More on AF

Dronedarone, discovered and developed by sanofi-aventis, is one of the major therapeutic innovations in AF (atrial Fibrillation) in the last twenty years. The comprehensive clinical development program for dronedarone provides compelling evidence that a twice-daily dose of 400mg reduces symptomatic/asymptomatic episodes of AF; decreases rapid ventricular rate; and significantly reduces cardiovascular hospitalizations or death in patients with AF.

The landmark ATHENA¹ study (A Placebo-Controlled, Double-Blind, Parallel Arm Trial to Assess the Efficacy of Dronedarone 400 mg BID for the Prevention of Cardiovascular Hospitalization or Death from Any Cause in PatiENts with Atrial Fibrillation/Atrial Flutter) was the largest anti-arrhythmic drug trial ever conducted in AF patients and the first to assess morbidity and mortality end-points in this population. It was a double blind placebo-controlled randomized study in patients with AF (paroxysmal or persistent but not permanent), conducted in more than 550 sites in 37 countries and enrolled a total of 4,628 patients followed for up to 30 months (median 22 months).

The ATHENA trial was published in the New England Journal of Medicine on February 12, 2009.

Study design


The ATHENA study objectives were designed to show a potential benefit of dronedarone on the primary composite endpointⁱ of all-cause mortality combined with cardiovascular hospitalization compared with placebo. The pre-specified secondary end points were death from any cause, cardiovascular death, and hospitalization for cardiovascular reasons. The pre-specified safety endpoint was the incidence of treatment emergent adverse events (between first study drug intake and last study drug intake plus 10 days) including all adverse events, serious adverse events, and adverse events leading to study drug discontinuation.

Patients 75 years of age or older (with or without cardiovascular risk factors) were eligible, whether or not they had any previously specified risk factors, but patients 70 years of age or older were eligible only if they had at least one additional cardiovascular risk factor (hypertension, diabetes, previous ischemic cerebrovascular event, left atrium size greater than 50 mm or left ventricular ejection fraction lower than 40 percent). Patients with recently decompensated heart failure or in New York Heart Association (NYHA) class IV were excluded. Patients were randomized to receive dronedarone 400 mg BID or placebo, with a mean follow-up of 21 months.

The use of standard care for the patient’s cardiac condition was recommended and, in the overall study population, most patients were treated by multiple evidence-based cardiovascular and rate controlⁱ medications not only before but also after enrolment.

ATHENA patients were recruited at 550 centers in 37 countries.

Results
The ATHENA findings showed that dronedarone 440mg BID, in addition to standard therapy, significantly decreased the risk of cardiovascular hospitalization or death by 24 percent (31.9 percent vs. 39.4 percent, p<0.001) when compared to placebo, meeting the study’s primary endpoint. This reduction was generally consistent across study subgroups based on baseline characteristics or medications.
First cardiovascular hospitalization was reduced by 26 percent (p<0.001) in the dronedarone group and there were numerically fewer deaths (16 percent) from any cause in the dronedarone group compared to placebo (p=0.18). There was a significant decrease in the risk of cardiovascular death by 29 percent (p=0.03) in patients with AF. Dronedarone significantly decreased the risk of arrhythmic death by 45 percent (p=0.01)

Safety
Reported significant adverse events (p < 0.05) in the dronedarone arm vs. placebo arm included diarrhea (9.7 vs. 6.2 percent), nausea (5.3 vs. 3.1 percent), bradycardia (3.5 vs. 1.2 percent), QT-interval prolongation (1.7 vs. 0.6 percent), skin disorders (10.3 vs. 7.6 percent) consisting mainly of rash, and an increase in blood creatinine (4.7 vs. 1.3 percent)*. There was no difference in permanent study drug discontinuation between dronedarone and placebo (30.2 vs. 30.8 percent).
* The mechanism of blood creatinine increase was well defined in a separate study of healthy volunteers and is not indicative of renal toxicity.

ATHENA post hoc analysis

Strokeⁱ
The ATHENA stroke post hoc analysis² was conducted to confirm the consistent benefit of dronedarone in reducing major cardiovascular complications in AF or AFL patients, such as stroke, which is a leading cause of cardiovascular hospitalization or death in this patient population. Cardiovascular hospitalizations were a component of the primary endpoint. The post-hoc data presented during the European Society of Cardiology Congress (ESC) 2008 showed that dronedarone decreased the risk of stroke (ischemic or hemorrhagicⁱ) compared with placebo by 34 percent (46 vs. 70 stroke events respectively; p=0.027) in AF/AFL patients adequately treated by standard therapy including antithrombotics.

