Implantable cardioverter defibrillators and cardiac resynchronisation therapy for arrhythmias and heart failure

4.1 Clinical effectiveness

4.1.1 The Assessment Group and the manufacturers' submission took different approaches to this appraisal. The Assessment Group used study-level data, and its analyses addressed whether the devices are effective in the populations defined in the scope (described in sections 4.1.4–4.1.35). The manufacturers' submission used individual patient-level data from trials and its analyses addressed the subgroups in which the devices were most effective (described in sections 4.1.36–4.1.40).

4.1.2 The Assessment Group's systematic review identified 26 relevant randomised controlled trials covering the population groups defined in the scope. Although there was overlap between the trials included in the assessment report and the joint industry manufacturers' submission, the RESPOND, VECTOR and REVERSE trials were included only in the manufacturers' submission and the DINAMIT, IRIS and CABG Patch trials were included only in the assessment report. In addition, the 4 trials addressing the use of implantable cardioverter defibrillators (ICDs) for secondary prevention were not considered in the manufacturers' submission.

4.1.3 The Association of British Healthcare Industries submitted a joint submission on behalf of the 5 device manufacturers relevant to this appraisal (Biotronik UK, Boston Scientific, Medtronic UK, Sorin Group and St Jude Medical). The manufacturers' submission focused on adults with heart failure (New York Heart Association [NYHA] class I to IV) and a left ventricular ejection fraction (LVEF) of 35% or less, and at risk of sudden cardiac death. No evidence was presented for secondary prevention of sudden cardiac death or for primary prevention in patients with familial cardiac conditions. The manufacturers identified 22 published clinical-effectiveness studies for ICDs and for cardiac resynchronisation therapy with pacing (CRT‑P) and with a defibrillator (CRT‑D) in patients with heart failure and presented an individual patient data network meta-analysis (IPD NMA) based on 13 of these trials, including over 12,638 patients and accounting for around 95% of patients from all 22 studies.

4.2 Cost effectiveness

4.2.1 The differences in approach taken to this appraisal by the Assessment Group and the manufacturers and the different data sources available to them (described in sections 4.1.1–4.1.3) were carried through to the economic analyses. The Assessment Group presented cost-effectiveness results for each of the 3 populations outlined in the scope, whereas the manufacturers modelled the individual patient data for 12,638 patients, splitting them into subgroups according to NYHA class, QRS duration, LBBB status and aetiology of heart disease, and reporting cost-effectiveness results for each subgroup. The sections below briefly summarise the Assessment Group's model and results, the manufacturers' approach and the Assessment Group's critique of these analyses.

4.3 Consideration of the evidence

4.3.1 The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of ICD, CRT‑P and CRT‑D devices, having considered evidence on the nature of arrhythmias and heart failure and the value placed on the benefits of implantable devices by people with these conditions, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.

4.3.2 The Committee considered the nature of both conditions, and noted evidence submitted and presented by the patient experts and clinical specialists on the clinical symptoms associated with arrhythmias and heart failure. The Committee noted that heart failure, if left untreated, is associated with a poor prognosis. It heard from the patient experts that people with heart failure may have breathing difficulties, swelling in the ankles, legs and abdomen, feel very tired, and become mentally less alert; and consequently experience poor quality of life. The Committee heard that people with heart failure also have an increased risk of developing life-threatening ventricular arrhythmias. The Committee heard that people who survive a cardiac arrest, or have a higher risk of sudden death due to ventricular arrhythmia, may live in constant fear of death. Moreover, the side effects of antiarrhythmic treatment, the only alternative to treatment with a defibrillating device, include fatigue which can result in people becoming dependent on their family and carers for day-to-day activities. The patient experts emphasised the negative psychological impact both of living with the condition and of receiving antiarrhythmic treatments. The Committee noted that antiarrhythmic treatment needs to be adjusted frequently for optimal effect and this may be demanding for many people. The Committee also noted that antiarrhythmic treatment can have adverse effects on the thyroid, liver or lungs. The Committee concluded that people with ventricular arrhythmias and people with heart failure have a significantly reduced quality of life and an increased risk of death.

