Effects of Dronedarone on Cardiovascular Events: a New Antiarrhythmic Drug

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: 668-678 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: • 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 30 2006 • Follow up: until common end day of December 30 2007

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 0.69-0.86, 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