Grace Thacker
Xavier University of Louisiana
LSUHC – Internal Medicine
April 7, 2009

Hohnloser, S., Crijns, H., van Eickels, M., Gaudin, C.,
Page, R., Torp-Pederson, C., & Connolly, S.

 Novel drug
 Recent FDA approval of Multaq
 First study of its kind
– Antiarrhythmic
– Hospitalization

 Randomized double blind placebo controlled trial
 Multi-center
– 551 centers
– 37 countries
 Phase III research

 Abstract:
– Clear and concise
– No new information
– Lets the reader know if article is worth reading
 Title
– Does not! Not very representative!

 Authors are affiliated with various universities and medical centers
 All received monies from Sanofi-Aventis
 Investigators from ATHENA contributed to study design and protocol
 Study was funded by Sanofi-Aventis

 Purpose: more data for new drug
 Background: current atrial fibrillation therapy is limited by toxicities
– Dronedarone formulated to avoid some toxicities
 Goal: determine if dronedarone reduced hospitalizations due to cardiovascular causes

dronedarone
O
O
I
N
CH
3
CH
3
CH
3 I
O amiodarone
Dronedarone is a modification of amiodarone. Note that dronedarone does not contain iodine, and has the addition of a methane-sulfonyl group that reduces lipophilicity to decrease accumulation in tissue.

 Randomized double blind placebo controlled
 Enrollment: June 2005 – December 30
2006
 Follow up: until common end day of
December 30 2007

 Inclusion criteria:
– Atrial fibrillation or flutter demonstrated by
EKG within last 6 months
– Plus EKG showing normal sinus rhythm in same time period
– Plus one or more additional requirements

 Inclusion criteria:
 One or more of the following:
– Age of at least 70
– HTN
– DM
– Previous stroke, systemic embolism, or TIA
– LA diameter >/= 50 mm, or LEF </= 40%.

 Exclusion criteria:
– Heart failure. NYHA class IV, or recent decompensation
– bradycardia or PR interval >0.28 seconds
– Permanent A fib, acute myocarditis, sinus node disease
– Need for class I or class III antiarrhythmic

 Changes in May 2006:
– Inclusion criteria altered to include
• Patients age 75 or older with no additional factors present
• Patients age 70 – 74 had to demonstrate one or more additional factors

 Primary: composite outcome of hospitalization due to cardiovascular events, and death from any cause
 Secondary: death from any cause, death from cardiovascular events, hospitalization due to cardiovascular events

 Required 970 primary outcome events to be powered at 80% to detect a 15% difference
 Minimum follow up 1 year; maximum follow up 2.5 years
 Assumed enrollment of 2150 patients per group

 Dronedarone: 2301; 10 not treated; 696 discontinued drug prematurely
 Placebo: 2325; 2 lost to follow up; 14 not treated; 716 discontinued drug prematurely
 Randomization stratified per center and by presence of A fib or A flutter at enrollment

 Baseline characteristics: no difference between groups
– Most common CV disorder: HTN
– A fib or A flutter present in 25%
– Structural heart disease in 59.6%
– Heart failure: Class II in 17%; Class III in
4.4%

 Primary Outcome:
– Dronedarone: 31.9%
– Placebo: 39.4%
– Hazard ratio 0.76 (95% CI 0.69-0.86, P <
0.001)

 Secondary Outcomes:
– Death from any cause: no difference
– Death from cardiovascular causes: dronedarone 2.7%, placebo 3.9%, P = 0.03
– Death from arrhythmias: dronedarone
1.1%, placebo 2.1%, P = 0.01
– Hospitalization for CV events: dronedarone
36.9%, placebo 29.3%, P< 0.001

 Over 30% in both groups
 Dronedarone: adverse events.
– Most significant: rash, nausea, diarrhea, bradycardia, QT prolongation, increased serum creatinine
 Placebo: “ other ”
– Required drugs not allowed by the study

 Unlike ANDROMEDA, dronedarone demonstrated a decrease in death
– Excluded severe heart failure
– Heart failure subgroup showed same benefit
– Amiodarone still drug of choice in severe heart failure
 Decrease in hospitalizations
– Cannot be compared to other drugs

 Fewer side effects than amiodarone
– Short term study
– Need longer follow up to assess long term toxicities
– Need comparison trial with amiodarone
• Study completed March 2009
• Compares amiodarone and dronedarone in preventing recurrent atrial fibrillation

 High rates of discontinuation
 Inclusion criteria
– Only age 70 and up
– Change in inclusion criteria
 Not comparable to other antiarrhythmic trials

 Consider dronedarone to avoid toxicities such as thyroid dysfunction or pulmonary toxicities
 Continue to rely on amiodarone or dofetilide for patients with NYHA HF III or IV
 Keep cost and formulary issues in mind
 Refer to handout for additional information on dronedarone