Intracardiac Devices for Stroke Prevention: The Heart Brain Team

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1 Intracardiac Devices for Stroke Prevention: The Heart Brain Team CREIGHTON W. DON, MD, PHD ASSOCIATE PROFESSOR OF MEDICINE DIRECTOR, INTERVENTIONAL AND STRUCTURAL HEART FELLOWSHIPS DIVISION OF CARDIOLOGY UNIVERSITY OF WASHINGTON

3 The heart and brain Heart attacks Brain attacks PCI for acute MI Mechanical thrombectomy for stroke

4 Where do strokes come from? Cardioembolic strokes 20% of all stroke Atrial fibrillation atrial clots LV dysfunction LV clots Valvular disease Venous clot, passing through heart PFO (Patent foramen ovale)

5 Devices for stroke reduction Left Atrial Appendage Closure Patent Foramen Ovale Closure

6 Atrial Fibrillation and Stroke

7 Atrial Fibrillation Prevalence Prevalence 2.7 to 6.1 million in US Underestimated Subclinical afib 10-30% patients 65 yrs Ischemic stroke HR 2.50 ~20% for patients 80 years Mozaffarian D. Heart Disease and Stroke Statistics 2016 Update. Circulation. 2016

8 Atrial fibrillation and Stroke Risk Overall 4 to 5 fold increase in the risk for stroke Similar for paroxysmal, persistent, permanent Risk factor for stroke severity Age Prevalence Proportion of attributable risk Relative Risk Goldstein LB. Stroke Feb;42(2): Lin HJ. Stroke. 1996;27:

9 Proportional attributable risk: AFIB 30.0% Men Women 25.0% Atrial Fibrillation 20.0% 15.0% 10.0% 5.0% 0.0% Mozaffarian D. Heart Disease and Stroke Statistics 2016 Update. Circulation. 2016

10 Left Atrial Appendage and Stroke

11 70 year old with stroke HTN Dyslipidemia Amyloidosis Renal Insufficiency Myocardial Infarction LV dysfunction EF 45% Atrial fibrillation

12 Mechanisms of Stroke with Atrial Fibrillation Stasis of blood Spontaneous echo contrast Increased thrombus with larger left atria Left atrial appendage anatomy LAA Courtesy Mark Reisman. Seattle Science Foundation

13 Thrombus location Approximately 75% of embolic events in afib are from atrial thrombi Rheumatic atrial fibrillation Thrombus in LA appendage: 57% Non-rheumatic atrial fibrillation Thrombus in LA appendage: 91% Study N LA Appendage LA chamber TEE TEE Autopsy TEE TEE TEE + surgery TEE (SPAF 3) TEE TEE Total Blackshear JL. Annals of Thoracic Surg

14 Left atrial appendage anatomy and risk for embolism Morphology Number of lobes Shape of lobes Volume Tribeculation Flow velocity

15 Left Atrial Appendage Anatomy Chicken Wing Windsock Cactus Cauliflower Don C et al. Catheter Interventions for Structural Heart Disease

16 LAA Morphology and Stroke Risk CHADS2 Stroke risk 1yr to 1.7% to 2.2% to 7.9% Goldstein LB.Stroke Di Baise L. JACC

17 Atrial Fibrillation and Anticoagulation

Anticoagulation and stroke reduction Treatment Placebo 8.0% 7.

18 Anticoagulation and stroke reduction Treatment Placebo 8.0% 7.4% Stroke Incidence 6.0% 4.0% 2.0% 2.3% 3.6% 6.3% 2.9% 3.1% 3.0% 2.3% 2.6% 2.2% 4.2% 4.5% 0.0% SPAF Investigators. Circulation. 1996; Patel MR. NEJM. 2011; Granger CB. NEJM. 2011; Giugliano RP. NEJM Don C et al. Catheter Interventions for Structural Heart Disease Adapted from Go AS et al. JAMA 2003.

