1 Appraisal Committee's preliminary recommendations

1.1 Implantable cardioverter defibrillators (ICDs) are recommended as options for:

• treating people with previous serious ventricular arrhythmia, that is, for people who, in the absence of a treatable cause:

- have survived a cardiac arrest caused by either ventricular tachycardia (VT) or ventricular fibrillation or

- have spontaneous sustained VT causing syncope or significant haemodynamic compromise or

- have sustained VT without syncope or cardiac arrest, and have an associated reduction in left ventricular ejection fraction (LVEF) of less than 35% but their symptoms are no worse than class III of the New York Heart Association (NYHA) functional classification of heart failure.

• treating people who:

- have a familial cardiac condition with a high risk of sudden death, such as long QT syndrome, hypertrophic cardiomyopathy, Brugada syndrome or arrhythmogenic right ventricular dysplasia, or

- have undergone surgical repair of congenital heart disease, or

- with heart failure who have left ventricular dysfunction with an LVEF of 35% or less, and have:

       - NYHA class I–II symptoms, and a QRS duration of 120–149 milliseconds or

       - NYHA class III symptoms and a QRS duration of 120–149 milliseconds with no left bundle
         branch block.

1.2 Cardiac resynchronisation therapy with a defibrillator (CRT‑D) device is recommended as a treatment option for people with heart failure who have left ventricular dysfunction with an LVEF of 35% or less, NYHA class I–II symptoms, and a QRS duration of 150 milliseconds or more.

1.3 Cardiac resynchronisation therapy with a CRT‑D device or with a pacing (CRT‑P) device is recommended as a treatment option for people with heart failure who have left ventricular dysfunction with an LVEF of 35% or less, and have:

• NYHA class III symptoms and a QRS duration of 120–149 milliseconds with left bundle branch block or
• NYHA class III symptoms and a QRS duration of 150 milliseconds or more without left bundle branch block.

1.4 CRT‑P is recommended as a treatment option for people with heart failure who have left ventricular dysfunction with an LVEF of 35% or less, and have:

• NYHA class III symptoms and a QRS duration of 150 milliseconds or more with left bundle branch block or
• NYHA class IV symptoms and a QRS duration of 120 milliseconds or more.

2 Clinical need and practice

Arrhythmia

2.1 Arrhythmia is a condition where the heart contracts irregularly or at a faster or slower pace than normal. It is caused by an abnormality in the myocardial tissue, or in the electrical conduction system of the heart. Arrhythmias that arise from ventricles (ventricular arrhythmias) can occur unexpectedly and can cause sudden death. Ventricular arrhythmias include ventricular tachycardia and ventricular fibrillation. In ventricular tachycardia, the ventricles beat faster than normal (at between 120 and 200 beats per minute). In ventricular fibrillation, electrical impulses rapidly start firing from multiple sites in the ventricles, resulting in an uncoordinated, irregular rhythm. Ventricular arrhythmias can result in insufficient blood being pumped out by the heart to sustain life.

2.2 Ventricular arrhythmias most commonly occur in people with underlying heart disease. Approximately 75–80% of the 70,000 sudden cardiac deaths in England and Wales in 2010 could be attributed to ventricular arrhythmias. The average chance of survival of adults after an out-of-hospital episode of ventricular arrhythmia has been reported to be as low as 7%.However,  with appropriate treatment, recent studies have reported 5-year survival of 69–100% in people who had survived a cardiac arrest.

2.3 Many patients presenting with arrhythmias, with or without symptoms, are treated with antiarrhythmic drug therapy. However, antiarrhythmic drugs may not be optimally effective and need careful and frequent adjustment. This can be confusing for patients and may lead to missed doses, taking the wrong dose or overdose. Many antiarrhythmic drugs result in tiredness, inability to perform day-to-day activities and dependence on carers, and consequently increase the risk of depression. Antiarrhythmic drugs also have many side effects on a range of organs including the thyroid, liver and lungs.

2.4 Chronic prophylactic antiarrhythmic drug therapy aims to suppress the development of arrhythmias, but does not stop an arrhythmia once it has started. People who survive a first episode of life-threatening ventricular arrhythmia are at high risk of further episodes. For preventing further life-threatening events in survivors of previous serious ventricular arrhythmias, people are usually treated with implantable cardioverter defibrillators (ICDs). Preventing sudden cardiac death in someone who has never had a cardiac arrest or ventricular arrhythmia is challenging because it requires identifying a person with substantial level of risk. Many risk factors for sudden cardiac death have been reported such as age, hereditary factors, having a high risk for coronary artery disease, inflammatory markers, hypertension, left ventricular hypertrophy, conduction abnormalities (for example, left bundle branch block), obesity, diabetes and lifestyle factors. There is currently no optimal strategy for risk stratification.

Heart failure

2.5 Heart failure is caused by any structural or functional cardiac disorder that impairs the heart’s ability to function efficiently as a pump to support circulation. It causes breathlessness, fatigue and fluid retention. Clinically it is classified using the New York Heart Association (NYHA) functional class system, ranging from class I (no limitation of physical activity or symptoms, but heart failure symptoms in the past) to class IV (symptomatic at rest and discomfort from any physical activity). Heart failure is also classified based on which heart function or which side of the heart is most affected: some patients have heart failure due to left ventricular systolic dysfunction, which is associated with a reduced left ventricular ejection fraction (left heart failure or biventricular failure); while others have only right heart failure with a preserved left ventricular ejection fraction. The scope for this appraisal focuses on left and biventricular heart failure.

2.6 Heart failure is a chronic condition predominantly affecting people over the age of 50 years. The incidence of heart failure in the UK is 140 per 100,000 men and 120 per 100,000 women. Approximately 900,000 people in England and Wales have heart failure, of which at least half have left ventricular systolic dysfunction. The incidence and prevalence of heart failure increases with age and the average age at first diagnosis is 76 years. People with heart failure are at risk from sudden cardiac death; this is the most common cause of death in people with mild to moderate heart failure.

2.7 Treatment of heart failure aims to improve life expectancy and quality of life. Chronic heart failure: management of chronic heart failure in adults in primary and secondary care (NICE clinical guideline 108) recommends pharmacological treatment initially. However, as the condition becomes more severe, cardiac function and symptoms may no longer be controlled by pharmacological treatment alone, and can be improved by the implantation of a cardiac rhythm device which can sense and stimulate the atria and right and left ventricles independently. These devices are known as cardiac resynchronisation therapy pacing (CRT‑P) devices or cardiac resynchronisation therapy defibrillator (CRT‑D) devices.

3 The technologies

3.1 ICDs are small, battery-powered devices that are implanted under the skin just below the collarbone, with leads (tiny wires) inserted into the heart. The devices operate by sensing and analysing the electrical activity of the heart, thereby monitoring for arrhythmia, and delivering electrical pulses or shocks to restore normal rhythm if necessary. Based on average selling prices aggregated across all manufacturers of ICDs sold in the UK to the NHS in the financial year of 2011, the cost of a complete ICD system was estimated at £9692.

3.2 Cardiac resynchronisation therapy with pacing (CRT‑P), also known as biventricular pacing, involves implanting a pulse generator in the upper chest. Three leads connect this to the right atrium and both ventricles, and the device resynchronises the contraction of the ventricles, thereby improving the heart’s pumping efficiency. Based on average selling prices aggregated from devices sold in the UK to the NHS across all manufacturers in the financial year of 2011, the cost of a complete CRT‑P system is estimated to be £3411.

3.3 CRT‑D devices combine CRT‑P and ICD devices. A CRT‑D device defibrillates the heart internally in the event of an acute arrhythmic event and improves ventricular efficiency and blood flow. Based on average selling prices aggregated from devices sold in the UK to the NHS across all manufacturers in the financial year of 2011, the cost of a complete CRT‑D system is estimated to be £12,293.

3.4 Adverse events from implantable devices are mostly related to implantation-related complications and include coronary vein dissection, coronary vein perforation, lead dislodgement, infection and death. Patients with defibrillator devices (ICD and CRT‑D) who experience defibrillator shocks may have adverse psychological symptoms (notably anxiety).

3.5 Costs may vary in different settings because of negotiated procurement discounts.

4 Evidence and interpretation

The Appraisal Committee (section 9) considered evidence from a number of sources (section 10).

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 4.1.4–4.1.34). 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 4.1.35–4.1.39).

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 (ABHI) 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 ICD 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 95% of patients from all 22 studies.

Assessment Group report

People at risk of sudden cardiac death as a result of ventricular arrhythmias (population 1)

4.1.4  The Assessment Group identified 13 unblinded randomised controlled trials in people at risk of sudden cardiac death as a result of ventricular arrhythmias (population 1) and synthesised the trial results based on the different risk criteria for sudden cardiac deaths used in the trials. Patients in the intervention arm of most trials received medical therapy in addition to the intervention.  ICD for secondary prevention was studied in 4 trials: AVID (n=1016), CASH (n=288), CIDS (n=659) and DEBUT (n=66; pilot=20 and main study=46). The average length of follow-up varied from 18 months to 57 months across the trials. LVEF varied from 30% to 70% across the trials. All patients in the DEBUT trial had NYHA class I congestive heart failure and the majority of patients in the remaining trials were in NYHA class I or II.

4.1.5 The Assessment Group conducted a meta-analysis that indicated that, compared with medical treatment alone, ICD treatment resulted in reductions in all-cause mortality (relative risk [RR] 0.75, 95% confidence interval [CI] 0.61 to 0.93), total cardiac death (RR 0.74 95% CI 0.61 to 0.91) and sudden cardiac death (RR 0.49, 95% CI 0.34 to 0.69). The AVID and CIDS trials assessed quality of life through separate sub studies using a range of generic and condition-specific measures. The AVID trial reported that there were no statistically significant differences in SF‑36 scores between groups at 12-month follow-up. Adverse symptoms and ICD shocks were reported to have a negative impact on quality of life scores for ICDs across the different measures. The most frequently reported adverse events with ICDs included defibrillation discharges caused by supraventricular tachycardia or sinus tachycardia (19%, DEBUT); T-wave oversensing (8%, DEBUT); device-related discomfort (7.6%, CIDS); ICDs permanently or temporarily explanted because of infection, heart transplantation or patient preference (5%, CIDS); device dysfunction (5%, CASH); pocket erosion requiring removal of ICD (3%, DEBUT); dislodgement or migration of system leads (3%, CASH); ICD dislodgement/fracture (2.4%, CIDS); bleeding requiring reoperation or transfusion (1.2%, AVID); and unsuccessful first attempt at ICD implantation without thoracotomy (1.0%, AVID).

