Occlusion de l'auricule gauche: Niche ou réel avenir ?

D Gras, MD, Nantes, France

LAA Occlusion Is there a real future ?

• Background • Protect AF Trial • Other Studies

– CAP, ASAP, Prevail • Left Atrial Appendage

Occlusion Procedure

AF and Stroke

. 3 million in US, 4.5 million in the EU have AF1

. 2/3 of AF population are at high-risk of stroke1

35% of patients with AF will have a stroke in their lifetime2

. AF responsible for 15-20% of ischemic strokes1

. AF Incidence increases with age2

. 0.4% in general population

. 0.2% of 25-34 yrs of age Estimated age-specific AF prevalence2

1. Fuster, et al., ACC/AHA/ESC Practice Guidelines, Circulation. 2006;114:700-752 2. Wolf PA, et al., Atrial fibrillation as an independent risk factor for stroke: the Framingham study. Stroke 1991;22:983–8

. 2-5% of >60 yrs of age

. 10% of > 80 yrs of age Relationship of AF and stroke2

Warfarin: The cornerstone therapy

• Adjusted-dose Warfarin agents reduce stroke by 60%1

• Inadequate warfarin usually seen in pts admitted for Stroke2 (High-risk pts with AF candidates for OAC): – Only 29% on therapeutic level for Warfarin dose – Of the remaining: 10% were sub-therapeutic, 31% were on

Antiplatelet, 29% no therapy was prescribed • Warfarin is CI in 14-47% of pts at risk of stroke4

• It is not prescribed in 21% of the indicated patients3

• Less than 50% of pts eligible are being treated with warfarin due to tolerance or non-compliance issues

1. Hart, et al, Meta-analysis 28044 pts, Ann Intern Med. 2007;146:857-867 2. Gladstone et al, Stroke, 2009; 40:235-240 3. Waldo AL, et al. J AM Coll Cardiol 2005;46:1729

4. Holmes at ACC & i2 Summit 2009 5. Wikipedia. Warfarin. http://en.wikipedia.org/wiki/Warfarin. Accessed November 1, 2011.

CI and reasons for not initiating Warfarin • Contraindicated patients1:

– 40% increased risk of stroke – 26% increased risk of mortality

1. Hart, et al., Meta-analysis: Antithrombotic Therapy to Prevent Stroke in Patients Who Have Nonvalvular Atrial Fibrillation; Ann Intern Med. 2007;146:857-867. 2. Srivastava, et al. Examining warfarin underutilization rates in patients with atrial fibrillation: Detailed chart review essential to capture contraindications to

warfarin therapy; Thrombosis Journal 2008, 6:6doi:10.1186/1477-9560-6-6

Fall Risk20%

Not documented22%

Transient / Secondary AF

22%

Gastrointestinal Bleed 29%

Physician's Perceived Reasons for Not Initiating Warfarin Therapy2

Country distribution of mean time in therapeutic range in the RE-LY trial

• 5791 Patients on warfarin • A large proportion of patients were outside the therapeutic range • Major variations between countries

– Europe: about 3 out of 10 patients out of therapeutic range – Sweden: 23% out of range – Taiwan: 56%

Wallentin, 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; The Lancet, 2010: 376; 975 - 983

In AF, 91% of the thrombi formed in the LA appendage. Rationale for excluding the LAA from the circulation

Blackshear JL, Odell JA. Appendage obliteration to reduce stroke in cardiac surgical patients with atrial fibrillation. Ann Thorac Surg 1996;61:755–9.

80 % reduction in

stroke > LAA surgical

occlusion

Garcia-Fernandez et al.: Role of left atrial appendage obliteration in stroke reduction in patients with mitral valve prosthesis: a transesophageal echocardiographic study. J Am Med Assoc 2003, 42:1253-1258.

LAA Occlusion Is there a real future ?

