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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 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 EU 3.0 million US 0 1 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 2 3 4 5 3 Lifetime risks for development of AF are 1 in 4 for men and women 40 years of age and older Framingham Women Men 30 Lifetime risk of AF (%) 26.0 25 25.9 23.4 23.2 23.0 25.8 23.0 24.3 21.6 22.7 20 15 10 5 0 40 50 60 70 80 Age (years) Lloyd-Jones DM, et al. Circulation 2004;110:1042-46 4 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. AF May Adversely Affect Quality of Life SF-36 score from QoL Questionnaire 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 88 80 78 68* 60 40 54* 70 85 92 71* 68* 76 81 59 20 0 General health Physical function AF patients (n=152) Dorian P et al. J Am Coll Cardiol. 2000;36:1303-1309. Social function Post MI patients (n=69) Mental health Healthy subjects (n=47) 6 AF increases risk of death and CV outcomes Renfrew/Paisley Rate ratio (95% Confidence Interval [CI])* All-cause mortality CV events Women n=8,354 Fatal or non-fatal stroke Heart failure All-cause mortality CV events Fatal or non-fatal stroke Men n=7,052 Heart failure -1 0 * Adjusted for age; follow-up 20 years Stewart S, et al. Am J Med 2002;113:359-64. 1 2 3 4 5 6 7 CV events: death or hospitalisation 8 7 REACH Registry: Association of AF with CV Outcomes in Atherothrombotic Patients* The REACH registry Patients with AF Patients without AF n 6814 56775 All-cause mortality 4.27 % 2.32 % <0.0001 CV death 3.16 % 1.42 % <0.0001 Non-fatal MI 1.36 % 1.11 % 0.1205 Non-fatal stroke 2.43 % 1.55 % <0.0001 Variable p value Major CV events 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. 8 Studies reveal high hospitalisation rates among AF patients % follow-up 1 year % hospitalised for CV reasons 80 50 AF control mean follow-up 21 40 months follow-up 1 year 30 36.9% 36.9% AF not controlled 60 40 follow-up 1 year 20 28.1 20 17.0% 10 29.8 0 0 ATHENA* (placebo arm)1 Euro Heart Survey2,3 RecordAF Registry4 At least one cardiovascular event RealizeAF Registry * First hospitalisation due to CV event 1. 2. 3. 4. 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. 9 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 1.53 billion dollars (Diagnosis of AF) Incremental inpatient costs 1.95 billion dollars (AF as comorbid condition) Hospitalization 2.93 billion dollars (Principle discharge diagnosis of AF) 0 * Does not include prescription costs. Coyne K., et al. Value Health 2006;9(5):348-356. 1 2 3 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) AFFIRM Inclusive cohort* HR (95% CI) Censored cohort* HR (95% CI) Rate control 2.15 (1.69 – 2.74) 2.39 (1.86 – 3.07) Rhythm control 1.71 (1.37 – 2.13) 1.98 (1.52 – 2.57) 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. 