Disclosure Left Atrial Appendage Closure SentreHeart, Inc - - PDF document

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Left Atrial Appendage Closure – Identifying the Patients Who Will Benefit the Most

Disclosure SentreHeart, Inc

• Consultant
• Equity holder

A cardiac disease that kills by producing emboli The most severe consequence of AF is potentially life threatening embolic events

It’s Not the Answer Too little = Stroke Too much = Hemorrhage

INR 1 2 3 4 5

TARGET

WARFARIN

Risks increase with age Low compliance Contraindications

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Endocardial vs Pericardial

No LA foreign body Ease of Use Closure Efficacy Complications

LAA Closure Devices Available in the US

Watchman is FDA approved for stroke prevention Atriclip and LARIAT are FDA approved, but not for stroke prevention Watchman Atriclip LARIAT

WATCHMAN Clinical History

In the US, WATCHMAN is an investigational device, limited by applicable law to investigational use only and not available forsale. CE Mark 2005

CAP Registry 566 pts, 26 sites PREVAIL 400 pts, < 50 sites Significantly improved safety results Improved success and procedural safety confirmed with new and experienced operators PROTECT-AF 800 pts, 59 sites Watchman device was non-inferior to warfarin in preventing strokes; FDA concerned with acute safety events PROTECT-AF Long-term F/U Superior to warfarin for primary efficacy, CV death, and all-cause mortality at 4 years

PROTECT AF 4 Year: CV and All-Cause Mortality

Reddy, VY et al. JAMA. 2014; 312(19):1988-1998.

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Watchman FDA Approval

• Are at increased risk for stroke and systemic embolism

based on CHADS2 or CHA2DS2-VASc scores and are recommended for anticoagulation therapy

• Are deemed by their physicians to be suitable for warfarin
• 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.

This device is indicated to reduce the risk of thromboembolism from the left atrial appendage (LAA) in patients with non-valvular atrial fibrillation who:

INDICATIONS FOR USE

• Intracardiac thrombus is visualized by echocardiographic

imaging.

• An ASD repair or closure device or a PFO repair or closure

device is present.

• The LAA anatomy will not accommodate a device Any of the

customary contraindications for other percutaneous catheterization procedures (e.g., patient size too small to accommodate TEE probe or required catheters) or conditions (e.g., active infection, bleeding disorder) are present.

• There are contraindications to the use of warfarin, aspirin, or

clopidogrel.

• The patient has a known hypersensitivity to any portion of the

device material or the individual components

Watchman FDA Approval

CONTRAINDICATIONS

Dabigatran Rivaroxaban Apixaban

Mechanism Direct Thrombin Inhibitor Factor Xa Inhibitor Factor Xa Inhibitor Dose 110 mg or 150 mg 2x/ day 20 mg/day 5 mg 2x/ day *2.5 mg 2x/day Efficacy in preventing embolic events Superior (150 mg) Noninferior (110 mg) noninferior superior Hemorrhagic stroke Significantly less (110 mfg) More (150 mg) at less less GI bleeding Not specified (110mg) Major GI bleeding Epitaxis and hematuria less All bleeding events Less (at 110 mg) Similar (at 150mg) less *2.5 mg twice daily if two or more: age >80, weight <60 kg or Cr > 1.5 (25% renal excretion). Excluded if Cr > 2.5

Oral Anticoagulants DISCONTINUATION RATES

5 10 15 20 25 RE-LY ARISTOTLE ROCKET-AF

NOAC Warfarin

Rivaroxaban NEJM 2011;365:883-91 Apixaban NEJM 2011;365:981-92 Dabigatran NEJM 2009;361:1139-51

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Potential Incidence of Major Bleeding

Anticoagulatant Annual Rate for Major Bleed *Potential number of patients >65 yo with major bleeding/year (x1000) Dabigatran 150 mg 2x/day 3.32% 60.4 Rivaroxaban 15 – 20 mg/day 3.6% 65.6 Apixaban 5 mg 2x/day 2.13% 38.8 Warfarin 3.09% - 3.57% 56.2 - 65.0

Wallentin, L., 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. Lancet, 2010, 376(9745), 975-983. Patel, M. R., et al.. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med, 2011, 365(10), 883-891. Granger, C.B., et al., Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med, 2011. 365(11): p. 981-92.

