The Department of Health has asked the National Institute for Health and Clinical Excellence (NICE) to produce guidance on using dronedarone in the NHS in England and Wales. The Appraisal Committee has considered the evidence submitted by the manufacturer and the views of non-manufacturer consultees and commentators, and clinical specialists and patient experts.

This document has been prepared for consultation with the consultees. It summarises the evidence and views that have been considered, and sets out the draft recommendations made by the Committee. NICE invites comments from the consultees and commentators for this appraisal (see appendix B) and the public. This document should be read along with the evidence base (the evaluation report), which is available from www.nice.org.uk

The Appraisal Committee is interested in receiving comments on the following:

• Has all of the relevant evidence been taken into account?
• Are the summaries of clinical and cost effectiveness reasonable interpretations of the evidence?
• Are the provisional recommendations sound and a suitable basis for guidance to the NHS?
• Are there any aspects of the recommendations that need particular consideration to ensure we avoid unlawful discrimination against any group of people on the grounds of gender, race, disability, age, sexual orientation, religion or belief?

Note that this document is not NICE's final guidance on this technology. The recommendations in section 1 may change after consultation.

After consultation:

• The Appraisal Committee will meet again to consider the evidence, this appraisal consultation document and comments from the consultees.
• At that meeting, the Committee will also consider comments made by people who are not consultees.
• After considering these comments, the Committee will prepare the final appraisal determination (FAD).
• Subject to any appeal by consultees, the FAD may be used as the basis for NICE’s guidance on using dronedarone in the NHS in England and Wales.

For further details, see the ‘Guide to the technology appraisal process’ (available at www.nice.org.uk).

The key dates for this appraisal are:

Closing date for comments: 28 January 2010

Second Appraisal Committee meeting: 24 February 2010

Details of membership of the Appraisal Committee are given in appendix A, and a list of the sources of evidence used in the preparation of this document is given in appendix B.

Note that this document is not NICE's final guidance on this technology. The recommendations in section 1 may change after consultation.

1 Appraisal Committee’s preliminary recommendations

1.1 Dronedarone is not recommended for the treatment of atrial fibrillation.

1.2 People with atrial fibrillation who are currently receiving dronedarone should have the option to continue treatment until they and their clinicians consider it appropriate to stop.

2 The technology

2.1 Dronedarone (Multaq, Sanofi-Aventis) is an anti-arrhythmic drug belonging to the benzofurane class of anti-arrhythmic compounds. Dronedarone has a marketing authorisation for the treatment of adult clinically stable patients with a history of, or current non-permanent atrial fibrillation to prevent recurrence of atrial fibrillation or to lower ventricular rate.

2.2 The summary of product characteristics (SPC) states that the use of dronedarone in unstable patients with New York Heart Association (NYHA) class III and IV heart failure is contraindicated. The SPC also states that the use of dronedarone in stable patients with recent NYHA class III heart failure or with left ventricular ejection fraction less than 35%, is not recommended.

2.3 According to the SPC, the most frequently observed adverse events in people receiving dronedarone are elevated blood creatinine levels and prolongation of the QT interval. Other common adverse events include bradycardia, gastrointestinal events such as diarrhoea and vomiting, rashes, pruritus, fatigue and asthenia. For full details of side effects and contraindications, see the SPC.

2.4 The recommended dosage of dronedarone is 400 mg twice daily. Dronedarone is available in 400 mg tablets and comes in packs of 20 tablets or 60 tablets. The manufacturer has stated that the cost to the NHS of a pack of 20 tablets will be £22.50 and the cost of a pack of 60 tablets will be £67.50 (excluding VAT). The cost per day based on the recommended dosage will be £2.25 (excluding VAT). Costs may vary in different settings because of negotiated procurement discounts.

3 The manufacturer’s submission

The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of dronedarone and a review of this submission by the Evidence Review Group (ERG; appendix B).

3.1 The manufacturer’s submission presented the use of dronedarone in two positions in the in rhythm control treatment pathway for paroxysmal and persistent atrial fibrillation. According to ‘The management of atrial fibrillation’ (NICE clinical guideline 36), beta-blockers should be the first-line treatment for people with paroxysmal atrial fibrillation and people with persistent atrial fibrillation in whom an anti-arrhythmic drug is needed to maintain sinus rhythm after cardioversion (in addition to anti-coagulation). For those in whom beta-blockers are contraindicated, not tolerated or ineffective, the guideline states that amiodarone, sotalol or a class 1c agent should be used. The choice of second-line anti-arrhythmic drug depends on the type of atrial fibrillation (persistent or paroxysmal) and the presence or absence of structural heart disease, left ventricular dysfunction or coronary heart disease. The manufacturer’s submission considered the use of dronedarone as an alternative to amiodarone, sotalol and class 1c agents for people in whom a second-line anti-arrhythmic drug is indicated. The submission also considered the use of dronedarone as a first-line treatment in addition to standard baseline therapy consisting of beta-blockers and anti-coagulation, for people with a CHADS₂ score of 4 or more. The CHADS₂ score is used to estimate the risk of stroke in people with atrial fibrillation so that the potential benefits of anticoagulation can be determined. The score is calculated by giving one point each for the presence of congestive heart failure, hypertension or diabetes mellitus, and being aged 75 years or older. Two points are given if people have had a prior ischaemic stroke or transient ischaemic attack.

3.2 The main clinical evidence on dronedarone in the manufacturer’s submission was based on three randomised controlled trials comparing dronedarone with placebo and one comparing it with amiodarone:

• EURIDIS and ADONIS (n = 1237, 12 months follow-up), phase III multicentre, parallel, randomised, double-blind, placebo-controlled trials. EURIDIS and ADONIS were European and non-European trials of the same design and the results were combined and reported together. Both dronedarone and placebo were taken in addition to baseline therapy, which included beta-blockers and anticoagulation.
• ATHENA (n = 4628, mean follow-up: 21 months), a phase III multicentre, parallel, randomised, double-blind, placebo-controlled trial. Both dronedarone and placebo were taken in addition to baseline therapy, which included beta-blockers and anticoagulation.
• DIONYSOS (n = 504, 6 months follow-up), a phase III multicentre, parallel, randomised, double-blind trial comparing dronedarone with amiodarone.

