Left Atrial Appendage Closure

Transcription

1 Left Atrial Appendage Closure Matthew J. Price MD Director, Cardiac Catheterization Laboratory Scripps Clinic La Jolla, CA, USA

2 Risk Factors for Stroke From The Perspective of the 17 th Century Physician th - To this variety of apoplexy those are most liable who lead an idle life, who are obese, whose face and hands are constantly livid and whose pulse constantly unequal. Historiae Apoplecticorum Johann Jakob Wepfer, 1658 Apoplexy: Incapacity resulting from a cerebral hemorrhage or stroke.

3 Prevalence of Antithrombotic Therapies in AF Patients Across the Spectrum of Stroke Risk: Data from the NCDR-PINNACLE Registry N=429,417 <50% of high- risk patients get OACs Hsu JC et al, JAMA Cardiol. 2016;1(1):

4 Adherence to OAC Proportion of Days Covered CHA 2 DS 2 VASc score 4 erence Median: 1.1 yrs 42 % Adh Apixaban Dabigatran Rivaroxaban All NOACs Warfarin Yao et al: J Am Heart Assoc doi: /jaha , MFMER slide-23

5 The Non-Vitamin K Oral Anticoagulants (NOACs): Clinical Trial Summary Drug RE-LY Dabigatran 150mg/d ROCKET-AF Rivoraxaban 20mg/day ARISTOTLE Apixaban 5mg bid ENGAGE-AFAF Edoxaban 60mg/day CHADS TTR, control 67% 58% 66% 68% Hemorrhagic stroke All-cause mortality Ischemic 0.76 ( ( ( (0.83- stroke 0.98) 1.17) 1.14) 1.19) 0.26 ( ) 0.59 ( ) 0.51 ( ) 0.54 ( ) 0.88 ( ) 0.85 ( ) 0.89 ( ) 0.92 ( ) Major bleed 0.93 ( ) 1.04 ( ) 0.69 ( ) 0.80 ( ) GI bleeding 1.50 ( ) 1.39 ( ) 0.89 ( ) 1.23 ( )

6 The Bad Actor: The Left Atrial Appendage Why not a local therapy for a local problem? >90% of stroke-causing thrombus originates in the LAA Thromboembolic stroke from AF more debilitating due to size of clots Blackshear J.L. Odell J.A., Annals of Thoracic Surgery, 1996;61:

7 Preventing Stroke in AF Using a Local Approach is Not A Novel Idea

8 WATCHMAN Left Atrial Appendage Occluder Catheter--based Delivery Catheter Available sizes: 21, 24, 27, 30, 33 mm diameter Intra--LAA design Intra Avoids contact with left atrial wall to help prevent complications Nitinol Frame 10 active fixation anchors - designed to engage tissue for stability Proximal Face 160 micron membrane PET cap designed to block emboli and promote healing

9 Center for Medicare and Medicaid Services (CMS) Coverage CHADS2 score 2 or a CHA2DS2-VASc score 3 Patients must be suitable for short-term warfarin, but deemed unable to take long-term oral anticoagulation Documented evidence of a formal shared decision interaction between the patient and an independent, non-interventional physician

10 U.S. Dataset for WATCHMAN LAA Closure in WarfarinEligible Patients (For FDA Approval) Key Trials N Design PROTECT AF ( ) 707 Prospective RCT - 2:1, non-inferiority trial of LAA closure vs. warfarin. CAP ( ) 566 Prospective continuing access registry to gain further information prior to PMA approval. PREVAIL ( ) 407 Prospective RCT - 2:1, non-inferiority trial to collect additional information on the WATCHMAN Device. CAP2 ( ) 579 Prospective continuing access registry prior to PMA approval. Total patients >2,000 Reddy, et al. JAMA ;312(19): Reddy VY et al. Circulation. 2011; 123: Holmes, Kar, Price MJ et al., JACC 2014,4(1): 1-11

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12 PROTECT-AF and PREVAIL: Numbers of Patients and Duration of Follow-up Number of Patients Trial Total Mean Follow-up (months) Total Patient Years Device Control PROTECT AF ± ,717 PREVAIL ± ,626 Total Reddy VY et al. JACC 2017; 70(24): ,343

13 Post-Procedural Adjunctive Pharmacotherapy in the PostWATCHMAN Clinical Trials Price MJ et al, JACC Cardiovasc Interv 2015; 8:1925 8:

14 Patient-Level PROTECT AF/PREVAIL Meta PatientMeta--Analysis at 5 Years: WATCHMAN LAAC Compared With Warfarin HR p-value Ischemic stroke or SE Hemorrhagic stroke Ischemic stroke or SE >7 days All-cause death Major bleed, all Major bleeding, non procedure-related Efficacy All stroke or SE CV/unexplained death Favors WATCHMAN JACC Favors warfarin 1 Hazard Ratio (95% CI) 10