*Assumes 50% of AF patients treated with AF on OAC

• 82 year old woman with

paroxsysmol AF

• History of both ICH and

cardioembolic stroke, hypertension

• TEE reveals LAA thrombus

Patients with Limited to NO options

Patients with contraindications to OAC therapy

Stroke and Bleeding Risk in Patients with AF and OAC Contraindications

Bjorn Redfors, MD, PhD, William A. Gray, MD, Randall J. Lee MD, Kenneth A. Ellenbogen MD, Machaon Bonafete PhD, PhD, Ori Ben-Yehuda, MD

Presented by Ben-Ydhuda at TCT 2015

2 4 6 8 10 12 14 16 18 20

%

Study population Adjusted stroke rate in the general AF population (adapted from Lip et al. ‡)

Ischemic Stroke : AF and previous Intracranial bleeding as contraindication for OAC (n=5,441) by CHADS2-VASC

n=141

1

n=330

2

n=642

3

n=1,202

4

n=1,330

5

n=883

6

n=593

7

n=272

8

n=47

9

n=1 ‡Stroke 2010;41(12):2731-8

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Bleeding Rates- by CHADS2

0.0% 2.0% 4.0% 6.0% 8.0% 10.0% 12.0% 14.0% 16.0% 1 2 3 4 5 6

Bleeding

CHADS2 Score

n=5,693 n=12,017 n=15,071 n=6,191 n=3,033 n=1,162 n=81

Gastrointestinal, genitourinary, or respiratory tract bleeding that required transfusion or surgical intervention.

Incidence and Outcomes of Patients with Atrial Fibrillation and Major Bleeding Complications: Findings from the TREAT-AF Study

• In the mean follow-up of 4.2 years, 11.5% of patients had

a major bleed

• Patients with prior bleeding complications had greater

risk of subsequent events including TIA, ischemic stroke, repeat bleeding events, and death.

• OAC started in 25% within 90 days of major bleeding

event and was associated with a reduced stroke risk (HR 0.85), reduced risk of death (HR 0.88), and increased risk of major bleed (HR 1.49).

Daniel W. Kaiser MD1, Randall J. Lee MD PhD2, Jun Fan MS3, Susan S. Schmitt PhD3, Mintu P. Turakhia MD MAS FACC1,3

1Department of Medicine, Stanford University School of Medicine (Stanford, CA); 2University of California San Francisco 3Veterans Affairs Palo Alto Health Care System (Palo Alto, CA)

Presented by Kaiser at ACC 2015

Watchman

Reddy et al JACC 2013

ACP

Tzikas et al EuroIntervention 2015

LARIAT

Sievert et al JACC EP 2015

Number of patients 150 1,047 139 Age 72.5 7.4 75±8 67±11 Mean CHADs2 score 2.8 1.2 4.43 2.4 +1.2 Mean follow-up 14.4 + 8.6 months, 13 months 35 + 12 months Patient-years 176.9 1,349 401 Absolute # strokes/systemic embolism 4 (stroke) 9 (strokes), 9 (TIA) 31 (systemic embolism) 4 (strokes) Event rate (patient- years) 2.3% 0.7% stroke 0.7% TIA 2.3% systemic embolism 1%

LAA Exclusion in OAC Contraindicated Patients

Watchman Safety Profile

Boersma et al. Eur Heart J. 2016

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Acute & Longterm Outcomes of Percutaneous Left Atrial Appendage Suture Ligation: Results From A United States Multicenter Evaluation

Lakkireddy et al. Heart Rhythm 2016 0.2% 0.2% 0.7% 0.5% 0.0% 0.5% 2.0%

0.0% 1.0% 2.0% 3.0% 4.0% 5.0% 6.0% Procedural Related Mortality Pts requiring surgery Cardiac Perfs (no surgery) Pts needing transfusion Peri-procedural stroke Structural Injury All Complications

