new agents heather kertland, pharmd. dronedarone has key structural differences to amiodarone...
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New Agents
Heather Kertland, PharmD
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Dronedarone has Key Structural Differences to Amiodarone
Dronedarone
CH3SO2HN O(CH2)3
N
O
O
(CH2)3CH3
(CH2)3CH3
Amiodarone
O(CH2)2N
O
O
CH2CH3
CH2CH3
(CH2)3CH3
(CH2)3CH3
I
I
Kathofer et al. Cardiovasc Drug Rev. 2005;23(3):217-30.
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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
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Results - N Engl J Med 2009;360:668-78
Outcome Droned Amio P value
Primary 31.9% 39.4% <0.001First hospitaliztion 29.3% 36.9% <0.001
- for a fib 14.6% 21.9% <0.001
- 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
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• 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
Dionysos Trial
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J Cardiovasc Electrophy 2010:epubApril 6
Results
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JACC 2010;55:1569-76
A fib recurrence
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JACC 2010;55:1569-76
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Role in maintaining SR
Circulation 2006;114:257-354
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Side EffectsOverall Requiring d/c
Dron Plac Dron Plac
Overall 11.8% 7.7%
Diarrhea 9.0% 5.8% 1.3% 0.5%
N & V 6.0% 2.8% 1.0% 0.3%
Renal 5.8% 1.6%
Rash 2.7% 1.6% 1.2% 0.6%
QT 1.2% 0.6%
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Side Effects• Compared to placebo no difference in
– Thyroid dysfunction– Liver enzyme elevations– Opthamologic – Pulmonary*
• Skin– Photosensitivity (0.4% vs 0.1%)
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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
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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)
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Drug Interactions• Statins– 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
Drug Interactions
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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
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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
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ResultsPrimary outcome• CV death,
hospitalization for HF, stroke, bleeding, arrhythmia
NEJM 2010 epubmarch 15th
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Choice of agentsAgent 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 5.8% 9.6%
BB + dig + CCB 1.0% 8.9%
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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
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Torsade de points
J Am Coll Cardiol 2010;55:934-47
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