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ATRIAL FIBRILLATION Nora Goldschlager, M.D. MACP, FACC, FAHA, FHRS

ATRIAL FIBRILLATION Nora Goldschlager, M.D. MACP, FACC, FAHA, FHRS Cardiology – San Francisco General Hospital UCSF Disclosures: None. INCREASING PREVALENCE OF AF. 8 6 4 2 0. All. Individuals with AF only (millions). Men. Women. 2005 2015 2025 2035 2045. Year.

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ATRIAL FIBRILLATION Nora Goldschlager, M.D. MACP, FACC, FAHA, FHRS

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  1. ATRIAL FIBRILLATION Nora Goldschlager, M.D. MACP, FACC, FAHA, FHRS Cardiology – San Francisco General HospitalUCSF Disclosures: None

  2. INCREASING PREVALENCE OF AF 8 6 4 2 0 All Individuals with AF only (millions) Men Women 2005 2015 2025 2035 2045 Year Naccarelli et al AJC 2009;104:15334 Reuters database, US Census Bureau Projected Estimates

  3. INCIDENCE • Occurs in ≥ 2% of population (more than 5 million pts in US; projected >10 million by 2050)• Prevalence increases with age 1% in people > 60 5 - 6% of people > 65 14% of people > 80 • Associated with > 100,000 strokes / yr • Develops in 10 - 30% of pts with LV dysfunction; is a predictor of mortality (1 - 3x) • RR for death 1.5 (men) and 1.9 (women)

  4. CONSEQUENCES OF AF IN THE US: US DATABASE ANALYSIS 350,000 hospitalizations/yr 7 million office visits/yr 542,000 ED visits/yr $6.42 billion annually Coyne et al Circulation 2004; 110:III - 826Zimetbaum, Circulation 2005; 111:3141

  5. CLASSIFICATION Types • Paroxysmal – Self-terminating • Persistent – Requires cardioversion to restore sinus rhythm • Permanent – Complete inability to maintain sinus rhythm Etiologies • Rheumatic • Nonrheumatic • Lone

  6. ASYMPTOMATIC ATRIAL FIBRILLATION • Incidence 20 - 50% • Most asymptomatic pts have chronic AF • Up to 50% of pts with paroxysmal AF have no symptoms (pacemaker stored data) • Occurs in up to 20% of pts with no AF history (ICD stored data) • Is present in up to 30% of pts presenting with stroke without AF history

  7. AF IN HEART FAILURE Risk of AF in systolic dysfunction • Men 4.5x • Women 5.9x • Whites 38% • AA 20% • NYHA I-II 10% IV 50% AF in diastolic dysfunction • Prevalence ~ 10% • Risk related to degree of diastolic dysfunction (echo) - hazard ratio 3.3  5.3

  8. I II-III III-IV IV NEW YORK HEART ASSOCIATION FUNCTIONAL CLASS 60 40 20 0 Prevalence of AF (%) V-HeFT GESICA CHF-STAT CONSENSUS DIAMOND CHP SOLVD treatment SOLVD prevention Maisel, Stevenson AJC 2003;91:2-8

  9. DOES AF INCREASE CHF MORTALITY? Framingham Study: evaluated temporal effect of development of AF or CHF on mortality Wang et al. Circulation 2003;107(23)2920-2925

  10. AF AND RACE IN PATIENTS HOSPITALIZED WITH CHF Dx • Incidence: AA (n = 223) - 20% Caucasian - 38% • AA: younger (67 vs 74, p  .001) HT (87% vs 78%, p  .01) Prior CHF (79% vs 71%, p  .01) Less CAD Dx • AA lower odds of AF (49%) after adjustment for EF, age, gender, meds, DM, CHF etiology Ruo et al JACC 2004; 43:429 EPOCH study patients N = 1373; 37% with AF Kaiser database

  11. AF IN WOMEN • Although risk is higher in men, 53% of all AF pts are women • Women with CHF have 14x risk of AF, 8.5x risk in men • Suggestion that embolism in women > men • More sx, higher VR • Higher proarrhythmia risk with AARx

  12. EFFECT ON MORTALITY OF AF IN HEMODIALYSIS PTS (INDEPENDENT OF EF) 1.2 .8 .4 0 71.3 % SR N=164 Cumulative survival 19.2 % AF N=26 0 10 20 30 40 50 Mos Vazquez et al AJC 10.1.03 N = 190

