PREVENtion of Pump Thrombosis Through Clinical Management (PREVENT) John M. Stulak, MD Mayo Clinic

INTRODUCTION: Study Background Recent studies have indicated that incidence of pump thrombosis has gone up with the HM2 LVAD 1,2, with the rates continuing to increase 1 1 Starling, Moazami, Silvestry, et al NEJM Kirklin, Naftel, Kormos et al JHLT 2014 Confirmed thrombus at 3 Months 2.2% before March 1, % after March 1, 2011 ~15% predicted into 2013 and exponentially rising

516 patients at 3 centers: Michigan, Mayo Clinic, Vanderbilt Also experienced significant increase with a peak in 2012; But subsequent decrease in 2013, correlated with changes in management practices The issue of pump thrombosis is complex and undoubtedly multifactorial in nature 1 Stulak & Maltais NEJM 2014; 370: INTRODUCTION: Varying Experience

Schmitto et al. Hoefer et al. O.H. Frazier 2004 – /134 (2.2%) “No recent increasing trends….” in 6265 patient-days of support “inadequate AC…probable cofactor” ; 432 patients : 0/232, 2011: 7/88, 2012: 11/69 Since 2013: 3/54  “problem resolving” INTRODUCTION: Varying Experience

INTRODUCTION: Study Background & Rationale Causes and true risk of HMII pump thrombosis unclear –Significant variability in reported rates of pump thrombosis –Variability in patient management practices Recommended practices developed –Standardize the clinical management of HeartMate II patients –Reducing overall thrombosis risk –Minimizing center-to-center variability The PREVENT study was designed with 2 objectives in mind –a) assess risk of HM II pump thrombosis in the current era when recommended practices for management are adopted –b) identify risk factors associated with pump thrombosis

Study Design

1.Prospective, multi-center, single arm, un-blinded, non-randomized, study 2.Number of Patients: Up to Number of Sites: 24 Primary Objectives 1.Assess the incidence of HM II pump thrombosis in the current era when recommended practices for clinical management are adopted. 2.Identify risk factors associated with pump thrombosis events Secondary Objectives 1.The incidence of pre-defined anticipated adverse events and rehospitalizations while on support 2.Survival while on HM II LVAD support 3.Adherence to the recommended practices outlined in Appendix I of the protocol STUDY DESIGN: Primary & Secondary Objectives

STUDY DESIGN: Inclusion & Exclusion Criteria INCLUSION CRITERIA 1.Informed consent 2.Subject is receiving the HeartMate II as their first LVAD in accordance with FDA approved indications for use 3.Age ≥ 18 years EXCLUSION CRITERIA 1.Ongoing mechanical circulatory support (MCS) other than intra- aortic balloon pump 2.Participation in any other clinical investigation(s) involving a MCS device, or an investigation(s) that is likely to confound study results or affect study outcome

Primary Endpoint –Incidence of confirmed pump thrombosis within three (3) months of HM II implantation Secondary Endpoints –Incidence of Confirmed pump thrombosis within six (6) months of HM II implantation Suspected pump thrombosis within three (3) and six (6) months of HM II implantation Pump exchange, urgent transplantation or death due to pump thrombosis within three and six months of HM II implantation –Analysis of Risk factors for pump thrombosis Chest X-rays (baseline and 6 months) to assess pump position Pump parameters (power, speed, flow, pulsatility index) LDH and INR log data Adherence to recommended practices Anticoagulation and Antiplatelet logs Frequency, incidence and rates of pre-defined anticipated adverse events (bleeding, stroke, infection, right heart failure, etc) Frequency and incidence of rehospitalizations Subgroup analysis of subjects identified as having a hypercoagulable disorder prior to HM II implantation Survival on LVAD support at six (6) months post HM II implantation Endpoints

Overview of PREVENT Recommended Practices

PREVENT– Surgical Recommendations Adamson RM, Mangi AA, Kormos RL, Farrar DJ, Dembitsky WP. Principles of HeartMate II Implantation to Avoid Pump Malposition and Migration. J Card Surg Mar;30(3):296-9

PREVENT RECOMMENDED PRACTICES: Anticoagulation/ Antiplatelet Therapy Begin bridging with unfractionated heparin or LMWH within 48 hrs –goal PTT of sec in the first 48 hours –Titration to a PTT of sec by 96 hours –If heparin is contraindicated, consider other alternatives including argatroban, intravenous warfarin, and bivalirudin –Heparin therapy may be discontinued when goal INR is obtained Initiate warfarin within 48 hours to obtain goal INR by POD 5-7 –Goal INR: –Maintain a target INR throughout device support Initiate aspirin therapy ( mg daily) 2-5 days post HMII implantation 12

PREVENT RECOMMENDED PRACTICES: Pump Speed and Blood Pressure Run pump speeds above 9000 rpm and avoid speeds below 8600 RPM Average pump speed and flow in the clinical trial 1 –Day 1: 9150 ± 495 rpm; flow est: 5.1 ± 0.9 l/min; index: 2.6 ± 0.5 l/min/m 2 –Day 180: 9405 ± 448 rpm; flow est: 5.4 ± 0.9 l/min; index: 2.7 ± 0.5 l/min/m 2 Adjust pump speed to permit intermittent aortic valve opening only after the above goals are achieved Under certain circumstances, tailored approaches may be necessary –Smaller patients –Small LVs –Complete LV unloading happens at speeds < 9000 RPMs Maintain a mean arterial pressure (MAP) < 90 mmHg 13 1 Slaughter MS et al. J Heart Lung Transplant 2010;29:S1-39.

