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Burden of Stroke in Patients with Atrial Fibrillation and Recent European Guidelines

Burden of Stroke in Patients with Atrial Fibrillation and Recent European Guidelines. Prof. Roland KASSAB, MD, FESC Head of Division of Cardiology, HDF Congrès de l ’ Association Médicale Franco-Libanaise Movenpick Hotel, Beirut,15/07/2011. Atrial Fibrillation.

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Burden of Stroke in Patients with Atrial Fibrillation and Recent European Guidelines

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  1. Burden of Stroke in Patients with Atrial Fibrillation and Recent European Guidelines Prof. Roland KASSAB, MD, FESC Head of Division of Cardiology, HDF Congrès de l’Association Médicale Franco-Libanaise Movenpick Hotel, Beirut,15/07/2011

  2. Atrial Fibrillation • First described by Sir William Harvey in 17th century: observed chaotic motion of atria in open chest animal • ECG findings described in 1909 by Sir Thomas Lewis: “irregular or fibrillatory waves and irregular ventricular response” or “absent atrial activity with grossly irregular ventricular response”

  3. Atrial Fibrillation Continuing Medical Implementation …...bridging the care gap

  4. Pathophysiology of AF ?Inflammation • HTN and/or vascular disease ¯Compliance • Left ventricular hypertrophy • Diastolic dysfunction • Mitralregurgitation Atrial dilatation/stretch ?Inflammation ­Stretch-activated channels ­Dispersion of refractoriness ­Pulmonary vein focal/discharges? Increased vulnerability to AF? Adapted with permission from Gersh BJ, et al. Eur Heart J Suppl. 2005;7(suppl C):C5-C11.

  5. What Happens When AF Persists? Electro-physiologicRemodeling StructuralRemodeling • LA and LAA dilatation • Fibrosis • Decrease in Ca++ currents • Shortening of atrial action potential • Increased importance of early activating K+channels: IKur, IKto Remodeling explains why “AF begets AF”

  6. Most common sustained cardiac arrhythmia1 Most common diagnosis for arrhythmia-related hospitalization2 Estimated >2.3 million US adults have AF3 Prevalence of AF increases with age and with an aging population4 Atrial Fibrillation Prevalence 1 Bialy D et al. J Am Coll Cardiol 1992; 19-41A. 2 Fuster V et al. Circulation 2006; 114:e257-e354 3 Go AS et al. JAMA 2001; 285:2370-2375. 4 Chug SS et al. J Am Coll Cardiol 2001: 37:371-378

  7. Projection for Prevalence of Atrial Fibrillation: 5.6 Million by 2050 Projected number of adults with atrial fibrillation in the United States between 1995 and 2050 7.0 6.0 5.61 5.42 5.0 5.16 4.78 4.34 4.0 Adults with atrial fibrillation in millions 3.80 3.33 3.0 2.94 2.66 2.44 2.26 2.0 2.08 1.0 Upper and lower curves represent the upper and lower scenarios based on sensitivity analyses. 0 1990 1995 2000 2005 2010 2015 2020 2025 2030 2035 2040 2045 2050 Years Go AS et al. JAMA. 2001;285:2370-2375.

  8. Atrial Fibrillation: Twice as Common as Previously Suspected • Incidence increased 13% over past 20 years • In USA, 12-16 millions will be affected by 2050 • Increasing obesity and increasing age are risk factors that help explain rise in incidence Miyasaka Y. Circulation 2006; 114: 119-125

  9. AF Prevalence: Age and Gender Prevalence of atrial fibrillation with age Prevalence, percent Age, years JAMA 2001; 285: 2370

  10. With atrial fibrillation Without atrial fibrillation Atrial Fibrillation Is Associated With Increased Mortality 71.3 65.1* 62.4 54.5 51.0* 47.5 47.4* 38.6 36.1* Cumulative mortality over 3 years (%) 34.0 30.2* 25.4* Women Men Women Men Women Men 65 to 74 years of age 75 to 84 years of age 85 to 89 years of age * Significantly different from patients with atrial fibrillation (P<.05). Wolf PA et al. Arch Intern Med. 1998;158:229-234.

  11. 140 120 100 80 60 40 20 0 Increasing Hospitalizations in the United States When Atrial Fibrillation Is Principal Diagnosis(National Hospital Discharge Survey) Prevalence per 10,000 persons 1985 1987 1989 1991 1993 1995 1997 1999 Year Age (years) 85+ 75 to 84 65 to 74 55 to 64 35 to 54 Wattigney WA et al. Circulation. 2003;108:711-716.