4.1.6 The DINAMIT (n=674) and IRIS (n=898) trials compared ICDs with medical therapy alone in people with a recent myocardial infarction. Average length of follow-up was 30 and 37 months respectively. Approximately 60% of people in both trials were in NYHA class II; most of the remainder were NYHA class III in the DINAMIT trial and NYHA class I in the IRIS trial. Mean LVEF was 28% in the DINAMIT trial and 35% in the IRIS trial. A meta-analysis of the 2 trials conducted by the Assessment Group reported no significant difference in all-cause mortality (RR 1.04, 95% CI 0.86 to 1.25), total cardiac deaths (RR 0.97, 95% CI 0.79 to 1.20) or non-cardiac deaths (RR 1.39, 95% CI 0.86 to 2.27) with ICDs compared with medical therapy. However, people receiving ICDs had a lower risk of sudden cardiac death (RR 0.45, 95% CI 0.31 to 0.64), but a higher risk of non-arrhythmic cardiac death (RR 1.77, 95% CI 1.30 to 2.40; p=0.0002) than people receiving medical therapy. The IRIS trial found no statistically significant difference between groups for cumulative mortality. In the IRIS trial, 15.7% patients in the ICD group experienced clinically significant complications and 1.7% patients died within 30 days of implantation surgery. In the DINAMIT trial 8.1% of patients experienced device-related complications, but no related deaths were reported.

4.1.7 The MADIT I (n=196) and MADIT II (n=1232) trials compared ICDs with medical therapy in people who had had myocardial infarction at least 3 weeks or 1 month before trial entry respectively. The average length of follow-up was 27 months for MADIT I and 20 months for MADIT II. Approximately 70% of people in both trials had NYHA class II or III symptoms and the remaining had NYHA class I symptoms. Mean LVEF was approximately 26% in MADIT I and 23% in MADIT II. Both the MADIT I and MADIT II trials reported a reduction in all-cause mortality with ICDs compared with medical therapy alone, reporting hazard ratios of 0.46 (95% CI 0.26 to 0.82) and 0.69 (95% CI 0.51 to 0.93) respectively and these results were supported by a meta-analysis conducted by the Assessment Group (RR 0.57, 95% CI 0.33 to 0.97). The meta-analysis also supported the findings from the trials with regard to secondary outcomes reporting a relative risk of 0.59 (95% CI 0.42 to 0.83) for total cardiac deaths, and a relative risk of 0.36 (95% CI 0.23 to 0.55) for sudden cardiac death for ICDs compared with medical therapy. No differences between groups were found in the trials for non-arrhythmic cardiac deaths or for non-cardiac deaths. The MADIT I trial reported a similar hospitalisation rate for the groups per 1000 months follow-up (ICDs 11.3 months, medical therapy 9.4 months). It also reported that the proportion of hospitalisations due to heart failure was higher in the ICD group (ICDs 19.9%, medical therapy 14.9%). The MADIT II trial assessed quality of life using the Health Utility Index (HUI3), reporting that scores were lower (worse) in people in the ICD group (0.637) compared with medical therapy (0.646) at baseline and that differences were not statistically significant between groups at 3 years follow-up (ICD 0.019, medical therapy 0.013; p value not reported).

4.1.8 The AMIOVIRT (n=103), CAT (n=104) and DEFINITE (n=458) trials compared ICDs with medical therapy alone in people with non-ischaemic or idiopathic dilated cardiomyopathy (primary prevention). The medical therapy in the CAT trial was not considered optimal by current standards because of low beta-blocker use. None of the trials reported a statistically significant difference in all-cause mortality with ICDs compared with medical therapy alone. These results were supported by a meta-analysis by the Assessment Group that reported an all-cause mortality risk ratio of 0.77 (95% CI 0.52 to 1.15). The meta-analysis also found no statistically significant differences between groups for non-arrhythmic cardiac death (RR 1.13, 95% CI 0.42 to 3.03). A meta-analysis of the AMIOVIRT and DEFINITE trials found a statistically significant reduction in sudden cardiac death with ICDs, with a risk ratio of 0.26 (95% CI 0.09 to 0.77).

4.1.9 The CABG Patch trial (n=900) compared ICDs with medical therapy alone in people who were scheduled for coronary artery bypass graft surgery and were at risk of sudden cardiac death. The Assessment Group noted that the medical therapy in this trial was not optimal by current standards, and the excessive use of antiarrhythmic drugs in the ICD arm may have offset some of the benefits from ICDs. The mean follow-up was 32 months and mean LVEF was 27%. The majority of patients were in NYHA class II or III. The results showed no significant difference in all-cause mortality, total cardiac deaths, non-arrhythmic cardiac death, non-cardiac death and sudden cardiac death for the ICD group compared with medical therapy. The CABG Patch trial assessed health-related quality of life using measures of perception of health, ability to function and psychological well-being at 6-month follow-up. Scores were lower with ICDs compared with medical therapy for all measures, and the results were statistically significant for measures of perception of health transition, emotional role function and mental health, satisfaction with appearance and satisfaction with scar.

4.1.10 SCD-HeFT (n=2521) was a 3-arm trial that evaluated ICDs in a broad population of patients with mild to moderate heart failure. Mean follow-up was 46 months and mean LVEF was 25%. Over 70% of patients were in NYHA class II, with the remainder in NYHA class III. The primary outcome of all-cause mortality was lower in the ICD group than in the combined placebo and medical therapy group (hazard ratio [HR] 0.77, 97.5% CI 0.62 to 0.96). Lower rates of total cardiac death (HR 0.76, 95% CI 0.60 to 0.95) and sudden cardiac death (risk ratio 0.44, 95% CI 0.31 to 0.61) were also found for ICDs than in the combined placebo and medical therapy groups.

4.1.11 The SCD-HeFT trial reported health-related quality of life scores at baseline and 3, 12 and 30 months follow-up using the Duke Activity Status Index (DASI), Mental Health Inventory 5 (MHI-5), Minnesota Living with Heart Failure questionnaire (MLHFQ) and the global health status. The only statistically significant differences between ICDs and placebo were in median MHI scores and global health status at 3 and 12 months (but these differences were not maintained at 30 months); and in MLHFQ score at 3 months (but this benefit was not maintained at 12 months). A significant decrease in perception of quality of life was found using the SF‑36 among people who had received an ICD shock within the previous month compared with those who had not received a shock.

4.1.12 The 9 randomised controlled trials evaluating ICDs for primary prevention reported adverse event rates of between 5% (SCD‑HeFT) and 61% (CABG Patch) in people with an ICD, depending on the definition of adverse event and length of follow-up. Adverse event rates for the comparator treatment were between 12% and 55% in the 3 trials reporting them. Lead, electrode or defibrillator generator-related problems affected 1.8% (MADIT II) to 14% (CAT) of people in the 5 trials that reported them.

People with heart failure as a result of left ventricular systolic dysfunction and cardiac dyssynchrony (population 2)

4.1.13 The Assessment Group identified 4 multicentre randomised controlled trials comparing CRT‑P with medical therapy in people with heart failure as a result of left ventricular systolic dysfunction and cardiac dyssynchrony (population 2). The CARE‑HF (n=813) and COMPANION (n=1520) trials were unblinded, and therefore at high risk of bias. The MIRACLE (n=453) and MUSTIC (n=58) trials were blinded because all patients had a CRT‑P device implanted, but investigators inactivated the device in the control group. The MUSTIC trial used a randomised crossover design, with 3 months follow-up for each of the 2 crossover periods and the Assessment Group stated that the crossover design was appropriate. All trials included people with NYHA class III or IV heart failure, with the majority of patients in NYHA class III and with LVEF less than 35%. Average LVEF was about 22% in MIRACLE and COMPANION, and 25% in CARE-HF. The QRS duration was prolonged (more than 150 ms) across all 4 trials. An intention-to-treat analysis was performed in the trials.

CRT‑P compared with medical therapy

4.1.14 For CRT‑P compared with medical therapy, the CARE-HF trial reported a reduction in all-cause mortality after a mean follow-up of 37.4 months (HR 0.60, 95% CI 0.47 to 0.77). This difference persisted during long-term follow-up of 343 of 813 people originally enrolled, despite implantation of CRT devices in more than 95% of those originally assigned to the medical therapy group (HR 0.77, 95% CI 0.63 to 0.93). Differences in all-cause mortality observed in the other 3 trials were not statistically significant. A meta-analysis of all 4 trials conducted by the Assessment Group found that CRT‑P statistically significantly reduced all-cause mortality compared with medical therapy with a risk ratio of 0.75 (95% CI 0.58 to 0.96).

4.1.15 The COMPANION and MUSTIC trials measured total cardiac death and reported no statistically significant difference between the CRT‑P and medical therapy groups. The COMPANION trial also found no statistically significant differences between groups for non-cardiac deaths. In the CARE-HF trial, fewer patients in the CRT‑P group experienced sudden cardiac death than in the medical therapy group with a risk ratio of 0.59 (95% CI 0.39 to 0.89). The COMPANION and MUSTIC trials did not report any statistically significant difference between groups. The Assessment Group conducted a meta-analysis that demonstrated no difference in risk of sudden cardiac death between the CRT‑P and medical therapy groups with a risk ratio of 0.97 (95% CI 0.44 to 2.14).

4.1.16 In the CARE-HF trial, fewer patients in the CRT‑P group died from heart failure compared with the medical therapy group with a risk ratio of 0.59 (95% CI 0.40 to 0.86). The COMPANION trial, however, found no statistically significant differences between groups, reporting a risk ratio of 0.78 (95% CI 0.52 to 1.17). A meta-analysis by the Assessment Group found that CRT‑P relative to medical therapy decreased death due to heart failure (RR 0.67, 95% CI 0.51 to 0.88).