15 Patient-Level PROTECT AF/PREVAIL Meta PatientMeta--Analysis at 5 Years: WATCHMAN LAAC Compared With Warfarin HR p-value Ischemic stroke or SE Hemorrhagic stroke Ischemic stroke or SE >7 days All-cause death Major bleed, all Major bleeding, non procedure-related Efficacy All stroke or SE CV/unexplained death Favors WATCHMAN JACC Favors warfarin 1 Hazard Ratio (95% CI) 10

16 Patient-Level PROTECT AF/PREVAIL Meta PatientMeta--Analysis at 5 Years: WATCHMAN LAAC Compared With Warfarin HR p-value Ischemic stroke or SE Hemorrhagic stroke Ischemic stroke or SE >7 days All-cause death Major bleed, all Major bleeding, non procedure-related Efficacy All stroke or SE CV/unexplained death Favors WATCHMAN JACC Favors warfarin 1 Hazard Ratio (95% CI) 10

17 WATCHMAN Warfarin Free of Major 80 Bleeding Event 70 (%) HR 0.28 [95% CI, 0.23 to 0.35] 72% 60 Relative Reduction In Major Bleeding WATCHMAN Arm Warfarin +Aspirin 50 0 Warfarin +Aspirin 7 8 Price MJ et al, JACC Cardiovasc Interv 2015; 8:1925 8: Plavix +Aspirin Aspirin

18 Types and Frequencies of Late Bleeds in the WATCHMAN RCTs Price MJ et al, JACC Cardiovasc Interv 2015; 8:1925 8:

19 Procedural Safety: Serious Procedure/Device Related Events With Watchman LAA Closure Through 7 Days N=1021 Price MJ. Prog Cardiovasc Dis

20 Outcomes in the Initial WATCHMAN Post Post--Approval Commercial Experience (N=3822) Post-FDA Approval Experience Complications Pericardial Tamponade Treated with Pericardiocentesis Treated Surgically 12 (0.31%) Resulted in Death Pericardial Effusion No Intervention 3 (0.078%) 11 (0.29%) Procedure-Related Stroke 3 (0.078%) 9 (0.24%) Device Embolization Removed Percutaneously 3 Removed Surgically 6 Death Procedure-Related Mortality Additional Mortality within 7 days Holmes DR, JACC (1.02%) 24 (0.63%) 3 (0.078%) 1 (0.026%)

21 LAAC Complication Rates In Perspective: Tamponade Rates in PROGRESS CTO Registry In-hospital MACE: components N = 3,055 MI 1% Tamponade requiring pericardiocentesis 0.9% MACE 3% Death 0.8% Re-PCI 0.3% Emergent CABG 0.2% Stroke 0.2%

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23 Procedure Count LAAO Registry Quarterly Procedure Count Cumulative Total Procedure Count = 28,000

24 Thromboembolic Risk of Patients in NESTED PAS* Compared to Earlier Studies Anticoagulation Eligible High Risk 50% Patients (%) 40% PROTECT AF 30% CAP PREVAIL 20% CAP2 NESTED 10% 0% CHA2DS2-VASc Score Nested within the NCDR LAAO Registry

25 NESTED: Primary Safety Endpoint WATCHMAN N=941 Primary Safety Endpoint Performance Goal: < Events P= Event Rate (95% CI) The occurrence of one of the following between the time of the procedure and within 7 days of the procedure or by hospital discharge, whichever is later : all-cause death, ischemic stroke, systemic embolism, device or procedure related events requiring open cardiac surgery or major endovascular intervention such as pseudoaneurysm repair, AV fistula repair, or other major endovascular repair. )

26 LAA Closure: Unanswered Questions

27 LAA Closure: Unanswered Questions Device-related thrombus

28 Predictors of Device-Related Thrombus (DRT) after WATCHMAN using FDAIndicated Post-Procedural Regimen: Univariable and Multivariable Analyses Univariable Analysis Race/Ethnicity Caucasian Odds Ratio (95% CI) 0.53 (0.48, 0.60) LAA pulsed wave peak velocity* 0.96 (0.95, 0.97) <.001 LAA Diameter (mm) 1.05 (1.04, 1.07) <.001 CHA2DS2-VASc Score 1.28 (1.18, 1.39) <.001 Race/Ethnicity Hispanic/Latino 3.09 (2.05, 4.67) <.001 History of TIA/Stroke 1.80 (1.44, 2.26) < (1.28, 4.32) Permanent AF Spontaneous echo contrast visualized* Paroxysmal AF 2.77 (1.77, 4.33) < (1.21, 4.30) (1.22, 1.99) < (0.23, 0.69) <.001 Post-implant residual jet size (mm) 1.26 (1.09, 1.44) LVEF 0.96 (0.93, 0.99) (0.94, 0.99) CHF 1.51 (1.08, 2.10) History of Smoking 0.72 (0.55, 0.95) Vascular disease 1.89 (0.92, 3.90) (1.08, 3.91) # Full Device Recaptures 1.13 (0.98, 1.31) Variable Overall DRT rate: 3.7% Dukkipati SR et al. Circulation Multivariable Analysis P-value Odds Ratio (95% CI) P-value 1.06 (1.01, 1.12) <.001 PROTECT-AF, PREVAIL, CAP, CAP-2