  12. Atrial Fibrillation Adversely Affects Quality of Life (QoL) Lower scores = poorer QoL SF-36 score Dorian P et al. J Am Coll Cardiol. 2000;36:1303-1309.

  13. Total annual medical costs of AF in the USA estimated as US$6.65 billion (2001) Healthcare resource utilization included 350,000 hospitalizations 276,000 emergency department visits 234,000 outpatient visits The bulk of the costs related to direct and indirect inpatient care AF is associated with substantial healthcare costs 23% 44% 4% 29% Direct inpatient Indirect inpatient Drugs Outpatient Coyne KS et al. Value Health 2006;9:348–56

  14. Atrial Fibrillation: Major Cause of Stroke in the United States • 15% of all strokes attributable to atrial fibrillation • 75,000 strokes per year attributable to atrial fibrillation • 3- to 5-fold increase in risk of stroke in patients with atrial fibrillation • Stroke risk persists even in asymptomatic atrial fibrillation Go AS et al. JAMA. 2001;285:2370-2375; Go AS. Am J Geriatr Cardiol. 2005;14:56-61; Wolf PA et al. Stroke. 1991;22:983-988; Benjamin EJ et al. Circulation. 1998;98:946-952; Page RL et al. Circulation. 2003;107:1141-1145.

  15. One Sixth of all Strokes Attributable to AF Framingham Study 30 20 AF prevalence % Strokes attributable to AF 10 0 50–59 60–69 70–79 80–89 Age Range (years) Wolf et al. Stroke 1991; 22: 983-988

  16. NonvalvularAtrial Fibrillation Stroke Rates Without Anticoagulation According to Isolated Risk Factors Stroke Rate (%/year) Heart Failure  LVEF Female Diabetes Prior Stroke/TIA Hypertension Age > 75 years Hart RG et al. Neurology 2007; 69: 546.

  17. Natural History of “Lone” Atrial Fibrillation No Cardiopulmonary Disease: <60 Years Old 97 Patients Mean Age = 44 14.8 years Follow-up 0.35%/yr Stroke 0.40%/yr Mortality Kopecky S, et al. N Engl J Med 1987; 317:669.

  18. Stroke risk persists even in asymptomatic/intermittent AF • The risk of stroke with asymptomatic or intermittent AF is comparable to that with permanent AF1,2 Observed rate of ischaemic stroke1 14 Intermittent AF 12 Sustained AF 10 8 Annual risk of stroke, % 6 4 2 0 Low Moderate High Stroke risk category 1. Hart RG et al. J Am Coll Cardiol 2000;35:183–7;2. Flaker GC et al. Am Heart J 2005;149:657–63

  19. AF stroke survivors are at increased risk of death • In the Framingham study the 30-day mortality risk after stroke was increased 1.84-fold among patients with AF • Increased risk of death compared with non-AF patients persisted for up to 1 year after stroke 1.0 0.8 Patients without AF 0.6 Survival probability, % 0.4 Patients with AF P <0.001 0.2 0.0 0 60 120 180 240 300 360 Days post-stroke Lin HJ et al. Stroke 1996;27:1760–4

  20. AF patients face an increased risk of recurrent stroke Recurrent stroke 10 8 Patients with AF 6 Cumulative probability of recurrence, % Patients without AF 4 P = 0.0398 2 0 0 2 4 6 8 10 12 Years after first stroke Marini C et al. Stroke 2005;36:1115–9

  21. Decreasing Atrial Fibrillation Burden Is an Important Goal • As with heart failure or angina, success in managing atrial fibrillation is defined as a decrease in: • Decreasing atrial fibrillation burden offers potential to successfully treat atrial fibrillation by: • Decreasing mortality • Decreasing Stroke • Decreasing hospitalizations • Increasing QoL Frequency ofepisodes Duration ofepisodes Symptomsduringepisodes Prystowsky EN. J Cardiovasc Electrophysiol. 2006;17(suppl 2):S7-S10; Wolf PA et al. ArchIntern Med. 1998;158:229-234.