4.1.17 All 4 trials measured hospitalisations because of heart failure and all except MUSTIC reported lower rates with CRT‑P than with medical therapy. The Assessment Group’s meta-analysis showed a risk ratio for hospitalisation due to heart failure of 0.61 (95% CI 0.44 to 0.83). The Assessment Group calculated the rate of hospitalisation due to heart failure for each trial and combined these in a meta-analysis. This demonstrated a significant reduction in the rate of heart failure hospitalisations with CRT‑P compared with medical therapy (RR 0.58, 95% CI 0.35 to 0.96). Three trials (CARE-HF, MIRACLE and MUSTIC) reported a benefit with CRT‑P with regard to ‘worsening of heart failure’, the criteria for which differed across the trials. When the trials were combined in a meta-analysis, the risk of worsening heart failure was lower with CRT‑P (RR 0.71, 95% CI 0.63 to 0.80) than with medical therapy. Three trials (CARE-HF, COMPANION and MIRACLE) also reported a greater proportion of patients with improvement in NYHA class with CRT‑P than with medical therapy. The Assessment Group conducted a meta-analysis that showed an increase in the proportion of people with an improvement in NYHA status by 1 or more class with CRT‑P compared with medical therapy (RR 1.68, 95% CI 1.52 to 1.86).

4.1.18 The CARE-HF trial reported that the risk of arrhythmias was higher with CRT‑P than with medical therapy with a risk ratio of 1.54 (95% CI 1.07 to 2.23). The CARE-HF, COMPANION and MIRACLE trials reported a statistically significantly greater proportion of patients with an improvement in NYHA class with CRT‑P compared with medical therapy. The Assessment Group’s meta-analysis of these trials with respect to improvement in 1 or more NYHA class estimated a risk ratio of 1.68 (95% CI 1.52 to 1.86).The MIRACLE trial measured change in LVEF and reported an improvement with CRT‑P at 6 months (increase of 4.6%), compared with a decline (reduction of 0.2%) with medical therapy.

4.1.19 The COMPANION, MIRACLE and MUSTIC trials reported that CRT‑P improved exercise capacity more than medical therapy, as measured by the distance walked in 6 minutes. A meta-analysis of these trials showed a statistically significant improvement with CRT‑P compared with medical therapy (mean difference 38.14 m [95% CI 21.74 to 54.54, p<0.00001]).

4.1.20 All trials found that CRT‑P improved MLWHFQ score compared with medical therapy, and a meta-analysis by the Assessment Group indicated a mean difference of −10.33 (95% CI −13.31 to −7.36). CARE-HF also reported improvements in EQ-5D, with a mean increase of 0.13 in the EQ-5D scores for CRT‑P compared with medical therapy (95% CI 0.08 to 0.18, p=0.0001). In addition, the mean number of QALYs gained was higher with CRT‑P at 18 months (CRT‑P 0.95 versus medical therapy 0.82, p<0.0001).

CRT‑D compared with medical therapy

4.1.21 Data from the COMPANION trial were available for a comparison of CRT‑D with medical therapy. Results from this trial reported reductions with CRT‑D compared with medical therapy for the outcomes of all-cause mortality (HR 0.64, 95% CI 0.48 to 0.86), total cardiac deaths (RR 0.68, 95% CI 0.50 to 0.93), sudden cardiac deaths (HR 0.44, 95% CI 0.23 to 0.86) and heart failure hospitalisations (RR 0.77, 95% CI 0.63 to 0.93). There were no differences between CRT‑D and medical therapy for the outcomes of heart failure deaths (HR 0.73, 95% CI 0.47 to 1.11) and non-cardiac deaths (CRT‑D 2.3% versus medical therapy 3.6%). The proportions of people with improvements in 1 or more NYHA class (57% versus 38%, p<0.001), in exercise capacity (change in 6-minute walking distance; 46 m versus 1 m, p<0.001), and in health-related quality of life scores at 6 months measured by MLWHFQ score (−26 versus −12, p<0.001) were statistically significantly greater with CRT‑D than with medical therapy.

CRT‑P compared with CRT‑D

4.1.22 Data from the COMPANION trial were available for a comparison of CRT‑P with CRT‑D. However, the Assessment Group highlighted that the trial was not powered to compare CRT‑P with CRT‑D and therefore all results for this comparison should be interpreted with caution. The results indicated that rates of total cardiac deaths and sudden cardiac deaths were higher with CRT‑P than with CRT‑D, with risk ratios of 1.38 (95% CI 1.06 to 1.81) and 2.72 (95% CI 1.58 to 4.68) respectively.

4.1.23 The Assessment Group stated that reporting of adverse events was limited in all 4 trials. The rate of unsuccessful implantation ranged between 4.6% (CARE-HF) and 12.6% (COMPANION). Device-related deaths reported in the trials varied between 0.2% (CARE-HF) and 0.8% (COMPANION) for those with CRT‑P and 0.5% for those with CRT‑D (COMPANION). In the COMPANION trial, the rate of moderate or severe adverse events related to the implantation procedure was 10% with CRT‑P and 8% with CRT-D, with 13% and 9% of CRT‑P and CRT‑D implantations unsuccessful. Reported complications included lead displacements, infections and coronary sinus dissections.

People with heart failure as a result of left ventricular systolic dysfunction and cardiac dyssynchrony who are also at risk of sudden cardiac death as a result of ventricular arrhythmias (population 3)

4.1.24 The Assessment Group identified 9 trials comparing CRT‑D with ICDs in people with heart failure as a result of left ventricular systolic dysfunction and cardiac dyssynchrony who are also at risk of sudden cardiac death due to ventricular arrhythmia (population 3). In 6 trials (CONTAK-CD [n=490], MIRACLE ICD [n=369], MIRACLE ICD II [n=186], Pinter [n=72], RethinQ [n=172] and Rhythm ICD [n=179]), all patients had a CRT‑D device implanted, but the CRT function was switched off in the comparator group, therefore providing active ICD therapy only. In 3 trials (MADIT‑CRT [n=1820], RAFT [n=1798] and Piccirillo [n=31]), the comparator group received an ICD-only device. Participants also received medical therapy (except in the Piccirillo trial). No trials comparing CRT‑D with medical therapy or with CRT‑P were identified for this population.

4.1.25 The RethinQ and RHYTHM ICD trials were described as double blind but the Assessment Group stated that details were not reported. The MADIT‑CRT trial was considered to be at high risk of bias because diagnosis of heart failure and decisions on therapy or hospital admission were made by physicians who were aware of trial group assignments.

4.1.26 Most patients in MADIT‑CRT, MIRACLE ICD II and RAFT were in NYHA class II while in CONTAK‑CD, MIRACLE ICD, RethinQ and RHYTHM ICD the majority of patients were in NYHA class III. NYHA class was not reported by Pinter, although the eligibility criteria specified mild to moderate heart failure. The majority of patients in Piccirillo were in NYHA class I. Average length of follow-up ranged between 6 and 40 months across the trials. Prolonged QRS duration on ECG of 120 ms or more to 150 ms or more in different trials) was used to define cardiac dyssynchrony in all trials except RethinQ in which people with a short QRS interval (less than 130 ms) were included on the basis of mechanical dyssynchrony apparent on echocardiography. Mean LVEF ranged from 21% (CONTAK-CD) to 26% (RethinQ). Crossover between groups was reported in all trials. Crossover from the ICD to the CRT‑D treatment arm ranged from 2.8% (Pinter) to 12.4% (MADIT‑CRT) of patients, the most common reason for crossover being heart failure events. Crossover from CRT‑D to ICD ranged from 0% (RethinQ) to 7.5% (MADIT‑CRT) of patients, most commonly because of difficulties with the implanted device.

4.1.27 The Assessment Group stated that only 4 trials were adequately powered to show a difference in their primary outcomes. These were death or non-fatal heart-failure events (MIRACLE ICD), left ventricular end-systolic volume change from baseline (Pinter), composite outcome of death from any cause or heart failure leading to hospitalisation (RAFT), and proportion of patients with improved peak oxygen consumption during cardiopulmonary exercise testing and survival from CRT‑D system-related complications (RethinQ). However, the Assessment Group highlighted that the MIRACLE ICD trial was not powered to detect a morbidity or mortality difference.

4.1.28 All trials reported data on all-cause mortality, but not as a primary outcome, and only the MADIT‑CRT and RAFT trials compared the results statistically. The MADIT‑CRT trial found no statistically significant difference in all-cause mortality with a risk ratio of 0.94 (95% CI 0.67 to 1.32), whereas the RAFT trial found a statistically significant reduction in mortality with CRT‑D compared with ICDs with a risk ratio of 0.80 (95% CI 0.67 to 0.94). The Assessment Group’s analysis of reported data from the remaining trials suggested no statistically significant difference in all-cause mortality between groups in any of the trials. In the Piccirillo trial no deaths occurred in either group. The Assessment Group also conducted a meta-analysis pooling data from the trials, which found that CRT‑D reduced the risk of all-cause mortality significantly compared with ICDs with a risk ratio of 0.84 (95% CI 0.73 to 0.96). The Assessment Group commented that the results were strongly influenced by the RAFT trial and when this trial was removed from the analysis the differences were no longer statistically significant.

4.1.29 All but the MADIT‑CRT and Piccirillo trials reported data on total cardiac deaths, although only the RAFT trial compared results between groups statistically. When these trials were combined in a meta-analysis by the Assessment Group, the overall risk ratio was 0.82 (95% CI 0.67 to 1.00) in favour of CRT‑D compared with ICDs. The results were no longer significant if the RAFT trial was excluded from the meta-analysis. Rates of death due to heart failure or sudden cardiac death were not statistically significantly different across the CRT‑D and ICD groups in any of the trials reporting these, and this was also the case in the meta-analyses conducted by the Assessment Group. The pooled risk ratio for death due to heart failure for CRT‑D compared with ICD was 0.64 (95% CI 0.18 to 2.22, p=0.48) while for sudden cardiac death it was 1.45 (95% CI 0.43 to 4.92, p=0.55). No statistically significant differences between groups for 6-month cumulative survival were reported by the MIRACLE ICD or RethinQ trials, with rates of 92.4% and 94.2% for the CRT‑D group respectively and rates of 92.2% and 98.8%, for the ICD group respectively. The RAFT trial indicated that the probability of event-free survival at 5 years was 57.6% with CRT‑D and 48.7% with ICDs.