19 Undertreatment causes strokes

Difficult to manage 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 19% 48% % of Patients Within INR Range 1 54% 33% 37% 9% 11% 2 3 63% 27% Group Health Cooperative Kaiser Permanente SC ATRIA Below INR

20 Difficult to manage 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 19% 48% % of Patients Within INR Range 1 54% 33% 37% 9% 11% % 27% Group Health Cooperative Kaiser Permanente SC ATRIA Below INR Range Within Range Above Range INR 3+ 44% of bleeding events INR % of embolic events Warfarin is #1 cause for emergency hospitalizations due to adverse drug events 1 Glazer NL, Arch Intern Med (2007) 2 Shen AY, J Am Coll Cardiol (2007) 3 Go AS, JAMA (2003) 4 Rudnitz ME, Annals of Int Med (2007)

Left atrial appendage closure Warfarin Use by CHADS 2 Score Medicare claims data, 2006-2007 AF Patients Using Warfarin 100% 80% 60% 40% p < 0.

21 Left atrial appendage closure Warfarin Use by CHADS 2 Score Medicare claims data, AF Patients Using Warfarin 100% 80% 60% 40% p < (n=27,164) 20% 0% CHADS 2 Score Piccini, et al.. Pharmacotherapy in Medicare beneficiaries with atrial fibrillation. Heart Rhythm. 2012;9: J Thromb and Haemostasis.

22 Underutilization of anticoagulation 100% 90% Anticoagulant Use in Patients with NVAF and CHADS % 70% 60% 50% 40% 30% 20% Total on Oral Anticoagulation Warfarin DOACs 10% 0% 2011 Q Q Q Q Q Q Q Q4 n=25719 n=29194 n=31582 n=36490 n=67102 n=70667 n=70320 n=71396 Results from the NCDR PINNACLE Registry 1 1. Jani, et al. Uptake of Novel Oral Anticoagulants in Patients with Non-Valvular and Valvular Atrial Fibrillation: Results from the NCDR-Pinnacle Registry. ACC 2014

23 DOAC discontinuation clinical trials 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% 3.1% 33 % / 34% 2.8% / 1.6% Warfarin % % 1. Connolly, S. NEJM 2009; 361: Patel, M. NEJM 2011; 365: yrs follow-up, ITT 3. Granger, C NEJM 2011; 365: yrs follow-up, 4. Giugliano, R. NEJM 2013; 369(22): yrs follow-up.

24 DOAC discontinuation real world Martinez C, et al. Therapy Persistence in Newly Diagnosed Non-Valvular Atrial Fibrillation Treated with Warfarin or NOAC. A Cohort Study. Thromb Haemost Dec 22;115(1):31-9.

25 LAA LAA Closure and Stroke Prevention

mm diameter Transseptal puncture TEE guidance 30-60

26 Watchman LAA closure device 160 Micron Membrane Percutaneous femoral venous Sizes: 21, 24, 27, 30, 33 mm diameter Transseptal puncture TEE guidance min procedure Overnight hospitalization Nitinol frame with Anchors

27 Left Atrial Appendage Closure TEE planning

28 Left Atrial Appendage Closure

29 Left Atrial Appendage Closure

30 Left Atrial Appendage Closure

31 Left Atrial Appendage Closure Canine model 30 day Canine model 45 day Human pathology - 9 months (non-device related death)

32 PROTECT-AF Trial Randomized study of LAAO (Watchman) vs. Warfarin 2:1 707 Patients with CHADS2 1 Mean 2.2 to 2.3 Patients randomized to Watchman Warfarin for 45 days ASA + Clopidogrel 6 months ASA indefinitely

Left atrial appendage closure PROTECT AF:

33 Left atrial appendage closure PROTECT AF: 4-year results 16.0% 14.0% 12.0% * 13.9% Device Warfarin * 13.0% 11.1% % Patients 10.0% 8.0% 6.0% 4.0% 2.0% 0.0% 8.4% 8.2% 5.6% 5.2% 4.1% 4.1% 4.5% 1.7% 0.6% 3.7% 9.0% Reddy, VY et al. JAMA. 2014;312(19):

34 PROTECT-AF Trial: Mortality Reddy, VY et al. JAMA. 2014;312(19):

35 Left atrial appendage closure PROTECT AF: 4-year results Reddy, VY et al. JAMA. 2014;312(19):

36 Safety Endpoints 74% of safety events were periprocedural (within 7 days) Reddy, VY et al. JAMA. 2014;312(19):

37 WATCHMAN Clinical Studies 2002 Pilot study, non-randomized 2005 PROTECT AF (WATCHMAN v. warfarin) 2008 CAP registry (continuing access) 2009 ASAP (non-randomized in non-warfarin candidates) 2010 PREVAIL (WATCHMAN v. warfarin, new operators) 2012 CAP2 registry (continuing access) 2013 Asia/EU registry 2014 PREVENT (US Registry) Total ~2,400 patients and 6,000 patient-years of follow-up