29 LAA Closure: Unanswered Questions Device-related thrombus Optimal post-procedural medical regimen

30 DRT In EWOLUTION Stratified By Post-Implant Pharmacology Regimen Event rates too small and too many confounders to render conclusions Bergman MW et al, EuroIntervention 2017;13:

31 LAA Closure: Unanswered Questions Device-related thrombus Optimal post-procedural medical regimen LAA closure in patients contraindicated for OAC

32 ASAP-TOO Randomized Clinical Trial Study Objective Study Design Evaluate LAA Closure with WATCHMAN in NVAF patients deemed not suitable for OAC Prospective, multi-center Randomized 2:1 (Watchman vs Control) Effectiveness Endpoint Time to first occurrence of ischemic stroke or systemic embolism Primary Endpoint Safety Endpoint 7-day rate of all-cause death, ischemic stroke, systemic embolism, or device- or procedure- related events requiring open cardiac surgery or major endovascular intervention Patient Population 888 Number of Sites 100 global sites Follow-up* Holmes et al. AHJ 2017;189: month with TEE 6,18 month phone visit 12 month with TEE Bi-annually for years 2-5

33 ASAP-TOO: Device Group Medication Therapy Visit Interval Aspirin Clopidogrel* Discharge through 3-month visit Yes, suggested dose: mg Yes, suggested dose: 75mg 3-month visit through 12-month visit Yes, suggested dose: mg No, unless other indication No, unless other indication No, unless other indication Following the 12-month visit *Clopidogrel may be substituted with ticagrelor or prasugrel if the subject requires the medication for other indications (e.g. acute coronary syndromes treated with drug eluting stents) or if the subject has a known resistance to clopidogrel. **Patients are allowed to be on dual antiplatelet therapy (outside of the protocol required 3- months period) if indicated due to a condition other than WATCHMAN implantation. Holmes et al. AHJ 2017;189:

34 LAA Closure: Unanswered Questions Device-related thrombus Optimal post-procedural medical regimen LAA closure in patients contraindicated for OAC LAA closure compared with NOACs?

35 LAAC Trials involving NOACs in Control Arms CLOSURE AF N=1512 at ~50 centers in Germany RCT LAAC (WM or Amulet) vs medical therapy (NOAC or APT), CHADS-VASC2 2 and at least one of the following: - HASBLED 3, History or major bleed, or 15 GFR 30 Primary endpoint: Cardiac death/stroke/se/major bleed at 24 months ~30 patients enrolled to date data presentation potentially late 2022 PRAGUE-17 N=400 RCT LAAC vs NOAC in AF patients with one of the following: History of significant bleeding, CHADS-VASC2 3 and HASBLED 2, or history of cardioembolic event while on OAC Primary endpoint: CV death, stroke, SE, major bleed or significant device or procedure related event (including tamponade, embolization, significant peri-procedural bleed, procedural cardioembolic event and device thrombus with embolism) at 1 year >300 patients enrolled to date data presentation potentially late 2019

36 My Decision Making Scheme for Stroke Prevention Therapy in AF AF patient at high thromboembolic risk by CHA2DS2VASC score Low bleeding risk, compliant, can afford therapy, no strong patient preferences NOAC Not good candidate for long-term OAC (prior bleed, bleeding risk, on APT, non-compliant, treatment failure, poor VKA candidate & can t afford/take NOAC) but can tolerate short-term therapy Commercial Watchman LAA Closure Absolute or strong contraindication to even short-term OAC ASAP-TOO (WM vs no therapy)

37 Summary AF patients at thromboembolic risk are under-treated LAA closure provides comparable results to warfarin for the prevention of all stroke events Superiority for hemorrhagic stroke and for CV death Real world registries: Suggest procedural safety has improved substantially Substantial reduction in bleeding events after post-procedure adjunctive pharmacotherapy regimen was complete Curves continue to diverge Overall benefit with LAA closure would be expected to increase over time Unanswered questions: OAC contraindicated; newer devices (AMULET); comparison with NOACs

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