4.1.30 The RAFT trial found a reduction in heart failure hospitalisations with CRT‑D compared with ICD with a risk ratio of 0.75 (95% CI 0.63 to 0.89). The CONTAK-CD and Piccirillo trials found no significant difference between groups, but combining all 3 trials in a meta-analysis demonstrated that CRT‑D statistically significantly reduced the risk of hospitalisation by 25% compared with ICDs with a risk ratio of 0.75 (95% CI 0.64 to 0.88, p=0.0005). The CONTAK-CD, MICRACLE ICD, MIRACLE ICD II and Pinter trials reported the number of patients experiencing at least 1 episode of ventricular tachycardia or ventricular fibrillation. The Assessment Group stated that the proportions were similar between groups across the trials and a meta-analysis demonstrated no statistically significant difference in the number of people experiencing at least 1 arrhythmia with a risk ratio of 0.90 (95% CI 0.71 to 1.14, p=0.38).

4.1.31 The MIRACLE ICD, MIRACLE ICD II and RHYTHM ICD trials reported an improvement in mean or median NYHA class among people with CRT‑D compared with people with ICDs. Combining these studies in a meta-analysis resulted in a statistically significant mean difference of –0.19 (95% CI –0.34 to –0.05, p=0.008). The CONTAK-CD, RethinQ and Piccirillo trials reported the proportion of people who improved by 1 or more NYHA class; the RethinQ and Piccirillo trials found a statistically significant improvement with CRT‑D compared with ICDs but the CONTAK-CD trial found no statistically significant difference between groups in the number of people with improvement in NYHA class. The meta-analysis of these studies showed no statistically significant difference between the 2 groups, with a risk ratio of 1.81 (95% CI 0.91 to 3.60).

4.1.32 Three trials (CONTAK‑CD, MADIT‑CRT, MIRACLE ICD II) reported a statistically significant improvement from baseline in mean LVEF among people with CRT‑D compared with ICDs, whereas 3 trials (MIRACLE ICD, Pinter, RethinQ) reported no statistically significant difference between the groups in change from baseline. The Piccirillo and RHYTHM ICD trials reported data but did not provide a statistical analysis of change in LVEF. The Assessment Group’s meta-analysis indicated a statistically significant improvement in LVEF with CRT‑D compared with ICDs with a mean difference in mean LVEF of 2.15 (95% CI 0.45 to 3.86, p=0.01).

4.1.33 All except the RAFT and Piccirillo trials reported change in exercise capacity measured by distance walked in 6 minutes, exercise duration, peak VO₂ (peak oxygen uptake), and proportion of patients with an increase of at least 1.0 ml/kg body weight/minute in peak oxygen consumption. The Assessment Group’s meta-analysis indicated that there was a greater improvement in exercise capacity with CRT‑D than with ICD, as demonstrated by change from baseline in peak VO₂, with data pooled from 5 trials indicating a mean difference of 0.75 ml/kg body weight/minute between groups (95% CI 0.23 to 1.27, p=0.005) and as demonstrated by distance walked in 6 minutes, with data pooled from 6 trials indicated a mean difference of 14.5 metres between groups (95% CI 2.9 to 26.1, p=0.01).

4.1.34 All except the RAFT and Piccirillo trials reported changes in quality of life at 6 months using the MLWHF questionnaire. Meta-analysis of these trials indicated an statistically significant improvement in quality of life with CRT‑D compared with ICDs with a mean difference of –6.9 in MLWHFQ scores between groups (95% CI −10.4 to −3.4, p=0.0001). The Pinter trial also reported statistically significant improvements between groups for the General Health component of the SF-36 when comparing baseline to 6-month changes.

4.1.35 The Assessment Group stated that reporting of adverse events was inconsistent across the trials. The RAFT trial compared adverse events between groups statistically and found that rates of device- or implantation-related complications within 30 days of implantation were significantly higher in the CRT‑D group than in the ICD group (13.3% compared with 6.8%, p<0.001); this also applied to device-related hospitalisation (20% versus 12.2%, p<0.001), lead dislodgement requiring intervention (6.9% versus 2.2%) and coronary sinus dissection (1.2% versus 0%). After the first 30 days, MADIT‑CRT reported 4.5 serious device-related adverse events per 100 device-months with CRT‑D compared with 5.2 events with ICDs.

Manufacturers’ submission

4.1.36 The manufacturers presented an individual patient data network meta-analysis (IPD NMA) using meta-regression to assess the effectiveness of ICDs, CRT‑P and CRT‑D in different subgroups of people with heart failure. The manufacturers stated that given the heterogeneous patient population, an IPD NMA would allow the differences in baseline risk and relative treatment effects of the devices to be better captured. Although the outcome data for longer follow-up periods were available, only data up to the original trial protocol-specified ‘data-lock’ follow-up period were included in the analysis. The median ‘data-lock’ period in the included trials ranged from 3 to 41 months while the longest individual follow-up data in the IPD NMA were recorded at 7.5 years. Data from the data-lock’ follow-up period were included in the analysis to reduce bias introduced by crossover from a control group to a device when blinding was removed.

4.1.37 Data on outcomes relevant to the economic analysis, that is, all-cause mortality, all-cause hospitalisation and health-related quality of life were synthesised from the individual patient data. The data for all-cause mortality were aggregated from 13 trials, all-cause hospitalisation from 11 trials and health-related quality of life from 3 trials. The IPD NMA adopted a multivariate approach using meta-regression to assess the effects of the different interventions on people with heart failure for the 3 outcomes, taking into account the impact of different patient characteristics (covariables).

4.1.38 The manufacturers identified covariables using previous NICE guidance, a review of existing risk scores, a review of treatment effect modifiers in previous trials and clinical opinion. The following covariables were found to be important and were investigated further for the interactions with baseline risk and treatment effects of devices on mortality, hospitalisation and health-related quality of life: age, sex, country (US versus non-US), New York Heart Association (NYHA) class, ischaemic aetiology, LVEF, QRS duration and left bundle branch block (LBBB). The other covariables identified but not included in the analyses were history of myocardial infarction, sinus rhythm, mechanical dyssynchrony, prior pacing, history of prior ventricular tachycardia or ventricular fibrillation, non-sustained ventricular tachycardia on ECG, inducible ventricular tachycardia on electrophysiology testing and diuretic use.

4.1.39 For the IPD NMA the manufacturers estimated a baseline rate for each outcome, independent of the treatment effects of the devices, from pooled data of all patients randomised to medical therapy in the trials reporting the specific outcome irrespective of the device assessed. Device-specific treatment effects were then estimated using all available data from the trials. In both stages of the analysis, patient characteristics were included as covariables to incorporate baseline risk and treatment effect modifiers.

4.1.40 The manufacturers’ NMA found CRT‑D to have the greatest effect on all-cause mortality. Age, sex, QRS duration and LBBB status were found to independently predict the magnitude of benefit associated with the devices. For all-cause hospitalisation, therapy with all devices reduced admission rates across all NYHA classes. For health-related quality of life, baseline estimates using EQ-5D from the individual patient data showed that patients in NYHA classes I and II had similar values to the population norms, whereas patients in NYHA classes III and IV had values that were progressively lower. Limited EQ-5D data were available for all devices in patients in NYHA class IV, and defibrillator devices (ICD and CRT‑D) in patients in NYHA class III. The analyses showed that CRT‑D had an adverse impact on health-related quality of life of patients with NYHA class III and IV symptoms. This was in contrast to CRT‑P which statistically significantly improved health-related quality of life in these patients. The manufacturers stated that this result was counterintuitive and therefore assumed that CRT–D had the same effect on health-related quality of life as CRT‑P for patients in NYHA classes III and IV, and ICDs had an effect on health-related quality of life in patients in NYHA classes I and II only. The results from the IPD NMA are academic in confidence, and therefore cannot be presented here.

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 to 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, left bundle branch block (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.

Assessment Group’s model and results

4.2.2 The Assessment Group adapted the model developed by Fox et al. for Cardiac resynchronisation therapy for the treatment of heart failure (NICE technology appraisal guidance 120). This was a Markov model with monthly cycles over a lifetime time horizon and all future costs and benefits discounted at a rate of 3.5%. Population 1, that is, people at risk of sudden cardiac death as a result of ventricular arrhythmias, had not been included in the previous model and the Assessment Group adapted the pathways for this population based on reviews of other models and expert opinion. The Assessment Group model compared the strategies (devices or optimal pharmacological therapy [OPT]) as outlined in the scope. For population 1, ICD plus OPT was compared with OPT alone. For population 2, CRT‑P plus OPT and CRT‑D plus OPT were compared with each other and with OPT alone in a series of pairwise analyses.  For population 3, the Assessment Group reported an incremental analysis comparing OPT, ICD plus OPT, CRT‑P plus OPT, and CRT‑D plus OPT.

4.2.3 The treatment pathways in the model allowed crossover, that is, patients initially treated with OPT could subsequently receive devices when considered clinically necessary, for example if they were hospitalised for heart failure or for major arrhythmia. The model also allowed for upgrade of devices, that is, patients initially treated with a device could subsequently change devices if considered clinically necessary.

4.2.4 aplan–Meier curves for overall survival for the medical therapy arms of the relevant trials were used to derive the baseline mortality risk of patients receiving OPT. Parametric (Weibull) models were fitted to these curves to derive approximate hazard functions and to estimate survival beyond trial follow-up. For patients receiving devices, device-specific hazard ratios or relative risks from the Assessment Group’s meta-analyses were applied to baseline mortality. Data for the model parameters were sourced mainly from the trials but also from the literature.

4.2.5 The utility values for people in stable health states were modelled to vary according to their NYHA class. A utility value of 0.57 was used for hospitalisation and a decrement of 0.05 was applied to health states involving surgery (including initial device implantation, device-related complications and device replacement) and a decrement of 0.1 for infection was also included. The model assumed similar utility values for patients with CRT, ICDs, or OPT alone for the same NYHA class. To estimate resource use, the Assessment Group considered costs of devices, device implantation, device-related complications and maintenance, costs of hospitalisation because of heart failure or severe arrhythmia, and costs of medication and heart transplantation.

4.2.6 The Assessment Group’s economic model indicated that initial management of patients at increased risk of sudden cardiac death (population 1) with ICDs in combination with OPT had an ICER of £19,479 per QALY gained compared with initial treatment with OPT alone . The ICERs in other groups analysed (that is, people with remote myocardial infarction, a broad population with mild to moderate heart failure, and patients with non-ischaemic cardiomyopathy) ranged between £14,231 to £29,756 per QALY gained. For patients with heart failure as a result of left ventricular systolic dysfunction and cardiac dyssynchrony (population 2), the base-case analysis suggested the addition of either CRT‑P or CRT‑D to OPT in the initial stage of management of heart failure could be considered cost effective if the maximum acceptable ICER was £30,000 per QALY gained and that CRT‑D plus OPT when compared with CRT‑P plus OPT was also likely to be cost effective if the maximum acceptable ICER was £30,000 per QALY gained. For people with both conditions (population 3), the Assessment Group’s base-case analysis found that if the maximum acceptable ICER was £30,000 per QALY gained, initial management with any implantable device (ICD, CRT‑P or CRT‑D) was not a cost-effective strategy.

