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Atrial Fibrillation: From Sinus Rhythm Maintenance to Improving CV Outcomes – Should We Redefine Therapy Goals? Mila

Atrial Fibrillation: From Sinus Rhythm Maintenance to Improving CV Outcomes – Should We Redefine Therapy Goals? Milan Gupta , MD Department of Medicine McMaster University Hamilton, Canada. Overview. AF Epidemiology Antiarrhythmic Drugs and Outcomes New AF Treatment Options.

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Atrial Fibrillation: From Sinus Rhythm Maintenance to Improving CV Outcomes – Should We Redefine Therapy Goals? Mila

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  1. Atrial Fibrillation: From Sinus Rhythm Maintenance to Improving CV Outcomes – Should We Redefine Therapy Goals? Milan Gupta, MD Department of Medicine McMaster University Hamilton, Canada

  2. Overview AF Epidemiology Antiarrhythmic Drugs and Outcomes New AF Treatment Options

  3. AF is the most common cardiac arrhythmia • AF affects • 1 in 25 adults >60 years1 • 1 in 10 adults >80 years1 • 7.5 million patients with AF in EU and US2,3 4.5 million 3.0 million 1. Go AS et al. JAMA 2001;285:2370-2375 2. Fuster V et al. J Am Coll Cardiol 2006;38:1231-1265 3. Naccarelli GV et al. Am J Cardiol. 2009;104(11):1534-9

  4. Women Men Lifetime risks for development of AF are 1 in 4 for men and women 40 years of age and older Framingham 26.0 25.9 25.8 24.3 23.4 23.2 23.0 23.0 22.7 21.6 Lifetime risk of AF (%) Age (years) Lloyd-Jones DM, et al. Circulation 2004;110:1042-46

  5. AF is Associated with a High Prevalence of Co-morbidities • The Record AF registry including 5,604 patients with paroxysmal or persistent AF Le-Heuzey J-Y, et al. Am J Cardiol 2010;105:687-93.

  6. AF May Adversely Affect Quality of Life • QoL was significantly worse in AF patients than in controls(post MI patients and healthy subjects) Lower scores = poorer QoL 120 *p<0.05 vs. controls 100 92 88 85 80 81 78 76 71* 70 68* 68* 60 SF-36 score from QoL Questionnaire 59 54* 40 20 0 General health Physical function Social function Mental health AF patients (n=152) Post MI patients (n=69) Healthy subjects (n=47) Dorian P et al. J Am Coll Cardiol. 2000;36:1303-1309. 6

  7. All-cause mortality CV events Fatal or non-fatal stroke Heart failure All-cause mortality CV events Fatal or non-fatal stroke Heart failure AF increases risk of death and CV outcomes Renfrew/Paisley Rate ratio (95% Confidence Interval [CI])* Womenn=8,354 Menn=7,052 -1 0 1 2 3 4 5 6 7 8 * Adjusted for age; follow-up 20 years Stewart S, et al. Am J Med 2002;113:359-64. CV events: death or hospitalisation

  8. REACH Registry: Association of AF with CV Outcomes in Atherothrombotic Patients* The REACH registry Adjusted for age, sex, smoking, hypertension, diabetes, hypercholesterolaemia * out patient population with past history of coronary artery disease and/or past history of cerebrovascular disease and/or peripheral artery disease Goto S, et al. Am Heart J 2008; 156:855-63.

  9. Studies reveal high hospitalisation rates among AF patients follow-up1 year % 50 AF control follow-up 1 year mean follow-up 21 months AF not controlled 40 36.9% 36.9% 30 follow-up1 year % hospitalised for CV reasons 29.8 28.1 20 17.0% 10 0 At least one cardiovascular event RecordAF Registry4 ATHENA* (placebo arm)1 Euro Heart Survey2,3 RealizeAFRegistry * First hospitalisation due to CV event • Hohnloser SH et al. N Engl J Med 2009;360:668-78. • Nieuwlaat R et al. European Heart Journal 2008:29;1181–9. • Multaq European Public Assessment Report. • Camm J. RecordAF Registry. Scientific sessions AHA 2009.

