4 Consideration of the evidence

4 Consideration of the evidence

Please note that the recommendations in section 1 for dronedarone have been amended to reflect changes made to the UK marketing authorisation. The information in this section is based on dronedarone's marketing authorisation at the time the appraisal was initially considered in 2010. Please refer to the revised summary of product characteristics for dronedarone for further information.

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 the condition, those who represent them, and clinical specialists. It considered comments received at consultation on the ACDs. It also took into account the effective use of NHS resources.

4.2 The Committee discussed the positions for dronedarone in the treatment pathway for atrial fibrillation proposed by the manufacturer. It noted that the NICE guidance on atrial fibrillation (NICE clinical guideline 36) states that a standard beta-blocker should be the initial treatment for people with symptomatic atrial fibrillation (in addition to anticoagulation) and that an antiarrhythmic drug should be used when beta-blockers fail to control symptoms or are contraindicated (that is, as a second-line treatment). The Committee initially discussed using dronedarone in addition to standard baseline therapy of beta-blockers and anticoagulation (that is, as a first-line treatment). It noted that the manufacturer had only presented cost-effectiveness evidence at this position in the care pathway for the subgroup of people with a CHADS2 score of 4 or more (that is, people with a high risk of stroke). The Committee also noted that the licensed indication[1] for dronedarone was to prevent recurrence of atrial fibrillation or to lower ventricular rate, but that the only outcome that was presented in this subgroup was all-cause mortality. The Committee then discussed the use of dronedarone as an alternative antiarrhythmic drug for second-line treatment of atrial fibrillation and considered that the comparators assessed in the manufacturer's submission (sotalol, class 1c drugs and amiodarone) were appropriate.

4.3 The Committee considered that not all possible uses of dronedarone had been evaluated in the manufacturer's submission. It heard from clinical specialists and patient experts that a potential use of dronedarone would be in people who are unable to tolerate other antiarrhythmic drugs, in particular amiodarone. However, no evidence was provided relating to the clinical effectiveness and adverse effects of dronedarone in this group of people.

4.4 The Committee understood from clinical specialists and patient experts that they considered amiodarone to be an effective antiarrhythmic 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 antiarrhythmic treatment options for people with atrial fibrillation are limited and they would welcome an antiarrhythmic 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, who cannot take class 1c drugs or sotalol, might benefit from an antiarrhythmic drug that is more tolerable than amiodarone because of the longer length of time that they are likely to need treatment. It discussed comments received at consultation stating that younger people with atrial fibrillation who also had congenital heart problems would value dronedarone as a treatment option. However, the Committee concluded that because no evidence was presented for people with congenital heart disease, it could not make any recommendations specifically in this group.

4.5 The Committee considered it appropriate that dronedarone is initiated by a specialist in a secondary care setting, which clinical specialists commented is usual practice for second-line treatment with antiarrhythmic drugs. The Committee noted that the cost-effectiveness model submitted by the manufacturer assumed that treatment with dronedarone was initiated by a specialist during an outpatient visit.

Clinical effectiveness

4.6 The Committee discussed the evidence on the effect of dronedarone on atrial fibrillation recurrence. It considered that the randomised controlled trials (ATHENA, EURIDIS, ADONIS and DIONYSOS) demonstrated that dronedarone was more effective than placebo at reducing atrial fibrillation recurrence, but less effective than amiodarone. It discussed the results of the meta-analyses and mixed treatment comparison conducted by the manufacturer that indicated that all antiarrhythmic 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 antiarrhythmic drugs.

4.7 The Committee discussed the evidence on the effect of dronedarone on ventricular rate. It noted that the licensed indication[2] for dronedarone was to prevent recurrence of atrial fibrillation or to lower ventricular rate, but that the only studies that assessed ventricular rate in people with non-permanent atrial fibrillation were the EURIDIS and ADONIS trials. It noted that these trials reported a lower ventricular rate in the dronedarone group than the placebo group. The Committee was also aware that ventricular rate was not included in the manufacturer's economic model. It heard from clinical specialists that the ERATO trial had shown that dronedarone reduces ventricular rate compared with placebo. However, the Committee noted that this study was in people with permanent atrial fibrillation, which is not a licensed indication for dronedarone. The Committee considered that there was insufficient evidence to reach a definitive conclusion about the benefits of dronedarone for reducing ventricular rate in people with non-permanent atrial fibrillation.