Manufacturers’ submission

4.2.7 The manufacturers’ submission included a survival-based model to estimate the relative cost effectiveness of OPT, ICDs, CRT‑P and CRT‑D, compared with each other in a fully incremental analysis. The UK NHS and PSS perspective was adopted and the model included monthly cycles and a lifetime time horizon. Costs and health benefits were discounted at 3.5%.The model had 2 health states: alive and dead. The manufacturers stated that death is the main clinical event for the patient population considered in this appraisal and that by modelling mortality directly via a series of covariate-based regression equations (for baseline risk and treatment effect), the long-term data available could be used to carry out the analysis taking into account heterogeneity. The manufacturers stated that this approach would also allow for a coherent regression-based approach to modelling health-related quality of life and all-cause hospitalisation that was aligned with the mortality analysis, and that the alternative approach of capturing the effect on health-related quality of life using time-dependent progression through NYHA classes was technically difficult and less accurate.

4.2.8 Individual patient data from 12,638 adults were used to inform the manufacturers’ model. All had heart failure with LVEF equal to or less than 35%, and/or were at risk of sudden cardiac death. The results for this heterogeneous group of patients were generated in a 2-stage process. In the first stage, estimates of costs incurred and QALYs gained were derived for all relevant devices from 4992 patient profiles based on 4 LVEF categories, 4 NYHA classes of heart failure, 2 aetiologies of heart disease (ischaemic or non-ischaemic), 3 QRS categories, 2 LBBB categories, 2 sex groups and 13 age categories. In the second stage, results were aggregated over LVEF, age and sex categories and presented for 48 subgroups according to NYHA class, QRS duration, LBBB status and aetiology of heart disease (ischaemic or non-ischaemic). In the revised analysis, based on a request by the Committee, the manufacturers combined the ischaemic and non-ischaemic disease patient groups together, therefore presenting cost-effectiveness results for 24 subgroups rather than 48 as in the original submission.

4.2.9 In order to model baseline mortality risk, a parametric survival curve (Weibull) was fitted to a pooled data set of all patients randomised to medical therapy in the included trials. The baseline probability of all-cause hospitalisation was estimated as the number of events per month from patients randomised to medical therapy using individual patient data from 11 clinical trials. The relative effectiveness of devices was estimated from the IPD NMA. In the base case, the manufacturers assumed a constant duration of effect of 7.5 years for all-cause mortality, followed by linear tapering up to 20 years. The assumption that 7.5 years is the duration of constant effect was based on the longest individual follow-up duration included in the IPD.

4.2.10 The manufacturers justified this assumption of a constant treatment effect for 7.5 years on the basis that there was no evidence that the proportional hazards assumption in the Cox regression analysis was violated and that long-term follow-up in some trials showed maintenance of benefit beyond the data-lock period. Long-term data from the CARE-HF trial showed that the hazard ratio for all-cause mortality at a mean follow-up of 56 months in the CRT‑P arm and 50 months in the OPT arm was 0.77 (95% CI 0.63 to 0.93) compared with a hazard ratio of 0.64 (95% CI 0.48 to 0.85) at a mean follow-up of 29.4 months (data-lock period), despite 39% of patients in the OPT arms crossing over to receive a CRT device. Similarly long-term data from the MADIT II trial reported the hazard ratio for all-cause mortality as 0.77 (0.65, 0.91) at a median follow-up of 7.6 years compared with a hazard ratio of 0.69 (0.51, 0.93) at average follow-up of 20 months, despite 34% of control patients crossing over to a device during follow-up.

4.2.11 The manufacturers’ model introduced a conservative assumption that the benefit would taper linearly following the period of assumed constant benefit such that the hazard ratio would reach 1.0 at 20 years. However, the manufacturers also presented sensitivity analyses assuming lifelong constant treatment effects without any tapering as a more optimistic scenario, and assuming a constant duration of effect for 5 years followed by linear tapering up to year 20 as a more conservative scenario. The manufacturers also provided a sensitivity analysis assuming a constant duration of effect up to the average duration of trial-specific data-lock durations (2.54 years), followed by linear tapering thereafter up to 20 years.

4.2.12 UK device longevity estimates were derived from NHS data from the Central Cardiac Audit Database on all implants from 2000 to 2011 (around 40,000 implants). Device-specific median survival estimates were obtained by fitting Weibull curves to these data. Median time to device failure in the model was 7.1 years for ICDs, 10.4 years for CRT‑P and 5.8 years for CRT‑D.

4.2.13 The manufacturers’ model did not include short-term device-related adverse events because the costing approach used to derive total implant costs covered additional costs such as short-term adverse events. Infection following device implantation was included in the model for all procedures subsequent to the initial implant. The proportion of patients experiencing infection was estimated to be 0.8% and this was applied to all devices in the first cycle following battery replacement.

4.2.14 Resource use included device-related costs, medication costs, and costs related to disease progression. IPD from the trials were used to estimate the mean number of all-cause hospitalisation events per month and the mean number of days of hospitalisation per month. The hospital costs were derived from the NHS Schedule of Reference Costs and combined with the average mean length of hospital stay. The cost of hospitalisation because of heart failure was estimated to be £2295 and the non-heart failure hospitalisation cost was estimated to be £2448. Device costs were sourced from the average selling prices across the manufacturers for ICD, CRT‑P and CRT‑D devices and leads sold in the UK to the NHS. Implantation costs were taken from the Healthcare Resource Group tariff values. Device costs, including implantation costs, were estimated to be £15,248, £8281 and £17,849 for ICD, CRT‑P and CRT‑D devices respectively.

4.2.15 The manufacturers’ approach assumed that the medical therapy received before and during device treatment would be regarded as optimal by current standards. It also assumed that the drug costs in any given month were based on baseline NYHA class. The proportions of patients using different combinations of a range of drugs, according to their NYHA class, were derived from a combination of the clinical studies identified in the systematic review and expert opinion. The recommended daily dose for each commonly used drug was sourced from the British National Formulary (BNF). The total cost of medical therapy per 1-month cycle was £14.28 for NYHA class I patients and between £22.13 and £22.30 for patients in NYHA classes II to IV.

4.2.16 For modelling health-related quality of life, general UK population utilities were used at baseline and disease-specific decrements taken from the CARE-HF, MADIT‑CRT and RAFT trials were applied. The impact of each intervention on patients’ health-related quality of life was incorporated as an intervention-specific increment, calculated as the difference between baseline and the first follow-up period. These estimates were derived from published sources and IPD from the trials included in the manufacturers’ systematic review of clinical-effectiveness studies. It was assumed that the health-related quality of life benefit from an intervention observed at 6 months would be maintained for 5 years and thereafter would decrease in a linear manner. The model assumed that at 10 years a CRT or ICD device will have no additional benefit over OPT.

4.2.17 The manufacturers stated that combining the ischaemic and non-ischaemic groups (as described in section 4.2.8) resulted in more precise results because each subgroup included larger patient numbers. The base-case deterministic results were presented for 24 subgroups defined by NYHA class, QRS duration and LBBB status, highlighting the most cost-effective treatment strategy if the maximum acceptable ICER was £30,000, £25,000 and £20,000 per QALY gained for each subgroup, as requested by the Committee. The manufacturers highlighted that the ICERs were in some cases close to the threshold values and also predicted that the ICERs would fall because acquisition costs of the medical devices are expected to reduce over time.

The base-case ICERs for the predicted optimal treatment strategies are summarised in table 1. The ICERs at £30,000 per QALY gained are presented only when the higher threshold changes the optimal strategy.

Table 1 Predicted optimal treatment strategies and base-case ICERs at different ICER thresholds

		Optimal treatment strategy and base-case ICER
NYHA class	QRS duration (ms)	Maximum acceptable ICER £25,000 per QALY gained	Maximum acceptable ICER £30,000 per QALY gained
Without LBBB
I	<120	ICD £24,074	ICD
I	120-149	ICD £16,253	ICD
I	≥150	CRT‑D £21,759	CRT‑D
II	<120	ICD £24,465	ICD
II	120-149	ICD £16,813	ICD
II	≥150	CRT‑D £23,738	CRT‑D
With LBBB
I	<120	OPT	OPT
I	120-149	CRT‑D £21,672	CRT‑D
I	≥150	CRT‑D £17,470	CRT‑D
II	<120	OPT	OPT
II	120-149	CRT‑D £20,704	CRT‑D
II	≥150	CRT‑D £17,664	CRT‑D
Without LBBB
III	<120	OPT	ICD £27,826
III	120-149	CRT‑D £23,349	CRT‑D
III	≥150	CRT‑P £13,930	CRT‑D £25,200
IV	<120	OPT	OPT
IV	120-149	CRT‑P £22,578	CRT‑P
IV	≥150	CRT‑P £17,175	CRT‑P
With LBBB
III	<120	OPT	OPT
III	120-149	CRT‑D £24,875	CRT‑D
III	≥150	CRT‑P £10,494	CRT‑D £28,646
IV	<120	OPT	OPT
IV	120-149	CRT‑P £18,664	CRT‑P
IV	≥150	CRT‑P £14,500	CRT‑P
ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life year; ICD, implantable cardioverter defibrillator; CRT‑D, cardiac resynchronisation therapy with defibrillation; CRT‑P, cardiac resynchronisation therapy with pacing; LBBB, left bundle branch block; NYHA, New York Heart Association; OPT, optimal pharmacological therapy.

4.2.18 The manufacturer explored the impact of alternative assumptions about the duration of constant mortality benefit on the cost effectiveness of the devices (section 4.2.11). The results for the sensitivity analysis assuming constant mortality benefit for 5 years then linear tapering up to 20 years are summarised in table 2. The ICERs for ICD compared with OPT in the subgroup of patients with NYHA class II with a QRS duration between 120 and 149 ms with LBBB and in the patients with NYHA class III, a QRS duration of 120 and 149 ms without LBBB were not available in the manufacturers’ sensitivity analyses. Using the manufacturers’ additional analyses, the Assessment Group estimated the ICERs in these 2 subgroups to be £23,144 and 24,514 per QALY gained respectively.

