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

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.

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

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

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!

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

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

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

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

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

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%.

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

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

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

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

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

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%

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

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

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

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

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

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

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