  13. INFLAMMATION AS A RISK FACTOR FOR AF 100 95 90 85 80 0 c Pts w/CRP level < median (1.92 mg/liter) AF free survival (%) Pts w/CRP level > median (1.92 mg/liter) 0 1 2 3 4 5 6 7 Yrs Aviles et al Circulation 2003;108:3006 N = 5806 Cardiovascular Health Study (5% AF at baseline)

  14. OBSTRUCTIVE SLEEP APNEA AND INCIDENT AF 15 10 5 0 OSA Cumulative frequency of AF (%) No OSA 0 2 4 6 8 10 12 14 Years JACC 2007;49:565

  15. • Diastolic dysfunction with increase in LA size • Negative intrathoracic pressure fluctuations leading to transmural pressure changes and wall stress • Ion channel changes – stretch-sensitive – catacholamine-sensitive (apnea-related increase) – vagal tone increase (end-apneic periods) • Systemic inflammation associated with OSA • Hypoxemia • Hypercarbia • sympathetic drive POTENTIAL MECHANISMS OF ASSOCIATION OF AF AND OSA

  16. > Rathmore et al, Circulation 3.00, N = 106,780 medicare pts 65 yo ((79) AF DURING ACUTE MI Incidence: 11% on entry 11% during hospitalization Correlations: Age Anterior MI Killip IV Prior MI CHF* Outcomes: Higher death rates (indep. predictor) - In hospital* 25% (vs 16% no AF) - 30 days* 29% (vs 19%) - 1 yr 48% (vs 33%) Reinfarction * Higher in AF developing during MI

  17. AF AND SUDDEN CARDIAC DEATH MORTALITY •In the AVID Registry, AF present in 23% of patients AF independent risk factor of SCD mortality (RR=1.20; P=.02) • In MUSTT and MADIT II, AF was the second largest independent risk factor for SCD • CASS Registry: AF independent risk factor for SCD • V-HeFT I and V-HeFT II: no correlation between mortality and AF The Antiarrhythmics versus Implantable Defibrillators (AVID) Investigators. N Engl J Med. 1997;337:1576 Wyse et al. J Interv Card Electrophysiol. 2001;5:267 Zareba. Presented at NASPE 23rd Scientific Session; May 2002 Cameron el al. Am J Cardiol. 1988;61:714

  18. MANAGEMENT OPTIONS IN AF Ventricular rate control CA++ -blockers -blockers Digoxin AVN ablation Restoration of NSR Electrical conversion Antiarrhythmic drugs Maintenance of NSR Antiarrhythmic drugs Dual chamber pacing Atrial overdrive pacing Dual site atrial pacing Atrial septal pacing AF ablation

  19. REASONS TO PERFORM EARLY RESTORATION OF NSR IN PTS WITH AF • The longer the AF duration, the higher energy levels (transthoracic and internal) required for cardioversion • Repeated atrial burst pacing leads to longer episodes of AF, eventuating in chronic AF (goats) • The longer the AF episodes, the greater the atrial EP and histologic pathology

  20. ANTIARRHYTHMIC DRUGS TO MAINTAIN SINUS RHYTHM % of pts in Agentsinus rhythm at 1yr • None 25% • Class 1A, and Sotalol 50% • Class 1C (propafenone, flecainide) 50 - 60% • Dofetilide ~ 60% • Amiodarone 70 - 80% • Dronedarone about 60% Failure to convert AF to NSR does not mean that drug will not maintain NSR once it is achieved

  21. EVALUTION OF AARx THERAPYTO MAINTAIN SR • Time to 1st AF recurrence (should not be sole criterion of drug failure) • Frequency of AF recurrences • Duration of AF recurrences • Symptoms during AF recurrences

  22. 24 h before CV 24 h after CV AF: POST CONVERSION SR vs AF AND SERUM ALDOSTERONE LEVELS 200 150 100 50 0 Serum Aldo (pg/ml) SR maintained AF recurrence Wozakowska-Kaplon et al PACE 2010; 33:561

  23. EURIDIS/ADONIS • Patient enrollment: 1237 patients • Inclusion criteria: Presence of paroxysmal or persistent AF or AFL, with ≥ 1 documented episode in the 3 months prior to enrollment, and in normal sinus rhythm for at least 1 hour • Primary endpoint: Time from randomization to first AF/AFL recurrence • Study medication: Dronedarone 400 mg BID or placebo for 12 months • Results: Dronedarone prolonged time to first recurrence of AF/AFL Combined RR reduction: 25% Absolute RR reduction: 11% at 12 months N Engl J Med 2007;357:987-999