3.3 The EURIDIS and ADONIS trials included people with paroxysmal or persistent atrial fibrillation or atrial flutter, who had an episode of atrial fibrillation in the 3 months before study entry but were in sinus rhythm on entry into the study. Both trials excluded people with NYHA class III and IV heart failure. The trial population had a mean age of 63 years, and 69% were male. Eleven per cent of people had atrial flutter, 41% had structural heart disease and 17% of people had congestive heart failure. The results showed that fewer people in the dronedarone arm had atrial fibrillation recurrence at 12 months than in the placebo group (64% and 75% respectively, hazard ratio 0.75 95% confidence interval [CI] 0.65 to 0.87, p < 0.001). The median time to atrial fibrillation recurrence was 116 days in the dronedarone group and 53 days in the placebo group. In the dronedarone group, the mean ventricular rate during the first adjudicated atrial fibrillation recurrence was 103 beats per minute compared with 117 beats per minute in the placebo group (p < 0.001). Most adverse events were similar between the study groups (numbers not reported), although there was a lower incidence of hyperthyroidism in the dronedarone group (8.4% and 14.1% respectively, p = 0.002) and a higher incidence of serum creatinine elevation (2.4% and 0.2% respectively, p = 0.004). A post-hoc analysis showed that 23% of people in the dronedarone groups had been admitted to hospital or had died at 12 months versus 31% in the placebo groups (hazard ratio 0.73, 95% CI 0.57 to 0.93, p = 0.01).

3.4 The ATHENA trial included people with paroxysmal or persistent atrial fibrillation or atrial flutter with at least one of the following additional risk factors for a major cardiovascular event: aged 70 years or older; hypertension needing treatment with at least two antihypertensive drugs of different classes; diabetes mellitus; previous stroke; transient ischaemic attack or systemic embolism; left atrial diameter at least 50 mm; left ventricular ejection fraction of 40% or less. During the course of the trial, overall mortality figures were lower than expected. As a consequence the inclusion criteria were changed so that people were required to be aged 75 years or older to be eligible, or aged 70–75 years with at least one of the previously specified risk factors, and people younger than 70 years of age were no longer eligible. People were excluded from the ATHENA trial if they had permanent atrial fibrillation, an unstable haemodynamic condition, NYHA class IV congestive heart failure or an acute myocardial infarction.

3.5 The ATHENA trial population had a mean age of 72 years, and 53% were male. The primary outcome was a combination of first hospitalisation because of a cardiovascular event and death before hospitalisation.  In the dronedarone group, 31.9% of people had a primary composite outcome, of whom 29.3% had a first hospitalisation because of a cardiovascular event and 2.6% died before hospitalisation. In the placebo group, 39.4% of people had a primary composite outcome of whom 36.9% had a first hospitalisation because of a cardiovascular event and 2.5% died before hospitalisation. The hazard ratio for the primary composite outcome in the dronedarone group was 0.76 (95% CI 0.69 to 0.84, p < 0.001). There was a slightly lower rate of all-cause mortality in the dronedarone group than the placebo group; however, this difference was not statistically significant (5% and 6% respectively, hazard ratio 0.84, 95% CI 0.66 to 1.08, p = 0.18). There were fewer deaths from cardiovascular causes in the dronedarone group than the placebo group (2.7% and 3.9% respectively, hazard ratio 0.71, 95% CI 0.51 to 0.98, p = 0.03). A post-hoc analysis of the ATHENA trial found that dronedarone was associated with a statistically significant reduction in the risk of stroke compared with placebo (hazard ratio 0.66, 95% CI 0.46 to 0.96, p = 0.027). Another post-hoc analysis reported that dronedarone was associated with a statistically significant reduction in all-cause mortality compared with placebo in people with a CHADS₂ score of 4 or more (data were marked as commercial in confidence).

3.6 In the ATHENA trial, treatment was stopped early in 30.2% of the dronedarone group compared with 30.8% of the placebo group (statistical significance not reported). The main reasons for discontinuation were: adverse events (12.7% in the dronedarone group and 8.1% in the placebo group, p < 0.001), patient’s request (7.5% in each group), and other reasons (9.4% in the dronedarone group and 14.4% in the placebo group). Gastrointestinal events (including diarrhoea and nausea) were the most common adverse events in both groups but were more frequent in the dronedarone than the placebo group (26.2% and 22% respectively, p < 0.001). The dronedarone group also had higher incidences of bradycardia (p < 0.001), QT-interval prolongation (p < 0.001), rash (p = 0.006) and serum creatinine elevation (p < 0.001) than the placebo group.

3.7 The DIONYSOS trial included people with paroxysmal or persistent atrial fibrillation or atrial flutter in whom cardioversion and anti-arrhythmic treatment were indicated and who were also receiving anticoagulation. The trial population had a mean age of 64 years, and two thirds were male. The primary composite endpoint of recurrence of atrial fibrillation or premature study discontinuation because of intolerance or lack of efficacy occurred in 73.9% of the dronedarone group and 55.3% of the amiodarone group (hazard ratio 1.59, p < 0.0001) (disaggregated data for atrial fibrillation were marked as commercial in confidence). This difference was mainly because of fewer incidences of atrial fibrillation recurrence in the amiodarone group. The main safety endpoint was defined as the incidence of occurrence of thyroid-, hepatic-, pulmonary-, neurological-, skin-, eye- or gastrointestinal-specific events, or early study drug discontinuation after any adverse event. This endpoint occurred in 39.3% of the dronedarone group after 12 months of treatment compared with 44.5% in the amiodarone group (hazard ratio 0.80, 95% CI 0.60 to 1.07, p = 0.13). Dronedarone was associated with lower incidences of adverse drug reactions including thyroid dysfunction, significant bradycardia and effects on the central nervous system. There were two (0.8%) deaths in the on-treatment period in the dronedarone group compared with five (2.0%) in the amiodarone group. Additional results of the DIONYSOS trial were provided but marked academic in confidence.

