Birmingham October 20 th 2013 AFA Pa9ents Day Symptoma9c Atrial Fibrilla9on What therapies are available? GENERAL BACKGROUND Andrew Grace Papworth Hospital and University of Cambridge Consultant: Medtronic Inc, Xen9on Ltd. and Founder, Electus Medical Inc. Prevalence of AF predicted to more than double by 2050 Patients with atrial fibrillation (millions) 16 14 12 10 8 6 4 2 5,1 5,1 5,9 5,6 6,7 6,1 2,08 2,26 2,44 2,66 7,7 6,8 2,94 8,9 7,5 3,33 10,2 8,4 3,8 11,7 9,4 4,34 13,1 10,3 4,78 14,3 11,1 5,16 15,2 11,7 15,9 12,1 5,42 5,61 0 1990 1995 2000 2005 2010 2015 2020 2025 2030 2035 2040 2045 2050 Year Assuming a con9nued increase in the AF incidence Assuming no further increase in the AF incidence ATRIA study data Miyasaki Y et al. Circula9on 2006;114:119 25 Older Metabolic disease Hypertension Coronary disease Heart Failure Who Gets Atrial Fibrilla9on..? Any History of Physical Ac9vity in Your Family Gold Standard:- Electrocardiogram Paroxysmal and Persistent Atrial Fibrilla9on Regular rhythm P Irregularly irregular rhythm Normal sinus rhythm AF Normal heart rate Regular rhythm P waves Steady baseline Heart rate increased (tachyarrhythmia)* Irregularly irregular rhythm No P wave *Reduced heart rate (bradyarrhythmia) may also be observed Ashley EA, Niebauer J. Cardiology Explained. Remedica: London 2004 Camm et al. Eur Heart J 2010;31:2369-2429 1
Ambulatory ECG monitor Con9nuous monitoring for a short period of 9me (typically 24 hours) Useful for: Detec9ng asymptoma9c AF Evalua9ng pa9ents with paroxysmal AF Assessing response to treatment Strategic Op9ons in Atrial Fibrilla9on Symptoms of Atrial Fibrilla9on Atrial Fibrilla9on may be very symptoma9c Strategic Op9ons in Atrial Fibrilla9on 2
RATE CONTROL OF ATRIAL FIBRILLATION Conven9onal An9arrhythmic Drugs for AF Cumula9ve Mortality (%) 30 25 20 15 10 5 0 Rhythm Control vs. Rate Control (The AFFIRM Trial) Rhythm Control Rate Control 1 2 3 4 5 N = 4060 pa9ents, FU 5 years > 65 yr or other RF for Stroke or Death P=0.08 Years (%) D.G. Wyse et al. NEJM 2002; 347:1825 Rate Control in Atrial Fibrilla9on Rate Control Op9ons RHYTHM CONTROL OF ATRIAL FIBRILLATION Selecting the right drug for the patient: Recommendations for AADs used to treat AF Sotalol Flecainide Amiodarone Dronedarone Maintenance of sinus Treatment of paroxysmal Treatment of severe rhythm Maintenance of sinus rhythm following conversion AF, when other treatment is disorders, when other AADs rhythm in clinically stable of AF ineffective have failed paroxysmal or persistent AF Torsades de pointes (at doses effective for AAD) Exacerbation of ischaemic heart disease following sudden discontinuation Risk of pro-arrhythmia Cardiac toxicity Hepatotoxicity Pulmonary toxicity Neuropathy Visual problems Hepatotoxicity (very rare) Pulmonary toxicity (very rare) Stroke or cardiac mortality in permanent AF patients AAD: anti-arrhythmic drug. AF: Atrial fibrillation. BMI: Body mass index. CHF: Congestive heart failure. COPD: Chronic obstructive pulmonary disease. ECG: Electrocardiogram. LV: Left ventricular. LVEF: LV ejection fraction. LVSD: LV systolic dysfunction. MI: Myocardial infarction. 3
Selecting the right drug for the patient: Recommendations for AADs used to treat AF Sotalol Flecainide Amiodarone Dronedarone Maintenance of sinus Treatment of paroxysmal Treatment of severe rhythm Maintenance of sinus rhythm following conversion AF, when other treatment is disorders, when other AADs rhythm in clinically stable of AF ineffective have failed paroxysmal or persistent AF Torsades de pointes (at doses effective for AAD) Exacerbation of ischaemic heart disease following sudden discontinuation Risk of pro-arrhythmia Cardiac toxicity Hepatotoxicity Pulmonary toxicity Neuropathy Visual problems Hepatotoxicity (very rare) Pulmonary toxicity (very rare) Stroke or cardiac mortality