transcatheter left atrial appendage occlusion for stroke prevention in atrial … cme... ·...

Transcatheter left atrial appendage occlusion for stroke prevention in

atrial fibrillation

Sajjad A Sabir, MD Director, Structural Heart Disease Program Director, Interventional Echocardiography

Director, Heart Valve Clinic

AF is a Growing Problem Associated with Greater Morbidity and Mortality

~5 M people with AF in U.S., expected to more than

double by 20501

AF = most common cardiac arrhythmia,

and growing AF increases risk of

stroke

5x greater risk of stroke

with AF2

<

• Higher stroke risk for older patients and those with prior stroke or TIA

• 15-20% of all strokes are AF-related

• AF results in greater disability compared to non-AF-related stroke

• High mortality and stroke recurrence rate

1. Go AS. et al, Heart Disease and Stroke Statistics—2013 Update: A Report From the American Heart Association. Circulation. 2013; 127: e6-e245. 2. Holmes DR, Atrial Fibrillation and Stroke Management: Present and Future, Seminars in Neurology 2010;30:528–536.

‘15 ‘20 ‘30 ’40 ‘50

5M

12M

Connection Between AF-Related Stroke and the Left Atrial Appendage

57%

91%

Rheumatic AFNon Rheumaitc AF

23 studies of AF patients (n = 3,504) 1

LAA Location

Thrombi localized to LAA

N=222

N=446

P<.0001

Per

cent

age

Pop

ulat

ion

(%) 100%

LAA Location

3,504

1. Blackshear JL, et al. Ann Thorac Surg 1996:61:755-759

Percutaneous LAA Occlusion Systems

WATCHMAN Amulet Lariat

Wavecrest LAmbre Occluetech

Presenter

Presentation Notes

The WATCHMAN is currently the only percutaneous occlusion device approved in the United States. Several devices including the Amplatzer, WATCHMAN, Wavecrest, LAmbre, Occlutech and LARIAT devices have the Conformite Europeenne (CE) mark of approval.

Nitinol Frame • Radially expands to maintain position

in LAA

• Available sizes: • 21, 24, 27, 30, 33 mm (diameter)

• 10 Active fixation anchors around device perimeter engage LAA tissue for stability and retention

• Features an intra-LAA design to avoid contact with Left Atrial wall

160 Micron Membrane • Polyethylene terephthalate (PET) cap

• Designed to block emboli from exiting the LAA

Anchors

160 Micron Membrane

Designed specifically for the left atrial appendage

WATCHMAN™ Left Atrial Appendage Closure (LAAC) Device Overview

Presenter

Presentation Notes

Speaker Notes: Constructed of a nitinol frame that radially expands to maintain position in the LAA, the WATCHMAN Device comes in five sizes to accommodate various patient anatomies. Ten fixation anchors around the perimeter of the device are designed to engage LAA tissue for stability. The nitinol frame is covered by a polyethylene terephthalate (PET) cap designed to block emboli from exiting the LAA. Over time, tissue grows over the face of the PET cap. The WATCHMAN Device is designed specifically for the left atrial appendage. Featuring an intra-LAA design to avoid contact with the left atrial wall, the WATCHMAN Device is engineered to (1) conform to the unique anatomy of the LAA to reduce embolization risk and (2) minimize the surface area facing the left atrium to reduce the risk of post-implant thrombus formation.

WATCHMAN™ Device Clinical Program

Significantly improved safety results2

Pilot Early feasibility with >6 years of follow-up

Enrolled up to 1500 patients at ~ 60 sites

CAP Registry

CAP2

WATCHMAN primary efficacy, CV death, and all-cause mortality superior to warfarin at 4 years1

Expected rate of stroke reduced by 77% in patients contraindicated to warfarin3

Improved implant success; procedure safety confirmed with new and experienced operators4

PROTECT-AF

ASAP

PREVAIL

1 Reddy, VY et al. HRS 2013.. 2 Reddy, VY et al. Circulation. 2011;123:417-424; 3 Reddy, et al. JACC. 2013; In Press. 4 Holmes, DR Jr et al., CIT 2013

Pilot Study

• 66 patients implanted at 8 sites in U.S.& Germany – out of 75 attempted • 2 procedural – scar in groin, wire

malfunction

• 7 unsuitable anatomy

• 93% complete closure at 45 days

• 333 patient years of follow-up

• Mean follow-up 58 + 17 months

Courtesy of Dr. Turi

Stroke Rate

• Estimate risk based on CHADS2 score of 1.9: – 4.0 %

• Actual Stroke Rate – 0.6 %

(85% reduction compared to historical control)

Complications – Device Version 1.0

• 2 tamponades • 3 effusions • 1 air embolism - CPR • 1 delivery wire fracture – surgical removal • 2 device embolizations (retrieved) • 4 thrombus layer at 6 months

