Occlusion de l'auricule gauche: Niche ou réel avenir? D Gras, MD, Nantes, France

Occlusion de l'auricule gauche: Niche ou réel avenir? D Gras, MD, Nantes, France

LAA Occlusion Is there a real future? Background Protect AF Trial Other Studies CAP, ASAP, Prevail Left Atrial Appendage Occlusion Procedure

AF and Stroke. 3 million in US, 4.5 million in the EU have AF 1. 2/3 of AF population are at high-risk of stroke 1 35% of patients with AF will have a stroke in their lifetime 2. AF responsible for 15-20% of ischemic strokes 1. AF Incidence increases with age 2. 0.4% in general population. 0.2% of 25-34 yrs of age Estimated age-specific AF prevalence 2. 2-5% of >60 yrs of age. 10% of > 80 yrs of age Relationship of AF and stroke 2 1. Fuster, et al., ACC/AHA/ESC Practice Guidelines, Circulation. 2006;114:700-752 2. Wolf PA, et al., Atrial fibrillation as an independent risk factor for stroke: the Framingham study. Stroke 1991;22:983 8

Warfarin: The cornerstone therapy Adjusted-dose Warfarin agents reduce stroke by 60% 1 Inadequate warfarin usually seen in pts admitted for Stroke 2 (High-risk pts with AF candidates for OAC): Only 29% on therapeutic level for Warfarin dose Of the remaining: 10% were sub-therapeutic, 31% were on Antiplatelet, 29% no therapy was prescribed Warfarin is CI in 14-47% of pts at risk of stroke 4 It is not prescribed in 21% of the indicated patients 3 Less than 50% of pts eligible are being treated with warfarin due to tolerance or non-compliance issues 1. Hart, et al, Meta-analysis 28044 pts, Ann Intern Med. 2007;146:857-867 2. Gladstone et al, Stroke, 2009; 40:235-240 3. Waldo AL, et al. J AM Coll Cardiol 2005;46:1729 4. Holmes at ACC & i2 Summit 2009 5. Wikipedia. Warfarin. http://en.wikipedia.org/wiki/warfarin. Accessed November 1, 2011.

CI and reasons for not initiating Warfarin Contraindicated patients 1 : 40% increased risk of stroke 26% increased risk of mortality Physician's Perceived Reasons for Not Initiating Warfarin Therapy 2 Fall Risk 20% Gastrointestinal Bleed 29% Not documented 22% Transient / Secondary AF 22% 1. Hart, et al., Meta-analysis: Antithrombotic Therapy to Prevent Stroke in Patients Who Have Nonvalvular Atrial Fibrillation; Ann Intern Med. 2007;146:857-867. 2. Srivastava, et al. Examining warfarin underutilization rates in patients with atrial fibrillation: Detailed chart review essential to capture contraindications to warfarin therapy; Thrombosis Journal 2008, 6:6doi:10.1186/1477-9560-6-6

Wallentin, et al., Efficacy and safety of Dabigatran compared with Warfarin at different levels of international normalised ratio control for stroke prevention in atrial fibrillation: an analysis of the RE-LY trial; The Lancet, 2010: 376; 975-983 Country distribution of mean time in therapeutic range in the RE-LY trial 5791 Patients on warfarin A large proportion of patients were outside the therapeutic range Major variations between countries Europe: about 3 out of 10 patients out of therapeutic range Sweden: 23% out of range Taiwan: 56%

In AF, 91% of the thrombi formed in the LA appendage. Rationale for excluding the LAA from the circulation 80 % reduction in stroke > LAA surgical occlusion Garcia-Fernandez et al.: Role of left atrial appendage obliteration in stroke reduction in patients with mitral valve prosthesis: a transesophageal echocardiographic study. J Am Med Assoc 2003, 42:1253-1258. Blackshear JL, Odell JA. Appendage obliteration to reduce stroke in cardiac surgical patients with atrial fibrillation. Ann Thorac Surg 1996;61:755 9.

LAA Occlusion Is there a real future? Background Protect AF Trial Other Studies CAP, ASAP, Prevail Left Atrial Appendage Occlusion Procedure

PROTECT-AF: Overview Can the WATCHMAN device replace Warfarin? Efficacy Endpoint: Stroke CV death (& Unknown) Systemic embolism Safety Endpoint Non-inferiority & Superiority Bayesian Sequential Design Analysis at 600 pt-yrs & every 150 pt-yrs thereafter 1500 pt-yr Warfarin Non-Valvular AF CHADs 1 Randomization (1:2) Follow-Up: 5 Years Watchman Anticoagulation Regimen Implant to 6 weeks Warfarin (INR 2-3) for 6 weeks Aspirin (81 325 mg) 6 weeks to 6 months Clopidogrel (75 mg) Aspirin (81 325 mg) After 6 months Aspirin (81 325 mg)

PROTECT-AF: Inclusion/Exclusion Inclusion: Paroxysmal / Persistent / Permanent AF CHADS 1 (CHF, HTN, 75 yr, Diabetes, TIA/CVA) Eligible for long-term Warfarin therapy Exclusion Mechanical valve or long-term Warfarin needed Contraindication to Warfarin TEE exclusion: anatomy, atheroma, MV stenosis, tumor Symptomatic Carotid disease LVEF < 30% ASD / Atrial septal repair or closure device CV/Ablation planned within 30 days Unable to take ASA / Plavix

PROTECT-AF: Patient Demographics

PROTECT-AF: Primary Efficacy Endpoint Events include Stroke (ischemic and hemorrhagic), Systemic embolization, CV death

PROTECT-AF: Primary Efficacy Endpoint Events include Stroke (ischemic and hemorrhagic), Systemic embolization, CV death 1 2 3

