Transcript New_agents_10_handout

New Agents
Heather Kertland, PharmD
Dronedarone has Key Structural Differences to
Amiodarone
Dronedarone
O
(CH2)3CH3
CH3SO2HN
O(CH2)3N
(CH2)3CH3
(CH2)3CH3
O
O
(CH2)3CH3
I
O(CH2)2N
Amiodarone
O
I
Kathofer et al. Cardiovasc Drug Rev. 2005;23(3):217-30.
CH2CH3
CH2CH3
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
* 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
Results Outcome
Primary
N Engl J Med 2009;360:668-78
Droned
31.9%
First hospitaliztion 29.3%
- for a fib
14.6%
- for HF
4.9%
- for ACS
2.7%
- for syncope
1.2%
- for arrest/arrh 0.6%
Death
5.0%
Amio
39.4%
36.9%
21.9%
5.7%
3.8%
1.4%
0.5%
6.0%
P value
<0.001
<0.001
<0.001
0.22
0.03
0.54
0.57
0.18
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
Results
J Cardiovasc Electrophy 2010:epubApril 6
A fib recurrence
JACC 2010;55:1569-76
JACC 2010;55:1569-76
Role in maintaining SR
Circulation 2006;114:257-354
Side Effects
Overall
Diarrhea
N&V
Renal
Rash
QT
Overall
Dron
Plac
9.0%
6.0%
5.8%
2.7%
5.8%
2.8%
1.6%
1.6%
Requiring d/c
Dron
Plac
11.8%
7.7%
1.3%
0.5%
1.0%
0.3%
1.2%
1.2%
0.6%
0.6%
Side Effects
• Compared to placebo no difference in
– Thyroid dysfunction
– Liver enzyme elevations
– Opthamologic
– Pulmonary*
• Skin
– Photosensitivity (0.4% vs 0.1%)
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
The details
• Blocks multiple channels
• Active metabolite
– SR35021 30 – 40% activity
• Improve bioavailability when taken with food
– All trials to date have recommended to take with food
• Half-life 17.6 hrs (terminal 30 hrs)
– No loading doses
• Metabolized by CYP450 3A4
• Inhibitor of
– 3A4 (moderate), 2D6 (mild)
– PGP (P-glycoprotein)
• Statins
Drug Interactions
Drug Interactions
– 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
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
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
Results
Primary outcome
• CV death,
hospitalization
for HF, stroke,
bleeding,
arrhythmia
NEJM 2010 epubmarch 15th
Choice of agents
Agent
None
Beta-blockers
Dilt/Vera alone
Digoxin alone
BB + CCB
BB + dig
CCB + dig
BB + dig + CCB
Lenient
10.3%
42.4%
5.8%
6.8%
3.9%
19.3%
5.8%
1.0%
Strict
1.0%
20.1%
5.3%
1.7%
12.5%
37.3%
9.6%
8.9%
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
Torsade de points
J Am Coll Cardiol 2010;55:934-47