4.3.3 The Committee heard from the clinical specialists that ICDs have been shown to be superior to pharmacological therapy in people who have survived a cardiac arrest or have spontaneous sustained ventricular arrhythmia with haemodynamic compromise, and further clinical trials in these groups are therefore considered unethical. Because there was no new randomised evidence, the Committee was satisfied that the recommendations in Implantable cardioverter defibrillators for arrhythmias (NICE technology appraisal guidance 95) about secondary prevention of ventricular arrhythmias did not need to be changed.

4.3.4 The Committee also noted that in NICE technology appraisal guidance 95, ICDs were recommended for prevention of arrhythmic death in patients with certain familial conditions associated with high risk of sudden cardiac death (such as long QT syndrome, hypertrophic cardiomyopathy, Brugada syndrome or arrhythmogenic right ventricular dysplasia) and in people who have undergone surgical repair of congenital heart disease. The Committee heard that these conditions are relatively rare and there is no prospect of randomised trials of ICD therapy in these populations. The Committee noted that no additional evidence was presented for these populations for consideration in this appraisal. The Committee heard that the new evidence available since NICE technology appraisal guidance 95 was issued was observational and confirmed the effectiveness of ICDs in preventing sudden death in people with these cardiac conditions. The Committee concluded that the recommendation in NICE technology appraisal guidance 95 regarding familial cardiac conditions and after surgical repair of congenital heart disease did not need to be changed and that the current appraisal should focus on people at risk of sudden cardiac death because of left ventricular dysfunction (heart failure).

4.3.5 The Committee then discussed the clinical characteristics of the population likely to benefit from ICD therapy for the primary prevention of ventricular arrhythmias. The Committee heard from the clinical specialists that reduced left ventricular function (LVEF) is a significant predictor of risk of ventricular arrhythmia. It heard that the degree of left ventricular dysfunction is sometimes useful to guide ICD therapy, particularly in patients with a normal QRS duration (see section 4.3.17), but the measurement of LVEF in clinical practice is often imprecise. The Committee further heard from clinical specialists that a threshold of an LVEF of less than 35% is an important indicator, but further categorisation using this measure is generally not used in routine clinical practice. The Committee heard from the clinical specialists that other risk factors like non-sustained ventricular tachycardia on Holter monitoring, and ventricular tachycardia induced by electrophysiological testing have limited sensitivity or specificity for predicting response to ICD implantation and are no longer routinely used in clinical practice. The Committee also understood from the clinical specialists that damage to heart muscle (myocardium) predisposes patients to the risk of arrhythmia and although the extent of myocardial damage is an important consideration, the aetiology (ischaemic or non-ischaemic) does not influence the effectiveness of ICD therapy. However, the Committee understood that, in patients with previous myocardial infarction, a gap of 4 weeks between infarction and implant is established practice in the NHS and agreed that this is appropriate. The Committee further heard from clinical specialists that prolonged QRS duration and the presence of LBBB on ECG confirms an increased risk of sudden cardiac death. The Committee concluded that some of the stipulations in NICE technology appraisal guidance 95, including history of previous myocardial infarction, presence of non-sustained ventricular tachycardia on Holter monitoring and inducible ventricular tachycardia on electrophysiological testing are no longer used in clinical practice for making decisions on the use of ICD therapy.

