New Agents

Heather Kertland, PharmD

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.

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 - 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

• 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

J Cardiovasc Electrophy 2010:epubApril 6

Results

JACC 2010;55:1569-76

A fib recurrence

JACC 2010;55:1569-76

Role in maintaining SR

Circulation 2006;114:257-354

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%

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)

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

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

ResultsPrimary outcome• CV death,

hospitalization for HF, stroke, bleeding, arrhythmia

NEJM 2010 epubmarch 15th

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%

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