• Background • Protect AF Trial • Other Studies

– CAP, ASAP, Prevail • Left Atrial Appendage

Occlusion Procedure

• Efficacy Endpoint: – Stroke – CV death (& Unknown) – Systemic embolism

• Safety Endpoint

• Non-inferiority & Superiority – Bayesian Sequential Design – Analysis at 600 pt-yrs & – every 150 pt-yrs – thereafter 1500 pt-yr

Follow-Up: 5 Years

Non-Valvular AF CHADs ≥ 1

Randomization (1:2)

Warfarin Watchman

PROTECT-AF: Overview

Can the WATCHMAN device replace Warfarin?

Anticoagulation Regimen

• Implant to 6 weeks • Warfarin (INR 2-3) for 6 weeks • Aspirin (81 – 325 mg)

• 6 weeks to 6 months • Clopidogrel (75 mg) • Aspirin (81 – 325 mg)

• After 6 months • Aspirin (81 – 325 mg)

Inclusion: – Paroxysmal / Persistent / Permanent AF – CHADS ≥ 1 (CHF, HTN, ≥75 yr, Diabetes, TIA/CVA) – Eligible for long-term Warfarin therapy

Exclusion – Mechanical valve or long-term Warfarin needed – Contraindication to Warfarin – TEE exclusion: anatomy, atheroma, MV stenosis, tumor – Symptomatic Carotid disease – LVEF < 30% – ASD / Atrial septal repair or closure device – CV/Ablation planned within 30 days – Unable to take ASA / Plavix®

PROTECT-AF: Inclusion/Exclusion

PROTECT-AF: Patient Demographics

PROTECT-AF: Primary Efficacy Endpoint Events include Stroke (ischemic and hemorrhagic), Systemic embolization, CV death

PROTECT-AF: Primary Efficacy Endpoint

1

2

3

Events include Stroke (ischemic and hemorrhagic), Systemic embolization, CV death

Intention-to-Treat: All-Cause Mortality

Hazard Ratio with Watchman, 0.66 (95% CI, 0.45 – 0.98)

P = 0.0379

PROTECT AF: Primary Safety Endpoint

Primary Safety Endpoint: Components of the Safety Endpoint

Pericardial Tamponade – 22 requiring Tx (4.8% of patients)

• 15 treated percutaneously • 7 underwent surgical intervention

– Extended hospitalization – No Death or Long-term Disability

Effect of operator experience – 1st Half of Cohort: 6.3% – 2nd Half of Cohort: 3.7%

Early = First 7 days Late = After 7 days

LAA Occlusion Is there a real future ?

• Background • Protect AF Trial • Other Studies

– CAP, ASAP, Prevail, Amplatzer ….

• Left Atrial Appendage Occlusion Procedure

Characteristic PROTECT AF

N=463 CAP

N=566 PREVAIL

N=269 P value

Age, years 71.7 ± 8.8 (463)

(46.0, 95.0) 74.0 ± 8.3 (566)

(44.0, 94.0) 74.0 ± 7.4 (269)

(50.0, 94.0) <0.001

Gender (Male) 326/463 (70.4%) 371/566 (65.5%) 182/269 (67.7%) 0.252

CHADS2 Score (Continuous)

2.2 ± 1.2 (1.0, 6.0)

2.5 ± 1.2 (1.0, 6.0)

2.6 ± 1.0 (1.0, 6.0)

<0.001

CHADS2 Risk Factors

CHF 124/463 (26.8%) 108/566 (19.1%) 63/269 (23.4%)

Hypertension 415/463 (89.6%) 503/566 (88.9%) 238/269 (88.5%)

Age ≥ 75 190/463 (41.0%) 293/566 (51.8%) 140/269 (52.0%)

Diabetes 113/463 (24.4%) 141/566 (24.9%) 91/269 (33.8%)

Stroke/TIA 82/463 (17.7%) 172/566 (30.4%) 74/269 (27.5%)

Most notable differences: Age, Diabetes, and Prior Stroke/TIA

PROTECT AF and CAP data , from Reddy, VY et al. Circulation. 2011;123:417-424.

