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PREVEN tion of Pump T hrombosis Through Clinical Management (PREVENT)

PREVEN tion of Pump T hrombosis Through Clinical Management (PREVENT). John M. Stulak, MD Mayo Clinic. INTRODUCTION: Study Background. Confirmed thrombus at 3 Months 2.2% before March 1, 2011 8.4% after M arch 1, 2011 ~15% predicted into 2013 and exponentially rising.

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PREVEN tion of Pump T hrombosis Through Clinical Management (PREVENT)

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

  2. INTRODUCTION: Study Background • Confirmed thrombus at 3 Months • 2.2% before March 1, 2011 • 8.4% after March 1, 2011 • ~15% predicted into 2013 and exponentially rising 1Starling, Moazami, Silvestry, et al NEJM 2014 2Kirklin, Naftel, Kormos et al JHLT 2014 Recent studies have indicated that incidence of pump thrombosis has gone up with the HM2 LVAD1,2, with the rates continuing to increase1

  3. INTRODUCTION: Varying Experience 1Stulak & Maltais NEJM 2014; 370: 1467-1468 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

  4. INTRODUCTION: Varying Experience • Schmitto et al. • Hoefer et al. • O.H. Frazier 2004 – 2013 3/134 (2.2%) “No recent increasing trends….” 2007 - 2014 0 in 6265 patient-days of support “inadequate AC…probable cofactor” 2003-2013; 432 patients 2003-2011: 0/232, 2011: 7/88, 2012: 11/69 Since 2013: 3/54 “problem resolving”

  5. 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

  6. Study Design

  7. STUDY DESIGN: Primary & Secondary Objectives • Study Design • Prospective, multi-center, single arm, un-blinded, non-randomized, study • Number of Patients: Up to 300 • Number of Sites: 24 • Primary Objectives • Assess the incidence of HM II pump thrombosis in the current era when recommended practices for clinical management are adopted. • Identify risk factors associated with pump thrombosis events • Secondary Objectives • The incidence of pre-defined anticipated adverse events and rehospitalizations while on support • Survival while on HM II LVAD support • Adherence to the recommended practices outlined in Appendix I of the protocol

  8. STUDY DESIGN: Inclusion & Exclusion Criteria INCLUSION CRITERIA Informed consent Subject is receiving the HeartMate II as their first LVAD in accordance with FDA approved indications for use Age ≥ 18 years EXCLUSION CRITERIA Ongoing mechanical circulatory support (MCS) other than intra-aortic balloon pump 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 

  9. Endpoints • 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

  10. Overview of PREVENT Recommended Practices

  11. 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. 2015 Mar;30(3):296-9

  12. PREVENT RECOMMENDED PRACTICES: Anticoagulation/ Antiplatelet Therapy • Begin bridging with unfractionated heparin or LMWH within 48 hrs • goal PTT of 40-45 sec in the first 48 hours • Titration to a PTT of 50-60 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: 2.0-2.5 • Maintain a target INR 2.0-2.5 throughout device support • Initiate aspirin therapy (81-325 mg daily) 2-5 days post HMII implantation

  13. 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 trial1 • Day 1: 9150 ± 495 rpm; flow est: 5.1 ± 0.9 l/min; index: 2.6 ± 0.5 l/min/m2 • Day 180: 9405 ± 448 rpm; flow est: 5.4 ± 0.9 l/min; index: 2.7 ± 0.5 l/min/m2 • 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 1 Slaughter MS et al. J Heart Lung Transplant 2010;29:S1-39.

  14. Study Status

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

  16. PREVENT Enrollment by Site As of November 10th, 2105

  17. Study Schedule and Data Release Plan • Feb 5th, 2016: 3 month follow-up completed on all 300 subjects • March 1st, 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 30th, at 10:40 AM • Dr. Simon Maltais from the Mayo Clinic will be presenting the primary endpoint results

  18. 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

  19. 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

  20. Results – Baseline Characteristics 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

  21. 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

  22. Results - Adherence Pump implanted not adherent to the recommendations Distribution of Median INR/Pt. ( >14 days to outcome or 181 days) Pump implanted adherent to the recommendations Median INR/Patient: 2.2 [IQR: 1.9-2.4] Adherence to Other Recommended Practices • Deep Pocket • Cannula at ~20° • Pump almost 90° to spine • Pump anchored • Shallow Pump Pocket (Pump is High) • Cannula is vertical and appears to be pointing towards the lateral wall • Pump is not 90° to spine • Pump not anchored 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

  23. Results – Survival & Adverse Events Overall Survival 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

  24. Summary 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 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

  25. Questions?

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