Intention-to-Treat: All-Cause Mortality Hazard Ratio with Watchman, 0.66 (95% CI, 0.45 0.98) P = 0.0379

PROTECT AF: Primary Safety Endpoint

Primary Safety Endpoint: Components of the Safety Endpoint Pericardial Tamponade 22 requiring Tx (4.8% of patients) 15 treated percutaneously 7 underwent surgical intervention Extended hospitalization No Death or Long-term Disability Effect of operator experience 1st Half of Cohort: 6.3% 2nd Half of Cohort: 3.7% Early = First 7 days Late = After 7 days

LAA Occlusion Is there a real future? Background Protect AF Trial Other Studies CAP, ASAP, Prevail, Amplatzer. Left Atrial Appendage Occlusion Procedure

Characteristic PROTECT AF N=463 CAP N=566 PREVAIL N=269 P value Age, years 71.7 ± 8.8 (463) (46.0, 95.0) 74.0 ± 8.3 (566) (44.0, 94.0) 74.0 ± 7.4 (269) (50.0, 94.0) <0.001 Gender (Male) 326/463 (70.4%) 371/566 (65.5%) 182/269 (67.7%) 0.252 CHADS 2 Score (Continuous) CHADS 2 Risk Factors 2.2 ± 1.2 (1.0, 6.0) 2.5 ± 1.2 (1.0, 6.0) 2.6 ± 1.0 (1.0, 6.0) CHF 124/463 (26.8%) 108/566 (19.1%) 63/269 (23.4%) Hypertension 415/463 (89.6%) 503/566 (88.9%) 238/269 (88.5%) Age 75 190/463 (41.0%) 293/566 (51.8%) 140/269 (52.0%) Diabetes 113/463 (24.4%) 141/566 (24.9%) 91/269 (33.8%) Stroke/TIA 82/463 (17.7%) 172/566 (30.4%) 74/269 (27.5%) <0.001 Most notable differences: Age, Diabetes, and Prior Stroke/TIA PROTECT AF and CAP data, from Reddy, VY et al. Circulation. 2011;123:417-424.

Procedure Implant Success CAP Implant success PREVAIL Implant success 95,1% PROTECT AF Implant success 94,3% 90.9% Implant success defined as deployment and release of the device into the left atrial appendage p = 0.04 PROTECT AF and CAP data from Reddy, VY et al. Circulation. 2011;123:417-424.

7 Day Procedure/Device Related Vascular complications Cardiac perforation, pericardial effusion with tamponade, ischemic stroke, device embolization, and other vascular complications 1 10,0% 8,0% 8.7% p = 0.005 % of Patients 6,0% 4,0% 2,0% 0,0% 4.1% 4,4% n=39 n=23 n=12 PROTECT AF CAP PREVAIL No procedure-related deaths reported in any of the trials PROTECT-AF and CAP data from Reddy, VY et al. Circulation. 2011;123:417-424. 1 Includes observed PE not necessitating intervention, AV fistula, major bleeding requiring transfusion, pseudoaneurysm, hematoma and groin bleeding

At 18 months, the rate of the first coprimary efficacy endpoint (composite of stroke, systemic embolism [SE], and cardiovascular/unexplained death) was 0.064 in the device group versus 0.063 in the control group (rate ratio 1.07 [95% credible interval (CrI): 0.57 to 1.89]) and did not achieve the prespecified criteria noninferiority (upper boundary of 95% CrI $1.75).

The rate for the second coprimary efficacy endpoint (stroke or SE >7 days postrandomization) was 0.0253 versus 0.0200, achieving noninferiority

ASAP Registry, N=142 1 st EP: Occurrence of stroke (ischemic and hemorrhagic), CV death (cardiovascular and unexplained), system embolism Inclusion Criteria Paroxysmal, persistent or permanent non-valvular AF CHADS 2 score 1 Contraindication for Warfarin Exclusion Criteria ECHO: LVEF <30%, Intracardiac thrombi, Complex aortic atheroma, High-Risk PFO (Aneurysm >15mm or Length 15mm) Symptomatic Carotid disease History of stroke/tia (within last 30 days)

ASAP Registry Efficacy Outcome 77% Reduction 8,0% 7,0% 6,0% 7,3% Mean CHADS 2 Score = 2.8 ± 1.2 5,0% 4,0% 3,0% 2,0% 1,0% 1,7% Expected, based on CHADS2 Score Observed rate in ASAP 0,0% 1 Efficacy outcome: Occurrence of stroke (ischemic and hemorrhagic), CV death (cardiovascular and unexplained), system embolism

The Amplatzer Cardiac Plug Experience 974 Pts, 20 Sites, Europe and Canada

Indication for LAAO

Amplatzer Cardiac Plug Experience Success rate and complications

Amplatzer Cardiac Plug Experience: The Efficacy

LAA Occlusion Is there a real future? Background Protect AF Trial Other Studies CAP, ASAP, Prevail Left Atrial Appendage Occlusion Procedure

LAA Occlusion: Percutaneous, Transcatheter, Transseptal approach Barbs Engage LAA Wall 160 µ PET fabric Watchman AMPLATZER Cardiac Plug self-expanding nitinol frame with fixation anchors and a permeable fabric cover

TEE at 6 Weeks FU

LAA Occlusion: Summary LAA is critical to the pathogenesis of stroke (91%) Local therapy (LAAO) is to Warfarin 40% reduction of stroke, systemic embolism, CV death Efficacy preserved in pts at highest risk (prior stroke/tia) Procedural risks: Tamponade, Migration, Bleeding.. Learning Curve: 2.2% (CAP Registry), 1.9% (PREVAIL) Indications:. non valvular AF + CI to ACT + CHA2DS2-VASc 4,. Decrease in TE events > Procedural risks