4.3.6 The Committee then discussed the clinical characteristics of people with heart failure likely to benefit from cardiac resynchronisation therapy (CRT‑D and CRT‑P), and treatment pathways in this population. The Committee heard from the clinical specialists that heart failure is initially treated with pharmacological therapy, typically consisting of angiotensin-converting enzyme inhibitors, beta blockers and aldosterone antagonists, for at least 3 to 6 months before device implantation is considered. The Committee heard that CRT devices are indicated in people who have an LVEF of 35% or less and have heart failure symptoms despite receiving optimal pharmacological therapy. The Committee heard that CRT has a beneficial effect on patients with symptomatic heart failure with evidence of increased ventricular activation time (that is, prolonged QRS duration) or dyssynchrony (presence of LBBB) on ECG. The clinical specialists clarified that other measures such as mechanical dyssynchrony are no longer considered clinically useful.

4.3.7 The Committee also noted that CRT devices were not recommended for patients in NYHA classes I and II in Cardiac resynchronisation therapy for the treatment of heart failure (NICE technology appraisal guidance 120) and heard from clinical specialists that it is more appropriate to use the therapy in patients with more severe symptoms (that is, NYHA class III or IV) because it alleviates heart failure symptoms. The Committee asked the clinical specialists about the validity of classification based on NYHA criteria, noting that it is based on assessment of symptoms which may be subjective. The Committee heard that NYHA class I (no symptoms) and class IV (symptomatic at rest) are generally demarcated easily, but there is more likely to be overlap in the definitions of NYHA classes II and III. The Committee also heard that NYHA classification was in use in clinical practice, had been used in the trials, and was considered an important prognostic marker in heart failure. The Committee concluded that, based on current standard practice in the UK, severity of symptoms (NYHA class), duration of QRS complex and the presence or absence of LBBB are important clinical characteristics for identifying patients who are likely to benefit from CRT devices.

4.3.8 The Committee discussed the adverse events associated with implantable devices. The Committee was aware that implantation procedures are associated with adverse events, but heard that improvements in the quality of the devices and operator skills have resulted in a decline in adverse event rates during implantation. It heard from the patient experts that the shocks delivered by defibrillator devices (ICD and CRT‑D) may cause anxiety and have an adverse effect on quality of life. However, the Committee also heard that the reassurance that patients with defibrillators experience generally outweighs any disadvantages associated with shocks. The Committee also heard from clinical specialists that improvement in the algorithm for detection of arrhythmia and in the discrimination between physiological and pathological tachycardia, has reduced the incidence of inappropriate shocks. The Committee noted that patients with a defibrillator device have driving and employment restrictions, further affecting their quality of life. The patient experts and the clinical specialists emphasised the importance of pre- and post-placement counselling as well as access to counselling after defibrillator shocks, in maximising the benefits from device implantation. The Committee heard from the patient experts that comprehensive information about the condition, available treatment options, the differences between the devices and the risks of implantation is extremely important to enable people to make informed choices about therapy. The patient experts also stated that patients should be given information before implantation on expected outcomes, living with the device and having it switched off in old age. The Committee noted consultation comments that deactivation of defibrillators is a simple non-invasive re-programming process, and heard that it was important, after appropriate consultation and counselling with patients and their families, to deactivate implanted devices to prevent patients receiving painful and futile shocks at the end of their lives. The Committee agreed with the views of the clinical specialists and patient experts that careful, explicit and shared decision-making about appropriate use of these technologies in the context of end-of-life care planning is important.