Table 2 Predicted optimal treatment strategies with ICERs at different thresholds assuming 5-year duration of constant effect on mortality

		Optimal treatment strategy and ICER
NYHA class	QRS duration (ms)	Maximum acceptable £25,000 per QALY gained	Maximum acceptable £30,000 per QALY gained
Without LBBB
I	<120	OPT	ICD £25,714
I	120–149	ICD £16,253	ICD
I	≥150	CRT‑D £23,168	CRT‑D
II	<120	OPT	ICD £26,181
II	120–149	ICD £16,813	ICD
II	≥150	CRT‑D £21,888	ICD £25,267
With LBBB
I	<120	OPT	OPT
I	120–149	CRT‑D £23,080	CRT‑D
I	≥150	CRT‑D £18,615	CRT‑D
II	<120	OPT	OPT
II	120–149	CRT‑D £22,049	CRT‑D
II	≥150	CRT‑D £18,879	CRT‑D
Without LBBB
III	<120	OPT	ICD £29,309
III	120–149	CRT‑D £24,311	CRT‑D
III	≥150	CRT‑P £14,203	CRT‑D £26,586
IV	<120	OPT	OPT
IV	120–149	CRT‑P £22,702	CRT‑P
IV	≥150	CRT‑P £17,330	CRT‑P
With LBBB
III	<120	OPT	OPT
III	120–149	CRT‑P £14,489	CRT‑D £26,192
III	≥150	CRT‑P £10,769	CRT‑P
IV	<120	OPT	OPT
IV	120–149	CRT‑P £18,817	CRT‑P
IV	≥150	CRT‑P £14,666	CRT‑P
ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life year; ICD, implantable cardioverter defibrillator; CRT‑D, cardiac resynchronisation therapy with defibrillation; CRT‑P, cardiac resynchronisation therapy with pacing; LBBB, left bundle branch block; NYHA, New York Heart Association; OPT, optimal pharmacological therapy

4.2.19 In a sensitivity analysis, the manufacturers explored the impact of including costs of counselling for patients receiving defibrillator devices (ICD or CRT‑D) on the cost-effectiveness results. Based on clinical advice, the manufacturers assumed that all patients would need 1 consultation session with an arrhythmia nurse and a small proportion of patients (0.5%) would need 1 full psychiatry visit and 4 sessions of cognitive behavioural therapy. The expected per-patient cost of counselling was estimated to be £27.95 and was applied in the first model cycle for patients receiving defibrillator therapy (CRT‑D or ICD). The overall impact on the ICERs in all subgroups was negligible with no changes in predicted optimal treatment strategy at the maximum acceptable ICERs of £20,000, £25,000 or £30,000 per QALY gained.

4.2.20 The manufacturers conducted further univariate deterministic sensitivity analyses by varying by 25% non-purchase costs associated with defibrillator devices (ICD or CRT‑D) (£5556), all upfront implant costs for patients receiving a CRT‑P (£8281), battery replacement costs for defibrillator devices (ICD or CRT‑D) (£2748), and the cost of an outpatient visit (£110). Analyses using upper and lower quartile data for hospitalisation costs for heart failure and non-heart failure (£2295 and £2448 respectively) were also presented. The results indicated that the ICERs were robust to alterations in cost parameters. A full probabilistic sensitivity analysis, exploring uncertainties associated with all parameters simultaneously, was not conducted by the manufacturers. Limited information was presented on the probabilistic sensitivity analyses conducted for 4 different patient profiles, that is: men with and without LBBB, and women with and without LBBB with baseline characteristics of the MADIT-CRT trial (age of 65-years, NYHA class II, ischemic etiology, QRS >150ms, LVEF between 20 and 25% patients). The resulting cost-effectiveness acceptability curves indicated that CRT-D had a similar probability of being cost-effective as OPT at a maximum acceptable ICER of £20,000 per QALY gained.

4.2.21 The manufacturers also explored the likelihood of crossover or device upgrades in clinical practice. The manufacturers stated that information on device upgrades in the UK clinical practice is sparse because audit conducted by the National Institute for Cardiovascular Outcomes Research (NICOR) did not make a distinction between upgrades and new implants. The manufacturers identified a single-centre, retrospective observational study from the UK that reported an ICD to CRT‑D upgrade rate of 3.8% during a mean follow-up period of 48 months (Scott et al. 2012). The manufacturers also cited country-wide data from Sweden that indicated an annual upgrade rate from ICD to CRT (type unspecified) of 0.5%. Clinical opinion from interventional cardiologists also indicated that crossover or device upgrades were rare in clinical practice because of the complexity of the procedure and increased risk of complications. The cardiologists also considered that it was highly unlikely that patients with a CRT‑P indication would receive a CRT‑D device with the defibrillator function switched off but with the intention to switch it on if the patient developed a life-threatening arrhythmia in the future.

Assessment Group’s critique

4.2.22 The Assessment Group critiqued the manufacturers’ model and validated the results of the cost-effectiveness analyses. It stated that although the interventions compared in the submission were consistent with the NICE scope, not all of them were included as comparators for all patient subgroups in the submission. For example, ICDs were excluded for NYHA class IV, CRT‑P was excluded for NYHA classes I and II and QRS duration of less than120 ms across all NYHA classes, and CRT‑D was excluded for QRS duration of less than120 ms across all NYHA classes. The Assessment Group stated that these exclusions appeared to be reasonable based on clinical opinion. The Assessment Group stated that the fundamental features of the condition and the impact of the interventions seemed to be captured in the manufacturers’ model structure and although no assessment of internal validity of the model was included in the submission, it appeared to be reasonable. The Assessment Group stated that, overall, the derivation of costs and assumptions presented in the submission appeared to be appropriate and consistent with previous approaches. The Assessment Group stated that the manufacturers’ approach to estimating utility differed from that of most previous models (including Buxton et al. and Fox et al.) in which no benefit from the intervention had been assumed. In addition, the impact of treatment-related adverse events (such as infection and perioperative complications) on quality of life, which was considered in previous models, was not included in the manufacturers’ submission. The Assessment Group also stated that the manufacturers’ submission did not provide any details of the variables included in the probabilistic sensitivity analyses, such as mean values, distributions and variability of those variables. Credible intervals for mean ICERs for the most cost-effective interventions were also not reported. The Assessment Group therefore noted that it was not clear whether the methods of assessment of parameter uncertainty were appropriate and whether the estimates of variation in the probabilistic sensitivity analyses were appropriate to reflect uncertainty in parameter estimates.

4.2.23 The Assessment Group also undertook exploratory sensitivity analyses to determine the main drivers of cost effectiveness in the 3 out of 24 subgroups that consisted of the largest number of patients in the IPD network. These subgroups were patients in NYHA class II with a QRS duration equal to or more than 150 ms with LBBB (subgroup 1), patients in NYHA class III with a QRS duration equal to or more than 150 ms and with LBBB (subgroup 2), and patients in NYHA class II with a QRS duration of less than 120 ms without LBBB (subgroup 3). These exploratory univariate sensitivity analyses assessed the impact on the ICERs for the devices for the 3 subgroups of varying model parameters related to:

• the treatment effect on mortality (±10%) and hospitalisation (±25%)
• the duration for which tapering effect on mortality was modelled (no tapering effect, tapering effect up to 10 years)
• device costs (±10%) and
• utility increments with devices (±25%).

The results of these analyses showed that for these 3 subgroups the ICERs for the devices were most sensitive to changes to the assumptions regarding the magnitude of treatment effect on mortality and the duration for which the tapering effect was applied.

4.2.24 The Assessment Group commented that the manufacturers’ estimation that 0.5% of patients with defibrillators would need additional psychiatry visits and cognitive behavioural therapy sessions was an underestimate but noted that the costs used in the model were based on a more realistic proportion of 5%. The Assessment Group also commented that the per-patient cost of cognitive behavioural therapy was likely to be an underestimate because many patients would need more than 4 sessions and would attend in smaller groups or individual sessions. Based on a conservative assumption of 6 individual sessions per patient, the Assessment Group estimated that the per-patient counselling cost could be as high as £70 compared with the cost of £27.95 used by the manufacturers. The Assessment Group conducted sensitivity analyses using higher counselling costs for subgroups 1, 2 and 3 and stated that increasing counselling costs had a minimal impact on the ICERs.

4.2.25 The Assessment Group’s clinical advisers stated that an upgrade from ICD to CRT‑D was reasonable and would occur if someone with a pre-existing ICD developed a CRT indication (that is, progressive heart failure and QRS prolongation). The advisers also agreed with the manufacturers that it would be clinically implausible to implant a CRT‑D device and not switch the defibrillator on.

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 TA95, 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 the appraisal. The Committee heard that the new evidence available since TA95 was issued was observational and reconfirmed the effectiveness of ICDs in preventing sudden death in people with these cardiac conditions. The Committee concluded that the recommendation in TA95 regarding familial cardiac conditions and after surgical repair of congenital heart disease did not need to be changed and that the population to be considered in the current appraisal were 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 is a significant predictor of risk. It heard that measurement of left ventricular ejection fraction (LVEF) in clinical practice is often imprecise and therefore that, although a threshold of an LVEF of less than 35% is considered an important indicator, further stratification using this measure would not be a useful basis to guide 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 the aetiology of cardiomyopathy (ischaemic or non-ischaemic) does not influence the effectiveness of ICD therapy or the clinical judgement about its use in primary prevention. The Committee further heard from clinical specialists that prolonged QRS duration and the presence of left bundle branch block (LBBB) on electrocardiogram (ECG) increases the risk of sudden cardiac death. The Committee also noted that ICDs were not recommended for patients with severe symptoms of heart failure (NYHA class IV) in TA95. The Committee concluded that some of the clinical characteristics specified in TA95 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 relevant for clinical practice.

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 less than 35% 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 like mechanical dyssynchrony are not 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 with ease, 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 reactions associated with implantable devices. 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 noted that patients with a defibrillator device have driving and employment restrictions, further affecting their quality of life. 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 for patients in enabling them to make an informed choice. 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 patient experts and the clinical specialists emphasised the importance of pre- and post-placement counselling in maximising the benefits from device implantation. 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. The Committee concluded that post-implantation counselling and support are important elements of any care package, including the implantable devices being considered in this appraisal.