– Anticoagulation – resolved – Protocol added clopidogrel at 45 days

• 2 TIAs – 1 with thrombus • 1 non-device related death at 9 months

WATCHMAN LAA Closure Device for Stroke Prophylaxis and Atrial Fibrillation

PROTECT-AF Trial

Multicenter, prospective, randomized, unblinded trial

Anticoagulation and Antiplatelet Therapy

6 weeks 4.5 months

Warfarin INR 2 -3

Aspirin Warfarin

Aspirin Clopidogrel Aspirin

Percutaneous Left Atrial Appendage Closure vs Warfarin for Atrial Fibrillation: A Randomized Clinical Trial

JAMA. 2014;312(19):1988-1998. doi:10.1001/jama.2014.15192

Primary Efficacy Endpoint: Stroke, Cardiovascular death, Systemic embolism

Presenter

Presentation Notes

Kaplan-Meier Curves for the Primary Efficacy and Safety End PointsThe primary efficacy outcome (A) was stroke, systemic embolization, or cardiovascular death. The primary safety outcome (B) was a composite of major bleeding events and procedure-related complications. Incident probabilities for the intention-to-treat analysis are shown. HR indicates hazard ratio.

JAMA. 2014;312(19):1988-1998. doi:10.1001/jama.2014.15192


Presenter

Presentation Notes

Kaplan-Meier Curves for Ischemic Stroke, Cardiovascular Mortality, and All-Cause MortalityHR indicates hazard ratio; RR, rate ratio.


JAMA. 2014;312(19):1988-1998. doi:10.1001/jama.2014.15192

Primary Safety Endpoint: Hemorrhage, Hemorrhagic stroke, Procedure related events

Presenter

Presentation Notes

Kaplan-Meier Curves for the Primary Efficacy and Safety End PointsThe primary efficacy outcome (A) was stroke, systemic embolization, or cardiovascular death. The primary safety outcome (B) was a composite of major bleeding events and procedure-related complications. Incident probabilities for the intention-to-treat analysis are shown. HR indicates hazard ratio.

Procedural Complications: Substantial Learning Curve

• Pericardial effusion requiring drainage 5 % – Rate 50% ↓ > 3 cases

• Periprocedure ischemic stroke 1.1 % – Air or thromboemboli

All Device and/or procedure-related serious adverse events within 7 Days Source: FDA Oct 2014 Panel Sponsor Presentation.

Procedural Complications: Substantial Learning Curve

9.9%

4.8% 4.1% 4.1% 3.8%

0.0%

2.0%

4.0%

6.0%

8.0%

10.0%

12.0%

CAP PREVAIL CAP2

Patients with

Safety Event

(%)

PROTECT AF

1st Half 2nd Half n=232 n=231 n=566 n=269 n=579

All Device and/or procedure-related serious adverse events within 7 Days

Learning Curve

~50% New Operators in PREVAIL

Source: FDA Oct 2014 Panel Sponsor Presentation.

Implant Success & Warfarin Cessation

p = 0.04

Study 45-day 12-month

PROTECT AF 87% >93%

CAP 96% >96%

PREVAIL 92% >99%

Implant success defined as deployment and release of the device into the left atrial appendage

Warfarin Cessation PREVAIL Implant Success

No difference between new and experienced operators

Experienced Operators • n=26 • 96%

New Operators • n=24 • 93% p = 0.28

PROTECT AF and CAP: Reddy, VY et al. Circulation. 2011;123:417-424. PREVAIL: Holmes, DR et al. JACC 2014; 64(1):1-12.

Presenter

Presentation Notes

Speaker Notes: Safety outcomes in the PROTECT AF trial, CAP registry and PREVAIL trial demonstrated improvement in implant success.1 95% of patients were successfully implanted with a WATCHMAN Device in the PREVAIL trial. Additionally, the PREVAIL trial demonstrated that the WATCHMAN Device can be successfully implanted by both new and experienced operators, demonstrating the success of the WATCHMAN physician training program.1 In the PREVAIL trial, after 45 days, 92% of patients were able to stop taking warfarin, and over 99% were off warfarin at 1 year.1 1Holmes, DR et al. JACC 2014; Vol. 64, No. 1

The WATCHMAN Device is indicated to reduce the risk of thromboembolism from the left atrial appendage 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 by their physicians 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.

WATCHMAN™ Device FDA Approved Indications March 2015

Presenter

Presentation Notes

Speaker Notes: The WATCHMAN Device is indicated to reduce the risk of thromboembolism from the left atrial appendage in patients with non-valvular atrial fibrillation who are at increased risk for stroke and systemic embolism based on CHADS2 or CHA2DS2-VASc scores, are deemed by their physicians to be suitable for warfarin, and have an appropriate rationale to seek a non-pharmacologic alternative to warfarin.

