Left Atrial Appendage Occlusion in the Era of Novel Anticoagulants Saibal Kar, MD, FACC, FSCAI Professor of Medicine Director of Interventional Cardiac Research Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA Disclosure Statement of Financial Interest Saibal Kar Within the past 12 months, I or my spouse/partner have had a financial interest/arrangement or affiliation with the organization(s) listed below. Affiliation/Financial Relationship Grant/Research Support Consulting Fees/Honoraria Company Abbott Vascular, Boston Scientific, Gore Medical, Edwards Lifesciences, Mitralign Abbott Vascular, Boston Scientific, Gore Medical, Other Financial Benefit 1
Left Atrial Appendage(LAA) Closure Who The Unmet Need Atrial Fibrillation (AF) and Stroke 15-20% of all strokes are AF related AF results in a greater disability than non-af related strokes. It is important to differentiate valvular vs non-valvular AF Valvular AF = AF associated with mitral stenosis or prosthetic heart valve The incidence of AF continues rise with age 2
Connection Between NVAF-Related Stroke and the Left Atrial Appendage AF Creates Environment for Thrombus Formation in Left Atrium In non-valvular AF, >90% of stroke-causing clots that come from the left atrium are formed in the LAA In Valvular AF stasis and clot formation can occur in any part of the left atrium 1 1. Blackshear JL. Odell JA., Annals of Thoracic Surg (1996) Prevention of stroke in patients with non-valvular AF Warfarin and the new oral anticoagulant (NOAC) agents are effective in reducing the risk of ischemic stroke. Challenges of long term drug therapy Compliance Bleeding Failure 3
Despite NOAC Adoption and Ability to Switch NOACs, Adherence to Anticoagulation Remains a Challenge Martinez C, et al. Thromb Haemost. 2015 Dec 22;115(1):31-9. NOAC Trials Adherence and Bleeding Issues Treatment Study Drug Discontinuation Rate Major Bleeding (rate/year) Rivaroxaban 1 24% 3.6% Apixaban 2 25% 2.1% Dabigatran 3 (150 mg) Edoxaban 4 (60 mg / 30 mg) 21% 3.3% 33 % / 34% 2.8% / 1.6% Warfarin 1-4 17 28% 3.1 3.6% For those that remain adherent, there is an annual compounding bleeding risk 1Connolly, S. NEJM 2009; 361:1139-1151 2 yrs follow-up (Corrected) 2Patel, M. NEJM 2011; 365:883-891 1.9 yrs follow-up, ITT 3Granger, C NEJM 2011; 365:981-992 1.8 yrs follow-up, 4Giugliano, R. NEJM 2013; 369(22): 2093-2104 2.8 yrs follow-up. Results from different clinical investigations are not directly comparable. Information provided for educational purposes only 4
Left Atrial Appendage(LAA) Closure When? Indications for LAAC Validated Scoring Systems to Assess Stroke Risks 3. Chest. 2010 Feb;137(2):263-72. 5
Validated Scoring Systems to Assess Bleeding Risks Chest. 2010 Nov;138(5):1093-100. Stroke prevention in Non-valvular AF Oral anticoagulants vs LAA closure Low stroke risk (CHA2DS2-VASc <2) Low bleeding risk Single antiplatelet agent High bleeding risk Single antiplatelet agant or nothing High stroke risk (CHADS-VASc 2 NOACS or Warfarin? LAAC LAAC 6
Left atrial appendage closure(laac) strategies Only FDA approved LAA closure device For stroke prophylaxis Watchman Device Gen II Amulet Device Coherex Device ( Investigational in US) Lariat device Atriclip device 7
Left Atrial Appendage(LAA) Closure Results The Clinical Evidence Clinical Evidence Randomized studies (Watchman device) Two clinical trials Registries Post market registries 8
Watchman LAA closure Safety Comparison of Procedural Parameters Across Watchman Studies No Deaths during clinical trial Reddy VY, Holmes DR, et al. JACC 2016; 69(3): 253-261. 9
