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In September 2009, the European Union approved dronedarone ‘in adult clinically stable patients with a history of, or current non-permanent atrial fibrillation (AF) to prevent recurrence of AF or to lower ventricular rate’.1 This was the first new oral anti-arrhythmic agent to be approved in more than 20 years if dofetilide, which was never marketed in Europe, is discounted. The failure of multiple anti-arrhythmic drug development programmes for the prevention of ventricular arrhythmias led to a new but uncharted approach, the introduction of a drug specifically and only for the management of AF. This is an important therapeutic arena, which had not been directly addressed previously.2 The marketing authorisation for dronedarone followed an extensive development programme involving six trials that enrolled over 7000 patients (table 1).3–9
A small dose-ranging study (DAFNE—Dronedarone Atrial Fibrillation Study after Electrical Cardioversion) had identified that the smallest dose tested (dronedarone 400 mg bid) was the most suitable dose for the suppression of AF recurrence.3 EURIDIS (European Trial in Atrial Fibrillation or Flutter Patients Receiving Dronedarone for the Maintenance of Sinus Rhythm) and ADONIS (American–Australian–African Trial with Dronedarone in Atrial Fibrillation or Flutter for the Maintenance of Sinus Rhythm) were pivotal trials that showed a significant reduction in the time to recurrence of AF (HR 0.75; 95% CI 0.65 to 0.87; p<0.0001).4 A trial against an active comparator (amiodarone) was required by European regulators, and the DIONYSOS trial (Randomised Double Blind Trial to Evaluate Efficacy and Safety of Dronedarone (400 mg bid) vs Amiodarone (600 mg qd for 28 days, then 200 mg qd thereafter) for at least 6 months for the Maintenance of Sinus Rhythm in Patients with Atrial Fibrillation) clearly demonstrated that dronedarone was not nearly as effective at preventing the recurrence of AF even if the endpoint was a combination of time to AF recurrence and study drug discontinuation (HR 1.59; 95% CI 1.28 to 1.98; p<0.0001).6 The ERATO (Efficacy and Safety of Dronedarone for the Control of Ventricular Rate during Atrial Fibrillation) trial showed that dronedarone was a highly effective rate control agent in AF.5 Thattrial completed the standard assessment for anti-arrhythmic efficacy against AF, but lacked a substantial cardiovascular outcome study,10 which would ordinarily have been conducted in patients at risk of ventricular arrhythmias, but dronedarone was intended to be used only for the treatment of AF.
It was decided to explore further the safety of dronedarone by conducting a trial in a high-risk population liable to develop AF. The ANDROMEDA (Antiarrhythmic Trial with Dronedarone in Moderate-to-severe Congestive Heart Failure Evaluating Morbidity Decrease), was a major outcomes study in patients with severe heart failure (New York Heart Association (NYHA) class IV or decompensated heart failure within the previous 4 weeks).7 The study attempted to emulate a subgroup analysis of the DIAMOND–CHF (Danish Investigations of Arrhythmia and Mortality on Dofetilide in Congestive Heart Failure) trial with dofetilide.11–13 The primary endpoint was the composite of death from any cause or hospitalisation for heart failure. However, the trial was halted by the safety committee after only two-thirds of the planned recruitment and a 2-month median follow-up, because 37 deaths had occurred, 25 in the dronedarone group (HR 2.13; 95% CI 1.07 to 4.25; p=0.03).
Although ANDROMEDA clearly defined a population that should not receive dronedarone, it had done little else to clarify the safety profile of the drug. A retrospective meta-analysis of EURIDIS and ADONIS explored whether dronedarone might have an effect on mortality or hospitalisation in patients treated for recurrent AF.4 The pooled analysis (main paper) demonstrated that a combined endpoint of all-cause mortality and cardiovascular hospitalisations was associated with a relative risk reduction of 20% and would be a realistic endpoint for a large-scale outcomes study with dronedarone in ‘at-risk’ patients with AF, but not severe heart failure. The resulting study (ATHENA—A Placebo-controlled, Double-blind, Parallel Arm Trial to Assess the Efficacy of Dronedarone 400 mg bid for the Prevention of Cardiovascular Hospitalisation or Death from any Cause in Patients with Atrial Fibrillation/Atrial Flutter) became the most important study in the development portfolio.8 It was an outcomes study in patients with recurrent AF and moderate cardiovascular risk, as defined by the presence of hypertension resistant to at least two drugs, diabetes mellitus, previous stroke, systemic embolism or transient ischaemic attack, left atrial diameter of 50 mm or more, left ventricular rejection fraction less than 40% or age 70 years or over. It is the largest anti-arrhythmic study ever conducted in AF, in which 4628 patients were randomly assigned to receive dronedarone or matching placebo. The primary endpoint was time to all-cause mortality or unplanned cardiovascular hospitalisation. The trial continued for its planned duration (median follow-up 21 months) and patients treated with dronedarone had 24% fewer primary endpoint events (HR 0.76; 95% CI 0.69 to 0.84; p<0.0001).