3.8 The manufacturer carried out direct and indirect analyses and a mixed treatment comparison of dronedarone compared with amiodarone, sotalol and class 1c agents (flecainide and propafenone combined) and of each anti-arrhythmic drug compared with placebo. The analyses were conducted for five outcomes: atrial fibrillation recurrence, all-cause mortality, treatment discontinuation, treatment discontinuation because of adverse events and stroke. The meta-analysis demonstrated that atrial fibrillation recurrence was significantly lower with all anti-arrhythmic drugs compared with placebo and that dronedarone was the least effective of all anti-arrhythmic drugs. The analysis (using data from the head-to-head trial, DIONYSOS) showed that the risk of atrial fibrillation recurrence was lower for amiodarone than dronedarone (results were marked as academic in confidence). The results of the comparison of dronedarone with class 1c agents and sotalol for atrial fibrillation recurrence were marked academic in confidence. The mixed treatment comparison indicated that dronedarone was associated with a lower risk of all-cause mortality than amiodarone (odds ratio 3.19, 95% CI 1.16 to 8.76, p = 0.032) and sotalol (odds ratio 5.05, 95% CI 1.84 to 13.87, p = 0.009). There was no statistically significant difference in all-cause mortality between dronedarone and placebo and the manufacturer stated that there was not enough evidence to compare dronedarone with class 1c agents. The mixed treatment comparison showed that dronedarone was associated with a lower risk of stroke than placebo (odds ratio 1.44, 95% CI 1.19 to 1.76, p = 0.015), but there was no difference between dronedarone and sotalol or amiodarone. However, this analysis was based on limited data.

3.9 The manufacturer also submitted results of an analysis of safety using pooled data from five placebo-controlled dronedarone trials (ATHENA, EURIDIS and ADONIS plus two additional trials which did not meet inclusion criteria for the main clinical-effectiveness review: ERATO and DAFNE). The analysis included a total of 6285 people and the average duration of dronedarone exposure was 12 months. The main adverse events associated with dronedarone were diarrhoea, nausea or vomiting, serum creatinine elevation, rash, and cardiac events (bradycardia and QT prolongation). The incidence of serious adverse events was similar in the dronedarone and placebo groups (18.0% and 19.7% respectively) and these were mainly related to infections and infestations, gastrointestinal disorders, and cardiac disorders. There were more early discontinuations in the dronedarone group than the placebo group (11.8% and 7.7% respectively) and the most common reason for stopping dronedarone was diarrhoea (statistical significance not reported).

3.10 The model used in the manufacturer’s cost-effectiveness analysis was a discrete event simulation which predicts a person’s course if they are treated with dronedarone compared with the predicted course with alternative treatment pathways. The manufacturer stratified people depending on their type of atrial fibrillation and baseline risk factors into five groups in accordance with ‘The management of atrial fibrillation’ (NICE clinical guideline 36): paroxysmal atrial fibrillation without structural heart disease, paroxysmal atrial fibrillation with coronary heart disease, paroxysmal atrial fibrillation with left ventricular dysfunction, persistent atrial fibrillation without structural heart disease and persistent atrial fibrillation with structural heart disease. For each of these subgroups, the manufacturer evaluated the cost effectiveness of dronedarone at two positions in the care pathway for atrial fibrillation (see section 3.1). For the evaluation of dronedarone as a first-line treatment for people with a CHADS₂ score of 4 or more (in an addition to standard baseline therapy) the comparator was standard baseline therapy alone, that is, beta-blockers and anti-coagulation. For the evaluation of dronedarone as an alternative second-line anti-arrhythmic drug the comparators were amiodarone, sotalol and class 1c agents, depending on the type of atrial fibrillation and baseline risk factors described above.

3.11 The manufacturer’s model used a lifetime time horizon and included four health states: normal sinus rhythm, permanent atrial fibrillation with uncontrolled symptoms, permanent atrial fibrillation with controlled symptoms and death. From the normal sinus rhythm state, people could move to any of the other states. From the two permanent atrial fibrillation health states people could move between these states or to death. Transition between health states was determined by the following events: atrial fibrillation recurrence, acute coronary syndrome, stroke, congestive heart failure, treatment discontinuation, change in symptoms (for the permanent atrial fibrillation states) or death. The baseline risk of these events was taken from the ATHENA trial, extrapolated to a lifetime time horizon and adjusted for each treatment arm using odds ratios from the mixed treatment comparison. All-cause mortality was estimated using age-specific UK life tables (from the Government Actuary's Department) and adjusted for CHADS₂ score. The risk of death after stroke and congestive heart failure events was estimated using published sources.

3.12 The model included adverse events associated with each treatment. Adverse event rates were taken from the pooled analysis of clinical trials for dronedarone, from the DIONYSOS trial for amiodarone, and from the SPCs for sotalol and class 1c agents. Utilities for the health states were taken from the AFTER cohort of the European Heart Survey on atrial fibrillation. The disutilities associated with adverse events were taken from a study undertaken by the manufacturer (n = 127) using a time trade-off approach.

3.13 In the model, drug costs for comparators were taken from the British National Formulary (edition 57). Doses were based on the recommended dosage stated in the SPCs. Drug administration costs were sourced from NHS Reference Costs 2007–08. For dronedarone these consisted of a specialist outpatient visit for treatment initiation and a GP visit for a day-7creatinine test (£202). For comparators, it was assumed that hospitalisation was required for treatment initiation (£249) and 6-monthly GP visits and tests were required for monitoring (£58–76 depending on the treatment). Costs for the majority of health events occurring in the model were taken from published literature. Most events were assumed to incur a one-off cost; but for stroke and congestive heart failure, ongoing daily costs were assumed. Costs for adverse events came from NHS Reference Costs 2007–08. A proportion of adverse events were assumed to require hospitalisation (based on expert clinical opinion) and the rest were assumed to require an outpatient consultant visit. For short-term adverse events, a one-off cost at treatment initiation was incurred and for adverse events with lifetime effects, a 6-monthly GP visit was assumed to be required. Data on resource use were sourced from clinical opinion and published literature.