  24. DRONEDARONE* EURIDIS AND ADONIS TRIALS • incidence of 1st (symptomatic) AF recurrence • VR during AF recurrences • hospitalization or death rates (also ATHENA trial) • No substantial effect on QT interval (? Atrial selectivity) • Low Torsades de pointes risk • Avoid in HF patients (ANDROMEDA study) * Multiple ion-channel blockade; half-life 1-2 days

  25. DRONEDARONE FOR SR MAINTENANCE IN AF AND FLUTTER 80 60 40 20 0 Placebo Dronedarone Cumulative incidence (%) Hazard ratio, 0.75 P < 0.01 0 60 120 180 270 360 No. at risk Placebo 409 192 156 133 112 90 Dronedarone 828 450 389 347 307 262 Days Singh et al NEJM 2007; 357:987

  26. ATHENA: OVERVIEW - 1 • Objective A multicenter, multinational, double- blind, randomized placebo-controlled study of dronedarone in 4628 patients with a recent history of AF/AFL who were in sinus rhythm or who were to be converted to sinus rhythm to assess the efficacy of dronedarone 400 mg bid for the prevention of cardiovascular hospitalization or death from any cause Hohnloser SH et al J Cardiovasc Electrophysiol. 2008;19:69-73 Hohnloser SH et al N Engl J Med 2009;260:668-678

  27. ATHENA: OVERVIEW - 2 • Patients representative of general AF population – History of paroxysmal or persistent AF/AFL – Aged ≥ 75 years with or without additional risk factors – Aged ≥ 69 years and ≥ 1 risk factor (HT, DM prior CVA/TIA, LA diameter ≥ 50 mm, LVEF < 40) Hohnloser SH et al J Cardiovasc Electrophysiol. 2008;19:69-73: N Engl J Med 2009;260:668-678

  28. ATHENA: OVERVIEW - 3 • Primary endpoint: Time to first CV hospitalization or death from any cause • Secondary endpoints: All-cause mortality CV hospitalization Hohnloser SH et al J Cardiovasc Electrophysiol. 2008;19:69-73; N Engl J Med 2009;260:668-678

  29. ATHENA: SUMMARY • Dronedarone significantly prolongs time to first CV hospitalization in patients with paroxysmal or persistent AF and associated CV risk factors • Reduction in CV hospitalization mainly due to admissions for AF • The 24% reduction in cardiovascular hospitalization or death from any cause was generally consistent in all subgroups based on baseline chracteristics or medications

  30. ATHENA: DRONEDARONE AND CV EVENTS IN AF Primary outcome (1st hospitalization due to CV events or death) 50 25 0 Placebo Cumulative incidence (%) Dronedarone P < 0.001 0 6 12 18 24 30 No. at risk Placebo 2327 1858 1625 1072 385 3 Dronedarone 2301 1963 1776 1177 403 2 Mos Hohnloser et al NEJM 2009; 300:668

  31. Placebo ATHENA: DRONEDARONE AND CV EVENTS IN AF Death from CV causes 5.0 2.5 0 Cumulative incidence (%) P < 0.03 Dronedarone 0 6 12 18 24 30 No. at risk Placebo 2327 2290 2250 1629 636 7 Dronedarone 2301 2274 2240 1593 615 4 Mos Hohnloser et al NEJM 2009; 300:668

  32. ANDROMEDA: OVERVIEW -1 • Designed to evaluate dronedarone, 400 mg BID, on all-cause death or hospitalization for worsening heart failure • Enrolled 627 of 1000 patients (310 and 317 in the dronedarone and placebo groups, respectively) • Patients had relatively severe heart failure and had been hospitalized, or referred to a speciality heart failure clinic for worsening symptoms Kφber L: et al N Engl J Med 2008;358:2678-2687

  33. ANDROMEDA: OVERVIEW - 2 • 38% of subjects had a history of AF/AFL and 25% had AF/AFL at enrollment • Primary composite endpoint : all-cause mortality or hospitalization for heart failure • Trial terminated because of a two-fold increase in mortality in dronedarone group Kφber L: et al N Engl J Med 2008;358:2678-2687