11 Overview AF Epidemiology Antiarrhythmic Drugs and Outcomes New AF Treatment Options 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) 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 105 Placebo (n=725) Survival (%) 100 Encainide or flecainide (n=730) 95 90 p=0.0006 85 0 50 100 150 200 250 300 350 Days after randomization 400 450 500 Quinidine Treatment Was Associated With Increased 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 Quinidine better 1 2 3 4 5 6 7 8 9 10 11 12 Quinidine worse Odds ratio (Quinidine:Control) • There was a significant increase in total mortality in quinidine-treated group as compared with control group (OR=2.98; p<0.05). Coplen S., et al. Circulation 1990;82:1106-1116. 16 Patients without recurence (%) Patients remaining free of recurrence of AF (CTAF) 100 Amiodarone (n=201) 80 60 Propafenone (n=101) 40 Sotalol (n=101) 20 0 0 100 200 300 Days of follow-up Roy D et al. New Engl J Med 2000;342:913-920. 17 400 500 600 AFFIRM Results Post-hoc Analysis Covariate HR 99% CI P Value Sinus rhythm <.0001 Warfarin use <.0001 Digoxin use .0007 AAD use .0005 0 0.5 1 1.5 2 The benefits of sinus rhythm are offset by the toxicity of AADs used in AFFIRM Corley et al. Circulation. 2004;109:1509-1513. 2.5 Cumulative noncardiovascular mortality in AFFIRM Percent death (%) 30 Log rank statistic = 11.2 P=0.0008 25 20 15 Rhythm control 10 5 Rate control 0 0 1 2 3 4 5 Years No. events (%) Rate Rhythm 2027, 0 (100) 2033, 0 (100) 1926, 20 (1) 1932, 33 (2) Steinberg JS Circulation 2004;109:1973-1980. 1827, 49, (3) 1329, 70 (4) 1807, 76 (4) 1316, 120 (7) 774, 101 (7) 236, 109 (8) 780, 149, (9) 255, 167 (12) 1, 113 (14) 1, 169 (14) Amiodarone in AF Patients: Meta-analysis* Conversion/maintenance of sinus rhythm not associated with a reduction of all-cause death or all-cause hospitalisation Relative Risk [95% CI] p-value (test for overall effect) Conversion to sinus rhythm per patients-year follow up 3.22 [1.88–5.53] <0.0001 Incidence of all-cause mortality per patient-year follow up 0.95 [0.81–1.11] 0.51 Rate of all-cause hospitalisation per patients-year follow up 1.10 [0.57–2.13] 0.77 Outcome of Interest . * Eight studies compared amiodarone with a rate control drug, either beta-blocker or digoxin, and 4 trials compared amiodarone with 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 AF Increases the Risk of Stroke Framingham Relative Risk of Stroke 5 4.5 4.0 4 3.3 3 2.6 2 1 0 50-59 60-69 70-79 Age (years) p<0.001 vs. Non-AF patients Wolf et al. Stroke 1991:22:983-988 80-89 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 Underutilization of Warfarin in Atrial Fibrillation: Results from Recent Studies* Year Published Study Population % Treated with Warfarin 1999 ATRIA Go et al Ann Intern Med 1999 11,082 US patients from HMO 60 (high-risk) 2000 Samsa et al Arch Intern Med 2000 660 US patients: FP/GIM 35 2005 NABOR Waldo et al J Am Coll Cardiol 2005 945 US patients 55 (high-risk) 2006 Euro Heart Survey Nieuwlaat et al Eur Heart J 2006 2706 outpatients in 35 EU countries 64 2006 Hylek et al Stroke 2006 402 US patients, ≥65 years 51 2006 Birman-Deych et al Stroke 2006 16,0007 US Medicare patients 49 2006 Friberg et al Eur Heart J 2006 1898 Swedish patients 54 •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 Stroke or Systemic Embolism Non-inferiority p-value <0.001 Dabigatran 110 vs. Warfarin Superiority p-value <0.001 Dabigatran 150 