1. Hemolysis in Patients Supported with Durable, Long-Term Left Ventricular Assist Device Therapy Jason N. Katz, MD,MHS; Brian C. Jensen, MD; Patricia P. Chang, MD, MHS; Susan L. Myers, BBA; Francis D. Pagani, MD, PhD; James K. Kirklin, MD

2. DISCLOSURES None

3. BACKGROUND Despite the beneficial effects of LVAD therapy, most patients will suffer an adverse event after device implantation Hemolysis is a known complication of MCS – 1 out of 10 in patients with short-term support 1 – Rare early after durable LVAD placement? 2 1 Bennett M, et al. Perfusion 2004. 2 Genovese EA, et al. Ann Thorac Surg 2009.

4. BACKGROUND HeartMate II Destination Trial 1 – Hemolysis incidence  4% (0.02 events/pt-yr) HeartMate II Bridge-to-Transplant Trial 2 – Hemolysis incidence  4% (0.06 events/pt-yr) 1 Slaughter MS, et al. NEJM 2009. 2 Pagani FD, et al. JACC 2009.

5. BACKGROUND Hemocompatibility with LVAD impacted by: – Blood-surface interactions – Alterations in flow-dynamics – Changes in coagulation – Abnormalities of host immunity Not only is epidemiology of hemolysis in contemporary LVAD populations unclear, but so too are the clinical consequences All may increase hemolysis susceptibility

6. METHODS Data obtained from the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) – represents 117 centers All adult patients with a primary, intracorporeal, CF-LVAD between Jun 2006- Mar 2012 Descriptive statistics, χ 2, Fisher’s exact test, t- test, and Wilcoxon rank-sum test

7. METHODS Hemolysis Event  Plasma-free hemoglobin >40 mg/dL, in association with clinical signs of hemolysis, when occurring at least 72 hours following LVAD implantation

8. METHODS Survival analysis performed using Kaplan- Meier method, with censoring for heart transplantation or cardiac recovery Stratified time-to-event curves compared using the log-rank test

9. DERIVATION OF STUDY POPULATION

10. BASELINE CHARACTERISTICS VARIABLENO HEMOLYSISHEMOLYSISP-VALUE Age (yrs)56.352.7<0.0001 Male sex79.4%72.3%0.01 White race70.2%67.7%0.39 BMI (kg/m2)28.629.90.003 INTERMACS 114.3%14.2%0.99 INTERMACS 240.3%44.2%0.21 INTERMACS 326.0%22.3%0.18 INTERMACS 413.3%13.1%0.91 INTERMACS 53.3%3.1%0.84 INTERMACS 61.9%1.2%0.39 INTERMACS 70.9%1.9%0.11

11. BASELINE CHARACTERISTICS VARIABLENO HEMOLYSISHEMOLYSISP-VALUE Destination Therapy29.0%28.5%0.85 Diabetes39.2%41.5%0.46 CVD7.9%8.7%0.68 Prior CABG22.9%17.7%0.05 Prior Valve Surgery7.3%5.4%0.24 Concomitant Rx Inotrope80.2%82.7%0.32 IABP31.6%33.1%0.62 ECMO2.0%2.7%0.20 No differences in baseline lab values, baseline hemodynamics, or other evaluable characteristics prior to implant

12. Average time to first event = 7.4 ± 0.4 months Younger age (<60yrs) independently associated with hemolysis, p=0.01

13. Average Hematocrit = 28.3% Average Plasma-free Hgb = 115.3 mg/dL

15. CAUSE OF DEATH PRIMARY CAUSE OF DEATHNO HEMOLYSIS (N=863)HEMOLYSIS (N=80) CVA10.2%16.3% Infection10.3%3.8% Right Ventricular Failure4.6%7.5% Hepatic Failure1.0%6.3% Renal Failure2.0%2.5% Device Malfunction1.6%3.8% Hemorrhage9.4%5.0% Unknown/Undocumented12.2%22.5% Other22.9%21.3%

16. Device Malfunction Due to Suspected or Confirmed Thrombosis

17. Patients, N=260 Device malfunction due to thrombus, N=27

18. Need for Device Exchange

19. ≈20% chance of needing device exchange early after event

20. Events Stratified by Year

21. Adult Primary Continuous Flow LVADs, n=4850 Time to 1 st Hemolysis Event by Implant Year Months post implant Freedom from Hemolysis % freedom post Implant Year n events implant at 3 months 2008 442 3097% 2009 825 4498% 2010 1515 8298% 2011 1671 9396% 2012 (March) 397 1195% P(overall) =.005

22. STUDY LIMITATIONS Retrospective study design Candidate variables limited to those collected routinely in INTERMACS – no reliable data on pump speed, cannula position Limited data on concomitant meds (esp. antiplatelet & antithrombotic therapies) More contemporary INTERMACS hemolysis definition (employing LDH & risk stratifying “minor and major” events) not used

23. CONCLUSIONS Hemolysis is relatively common in “real- world” CF-LVAD populations Survival is significantly reduced following a hemolytic event and device exchange is common Need to develop consistent definitions for hemolysis, particularly ones that are reliable despite evolving technologies, patient characteristics, and indications

24. CONCLUSIONS These findings should not temper our enthusiasm for VAD therapy, but rather should compel us to focus on key care processes and best practice principles which will allow our patients to reap greater benefits from the technology Future evaluation should focus on device and implant characteristics leading to hemolysis, as well as appropriate strategies for optimally defining, detecting and managing these events

25. THANK YOU.