4.8 The Committee discussed the trial evidence on the effect of dronedarone on mortality. It considered the results of the ATHENA trial, which reported lower cardiovascular mortality in the dronedarone group compared with the placebo group but no statistically significant difference in all-cause mortality (for the whole trial population). 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. 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 heard from clinical specialists that the CHADS2 score was a useful method of assessing stroke risk in people with atrial fibrillation to determine the need for anticoagulation treatment, but that it was not used to predict mortality. It noted published evidence that reported an association between CHADS2 score and risk of all-cause mortality for people who have had a stroke. However, the Committee considered 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.

4.9 The Committee discussed the issue of all-cause mortality in relation to the DIONYSOS trial, which provided the only direct head-to-head comparison of dronedarone with another antiarrhythmic drug, and reported fewer deaths in the dronedarone group than in the amiodarone group. However, the Committee noted the short follow-up of the trial and the small number of deaths in the study, and it considered whether all the deaths in the amiodarone group were because of cardiovascular causes (noting that the causes of death were marked commercial in confidence). Therefore the Committee considered that no conclusion about the relative effect of dronedarone and amiodarone on mortality could be made on the basis of this trial.

4.10 The Committee discussed the results of the manufacturer's mixed treatment comparison, which reported a lower risk of all-cause mortality for dronedarone compared with placebo. It noted the ERG's criticism about the methodology used for the mixed treatment comparison. It also noted that the CIs for this analysis crossed the null effect value, indicating that the difference was not statistically significant. The Committee considered that the mixed treatment comparison was largely based on the difference in all-cause mortality between the treatment arms in the ATHENA trial, which itself was not statistically significant. 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 had been demonstrated by the mixed treatment comparison.

4.11 The Committee then discussed the evidence on the risk of all-cause mortality for the other antiarrhythmic drugs. It noted results from the mixed treatment comparison showing that sotalol and amiodarone were associated with a higher risk of mortality than placebo. It discussed the results of the ERG's reanalysis of the mixed treatment comparison and also considered evidence from two published meta-analyses of antiarrhythmic drugs. The Committee noted that all of these analyses reported a trend towards increased all-cause mortality with sotalol and amiodarone compared with placebo, albeit less than that reported in the manufacturer's mixed treatment comparison. It also noted that only the hazard ratio for the comparison of sotalol with placebo for all-cause mortality had a CI that did not cross 1.0, indicating a statistically significant difference between these drugs. The Committee was aware that there were limited data on class 1c drugs. It considered comments received at consultation and from the clinical specialists that amiodarone, sotalol and class 1c drugs were associated with an increased risk of mortality. Overall, the Committee accepted that the risk of mortality with the other antiarrhythmic drugs was likely to be higher than with dronedarone.

4.12 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 resulted in reduced risk of stroke with dronedarone compared with placebo. It noted that this analysis was 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 antiarrhythmic drugs had been demonstrated.

4.13 The Committee discussed the adverse events associated with dronedarone. It was aware of the ANDROMEDA trial in which dronedarone was associated with an increased risk of mortality in people with severe congestive heart failure and noted that having atrial fibrillation was not an inclusion criterion for this trial. It was also aware that the SPC[3] states that dronedarone is contraindicated in people with unstable NYHA class III and IV heart failure, and that it is not recommended in people with stable, recent NYHA class III heart failure and people with left ventricular ejection fraction less than 35%. The Committee noted that the most common adverse events reported across the trials of dronedarone were gastrointestinal. It discussed the possibility of serious adverse events such as pulmonary fibrosis, thyroid disease and torsades de pointes (an arrhythmia). It noted that there were very few cases reported in the randomised controlled trials, but that these trials were all relatively short term. The Committee 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, it noted that these results were also based on short-term data. It noted there was no direct evidence comparing the adverse effects of dronedarone with sotalol or class 1c drugs. 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. It noted comments from patients and clinical specialists received during consultation on the first ACD that all current antiarrhythmic drugs had side effects that had a significant impact on quality of life, but particularly amiodarone, with long-term use. Overall, the Committee concluded that the adverse effect profile of dronedarone was likely to be more favourable than amiodarone.