3.14 In the manufacturer’s base-case analysis, the incremental cost-effectiveness ratios (ICERs) for the analysis of dronedarone if given in addition to standard baseline therapy (for people with a CHADS₂ score of 4 or more) compared with standard baseline therapy alone ranged from £6757  to £7890 per quality-adjusted life year (QALY) gained (incremental costs £3053 and £3307 and incremental benefits 0.45 and 0.42 QALYs for these two ICERs respectively) depending on the type of atrial fibrillation and the presence of structural heart disease, coronary heart disease or left ventricular dysfunction. For the analysis of dronedarone as an alternative anti-arrhythmic drug to amiodarone, the ICERs were £2645 per QALY gained (incremental cost £3528 and incremental benefit 1.33 QALYs) for paroxysmal atrial fibrillation with left ventricular dysfunction and £3113 per QALY gained (incremental cost £3986 and incremental benefit 1.28 QALYs) for persistent atrial fibrillation with structural heart disease. For the comparison of dronedarone with class 1c agents, the ICERs were £20,003 per QALY gained (incremental cost £1980 and incremental benefit 0.10 QALYs) for paroxysmal atrial fibrillation with no structural heart disease and £20,761 per QALY gained (incremental cost £2069 and incremental benefit  0.10 QALYs respectively) for persistent atrial fibrillation with no structural heart disease. For the comparison of dronedarone with sotalol, the ICERs ranged from £1929 to £2197 per QALY gained (incremental costs £3986 and £4384 and incremental benefits 2.07 and 2.00 QALYs for these two ICERs respectively) (depending on the type of atrial fibrillation and the presence or absence of underlying heart disease).

3.15 The manufacturer conducted a number of sensitivity analyses including:

• subgroup analyses based on CHADS₂ scores and gender
• using alternative sources for the baseline distribution of CHADS₂ score
• varying the model time horizon
• assuming a minimum mortality benefit from dronedarone relative to comparators by using the lower end of the 95% CI of the mortality estimate for comparators and the upper end of the 95% CI for dronedarone (rather than the point estimates), and vice versa (that is, assuming a maximum relative mortality benefit from dronedarone)
• using different curve fits for the modelled clinical events such as stroke and treatment discontinuations.
• using different estimates for various parameters including mortality treatment effect, stroke treatment effect, treatment discontinuation, adverse event rate, costs of dronedarone and utilities.

The analyses that had the greatest effect on the ICERs were using a 1-year time horizon (rather than a lifetime time horizon) and assuming a minimum mortality benefit from dronedarone relative to comparators.

3.16 The ERG considered that all relevant trials of dronedarone had been included in the manufacturer’s submission. It noted that the ATHENA trial included people who were older and had a higher risk of a major cardiovascular event than people in the other trials and that the generalisability of this evidence to a lower-risk and younger population was uncertain. The ERG commented that the DIONYSOS trial was the only head-to-head trial of dronedarone versus an anti-arrhythmic drug and therefore the relative efficacy of dronedarone compared with anti-arrhythmic drugs other than amiodarone was unknown. It also noted that the DIONYSOS trial was short-term (6 months). The ERG commented on a number of limitations of the meta-analyses and mixed treatment comparison in the manufacturer’s submission. These included:

• a lack of consideration of clinical and statistical heterogeneity of the studies included in the analyses
• uncertainty about the validity of pooling the individual studies in the different analyses
• few events in the studies
• the use of outcomes that were neither pre-specified endpoints nor centrally adjudicated
• inconsistencies in the selection of studies across the different analyses
• the restriction of randomised controlled trials in the mixed treatment comparison.

The ERG considered that the assumption that class 1c agents have a similar effect on all-cause mortality to dronedarone and no effect on the risk of stroke (made because of a lack of evidence) might not be valid. The ERG noted the inconsistency of direction of effect between results of the direct and indirect analyses and the mixed treatment comparison. For example, none of the differences estimated between the anti-arrhythmic drugs for all-cause mortality based on the head-to-head randomised controlled trial (DIONYSOS) or the results of the indirect meta-analysis were statistically significant; but the mixed treatment comparison showed that dronedarone statistically significantly reduced the odds of all-cause mortality compared with both sotalol and amiodarone. Therefore, the ERG considered that the relative efficacy of dronedarone compared with the other anti-arrhythmic drugs was relatively robust for atrial fibrillation recurrences but was much more uncertain for the other major clinical endpoints. The ERG concluded that the efficacy of dronedarone relative to other anti-arrhythmic drugs remains uncertain because there is only one short-term head-to-head randomised controlled trial comparing dronedarone with another anti-arrhythmic drug. The ERG also noted that although the marketing authorisation for dronedarone states that it should be used to lower ventricular rate, there was little evidence presented on this outcome.

3.17 The ERG considered that in general, the manufacturer’s approach to the economic evaluation met the requirements of the NICE reference case, had an appropriate structure for the decision problem, and was overall, of high quality. However, the ERG noted a number of issues with the cost-effectiveness analysis including concern over the pivotal assumption of mortality benefit:

• The treatment pathways evaluated by the manufacturer might not represent the full range of treatment strategies or sequences for dronedarone.
• The baseline data from the ATHENA trial, used in the model, might not be generalisable to people with atrial fibrillation in the NHS.
• The results of the meta-analyses and mixed treatment comparisons, used in the model, might not be appropriate due to concerns about the methodology of these analyses.
• The lack of health-related quality-of-life data from any of the dronedarone studies.
• The costs attributed to dronedarone and comparators in the model
• The modelled benefits of dronedarone over the longer term because of the short duration of the trials.