in permanent AF patients Ectopic focus leads to wavefront from LSPV invading LA body Appropriate condi9ons of heterogeneity lead to wave break with counter- rota9ng vor9ces AAD: anti-arrhythmic drug. AF: Atrial fibrillation. BMI: Body mass index. CHF: Congestive heart failure. COPD: Chronic obstructive pulmonary disease. ECG: Electrocardiogram. LV: Left ventricular. LVEF: LV ejection fraction. LVSD: LV systolic dysfunction. MI: Myocardial infarction. Jalife et al. Cardiovasc Res 2002 54: 204-216 Atrial Fibrilla9on and Amiodarone Atrial Fibrilla9on and Amiodarone N Engl J Med. 2007 Mar 1;356(9):935-41 N Engl J Med. 2007 Mar 1;356(9):935-41 Patients without AFib (%) Amiodarone to Prevent Recurrence of AF CTAF Study: mean follow-up 16 months 100 p<0.001 80 60 40 20 Amiodarone Sotalol Propafenone 0 0 100 200 300 400 500 600 Follow-up (days) Conventional Antiarrhythmic Drugs for AF ACC/AHA/ESC 2006 guidelines for the management of AF No Heart Disease Flecanide Sotalol AMIODARONE Catheter Ablation Coronary Artery Disease Sotalol AMIODARONE Catheter Ablation Heart Failure or Hypertension with LVH AMIODARONE Catheter Ablation Roy D, et al. N Engl J Med 2000; 342:913 Fuster et al, Circulation 2006;108:1979 4
Amiodarone is a difficult drug Acute Liver Failure associated with Dronedarone 70-year old female 6-month Rx Dronedarone Hepatic encephaolopathy A. Cholestatic organ B. Widespread necrosis C. Canalicular cholestasis D. Mixed pattern of inflammatory cells Joghetaei et al. Circ Arrhythm Electrophysiol 2011;4;592-593 Selecting the right drug for the patient: Recommendations for AADs used to treat AF Sotalol Flecainide Amiodarone Dronedarone Not used in patients with: Not used in patients with: Not used in patients with: Not used in patients with: COPD and asthma LV hypertrophy Thyroid dysfunction Permanent AF, no LV hypertrophy (LVEF < 40%) Sinus bradycardia restoration of sinus rhythm (LVEF < 40%) Heart failure Heart failure Renal failure or low BMI Coronary artery disease LVSD or LVEF < 40% Heart failure CHF or history of MI Severe hepatic or renal Sinus bradycardia Longstanding AF, no impairment restoration of sinus rhythm Sinus bradycardia Previous lung or liver toxicity from amiodarone use Initiate in secondary care with ECG Initiate in secondary care with ECG Initiate only in hospital or Initiate under specialist under specialist supervision supervision AAD: anti-arrhythmic drug. AF: Atrial fibrillation. BMI: Body mass index. CHF: Congestive heart failure. COPD: Chronic obstructive pulmonary disease. ECG: Electrocardiogram. LV: Left ventricular. LVEF: LV ejection fraction. LVSD: LV systolic dysfunction. MI: Myocardial infarction. Systems Approach to Atrial Fibrillation CLINICAL PHENOTYPES (A) GENETICS (B) NEW DRUG DEVELOPMENT SYSTEMS ARCHITECTURE (computation) MOLECULAR, CELLULAR, WHOLE HEART AND SIMULATION STUDIES (C) CLINICAL CARE Improved taxonomy Prevention Targeted therapeutics 5
Extending the ARP Safely modulate only atrial channels Efficacy in Human Tissue Atrial Tissue Ventricular Tissue 0 mv Kv1.5 IKACh Targe9ng atrium- specific channels avoids the risk of QT Very few channels are expressed only in the atria Our preferred targets: Kv1.5-80 mv IKACh (aka Kir3.1/3.4) Human Atrial Myocyte XEN- D0101 selec9vely prolongs ARP Ideal profile for an AF therapeu9c Disease Ion Channel Discovery Pre-Clinical Clinical Development Indication Target Development Phase I Phase II Atrial Fibrillation Kv1.5 IKACh XEN-D0103 Collaborative Research Ono Pharmaceutical Co Ltd Grünenthal GmbH INITIAL ASSESSMENT CONCLUSIONS Stroke risk Causes lifestyle/echocardiogram Quality of life 6
STRATEGIC OPTIONS CONSIDER REFERRAL Rate control beta block/calcium channel blocker Rhythm control beta block/an9arrhythmic Refer Rate control difficult Younger pa9ents Pa9ents with hospital admissions 7