38 Left Atrial Appendage Closure Learning Curve 12.0% 10.0% 9.9% PROTECT AF v. PREVAIL Pericardial effusion 4.0% v. 1.4% Periprocedure CVA 1.1% v. 0% Patients with Safety Event (%) 8.0% 6.0% 4.0% 4.8% 4.1% 4.1% 3.8% 2.8% 2.0% 0.0% PROTECT AF CAP PREVAIL CAP2 Ewolution N=232 N=231 N=566 N=269 N=579 1 st Half 2 nd Half N=1019

39 Procedural Complications 5.00% 4.00% 3.00% 2.00% 1.00% 0.00% PROTECT AF (n=463) CAP (n=566) PREVAIL (n=269) CAP2 (n=579) EWOLUTION (n=1021) US Cohort (n=3822) Pericardial Tamponade Procedure-Related Stroke Device Embolization Procedure-Related Death

40 5 year outcomes meta-analysis PROTECT AF/PREVAIL Reddy VY et al. J Am Coll Cardiol Dec 18;70(24):

41 DOACs and Warfarin Ruff et al: Lancet 383: 955, 2014

2% 4.5% 5.6% 8.2% 4.4% 3.0% 0.0% SPAF Investigators. Circulation.

42 Anticoagulation and stroke reduction Treatment Placebo Stroke Incidence 10.0% 8.0% 6.0% 4.0% 2.0% 2.3% 7.4% 3.6% 6.3% 2.9% 3.1% 2.3% 2.6% 3.0% 2.2% 4.2% 4.5% 5.6% 8.2% 4.4% 3.0% 0.0% SPAF Investigators. Circulation. 1996; Patel MR. NEJM. 2011; Granger CB. NEJM. 2011; Giugliano RP. NEJM

0% 0.0% HTN--SHEP LAA closure (3.8 yr f/u) LAA closure (2 yr f/u) 1.

43 Clinical trials of stroke reduction Treatment Placebo 9.0% 8.0% 8.2% 8.2% 7.0% % Stroke 6.0% 5.0% 4.0% 3.0% 5.2% 5.6% 3.0% 4.4% 2.0% 1.0% 0.0% HTN--SHEP LAA closure (3.8 yr f/u) LAA closure (2 yr f/u) 1.1% 1.0% 1.2% Physician's Health Study 1.4% HPS 5y 0.3% 0.7% JUPITER

44 Absolute stroke reduction 6.0% 5.0% 5.1% 4.0% 3.0% 2.7% 3.0% 2.6% 2.0% 1.0% 0.0% 1.4% 0.7% 0.6% 0.5% 0.3% 0.3% 0.2%

Stroke Rate Imputed Ischemic Stroke Rate* 6.9 7.1 6.2 2.3 1.

45 Hypothetical benefit vs. No Therapy Ischemic Stroke Risk % (Events/100 Patient-Years) Observed WATCHMAN Ischemic Stroke Rate Imputed Ischemic Stroke Rate* PROTECT AF PREVAIL Only CAP Baseline CHA 2 DS 2 -VASc = 3.4 Baseline CHA 2 DS 2 -VASc = 3.8 Baseline CHA 2 DS 2 -VASc = 3.9 * Imputation based on published rate with adjustment for CHA 2 DS 2 -VASc score (3.0); Olesen JB. Thromb Haemost (2011)

46 HAS-BLED Score Risk Factor Score Hypertension (SBP >160) 1 Abnormal renal/liver function 1-2 Stroke 1 Bleeding 1 Labile INR 1 Elderly (>65) 1 Drugs that increase bleeding/alcohol 1-2 Lip et al: Chest 137:263, 2010; Camm AJ et al: Eur Heart J 31:2369, 2010

47 Stroke reduction versus bleeding CHA 2 DS 2 -VASc* Score Annual % Stroke Risk HAS-BLED** Score Annual % Bleed Risk 10-Year Bleeding Risk (%)*** AHA / ACC / HRS Guidelines ** Lip. JACC (2011)

48 HAS-BLED score % Major Bleeding per 100 Patient Years HAS-BLED Observed Major bleeding: hospitalization for >2 unit hgb decrease or hemorrhagic stroke 0 Pisters R. Chest Journal