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 to 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 were 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 was based on the 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 IPD available from approximately 12,500 patients, which covered 95% of the patients included in studies identified in the systematic review, was a rich and very 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 full transparency and the benefit of peer review. However, the Committee noted that the results, where comparable, were largely consistent with the Assessment Group’s analyses. 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 and also 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. 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 rare 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. 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. The Committee also noted that the assumption of a constant effect was followed by tapering up to 20 years. The manufacturers stated that the assumption of 20 years was more conservative than the assumption used in the models informing the TA95 and TA120 recommendations. 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. In the absence of 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 concluded that, on balance, a constant mortality benefit for 5 years followed by tapering up to 20 years would be the most reasonable assumption.

4.3.14 The Committee noted that the base-case ICERs were not particularly sensitive to alterations in 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 technologies. 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 ms were clinically implausible because LBBB cannot occur with a normal QRS duration (less than 120 ms). In addition, there was 1 subgroup (NYHA class IV, QRS duration less than120 ms, 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.

4.3.15 The Committee discussed the cost-effectiveness results in the 3 subgroups with a normal QRS duration (less than 120 ms) across NYHA classes I, II and III. The Committee noted that ICDs were compared with OPT and were associated with ICERs above £25,000 per QALY gained. The Committee heard from the clinical specialists that the group most likely to benefit from ICDs are young and no longer symptomatic. However, the Committee stated that it could not make recommendations based on age. Having heard of the distress caused by shocks from ICDs, the Committee queried whether ICDs were used in practice for asymptomatic people in NYHA class I and a QRS duration of less than 120 ms. The Committee heard that patients would have been symptomatic at presentation with heart failure but would have become classified as NYHA I as a result of optimal pharmacological therapy. Taking into consideration the uncertainties of evidence synthesis identified in section 4.3.11, and the lack of a full exploration of parameter uncertainty in the model (section 4.3.14), the Committee concluded that ICDs were not a cost-effective option in these subgroups.

4.3.16 The Committee then discussed the cost-effectiveness results for the 4 subgroups with NYHA class IV, a QRS duration of more than 120 ms 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 in these patients and defibrillator devices may worsen quality of life because of defibrillator shocks. The Committee considered that, because of this, CRT‑D would also not be used in these subgroups and noted that this was in line with the scope of the appraisal. 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 ms), both with and without LBBB.

4.3.17 The Committee discussed whether resynchronisation therapy was appropriate in the subgroups with a QRS duration between 120 and 149 ms. 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 ms, the prognosis could be adversely affected with CRT‑D. The Committee also heard that another recently published individual patient meta-analysis reported that the clinical benefit of CRT in patients with QRS durations between 120 and 140 ms was uncertain (Cleland et al. 2013). The Assessment Group also highlighted a small trial (RethinQ) in people with narrow or slightly prolonged QRS durations of less than130 ms, which was inconclusive overall on mortality, with wide confidence intervals, but the point estimate of effect favoured ICDs. The Committee was concerned that the subgroups with a QRS duration between 120 and 149 ms were heterogeneous, containing 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 would benefit from resynchronisation. The Committee concluded that because it had not been formally presented with this trial evidence, clinical opinion on other factors that affect the decision about CRT devices in patients with slightly prolonged QRS duration would need to be taken into consideration when making recommendations for subgroups with QRS durations between 120 and 149 ms.

4.3.18 The Committee discussed the results for people in NYHA class I or II with a QRS duration between 120 and 149 ms. It noted that for the 2 subgroups without LBBB, ICDs were presented as the optimal strategy compared with OPT, with ICERs of approximately £17,000 per QALY gained. For the 2 subgroups with LBBB, however, the Committee noted that CRT‑D was presented as the optimal strategy. Following the discussion in 4.3.17, the Committee considered that CRT‑D could not be clearly recommended in this group of patients 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, and around £23,000 per QALY gained for NYHA class II. The Committee concluded that ICDs are a cost-effective treatment option in patients in NYHA classes I and II, with a QRS duration between 120 and 149 ms, both with and without LBBB.

4.3.19 The Committee then discussed the results for the 2 subgroups including people in NYHA class III with a QRS duration between 120 and 149 ms. It noted that CRT‑D was presented as the optimal strategy for the subgroups with and without LBBB. In line with section 4.3.17, 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 provided 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. The Committee was conscious 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 to 149 ms, ICDs could be considered cost effective in the subgroup without LBBB and CRT‑D could be considered cost effective in the subgroup with LBBB.

4.3.20 The Committee discussed the 4 subgroups of people in NYHA class I and II with a prolonged QRS duration of 150 ms or more, both with and without LBBB. The Committee was aware that a QRS duration of more than 150 ms indicates cardiac dyssynchrony as well as an increased risk of arrhythmic death. 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 ms, both with and without LBBB.

4.3.21 The Committee discussed the results in the 2 subgroups including people in NYHA class III with a QRS duration of 150 ms or more. 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 greater than £30,000 per QALY gained. The Committee noted that the ICER for CRT‑P compared with OPT was estimated to be £10,000 per QALY gained. The Committee concluded that for people in NYHA class III, with QRS duration more than 150 ms, CRT‑D could be considered cost effective in those without LBBB and CRT‑P could be considered cost effective in those with LBBB.

Summary of Appraisal Committee’s key conclusions

TAXXX	Appraisal title:		Section
Key conclusion
ICDs are recommended for treating people: ·         with previous serious ventricular arrhythmia, or ·         who have a familial cardiac condition with a high risk of sudden death, or ·         who have undergone surgical repair of congenital heart disease, or ·         with heart failure who have an LVEF of 35% or less, and have NYHA class I–II symptoms, and a QRS duration of 120–149 milliseconds or NYHA class III symptoms and a QRS duration of 120–149 milliseconds with no left bundle branch block. CRT‑D is recommended for people with heart failure who have LVEF of 35% or less, NYHA class I–II symptoms, and a QRS duration of 150 milliseconds or more. CRT‑D or CRT‑P is recommended for people with heart failure with an LVEF of 35% or less, and have NYHA class III symptoms and a QRS duration of 120–149 milliseconds with left bundle branch block or NYHA class III symptoms and a QRS duration of 150 milliseconds or more without left bundle branch block. CRT‑P is recommended for people with heart failure with an LVEF of 35% or less, and have NYHA class III symptoms and a QRS duration of 150 milliseconds or more with left bundle branch block or NYHA class IV symptoms and a QRS duration of 120 milliseconds or more.			1.1 1.2 1.3 1.4
Current practice
Clinical need of patients, including the availability of alternative treatments		The Committee heard from the patient experts that people with heart failure may have breathing difficulties, swelling in the ankles, legs and abdomen and severe tiredness, and become mentally less alert; and consequently experience poor quality of life. The Committee also heard that people who have a higher risk of ventricular arrhythmia may live in constant fear of sudden death. Antiarrhythmic drug treatment needs to be adjusted frequently which may be demanding for many patients, and the side effects of antiarrhythmic treatment include fatigue which can result in people becoming dependent on their family and carers for day-to-day activities. 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.	4.3.2
The technology
Proposed benefits of the technology How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?		The Committee noted that the use of implantable devices was associated with favourable outcomes compared with medical therapy and 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. No claim for innovation was presented to the Committee.	4.3.9
What is the position of the treatment in the pathway of care for the condition?		The Committee heard from the clinical specialists that reduced left ventricular function is a significant predictor of risk of sudden cardiac death in patients with heart failure, and prolonged QRS duration and the presence of left bundle branch block further increase the risk. The Committee heard from the clinical specialists that patients in NYHA class IV are severely symptomatic and are at a very high risk of death from progressive heart failure, and improving heart function by biventricular pacing is regarded as more important for this group than prevention of arrhythmic death by ICD. The Committee heard that CRT devices are indicated in people who have a reduced LVEF and have heart failure symptoms despite receiving optimal pharmacological therapy.	4.3.5 4.3.6
Adverse reactions		The Committee heard that the shocks delivered by defibrillator devices (ICD and CRT‑D) may cause anxiety and have an adverse effect on quality of life. 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.	4.3.8
Evidence for clinical effectiveness
Availability, nature and quality of evidence		The systematic reviews conducted by the Assessment Group and the manufacturers identified largely the same trial evidence. Different approaches were taken by the Assessment Group and the manufacturers for synthesising the results. The Committee considered that the individual patient data available from approximately 12,500 patients, which covered 95% of the patients included in studies identified in the systematic review, was a rich and very important data source and agreed that results from the IPD NMA should be used to inform the economic modelling.	4.3.9 4.3.10
Relevance to general clinical practice in the NHS		The Committee noted that the approach taken by the manufacturers allows consideration of population groups based on clinical characteristics that are considered important by clinicians in making decisions about device implantation in current clinical practice.	4.3.10
Uncertainties generated by the evidence		The Committee was aware that the IPD network meta-analyses have not yet been published and therefore lacked full transparency and the benefit of peer review. 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 and also 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. The Committee also noted the improvement of pharmacological treatment over time and concluded that treatment effects derived from older trials could be overestimated and that results should be interpreted with caution.	4.3.11
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?		The manufacturers’ NMA indicated that age, sex, QRS duration and LBBB status independently predicted the magnitude of benefit on all-cause mortality associated with the devices. The Committee was concerned that emerging evidence showed that the subgroups with a QRS duration between 120 and 149 ms were heterogeneous, containing some patients in whom CRT may be inappropriate.	4.1.38 4.3.17
Estimate of the size of the clinical effectiveness including strength of supporting evidence		The results from the manufacturers’ IPD NMA are academic in confidence. The Committee noted 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.	4.1.38 4.3.9
For reviews (except rapid reviews): How has the new clinical evidence that has emerged since the original appraisals (TA95 and TA120) influenced the current (preliminary) recommendations?		The Committee concluded that some of the clinical characteristics specified in TA95 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. The clinical specialists clarified that measures like mechanical dyssynchrony (described in TA120) are not considered clinically useful. 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.	4.3.5 4.3.7 4.3.7
Evidence for cost effectiveness
Availability and nature of evidence		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, left bundle branch block (LBBB) status and aetiology of heart disease, and reported cost-effectiveness results for each subgroup. The Committee noted that the approach taken by the manufacturers allows consideration of population groups based on clinical characteristics that are considered important by clinicians in making decisions about device implantation.	4.2.1 4.3.10
Uncertainties around and plausibility of assumptions and inputs in the economic model		The Committee agreed that the duration of constant mortality benefit of 7.5 years was too optimistic because average duration across the trials was 2.54 years. The Committee was concerned that the combined effect of uncertainty in some parameters had not been explored in a probabilistic sensitivity analysis and 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 technologies.	4.3.13 4.3.14
Incorporation of health-related quality-of-life benefits and utility values Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?		The manufacturers’ model assumed that the health-related quality of life benefit from a device would be maintained for 5 years and thereafter would decrease in a linear manner so that there would be no additional benefit after 10 years. No	4.2.16
Are there specific groups of people for whom the technology is particularly cost effective?		The base case deterministic results were presented for 24 subgroups defined by NYHA class, QRS duration and LBBB status, highlighting the most cost-effective strategy at a maximum acceptable ICER of £30,000, £25,000 and £20,000 per QALY gained for each subgroup.	4.2.17
What are the key drivers of cost effectiveness?		The manufacturers’ base-case ICERs for the devices were most sensitive to changes to the assumptions regarding the magnitude of treatment effect on mortality, duration of constant effect and the duration for which the tapering effect was applied.	4.2.19, 4.2.23
Most likely cost-effectiveness estimate (given as an ICER)		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. Most likely ICERs for the Committee’s preferred assumption are presented in table 2 of the evidence section.	4.3.14 4.2.19
Additional factors taken into account
Patient access schemes (PPRS)		N/A
End-of-life considerations		N/A
Equalities considerations and social value judgements		Potential equality issues raised during the appraisal were outside the remit of NICE technology appraisal guidance.

