Effects of Dronedarone on Cardiovascular

Events: a New Antiarrhythmic Drug

Grace ThackerXavier University of LouisianaLSUHC – Internal Medicine

April 7, 2009

Effects of Dronedarone on Cardiovascular

Events in Atrial Fibrillation

New England Journal of Medicine February 2009, 360: 668-678Hohnloser, 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:– 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

O

CH3

OI

I

O

N

CH3

CH3

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