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5th March 2009
In the ATHENA trial of 4,628 patients with atrial fibrillation (AF) or flutter, dronedarone was more effective than placebo in reducing cardiovascular (CV) hospital admissions or death from any cause. No other antiarrhythmic has been studied for such a primary endpoint; hence it is difficult to ascertain the exact role of dronedarone in therapy. Patients with severe heart failure were excluded from this trial, but excess mortality related to advanced and decompensated congestive heart failure has been reported in a previous study. Therefore, it may be advisable not to initiate therapy with dronedarone in patients with severe heart failure and left ventricular dysfunction.
Action
Treatment of AF is limited by the adverse effects and limited efficacy of available agents. Local decision making bodies on medicines are advised to engage with stakeholders and agree a protocol for use should dronedarone be licensed and launched. This includes identifying those patients for whom the drug may be appropriate as well as planning for possible NICE guidance.
What is the background to this?
Dronedarone is an anti-arrhythmic drug, similar to amiodarone but without the iodine moiety and with a shorter half-life. It is in licensing for the management of AF and flutter. AF is the commonest sustained cardiac dysrhythmia and prevalence increases with age.
Further information about AF can be found on the AF 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?
Dronedarone was more effective than placebo at reducing first hospitalisation for CV events or death from any cause. This occurred in 31.9% of dronedarone patients and 39.4% of placebo patients (hazard ratio (HR) 0.76, 95% confidence interval (CI) 0.69 to 0.84, P<0.001). This gives a number needed to treat (NNT) of around 13. The majority of patients were already taking other therapies for AF, including beta blockers.
How does this relate to other studies?
The DIONYSOS trial comparing dronedarone with amiodarone for the maintenance of sinus rhythm (n=504) has not yet been published, but is the subject of a press release. Patients were followed up for a mean of 7 months. Dronedarone was less effective than amiodarone but exhibited fewer adverse effects. The composite primary outcome was AF recurrence, or withdrawal due to intolerance or lack of efficacy. This occurred in 184 patients (73.9%) in the dronedarone group vs. 141 (55.3%) in the amiodarone arm (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.
The year-long EURIDIS and ADONIS trials looked at maintenance of sinus rhythm. The pooled results from the trials demonstrated that the time to first recurrence of atrial fibrillation was 116 days (median) for dronedarone as compared with 53 days for placebo patients.
In the small rate-control trial, ERATO (n=174), the primary end point was the change in mean 24-hour ventricular rate between baseline and day 14. The mean reduction in the dronedarone group was 11.0 beats per minute vs. an increase of 0.7 beats per minute in the placebo group (difference of 11.7 beats per minute, P<0.0001). The clinical significance of this is not known as the reduction in heart rate was not accompanied by improvement in exercise tolerance.
So what?
No antiarrhythmic agent, other than dronedarone, has been evaluated in a large trial for the prevention of hospitalisation due to CV events or death in patients with AF. Therefore it is difficult to ascertain the drug’s role in therapy in relation to existing standards of care. When the results of the DIONYSOS study are published it will be possible to compare the efficacy and tolerability of dronedarone versus amiodarone.
There was a high rate of premature discontinuation of dronedarone in the trial (30.2%). This may have resulted in both an underestimate of the benefit of the drug and of the likelihood of adverse effects.
Further data are required on the use of dronedarone in patients with heart failure. Patients with the most severe congestive heart failure were excluded from this study. The ANDROMEDA trial, which studied patients with symptomatic heart failure and severe left ventricular dysfunction, had to be stopped early as more patients in the dronedarone group died. This excess mortality was attributed to worsening heart failure. Therefore, the authors of the ATHENA study advise that dronedarone should not be initiated in patients with severe heart failure and left ventricular dysfunction.
Dronedarone is likely to be significantly more expensive than currently used anti‑arrhythmic drugs, which are mainly available generically.
Design: randomised, double-blind, placebo-controlled trial.
Patients: 4,628 patients with paroxysmal or persistent AF or flutter were included. Initially patients at least 70 years old or with at least one risk factor, such as diabetes, hypertension or previous stroke, were eligible. However, during the trial it was noted that mortality figures were lower than expected and the entry criteria were altered. Subsequently, patients aged 75 or older were eligible or patients 70 years old older with at least one of the other risk factors.
71% of patients were taking beta blockers at baseline, 14% were on calcium-channel blockers and 14% on digoxin. Exclusions included New York Heart Association (NYHA) class IV congestive heart failure, decompensated heart failure within the previous 4 weeks and permanent AF.
Intervention: dronedarone 400mg twice daily (n=2,301).
Comparison: placebo (n=2,327).
Outcomes and Results: primary outcome was first hospitalisation due to CV events or death from any cause in the intention-to-treat population.
After mean (+/- standard deviation, SD) follow up of 21(+/-5) months 734 (31.9%) of dronedarone patients had a primary outcome compared to 917 (39.4%) of placebo patients, HR 0.76, 95% CI 0.69 to 0.84, P<0.001).
Secondary outcomes were death from any cause, death from CV causes and hospitalisation due to CV events. There were 116 deaths from any cause (5%) in the dronedarone group and 139 (6.0%) in patients receiving placebo, P=0.18. Deaths from CV causes included those due to arrhythmias which were 26 (1.1%) in the dronedarone group and 48 (2.1%) in the placebo group; P=0.01 and death from non-cardiac vascular causes, such as stroke, where no difference was seen between the two groups (0.9% vs. 1.0%, HR 0.84, 95% CI 0.47 to 1.52, P=0.57).
In the dronedarone group, 675 patients (29.3%) had a first hospitalisation due to a CV event as compared with 859 patients (36.9%) in the placebo group (HR 0.74, 95% CI 0.67 to 0.82; P<0.001). This result was driven mainly by a reduction in admissions due to AF.
Adverse events: 12.7% of patients in the dronedarone group withdrew due to adverse events compared to 8.1% of placebo patients (P<0.001). Adverse events seen more frequently in the dronedarone group included bradycardia (3.5% vs. 1.2%, P<0.001), QT prolongation (1.7% vs. 0.6%, P<0.001), diarrhoea (9.7% vs. 6.2%, P<0.001) and increased serum creatinine (4.7% vs. 1.3%, P<0.001). Interstitial lung disease and effects on thyroid function were not statistically different between the groups. However, the trial may not have lasted for long enough. It should be noted that pulmonary toxic effects with amiodarone commonly occur more than two years after starting treatment.
Sponsorship: Sanofi-Aventis
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