Study Status

-Note Projected Numbers (green) are for the end of the month As of November 10 th, 2105 PREVENT Enrollment

PREVENT Enrollment by Site As of November 10 th, 2105

Study Schedule and Data Release Plan Feb 5 th, 2016: 3 month follow-up completed on all 300 subjects March 1 st, 2016: 3 month data locked on all 300 patients ISHLT 2016: –Late breaking clinical science abstract accepted, and will be presented as a featured abstract presentation on Saturday, April 30 th, at 10:40 AM –Dr. Simon Maltais from the Mayo Clinic will be presenting the primary endpoint results

PREVENtion of HeartMate II Pump Thrombosis Through Clinical Management (PREVENT) Preliminary Experience – First 100 Patients Poster presented at AHA, Nov 2015 by Ramesh Emani, MD, Ohio State University, on behalf of the PREVENT Study Investigators

Poster presented at AHA, Nov 2015 by Ramesh Emani, MD, Ohio State University, on behalf of the PREVENT Study Investigators Note: Thrombosis events were not adjudicated in this preliminary analysis, but will be for the final analysis

Results – Baseline Characteristics CharacteristicValue Age (years)58 ± 13 Males (%)87 (87%) DT (%)79 (79%) INTERMACS Profiles: Profile 19 (9%) Profile (69%) Profile (22%) NYHA Class IV86 (86%) Ischemic Etiology (%) 46 (46%) BSA (m 2 )2.15 ± 0.30 CharacteristicValue LVEF (%)18 ± 7 Cardiac Index (L/min/m 2 ) 1.94 ± 0.52 CVP (mmHg)12.1 ± 6.5 PCWP (mmHg)24 ± 8 Creatinine1.39 ± 0.64 Total Bilirubin1.18 ± 1.1 Albumin3.56 ± 0.45 Inotropes69 (69%) Preliminary analysis: Results of the first 100 PREVENT subjects followed up to 6 months Poster presented at AHA, Nov 2015 by Ramesh Emani, MD, Ohio State University, on behalf of the PREVENT Study Investigators

Results – Pump Thrombosis Preliminary analysis: Results of the first 100 PREVENT subjects followed up to 6 months Poster presented at AHA, Nov 2015 by Ramesh Emani, MD, Ohio State University, on behalf of the PREVENT Study Investigators Note: Thrombosis events were not adjudicated in this preliminary analysis, but will be for the final analysis

Results - Adherence Preliminary analysis: Results of the first 100 PREVENT subjects followed up to 6 months Poster presented at AHA, Nov 2015 by Ramesh Emani, MD, Ohio State University, on behalf of the PREVENT Study Investigators Distribution of Median INR/Pt. ( >14 days to outcome or 181 days) Median INR/Patient: 2.2 [IQR: ] Adherence to Other Recommended Practices Pump implanted adherent to the recommendations Pump implanted not adherent to the recommendations 1)Deep Pocket 2)Cannula at ~20° 3)Pump almost 90° to spine 4)Pump anchored 1)Shallow Pump Pocket (Pump is High) 2)Cannula is vertical and appears to be pointing towards the lateral wall 3)Pump is not 90° to spine 4)Pump not anchored

Adverse Event PREVENT (N=100) Bleeding45 (45%) GI Bleeding27 (27%) Right Heart Failure9 (9%) RVAD Use3 (3%) Any Infection28 (28%) Driveline Infection6 (6%) Ischemic Stroke5 (5%) Hemorrhagic Stroke1 (1%) Hemolysis9 (9%) Associated with PT Event3 (3%) Isolated hemolysis6 (6%) Pump Exchanges4 (4%) Results – Survival & Adverse Events Preliminary analysis: Results of the first 100 PREVENT subjects followed up to 6 months Poster presented at AHA, Nov 2015 by Ramesh Emani, MD, Ohio State University, on behalf of the PREVENT Study Investigators Overall Survival

Summary Preliminary results from the PREVENT study are encouraging Suggest that adherence to recommended practices may result in lower pump thrombosis rate Thrombosis events in this preliminary analysis were not adjudicated, but will be for the final analysis Overall mortality and strokes rates continue to remain low Results in all 300 patients will be available after final follow-up Preliminary analysis: Results of the first 100 PREVENT subjects followed up to 6 months Poster presented at AHA, Nov 2015 by Ramesh Emani, MD, Ohio State University, on behalf of the PREVENT Study Investigators

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