The HeartMate 3 LVAD Mandeep R. Mehra, MD Medical Director, BWH Heart and Vascular Center Professor of Medicine, Harvard Medical School Editor in Chief, The Journal of Heart and Lung Transplantation Disclosures: Thoratec, St. Judes, Boston Scientific, J and J (Janssen), NIH, ABIM, Stealth Peptides, TEVA

The Achilles Heel: Hemocompatibility Loscalzo 2012 NEJM

Device Configuration HM II P1P2 R C D E HM 3 Full MagLev Centrifugal, wide gaps 2-10 L/min Modular Drive Line Intrinsic Pulsatility

Wider and “Consistent” Gaps – HeartMate 3 secondary flow paths are ~0.5 mm along the side, and ~1.0 mm pump above and below the rotor. – Conversely, hydrodynamic bearings are typically operated with much smaller gaps, 0.05 of a millimeter or so

Relevance of Wider Gaps? From a Red Blood Cell’s Point of View Gap Size# of Red Blood Cells Full MagLev1,000μm167 Hydrodynamic Bearing 50μm8 6-8 μm Stacked RBCs

Novel LVADs: Instrinsic Pulsatility Potential benefits: Designed to promote washing of the pump Prevents the formation of zones of recirculation and stasis. Zero Net Change in Flow Speed ramps up and down (zero net change) Potential Clinical Benefits 1-3 Decrease in arteriovenous malformations, a syndrome associated with persistently low pulse pressure? FS 0.20 FS-2000 FS+2000 time [ s ] rotor speed [ rpm ] 1.Tsai H. S., et al. Semin Thromb Hemost 2003;29(5): Malehsa D, Meyer AL, Bara C, Struber M. Eur J Cardiothorac Surg 2009;35: Crow S, John R, Boyle A, Shumway S, Liao K, Colvin-Adams M, Toninato C, Missov E, Pritzker M, Martin C, Garry D, Thomas W, Joyce L. J Thorac Cardiovasc Surg 2009;137: Exclusively for clinical investigations. CAUTION - Investigational device. Limited by US Federal law to investigational use.

HQ Curves of the HM II (Orange) and HM 3 (Green) HM 9000 RPM HM 5400 RPM a pressure change of 10 mmHg has a more profound efect on flow on the HM II than HM 3

HeartMate 3 CE Mark Trial GI Bleeding numerically lower than previous trials Neurological events open to some debate Netuka et al JACC December 2015

MOMENTUM 3 (Multi-center Study of MagLev Technology in Patients Undergoing MCS Therapy with HeartMate 3™) Heatly G et al JHLT 2016

“Despite being listed at the time of implant, nearly 30% of patients receiving implantation as BTT were still on support at 2 years. Furthermore the strategic intent remains fluid over time; at 2 years 43.5% of BTT who were still on support were no longer listed for transplant. These results challenge the current paradigm of implant strategy as either BTT or DT.” Teuteberg, J.J., et al. Implant Strategies Change Over Time and Impact Outcomes Insights From INTERMACS. JACC HF, (5): p Challenging the current BTT/DT Paradigm

All Comers Trial: Patients randomized to HM 3 or HM II cohort regardless of intended use at the time of implant –Single Inclusion/Exclusion criteria for both Short Term (BTT) and Long Term (DT) use –Global Indication for Use: A step in the Heart Failure Journey irrespective of “forks” –Hypothesis driven test at 6 (short term) and 24 months (long term) to demonstrate HM 3 is non-inferior to HM II with a 10% margin and alpha = HM 3 IDE: “All Comers” ADAPTIVE Trial Design Primary endpoint is a composite of survival free of debilitating stroke (Modified Rankin Score > 3) or the need for a pump exchange Secondary objectives include assessment of adverse events, quality of life (EuroQol-5D-5L and Kansas City Cardiomyopathy Questionnaire), functional status as measured by the six-minute walk test and New York Heart Association (NYHA) Class, device malfunctions, and need for reoperations or rehospitalization

Adaptive “seamless” design will be used to determine if sample size adjustments needed at pre- specified times during the study –Pre-specified interim analysis for Short Term indication when first half (147) have reached 6 months F/U Study calls for required sub-group analysis for gender, ethnicity, and intended use at time of implant Avoid “CAP Gap” by pre-specifying a powered secondary endpoint analysis (pump replacement) to evaluate HM 3 for superiority MOMENTUM 3: “ADAPTIVE” Trial Design

HM 3 IDE TRIAL: STUDY FLOW Heatley et al. JHLT April 2016 * Economic analysis of cost of care embedded in trial

MOMENTUM 3

The Opportunity –A novel device with features that promises better hemocompatibilty –A unique trial design that promises to change the way we think and apply durable MCS therapy The Outcome Expectation –Advance the field, improve the way we think - all while reducing suffering and cost of care Key Points