  10. Hospitalizations Represent a Major Driver in Cost of Care of AF Patients (US) • In 2001, AF management cost about 6.65 billion dollars* in the US and was mainly driven by inpatient care. Outpatient costs (Diagnosis of AF) 1.53 billion dollars Incremental inpatient costs (AFas comorbid condition) 1.95 billion dollars Hospitalization (Principle discharge diagnosis of AF) 2.93 billion dollars 0 1 2 3 * Does not include prescription costs. Coyne K., et al. Value Health 2006;9(5):348-356.

  11. Patients hospitalised with AF have a higher risk of death in subsequent years • AFFIRM trial – 4,060 patients analyzed • CV hospitalisation highly predictive of death in both rhythm and rate control arms (p<0.0001) • Time to death did not differ between 2 treatment groups • CV hospitalisation, occurring sooner and more often than death, is highly predictive of death Wyse, et al. Heart Rhythm 2004;1;531-37. Camm AJ, Reiffel JA. Eur Heart J Suppl 2008;10:H55-78. * Inclusive cohort = all CV hospitalisations. * Censored cohort = cardioversion or drug change excluded.

  12. Overview AF Epidemiology Antiarrhythmic Drugs and Outcomes New AF Treatment Options

  13. Traditional Goals in Managing AF Restoration of sinus rhythm Ventricular rate control Identification and treatment of predisposing conditions and underlying heart disease Improvement in symptoms Improved exercise tolerance Improved quality of life Stroke prevention (with antithrombotic drugs)

  14. AF Treatment – A brief history • Digitalis – 1785, William Withing • Quinidine – 1951 • Amiodarone and disopyramide – 1970’s • Vaughan Williams classification – 1984 • Encainide and propafenone – late 1980’s • And then came 1989

  15. Placebo(n=725) Encainide or flecainide(n=730) 105 100 95 Survival (%) 90 p=0.0006 85 0 50 100 150 200 250 300 350 400 450 500 Days after randomization

  16. Quinidine Treatment Was Associated WithIncreased Total Mortality RCT Boissel, et al. Byrne-Quinn, et al. Hartel, et al. Hillestad, et al. Lloyd, et al. Sodermark, et al. TOTAL: ALL STUDIES N=808 0 1 2 3 4 5 6 7 8 9 10 11 12 Quinidine better Quinidine worse Odds ratio (Quinidine:Control) • There was a significant increase in total mortality in quinidine-treatedgroup as compared with control group (OR=2.98; p<0.05). Coplen S., et al. Circulation1990;82:1106-1116. 16

  17. 100 Amiodarone (n=201) 80 60 Propafenone (n=101) Patients without recurence (%) 40 Sotalol (n=101) 20 0 0 100 200 300 400 500 600 Days of follow-up Patients remaining free of recurrence of AF (CTAF) Roy D et al. New Engl J Med 2000;342:913-920.

  18. AFFIRM Results Post-hoc Analysis Covariate P Value HR 99% CI Sinus rhythm <.0001 Warfarin use <.0001 Digoxin use .0007 .0005 AAD use The benefits of sinus rhythm areoffset by the toxicity of AADs used in AFFIRM Corley et al. Circulation. 2004;109:1509-1513.

  19. Cumulative noncardiovascular mortality in AFFIRM 30 Log rank statistic = 11.2 P=0.0008 25 20 15 Rhythm control Percent death (%) 10 5 Rate control 0 0 1 2 3 4 5 Years No. events (%) Rate 2027, 0 (100) 1926, 20 (1) 1827, 49, (3) 1329, 70 (4) 774, 101 (7) 236, 109 (8) 1, 113 (14) Rhythm 2033, 0 (100) 1932, 33 (2) 1807, 76 (4) 1316, 120 (7) 780, 149, (9) 255, 167 (12) 1, 169 (14) Steinberg JS Circulation 2004;109:1973-1980.