FDA Approval

. CMS

Approval

Presenter

Presentation Notes

Annals paper: Approval by the FDA, while often necessary, is by itself rarely sufficient to obtain coverage from Medicare, managed care, and third-party payers (3, 40). The Centers for Medicare & Medicaid Services (CMS) (formerly the Health Care Financing Administration) and private insur- ers may choose not to reimburse an FDA-approved device or an FDA-approved indication for a device. Although the FDA and CMS review scientific data, the legislation and statutes that guide their decision making are different (41). The FDA must determine that a device is “safe and effective” as a condition of approval, whereas CMS must determine that the device is “reasonable and necessary” for the Medicare population as a condition of coverage (41). His- torically, “reasonable and necessary” has been ill defined, and CMS has made decisions on a case-by-case basis (41, 42). Although the FDA does not consider issues of cost- effectiveness and CMS does not formally consider issues of cost-effectiveness, cost may play some role in the CMS decision process, particularly for expensive therapies (42– 44). Because of differences in the statutes and the review process, FDA and CMS decisions may occasionally diverge.

FDA Approval

. CMS

Approval

Device is “safe &

effective”

Device is “reasonable &

necessary”

Presenter

Presentation Notes

Annals paper: Approval by the FDA, while often necessary, is by itself rarely sufficient to obtain coverage from Medicare, managed care, and third-party payers (3, 40). The Centers for Medicare & Medicaid Services (CMS) (formerly the Health Care Financing Administration) and private insur- ers may choose not to reimburse an FDA-approved device or an FDA-approved indication for a device. Although the FDA and CMS review scientific data, the legislation and statutes that guide their decision making are different (41). The FDA must determine that a device is “safe and effective” as a condition of approval, whereas CMS must determine that the device is “reasonable and necessary” for the Medicare population as a condition of coverage (41). His- torically, “reasonable and necessary” has been ill defined, and CMS has made decisions on a case-by-case basis (41, 42). Although the FDA does not consider issues of cost- effectiveness and CMS does not formally consider issues of cost-effectiveness, cost may play some role in the CMS decision process, particularly for expensive therapies (42– 44). Because of differences in the statutes and the review process, FDA and CMS decisions may occasionally diverge.

CMS will cover percutaneous LAAC implants when specific criteria are met: • Eligible patients must have a CHADS2 score of >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

National Coverage Determination Effective Feb 2016

Presenter

Presentation Notes

Appropriate pt Institution criteria Individual operator criteria registry


VASc score >3


• Assess stroke risk with CHA2DS2-VASc score – If CHA2DS2-VASc score ≥2: Annual stroke risk 2%-15%, oral

anticoagulants are recommended


Presenter

Presentation Notes

Appropriate pt Institution criteria Individual operator criteria registry


VASc score >3


• Documented evidence of a formal shared decision interaction between the patient and an independent non-interventional physician



CMS will cover percutaneous LAAC implants when specific criteria are met: • Facility requirements: the procedure must be furnished in a hospital

with an established structural heart and/or EP program

• Operator requirements: Must be performed by an IC, EP, or cardiovascular surgeon who: – has received manufacturer prescribed training on safe and effective use of

the device – has performed at least 25 TSP through intact septum – Must maintain at least 25 TSP over a two year period (at least 12 are

LAAC)

CMS will cover percutaneous LAAC implants when specific criteria are met:

• Registry: Patients must be enrolled in a prospective national registry

– NCDR LAAO Registry


Appropriate Patients?

• Poor long term candidates for anti-coagulation – History of major bleeding – Risk of major bleeding (high fall risk) – Poor tolerance of anti-coagulation

• Favorable anatomy for LAA closure • Lifestyle • ? Other factors:

– noncompliance – those requiring dual anti-platelet therapy after stenting

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

0.01 0.1 1 10

Favors WATCHMAN Favors warfarin

Hazard Ratio (95% CI) Reddy VY, Holmes, DR et al. JACC 2017 in Press.

PROTECT AF/PREVAIL Meta-Analysis (5 Years): WATCHMAN Efficacy Comparable to Warfarin

HR p-value

Efficacy 0.82 0.3









0.01 0.1 1 10


Hazard Ratio (95% CI)

PROTECT AF/PREVAIL Meta-Analysis (5 Years): WATCHMAN Stroke-Risk Reduction Comparable to Warfarin

Reddy VY, Holmes, DR et al. JACC 2017 in Press.