  22. Priorities in the Management of AFThe Patient Care Pathway Rhythm Control Prevention of Thromboembolism Rate Control

  23. Atrial Fibrillation: A Risk Factor for Vascular Events RISK FACTORS for THROMBOSIS •Hypertension •Hyperlipidemia • Age •Diabetes Mellitus • Smoking Atherosclerosis/Atherothrombosis Atherosclerosis/Atherothrombosis MI AF CHF MI AF CHF Stroke, MI, Vascular Death Wolf PA et al. Arch Intern Med 1987; 147: 1561-1564 Leckey R et al. Can J Cardiol 2000; 16: 481-485

  24. Modifiable Risk Factors in Stroke Prevalence varies by age, gender, race, ethnicity and stroke risk factor * AF has the highest relative risk Adapted from Sacco RL. Neurology 1995;45(Suppl 1):S10-S14. Continuing Medical Implementation …...bridging the care gap

  25. Risk Stratification for Patients with AFib-Flutter

  26. Risk Factor Stratification

  27. Predictors of CVA or Embolism • Univariate analysis • LA thrombi RR 1.4 • Atrial appendage length 44 (43-45 mm) RR 1.6 • Atrial appendage width 23 (22-23mm) RR 2.4 • Multivariate analysis • Hypertension RR 3.6 • Previous stroke RR 3.7 • Age RR 1.1

  28. Thrombus in Left Atrial Appendage Associated with Stroke Thrombus Left Atrial Appendage Thrombus in left atrial appendage is correlated with increased thromboembolic risk in AF Chimowitz. Stroke 1993; 24: 1015 Zabalgoitia. J Am Coll Cardiol 1998; 31: 1622

  29. Congestive heart failure Hypertension Age > 75 years Diabetes mellitus Stroke or TIA PointsRisk of stroke/100pt-years 0 1.9 1 2.8 2 4.0 3 5.9 4 8.5 5 12.5 6 18.2 Stroke Prevention in Atrial Fibrillation: CHADS2 JAMA 2001;285:2864

  30. The CHADS2 Index Stroke Risk Score for Atrial Fibrillation Score (points) Risk of Stroke (%/year) 0 1.9 1 2.8 2 4.0 3 5.9 4 8.5 5 12.5 6 18.2 Approximate Risk threshold for Anticoagulation 3%/year Van Walraven C, et al. Arch Intern Med 2003; 163:936. Go A, et al. JAMA 2003; 290: 2685. Gage BF, et al. Circulation 2004; 110: 2287.

  31. Desirable Characteristics of Pharmacologic Converting Agents Efficacy • High rate of restoring sinus rhythm with relief of symptoms • Rapid onset of action Safety • Low rate of adverse effects • Low incidence of drug interactions • Lack of interference with electrical cardioversion

  32. Limited efficacy of aspirin in reducing the risk of stroke in patients with AF Aspirin better Placebo better AFASAK SPAF EAFT ESPS II LASAF 125 mg/d 125 mg QOD UK-TIA 300 mg/d 1200 mg/d JAST RRR = 19%95% CI: –1 to 35% All trials 100 50 0 –50 –100 Relative risk reduction (%)* Error bars = 95% CI; *Relative risk reduction for all strokes (ischaemic and haemorrhagic) 34 Hart RG et al. Ann Intern Med 2007;146:857–67

  33. Anticoagulation in Atrial FibrillationThe Standard of Care for Stroke Prevention Warfarin Better Control Better AFASAK Unblinded SPAF Unblinded BAATAF Unblinded CAFA Terminated early SPINAF Double-blind; Men only EAFT 2o prevention; Unblinded Aggregate -100% 50% -50% 100% 0 Hart R, et al. Ann Intern Med 2007;146:857.

  34. Oral Anticoagulant and Aspirin Use in Atrial Fibrillation from 1980 to 2000 Minidose Warfarin Study AFASAK II LASAF EAFT Oral Anticoagulant PATAF SPAF II Aspirin SPINAF SPAF III Japanese NVAF study SPAF I CAFA BAATAF AFASAK I

  35. Risk Stratification and Anticoagulation Stroke Reduction with Warfarin Instead of Aspirin CHADS2 Score ~ 3 2 1 0 Number of patients Needed-to-treat to prevent 1 stroke/year 42 13 83 250 EAFT Study Group. Lancet 1993; 324:1255. Zabalgoitia M, et al. J Am Coll Cardiol 1998; 31:1622.

  36. Antithrombotic Therapy for Atrial FibrillationStroke Risk Reduction Treatment Better Treatment Worse 6 Trials n = 2,900 Warfarin vs. Placebo/Control Antiplatelet drugs vs. Placebo 8 Trials n = 4,876 50% -50% 100% 0 Hart R, et al. Ann Intern Med 2007;146:857.