Post-hoc analysis of the result of ATHENA demonstrated that patients assigned to dronedarone with moderate heart failure (NYHA II–III) and depressed left ventricular function (ejection fraction ≤0.40 at baseline) had fewer primary endpoint events (59/114 placebo patients compared with 42/95 dronedarone patients; HR 0.78, 95% CI 0.52 to 1.16).14 A retrospective analysis surprisingly demonstrated a reduction in stroke in those treated with dronedarone from 1.8% per year to 1.2% per year (HR 0.66, 95% CI 0.46 to 0.96, p=0.027).15 After the completion of ATHENA the clinical dossier was complete and applications were made for marketing authorisation. Subsequent meta-analysis suggested that dronedarone was an effective anti-arrhythmic drug with few side effects, especially when compared with other anti-arrhythmic agents,16 ,17 although one analysis was less favourable.18
In the USA, the drug was approved by the US Food and Drug Administration (FDA) in July 200919 as an ‘antiarrhythmic drug indicated to reduce the risk of cardiovascular hospitalization in patients with paroxysmal or persistent atrial fibrillation or atrial flutter, with a recent episode of atrial fibrillation or atrial flutter and associated cardiovascular risk factors…’, which reflected the major importance of the ATHENA result, but in Europe the regulators insisted that dronedarone should be labelled as an anti-arrhythmic agent to prevent AF recurrence, and ATHENA was regarded largely as a safety study. However the European Society of Cardiology (ESC) AF task force wrote recommendations in the 2010 ESC guidelines for the management of AF that dronedarone was an anti-arrhythmic agent for recurrent AF (class I, level of evidence A), and that dronedarone should be considered in order to reduce cardiovascular hospitalisations in patients with non-permanent AF and cardiovascular risk factors (class IIa, level of evidence B).20
In March 2010, the National Institute for Health and Clinical Excellence (NICE) issued guidance relating to dronedarone, recommending it as second-line therapy for the treatment of patients with non-permanent AF who had one of the entry criteria for ATHENA (see above), but did not have characteristics of patients who had been enrolled in the ANDROMEDA trial, described as ‘unstable NYHA class II or IV heart failure’.21
Since then several unsuspected toxicities have been reported. In November 2010, two cases of hepatic toxicity leading to successful liver transplantation were reported almost simultaneously.22 Both cases occurred before 6 months of therapy had elapsed and both were very sudden; in neither case was there any realistic alternative explanation. Analysis of the pre-approval placebo-controlled studies revealed no excess of liver function test abnormalities, but hepatic adverse events were more numerous in association with dronedarone. In the DIONYSOS study hepatic enzyme elevation occurred at a similar rate with amiodarone and dronedarone.
On the whole it seemed probable that dronedarone was associated with hepatic toxicity, but that the event rate was likely to be very small. This was subsequently borne out by the report of no further liver transplantation. Both basic science and epidemiological studies are now underway, but meanwhile the toxicity has been the subject of regulatory re-appraisal. In the USA, the FDA stipulated that occasional liver function testing could be undertaken,23 but in Europe a more active approach was deemed necessary, with liver function tests at baseline, after 1 week, and then monthly for 6 months, 3-monthly until 1 year and occasionally thereafter.24 This has added a substantial burden and cost to the use of dronedarone, perhaps not an intention but certainly a result of the regulators’ demands.
There have also been a few reports of pulmonary toxicity, almost always in patients who have previously taken amiodarone.25 ,26 It is uncertain whether the toxicity is due directly to amiodarone or to an increased sensitivity to dronedarone in patients previously exposed to amiodarone. Regulators on both sides of the Atlantic have decided that dronedarone should be contraindicated in patients who have had any previous pulmonary or hepatic disorder associated with amiodarone. NICE did not respond to these regulatory changes.
The most recent development that has resulted in major changes to regulations, professional guidelines and NICE guidance relating to dronedarone has been the result of PALLAS (Permanent Atrial Fibrillation Outcome Study).9 In the ATHENA study there were 473 patients who seemed to remain in AF throughout the study. A retrospective analysis of these patients showed that fewer of these patients were in the dronedarone group (178 vs 295), and that those treated with dronedarone had a similar reduction of the primary ATHENA endpoint (HR=0.76) as for the trial population in general.27 This gave rise to speculation that effects other than those attributable to maintenance of sinus rhythm (reduction of blood pressure, ventricular rate control, ventricular anti-arrhythmic action, improved coronary blood flow, anti-sympathetic effects) might have accounted for the result. It was therefore decided to investigate dronedarone in patients with permanent AF, defined by documented AF on enrolment and at least 6 months previously with no evidence of intervening sinus rhythm.