4.3.9 The Committee discussed the evidence base available for the effectiveness of ICDs, CRT‑P and CRT‑D compared either with medical therapy or with each other. The Committee noted that the systematic reviews conducted by the Assessment Group and the manufacturers identified largely the same trial evidence. The Committee was aware that the manufacturers' submission excluded trials evaluating ICDs for secondary prevention and noted that this was appropriate for the specific focus of this appraisal (see section 4.3.4). The Committee noted that different approaches were taken by the Assessment Group and the manufacturers for synthesising the results (see section 4.1.1). The Committee considered the results presented in the assessment report and noted that patients receiving ICDs had lower risk of sudden cardiac death than patients receiving medical therapy across all the trials. The Committee also noted that implantation of ICDs for prevention of ventricular arrhythmia decreased all-cause mortality and cardiac mortality in people with mild to moderate heart failure or in those who had a previous history of myocardial infarction. The Committee also noted that the benefits of implantation of a CRT device are related to improvements in the symptoms of heart failure (NYHA class and 6‑minute walking distances) and health-related quality of life, and a reduction in the deaths due to heart failure. The Committee then considered the results of the IPD NMA conducted by the manufacturer and noted that compared with optimal pharmacological therapy, devices (ICD, CRT‑P and CRT‑D) were associated with favourable outcomes. The Committee also noted that some patient characteristics, such as age, sex, QRS duration and LBBB, were predictors of benefit from the different devices (effect modifiers). The Committee also noted that results of the 2 analyses were largely consistent and the use of implantable devices was associated with favourable outcomes compared with medical therapy. The Committee concluded that, in general, ICD, CRT‑D and CRT‑P devices were effective in improving survival and health-related quality of life in people with heart failure.

4.3.10 The Committee then considered which of the 2 available analyses was more appropriate for its decision-making, the manufacturers' IPD NMA and associated economic modelling or the Assessment Group's analyses, noting that the latter were more aligned with the scope of the appraisal and based on published data. However, the Committee was aware of comments received during consultation on the assessment report that there were no clinical criteria that allowed most of the trials in this review to be related specifically to the groups defined in the scope. The Committee considered that the individual patient data available from approximately 12,500 patients, including around 95% of the patients included in studies identified in the systematic review, were a rich and important data source. The Committee also noted that the approach taken by the manufacturers allows consideration of population groups based on clinical characteristics that are considered important by clinicians in current clinical practice for making decisions about device implantation. The Committee concluded that, in this instance, results from the IPD NMA should be used to inform the economic modelling.

4.3.11 The Committee discussed the uncertainties in the manufacturers' IPD NMA. The Committee was aware that the IPD NMA has not yet been published and therefore lacked the benefit of peer review. However, the Committee noted that the results, where comparable, were largely consistent with the Assessment Group's analyses carried out at study level. The Committee noted that trials included were heterogeneous in terms of baseline patient characteristics, length of follow-up and pharmacological therapy, but acknowledged that the meta-regression approach allowed for baseline heterogeneity to be taken into account in evaluating the effectiveness of the devices. However, the Committee noted that heterogeneity introduced by different pharmacological treatment and different length of follow-up across the trials had not been explored. The Committee also noted that some patient groups such as those in NYHA classes I and IV and women were under-represented in the analyses. The Committee heard from the clinical specialists that, in general, patients in the trials were about 10 years younger than the average age of people with heart failure in the UK, although the Committee also noted that the age of patients in the trials was comparable with that of people in the UK who receive devices. The Committee noted that some subgroups defined by clinical covariables were very small, which led to uncertain results. The Committee also discussed the improvement of pharmacological treatment over time and whether it could affect treatment effectiveness associated with devices. It heard from the clinical specialists that treatment of heart failure has improved considerably with the availability of medicines such as angiotensin-converting enzyme inhibitors. It also heard from the patient experts that initiatives such as care by heart failure specialist nurses had resulted in improved compliance. Because of that, the Committee concluded that treatment effects derived from older trials could be overestimated and that results should be interpreted with caution. The Committee also noted that both relative treatment effects and baseline risk in the manufacturers' model were based on the IPD NMA, whereas the baseline risk should ideally be inferred from data relating to routine use. The Committee concluded that the considerable uncertainties needed to be taken into account when deciding whether the technologies represented an acceptable use of NHS resources.

