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

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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 gt/ 50 mm, or LEF lt/ 40.

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Enrollment

• Exclusion criteria
• Heart failure. NYHA class IV, or recent
  decompensation
• bradycardia or PR interval gt0.28 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

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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 lt 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, Plt 0.001

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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

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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