5 Implementation

5.1 Section 7(6) of the National Institute for Health and Care Excellence (Constitution and Functions) and the Health and Social Care Information Centre (Functions) Regulations 2013 requires clinical commissioning groups, NHS England and, with respect to their public health functions, local authorities to comply with the recommendations in this appraisal within 3 months of its date of publication.

OR

Section 7(6) of the National Institute for Health and Care Excellence (Constitution and Functions) and the Health and Social Care Information Centre (Functions) Regulations 2013 requires clinical commissioning groups, NHS England and, with respect to their public health functions, local authorities to comply with the recommendations in this appraisal within [insert number] months of its date of publication. The normal period of compliance, of 3 months, has been extended for this technology because [insert reason]. This extension is made under Section 7(5) of the Regulations.

5.2  [Please delete this paragraph if the technology is not recommended] When NICE recommends a treatment ‘as an option’, the NHS must make sure it is available within the period set out in the paragraph above. This means that, if a patient has [indication] and the doctor responsible for their care thinks that [technology name] is the right treatment, it should be available for use, in line with NICE’s recommendations.

5.3 [Please delete this paragraph if not applicable] The Department of Health and the manufacturer have agreed that [technology] will be available to the NHS with a patient access scheme which makes [technology] available with a discount. The size of the discount is commercial in confidence. It is the responsibility of the manufacturer to communicate details of the discount to the relevant NHS organisations. Any enquiries from NHS organisations about the patient access scheme should be directed to [NICE to add details at time of publication]

5.4 NICE has developed tools [link to www.nice.org.uk/guidance/TAXXX] to help organisations put this guidance into practice (listed below). [NICE to amend list as needed at time of publication]

• Slides highlighting key messages for local discussion.
• Costing template and report to estimate the national and local savings and costs associated with implementation.
• Implementation advice on how to put the guidance into practice and national initiatives that support this locally.
• A costing statement explaining the resource impact of this guidance.
• Audit support for monitoring local practice.

6 Related NICE guidance

Details are correct at the time of consultation. Further information is available on the NICE website.

Published

• Insertion of a subcutaneous implantable cardioverter defibrillator for prevention of sudden cardiac death. NICE interventional procedure guidance 454 (2013).
• Chronic heart failure: Management of chronic heart failure in adults in primary and secondary care. NICE clinical guideline 108 (2010).
• Cardiac resynchronisation therapy for the treatment of heart failure. NICE technology appraisal guidance 120 (2007).
• Implantable cardioverter defibrillators for arrhythmias. NICE technology appraisal guidance 95 (2006).

7 Proposed date for review of guidance

7.1 NICE proposes that the guidance on this technology is considered for review by the Guidance Executive in May 2017. NICE welcomes comment on this proposed date. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.

Professor Ken Stein
Vice Chair, Appraisal Committee
December 2013

8 Appraisal Committee members, guideline representatives and NICE project team

8.1 Appraisal Committee members

The Appraisal Committees are standing advisory committees of NICE. Members are appointed for a 3-year term. A list of the Committee members who took part in the discussions for this appraisal appears below. There are 4 Appraisal Committees, each with a chair and vice chair. Each Appraisal Committee meets once a month, except in December when there are no meetings. Each Committee considers its own list of technologies, and ongoing topics are not moved between Committees.

Committee members are asked to declare any interests in the technology to be appraised. If it is considered there is a conflict of interest, the member is excluded from participating further in that appraisal.

The minutes of each Appraisal Committee meeting, which include the names of the members who attended and their declarations of interests, are posted on the NICE website.

Dr Amanda Adler (Chair)
Consultant Physician, Addenbrooke's Hospital

Professor Ken Stein (Vice Chair)
Professor of Public Health, University of Exeter Medical School

Dr Ray Armstrong
Consultant Rheumatologist, Southampton General Hospital

Dr Jeff Aronson
Reader in Clinical Pharmacology, University Department of Primary Health Care, University of Oxford

Professor John Cairns
Professor of Health Economics Public Health and Policy, London School of Hygiene and Tropical Medicine

Matthew Campbell-Hill
Lay member

Dr Lisa Cooper
Echocardiographer, Stockport NHS Foundation Trust

Dr Maria Dyban
General Practitioner

Professor Fergus Gleeson
Consultant Radiologist, Churchill Hospital, Oxford

Robert Hinchliffe
HEFCE Clinical Senior Lecturer in Vascular Surgery and Honorary Consultant Vascular Surgeon, St George's Vascular Institute

Dr Neil Iosson
General Practitioner

Anne Joshua
Associate Director of Pharmacy, NHS Direct

Dr Rebecca Kearney
Clinical Lecturer, University of Warwick

Terence Lewis
Lay Member

Dr Miriam McCarthy
Consultant, Public Health, Public Health Agency

Professor Ruairidh Milne
Director of Strategy and Development and Director for Public Health Research at the National Institute for Health Research (NIHR) Evaluation, Trials and Studies Coordinating Centre at the University of Southampton

Dr Peter Norrie
Principal Lecturer in Nursing, DeMontfort University

Christopher O’Regan
Head of Health Technology Assessment and Outcomes Research, Merck Sharp and Dohme

Professor Stephen Palmer
Professor of Health Economics, Centre for Health Economics, University of York

Dr Sanjeev Patel
Consultant Physician and Senior Lecturer in Rheumatology, St Helier University Hospital

Dr John Pounsford
Consultant Physician, Frenchay Hospital, Bristol

Dr Danielle Preedy
Lay Member

Dr John Rodriguez
Assistant Director of Public Health, NHS Eastern and Coastal Kent

Alun Roebuck
Consultant Nurse in Critical and Acute Care, United Lincolnshire NHS Trust

Cliff Snelling
Lay Member

Dr Nerys Woolacott
Senior Research Fellow, Centre for Health Economics, University of York

Dr Nicky Welton
Senior Lecturer in Biostatistics/Health Technology Assessment, University of Bristol

8.2 NICE project team

Each technology appraisal is assigned to a team consisting of 1 or more health technology analysts (who act as technical leads for the appraisal), a technical adviser and a project manager.

Anwar Jilani
Technical Lead

Raisa Sidhu
Technical Adviser

Jeremy Powell
Project Manager

9 Sources of evidence considered by the Committee

A. The assessment report for this appraisal was prepared by Southampton Health Technology Assessments Centre:

• Colquitt Jl, Mendes D, Clegg AJ et al, Implantable cardioverter defibrillators for the treatment of arrhythmias and cardiac resynchronisation therapy for the treatment of heart failure: systematic review and economic evaluation, January 2013

B. The following organisations accepted the invitation to participate in this appraisal as consultees and commentators. They were invited to comment on the draft scope, assessment report and the appraisal consultation document (ACD). Organisations listed in I, II and III were also invited to make written submissions and have the opportunity to appeal against the final appraisal determination.

I. Manufacturers/sponsors:

• Biotronik UK
• Boston Scientific
• Medtronic UK
• Sorin Group
• St Jude Medical UK

II. Professional/specialist and patient/carer groups:

• Arrhythmia Alliance
• British Association for Nursing in Cardiovascular Care
• British Cardiovascular Society
• British Heart Foundation
• Heart Rhythm UK
• Primary Care Cardiovascular Society
• Royal College of Nursing
• Royal College of Pathologists
• Royal College of Physicians
• SADS UK

III. Other consultees:

• Department of Health
• Welsh Assembly Government

IV. Commentator organisations (without the right of appeal):

• Actavis UK
• Association of British Healthcare Industries
• Commissioning Support Appraisals Service
• Department of Health, Social Services and Public Safety for Northern Ireland
• Healthcare Improvement Scotland

C. The following individuals were selected from clinical specialist and patient expert nominations from the consultees and commentators. They participated in the Appraisal Committee discussions and provided evidence to inform the Appraisal Committee’s deliberations. They gave their expert personal view on implantable cardioverter defibrillators and cardiac resynchronisation therapy by attending the initial Committee discussion and/or providing written evidence to the Committee. They are invited to comment on the ACD.

• Wendy Churchouse, BNF Arrhythmia Specialist Nurse, nominated by the Royal College of Nursing - clinical specialist
• Dr Roy Gardner, Consultant Cardiologist, nominated by the British Society for Heart Failure - clinical specialist
• Dr Chris Plummer, Consultant Cardiologist, nominated by Heart Rhythm UK - clinical specialist
• Caroline Holmes, Senior Associate, Patient Services at Arrhythmia Alliance nominated by Arrhythmia Alliance - patient expert

D. Representatives from the following manufacturers/sponsors attended Committee meetings. They contributed only when asked by the Committee chair to clarify specific issues and comment on factual accuracy.

• Biotronik UK
• Boston Scientifi
• Medtronic UK
• Sorin Group
• St Jude Medical UK