vs. Warfarin 0.34 <0.001 Margin = 1.46 0.50 Dabigatran better 0.75 1.00 1.25 HR (95% CI) 1.50 Warfarin better Connolly S, et al. N Engl J Med 2009 Apixaban 0 3 6 2791 2809 9 12 18 21 Months No. at Risk ASA Apix ASA 0.03 0.05 RR= 0.46 95%CI= 0.33-0.64 p<0.001 0.0 0.01 Cumulative Risk AVERROES: Stroke or Systemic Embolic Event (Pts ineligible for warfarin) 2720 2761 2541 2567 2124 2127 preliminary Results 1541 1523 626 617 329 353 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? Dronedarone has Key Structural Differences to Amiodarone Dronedarone O No iodine-related toxicity (CH2)3CH3 CH3SO2HN Less lipophilic – shorter t1/2 and reduced tissue accumulation O(CH2)3N O I O(CH2)2N Kathofer et al. Cardiovasc Drug Rev. 2005;23(3):217-30. (CH2)3CH3 O (CH2)3CH3 Amiodarone (CH2)3CH3 O CH2CH3 CH2CH3 I 30 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%) EURIDIS/ADONIS: Primary Endpoint Time to First AF Recurrence 0.8 Cumulative Incidence 0.7 25% RRR 0.6 0.5 0.4 Placebo + standard therapy Dronedarone 400 mg BID + standard therapy 0.3 HR: 0.75 (95% CI: 0.65-0.87) P<0.001 0.2 0.1 0 0 60 120 180 Time (d) HR = hazard ratio; RRR = relative risk reduction; CI = confidence interval. Singh BN, et al. N Engl J Med. 2007;357:987-999. 240 300 360 Dronedarone Showed a Significant and Consistent Decrease in Ventricular Rate at First AF/AFL Recurrence Placebo + standard therapy* Dronedarone + standard therapy* Mean Ventricular Rate (TTEM) 120 116.6 p<0.001 117.5 p<0.001 117.1 p<0.001 115 -15 bpm -12 bpm -14 bpm 110 104.6 105 103.4 102.3 100 95 90 n=102 n=188 ADONIS n=117 n=199 EURIDIS n=219 n=387 Combined *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. 33 ERATO: Ventricular Rate Reduction with Dronedarone in Permanent AF Mean Reduction in 24-Hour Holter Heart Rate (bpm) All Patients Beta-Blockers Digoxin Calcium Antagonists 0 -4 -5.1 -5.1 95% CI, -11 to 0.92 P=0.10 -8 -12 -11.7 -11.7 -11.5 -11.5 95% CI, -14.8 to -8.5 P<0.0001 95% CI, -17 to -6.4 P<0.0001 -16 -14.9 -14.9 95% CI, -20 to -10 P<0.0001 Concomitant Treatment Davy JM, et al. Am Heart J. 2008;156:527.e1-527.e9. DIONYSOS Primary Endpoint: AF Recurrence or Premature Study Drug Discontinuation Dronedarone Cumulative incidence 1.0 Amiodarone 0.8 184 (73.9%) 0.6 141 (55.3%) 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 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. Months ANDROMEDA: All-cause Mortality in Severe HF 0.8 Number of patients who died 0.7 Cumulative Incidence Placebo n=317 12 2.13 Hazard Ratio 95% CI Log rank p value 0.6 Dronedarone 800mg n=310 25 [1.07; 4.25] 0.03 0.5 0.4 Placebo DR 400mg bid 0.3 0.2 0.1 Time (days) 0.0 0 30 60 90 120 150 180 210 Placebo 317 256 181 103 50 18 6 1 DR 400mg bid 310 257 174 104 59 22 5 1 Patients at risk: Køber L, et al. N Engl J Med. 2008;358:2678-87. 36 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. 