Transcript Effects of Dronedarone on Cardiovascular Events

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:
– 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
O
O
CH3
I
N
CH3
O
CH3
I
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.
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