Evolving pharmacologic antiarrhythmic treatment targets Ready for clinical practice?

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1 Evolving pharmacologic antiarrhythmic treatment targets Ready for clinical practice? David O. Arnar MD PhD EMPH Landspitali The National University Hospital of Iceland, Reykjavik

2 Disclosures Consultant to Medtronic, St Jude Medical Speakers fee/honoraria from MSD, Pfizer, Astra-Zeneca

3 Advances in arrhythmia therapy in the past two decades

4 Pro-arrhythmia

5 New antiarrhythmic drugs

6 Multi channel blocker (Na +, K +, Ca ++ ), similar to amiodarone but without iodine Better than placebo in maintaining sinus rhythm in AF patients Less effective than amiodarone Appears to have a better side effect profile than amiodarone with increased tolerabillty Associated with liver failure? Dronedarone

7 ATHENA trial decrease in Cardiovascular Hospitalization or Death 50 Cummulative Incidence (%) HR=0.76 p<0.001* Placebo Dronedarone 24% reduction in relative risk Months Placebo Dronedarone Mean follow-up 21 ± 5 months

8 Dronedarone Dronedarone decreased relative risk of stroke by 34% compared to placebo in ATHENA, independent of anticoagulation/antiplatelet status The PALLAS trial (dronedarone vs. placebo in permanent AF) stopped prematurely due to a 2.3 fold increase of cardiovascular (CV) events (stroke, systemic emboli, MI and CV death) and 1.5 fold increase in CV hospitalizations and all cause mortality in the dronedarone arm What will the future role of dronedarone be in the treatment of AF?

9 New amiodarone analogues Two amiodarone derivatives, budiodarone (containing iodine) and celivarone (noniodinated), are undergoing phase II testing for atrial fibrillation and ventricular arrhythmias. Initial results appear promising, but their future role in AF therapy is currently unclear.

10 Vernakalant (Brinavess) Inhibits the atrial selective I Kur and I KAch in addition to blocking rapid unbinding Na + channels Prolongs atrial refractoriness without significantly increasing the ventricular refractory period Effective for terminating AF of relatively short (< 7 days) duration compared to placebo Currently only available for intravenous use due to short half life, but an oral formulation is being developed

11 AVRO study

12 Potential antiarrhythmic treatment targets

13 Inhibition of the peak and late sodium currents with ranolazine Ranolazine is an anti-anginal drug with complex electrophysiologic effects, including inhibition of the peak and late I Na Ranolazine produces potent use dependent depression of I Na leading to an increased diastolic threshold of exitation and post repolarization refractoriness in the atria but not in the ventricle Antzelevitch, Heart Rhythm 2011 Burashnikov, Circulation 2007

14 Ranolazine and arrhythmias Ranolazine inhibits atrial arrhythmias in vitro In the MERLIN-TIMI 36 trial ranolazine reduced the occurrence of supraventricular arrhythmias and 30% reduction in new onset AF was seen The drug appears safe in structural heart disease and small studies have suggested that it might be useful as a pill in the pocket for AF No randomized placebo controlled clinical trials that have primarily tested the antiarrhythmic effect of Ranolazine have been published

15 Abnormal calcium homeostasis in AF Atrial proteins that are involved in intracellular Ca ++ handling undergo remodeling in AF Among those affected is the RyR2, resulting in a diastolic Ca ++ leak from the sarcoplasmic reticulum The subsequent Ca ++ overload can be proarrhytmic and leads to increased propensity for both induction and maintainance of AF Dobrev & Nattel, Lancet 2010

16 Potential drug targets to improve calcium handling and possibly reduce arrhythmias Stabilizing the RyR2 function reducing diastolic Ca ++ leak from SR SERCA enhancement stimulating Ca ++ re-uptake NCX inhibition preventing depolarizing Na + influx in response to Ca ++ overload Calmodulin kinase II inhibition promoting the closed state of RyR2

17 Other potential pharmacological targets I KAch inhibition another atrial selective therapy. Might be specific for vagally induced AF. Tertiapin-Q and NIP-151 have shown antiarrhytmic activity against AF in animal models Stretch activated channels The electrical consequences of increased atrial size and subsequent stretch contribute to initiation and maintenace of AF. Non selective stretch-activated channels and two pore K + selective stretch activated channels have been described in the human atrium Gadolinium, GsMTx -4 (Chilean Rose tarantula toxin) and streptomycin may prevent stretch induced vulnerability to AF in animal models Blockade of stretch activated channels may a future target for AF therapy Ninio DM, 2008

18 Modification af gap junctions Gap junctions are made up of connexins and in the heart the isoforms are mainly of the Cx43, Cx40 and Cx45 subtypes Alterations in cell to cell electrical coupling due to inflammation, ischemia and fibrosis may be pro-arrhythmic Antiarrhythmic peptides (AAPs) improve intercellular communication by enhancing gap junction conductance Clinical application for AAPs in atrial fibrillation is as of yet unclear, although this approach has shown some promise for ventricular arrhythmias in experimental models

19 Upstream therapy

20 ACEI/ARBs RAAS inhibition can attenuate fibrosis in experimental models There may be some benefit of these ACEI/ARBs in primary prevention of AF in selected populations, particularly in those with heart failure due to left ventricular dysfunction and those with left ventricular hypertrophy due to hypertension Recent large GISSI-AF trial showed no benefit of valsartan 320 mg/day vs placebo in preventing recurrence of AF. Similar results were seen in ANTIPAF with olmesartan and in ACTIVE-I with irbesartan

21 Statins Value of statins for primary prevention of AF has not been sufficiently demonstrated, except perhaps in postoperative AF Role of statins in secondary prevention of AF is presently unclear with a number of ongoing trials to be completed

22 n-3 polyunsaturated fatty acids (PUFA) Anti inflammatory effects Electrophysiologic effects Antioxidant actions Well tolerated without serious side effects

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26 Eur J Clin Invest 2011

27 Atrial-selective agents Vernakalant Ranolazine I KAch inhibitors Amiodarone derivatives Dronedarone Budiodarone Celivarone Evolving pharmacologic targets for AF management Upstream therapy ACEI/ARBs Statins n-3 PUFA Abnormal Ca ++ handling Drugs that stabilize the RyR2 SERCA modulation? Novel targets Atrial stretch receptor blockade Gap junction modification Modified from Carlsson L, et al, Trends Pharmacol Sci 2010

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29 Synergistic effects of ranolazine and dronedarone in a pulmonary sleeve preparation in vitro Burashnikov et al, JACC 2010

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31 The promise of genetic discoveries? Diagnostics Improved measures of individual etiological processes Personalized medicine Prognostics Therapeutic optimization Identification of genetic susceptibility variants Therapeutic agents Novel biological insights Clinical advances Biomarkers Prevention