therapy.
New York Heart Association class IV The recommendation of CRT-P for patients in NYHA class IV with QRS ≥ 120 ms is justified on the grounds that such patients are unlikely to benefit from defibrillation. This is supported by the findings from COMPANION (COmparison of Medical therapy, PAcing, aNd defibrillatION in heart failure) in which neither CRT-P nor CRT-D reduced all-cause mortality in NYHA class IV patients.9
NYHA class III with QRS 120 –149 ms and left bundle-branch block or ≥150 ms In these groups, a choice is offered between CRT-P and CRT-D, although no guidance is offered on which treatment is preferred. The network meta-analysis used by NICE shows CRT-D to be the most clinically effective treatment in a wide range of patient groups. Using a constant mortality treatment effect for 5 years followed by tapering over 20 years, the ICERs were £14 489 for CRT-P and £26 192 for CRT-D in those in NYHA III with QRS 120 –149 ms, £14 203 for CRT-P and £26 586 for CRT-D in those with ≥150 ms without LBBB, and £10 769 for CRT-P and £30 548 for CRT-D in those with ≥150 ms with LBBB. In practice, clinicians are likely to offer CRT-D implantation to these patients, except where specific patient wishes or characteristics make CRT-P more appropriate.
Other considerations Not all aspects of device therapy can be included in the clear and concise guidance which NICE have produced. However, it must be remembered that all patients should undergo appropriate diagnostic tests to establish the aetiology and optimal management of their heart condition and that they should receive optimal pharmacological therapy, revascularization, and corrective valve surgery when indicated. All patients should have their condition and its management options discussed with them to make a fully informed decision. If a decision is made not to implant a device, this should be reviewed at least annually or when there is a significant change in the patient’s condition. The current ESC and North American guidance do not advocate primary prevention ICD implantation within 40 days of acute myocardial infarction. This was not included in NICE guidance, although it is likely that clinicians will observe this restriction in view of the clinical trial data showing no benefit. It is also clear that heart failure is a progressive condition with worsening symptoms and QRS prolongation over time. Upgrading a device from ICD to CRT-D carries a significant complication rate and is expensive. Implanters would clearly want to choose the most appropriate device for their patient’s lifetime based on the likely progression of the disease, but these aspects of personalized care were not considered in the NICE guidelines because of the lack of clinical trial data to support these decisions.
Conclusions The 2014 NICE guidance on ICDs and CRT for arrhythmias and heart failure is the most up-to-date available. It is unique, in that it has
342 systematically evaluated clinical and cost-effectiveness through a transparent, formal, and independent health technology appraisal. It has recommended simplified selection criteria, which should reduce the time taken and costs of identifying patients for device therapy. We expect the guidance to further contribute to the organization’s goal of reducing variation in the availability and quality of treatments and care, by increasing the number of patients receiving evidence-based device treatment. This is likely to influence the further development of guidelines and the delivery of device therapy worldwide. Conflict of interest: F.L. is a consultant and has received research sponsorship from Medtronic, Inc., St Jude Medical, Boston Scientific and Sorin. He has previously been a medical advisor to NICE health technology appraisals on CRT and ICD.
Editorial
3.
4.
5.
6.
7.
References 1. Daubert JC, Saxon L, Adamson PB, Auricchio A, Berger RD, Beshai JF et al. 2012 EHRA/HRS expert consensus statement on cardiac resynchronization therapy in heart failure: implant and follow-up recommendations and management. Europace 2012;14:1236 –86. 2. Brignole M, Auricchio A, Baron-Esquivias G, Bordachar P, Boriani G, Breithardt OA et al. 2013 ESC guidelines on cardiac pacing and cardiac resynchronization therapy: the task force on cardiac pacing and resynchronization therapy of the European
8. 9.
Society of Cardiology (ESC). Developed in collaboration with the European Heart Rhythm Association (EHRA). Europace 2013;15:1070 – 118. National Institute of Health and Care Excellence. NICE technology appraisal [TA 314]: implantable cardioverter defibrillators and cardiac resynchronisation therapy for arrhythmias and heart failure (review of TA95 and TA120). http://www.nice.org. uk/Guidance/TA314. Devlin N, Parkin D. Does NICE have a cost effectiveness threshold and what other factors influence its decisions? A discrete choice analysis. http://www.city.ac.uk/ arts-social-sciences/economics/research/discussion-papers (last accessed 9th September 2014). Sorenson C, Drummond M, Kanavos P, McGuire A. National Institute for Health and Clinical Excellence (NICE): how does it work and what are the implications for the US? (executive summary). http://www.scribd.com/doc/8737637 (last accessed 6th September 2014). Gold MR, Thebault C, Linde C, Abraham WT, Gerritse B, Ghio S et al. Effect of QRS duration and morphology on cardiac resynchronization therapy outcomes in mild heart failure: results from the resynchronization reverses remodeling in systolic left ventricular dysfunction (REVERSE) study. Circulation 2012;126:822–9. Cleland JG, Abraham WT, Linde C, Gold MR, Young JB, Claude Daubert J et al. An individual patient meta-analysis of five randomized trials assessing the effects of cardiac resynchronization therapy on morbidity and mortality in patients with symptomatic heart failure. Eur Heart J 2013;34:3547 –56. Leyva F, Nisam S, Auricchio A. 20 years of cardiac resynchronization therapy. J Am Coll Cardiol 2014;64:1047 –58. Lindenfeld J, Feldman AM, Saxon L, Boehmer J, Carson P, Ghali JK et al. Effects of cardiac resynchronization therapy with or without a defibrillator on survival and hospitalizations in patients with New York Heart Association class IV heart failure. Circulation 2007;115:204 –12.
