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27 October 2009,
An indirect comparison meta-analysis found that dronedarone was significantly less effective than amiodarone in preventing recurrence of AF, but was associated with fewer side effects requiring discontinuation. It was predicted that for every 100 people treated for one year for AF with dronedarone rather than amiodarone, there would be 23 more recurrences of AF and 6 fewer adverse events requiring discontinuation.
Level of evidence
Level 2 (limited quality, patient-orientated evidence) according to the SORT criteria
Action
Dronedarone may be launched in the UK by the end of 2009. It is likely to be indicated in clinically stable adult patients with history of, or current non-permanent atrial fibrillation (AF) to prevent recurrence of AF or to lower ventricular rate. Contraindications, special warnings, and monitoring requirements (as will be described in the summary of product characteristics [SPC]) are not yet published.
The exact place in therapy of dronedarone is uncertain. Until NICE guidance on dronedarone is published (due June 2010) prescribers should continue to follow the existing NICE guideline for the management of AF. Dronedarone could be considered as an option, within its licensed indications, by specialists for those patients for whom amiodarone is indicated, but not appropriate, e.g. if there are intolerable adverse effects. Clinicians will need to balance whether the use of dronedarone — a less efficacious but possibly safer antiarrhythmic drug than amiodarone — is justified for their patients with AF. For patients who are already receiving and tolerating amiodarone and have not developed unacceptable side effects, there would appear to be no good reason to switch to dronedarone.
Dronedarone is likely to be significantly more expensive than currently used anti‑arrhythmic drugs, which are mainly available generically. Local decision making bodies on medicines are advised to engage with stakeholders and agree a protocol for use when dronedarone is launched. This includes identifying those patients for whom the drug may be appropriate and planning for possible NICE guidance. It is important that steps are taken to inform prescribers of any contraindications and precautions, to ensure that dronedarone is used appropriately.
What is the background to this?
On 24 September 2009, the EMEA Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion for dronedarone (Multaq®). It recommended granting a marketing authorisation for adult clinically stable patients with history of, or current non-permanent AF, to prevent recurrence of AF or to lower ventricular rate. A key study considered in providing this opinion was the ATHENA trial, which we have reviewed in a previous blog. In the ATHENA trial of 4,628 patients with AF or flutter, dronedarone was more effective than placebo (mean follow-up of 21 months) in reducing cardiovascular (CV) hospital admissions or death from any cause (31.9% vs. 39.4%; hazard ratio 0.76, 95% confidence interval (CI) 0.69 to 0.84, P<0.001), as well as other trials.
Because of the limited information available from studies that directly compare the efficacy and safety of dronedarone with amiodarone, Piccini and colleagues carried out a systematic review and indirect comparison meta-analysis using data from placebo-controlled trials of the two drugs in over 6000 people with AF.
Further information about AF can be found on the cardiovascular floor of NPC. Dronedarone has been reviewed in an On the Horizon bulletin. Dronedarone is part of the 19th wave of technology appraisals from NICE, but a NICE clinical guideline on the management of AF is already available.
What does this study claim?
The study claims that dronedarone is less effective than amiodarone for the maintenance of sinus rhythm, but has fewer side effects.
The meta-analysis identified a statistically significant estimated reduction in recurrent AF with amiodarone versus placebo (odds ratio [OR] 0.12; 95%CI 0.08 to 0.19) but not for dronedarone versus placebo (OR 0.79; 95% CI 0.33 to 1.87). Using a logistic regression model incorporating all trial evidence, amiodarone was found to be superior to dronedarone (OR 0.49; 95% CI 0.37 to 0.63; P<0.001) for the prevention of recurrent AF, but was more likely to result in adverse events requiring drug discontinuation (OR 1.81; 95% CI 1.33 to 2.46; P<0.001).
The authors also suggest a ‘trend’ for reduced mortality in favour of dronedarone, although no statistically significant difference between treatments was identified (P=0.066).
How does this relate to other studies?
These results are consistent with the results of the DIONYSOS trial that directly compared dronedarone with amiodarone for the maintenance of sinus rhythm. However, results of DIONYSOS are only reported in a press release and are yet to be published in a peer-reviewed journal. DIONYSOS was a study of 504 patients with AF (mean follow-up 7 months). Dronedarone was less effective than amiodarone in preventing AF recurrence, or withdrawal due to intolerance or lack of efficacy (74% vs. 55%, P<0.001). Fewer thyroid and neurological events were reported in the dronedarone patients, but there were more reports of diarrhoea, vomiting and nausea. Amiodarone caused more bradycardia and QT prolongation. No cases of Torsade de Pointes were reported.