It was intended to enrol 10 800 patients but the trial was stopped by the safety committee when 3236 patients had been randomly assigned with a median follow-up of 3.6 months. Only 64 of the anticipated 844 first co-primary outcome events had occurred, but the HR for both co-primary endpoints were already significantly adverse (stroke, myocardial infarction, systemic embolus or cardiovascular death (HR, 2.29; 95% CI 1.34 to 3.94; p=0.002); cardiovascular hospitalisation or death (HR 1.95; 95% CI 1.45 to 2.62; p<0.001). The results contrasted markedly from those of ATHENA. The stroke and death rates were approximately double in the dronedarone group compared with placebo. At baseline there were greater proportions of patients in PALLAS with coronary artery disease, previous stroke, heart failure, or low ejection fraction. However, the subgroup analysis did not show that the adverse outcome events were concentrated in the high-risk patients. The excess deaths were sudden, perhaps arrhythmic, and there was speculation that this might have been related to a dronedarone/digoxin drug interaction, but this could not have accounted for the size of the effect. The excess strokes mostly occurred early and the possibility of under-anticoagulation, or sudden reversion to sinus rhythm was investigated as a potential mechanism, but remains unsubstantiated. In general there was concern that the bradycardia effect of dronedarone might have been responsible for adverse events, but this could not be demonstrated.
The major difference between PALLAS and ATHENA was that the patients in PALLAS were very largely in permanent AF, whereas the majority of patients in ATHENA had recurrent forms of AF and many were in sinus rhythm for the majority of the trial. Any advantage from achieving sinus rhythm was not possible in PALLAS. The main clinical implication of the result is that patients with permanent AF should not receive dronedarone. All regulatory statements, professional guidelines28 ,29 and NICE guidance unanimously agree. An important corollary is that dronedarone should not be used for ventricular rate control in patients with permanent AF and the European summary of product characteristics has been changed accordingly.23
Differences exist in the changes to recommendations with regard to heart failure. ANDROMEDA clearly defined a group with severe heart failure that should not be treated with dronedarone. From the beginning all authorities ruled out patients with class IV or unstable heart failure; NICE and European guidelines also excluded patients with class III heart failure, and American guidelines added that heart failure associated with a left ventricular ejection fraction below 35% should particularly deter treatment with dronedarone. After PALLAS European regulators, but not their American counterparts, extended the ban to include any patient with current or previous heart failure or current or previous systolic dysfunction. In fact, the European regulator went as far as to include this contraindication within the indication for dronedarone. On the other hand, the regulatory wording is loose and imprecise with regard to the definition of heart failure or left ventricular systolic dysfunction.
European guideline writers reinforced previous recommendations in severe or moderate heart failure, warned against using dronedarone in any patient with heart failure unless no alternative existed, and dropped dronedarone from the heart failure section of the flow chart (figure 1).30 NICE elected to follow the European regulator to a large extent and changed the primary indication from ‘an option for the treatment of non-permanent AF’ to ‘as an option for the maintenance of sinus rhythm after successful cardioversion in people with paroxysmal or persistent AF’ and added to the contraindications: ‘(patients) who … have left ventricular systolic dysfunction and who … have a history of, or current, heart failure’.
In principle this advice appears straightforward but it is partly difficult to understand and it cannot be completely endorsed or easily followed in clinical practice. It is not clear whether dronedarone can be given when the patient is in AF. However, American regulators express this more precisely, as: ‘… (patients) who are in sinus rhythm or who will be cardioverted’. Systolic dysfunction is not easy to measure precisely when AF is present and may be depressed because of the arrhythmia. Restoration and maintenance of sinus rhythm, for example, using dronedarone, often results in an increase in ejection fraction and resolution of heart failure. The diagnosis of past episodes of heart failure or systolic dysfunction may be distant, undocumented and wrong. Minor heart failure is often difficult to distinguish from other causes of mild dyspnoea.
A potentially difficult issue is to determine whether the arrhythmia has become permanent. In Europe regulators have advised ECG recordings at 6-month intervals and in the USA at 3-month intervals.31 ,32 In PALLAS the definition of permanent AF was a history of 6 months or more but the majority (69%) of patients had at least a 2-year history. In practice, when an ECG records AF, the physician must decide with the patient whether to plan cardioversion if the arrhythmia does not convert spontaneously. If an active rhythm control strategy is pursued, dronedarone can be continued. However, if cardioversion is unsuccessful and the strategy changes to rate control, dronedarone should be discontinued (figure 2).3,2
Dronedarone is now difficult to use except in a well administered setting where the detailed schedule of follow-up including ECG recording and blood testing can be ensured. The physician must carefully follow patients and educate them to report symptoms of heart or liver failure. Because of the cumbersome follow-up and the need for very close primary/secondary care dialogue dronedarone, which was thought to be a wonder drug after the impressive results from the ATHENA study, is now relegated in the approach of the practising physician to a drug of last resort, largely because of the inexplicable results of PALLAS and an extremely cautious European regulatory attitude. NICE, however has taken a positive position: ‘the therapeutic indication of the revised marketing authorisation is more restricted than that originally appraised’ but there is ‘no new evidence to indicate that dronedarone would be less safe or less effective in the population that meets the revised marketing authorisation’.3,3
Competing interests Both authors have acted as advisors to Sanofi.
Provenance and peer review Commissioned; internally peer reviewed.