PROTECT AF/PREVAIL Meta-Analysis (5 Years): WATCHMAN Significant Reduction in Disabling Strokes

0.00%0.20%0.40%0.60%0.80%1.00%1.20%1.40%1.60%1.80%2.00%

WATCHMAN warfarin

Disabling/Fatal Strokes Non-Disabling Strokes

Disabling Stroke defined as MRS ≥2 Two strokes in PREVAIL are excluded because the baseline MRS score was unavailable

HR 0.45 (0.21 – 0.94) P=0.03

55% Lower


HR p-value

Efficacy 0.82 0.3









0.01 0.1 1 10



PROTECT AF/PREVAIL Meta-Analysis (5 Years): WATCHMAN Mortality Reduction Significant When Compared to Warfarin


HR p-value

Efficacy 0.82 0.3









0.01 0.1 1 10



PROTECT AF/PREVAIL Meta-Analysis (5 Years): WATCHMAN Post-Procedure Bleeding Reduction Significant When Compared to Warfarin


WATCHMAN is the most studied LAAC Device with Long-term Clinical Data

Results

Safety WATCHMAN procedure is safe 95% implant success; ~4% complication rates1

Primary Efficacy

WATCHMAN comparable to warfarin 18% reduction in events (p=0.27)2

Stroke WATCHMAN comparable to warfarin

55% reduction in disabling/fatal stroke (p=0.03)*, largely driven by

80% reduction in hemorrhagic stroke (p=0.003)2

Mortality WATCHMAN statistically significant to warfarin

27% reduction in all-cause mortality (p=0.04)2

41% reduction in CV/unexplained mortality (p=0.03)2

Major Bleeding

WATCHMAN statistically significant to warfarin post-

procedure 72% reduction after 6-months (p=0.001)3

Warfarin Cessation

WATCHMAN allows the majority of patients to discontinue warfarin

92% of patients discontinue after 45-days; 99% of patients discontinue after 1 year4

1. WATCHMAN FDA Panel Sponsor Presentation. Oct 2014.; 2 Reddy VY et al. JACC. 2017; In Press; 3. Price, M. J., V. Y. Reddy, et al. JACC: CV Interv 2015; 8(15): 1925-1932; 4. Holmes, DR et al. JACC 2014; 64(1): 1-12; 6.

Percutaneous LAA Occlusion Systems

WATCHMAN Amulet Lariat

Wavecrest LAmbre Occluetech

Presenter

Presentation Notes

The WATCHMAN is currently the only percutaneous occlusion device approved in the United States. Several devices including the Amplatzer, WATCHMAN, Wavecrest, LAmbre, Occlutech and LARIAT devices have the Conformite Europeenne (CE) mark of approval.

Amulet LAAO

Lobe Positioned inside the LAA

neck Designed to conform to

different sizes and shapes of LAA anatomy

Stabilizing Wires Engage with the wall of the LAA Help hold the device in place

Waist Maintains tension between lobe and

disc Flexible connection allows device to

self-orient

Disc Designed to

completely seal the LAA at the orifice

Disc

Waist

Proximal End Screw

Lobe Stabilizing

Wires

Platinum Thread

Distal End Screw

Study Design

• A prospective, randomized, multicenter, active control worldwide trial to evaluate safety and effectiveness of the Amulet device

• Purpose: To evaluate the safety and effectiveness of the Amulet

device by demonstrating that the device is non-inferior to the commercially available Boston Scientific LAA closure (LAAC) device (Control) in subjects with non-valvular atrial fibrillation

• Randomization will be 1:1 between Amulet (treatment) and the Boston Scientific LAA closure device (Control)

38

AF Team selects study candidate

Subject signs consent

Baseline TEE (echo done within 90d prior to consent may be used)

Roll-in

Amulet

Randomization 1:1

Control Amulet

Study Design

39

Endpoints Primary Endpoints

• Safety

– A composite of procedure-related complications, or all-cause death, or major bleeding through 12 months

• Effectiveness

– A composite of ischemic stroke or systemic embolism through 18 months

• Mechanism of Action

Device closure (defined as residual jet around the device ≤ 5 mm) at the 45-day visit documented by transesophageal echocardiogram (TEE/TOE) defined by Doppler flow

Presenter

Presentation Notes

Bleeding Academic Research Consortium Definitions (BARC): Type 3 (major): Type 3a: Any transfusion with overt bleeding Overt bleeding plus a hemoglobin drop of ≥ 3 to < 5 g/dL (provided hemoglobin drop is related to bleeding) Type 3b: Overt bleeding plus hemoglobin drop ≥ 5 g/dL (provided hemoglobin drop is related to bleed) Cardiac tamponade Bleeding requiring surgical intervention for control (excluding dental/nasal/skin/ hemorrhoid) Bleeding requiring intravenous vasoactive drugs Type 3c: Intracranial hemorrhage including subdural hemorrhages (does not include microbleeds or hemorrhagic transformation, does include intraspinal) Subcategories confirmed by autopsy or imaging or lumbar puncture Intraocular bleed compromising vision

transcatheter left atrial appendage occlusion for stroke prevention in atrial … cme... ·...

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