1. Effects of Dronedarone on Cardiovascular Events: a New Antiarrhythmic Drug
Grace Thacker
Xavier University of Louisiana
LSUHC – Internal Medicine
April 7, 2009

2. Effects of Dronedarone on Cardiovascular Events in Atrial Fibrillation
New England Journal of Medicine February 2009, 360:
Hohnloser, S., Crijns, H., van Eickels, M., Gaudin, C., Page, R., Torp-Pederson, C., & Connolly, S.

3. Why ATHENA? Novel drug Recent FDA approval of Multaq
First study of its kind
Antiarrhythmic
Hospitalization

4. What is ATHENA? Randomized double blind placebo controlled trial
Multi-center
551 centers
37 countries
Phase III research

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

6. Authors & Funding
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

7. Background 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

8. Dronedarone
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.
dronedarone
amiodarone

9. Methods Randomized double blind placebo controlled
Enrollment: June 2005 – December
Follow up: until common end day of December

10. Enrollment 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

11. Enrollment 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%.

12. Enrollment 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

13. Enrollment 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

14. Outcomes
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

15. Study power
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

16. Randomization
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

17. Randomization 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%

18. Results Primary Outcome: Dronedarone: 31.9% Placebo: 39.4%
Hazard ratio 0.76 (95% CI , P < 0.001)

19. Results 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

20. Drug discontinuation 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

21. Discussion
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

22. Discussion 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

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

24. Application
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