  37. Antithrombotic Therapy for Atrial FibrillationStroke Risk Reductions Warfarin Better Antiplatelet Rx Better ACTIVE-W Anticoagulation vs. Aspirin + Clopidogrel n = 6,706 Anticoagulation vs. Antiplatelet drugs 7 Trials n = 4,232 50% -50% 100% 0 Connolly S, et al. Lancet 2006; 367:1903. Hart R, et al. Ann Intern Med 2007;146:857.

  38. ACTIVE-ATotal Stroke Rates 28% RRR HR 0.72 (95% CI, 0.62–0.83) p <0.001 0.15 408 (3.3%/year) Aspirin 0.10 296 (2.4%/year) Cumulative Incidence Clopidogrel + Aspirin 0.05 0.0 0 1 2 3 4 Years Connolly SJ, et al. N Engl J Med 2009; 360:2066.

  39. Hylek, EM et al. N Engl J Med. 2003;349:1019-2614

  40. “Most intracranial hemorrhages (62%) occur at INRs < 3.0” Fang MC et al. Ann Intern Med. 2004;141:745-52

  41. Intracerebral Hemorrhage >10% of intracerebral hemorrhages (ICH) occur in patients on antithrombotic therapy Aspirin increases the risk by ~ 40% Warfarin (INR 2–3) doubles the risk to 0.3–0.6%/year ICH during anticoagulation is catastrophic The Most Feared Complication of Antithrombotic Therapy Hart RG, et al. Stroke 2005;36:1588

  42. Challenges of Oral Anticoagulation Therapy Narrow efficacy window + complex kinetics + multiple interactions = hard to use/take 15.0 STROKE INTRACRANIAL BLEED 10.0 Odds Ratio 5.0 1.0 0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 INR Hylek EM et al. N Eng J Med. 1996; 335(8): 540-6 Hylek EM et al. Ann Intern Med. 1994; 120(11): 897-902

  43. Antithrombotic Therapy for Atrial FibrillationACC/AHA/ESC Guidelines 2006

  44. ACC/AHA/ESC 2006 Atrial Fibrillation Guidelines Rhythm Control Therapies to Maintain Sinus Rhythm Maintenance of SR No (or minimal)heart disease Hypertension CAD HF Flecainide Propafenone Sotalol Substantial LVH Dofetilide Sotalol Amiodarone Dofetilide No Yes Amiodarone Dofetilide Catheter ablation Amiodarone Catheter ablation Catheter ablation Note: In 2009, the FDA approved dronedarone to reduce the risk of CV hospitalization in patients with paroxysmal or persistent AF or AFL, with a recent episode of AF/AFL and associated CV risk factors, who are in sinus rhythm or who will be cardioverted. Consensus regarding its place in the treatment paradigm is not yet available. Amiodarone Flecainide Propafenone Sotalol Catheter ablation Amiodarone Dofetilide Catheter ablation Reproduced with permission from Fuster V, et al. Circulation. 2006;114(7):e257-e354.

  45. The new ESC guidelines further differentiated stroke risk & added a bleeding risk stratification CHADS2 CHA2DS2-VASc HAS-BLED Note: 1) Prior myocardial infarction, peripheral artery disease, aortic plaqueSource: ESC Guidelines for the Management of Atrial Fibrillation, European Heart Journal 2010

  46. New approach to thromboprophylaxis

  47. VII IX X II Direct thrombin inhibitors Ximelagatran, Dabigatran IIa Targets for anticoagulant drugs Intrinsic pathway (surface contact) Extrinsic pathway (tissue damage) XII XIIa Tissue factor XI XIa IXa VIIa VIII VIIIa Heparin(s) Vitamin K antagonists Xa V Va (Thrombin) IIa Fibrinogen Fibrin

  48. Investigational Anticoagulant Targets ORAL PARENTERAL TF/VIIa TFPI (tifacogin) TTP889 X IX APC (drotrecogin alfa) sTM (ART-123) IXa VIIIa RivaroxabanApixabanLY517717YM150 DU-176bBetrixaban TAK 42 Va AT Xa Idraparinux II (thrombin) DX-9065aOtamixaban IIa Dabigatran APC activated protein C AT antithrombin sTM soluble thrombomodulin TF tissue factor FPI tissue factor pathway inhibitor Fibrinogen Fibrin Adapted from Weitz JI. Thromb Haemost 2007; 5 Suppl 1:65-7.

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