Role of LAA Occlusion in Patients With Atrial Fibrillation After PCI Marco Mennuni, MD Interventional Cardiologist Hopital Europeen George Pompidou, Paris (France)

Disclosure Statement of Financial Interest 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 Company Grant Consulting Fees EAPCI - European Society of Cardiology Boston Scientific

Epidemiology of atrial fibrillation and PCI in US and EU 20 Million people with AF (1-2% of population) 16 Million anticoagulation indicated (80%) 4.8 Million have CAD as well (20%-45%) 1- 2 Million potential revascularization (20%-25%) The AFFIRM Investigators. Am Heart J 2002;143:991–1001; Carpodanno D et al, Circ Cardiovasc Interv 2014;7:113–124; Kralev S et al, PLoS One 2011;6:e24964; Bahit MC et al, Int J Cardiol 2013;170:215–220

Stroke in AF and ACS are mediated by a thrombotic process Coronary/stent thrombosis Stroke + DAPT OAC Bleeding

HR for Risk of Bleeding Arch Intern Med. 2010;170(16):1433-41

AVIATOR registry: 900 pts with Afib undergoing PCI Triple therapy at discharge among different risk strata Highest Risk * p = NS * * * % of patients on TT p<0.01 for trend HAS-BLED score CHADS2 score Lowest risk Mennuni et al Am J Cardiol. 2015 Jul 1;116(1):37-42

Bleeding and mortality Increased HR of mortality at 1 y, after bleeding post-PCI Mehran et al JACC Cardiovasc Interv. 2011 Jun;4(6):654-64.

How to manage the high bleeding risk… Evidence suggestion: to drop off Aspirin from TT (WOEST trial) Reduce the duration of TT at 1 month (ISAR-triple trial) The problems: Both trials not powered for ischemic events In WOEST, the primary endpoint was driven by minor bleedings DAPT benefit in ACS patients is well established ESC Guidelines on AF. Eur Heart J 2016; 37:2893-2962 ACC/AHA Guidelines on AF. Circulation 2014; 130: 20171-2104 Bhatt et al JACC 2015

NOACs and antiplatelets are just empirical… Recommendations on combined use of NOACs and antiplatelets are just empirical… RE-LY Dabigatran ROCKET- AF Rivaroxaban ARISTOTLE Apixaban ENGAGE Edoxaban Concomitant use of aspirin alone 32% ≈37% ≈31% ≈29% Concomitant use of clopidogrel alone ≈2% <2% Concomitant use of DAPT ≈5% Excluded Capodanno D, et al. EuroIntervention. 2015;10:1015-21

Requiring Medical Attention (%) Except for Rivaroxaban. PIONEER Trial adds a new alternative to reduce bleeding in Afib patients undergoing PCI. TIMI Major, TIMI Minor, or Bleeding Requiring Medical Attention (%) 26.7% VKA+ DAPT VKA+ DAPT 18.0% 16.8% Riva + DAPT Riva + DAPT Riva + P2Y12 Riva + P2Y12 Riva + P2Y12 v. VKA + DAPT 180 360 Days Gibson et al. N Engl J Med. 2016 Dec 22;375(25):2423-2434

The New Oral Anticoagulants work better than Warfarin but … They are good, but they are still coagulation blockers, with an intrinsic rate of bleeding events which increase permanently over the time 2) They have a not negligible discontinuation rate Study Treatment Major Bleeding Discontinuation in the study RE-LY Dabigatran (110mg) 2.71 % 20.7 % Dabigatran (150mg) 3.11 % 21.2 % Warfarin 3.36 % 16.6 % ROCKET-AF Rivaroxaban 3.6 % 23.7% 3.4 % 22.2 % ARISTOLE Apixaban 2.13 % 25.3 % 3.09 % nc ENGAGE AF Edoxaban HD 2.7% 34% Edoxaban LD 1.6% 32% 3.4%

May be LAA Occlusion in AF Patients undergoing PCI an Option? Evidence available is weak 1) ACP Registry (1,000 patients treated with Watchman) 36% with CAD and 22% with previous PCI. No further analysis performed. 2) Single center series: 15 patients with AF undergoing PCI for acute coronary syndrome. Procedural success in 14/15 patients (1 pericardial effusion before transeptal without implantation of the device). No peri-procedural major adverse events. At a 6 months follow-up 1 peri-procedural minor bleeding and 2 non-CV death. LAA occlusion in AF and PCI patients is based on empirical data. Ciccarelli G et al., Int J Cardiovasc Res 2017; 6, 1 Tzikas A et al.,EuroIntervention 2016;11:1170-1179