• Multicenter registry. 18 US centers.
• Safety results of 424 consecutive LARIAT procedures.
• Micropuncture access technique utilized

Restore Maintain Protect

Electrical Isolation LAA Exclusion

Merits of an Epicardial LAA Closure Approach

Thoracoscopic Appendage Exclusion With an Atriclip Device As a Solo Treatment for Focal Atrial Tachycardia

Stefano Benussi, Patrizio Mazzone, Giuseppe Maccabelli, Pasquale Vergara, Antonio Grimaldi, Alberto Pozzoli, Pietro Spagnolo, Ottavio Alfieri, and Paolo Della Bella Circulation 123(14):1575-1578, 2011

Clinical success of various ablation techniques for persistent/long-standing persistent atrial fibrillation

Brooks AG, et al. Outcomes of long standing persistent AF: A systematic review. Heart Rhythm. 2010; 7:835-46

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Catheter Ablation of Long-Standing Persistent Atrial Fibrillation

5-Year Outcomes of the Hamburg Sequential Ablation Strategy Roland Richard Tilz, MD, Andreas Rillig, MD, Anna-Maria Thum, Anita Arya, MD, Peter Wohlmuth,Andreas Metzner, MD, Shibu Mathew, MD, Yasuhiro Yoshiga, MD, Erik Wissner, MD, Karl-Heinz Kuck, MD, Feifan Ouyang, MD JACC 2012;60:1921–9.

After the first ablation procedure, sinus rhythm was documented in 41 of 202 (20.3%) patients. After multiple procedures, sinus rhythm was maintained in 91

• f 202 (45.0%) patients

Fibrillating Areas Isolated within he the Left Atrium after Radiofrequency Linear Catheter Ablation

Rostock…..Haissaguerre JCE 17:807-812, 2006

Conversion of Persistent Atrial Fibrillation to Sinus Rhythm After LAA Ligation

Badhwar et al., HRS abstract 2015 Courtesy of David Wilbur

• Multi-center, prospective randomized

superiority trial

• Comparing LAA ligation and PVI versus

PVI in patients with persistent and longstanding persistent AF

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Participating Study Sites

Bryn Mawr Mass General NYU Southside Valley Yale Loyola Northwestern Vanderbilt Austin Heart Baylor-St. Luke’s UT San Antonio MUSC USCF Santa Barbara Cottage Scripps KUMC UCSD

• St. Vincent’s

Albany Med U of Utah Oshner Rogue Valley Emory Fairview Southdale / UofM UPMC Ohio St John Hopkins

Case Discussions

Case 1

• 72 yo woman with persistent AF.
• Intolerant to OAC due to fall risk and

hx of traumatic injury

• Hx of prior cardioembolic stroke, DM,

HTN and CABG

Case 1

• Recommend LAA occlusion device
• CABG is a contraindication to the

LARIAT procedure

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Case 2

• 68 yo man with PAF
• Hx of ICH, HTN,DM

Case 2

• Consider LARIAT or Atriclip
• Watchman requires at least 45 days
• f warfarin therapy post-implantation

Triple Therapy: Benefit vs Risks

• Stent thrombosis: highest in the early phase

after PCI

• Bleeding: risk of bleeding with triple therapy

increases with duration of therapy

Should We Recommend Oral Anticoagulation Therapy in Patients With Atrial Fibrillation Undergoing Coronary Artery Stenting

Case 3

• 65 yo man with persistent AF
• Hx of recent stent on ASA and plavix
• Hx of DM, HTN

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Case 4

• 87 yo woman with PAF
• Hx of both ICH and cardioembolic

stroke, HTN

• TEE reveals LAA thrombus

Case 5

• 63 yo man with PAF
• Hx HTN

Major Registry Studies Comparing Bleeding on Combinations of Antiplatelet and OAC Therapy