Watchman LAA closure Efficacy J Am Coll Cardiol 2017;70:2964-2975 Patient-Level Meta-Analysis PROTECT AF and PREVAIL 5 years HR p- value Efficacy 0.82 0.3 All stroke or SE 0.96 0.9 Ischemic stroke or SE 1.7 0.08 Hemorrhagic stroke 0.2 0.0022 Ischemic stroke or SE >7 days 1.4 0.3 CV/unexplained death 0.59 0.03 All-cause death 0.73 0.04 Major bleed, all 0.91 0.6 Major bleeding, non procedure-related 0.48 0.0003 Favors WATCHMAN Favors warfarin 0.01 0.1 1 10 Hazard Ratio (95% CI) 10
Patient-Level Meta-Analysis WATCHMAN Comparable To Warfarin For Ischemic Stroke HR p- value Efficacy 0.82 0.3 All stroke or SE 0.96 0.9 Ischemic stroke or SE 1.7 0.08 Hemorrhagic stroke 0.2 0.0022 Ischemic stroke or SE >7 days 1.4 0.3 CV/unexplained death 0.59 0.03 All-cause death 0.73 0.04 Major bleed, all 0.91 0.6 Major bleeding, non procedure-related 0.48 0.0003 Favors WATCHMAN Favors warfarin 0.01 0.1 1 10 Hazard Ratio (95% CI) Results WATCHMAN Comparable to Warfarin for Ischemic Stroke Ischemic Stroke Risk (events per 100 pt-yrs) 10 8 6 4 Untreated AF Treated with Warfarin WATCHMAN Arm 2 CAP2 PREVAIL 2.3 WASP 1.7 PROTECT AF 1.5 EWOLUTION 1.3 CAP 1.1 1.2 0 1 2 3 4 5 Baseline CHA 2 DS 2 -VASc Score EWOLUTION: Boersma Lva et al Heart Rhythm 2017;doi-10.1016/j.hrthm.2017.05.038; WASP: Philips K, et al.journal of Arrhythmia (in press). 11
Patient-Level Meta-Analysis WATCHMAN Superior for Hemorrhagic Stroke, CV Death, All-Cause Death, Post-procedure Bleeding HR p- value Efficacy 0.82 0.3 All stroke or SE 0.96 0.9 Ischemic stroke or SE 1.7 0.08 Hemorrhagic stroke 0.2 0.0022 Ischemic stroke or SE >7 days 1.4 0.3 CV/unexplained death 0.59 0.03 All-cause death 0.73 0.04 Major bleed, all 0.91 0.6 Major bleeding, non procedure-related 0.48 0.0003 Favors WATCHMAN Favors warfarin 0.01 0.1 1 10 Hazard Ratio (95% CI) Patient-Level Meta-Analysis WATCHMAN Superior Reduction in Disabling Strokes 2.00% Disabling/Fatal Strokes Non-Disabling Strokes 1.50% 1.00% 0.50% 55% Reduction 0.00% WATCHMAN HR 0.45 (0.21 0.94) P=0.03 warfarin Disabling Stroke defined as MRS 2 Two strokes in PREVAIL are excluded because the baseline MRS score was unavailable 12
PROTECT and PREVAIL 5 year follow up All-Cause Death P=0.04 Reddy V, Doshi S, Kar S et al. J Am Coll Cardiol 2017;70:2964-2975 Summary: 5 year follow up Long term 5-year outcomes of 2 RCTs demonstrate LAAC with the Watchman device provides stroke prevention in NVAF patients to a similar degree as oral anticoagulation By minimizing major bleeding, particularly hemorrhagic stroke, LAAC results in less disability or death than warfarin Reddy V, Doshi S, Kar S et al. J Am Coll Cardiol 2017;70:2964-2975 13
Cost effectiveness LAAC versus NOAC versus coumadin Warfarin vs NOACs vs LAAC: Cummulative cost and Time to Cost-Effectiveness QALY = Quality-adjusted life year Reddy, V.Y. et al. J Am Coll Cardiol 2015;66:2728-39 14
WATCHMAN FDA Indications for Use March 2015 The WATCHMAN Device is indicated to reduce the risk of thromboembolism from the LAA in patients with non-valvular atrial fibrillation who: Are at increased risk for stroke and systemic embolism based on CHADS2 or CHA2DS2-VASc scores and are recommended for anticoagulation therapy; Are deemed to be suitable for warfarin; and Have an appropriate rationale to seek a non-pharmacologic alternative to warfarin, taking into account the safety and effectiveness of the device compared to warfarin Conclusions Thrombus arising from the Left atrial appendage is important cause of ischemic stroke in non-valvular AF Left atrial appendage closure (LAAC) is a safe and effective alternative to coumadin for the prevention of stroke LAAC is a cost effective over NOACs in the long term. Further modifications of the device/therapy will hopefully make LAAC a front line therapy in patients with atrial fibrillation 15
Who is the ideal patient with non-valvular AF for LAA closure: be a good clinician Ideal for patients who Cannot not Should not Will not Take long term anticoagulants 16