La chiusura dell auricola per la prevenzione dello stroke nel paziente con FA

Antonio Manari U.O. Cardiologia Interventistica Azienda Ospedaliera Santa Maria Nuova Reggio Emilia Istituto di Ricovero e Cura a Carattere Scientifico La chiusura dell auricola per la prevenzione dello stroke nel paziente con FA S. Margherita 17 febbraio 2012

Who Gets Atrial Tachyarrhythmias? Atrial Fibrillation Demographics by Age Feinberg WM, Blackshear JL, Laupacis A. Arch Intern Med. 1995;155:469-473

Prevalence of AF and Strokes attributable to AF by age. 40% 35% 30% 25% 20% 15% Prevalence of AF Strokes Attributable to AF 10% 5% 0% 50-59 60-69 70-79 80-89 Framingham Study, Wolf, 1991

Efficacy of Antithrombotic Treatment in Non-Valvular Atrial Fibrillation META ANALYSIS 26 Trials 28,044 Patients Mean Age 71 Years Mean Follow up 1.5 years Comparison Trials Patients Reduction in Stroke Warfarin Vs. Control 6 2,900 64% Antiplatelet agents vs. control 8 4,876 22% Warfarin vs. Antiplatelet 12 12,963 39% Har RG, Ann Intern Med 2007; 146:857-86

Anticoagulation in atrial fibrillation Stroke risk reductions warfarin better control better AFASAK SPAF BAATAF Stroke: RRR 62% All-cause mortality: RRR 26% CAFA SPINAF EAFT Severe bleedings: 1.2%/year Aggregate 100% 50% 0-50% -100%

ESC Guidelines 2010 on the management of Atrial Fibrillation Warfarin is the gold standard in patients with atrial fibrillation. Eur Heart J 2010

REAL WORLD USE OF WARFARIN IN AF PATIENTS WITHOUT CONTRAINDICATIONS % Harrold et al, 2002 McCormick et al, 2001 Samsa et al, 2000 CQInv, 1998 Sudlow et al, 1998 Brass et al, 1997 Gurwitz et al, 1997 Whittle et al, 1997 Albers et al, 1997 Stafford & Singer, 1996 Lip et al, 1994 Bath et al, 1993 53 42 34 24 23 28 31 44 20 32 36 29 0 10 20 30 40 50 60

Non-Valvular Atrial Fibrillation Warfarin use in AF Patients by Age % 70 60 50 40 30 20 10 0 58,1 60,7 57,3 44,3 35,4 <55 55-64 65-74 75-84 85 Only 55% of AF patients with no contraindications have evidence of warfarin use in previous 3 months Other studies cite warfarin use in AF patients from 17-50% Elderly patients with increased absolute risk least likely to be taking warfarin Contraindications 30-40% Ann Int Med 131(12), 1999

Age-related trends in AF 100 80 60 40 Unmet need 20 0 69-79 80-89 >89 Age, years Wolf PA, Arch Intern Med 1987; 147:1561-4 White RH, Am J Med 1999; 106:165-71

Narrow anticoagulant therapeutic window Hylek EM et al, N Engl J Med 1996; 335: 540-546 Stroke risk increases at INR < 2 Bleeding risk increases at INR >3

Non-Valvular Atrial Fibrillation Adequacy of Anticoagulation in Clinic Low INR <1.6 Therapeutic INR 2-3 Efficacy 4-fold High INR >3.2 Bungard, Pharmacotherapy 20:1060, 2001 0 20 40 60 80 100 % 11

ORAL ANTICOAGULATION AND RISK OF BLEEDING ISCOAT Study 2,745 pts 10 9.9 ns PT / YEAR % 8 6 4 2 0 2.1 ELDERLY PTS Major bleeds N= 461 Age > 75 (79.9) 6.6 1.1 YOUNG PTS All bleeds N= 461 Age < 70 (56.5) Palareti et al, Arch Intern Med 2000; 160: 470-478

RCT s & Warfarin INR al momento dello Stroke 4.0 1.8 1.7 3.0 INR Ratio 2.0 1.0 AFASAK CAFA SPAF I BAATAF SPINAF 1.6 1.5 1.4 1.3 1.2 1.1 1.0 PT Ratio (ISI 2.4) ACCP raccomandazioni: INR: 2.0 3.0 Target range per ogni studio

Risk adjusted percent time in therapeutic range as a quality indicator for out-patient oral anticoagulation: results of the Veterans Affairs Study to Improve Anticoagulation (VARIA). Rose AJ, Circ Cardiovasc Qual Outcomes 2011;4:22-9 In a recent analysis of anticoagulation management involving more than 120,000 patients in the Veterans Affairs health care system, the mean proportion of time in the therapeutic range was 58%, with significant variation across Sites.