Study

• No. of

Patient s Follow

• up, y

ASA Clopidogrel DAPT OAC OAC + ASA OAC + Clopi dogrel TOAT Buresly et al 21 443 1.8 3.2 NA 6.8 5.9 8.3 NA 8.5 Sørensen et al 40 812 1.3 2.6 4.6 3.7 4.3 5.1 12.3 12.0 Lamberts et al 11 480 1.0 7.0 6.6 7.0 7.0 9.5 10.6 14.2 Hansen et al 118 60 6 3.3 3.7 5.6 7.4 3.9 6.9 13.9 15.7 Clinical Cardiology 36: 585-594, 2013

Unexpectedly High Incidence of Stroke and Left Atrial Appendage Thrombus Formation after Electrical Isolation of the Left Atrial Appendage for Treatment of Atrial Tachyarrhythmias: An undescribed and under recognized complication

• f left atrial catheter ablation

Andreas Rillig , MD, Roland R. Tilz, MD, Tina Lin, MD, Christian Heeger, MD, Anita Arya, PHD, Andreas Metzner, MD, Shibu Mathew, MD, Erik Wissner, MD, Hisaki Makimoto, MD, PHD, Peter Wohlmuth, Karl-Heinz Kuck, MD, Feifan Ouyang, MD LAA thrombus

Mechanical standstill Thrombus formation

LAA thrombus in 21%, and three patients had a stroke while on OAC

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AF Stroke Prevention and Coronary Events

Adapted from ACCP guidelines (You at al, Chest 2012

Long term follow-up from the Prevail Trial

• The results of PROTECT AF and PREVAIL appear to be

diverging, which introduces challenges in the interpretation of results of the pre-specified Bayesian analysis.

• PROTECT AF demonstrated a benefit of the WATCHMAN

device driven by a reduction in hemorrhagic stroke rate; however, the Control group hemorrhagic stroke rate was substantially higher than observed in contemporary anticoagulation trials, and there are questions regarding the robustness of this potential benefit.

0% 2% 4% 6% 8% 10% 12% 14% 16% 18% 20% 1 2 3 4 5 6

CHADS2 score Event Rate (% patient-years)

CHADS2 score of the LARIAT Population

National Registry of AF Stroke rate National Registry of AF Stroke rate with ASA

6.2% Expected ER Observed ER: 1% Reduction of 80% N=139 patients Mean F/U 2.9 +/- 1.1 years 405 patient-years

LAA ligation in patients with contraindications to OAC therapy

Sievert et al., JACC EP 2015 Figure 2: Kaplan-Meier Curves A B

Kaplan-Meier Curves

Survival Stroke

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Tzikas et al EuroIntervention 2015 5.62% 2.30%

• 58%

6.0 5.0 4.0 3.0 2.0 1.0

% Effectiveness in Stroke Reduction vs. Estimated

Estimated based on CHA2DS2-VASc score Observed rate in study

LARIAT device in AF patients with contraindications to OAC

Reddy and Sievert et al., JACC 61: 2551–6, 2013

Watchman device in AF patients with contraindications to OAC

Expected rate: 7.3% Observed ischemic stroke rate 1.7% 77% reduction in stroke rate

Preadmission medications with known AF & were admitted with acute ischemic stroke (high-risk cohort, n=597) Preadmission medications in patients AF and a previous ischemic stroke/TIA who were admitted with acute ischemic stroke (very high-risk cohort, n=323).

• Stroke. 2009;40:235-240

Warfarin use decreases with increasing age & stroke risk

Journal of Thrombosis and Haemostasis, 6: 1500–1506

UK General Practice database n= 41,910

Proportion of patients persisting with warfarin

Journal of Thrombosis and Haemostasis, 6: 1500–1506

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Should we use LAA closure as an option to prevent stroke

• Medical rationale
• Efficacy
• Safety
• Reimbursement

Long term follow-up from the Prevail Trial

• Greater event rate of embolic stroke and systemic embolism in the

Watchman arm compared to the control

• The new ischemic strokes in the updated PREVAIL dataset occurred

more than 1 year post-WATCHMAN implantation, raising questions about long-term device effectiveness.