  20. Amiodarone in AF Patients: Meta-analysis* • Conversion/maintenance of sinus rhythm not associated with a reduction of all-cause death or all-cause hospitalisation . * Eightstudiescomparedamiodaronewith a rate control drug, either beta-blocker or digoxin, and 4 trials comparedamiodaronewith placebo. Doyle JFD, et al. Mayo Clin Proc. 2009;84(3):234-242 Source of slide: John Camm

  21. Overview AF Epidemiology Antiarrhythmic Drugs and Outcomes New AF Treatment Options

  22. AF Increases the Risk of Stroke Framingham 5 4.5 4.0 4 3.3 2.6 3 Relative Risk of Stroke 2 1 0 50-59 60-69 70-79 80-89 Age (years) p<0.001 vs. Non-AF patients Wolf et al. Stroke 1991:22:983-988

  23. Warfarin reduces strokes RRR 64%; 95% CI: 49-75% 6 trials, n=2,700 Hart RG, et al. Ann Intern Med 2007; 146: 857-867

  24. Underutilization of Warfarin in Atrial Fibrillation: Results from Recent Studies* • Adapted from Connolly SJ, et al. Circulation 2007:116;449-455 • ATRIA: Anticoagulation and Risk Factors in Atrial Fibrillation • FP/GIM: Family practice / general internal medicine • NABOR: National Anticoagulation Benchmark and Outcomes Report Connolly SJ, et al. Circulation 2007:116;449-455

  25. Non-inferiority Superiority p-value p-value <0.001 0.34 Dabigatran 110 vs. Warfarin <0.001 <0.001 Dabigatran 150 vs. Warfarin Margin = 1.46 0.50 0.75 1.00 1.25 1.50 HR (95% CI) Stroke or Systemic Embolism Dabigatran better Warfarin better Connolly S, et al. N Engl J Med 2009

  26. AVERROES: Stroke or Systemic Embolic Event (Pts ineligible for warfarin) RR= 0.46 95%CI= 0.33-0.64 p<0.001 0.05 ASA Cumulative Risk 0.03 Apixaban 0.01 0.0 0 3 6 9 12 18 21 Months No. at Risk ASA 2791 2720 2541 2124 1541 626 329 Apix 2809 2761 2567 2127 1523 617 353 preliminary Results

  27. Traditional Goals in Managing AF Restoration of sinus rhythm Ventricular rate control Identification and treatment of predisposing conditions and underlying heart disease Improvement in symptoms Improved exercise tolerance Improved quality of life Stroke prevention (with antithrombotic drugs) What about prevention of cardiovascular events and hospitalizations?

  28. Dronedarone has Key Structural Differencesto Amiodarone Dronedarone O No iodine-related toxicity (CH2)3CH3 CH3SO2HN (CH2)3CH3 O(CH2)3N Less lipophilic – shorter t1/2 and reduced tissue accumulation (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.

  29. Dronedarone Multichannel blocker like amiodarone but with structural differences Similar electrophysiologic properties to amiodarone Low proarrhythmic potential Lower potential for organ toxicity Shorter half-life (24 hrs) Food increases bioavailability by 2- to 4.5-fold Metabolized by CYP3A4 Mostly excreted in feces (84%)

  30. EURIDIS/ADONIS: Primary EndpointTime to First AF Recurrence 0.8 0.7 25% RRR 0.6 0.5 Cumulative Incidence 0.4 Placebo + standard therapy 0.3 Dronedarone 400 mg BID + standard therapy HR: 0.75 (95% CI: 0.65-0.87) P<0.001 0.2 0.1 0 300 0 60 120 180 240 360 Time (d) HR = hazard ratio; RRR = relative risk reduction; CI = confidence interval. Singh BN, et al. N Engl J Med. 2007;357:987-999.