37 Baseline patient characteristics Placebo n=2327 Dronedarone n=2301 All patients n=4628 71.7 ±9.0 71.6 ±8.9 72 ±9.0 <65yr 442 (19.0%) 431 (18.7%) 873 (18.9%) 65 to 75yr 907 (39.0%) 923 (40.1%) 1830 (39.5%) ≥75yr 978 (42.0%) 947 (41.2%) 1925 (41.6%) Female gender 1038 (44.6%) 1131 (49.2%) 2169 (46.9%) AF/AFL at baseline 586 (25.2%) 569 (24.7%) 1155 (25.0%) Structural heart disease 1402 (60.9%) 1330 (58.3%) 2732 (59.6%) Hypertension 1996 (85.8%) 1999 (86.9%) 3995 (86.3%) 737 (31.7%) 668 (29.0%) Age (mean ±SD, years) Coronary heart disease 1405 (30.4%) Valvular heart disease 380 (16.3%) 379 (16.5%) 759 (16.4%) Non-ischemic cardiomyopathy 131 (5.6%) 123 (5.3%) 254 (5.5%) History of CHF NYHA II/III 515 (22.1%) 464 (20.2%) 979 (21.2%) LVEF <0.45 285/2281 (12.5%) 255/2263 (11.3%) 540/4544 (11.9%) LVEF <0.35 87/2281 (3.8%) 92/2263 (4.1%) 179/4544 (3.9%) Lone atrial fibrillation 139 (6.0%) 140 (6.1%) 279 (6.0%) Pacemaker 243 (10.4%) 214 (9.3%) 457 (9.9%) Hohnloser SH, et al. J Cardiovasc Electrophysiol 2008;19:69-73. 38 Dronedarone Significantly Decreased Risk of CV Hospitalisation or Death by 24% Cumulative Incidence (%) 50 Placebo on top of standard therapy* DR 400mg bid on top of standard therapy* 40 24% RRR 30 20 HR=0.76 p<0.001 10 Months 0 0 6 12 Placebo 2327 1858 1625 DR 400mg bid 2301 1963 1776 18 24 30 1072 385 3 1177 403 2 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. 39 Dronedarone Significantly Decreased Risk of Cardiovascular Death by 29% Cumulative Incidence (%) 7.5 Placebo on top of standard therapy* DR 400mg bid on top of standard therapy* 5.0 29% RRR 2.5 HR=0.71 p=0.03 Months 0 0 6 12 Placebo 2327 2290 2250 DR 400mg bid 2301 2274 2240 18 24 30 1629 636 7 1593 615 4 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. 40 Dronedarone Reduced CV Hospitalisation or All-cause Death Across Important Subgroups Characteristic Age (years) <75 75 Gender Male Female Presence of AF/AFL Yes No Structural Heart Disease Yes No Congestive Heart Failure Yes No LVEF (%) <35 [35-45[ 45 ACE/ARB Yes No Beta Blocking Agents Yes No n HR (95% CI) 0.93 2703 1925 0.76 (0.67–0.87) 0.75 (0.65–0.87) 0.65 2459 2169 0.74 (0.64–0.85) 0.77 (0.67–0.89) 1155 3473 0.74 (0.61–0.91) 0.76 (0.68–0.85) 0.85 0.85 2732 1853 0.76 (0.67–0.85) 0.77 (0.65–0.92) 1365 3263 0.75 (0.64–0.88) 0.76 (0.68–0.86) 0.83 0.55 179 361 4004 0.68 (0.44–1.03) 0.66 (0.47–0.92) 0.78 (0.70–0.86) 0.59 3216 1412 0.74 (0.66–0.83) 0.79 (0.66–0.95) 0.41 3269 1359 0.78 (0.69–0.87) 0.71 (0.58–0.86) 0.1 1.0 Dronedarone Better Hohnloser SH et al. N Engl J Med 2009;360:668-78. p value for interaction 10.0 Placebo Better 41 Dronedarone Significantly Decreased CV Hospitalisations by 26% Reason for first CV hospitalisation Placebo n=2327 Dronedarone n=2301 HR 95% CI p value 859 675 0.74 0.67; 0.82 <0.001 Atrial Fibrillation 510 335 0.63 0.55; 0.72 <0.001 CHF 132 112 0.86 0.67; 1.10 0.22 ACS 89 62 0.70 0.51; 0.97 0.03 Syncope 32 27 0.85 0.51; 1.42 0.54 Ventricular arrhythmia or cardiac arrest 12 13 1.09 0.50; 2.39 0.83 Any reason Hohnloser SH et al. N Engl J Med 2009;360:668-78. 