4.3.12 Having concluded that the manufacturers' IPD NMA and economic model would inform its decision-making, the Committee discussed whether there were any key points from the Assessment Group's approach that should also be taken into consideration. It noted that the Assessment Group's model allowed for device crossover, that is, patients initially receiving pharmacological therapy could receive a device on disease progression, and patients with a device could have an upgrade if clinically appropriate. The Committee also noted that observational data as well as clinical specialist opinion, including clinical input received by the Assessment Group, indicated that device upgrades are not common in clinical practice. The Committee therefore concluded that the manufacturers' approach excluding crossover was appropriate for this appraisal.

4.3.13 The Committee then discussed the key assumptions in the manufacturers' model. The Committee heard from the manufacturers that the constant mortality benefit of 7.5 years assumed in the base case was the maximum duration of follow-up in the IPD. The Committee was concerned about the validity of this assumption, noting that the IPD NMA included outcome data observed over protocol-specified data-lock periods in the individual trials. It noted that the duration of the data-lock period across the trials ranged from 3 to 41 months and average duration was 2.54 years, substantially lower than the 7.5 years assumed in the model. The Committee also noted the manufacturers' comment that analysis from the IPD NMA suggested that the treatment effects on all-cause mortality did not vary over time. When considering the analyses based on alternative assumptions the Committee agreed that a constant mortality benefit of 2.54 years may be too pessimistic but that 7.5 years was too optimistic. It also noted that the modelling of device effectiveness for all-cause mortality differed from that for health-related quality of life, in that a constant health-related quality of life benefit was applied for 5 years before tapering. The Committee noted that long-term follow-up data from the CARE‑HF trial showed that treatment effects of CRT‑P were maintained at around 4 years despite crossover, which was consistent with the Committee's preferred assumption. The Committee was also aware that long-term data from MADIT‑II indicated that effects of ICDs were maintained at around 7.5 years despite crossover. However, the Committee concluded that this would not necessarily apply to CRT devices.

4.3.14 The Committee noted that after the constant effect period, the modelling included tapering (a gradual linear decrease) of the effectiveness up to 20 years. The manufacturers stated that this assumption was more conservative than the assumption used in the models informing the NICE technology appraisal guidance 95 and NICE technology appraisal guidance 120 recommendations which did not include any tapering effect. However, the Committee noted that in the current appraisal the manufacturer had modelled treatment effect of the devices on all-cause mortality, making tapering essential because the risk of mortality would increase with age due to other factors, whereas in the previous models tapering was implicit because constant treatment effect was applied to disease-specific mortality from arrhythmia or worsening of heart failure. The Committee therefore did not consider the current approach including tapering to be necessarily more conservative. The Committee was aware that assuming no benefit after the duration of constant effect or assuming a more rapid decline of effectiveness increased the ICERs in the Assessment Group's exploratory sensitivity analyses. Without any evidence to indicate that these alternative assumptions were more appropriate, the Committee saw no reason to deviate from the manufacturers' assumption of tapering up to 20 years. The Committee maintained that, on balance, a constant mortality benefit for 5 years followed by tapering up to 20 years would be the most reasonable assumption.

4.3.15 The Committee noted that the base-case ICERs were not particularly sensitive to alterations in most cost parameters, including counselling costs. The Committee was, however, concerned that the combined effect of uncertainty had not been explored in a probabilistic sensitivity analysis and heard that this was because, given the nature of the data, it would have taken several months to run it across all patient profiles. However, the Committee concluded that the absence of probabilistic sensitivity analyses made it more difficult to allow for uncertainty when reaching decisions about the cost effectiveness of the devices. The Committee discussed the results of the manufacturers' analyses for 24 subgroups after combining the ischaemic and non-ischaemic subgroups, based on its preferred assumption of constant mortality benefit being maintained for 5 years followed by tapering up to 20 years. It noted that the 4 subgroups with the combination of LBBB and a QRS duration of less than 120 milliseconds were clinically implausible because LBBB cannot occur with a normal QRS duration (less than 120 milliseconds). In addition, there was 1 subgroup (NYHA class IV, QRS duration of less than 120 milliseconds, without LBBB) in which no device was evaluated. The Committee concluded that the ICERs based on fully incremental analyses and the predicted optimal strategies for the remaining 19 subgroups were an appropriate basis for making recommendations.

