1. New Agents
Heather Kertland, PharmD

2. Dronedarone has Key Structural Differences to Amiodarone
(CH2)3CH3
CH3SO2HN
(CH2)3CH3
O(CH2)3N
(CH2)3CH3 O O
(CH2)3CH3
Dronedarone is a benzofuran derivative structurally related to amiodarone but without the iodine on the benzene ring and with a sulfonamide group added to the benzofuran ring
Dronedarone was originally developed with the aim of leveraging amiodarone’s antiarrhythmic efficacy and cardiac safety but with improved organ toxicity
The electrophysiological properties of dronedarone are similar to those of amiodarone and their structural differences may be responsible for the improved clinical profile of dronedarone compared to amiodarone
The most significant structural changes are the removal of iodine and the addition of a methane sulfonyl group. The removal of iodine should result in freedom of amiodarone’s iodine-related organ toxicity, and the second molecular change is thought to decrease lipophilicity, thus shortening the half-life and reducing tissue accumulation
A consequence of this toxicity is that amiodarone administration requires dose titration to determine the minimum effective dose, as adverse effects are often dose-related. On the other hand, due to its amended profile, dronedarone is administered as a fixed dosing regimen with no loading dose or need for titration.
Reference
Kathofer et al. Cardiovasc Drug Rev 2005;23(3):
Wegener F et al. J Cardiovasc Electrophysiol. 2006;17(S2):S17-S20 I
CH2CH3
O(CH2)2N
CH2CH3 O
Amiodarone I
Kathofer et al. Cardiovasc Drug Rev. 2005;23(3): 2

3. ATHENA - Objective
Evaluate the efficacy and safety of dronedarone 400mg bid vs placebo on top of standard therapy* in the prevention of CV hospitalisation or death from any cause over a minimum treatment and follow-up duration of 12 months in patients with paroxysmal or persistent AF/AFL
ATHENA was a double-blind, randomised, multinational trial designed to evaluate the efficacy and safety of dronedarone vs placebo on top of standard therapy in the prevention of CV hospitalisation or death from any cause over a minimum treatment and follow-up duration of 12 months in patients with paroxysmal or persistent AF/AFL
Patients in both arms were receiving standard therapy. Standard therapy may have included rate control agents (beta-blockers, and/or Ca-antagonist and/or digoxin) and/or anti-thrombotic therapy (Vit. K antagonists and /or aspirin and other antiplatelets therapy) and/or other cardiovascular agents such as ACEIs/ARBs and statins.
Reference
Hohnloser SH et al. J Cardiovasc Electrophysiol 2008;19:69-73.
* Standard therapy may have included rate control agents (beta-blockers, and/or Ca-antagonist and/or digoxin) and/or anti-thrombotic therapy (Vit. K antagonists and /or aspirin and other antiplatelets therapy) and/or other cardiovascular agents such as ACEIs/ARBs and statins.
N Engl J Med 2009;360:668-78 3 3

4. Results - N Engl J Med 2009;360:668-78
Outcome
Droned
Amio
P value
Primary
31.9%
39.4%
<0.001
First hospitaliztion
29.3%
36.9%
- for a fib
14.6%
21.9%
- for HF
4.9%
5.7%
0.22
- for ACS
2.7%
3.8%
0.03
- for syncope
1.2%
1.4%
0.54
- for arrest/arrh
0.6%
0.5%
0.57
Death
5.0%
6.0%
0.18

5. Dionysos Trial N= 504 subjects A fib > 72 hours
Dronedarone 400 mg BID vs Amio 600 mg daily x 28 days then 200 mg daily x 12 mos
D/C therapy
Overall 38.6% dronedarone 27.1% amio
S/E 12.9% dronedarone 17.6% amio
J Cardiovasc Electrophy 2010;epub april 6

6. Results
J Cardiovasc Electrophy 2010:epubApril 6

7. A fib recurrence
JACC 2010;55:

8. JACC 2010;55:

9. Role in maintaining SR
Circulation 2006;114:

10. Side Effects Overall Requiring d/c Dron Plac 11.8% 7.7% Diarrhea 9.0%
5.8%
1.3%
0.5%
N & V
6.0%
2.8%
1.0%
0.3%
Renal
1.6%
Rash
2.7%
1.2%
0.6% QT

11. Side Effects Compared to placebo no difference in Skin
Thyroid dysfunction
Liver enzyme elevations
Opthamologic
Pulmonary*
Skin
Photosensitivity (0.4% vs 0.1%)

12. Renal effects Approx 10 umol/L increase in serum creatinine
Occurs early, within 7 days
Reversible
Does not reflect change in renal function
Recommend serum Cr at 7 days to determine baseline

13. The details Blocks multiple channels Active metabolite
SR – 40% activity
Improve bioavailability when taken with food
All trials to date have recommended to take with food
Half-life hrs (terminal 30 hrs)
No loading doses
Metabolized by CYP450 3A4
Inhibitor of
3A4 (moderate), 2D6 (mild)
PGP (P-glycoprotein)

14. Drug Interactions Drug Interactions Statins Beta-blockers CCB Digoxin
Simvastatin, lovastatin, atorvastatin, pravastatin
Increased statin conc, potential increased SE
Fluvastatin and rosuvastatin – ok
Beta-blockers
Increase metoprolol and probably carvedilol, bisprolol and timolol
Additive effects
CCB
Increased verapamil concentration
Digoxin
Increased digoxin concentrations
CYP3A4 inhibitors
Ketoconazole, cyclosporin, clarithromycin, ritonavir
St John’s Wort
Grapefruit juice

15. Rate Control
Criteria for rate control vary but typically ventricular rates between 60 and 80 bpm at rest and between 90 and 115 bpm during moderate exercise
AFFIRM trial, adequate control was defined as an average heart rate up to 80 bpm at rest and either an average rate up to 100 bpm over at least 18-h ambulatory Holter monitoring with no rate above 100% of the maximum age-adjusted predicted exercise heart rate or a maximum heart rate of 110 bpm a 6-min walk test
Goal is to decrease symptoms, improve QOL, improve exercise tolerance, decrease heart failure

16. RACE II
the hypothesis that lenient rate control is not inferior to strict rate control in preventing cardiovascular events in patients with permanent atrial fibrillation
614 pts, open label
Lenient – resting heart rate < 110 bpm
Strict – resting heart rate < 80 bpm, <110 bpm during moderate exercise
NEJM 2010 epub March 15th

17. Results Primary outcome
CV death, hospitalization for HF, stroke, bleeding, arrhythmia
NEJM 2010 epubmarch 15th

18. Choice of agents Agent Lenient Strict None 10.3% 1.0% Beta-blockers
42.4%
20.1%
Dilt/Vera alone
5.8%
5.3%
Digoxin alone
6.8%
1.7%
BB + CCB
3.9%
12.5%
BB + dig
19.3%
37.3%
CCB + dig
9.6%
BB + dig + CCB
8.9%

19. Conclusions
Strict heart rate control targets do not result in better clinical outcomes
Long term effects on heart rate control on HF still to be determined
QOL, symptoms, exercise tolerance are key endpoint in monitoring patient

20. Torsade de points
J Am Coll Cardiol 2010;55:934-47