SCRIPPS CLINIC A Cost Analysis of Bleed Complications from Two Stroke Prevention Strategies in Non-valvular Atrial Fibrillation: Left Atrial Appendage Closure versus Warfarin Matthew J Price 1, Stacey L Amorosi 2, Shannon O Armstrong 3, Meghan B Gavaghan 3, Douglas Gibson 1, Miguel Valderrabano 4, and Vivek Y Reddy 5 1 Scripps Clinic, La Jolla, CA, USA, 2 Boston Scientific, Marlborough, MA, USA 3 GfK, Wayland, MA, USA 4 Methodist Hospital, Houston, TX USA, 5 Mount Sinai School of Medicine, New York, NY USA

SCRIPPS CLINICDisclosures  This study was funded by Boston Scientific  The authors report the following disclosures:

SCRIPPS CLINICBackground  Warfarin is commonly used to reduce the risk of stroke in patients with atrial fibrillation (AF).  While inexpensive and effective, warfarin is associated with increased bleeding, which contributes to the overall costs for this management strategy.  The PROTECT-AF and PREVAIL trials demonstrated that left atrial appendage closure (LAAC) reduces thromboembolic risk and enables most patients to discontinue lifelong oral anticoagulation (OAC).  This analysis sought to quantify the total cost to the Centers for Medicare & Medicaid Services (CMS) of all bleed-related complications with warfarin compared to WATCHMAN LAAC using a health economic model.

SCRIPPS CLINICMethods  A Markov model was developed to assess the total cost of all bleeding complications with LAAC compared with warfarin from a CMS perspective over a 20-year time horizon. Population: Patients enrolled in PROTECT AF and PREVAILPopulation: Patients enrolled in PROTECT AF and PREVAIL Perspective: CMS (United States)Perspective: CMS (United States) Intervention: LAAC with WATCHMANIntervention: LAAC with WATCHMAN Comparator: WarfarinComparator: Warfarin Time horizon: 20 yearsTime horizon: 20 years

SCRIPPS CLINIC Methods – Clinical Inputs Bleeding events  Probabilities for all bleeding events were determined from a pooled intention-to-treat (ITT) analysis of the PROTECT AF and PREVAIL trials.  In this analysis, rates of bleeding reflect all bleeds, including first and subsequent bleed events as well as major and minor bleeds.

SCRIPPS CLINIC Methods – Clinical Inputs Bleeding risk and mortality  Prior bleeding events and age were incorporated to project bleeding risk over time, consistent with published data.  Bleed-related mortality risk was obtained from 2012 US Healthcare Utilization Project (HCUP) data.* * Healthcare Utilization Project (HCUP) = longitudinal US hospital encounter-level data

SCRIPPS CLINIC Methods – Cost Inputs  Costs of bleeds included direct costs due to in-patient care as well as long-term disability costs.  Cost data were taken from 2015 US DRGs/CPT ® s and the literature.  For costing purposes, LAAC patients were assumed to adhere to the OAC regimen in the study protocols for PROTECT-AF and PREVAIL.

SCRIPPS CLINIC LAAC Patient Pathway * The model assumes no therapy discontinuation for successful LAAC procedure LAAC Procedure Warfarin Therapy NO Hemorrhagic Stroke Extracranial Hemorrhage Pericardial Effusion Other Major Bleeding YES* Unrelated Mortality No Neurological Impact Moderate Disability Severe Disability Death Well Death Implant Successful? Procedural Complications? NO YES Intracranial Hemorrhage No Neurological Impact Moderate Disability Severe Disability Death

SCRIPPS CLINIC Warfarin Patient Pathway Warfarin Therapy No Therapy Hemorrhagic Stroke Extracranial Hemorrhage Unrelated Mortality No Neurological Impact Moderate Disability Severe Disability Death Well Death Therapy Discontinuation? NO YES Intracranial Hemorrhage No Neurological Impact Moderate Disability Severe Disability Death

SCRIPPS CLINIC Methods – Clinical Inputs LAAC ITT procedural event rates   Pooled data represents PROTECT AF at 5-years follow up and PREVAIL at 2.2-years follow up

SCRIPPS CLINIC Methods – Clinical Inputs ITT Post-procedural events* (>7 days) * Pooled data represents PROTECT AF at 5-years follow up and PREVAIL at 2.2-years follow up

SCRIPPS CLINIC Methods – Cost Inputs Direct inpatient and long-term disability costs to CMS * Major extracranial bleeding assumed to be GI for costing purposes

SCRIPPS CLINIC Post-Procedural Bleeding events per 100 patient-years at 20 years  Post-procedural rates of bleeding were substantially lower after LAAC than with long-term warfarin therapy  This reduction was driven mainly by decreased gastrointestinal bleeding and to a lesser extent by decreased hemorrhagic stroke

SCRIPPS CLINIC Bleeding events per 100 patient-years over 20-year time horizon  Over 20 years, the risk of bleeding after LAAC would be three times less than ongoing treatment with warfarin  This reduction was driven mainly by decreased GI bleeding and to a lesser extent by decreased hemorrhagic stroke 3.4% 10.0%

SCRIPPS CLINIC Average cumulative per patient direct costs* for all bleeding events (20 years)  Cumulative per patient direct costs for bleeding events (hospitalization, procedures) were nearly 3 times less (65%) for patients undergoing LAAC with WATCHMAN (∆ = $5,890) ECH = extracranial hemorrhage; HS = hemorrhagic stroke; ICH = intracranial hemorrhage *Costs to CMS for hospital care

SCRIPPS CLINIC Total bleeding-related bed-days (20 years)  Due to the reduced rate of bleeding following LAAC placement, associated bed-days are reduced by more than 50%

SCRIPPS CLINIC Average cumulative per patient direct + long-term disability costs for bleeding events (20 years)  Total bleeding-related costs to CMS are 64% less with warfarin compared to LAAC with WATCHMAN

SCRIPPS CLINICLimitations  Study data with different lengths of follow-up were utilized and then extrapolated to 20 years.  Model allowed for one clinical event per 3-month cycle, when multiple events might occur.  Treatments administered in clinical practice may vary in effectiveness as compared to that observed in randomized trials.

SCRIPPS CLINICConclusions  While there was a hazard for procedural bleeding with LAAC, modeled post-procedural rates of bleeding were substantially lower for LAAC with WATCHMAN than long- term warfarin therapy (3.3 vs 10.0)  Bleeding-related costs to CMS are ~65% less with LAAC with WATCHMAN compared to long-term warfarin for direct costs ($3,219 vs $9,109 per patient) and total costs ($7,032 vs $19,430 per patient) Bleeding-related risk and associated costs should be considered when assessing the overall cost benefit for non- pharmacological, stroke risk reduction therapies in AF.

SCRIPPS CLINIC Major extracranial bleeding ITT Post-procedural events (>7 days)  Major extracranial bleeding assumed to be GI for costing purposes