  31. Placebo + standard therapy* Dronedarone + standard therapy* p<0.001 116.6 -15 bpm -12 bpm -14 bpm 104.6 Dronedarone Showed a Significant and Consistent Decrease in Ventricular Rate at First AF/AFL Recurrence 120 117.5 p<0.001 p<0.001 117.1 115 110 Mean Ventricular Rate (TTEM) 103.4 105 102.3 100 95 90 n=102 n=188 n=117 n=199 n=219 n=387 Combined EURIDIS ADONIS *Standard therapy may have included rate control agents (beta-blockers, and/or Ca-antagonists and/or digoxin) and/or anti-thrombotic therapy (oral anticoagulation and/or long-term antiplatelet therapy) and/or other cardiovascular therapy such as ACE inhibitors and statins. TTEM=Trans Telephonic Electrocardiogram Monitoring. Singh BN, et al. N Engl J Med. 2007;357:987-99.

  32. -5.1 95% CI, -11 to 0.92 P=0.10 -11.5 -11.7 95% CI, -17 to -6.4 P<0.0001 95% CI, -14.8 to -8.5 P<0.0001 -14.9 95% CI, -20 to -10 P<0.0001 ERATO: Ventricular Rate Reduction with Dronedarone in Permanent AF Beta-Blockers Digoxin Calcium Antagonists All Patients 0 -4 -5.1 Mean Reduction in 24-Hour Holter Heart Rate (bpm) -8 -11.7 -11.5 -12 -14.9 -16 Concomitant Treatment Davy JM, et al. Am Heart J. 2008;156:527.e1-527.e9.

  33. DIONYSOS PrimaryEndpoint: AF Recurrence or Premature Study Drug Discontinuation Dronedarone 1.0 Amiodarone 0.8 184 (73.9%) 0.6 141 (55.3%) Cumulative incidence 0.4 RRR (95%CI) = 1.59 (1.275;1.98) p-value <0.001 0.2 0.0 0 3 6 9 12 15 Months • AF recurrence after electrical cardioversion: Dronedarone 36.5 % Amiodarone 24.3 % • Premature drug discontinuation: Dronedarone 10.4 % Amiodarone 13.3 % Le Heuzey JY, et al. J Cardiovasc Electrophysiol. 2010;21:597-605.

  34. Placebo DR 400mg bid ANDROMEDA: All-cause Mortality in Severe HF 0.8 0.7 0.6 0.5 Cumulative Incidence 0.4 0.3 0.2 0.1 Time (days) 0.0 0 30 60 90 120 150 180 210 Patients at risk: Køber L, et al. N Engl J Med. 2008;358:2678-87.

  35. ATHENA is a Unique Trial • The largest single antiarrhythmic drug trial ever conducted in AF • >4,600 patients with a history of paroxysmal or persistent atrial fibrillation or atrial flutter (permanent AF and class IV heart failure excluded) • More than 550 investigational sites in 37 countries • Aged ≥75 years with or without additional risk factors • Aged ≥70 years and ≥1 risk factor (hypertension; diabetes; prior stroke/TIA; LA ≥50 mm;LVEF <0.40) • Unique endpoints for an AF trial • Combined endpoint of cardiovascular hospitalisation or death • First AF trial to use "non-conventional" endpoints Hohnloser SH, et al. J Cardiovasc Electrophysiol 2008;19:69-73.

  36. Baseline patient characteristics Hohnloser SH, et al. J Cardiovasc Electrophysiol 2008;19:69-73.

  37. 50 40 30 20 24% RRR 10 Placebo on top of standard therapy* DR 400mg bid on top of standard therapy* 0 Dronedarone Significantly Decreased Riskof CV Hospitalisation or Death by 24% Cumulative Incidence (%) HR=0.76 p<0.001 Months 0 6 12 18 24 30 Patients at risk: *Standard therapy may have included rate control agents (beta-blockers, and/or Ca-antagonists and/or digoxin) and/or anti-thrombotic therapy (oral anticoagulation and/or long-term antiplatelet therapy) and/or other cardiovascular therapy such as ACE inhibitors and statins. Hohnloser SH et al. N Engl J Med 2009;360:668-78.