So what?
The present study found that dronedarone was significantly less effective in preventing recurrence of AF, but was associated with fewer side effects leading to discontinuation than with amiodarone. The indirect meta-analytical approach used in this study has many limitations (see accompanying Editorial) and the findings of this study can only be considered hypothesis generating and require confirmation from direct comparisons in adequately powered trials. Nevertheless, the reduction in efficacy and reduction in adverse effects seen in this study are consistent with the preliminary results from DIONYSOS.
Although the ATHENA study identified a significant benefit for preventing hospitalisation for CV events or death for dronedarone over placebo, no benefit over amiodarone has yet been demonstrated in this regard. Whether or not dronedarone offers any particular advantage over amiodarone for an individual with AF will require a value judgement of whether likely benefits from reduced side effects outweigh the disadvantage of a shorter time to recurrence of AF. At present there is no good quality clinical evidence from comparative studies measuring important patient-oriented outcomes (e.g. quality of life) demonstrating whether or not dronedarone offers any net clinical benefit over amiodarone at a population level.
NICE guidelines on the management of atrial fibrillation detail those situations where amiodarone might be considered. However, there are many other approaches that should be considered before, or as alternatives to, the use of amiodarone.
Full prescribing details (including dosage, contraindications, drug and food interactions, and monitoring requirements) for dronedarone have yet to be published. As discussed in a previous blog of the ATHENA trial, it may be advisable not to initiate therapy with dronedarone in patients with severe heart failure and left ventricular dysfunction.
Dronedarone is already licensed for use in the US. Contraindications in the US include patients with severe heart failure or those with NYHA 2 or 3 heart failure with a recent decompensation requiring hospitalisation or referral to a specialised heart failure clinic. Increases in serum creatinine have occurred in clinical trials with dronedarone, and there are potentially important drug interactions to consider (e.g. with strong CYP3A inhibitors such as voriconazole, and with drugs that prolong the QT interval, which might increase the risk of Torsade de Pointes). It is important that steps are taken to inform prescribers of any contraindications and precautions, to ensure that dronedarone is used and monitored appropriately.
Study details
Design: Systematic review and indirect comparison meta-analysis of RCTs of amiodarone (4 studies) and dronedarone (4 studies) versus placebo for the prevention of AF.
Patients: The dronedarone and amiodarone trials included 5,967 and 669 patients respectively. The mean age across all trials was 65 years. Studies of subjects age <18 years and subjects with acute cardioversion, catheter ablation, and post-operative AF were excluded. In all 4 dronedarone trials, patients with permanent AF were excluded. Additional exclusion criteria included advanced symptomatic heart failure, a corrected QT interval >500ms, and bradycardia with a heart rate <50 beats/min. In contrast to the dronedarone trials, the amiodarone trials predominantly included patients with persistent and permanent AF.
Interventions: Dronedarone or amiodarone versus placebo. All trials had a follow up of at least 6 months (means of 13 and 16 months, respectively).
Comparison: The effect of amiodarone versus dronedarone was summarised by the use of indirect comparison meta-analysis and normal logistic meta-regression models.
Outcomes and Results:
There was a significant estimated reduction in recurrent AF with amiodarone versus placebo (OR 0.12; 95%CI 0.08 to 0.19) but not dronedarone versus placebo (OR 0.79; 95%CI 0.33 to 1.87). A normal logistic regression model incorporating all trial evidence found amiodarone superior to dronedarone (OR 0.49; 95%CI 0.37 to 0.63; P<0.001) for the prevention of recurrent AF. There was no statistically significant difference between amiodarone and dronedarone identified with regard to all-cause mortality (OR 1.61; 95% CI 0.97 to 2.68; P=0.066). More patients discontinued treatment because of adverse effects with amiodarone than with dronedarone (OR 1.81; 95%CI 1.33 to 2.46; P<0.001). For every 1,000 patients treated with dronedarone instead of amiodarone, it was estimated that there would be approximately 228 more recurrences of AF in exchange for 62 fewer adverse events requiring discontinuation of drug.
Sponsorship: The lead author is supported by an American College of Cardiology Foundation/Merck award.
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