4.3.16 The Committee discussed the cost-effectiveness results in the 3 subgroups with a normal QRS duration (less than 120 milliseconds) across NYHA classes I, II and III. The Committee noted that ICDs were compared with OPT and were associated with ICERs between £25,000 and £30,000 per QALY gained. Having heard of the distress caused by shocks from ICDs, the Committee queried whether ICDs were used in practice for asymptomatic people (that is, NYHA class I) with a QRS duration of less than 120 milliseconds. The Committee heard that patients would have been symptomatic at presentation with heart failure but would have become classified as NYHA class I as a result of optimal pharmacological therapy. Taking into consideration the uncertainties of evidence synthesis identified in section 4.3.12, and the lack of a full exploration of parameter uncertainty in the model (section 4.3.15), the Committee debated whether ICDs were a cost-effective option in these subgroups. The Committee noted comments from consultation that the clinical evidence does not support restricting the use of ICDs in patients with a normal QRS duration. The Committee heard from the clinical specialists that some patients with normal QRS duration are at high risk of sudden death and that it was important to have treatment options available for this population.

4.3.17 The Committee then explored the approaches used by clinical specialists in defining high risk in people with normal QRS duration. The Committee heard that while age and sex were regarded as important considerations in assessing risk of sudden cardiac death, and correspondingly inform the indication for ICD, these are not the only factors used in clinical practice. Other factors may include the degree of left ventricular dysfunction, history of myocardial infarction including the extent and location of myocardial damage (particularly the presence of a large anterior infarct), and presence of cardiomyopathy. In addition, a range of other potential prognostic factors may be used, like B-type natriuretic peptide. The Committee also noted consultation comments suggesting that most patients with normal QRS would require only a single chamber ICD which has a lower cost and greater battery longevity than conventional dual chamber ICDs. The Committee heard that the model included the average cost of all ICDs sold to the NHS in a year, which may therefore have overestimated the costs for ICD for some people in these subgroups. Taking into account the high burden of premature deaths in these subgroups, the Committee was persuaded to recommend ICDs in patients with an LVEF of 35% or less with a normal QRS duration (less than 120 milliseconds) with NYHA class I, II and III symptoms, who are considered to be at high risk of sudden cardiac death.

4.3.18 The Committee noted that the manufacturers did not evaluate any device (ICD, CRT‑D or CRT‑P) in the subgroup with a normal QRS duration (less than 120 milliseconds) and with NYHA class IV symptoms. The Committee also noted that very limited data were available for this subgroup from the manufacturers' IPD NMA. The Committee heard that CRT devices are only indicated in patients with prolonged QRS duration and that ICDs are not suitable in severely symptomatic patients due to the risk of frequent defibrillator shocks. The Committee also noted that ICDs were not recommended for patients with severe symptoms of heart failure (NYHA class IV) in NICE technology appraisal guidance 95. The Committee was therefore satisfied that it is reasonable not to evaluate ICD or CRT devices in this subgroup.

4.3.19 The Committee then discussed the cost-effectiveness results for the 4 subgroups with NYHA class IV, a QRS duration of more than 120 milliseconds and with or without LBBB. It noted that OPT, CRT‑P and CRT‑D were compared in a fully incremental analysis. ICDs were excluded from the analyses based on clinical opinion. The Committee noted that patients in NYHA class IV have severe symptoms, poor quality of life and limited life expectancy. The Committee heard that alleviation of heart failure symptoms is the main goal for these people and defibrillator devices may worsen quality of life because of defibrillator shocks. The Committee agreed that, because of this, like ICDs, CRT‑D should also not be used in these subgroups. The Committee noted that the comparison of CRT‑P with OPT resulted in ICERs ranging from £14,000 to £23,000 per QALY gained, depending on QRS duration and the presence or absence of LBBB. The Committee concluded that CRT‑P is a cost-effective treatment option for people in NYHA class IV with a prolonged QRS duration (more than 120 milliseconds), both with and without LBBB.