3.18 The ERG made revisions to the manufacturer’s model to correct coding errors (relating to adverse events costs and the length of time that mortality treatment benefits were applied). The revisions resulted in considerably lower ICERs than those reported in the manufacturer’s base case for the comparisons of dronedarone with sotalol and amiodarone (ICERs ranged from £1895 to £4014 in the ERG’s analysis applying a lifetime mortality benefit compared with £1980 to £8142 in the base case). The results for dronedarone compared with class 1c agents were unaffected because both drugs were assumed to have the same mortality benefit.

3.19 The ERG stated that the manufacturer’s base case ICERs were based on the estimates of relative effectiveness of dronedarone compared with other anti-arrhythmic drugs derived from the manufacturer’s mixed treatment comparison which it had previously noted concerns about (section 3.16). Therefore, it performed a number of analyses exploring the impact of assumptions about treatment effects on the ICERs. These included:

• assuming that dronedarone has the same effect on mortality across all CHADS₂ subgroups (for the comparison of dronedarone with standard baseline therapy)
• assuming that sotalol and amiodarone have no effect on mortality but keeping the assumed mortality benefit of dronedarone
• assuming that class1c agents, sotalol and amiodarone have the same effect on mortality as dronedarone
• assuming that class 1c agents have a more beneficial effect on mortality than dronedarone
• assuming that class 1c agents have the same effect on stroke as dronedarone
• using effect estimates from a reanalysis of the mixed treatment comparison of all-cause mortality using a wider range of studies than that used in the manufacturer’s analysis.

For most analyses, the ICERs increased but remained below £20,000 per QALY gained. However, when sotalol and amiodarone were assumed to have the same effect on mortality as dronedarone, the ICERs increased to between £55,063 and £119,704. When class 1c agents were assumed to have the same effect on the risk of stroke as dronedarone, the ICERs approximately doubled (to about £38,000 per QALY gained) and when class 1c agents were assumed to have greater mortality benefits than dronedarone, class 1c agents had both higher effectiveness and lower costs than dronedarone. The ERG also explored the uncertainty around treatment initiation, monitoring costs and utility weights used in the model. The impact on the ICERs for all analyses and comparisons was marginal.

3.20 The ERG conducted exploratory analyses to identify the main drivers of the cost-effectiveness results. The first was to explore the effect on the ICERs when all treatment effects are excluded from the economic analysis except atrial fibrillation recurrence. The ICERs either increased to over £1 million per QALY gained or dronedarone was shown to have both higher costs and lower effectiveness than the comparators. The ERG then explored the effect on the ICERs when the treatment effects on all-cause mortality were included in the analysis in addition to atrial fibrillation recurrence. The ICERs decreased to below £10,000 per QALY gained for the comparisons of dronedarone with standard baseline therapy, sotalol and amiodarone but remained high (more than £300,000 per QALY) for the comparison of dronedarone with class 1c agents (because both drugs were assumed to have the same effect on mortality). Based on these analyses, the ERG concluded that the main driver of cost effectiveness of dronedarone compared with standard baseline therapy, sotalol or amiodarone is the reduction in all-cause mortality associated with dronedarone. To explore the main driver of cost effectiveness of dronedarone compared to class 1c agents, the ERG conducted a further analysis including the treatment effects on stroke in addition to atrial fibrillation recurrence and mortality which resulted in ICERs of about £45,000 per QALY gained. The ERG noted that when treatment effects on adverse events were included in the analysis (as in the manufacturer’s base-base analysis), the ICERs were about £18,000 per QALY gained. It therefore concluded that the combined effect of reduced risk of stroke and fewer adverse events was the main driver of cost effectiveness for dronedarone compared with class 1c agents.

3.21 Full details of all the evidence are in the manufacturer’s submission and the ERG report, which are available from www.nice.org.uk/TAXXX

4 Consideration of the evidence

4.1 The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of dronedarone, having considered evidence on the nature of atrial fibrillation and the value placed on the benefits of dronedarone by people with this condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.

4.2 The Committee discussed the positions for dronedarone in the care pathway for atrial fibrillation proposed by the manufacturer. It understood from clinical experts that dronedarone could have a place in the management of atrial fibrillation as a first or second line treatment. It discussed the use of dronedarone as a first line treatment in addition to standard baseline therapy. It noted that the manufacturer had only presented cost effectiveness evidence at this place the care pathway for subgroup of people with a CHADS₂ score of 4 or more. It also noted that the licensed indication for dronedarone is to prevent recurrence of atrial fibrillation or to lower ventricular rate but that the only outcome for which the manufacturer presented analysis in this subgroup was all-cause mortality. The Committee then discussed the use of dronedarone as a second line anti-arrhythmic treatment for atrial fibrillation and considered that the comparators assessed in the manufacturer’s submission; sotalol, class 1c agents and amiodarone, were appropriate.

4.3 The Committee considered that not all possible uses of dronedarone, within its marketing authorisation, had been evaluated in the manufacturer’s submission. In particular, it heard from clinical and patient experts that a potential use of dronedarone would be in people who are unable to tolerate other anti-arrhythmic drugs, in particular amiodarone. However, it was not presented with any data relating to the clinical effectiveness and adverse effects of dronedarone in this group of people. The Committee understood from clinical specialists and patient experts that they considered amiodarone to be an effective anti-arrhythmic drug for controlling atrial fibrillation symptoms but that it had a high level of toxicity and many people were not able to tolerate it. The clinical specialists and patient experts commented that anti-arrhythmic treatment options for people with atrial fibrillation are limited and they would welcome an anti-arrhythmic drug that was effective at controlling atrial fibrillation symptoms and that was more tolerable than amiodarone. The Committee also heard from patient experts that younger people in particular might benefit from an anti-arrhythmic drug that is more tolerable than amiodarone because of the longer length of time that they are likely to need treatment.