  34. ACC / AHA / ESC GUIDELINES: RISK-STRATIFIED ANTITHROMBOTIC Rx Risk factors:HF, LV EF  0.35, Hx HT Rx ASA (325 mg/d or no Rx) ASA (325 mg/d) Warfarin (INR 2.0 - 3.0) Warfarin (INR 2.0 - 3.0)  low dose ASA (class IIb) Warfarin (INR 2.0 - 3.0) Age < 60, no HD Age < 60 + HD, no risk factors Age > 60 Age  60, DM or CAD Any age + risk factors or thyrotoxicosis Fuster et al Eur Heart J. 2001;22:1852-1923

  35. ACC / AHA / ESC GUIDELINES: RISK-STRATIFIED ANTITHROMBOTIC Rx Risk factors:HF, LV EF  0.35, Hx HT Rx Age  75 (pts c risk Warfarin (INR -2.0) bleed - esp ) Rheumatic HD, prosthetic Warfarin (INR 2.5-3.5 heart valves, prior or higher may thromboembolism, be appropriate) persistent atrial thrombus on TEE Fuster et al Eur Heart J 2001;22:1852-1923

  36. RISK STRATIFICATION FOR ANTICOAGULATION IN AF: CHADS2 Score Points •Congestive heart failure1 • Hypertension 1 • Age 75 years or older 1 • Diabetes mellitus 1 • Stroke or TIA history 2 Gage BF et al JAMA 285: 2864-2870; 2001

  37. ANTICOAGULATION RECOMMENDATIONS BY CHADS2 SCORE • CHADS2 0 – Low risk (0.5%/yr) – ECASA 325 mg qd • CHADS2 1-2 – Intermediate risk (1.5-2.5%/yr) – Warfarin (INR 2.0-3.0) > ECASA 325 mg qd • CHADS2  3 – High risk (5.3-6.9%/yr) – Warfarin (INR 2.0-3.0) unless contraindicated

  38. VITAMIN K ANTAGONISTS IN AF Reduce stroke by 38%, compared to aspirin Recommended in high risk patients with AF Only 40-50% of ideal patients receive VKA in Western countries Many patients considered unsuitable Due to poor INR control, concern about bleeding Patient preference

  39. In patients with AF, unsuitable for VKA therapy, addition of clopidogrel to aspirin will reduce the risk of major vascular events, at acceptable risk of major bleeding HYPOTHESIS OF ACTIVE A

  40. All patients received aspirin at a recommended daily dose of 75-100 mgs Patients were randomized, double blind, to clopidogrel, 75 mg per day, or matching placebo ACTIVE A - STUDY TREATMENT

  41. OUTCOMES AND STATISTICAL POWER Primary outcome was a composite of major vascular events: Stroke, myocardial infarction, non-CNS systemic embolism or vascular death Secondary outcomes Stroke Major hemorrhage 7500 patients planned to achieve 88% power to detect 15% reduction in primary outcome (1600 events)

  42. STUDY CONDUCT 33 Countries, 580 centers 7554 patients enrolled between June 2003 and May 2006 Final follow up in November 2008 Median follow up 3.6 years Follow up was complete in 99.4% of patients

  43. Primary Outcome (Stroke, MI, non-CNS Systemic Embolism, Vascular Death)

  44. Stroke

  45. Myocardial Infarction

  46. BENEFITS AND RISKS: COMPARED TO WARFARIN *Hart RC et al. Meta-analysis: Antithrombotic therapy to prevent stroke in patients who have non-valvular AF . Ann Intern Med 2007: 146: 857-67

  47. RE-LY: A Non-inferiority Trial Atrial fibrillation ≥1 Risk Factor Absence of contra-indications 951 centers in 44 countries R Blinded Event Adjudication. Open Blinded Dabigatran Etexilate 150 mg BID N=6000 Warfarin adjusted (INR 2.0-3.0) N=6000 Dabigatran Etexilate 110 mg BID N=6000

  48. RE-LY: A Non-inferiority Trial Atrial fibrillation ≥1 Risk Factor Absence of contra-indications 951 centers in 44 countries R Blinded Event Adjudication. Open Blinded Dabigatran Etexilate 150 mg BID N=6000 Warfarin adjusted (INR 2.0-3.0) N=6000 Dabigatran Etexilate 110 mg BID N=6000

  49. Ischemic/Unspecified Stroke 0.08 0.06 Cumulative Hazard Rates 0.04 Dabigatran110 Warfarin 0.02 Dabigatran150 0.0 0 0.5 1.0 1.5 2.0 2.5 Years of Follow-up

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