Hospitalization
Cardiovascular hospitalization was a component of the primary endpoint of the ATHENA study. A further post hoc analysis³ was conducted to better understand the impact of dronedarone on hospitalization burden within the AF/AFL population.

The data presented during the American Heart Association (AHA) annual congress 2008, showed dronedarone significantly reduced the total number of hospital days by 28 percent (p<0.001) versus placebo (9,995 days vs. 13,986 days) and decreased the total length of time spent in hospital for cardiovascular reasons by 35 percent (p<0.001; 5,875 days vs. 9,073 days).

In addition to demonstrating a 37 percent (p<0.001) reduction of AF-related hospitalizations, dronedarone reduced the incidence of first non-AF related CV hospitalization (e.g. myocardial infarction or unstable angina) by 14 percent (p=0.016). Dronedarone did not increase the incidence of non-cardiovascular hospitalizations in comparison to the placebo arm which is indicative of not deleterious effects.

A new post hoc analysis on hospitalization will be presented during the ESC 2009 congress.

Rhythm and rate
This post hoc analysis from ATHENA⁴ confirmed the rhythm and rate controlling properties of dronedarone, which had previously been demonstrated in lower risk populations in the EURIDIS, ADONIS, and ERATO trials. The analysis presented during the AHA annual congress 2008, showed dronedarone reduced the incidence of first AF recurrence by 25 percent in patients in sinus rhythmⁱ at study initiation (p<0.001) and the incidence of first electrical cardioversionⁱ by 31 percent (p<0.001), compared with placebo.

Median heart rateⁱ during AF/AFL was also significantly lower in the dronedarone group with 78 beats per minute (bpm) versus 87 bpm in the placebo group (p<0.001). Fewer patients developed permanent AF during the study in the dronedarone group – 178 patients (7.7 percent) compared with 295 patients (12.7 percent) in the placebo arm (p<0.001). In these patients, the non-significant reduction of CV hospitalization or death was 26 percent lower for those receiving dronedarone (p=0.096). These results are consistent with the overall study results.

Congestive heart failureⁱ
This post hoc analysis⁵ presented during the Heart and Rhythm Society (HRS) congress 2009 highlight that patients with congestive heart failure showed results that were consistent with the overall ATHENA population.

Patients with recently decompensated heart failure or in New York Heart Association (NYHA) class IV were excluded from the study.

In stable patients with atrial fibrillation and CHF classe III, dronedarone showed a decrease on the primary endpoint of CV hospitalisation or death (44%, P=0,0028) with a trend toward reduction of all-cause mortality (34%, P=0,247).

There was also a trend toward a decrease in CHF hospitalizations in the dronedarone arm. Those patients who did develop CHF during the study had a trend toward reduction of all-cause mortality (49% P= 0.0515).

Coronary heart disease
A new post hoc analysis on the effects of dronedarone on clinical outcomes in patients with atrial fibrillation and coronary heart disease will be presented during the ESC congress 2009.


References:

1. Hohnloser SH, Crijns HJ, van Eickels M, Gaudin C, Page RL, Torp-Pedersen C, Connolly SJ; ATHENA Investigators. Effect of dronedarone on cardiovascular events in atrial fibrillation. N Engl J Med. 2009;360(7):668-78.
2. Connolly SJ. ATHENA: The effect of dronedarone on cardiovascular outcomes and stroke in patients with atrial fibrillation. European Society of Cardiology Congress 2008; September 3, 2008; Munich, Germany. Clinical trials update 3.
3. Torp-Pedersen C, Page RL, Conolly SJ, Crijns HJ, van Eickels M, Gaudin C, et al. Abstract 4101: The effect of dronaderone on hospitalizations in patients with atrial fibrillation. Results from the ATHENA Study. Circulation 118: S_828-c.
4. Page RL, Connolly SJ, Crijns HJ, van Eickels M, Gaudin C, Torp-Petersen C et al. Abstract 4097: Rhythm-and rate-controlling effects of dronedarone in patients with atrial fibrillation: insights from the ATHENA trial. Circulation 118: S_827-c.
5. Hohnloser SH, Connolly SJ, Crijns HJ, Gaudin C, van Eickels M, Page RL, Torp-Pedersen C. Effects of Dronedarone on Clinical Outcomes in Patients with Atrial Fibrillation and Congestive Heart Failure: Insights from ATHENA. Heart Rhythm Society Congress 2009; May 15, 2009; Boston, USA. Available at: http://www.hrsonline.org/News/Media/press-releases/
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