Procedure Implant Success

90.9%

PROTECT AF Implant success

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

PROTECT AF and CAP data from Reddy, VY et al. Circulation. 2011;123:417-424.

94,3%

CAP Implant success

95,1%

PREVAIL Implant success

p = 0.04

7 Day Procedure/Device Related Vascular complications

PROTECT-AF and CAP data from Reddy, VY et al. Circulation. 2011;123:417-424. 1Includes observed PE not necessitating intervention, AV fistula, major bleeding requiring transfusion, pseudoaneurysm, hematoma and groin bleeding

8.7%

4.1% 4,4%

0,0%

2,0%

4,0%

6,0%

8,0%

10,0%

% o

f Pat

ient

s

PROTECT AF CAP PREVAIL

n=39 n=23 n=12

p = 0.005

Cardiac perforation, pericardial effusion with tamponade, ischemic stroke, device embolization, and other vascular complications1

No procedure-related deaths reported in any of the trials

At 18 months, the rate of the first coprimary efficacy endpoint (composite of stroke, systemic embolism [SE], and cardiovascular/unexplained death) was 0.064 in the device group versus 0.063 in the control group (rate ratio 1.07 [95% credible interval (CrI): 0.57 to 1.89]) and did not achieve the prespecified criteria noninferiority (upper boundary of 95% CrI $1.75).

The rate for the second coprimary efficacy endpoint (stroke or SE >7 days’ postrandomization) was 0.0253

versus 0.0200, achieving noninferiority

ASAP Registry, N=142 • 1st EP: Occurrence of stroke (ischemic and hemorrhagic),

CV death (cardiovascular and unexplained), system embolism • Inclusion Criteria

– Paroxysmal, persistent or permanent non-valvular AF – CHADS2 score ≥1 – Contraindication for Warfarin

• Exclusion Criteria – ECHO: LVEF <30%, Intracardiac thrombi, Complex

aortic atheroma, High-Risk PFO (Aneurysm >15mm or Length ≥15mm)

– Symptomatic Carotid disease – History of stroke/TIA (within last 30 days)

ASAP Registry Efficacy Outcome

77% Reduction 7,3%

1,7%

0,0%

1,0%

2,0%

3,0%

4,0%

5,0%

6,0%

7,0%

8,0%

1

Expected, based onCHADS2 Score

Observed rate inASAP

Mean CHADS2 Score = 2.8 ± 1.2

Efficacy outcome: Occurrence of stroke (ischemic and hemorrhagic),

CV death (cardiovascular and unexplained), system embolism

The Amplatzer Cardiac Plug Experience 974 Pts, 20 Sites, Europe and Canada

Indication for LAAO

Amplatzer Cardiac Plug Experience Success rate and complications

Amplatzer Cardiac Plug Experience: The Efficacy

LAA Occlusion Is there a real future ?

• Background • Protect AF Trial • Other Studies

– CAP, ASAP, Prevail • Left Atrial Appendage

Occlusion Procedure

LAA Occlusion: Percutaneous, Transcatheter, Transseptal approach

AMPLATZER Cardiac Plug

Barbs Engage LAA Wall

160 µ PET fabric

Watchman®

self-expanding nitinol frame with fixation anchors and a permeable fabric cover

TEE at 6 Weeks FU

• LAA is critical to the pathogenesis of stroke (91%) • “Local” therapy (LAAO) is to ≥ Warfarin

– 40% reduction of stroke, systemic embolism, CV death • Efficacy preserved in pts at highest risk (prior stroke/TIA) • Procedural risks: Tamponade, Migration, Bleeding .. • Learning Curve: 2.2% (CAP Registry), 1.9% (PREVAIL) Indications: . non valvular AF + CI to ACT + CHA2DS2-VASc ≥ 4, . Decrease in TE events > Procedural risks

LAA Occlusion: Summary