4.14 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 antiarrhythmic drug that has better tolerability, despite it having less effect on atrial fibrillation recurrence. It also heard that effectiveness of an antiarrhythmic 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 aware of the potential value placed on dronedarone by patients when it examined the cost-effectiveness analyses.

Cost effectiveness

4.15 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 there was a beneficial effect of dronedarone on mortality and that the ATHENA trial was an appropriate source of data for the baseline risk of events. It also had concerns about the modelled costs of dronedarone and other antiarrhythmic drugs and the utilities used in the model. In addition, the Committee noted that the economic analysis was based on pair-wise comparisons of two treatments and did not use incremental analyses to compare all treatments simultaneously. It also noted that the economic analysis did not evaluate all possible uses of dronedarone.

4.16 The Committee discussed the use of the placebo arm of the ATHENA trial to inform the baseline event rates in the model. It considered that this was based on an assumption that the ATHENA population was representative of people with atrial fibrillation in the UK. The Committee noted that the ATHENA trial included people who were older and had higher cardiovascular risk than people in the other dronedarone trials. It considered that the ATHENA population represented a higher-risk group than the more general population of people with atrial fibrillation in the UK in whom dronedarone would be used. Therefore, the Committee concluded that the cost-effectiveness estimates it had been presented with were only relevant to the population represented by the ATHENA trial (that is, people with additional cardiovascular risk).

4.17 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, the presence of structural heart disease, left ventricular dysfunction and coronary heart disease, and the comparator. It considered the ERG's revisions to the model to be appropriate, 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. However, it noted that these figures did not incorporate changes in other key assumptions such as the mortality benefit associated with dronedarone.

4.18 The Committee discussed the ERG's analyses exploring the main factors that influenced the cost effectiveness of dronedarone. It considered that the relative effect of dronedarone and antiarrhythmic drugs on mortality was a key factor in the economic analysis. It again considered comments received during consultation on the first ACD and from the clinical specialists about the likely excess mortality associated with other antiarrhythmic drugs. In light of the uncertainty about the effect of dronedarone on mortality, the Committee discussed several exploratory scenario analyses conducted by the ERG in which the relative all-cause mortality effects of each antiarrhythmic drug were varied. It considered the scenario in which dronedarone had no effect on mortality compared with placebo, and other antiarrhythmic drugs were associated with some increase in mortality (as calculated in the ERG's meta-analysis), to be the most appropriate, given the uncertainty about the mortality effect of dronedarone. It noted the ICERs from this analysis were below £15,000 per QALY gained for the use of dronedarone as a second-line treatment alternative to sotalol, class 1c drugs and amiodarone. It also noted the ICERs from this analysis were above £50,000 per QALY gained for the use of dronedarone as part of first-line treatment in addition to standard baseline therapy (in people with a CHADS2 score of 4 or more). The Committee concluded that these cost-effectiveness estimates were the most plausible of all those presented.

4.19 The Committee discussed the costs and utilities included in the economic analysis. It noted that lower initiation and monitoring costs were attributed to dronedarone than other antiarrhythmic drugs. The Committee also noted the ERG's criticism that the utilities used in the model appeared to exceed general population values for healthy states. It considered the ERG's analyses that used revised drug administration costs and utilities, and concluded that these changes had a marginal impact on the cost-effectiveness estimates of dronedarone.

