David R. Holmes, Jr., M.D. Mayo Clinic, Rochester LAA: Who and When David R. Holmes, Jr., M.D. Mayo Clinic, Rochester CRT 2016 Washington, D.C. February 2016 test

Presenter Disclosure Information David R. Holmes, Jr., M.D. “LAA: Who and When” The following relationships exist related to this presentation: Both Mayo Clinic and I have a financial interest in technology related to this research. That technology has been licensed to Boston Scientific.

Confirms Role of LAA in CVA Event-free probability Proof of Concept Device Intent-to-Treat All Stroke Randomization allocation (2 device:1 control) WATCHMAN Control Key Implication: Confirms Role of LAA in CVA Event-free probability 900 patient-year analysis Days 244 147 52 12 463 270 92 22 Holmes et al, Lancet 2009

PROTECT AF/PREVAIL Meta-Analysis: WATCHMAN Comparable to Warfarin HR P Efficacy 0.79 0.22 All stroke or SE 1.02 0.94 Ischemic stroke or SE 1.95 0.05 Hemorrhagic stroke 0.004 Ischemic stroke or SE >7 days 1.56 0.21 CV/unexplained death 0.48 0.006 All-cause death 0.73 0.07 Major bleed, all 1.00 0.98 Major bleeding, non procedure-related 0.51 0.002 Favors WATCHMAN   Favors warfarin Hazard Ratio (95% CI)

Indications for Use 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

The Centers for Medicare & Medicaid Services (CMS) covers percutaneous left atrial appendage closure (LAAC) for non-valvular atrial fibrillation (NVAF) through Coverage with Evidence Development (CED) under 1862(a)(1)(E) of the Social Security Act with the following conditions: LAA closure devices are covered when the device has received Food & Drug Administration (FDA) Premarket Approval (PMA) for that device’s FDA-approved indication and meet all of the conditions specified below: CHADS2 – ≥2 CHADS2DS2-VASc – ≥3 Shared decision making with independent non- interventional MD Suitable for short-term AC but deemed unable or unsuitable for long-term Trained physicians Enrolled in a registry

NOACS

ORBIT AF Trial OAC Contraindications CHA2DS2-VASc Contraindication Overall (n=1330) <2 (n=81) ≥2 (n=1249) P Prior bleed 27.7 13.6 28.7 0.003 Patient refusal 27.5 48.2 26.2 <0.0001 High bleeding risk 18.0 6.2 18.7 0.004 Frequent falls/frailty 17.6 2.5 18.6 0.0002 Need for dual APT 10.4 4.9 10.7 0.10 Unable to adhere 6.0 0.95 Comorbid illness 5.3 5.4 0.24 Prior intracranial hemorrhage 5.0 3.7 0.59 Allergy 2.4 2.3 0.43 Occupational risk 0.8 0.7 0.09 Pregnancy 0.2 0.0 0.66 Other 12.6 24.7 11.8 0.001 O’Brien et al: Am Heart J 167:601-9, 2014

ASAP-TOO Study Design Prospective, randomized, multi-center, global Non-valvular atrial fibrillation deemed not suitable for oral AC to reduce the risk of stroke with CHA2DS2VASC ≥2 Randomized 2:1 (Watchman vs Control) ASA & Plavix Group Sequential Design Allows early looks; potential to stop early for benefit 900 subjects at up to 100 global sites Follow-Up 45 Day with TEE 6,18 month phone visit 12 month with TEE Years 2-5 annually Brain imaging required at baseline if prior stroke or TIA

ASAP-TOO Efficacy Composite: All cause mortality CV mortality Stroke Systemic embolism Significant bleeding Statistical assessment: Non-inferiority or superiority

Novel Oral Anticoagulants Discontinuation and Bleeding Rates Treatment Discontinuation rate in study (%) Major bleeding (rate/year) (%) Dabigatran1 (150 mg) 21 3.1 Rivaroxaban2 24 3.6 Apixaban3 22 2.1 Connolly SJ: N Engl J Med, 2009 Patel MR: N Engl J Med, 2011 Granger CB: N Engl J Med, 2011

LAAC + NOACS Prospective, randomized, multicenter, global Non-valvular AF at risk for stroke CHA2DS2VASc ≥2 Randomization 2:1 (Watchman vs NOAC) Group sequential design Allows early looks 900 subjects Follow-Up 45 Day with TEE 6,18 month phone visit 12 month with TEE Years 2-5 annually Brain imaging required at baseline if prior stroke or TIA

LAAC + NOACS Efficacy Composite: All cause mortality CV mortality Stroke Systemic embolism Significant bleeding Statistical assessment: Non-inferiority or superiority Bayesian design

A Twofer

Twofer Prospective registry, multicenter, global Patients with non-valvular AF at risk for stroke CHA2DS2VASc ≥2 undergoing TAVR (n=100) Atrial fibrillation ablation (n=100) Endpoints Early stroke Embolization Bleeding Death Pericardial effusion Late stroke

NOACS

Stroke and Atrial Fibrillation Alternative to Warfarin or NOACS Patients who could be treated with warfarin/NOACS Patients who choose not to be treated with warfarin/NOACS Contraindications to warfarin/NOACS Patients treated with DAPT In concert with ablation