42 Adverse Event Rates were Not Significantly Different Between Dronedarone and Placebo Groups Placebo n=2313 Dronedarone n=2291 p value 1603 (69.3%) 1649 (72.0%) 0.048 221 (9.6%) 260 (11.3%) 0.048 Bradycardia 28 (1.2%) 81 (3.5%) <0.001 QT-interval prolongation 14 (0.6%) 40 (1.7%) <0.001 Gastrointestinal 508 (22.0%) 600 (26.2%) <0.001 Respiratory 337 (14.6%) 332 (14.5%) 0.97 176 (7.6%) 237 (10.3%) 0.001 31 (1.3%) 108 (4.7%) <0.001 489 (21.1%) 456 (19.9%) 0.31 Cardiac events 15 (0.6%) 15 (0.7%) 1.00 Respiratory 45 (1.9%) 41 (1.8%) 0.74 Gastrointestinal 68 (2.9%) 81 (3.5%) 0.28 Creatinine increase 1 (<0.1%) 5 (0.2%) 0.12 6 (0.3%) 7 (0.3%) 0.79 187 (8.1%) 290 (12.7%) <0.001 Randomised and treated patients Patients with any TEAE Cardiac events Skin Creatinine increase Patients with any serious TEAE Skin Patients permanently discontinued study drug for any TEAE TEAE=Treatment Emergent Adverse Events. Adapted from Hohnloser SH et al. N Engl J Med 2009;360:668-78. 43 ATHENA Post-hoc Analysis Dronedarone reduces the risk of stroke Cumulative incidence (%) 5 Placebo on top of standard therapy Dronedarone 400 mg b.i.d. on top of standard therapy 4 34% reduction in relative risk 3 Hazard ratio = 0.66 2 p = 0.027 Mean follow-up 21 ± 5 months 1 0 0 6 12 18 24 30 Follow-up time, months Patients at risk Placebo 295 244 224 151 60 0 Dronedarone 400 mg b.i.d. 178 160 150 110 47 1 Connolly SJ, et al. Circulation. 2009;120:1174-80. 44 Stroke Prevention in Rate vs. Rhythm Control Trials n AFFIRM Rate control Rhythm control RR (95% CI) p 4,917 5.7% 7.3% 1.28 (0.95-1.72) 0.12 RACE 522 5.5% 7.9% 1.44 (0.75-2.78) 0.44 STAF 266 1.0% 3.0% 3.01 (0.35-25.3) 0.52 PIAF 252 0.8% 0.8% 1.02 (0.73-2.16) 0.49 Total 5,957 5.0% 6.5% 1.28 (0.98-1.66) 0.08 Verheugt F, et al. J Am Coll Cardiol 2003;41(suppl):130A. Choice of AAD - Underlying Pathology www.escardio.org Normal Ventricular Function Dronedarone Flecainide* Propafenone* Sotalol Catheter Ablation Abnormal Left Ventricular Function EF > 35% EF ≤ 35% Amiodarone Dronedarone Sotalol* Amiodarone Amiodarone * Sotalol should be used with caution with EF 35-40% Contra-indicated in women >65 yrs taking diuretics 47 * Class I agents should be AVOIDED in CAD They should be combined with an AV-nodal blocking agents Leadership. Knowledge. Community. ATHENA: Benefits of dronedarone in ‘permanent’* patients consistent with overall population 50 Non-significantly Dronedarone thetherapy Risk of Unplanned CV Placebo onReduced top of standard Hospitalisation or DeathDR in400mg "Permanent" Patients bid on top of AF standard therapy Cumulative Incidence (%) 40 26% RRR 30 20 HR=0.74 p=0.096 10 Months 0 Patients at risk: 0 6 12 18 24 30 Placebo 295 244 224 151 60 0 DR 400mg bid 178 160 150 110 47 1 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 stay Mean follow-up 21 ±5 months. in the hospital) was classified by the investigator as a hospitalisation due to Page R, et al. AHA Scientific Sessions 2008. either cardiovascular or non-cardiovascular causes Page R, et al. Circulation. 2008;118:S_827. 48 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 Registration at time of consent Variable – Event Driven BL FFUV Scheduled visits on D7, M1, M4, M8, M12, M16, M22, M28, M34 and phone contacts on M19, M25, M31 49 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) Defining Endpoints in Clinical Trials of Atrial Fibrillation – A New Era with Dronedarone CV Events Adapted from Camm J, et al. Eur Heart J Suppl 2008; 10:H55-H78