Percentuale di tempo con INR in range in RCTs in era contemporanea 100 90 80 70 60 % 50 40 30 20 10 0 62,2 64 55 Rivaroxaban Apixaban Dabigatran (2011) (2011) (2009)

Aderenza alla terapia nei RCTs in era contemporanea Rocket-AF% sospensione del farmaco ARISTOTLE% sospensione del farmaco 27 23 19 15 23,7 Rivaroxaban 22,2 Warfarin 31 27 23 19 15 25,3 Apixaban 27,5 Warfarin 23 19 15 RE LY% sospensione del farmaco 21 21 17 Dab 110 Dab 150 Warfarin

Rocket-AF % sospensione del farmaco The median duration of treatment exposure was 590 days; the median follow-up period was 707 days 27 23 19 23,7 22,2 15 Rivaroxaban Warfarin

6 5 4,43 5,1 4,37 4 3 2 2,29 2,6 2,43 3,25 1 0,82 0,89 0 Dab 110 Dab 150 Warfarin < 65 65-74 >75

6 5 5,29 5,44 5,41 4 3 2 2,89 1,53 3,33 2,09 3,76 2,36 1 0 Dab 110 Dab 150 Warfarin Cl Crea<50 Cl Crea50-70 Cl Crea >80

6 5,95 5 4 3 4,3 2,91 2,56 4,92 3,13 4,01 3,75 3,34 2 1 0 Dab 110 Dab 150 Warfarin Peso<50 Peso50-99 Peso100

ARISTOTLE Apixaban vs Warfarin

a high risk of bleeding (e.g., active peptic ulcer disease, a platelet count of <100,000 per cubic millimeter or hemoglobin level of <10 g per deciliter, stroke within the previous 10 days, documented hemorrhagic tendencies, or blood dyscrasias),

Prevenzione dello stroke embolico nella Fibrillazione Atriale

Mechanism of Stroke in Patients with AF

Devices per la chiusura percutanea

Left atrial appendage closure

Left atrial appendage closure

Left atrial appendage closure

Left atrial appendage closure

Left atrial appendage closure

Left atrial appendage closure

Left atrial appendage closure

Left atrial appendage closure

Left atrial appendage closure

Left atrial appendage closure

Left atrial appendage closure

PROTECT-AF Trial Enrollment Summary Randomized Patients N=707 Implant successful in 90.9% (408/449) of attempts Warfarin Control Group N=244 WATCHMAN Device Group N=463 Warfarin Started N=241 Warfarin Never Started N=3 Implant Attempted N=449 No Attempt N=14 Window For Procedure Lapsed N=10 Procedural Event N=12 Device Release Criteria Not Met* N=29 Unable to Implant N=41 Device Implanted N=408 Other N=3 Patient Died Before Procedure N=1 Included In Primary Analysis * One or more of the release criteria of acceptable device position, in-situ size (compression), stability, and LAA seal were not met for device release. 41 April 23, 2009

Primary Efficacy Results (CV deaths, stroke, systemic embolization) 707 pts with non-valvular AF (CHADS 2 1) Device Randomization allocation (2 device : 1 control) Control Posterior Probabilities Events Total Rate Events Total Rate Rel. Risk Non- Cohort (no.) pt-yr (95% CI) (no.) pt-yr (95% CI) (95% CI) inferiority Superiority 900 pt-yr 20 582.3 3.4 16 318.0 5.0 0.68 0.998 0.837 (2.1, 5.2) (2.8, 7.6) (0.37, 1.41) 1 Event-free probability 0,9 WATCHMAN Control ITT Cohort: patients analyzed based on their randomly assigned group (regardless of treatment received) 0,8 244 147 52 12 Days 463 270 92 22

All Stroke Device Control Posterior probabilities Events Total Rate Events Total Rate RR Non- Superiority Cohort eve pt-yr (95% CI) (no.) pt-yr (95% CI) (95% CI) inferiority 600 14 409.3 3.4 8 223.6 3.6 0.96 0.927 0.488 pt-yr (1.9, 5.5) (1.5, 6.3) (0.43, 2.57) 900 15 582.9 2.6 11 318.1 3.5 0.74 0.998 0.731 pt-yr (1.5, 4.1) (1.7, 5.7) (0.36, 1.76) Event-free probability 1 0,9 0,8 900 patient-year analysis 0,7 0 365 730 1095 244 147 52 12 463 270 92 22 Days Device Control Randomization allocation (2 device:1 control) ITT cohort: patients analyzed based on their randomly assigned group (regardless of treatment received) 3001664-2

Hemorrhagic Stroke Device Control Posterior probabilities Events Total Rate Events Total Rate RR Non- Superiority Cohort (no.) pt-yr (95% CI) (no.) pt-yr (95% CI) (95% CI) inferiority 600 1 416.7 0.2 4 224.7 1.8 0.13 0.998 0.986 pt-yr (0.0, 0.9) (0.5, 3.9) (0.00, 0.80) 900 1 593.6 0.2 6 319.4 1.9 0.09 >0.999 0.998 pt-yr (0.0, 0.6) (0.7, 3.7) (0.00, 0.45) Event-free probability 900 patient-year analysis Device Control 244 147 Days 53 12 463 275 95 23 Randomization allocation (2 device:1 control) ITT cohort: patients analyzed based on their randomly assigned group (regardless of treatment received) 3001664-2

Intent-to-Treat Primary Safety Results Randomization allocation (2 device : 1 control) Device Control Events Total Rate Events Total Rate Rel. Risk Cohort (no.) pt-yr (95% CI) (no.) pt-yr (95% CI) (95% CI) 900 pt-yr 48 554.2 8.7 13 312.0 4.2 2.08 (6.4, 11.3) (2.2, 6.7) (1.18, 4.13) 1 Event-free probability 0,9 WATCHMAN Control ITT Cohort: patients analyzed based on their randomly assigned group (regardless of treatment received) 0,8 244 143 51 11 463 261 87 19 Days

LAA occlusion Atrial fibrillation High risk of stroke Contraindication to OAC High risk of bleeding with OAC Difficult to maintain INR within the therapeutic range Poor compliance Difficulty to manage the patient because ol ogistic problems