Clinical effectiveness

4.4 The Committee discussed the evidence on the effect of dronedarone on atrial fibrillation recurrence and ventricular rate. It considered that the randomised controlled trials demonstrated that dronedarone was more effective than placebo at reducing atrial fibrillation recurrence but less effective than amiodarone. The Committee also noted that the EURIDIS/ADONIS trials showed that the mean ventricular rate during the first adjudicated atrial fibrillation recurrence was statistically significantly lower in the dronedarone group compared with the placebo group. It discussed the results of the meta-analyses and mixed treatment comparison conducted by the manufacturer that indicated that all anti-arrhythmic drugs, including dronedarone, were effective at reducing atrial fibrillation recurrence but that dronedarone was the least effective. The Committee concluded that dronedarone reduced atrial fibrillation recurrence compared with placebo but that it appeared to be less effective for atrial fibrillation recurrence than other anti-arrhythmic drugs.

4.5 The Committee discussed the evidence on the effect of dronedarone on all-cause mortality. It first discussed the results of the DIONYSOS trial, which provided the only direct head-to-head comparison of dronedarone with another anti-arrhythmic drug, and reported fewer deaths in the dronedarone group than the amiodarone group. The Committee noted the small number of deaths in the study and the short follow-up of the trial, and it considered whether all the deaths in the amiodarone group were because of cardiovascular causes (causes of death were marked commercial in confidence). The Committee then considered the results of the ATHENA trial which reported lower cardiovascular mortality in the dronedarone group compared with the placebo group and lower all-cause mortality, although the latter difference was not statistically significant (for the whole trial population). The Committee discussed the cumulative incidence curves for all-cause mortality in the dronedarone and placebo groups. These indicated a marginal difference between the curves until approximately 24 months of follow-up, at this time the curves appeared to diverge. The Committee considered that the result for all-cause mortality (hazard ratio 0.84) was, in part, driven by the number of deaths after 24 months when a relatively small number of people were followed-up. Therefore, the Committee was concerned about the plausibility of the effect of dronedarone on all-cause mortality from the ATHENA trial. The Committee concluded that a reduction in all-cause mortality with dronedarone compared with placebo had not been demonstrated by the ATHENA trial for the whole trial population.

4.6  The Committee discussed the post-hoc subgroup analysis of the ATHENA trial that reported a lower risk of all-cause mortality in the dronedarone group compared with the placebo group for people with a CHADS₂ score of 4 or more. It discussed the use of the CHADS₂ score to predict mortality. It noted published evidence that reported an association between CHADS₂ score and risk of mortality for people who have had a stroke. However, it noted that no evidence had been presented to validate the use of CHADS₂ score for more generally predicting all-cause mortality in people with atrial fibrillation.

4.7 The Committee discussed the results of the manufacturer’s meta-analyses and mixed treatment comparison, which reported a lower risk of all-cause mortality for dronedarone compared with amiodarone, sotalol and placebo. It noted the ERG’s concerns about the methodology used for these analyses. The Committee considered that the results of the mixed treatment comparison and meta-analyses were largely based on the difference in all-cause mortality between dronedarone and placebo in the ATHENA trial. The Committee had previously noted that this difference was not statistically significant and furthermore had concerns about the plausibility of the difference. It also considered that the mixed treatment comparison of dronedarone and amiodarone was, in part, based on the DIONYSOS trial that reported a very small number of deaths in each treatment arm. Overall, the Committee concluded that there was considerable uncertainty about the effect of dronedarone on all-cause mortality. It was not persuaded that a reduction in the risk of all-cause mortality for dronedarone compared with placebo and other anti-arrhythmic drugs had been demonstrated.

4.8 The Committee considered the evidence on the effect of dronedarone on the risk of stroke. It heard from clinical specialists that stroke was a known complication of arrhythmias such as atrial fibrillation. Therefore, drugs that are more effective in reducing atrial fibrillation might be expected to have a greater long-term benefit in relation to stroke prevention. The Committee discussed the post-hoc analysis of the ATHENA trial and noted that the ATHENA investigators concluded that ‘the observation of a reduced rate of stroke in patients receiving dronedarone cannot be considered a definitive conclusion’. It discussed the mixed treatment comparison that demonstrated reduced risk of stroke with dronedarone compared with placebo. It noted that the mixed treatment comparison results were based on a small number of studies with very few events and no studies had any prospective collection of data on stroke incidence. The Committee concluded there was considerable uncertainty about the effect of dronedarone on the risk of stroke. It was not persuaded that a reduction in the risk of stroke with dronedarone compared with other anti-arrhythmic drugs had been demonstrated.

4.9 The Committee discussed the adverse events associated with dronedarone. It noted that the most common adverse events were gastrointestinal. The Committee was aware of evidence from a randomised controlled trial (ANDROMEDA) in which dronedarone was found to be associated with an increased risk of mortality in people with severe congestive heart failure and noted that this trial did not include people with atrial fibrillation. The Committee discussed the SPC which states that dronedarone is contraindicated in people with unstable NYHA class III and IV heart failure, people with stable, recent NYHA class III heart failure and people with left ventricular ejection fraction less than 35%. It considered evidence from the DIONYSOS trial that showed that people in the dronedarone group had fewer adverse events than those in the amiodarone group. However, the Committee noted that this evidence was based on short-term follow-up. It discussed the possibility of serious adverse events such as pulmonary fibrosis, thyroid disease and torsades. The Committee noted that there were very few cases reported in the randomised controlled trials; but it considered that these trials were all relatively short term. The Committee heard from patient experts that they did not consider that the adverse events associated with dronedarone would impact significantly on quality of life for people with atrial fibrillation. Overall, the Committee concluded that the adverse effect profile of dronedarone was likely to be more favourable than amiodarone in the short term but that the risk of adverse events in the long term was unknown.

4.10 The Committee specifically considered the balance between the better short-term side-effect profile and the lower effectiveness of dronedarone compared with amiodarone. It heard from patient experts that some people with atrial fibrillation might prefer to take an anti-arrhythmic drug that has better tolerability, despite it having less effect on atrial fibrillation recurrence. It also heard that effectiveness of an anti-arrhythmic drug for reducing atrial fibrillation recurrence and its tolerability could be more important to some people with atrial fibrillation than longer-term benefits such as a reduction in the risk of stroke or death. The Committee was mindful of the potential value placed on dronedarone by patients when it examined the cost-effectiveness analyses.