  38. 7.5 5.0 2.5 29% RRR Placebo on top of standard therapy* DR 400mg bid on top of standard therapy* 0 Dronedarone Significantly DecreasedRisk of Cardiovascular Death by 29% Cumulative Incidence (%) HR=0.71 p=0.03 Months 0 6 12 18 24 30 Patients at risk: *Standard therapy may have included rate control agents (beta-blockers, and/or Ca-antagonists and/or digoxin) and/or anti-thrombotic therapy (oral anticoagulation and/or long-term antiplatelet therapy) and/or other cardiovascular therapy such as ACE inhibitors and statins. Mean follow-up 21 ±5 months. Hohnloser SH et al. N Engl J Med 2009;360:668-78.

  39. 0.1 1.0 10.0 Dronedarone Better Placebo Better Dronedarone Reduced CV Hospitalisation or All-cause Death Across Important Subgroups Hohnloser SH et al. N Engl J Med 2009;360:668-78.

  40. Dronedarone Significantly Decreased CVHospitalisations by 26% Hohnloser SH et al. N Engl J Med 2009;360:668-78.

  41. Adverse Event Rates were Not Significantly Different Between Dronedarone and Placebo Groups TEAE=Treatment Emergent Adverse Events. Adapted from Hohnloser SH et al. N Engl J Med 2009;360:668-78.

  42. ATHENA Post-hoc Analysis Hazard ratio = 0.66 p = 0.027 Placebo on top of standard therapy Dronedarone 400 mg b.i.d. on top of standard therapy Dronedarone reduces the risk of stroke 5 4 34% reductionin relativerisk 3 Cumulative incidence (%) 2 Mean follow-up 21 ± 5 months 1 0 0 6 12 18 24 30 Follow-up time, months Patients at risk Connolly SJ, et al. Circulation. 2009;120:1174-80.

  43. Stroke Prevention in Rate vs. Rhythm Control Trials Verheugt F, et al. J Am CollCardiol 2003;41(suppl):130A.

  44. Choice of AAD - Underlying Pathology

  45. Abnormal Left Ventricular Function Normal Ventricular Function EF > 35% EF ≤ 35% Dronedarone Flecainide* Propafenone* Sotalol Amiodarone Amiodarone Dronedarone Sotalol* Catheter Ablation Amiodarone * Sotalol should be used with caution with EF 35-40% Contra-indicated in women >65 yrs taking diuretics * Class I agents should be AVOIDED in CAD They should be combined with an AV-nodal blocking agents

  46. 26% RRR Placebo on top of standard therapy DR 400mg bid on top of standard therapy ATHENA: Benefits of dronedarone in ‘permanent’* patients consistent with overall population • Dronedarone Non-significantly Reduced the Risk of Unplanned CV Hospitalisation or Death in "Permanent" AF Patients 50 40 30 Cumulative Incidence (%) 20 HR=0.74 10 p=0.096 Months 0 Patients at risk: 0 6 12 18 24 30 Dronedarone is not indicated in permanent AF patient *Patients with AF/AFL at each ECG recording were classified as having "permanent AF" Any unplanned hospitalisation (i.e., admission with an overnight stayin the hospital) was classified by the investigator as a hospitalisation due to either cardiovascular or non-cardiovascular causes Mean follow-up 21 ±5 months. Page R, et al. AHA Scientific Sessions 2008. Page R, et al. Circulation. 2008;118:S_827.

  47. PALLAS: Dronedarone in permanent AF(Primary EP: CV death, MI, CVA) Dronedarone 400 mg BID 5400 patients R On top of Standard of Care 5400 patients Placebo BID Baseline Visit Variable – Event Driven Registration at time of consent BL FFUV Scheduled visits on D7, M1, M4, M8, M12, M16, M22, M28, M34 and phone contacts on M19, M25, M31

  48. Summary • AF is increasing in prevalence, and is associated with substantial morbidity and mortality: stroke prevention is the first priority in AF patients • A strategy of rhythm control has not been proven superior to rate control – this may in part relate to the modest efficacy and significant toxicity of contemporary antiarrhythmic drugs • New oral anticoagulants will offer similar or superior stroke prevention compared to oral VKA, without excessive bleeding • Dronedarone is the first AAD to demonstrate a reduction in cardiovascular outcomes in AF patients, including a reduction in CV hospitalization, CV death, and stroke (post-hoc)

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