4.3.20 The Committee discussed whether resynchronisation therapy was appropriate in the subgroups with a QRS duration between 120 and 149 milliseconds. The Committee heard from the clinical specialists that a recently published trial (EchoCRT, Ruschitzka et al. 2013) reported that in patients with QRS durations of less than 130 milliseconds, prognosis could be adversely affected with CRT devices. The Committee also heard that another recently published, individual patient meta-analysis study reported that the clinical benefit of CRT in patients with QRS durations between 120 and 140 milliseconds was smaller and less certain than those with a longer QRS duration (Cleland et al. 2013). The Committee noted that the Cleland et al. study demonstrated a significant interaction between CRT and QRS duration for mortality as well as for the composite endpoint of mortality and morbidity. In addition, the relationship between the effect of CRT and QRS duration as a continuous variable showed a progressive increase in the benefit of CRT as QRS duration increased, with a statistically significant mortality benefit in patients with a QRS duration of more than around 140 milliseconds. It also indicated that CRT could have a potentially harmful effect in patients with a QRS duration of less than 126 milliseconds. The Committee noted comments that Cleland et al. study did not include a sizeable number of patients from other relevant trials, the proportion of patients within the narrow QRS range was very small and that considering improvement in symptoms was as important as mortality benefits. However, the Committee was concerned that the population with a QRS duration between 120 and 149 milliseconds is heterogeneous and included some patients in whom CRT may be inappropriate. The Committee considered that further categorisation based on QRS duration would be needed to identify subgroups that may benefit from resynchronisation and noted that this was not presented, although the analysis would be possible using the manufacturers' IPD NMA. The Committee heard from the clinical specialists that in clinical practice CRT devices are usually considered in patients with a QRS duration of more than 130 milliseconds, and often more than 140 milliseconds. The clinical specialists also stated that for subgroups with intermediate QRS, most benefit with CRT occurs in patients with LBBB. The manufacturers also stated that the IPD NMA suggested that the proportion of patients with LBBB increased with increase in QRS duration. The Committee heard from clinical specialists that the presence of LBBB provided confirmation of the presence of dyssynchrony and therefore potential for benefit from CRT therapy. The Committee concluded that, without more robust analysis, it is appropriate to take a cautious approach to the use of CRT in this intermediate QRS group.

4.3.21 The Committee discussed the results for patients with a QRS duration between 120 and 149 milliseconds and NYHA class I or II symptoms. Based on the manufacturers' analysis it noted that, for the 2 subgroups without LBBB, ICDs were presented as the optimal strategy, with ICERs of approximately £17,000 per QALY gained compared with OPT. For those in NYHA class I or II with LBBB, however, the Committee noted that CRT‑D was presented as the optimal strategy. Following the discussion in section 4.3.20 regarding potential harm with CRT in patients with a slightly prolonged QRS duration, the Committee considered that CRT‑D could not be clearly recommended for people in NYHA class I because there is less potential for symptomatic benefit and instead took into consideration the ICERs for ICDs when CRT‑D was excluded. The Committee noted that the ICER for ICDs compared with OPT was approximately £22,000 per QALY gained for NYHA class I with LBBB. For NYHA class II with LBBB, the Committee took into consideration comments from consultation that NYHA class II is often difficult to distinguish from NYHA class III. In this scenario, the Committee considered that some degree of symptomatic impact (NYHA class II) with LBBB provides confirmation of the presence of dyssynchrony and therefore the potential to benefit from CRT. The Committee concluded, given unresolved concerns about the balance of benefits and harms with CRT devices, that within the QRS categories presented in the manufacturers' analyses, ICDs are a cost-effective treatment option in patients in NYHA class I with a QRS duration between 120 and 149 milliseconds, both with and without LBBB; and in patients in NYHA class II with a QRS duration between 120 and 149 milliseconds without LBBB. It further concluded that CRT‑D is a cost-effective treatment option in patients in NYHA class II with a QRS duration between 120 and 149 milliseconds with LBBB.