49 Clinical Practice Difficulty maintaining anticoagulation High bleeding risk Older, frail patients with multiple comorbidities and polypharmacy with bleeding risks Younger patients with long-term, lifetime risk for bleeding CHADS2-VASC 2 and high HAS-BLED 3

50 Patent Foramen Ovale Closure

PFO and stroke association PFO present in about 25% of the general population About 40-50% in patients with cryptogenic stroke Meta-analysis of case-control studies evaluating the association of

51 PFO and stroke association PFO present in about 25% of the general population About 40-50% in patients with cryptogenic stroke Meta-analysis of case-control studies evaluating the association of stroke and PFO 2020 control v stroke patients Any stroke OR 1.83 ( ) Cryptogenic stroke OR 2.95 ( ) PFO+ASA OR ( ) Age 55 Overell JR. Neurology (8)

52 Just a hypothesis? 60 yo man with embolic stroke

53 Clergeau, et al. Stroke. 2009;40(12): Kent DM. Neurology. 2013; Aug 13; 81(7): Paradoxical Emboli Right to left shunting of venous thrombus 60 patients with pulmonary emboli 6 patients with acute emboli on MRI 33% of patients with a PFO had emboli (5 of 15) 2.2% of patients without PFO had emboli (1/45) If you had brain emboli, 83% chance you had a PFO ROPE Score RoPE Score Prevalence of PFO 2y Stroke/TIA recurrence 7 54% 6% 8 67% 6% % 2%

54 But is the heart the right target? CLOSURE 1 PC RESPECT CLOSE RESPOND

55 CLOSURE-1 P = 0.37 Stroke or TIA in prior 6 months PFO on TEE Age subjects randomized 1:1 PFO closure with NMT Starflex device Medical therapy with ASA and/or Warfarin PFO Closure Medical Therapy P-value Stroke/TIA/Death 5.5% 6.8% 0.37 Stroke 2.9% 3.1% 0.79 TIA 3.1% 4.1% 0.44 Major vascular compl. 3.2% 0.0% <0.01 Major bleeding 2.6% 1.1% 0.11 Atrial Fibrillation 5.7% 0.7% <0.01 Furlan AJ. NEJM. 2012; 366:

56 PC Trial 414 patients with cryptogenic stroke within 1 year imaging verified Age 60 PFO on TEE PFO Closure Medical Therapy P-value Stroke/TIA/Death 3.4% 5.2% 0.34 Stroke 0.5% 2.4% 0.14 TIA 2.5% 3.3% 0.56 Major bleeding 0.5% 1.4% 0.62 Atrial Fibrillation 2.9% 1.0% 0.17 Meier B. NEJM. 2013; 368:

57 Take and aspirin and call me when you prove it works STEVEN MESSE, MD

58 RESPECT 980 patients with cryptogenic stroke imaging verified Age 60 PFO on TEE PFO Closure Medical Therapy P-value Major bleeding 0.4% 0.4% NS Atrial Fibrillation 0.2% 0.2% NS Carroll J. NEJM. 2013; 368:

59 RESPECT trial: extended outcomes Strokes 3.6% v 5.8% (p 0.046) Saver JL. NEJM. 2017; 377:

60 RESPECT Extended Follow-up Carroll JD. TCT

61 RESPECT Extended Follow-up Carroll JD. TCT

62 REDUCE 664 patients with cryptogenic stroke and PFO Randomized to 2:1 to Helex/Cardioform v. antiplatelet tx Sondergaard L. NEJM. 377:

63 CLOSE trial 663 pts with cryptogenic stroke and PFO with ASA or large shunt PFO closure (open label) v. ASA v. anticoagulation Stroke 0% v. 6.2% v. 1.4% Mas JL. NEJM. 377:

64 PFO Closure: Procedural Complications RESPECT CLOSE REDUCE CLOSURE-1 Stroke 0.4% 0.0% 0.0% 0.7% Atrial fibrillation 0.4% 4.6% 6.6% 5.7% Major Bleeding/Vasc 0.4% 0.8% 0.9% 3.2% Residual shunt 0.4% 5.5% 13.9% Device embolization 0.0% 0.0% 0.5% 0.0% Death/disability 0.0% 0.0% 0.0% 0.0% Furlan AJ. NEJM. 2012; 366: Carroll J. NEJM. 2013; 368: Sondergaard L. NEJM. 377: Mas JL. NEJM. 377:

65 What does this mean? FDA approval we will start seeing these patients Rates of recurrent cryptogenic stroke are low, but Potential benefit for PFO closure: Younger patients Atrial septal aneurysms Large shunts No other risk factors

66 RoPE Score Model derived from 12 studies of cryptogenic stroke Likelihood stroke related to PFO HTN Diabetes Smoker Prior Strokes Age RoPE Score Prevalence of PFO 2y Stroke/TIA recurrence % 20% 4 35% 12% 5 34% 7% 6 47% 8% 7 54% 6% 8 67% 6% % 2% Kent DM. Neurology. 2013; Aug 13; 81(7):

67 Future Directions

Heart Brain Teams Collaborative decision making Neurologists Accuracy of diagnosis Likelihood of stroke reduction with LAA/PFO closure Weighing

68 Heart Brain Teams Collaborative decision making Neurologists Accuracy of diagnosis Likelihood of stroke reduction with LAA/PFO closure Weighing relative benefit of medical v. device Cardiologists Anatomical risk of LAA/PFO Technical feasibility of procedure Evaluation of other cardioembolic sources

70 It s Not Like TAVR at All Challenges of Transcatheter Mitral Valve Therapies CREIGHTON W. DON, MD, PHD ASSOCIATE PROFESSOR OF MEDICINE DIRECTOR, INTERVENTIONAL AND STRUCTURAL HEART FELLOWSHIPS DIVISION OF CARDIOLOGY UNIVERSITY OF WASHINGTON

71 Cost Effectiveness Estimates $300 Dollars per Life Year or QALY ($thousands) $250 $200 $150 $100 $50 $0 aspirin MI prevention rosuvastatin high-crp ICD prim prev CRT-D v. medical Rx dabigatran AF PARTNER Cohort B AF ablation vs. AAD dialysis PCI stable CAD LVAD destination Rx

72 Epidemiology United States 1.7% of US population Olmstead County % Moderate to severe disease % Moderate to severe disease Nkomo VT. Et al. Lancet Sep 16;368(9540):

73 Percutaneous Valve Solutions MitraClip Percutaneous Valves TAVR in mitral Tiara (Neovasc), Tendyne, CardiAQ, Twelve

74 Percutaneous Annular Solutions Carillon (Cardiac Dimensions) Cardioband (Valtech) AccuCinch (Ancora Heart) Mitralign

75 Currently Available Therapies at UW High risk surgical patients Therapy MitraClip AccuCinch TIARA TAVR in Mitral Hybrid Surgical TAVR in Mitral Valvuloplasty Ideal patient Functional and degenerative MR with appropriate leaflet anatomy Functional MR Mitral regurgitation with appropriately sized annulus Mitral stenosis or mixed MR/MS Significant annular/leaflet calcification Moderate calcification Unfavorable LVOT-aortic-mitral relationship Rheumatic mitral stenosis without significant calcification

76 UW Clinical trials MITRAL AccuCinch TIARA

77 MITRAL Phase 1 study--calcific native mitral valve with annular calcification 90 patients with moderate-severe stenosis NYHA 2-4 Very high risk for surgery Outcomes Technical/procedural success Safety/MACE Mitral Regurg/PVL NYHA class, KCCQ, 6 min walk time, rehospitalizations

78 AccuCinch Phase I feasibility study 15 patients with moderate-severe FMR NYHA 2-4 High risk surgical candidate Outcomes Procedural/Technical success Safety at 1, 12 mo Hospitalizations, 6 min walk, QOL, NYHA class

79 TIARA Phase 1 study of patients 30 patients with severe mitral regurgitation High risk for surgery NYHA Class 2-4 Appropriate anatomy Outcomes Device success Mortality, stroke, MI, reintervention 1, 3, 6, 12 months Heart failure NYHA class, 6 min walk time, KCCQ

80 Tricuspid regurgitation Trialign

81 Tricuspid Valve

82 Tricuspid Valve Stenosis

83 Thank You Creighton Don (pager) Structural heart VALV (8258) Other interventional

Left Atrial Appendage Occlusion

Left Atrial Appendage Occlusion A new strategy to prevent stroke in atrial fibrillation Ashok Talreja MD and Arijit Chanda MD VHVI symposium 24th February 2018 Outline of presentation 1. Risk of stroke