Cost effectiveness

4.11 The Committee discussed the economic analysis provided by the manufacturer. It noted the ERG’s conclusion that the approach used was, in general, appropriate and in accordance with the NICE reference case. However, the Committee was concerned about some of the key assumptions in the model, in particular that of a beneficial effect of dronedarone on mortality, the costs of dronedarone and other anti-arrhythmic drugs and the utilities. The Committee noted that the economic analysis was based on pair-wise comparisons of two treatments and did not use incremental analyses that compared all treatments simultaneously. It also noted that the economic analysis did not evaluate all possible uses of dronedarone, within its marketing authorisation, such as after failure of other anti-arrhythmic drugs.

4.12 The Committee noted that in the manufacturer’s base-case analysis, the ICERs ranged from £1900 to £20,800 per QALY gained depending on the type of atrial fibrillation (persistent or paroxysmal), baseline risk factors (structural heart disease, left ventricular dysfunction and coronary heart disease) and the comparator (standard baseline therapy alone, class 1c agents, sotalol or amiodarone). It considered the ERG’s revisions to the model involving correction of coding errors and use of a lifetime time horizon for mortality benefits, which resulted in decreased ICERs ranging from £1700 to £19,000 per QALY gained to be appropriate but noted that these figures did not incorporate changes in other key assumptions, in particular about the magnitude of the mortality benefit associated with dronedarone.

4.13 The Committee discussed the ERG’s analyses that explored the main factors that influenced the cost effectiveness of dronedarone. It noted that when the only effect of all treatments was assumed to be reduction in atrial fibrillation recurrence, the ICER for all comparisons either increased to over £1 million per QALY gained or dronedarone was shown to have higher costs and lower effectiveness than the comparators. It also noted that when the treatment effect on all-cause mortality was included in the analysis in addition to atrial fibrillation recurrence, the ICERs decreased to below £10,000 per QALY gained for the comparisons with standard baseline therapy, sotalol and amiodarone. The Committee concluded that the assumed mortality benefit from dronedarone was a key factor in the economic analysis.

4.14 The Committee considered that the assumption of a beneficial effect of dronedarone on mortality compared with placebo was based on the mixed treatment comparison which itself was largely based on the results of ATHENA trial. It had previously noted concerns about the significance of the difference in all-cause mortality reported in the ATHENA trial. It also noted that no comparison was made between the predicted mortality over time included in the model and the mortality reported in the ATHENA trial. The Committee concluded that this added to the uncertainty about the assumption of a beneficial effect of dronedarone on all-cause mortality, which was a key factor in the economic analysis.

4.15 The Committee discussed the drug costs included in the economic analysis and noted that lower initiation and monitoring costs were attributed to dronedarone than other anti-arrhythmic drugs. It understood from clinical specialists that in practice anti-arrhythmic drugs were usually initiated by a specialist in an outpatient setting. The Committee discussed the manufacturer’s assumption that, in accordance with the SPC, dronedarone does not need ongoing monitoring. It understood from clinical specialists that some monitoring might be carried out as part of good clinical practice. It discussed the ERG’s analyses based on the assumptions that all treatments are initiated in an outpatient setting and that all treatments have the same monitoring costs and concluded that these had a marginal impact on the cost-effectiveness estimates of dronedarone.

4.16 The Committee considered the utilities used in the model and noted the ERG’s concerns about these, particularly that they appeared to exceed general population values for healthy states. It considered the ERG’s analysis that used revised utilities and noted that this had only a small effect on the cost-effectiveness estimates for dronedarone. The Committee considered that the utilities had a small impact on the cost effectiveness of dronedarone and were therefore not a key factor in decision making for this appraisal.

4.17 In light of the above considerations, the Committee discussed the cost effectiveness of dronedarone as a first-line treatment for atrial fibrillation in people with a CHADS₂ score of 4 or more (in addition to standard baseline therapy). It also noted that the licensed indication for dronedarone is to prevent recurrence of atrial fibrillation or to lower ventricular rate but that the only outcome for which the manufacturer presented analysis in this subgroup was all-cause mortality. The Committee was concerned about the validity of the CHADS₂ score as a method of grouping people by risk of all-cause mortality. In addition, the Committee considered that there was substantial uncertainty about the beneficial effect of dronedarone on all-cause mortality. It noted the main driver of cost effectiveness was mortality benefit and when this was removed the costs per QALY gained were extremely high (over £1 million). The Committee concluded that the use of dronedarone in people with a CHADS₂ score of 4 or more (in addition to standard baseline therapy) for the treatment of atrial fibrillation could not be considered to be a cost-effective use of NHS resources.

4.18 The Committee discussed the cost effectiveness of dronedarone as an alternative anti-arrhythmic drug for people whose atrial fibrillation is not controlled by standard baseline therapy. It was concerned about the way that clinical benefits had been modelled, in particular, the plausibility of dronedarone being less effective for atrial fibrillation recurrence than other anti-arrhythmic drugs, but more effective for all-cause mortality and stroke risk. It noted that no adequate explanation had been provided for this mechanism of action. It considered that the effect of dronedarone on stroke risk and all-cause mortality was uncertain and noted that when these treatment effects were not included in the economic analyses, the costs per QALY gained were extremely high (over £1 million). The Committee concluded that the use of dronedarone as an alternative to amiodarone, class 1c agents, or sotalol for anti-arrhythmic treatment of atrial fibrillation could not be considered a cost-effective use of NHS resources.

5 Implementation

5.1 The Secretary of State and the Welsh Assembly Minister for Health and Social Services have issued directions to the NHS on implementing NICE technology appraisal guidance. When a NICE technology appraisal recommends use of a drug or treatment, or other technology, the NHS must provide funding and resources for it within 3 months of the guidance being published. If the Department of Health issues a variation to the 3-month funding direction, details will be available on the NICE website. The NHS is not required to fund treatments that are not recommended by NICE.