Comparison between LAA Occlusion and Warfarin Pooled analysis of 1100 pts from 2 RCTs that compared WATCHMAN LAA closure with long-term warfarin therapy in AF. Overall: Bleeding Events Post Procedure: Bleeding Events p = ns Overall bleeding rates similar p = 0.002 51% reduction in bleeding events in WATCHMAN device arm Price MJ et al., J Am Coll Cardiol Interv 2015,

Indirect Comparison between LAA Occlusion and NOACs Network meta-analysis of 19 RCTs with a total of 87 831 patients with AF receiving anticoagulants, APT, placebo or LAAC. LAA occlusion NOAC Antiplatelet VKA ShwetSahay et al. Heart 2017;103:139-147

Comparison between LAA Occlusion and NOACs for Mortality and Stroke Shweta Sahay et al. Heart 2017;103:139-147

Comparison between LAA Occlusion and NOACs for Bleeding Events Shweta Sahay et al. Heart 2017;103:139-147

Implant Procedure Safety 7-Day SAEs procedure-related in WATCHMAN studies. 2.8% SAE: Serious Adverse Event - Composite of vascular complications includes cardiac perforation, pericardial effusion with tamponade, ischemic stroke, device embolization, and other vascular complications. PROTECT AF/CAP: Reddy et al. Circulation 2011 PREVAIL: Holmes et al. JACC 2014

PARIS Risk Score for Ischemic and Bleeding Events Which patients could be a potential candidate for LAA occlusion after PCI? PARIS Risk Score for Ischemic and Bleeding Events Data from 4,190 patients treated with DES and enrolled in the PARIS registry externally validated. Baber U et al., JACC 2016

DAPT study Predictors of Net Treatment Effect Characteristics Impact on Net Treatment Effect % of Variation Explained Age ≥ 75 Age 65 - < 75 Age < 65 (reference) -1.2% -0.5% - 6.0% 2.1% Prior PCI or MI 1.1% 14.6% Stent Diameter < 3 mm 0.9% 10.1% CHF or LVEF < 30% 1.9% 9.9% MI at Presentation 1.0% 9.6% Paclitaxel-Eluting Stent 8.8% Cigarette Smoker 0.7% 4.3% Diabetes 0.6% Vein Graft PCI 1.6% 3.7% Hypertension 0.2% 0.4% Renal Insufficiency 0.3% PAD -0.1% 0.04% Bleeding Predictors Ischemia Predictors Bleeding and Ischemia Predictors

The DAPT Score Distribution of DAPT Scores among all randomized subjects in the DAPT Study Variable Points Patient Characteristic Age ≥ 75 -2 65 - <75 -1 < 65 Diabetes Mellitus 1 Current Cigarette Smoker Prior PCI or Prior MI CHF or LVEF < 30% 2 Index Procedure Characteristic MI at Presentation Vein Graft PCI Stent Diameter < 3mm

Continued Thienopyridine vs Placebo after 12 months DAPT Score <2 (Low); N=5731 DAPT Score ≥ 2 (High); N=5917 Death, MI, or Stroke (MACCE) Death, MI or Stroke (MACCE) 10% Continued Thienopyridine Placebo 10% Continued Thienopyridine Placebo 8% 8% 6% 6% 4.9% vs. 7.6% P<0.001 Cumulative Incidence of MACCE Cumulative Incidence of MACCE 4% 3.7% vs. 3.8% P=0.73 4% 2% 2% 0% 0% 12 15 18 21 24 27 30 12 15 18 21 24 27 30 Months After Enrollment

Conclusions In patient with AF, need of DAPT, and high risk of bleeding LAA occlusion may represents a therapeutic option to reduce risk of stroke and bleeding at long-term follow-up. Potential candidate for LAA occlusion might be patients with high scores (PARIS or DAPT) which identify who might benefit from prolonged DAPT.

Conclusions Trials on NOACs and LAA occlusion in AF patients undergoing PCI are ongoing: ENTRUST AF PCI (Edoxaban+P2Y12 vs TT) AUGUSTUS (Apixaban+P2Y12+Aspirin vs TT) double randomization of (Apixaban vs Warfarin and Aspirin vs Placebo) RE-DUAL PCI (Dabigatran+P2Y12 vs TT) WATCHMAN vs Warfarin after PCI (results expected on Q4 2017) Amplazter Cardiac Plug vs Dabigatran+Aspirin vs Dabigatran+Clopidogrel (not yet recruiting) They will provide important indication on the best therapeutic strategy in this high risk population.

Thanks. marco.mennuni@gmail.com