4.3.22 The Committee then discussed the results for the 2 subgroups including people in NYHA class III with QRS duration between 120 and 149 milliseconds. It noted that CRT‑D was presented as the optimal strategy for the subgroups with and without LBBB. In line with section 4.3.20, the Committee noted that CRT‑D would not be recommended for these subgroups. However, the clinical specialists stated that for the subgroup with LBBB, CRT‑D is widely used in clinical practice and the presence of LBBB provides confirmation of the presence of dyssynchrony and therefore potential for benefit from CRT. Taking into account the severity of symptoms of NYHA class III patients and the potential for improvement with resynchronisation therapy, the Committee was persuaded that for this subgroup it was appropriate to consider CRT. The Committee noted that the ICER for CRT‑D compared with CRT‑P in this subgroup was approximately £26,000 per QALY gained and the ICER for CRT‑P compared with OPT was approximately £14,000 per QALY gained. The Committee was aware of the uncertainties surrounding the ICERs, but considered that given the severity of the symptoms and the clinical plausibility of benefit from CRT‑D, the ICER was acceptable. For the subgroup without LBBB, the Committee excluded CRT from consideration and noted that the ICER for ICDs compared with OPT would be around £24,000 per QALY gained. The Committee concluded that for people in NYHA class III, with QRS duration between 120 and 149 milliseconds, ICDs could be considered cost effective in the subgroup without LBBB and CRT‑D or CRT‑P could be considered cost effective in the subgroup with LBBB.

4.3.23 The Committee discussed the 4 subgroups of people in NYHA classes I and II with a prolonged QRS duration of 150 milliseconds or more, both with and without LBBB. The Committee was aware that QRS duration of more than 150 milliseconds indicates cardiac dyssynchrony and carries an increased risk of death from arrhythmia. The Committee noted that OPT, ICDs and CRT‑D were evaluated in these subgroups and CRT‑D was presented as the optimal strategy with ICERs compared with ICDs ranging from £18,000 to £25,000 per QALY gained. The Committee concluded that CRT‑D could be considered cost effective in people in NYHA classes I and II, with a QRS duration of more than 150 milliseconds, both with and without LBBB.

4.3.24 The Committee discussed the results in patients in NYHA class III with QRS duration of 150 milliseconds or more and with, or without, LBBB. It noted that in the subgroup without LBBB, CRT‑D was presented as the optimal strategy with an ICER of approximately £26,000 per QALY gained compared with CRT‑P. As discussed previously, given the severity and nature of the disease in this group of people, the Committee considered that the uncertainty around the ICERs was acceptable. For the subgroup with LBBB the Committee noted that CRT‑P was presented as the optimal strategy because the ICER for CRT‑D compared with CRT‑P was slightly above £30,000 per QALY gained. The Committee noted the consultation comments that it would be clinically counter-intuitive not to recommend CRT‑D in this patient group when CRT‑D was recommended in patients in lower risk categories (that is, without LBBB) as well as in patients with milder symptoms of heart failure (NYHA classes I and II). The Committee noted that patients in this group were severely symptomatic and at high risk of sudden cardiac death and have the most potential to benefit from a CRT‑D device. Because of the value placed on the benefits of CRT‑D in this patient group, the Committee concluded that it was justified to accept an ICER of just above £30,000 per QALY gained. The Committee therefore concluded that for people in NYHA class III, with QRS duration of more than 150 milliseconds with or without LBBB, both CRT‑D and CRT‑P could be considered cost effective.

Summary of Appraisal Committee's key conclusions