5.2 NICE has developed tools to help organisations put this guidance into practice (listed below). These are available on our website (www.nice.org.uk/TAXXX). [NICE to amend list as needed at time of publication]

• Slides highlighting key messages for local discussion.
• Costing report and costing template to estimate the 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

• Atrial fibrillation: national clinical guideline for management in primary and secondary care. NICE clinical guideline 36 (2006). Available from www.nice.org.uk/CG36
• Percutaneous radiofrequency ablation for atrial fibrillation. NICE interventional procedure guidance 168 (2006). Available from www.nice.org.uk/IPG168

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 December 2012. 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.

Peter Clark
Chair, Appraisal Committee
December 2009

Appendix A: Appraisal Committee members and NICE project team

A Appraisal Committee members

The Appraisal Committee is one of NICE’s standing advisory committees. Its 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. The Appraisal Committee meets four times a month except in December, when there are no meetings. There are four Appraisal Committees, each with a chair and vice chair. 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 Darren Ashcroft
Senior Clinical Lecturer, School of Pharmacy and Pharmaceutical Sciences, University of Manchester

Mr Mark Campbell
Director of Standards, Bury Primary Care Trust

Professor Usha Chakravarthy
Professor of Ophthalmology and Vision Sciences, The Queen’s University of Belfast

Professor Peter Clark (Chair)
Consultant Medical Oncologist, Clatterbridge Centre for Oncology

Dr Ian Davidson
Lecturer in Rehabilitation, The University of Manchester

Dr Simon Dixon
Senior Lecturer in Health Economics, University of Sheffield

Dr Martin Duerden
Medical Director, Conwy Local Health Board

Dr Alexander Dyker
Consultant Physician, Wolfson Unit of Clinical Pharmacology

Dr Jon Fear
Consultant in Public Health Medicine, Head of Healthcare Effectiveness NHS Leeds

Miss Paula Ghaneh
Senior Lecturer and Honorary Consultant, University of Liverpool

Professor Carole Haigh
Professor in Nursing, Manchester Metropolitan University

Kevin Hardy
Consultant Physician, St Helens & Knowsley Teaching Hospitals NHS Trust

Alison Hawdale
Lay Member

Professor John Hutton
Professor of Health Economics, University of York

Rachel Lewis
Practice Development Manager,

Professor Jonathan Michaels
Professor of Vascular Surgery, University of Sheffield

Dr Neil Milner
GP, Tramways Medical Centre

Professor Oluwafemi Oyebode
Professor of Psychiatry & Consultant Psychiatrist, The National Centre for Mental Health

Mr Mike Pinkerton
Chief of Business Development – The Rotherham NHS Foundation Trust

Dr Phillip Rutledge
GP and Consultant in Medicines Management, NHS Lothian

Dr Stephen Saltissi
Consultant Cardiologist, Royal Liverpool University Hospital

Mr Paddy Storrie
Lay Member

Dr Cathryn Patricia Thomas
GP and Associate Professor, The University of Birmingham

Mr Mike Wallace
Health Economics & Reimbursement Director, Johnson & Johnson Medical Ltd

Dr Lok Yap
Consultant in Acute Medicine & Clinical Pharmacology, Whittington Hospitals NHS Trust

C NICE project team

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

Sally Gallaugher
Technical Lead

Bhash Naidoo, Zoe Garrett
Technical Advisers

Philip Higham
Project Manager

Appendix B: Sources of evidence considered by the Committee

A The Evidence Review Group (ERG) report for this appraisal was prepared by Centre for Reviews and Dissemination (CRD), Centre for Health Economics (CHE), University of York

• Claire McKenna, et al., Dronedarone for atrial fibrillation and atrial flutter, October 2009.

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, the ERG report and the appraisal consultation document (ACD). Organisations listed in I were also invited to make written submissions. Organisations listed in II and III had the opportunity to give their expert views. Organisations listed in I and II also have the opportunity to appeal against the final appraisal determination.

I Manufacturer/sponsor:

• Sanofi-Aventis

II Professional/specialist and patient/carer groups:

• British Association of Stroke Physicians
• British Cardiovascular Society
• British Heart Foundation
• Coronary Prevention Group
• Heart Rhythm UK
• Primary Care Vascular Society
• Royal College of Nursing
• Royal College of Physicians
• Society of Cardiothoracic Surgeons of Great Britian
• Arrhythmia Alliance
• Atrial Fibrillation Association
• The Ashley Jolly SADS Trust

III Other consultees:

• Department of Health
• Hounslow Primary Care Trust
• Welsh Assembly Government

IV Commentator organisations (did not provide written evidence and without the right of appeal):

• Centre for Reviews and Dissemination (CRD), Centre for Health Economics (CHE), University of York
• Commissioning Support Appraisals Service
• Department of Health, Social Services and Public Safety – Northern Ireland
• Medicines and Healthcare Products Regulatory Agency
• NHS Quality Improvement Scotland
• Heart Failure Research Group, The
• National Collaborating Centre for Chronic Conditions
• NIHR Coordinating Centre for Health Technology Assessment

C The following individuals were selected from clinical specialist and patient expert nominations from the non-manufacturer/sponsor consultees and commentators. They gave their expert personal view on dronedarone for atrial fibrillation and atrial flutter by attending the initial Committee discussion and providing written evidence to the Committee. They are invited to comment on the ACD.

• Dr Andreas Wolff, nominated by Primary Care Cardiovascular Society – clinical specialist
• Dr Uday Trivedi, nominated by Society for Cardiothoracic Surgery – clinical specialist
• Dr Neil Sulke, nominated by Heart Rhythm UK – clinical specialist (provided written statement only)
• Mrs Jo Jerrome, nominated by Arrhythmia Alliance – patient expert
• Mrs Eileen Porter, nominated by Atrial Fibrillation Association – patient expert