4.20 The Committee noted comments received at consultation on the first ACD that the economic analysis had not taken into account the potential cost savings of the reduced cardiovascular hospitalisations associated with dronedarone (shown in the ATHENA trial). It considered that the costs and effects of hospitalisation were included in the analysis through the modelling of events such as atrial fibrillation recurrence and stroke for which hospitalisation costs may be incurred. The Committee also considered comments received at consultation on the first ACD that treatment with dronedarone would be stopped if it was not effective and this was not considered in the economic evaluation. It noted that the submission provided by the manufacturer did not specifically evaluate treatment stopping rules and also did not consider the full range of potential treatment sequences for dronedarone. However, the Committee considered that some element of treatment discontinuation had been accounted for in the modelling of withdrawal because of adverse events or lack of efficacy.

4.21 In light of the above considerations, the Committee discussed the cost effectiveness of dronedarone as a first-line treatment for atrial fibrillation (in addition to standard baseline therapy usually including beta-blockers). It noted that cost-effectiveness evidence for dronedarone as a first-line therapy had only been provided for the subgroup of people with a CHADS2 score of 4 or more. In addition to concerns about the validity of the CHADS2 score in this context, the Committee considered that the beneficial effect of dronedarone on all-cause mortality assumed in the manufacturer's submission was not proven. It noted that when this effect was removed from the economic analysis the cost per QALY gained was above £50,000. 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 first-line treatment of atrial fibrillation could not be considered a cost-effective use of NHS resources. The Committee also noted that no evidence had been provided for first-line treatment with dronedarone other than in people with a CHADS2 score of 4 or more. Therefore it could not make any conclusions about the first-line use of dronedarone in other people with non-permanent atrial fibrillation. The Committee concluded that dronedarone could not be recommended as a first-line treatment for atrial fibrillation (in addition to standard baseline therapy usually including beta-blockers).

4.22 The Committee discussed the cost effectiveness of dronedarone as a second-line treatment for people whose atrial fibrillation is not controlled by standard baseline therapy (that is, as an alternative to the antiarrhythmic drugs: amiodarone, sotalol and class 1c agents). It considered that a beneficial effect of dronedarone on all-cause mortality was not proven; however, it accepted that the risk of mortality with the other antiarrhythmic drugs was likely to be higher than with dronedarone. It considered that when this scenario was modelled, the costs per QALY gained were within an acceptable range. The Committee noted that these cost-effectiveness estimates were largely based on data from the ATHENA trial, which included people who had a higher risk of a major cardiovascular event, and it was uncertain whether these data were applicable to people in England and Wales who would receive second-line treatment for atrial fibrillation. Therefore the Committee concluded that using dronedarone as a second-line alternative to amiodarone, class 1c drugs, or sotalol for the treatment of non-permanent atrial fibrillation could be considered a cost-effective use of NHS resources in people who have the same characteristics as the population in the ATHENA trial, that is, they have at least one of the following additional cardiovascular risk factors: hypertension requiring drugs of at least two different classes, diabetes, previous transient ischaemic attack, stroke or systemic embolism, left atrial diameter at least 50 mm, left ventricular ejection fraction less than 40% or age 70 years or older. The Committee was mindful that there might be some overlap between people with cardiovascular risk factors and those in whom dronedarone is contraindicated (with unstable NYHA class III or IV heart failure) or not recommended (with left ventricular ejection fraction less than 35%). Therefore the Committee considered it important to emphasise in its recommendations that dronedarone should not be used in people with unstable NYHA class III or IV heart failure and to refer to the recommendation in the SPC about the use of dronedarone in people with left ventricular ejection fraction less than 35%.



[1] This refers to the licensed indication at the time of the appraisal and not the indication amended in 2011.

[2] This refers to the licensed indication at the time of the appraisal and not the indication amended in 2011.

[3] This refers to the licensed indication at the time of the appraisal and not the indication amended in 2011.

  • National Institute for Health and Care Excellence (NICE)