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New Agents

New Agents. Heather Kertland, PharmD. Dronedarone has Key Structural Differences to Amiodarone. Dronedarone. O. (CH 2 ) 3 CH 3. CH 3 SO 2 HN. (CH 2 ) 3 CH 3. O(CH 2 ) 3 N. (CH 2 ) 3 CH 3. O. O. (CH 2 ) 3 CH 3. I. CH 2 CH 3. O(CH 2 ) 2 N. CH 2 CH 3. O. Amiodarone. I.

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New Agents

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  1. New Agents Heather Kertland, PharmD

  2. Dronedarone has Key Structural Differences to Amiodarone Dronedarone O (CH2)3CH3 CH3SO2HN (CH2)3CH3 O(CH2)3N (CH2)3CH3 O O (CH2)3CH3 I CH2CH3 O(CH2)2N CH2CH3 O Amiodarone I Kathofer et al. Cardiovasc Drug Rev. 2005;23(3):217-30.

  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 causeover 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

  4. Results - N Engl J Med 2009;360:668-78

  5. 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 Dionysos Trial J Cardiovasc Electrophy 2010;epub april 6

  6. Results J Cardiovasc Electrophy 2010:epubApril 6

  7. A fib recurrence JACC 2010;55:1569-76

  8. JACC 2010;55:1569-76

  9. Role in maintaining SR Circulation 2006;114:257-354

  10. Side Effects

  11. Side Effects Compared to placebo no difference in 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 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)

  14. 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

  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

  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

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