1. Analysis of Pump Thrombosis in the Intermacs Database Michael Acker William Measey Professor of Surgery Chief of Division of Cardiovascular Surgery Director of Heart and Vascular Center University of Pennsylvania Health System 1

2. Disclosures Consultant for Thoratec and Heartware 2

3. 3 Perceived increase in incidence of HMII pump thrombosis after 2011 by several large VAD centers compared to HMII pivotal trial FDA/NHLBI request Intermacs to investigate

4. INTERMACS: HeartMate II Pump Analysis Implants: April 2008 – December 2012, n=6910 Follow-up: Through June 2013 4 Months post implant Event: Death – with a device in place (censored at transplant and recovery) % Survival Overall Survival Months post implant% Survival 1 95% 3 91% 6 87% 12 80% 24 69% 36 58% 48 46% n=6910, deaths=1772 Figure 1

5. INTERMACS: HeartMate II Pump Analysis Implants: April 2008 – December 2012, n=6910 Follow-up: Through June 2013 5 Months post implant Event: Death – with a device in place (censored at transplant and recovery) % Survival p(overall) =.63 Implant Year nDeaths (with a device in place) 2008 459139 2009 866247 20101585522 20111845481 2012 2155383 Totals6910 1772 Figure 2 No change in survival by Implant year

6. INTERMACS: HeartMate II Pump Analysis Implants: April 2008 – December 2012, n=6910 Follow-up: Through June 2013 6 Months post implant Event: Device Exchange (censored at death, transplant and recovery) % Freedom from Device Exchange Implant Year nEvents 2008 459 38 2009 866 60 20101585158 20111845157 2012 2155148 Totals6910561 p(overall) <.0001 Figure 3 Increase in pump exchange per year

7. 7 INTERMACS: HeartMate II Pump Analysis Implants: April 2008 – December 2012, n=6910 Follow-up: Through June 2013 Main Event Exchanges or deaths due to thrombus n=382 Device Removal Events n Removed (exchanged) due to a problem561 Thrombus 288 Elective 94 Emergent 177 Unknown 17 Probable Thrombus 49 Elective 25 Emergent 21 Unknown 3 Infection (Not thrombus) 76 Elective 38 Emergent 11 Unknown 27 Not Thrombus/Unknown Infection 120 Elective 52 Emergent 68 Not Thrombus/Not Infection 28 Unknown 28 Device removed due to recovery133 Death: Device not functionally normally 98 Thrombus 27 Probable Thrombus 18 Not Thrombus 53 Totals792 Table 1

8. % Freedom at Implant Year nEvents6 mos12 mos36 mos 2008 459 18 99% 98% 92% 2009 866 23 99% 99% 95% 20101585 88 98% 97% 90% 20111845118 96% 94% ---- 2012 2155135 94% 93% ---- Totals6910382 INTERMACS: HeartMate II Pump Analysis Implants: April 2008 – December 2012, n=6910 Follow-up: Through June 2013 8 Months post implant Event: Device Exchange or death due to thrombus* (censored at death, transplant and recovery) % Freedom from Device Exchange or death due to thrombus p(overall) <.0001 Increase in pump exchange/death due to thrombus or death from 1% to 6% *Thrombus events include ‘probable’ thrombus events Figure 5

9. INTERMACS: HeartMate II Pump Analysis Implants: April 2008 – December 2012, n=6910 Follow-up: Through June 2013 Pump Exchanges due to Thrombus: n=337 Exchange Era ElectiveEmergent Total 2008-2010 9 (24.3%) 28 (75.7%) 37 (100.0%) 2011-2013*110 (39.3%)170 (60.7%)280 (100.0%) Overall p value =.08 * 2013 includes exchanges from 01/01/2013 through 06/30/2013 Table 2

10. INTERMACS: HeartMate II Pump Analysis Implants: April 2008 – December 2012, n=6910 Follow-up: Through June 2013 10 Months post Implant Event: Device exchange or death due to thrombus % Freedom from exchange or death due to thrombus n=6910, events=382 Hazard Events/Month Figure 4 Months% Freedom 6 97% 12 95% 24 92% 48 86%

11. INTERMACS: HeartMate II Pump Analysis Implants: April 2008 – December 2012, n=6910 Follow-up: Through June 2013 11 Months post implant Event: Device Exchange or death due to thrombus* (censored at death, transplant and recovery) % Freedom from Device Exchange or death due to thrombus p(overall) <.0001 % Freedom by implant year *Thrombus events include ‘probable’ thrombus events Figure 6 Events/Month Hazard by implant year

12. Occurrence and Incidence of Confirmed Pump Thrombosis Stratified According to Implantation Date. Starling RC et al. N Engl J Med 2014;370:33-40

13. INTERMACS: HeartMate II Pump Analysis Implants: April 2008 – December 2012, n=6910 Follow-up: Through June 2013 Risk Factors for Device Exchange or Death due to Thrombus (Time Zero = 1 Month Post Implant) Table 4 Risk Factor hazard ratio p-value Implant year (later)1.46<.0001 Age (younger)1.25 1 <.0001 White race 1.42.0003 BMI (larger)1.20 2.01 LVEF above 20%1.44.003 LDH at 1 month (higher)3.16 3 <.0001 1 Hazard ratio denotes the increased risk for a 60 year compared to a 70 year old patient 2 Hazard ratio denotes the increased risk for a 10 unit increase in BMI 3 Hazard ratio denotes the increased risk for an increase in LDH from 500 to 1000 units BMI, body mass index; LVEF, left ventricular ejection fraction; LDH, lactate dehydrogenase

14. LDH group nEvents Missing4581223 0-4001318 52 401-1000 819 66 > 1000 192 41 Totals6910382 INTERMACS: HeartMate II Pump Analysis Implants: April 2008 – December 2012, n=6910 Follow-up: Through June 2013 14 Months post implant Event: Device Exchange due to Thrombus** (censored at death, transplant and recovery) % Freedom from Device Exchange or Death due to Thrombus p(overall) <.0001 By LDH Groups ** Thrombus events include ‘probable’ thrombus LDH, lactate dehydrogenase Figure 13

15. INTERMACS: HeartMate II Pump Analysis Implants: April 2008 – December 2012, n=6910 Follow-up: Through June 2013 15 Months post implant Event: Death – with a device in place (censored at transplant and recovery) % Survival 1 st device, n=6910, deaths=1604 Exchange due to Thrombus n=337, deaths=80 p(overall) <.0001 Figure 8 Exchange due to Infection/Other n=224, deaths=66

16. INTERMACS: HeartMate II Pump Analysis Implants: April 2008 – December 2012, n=6910 Follow-up: Through June 2013 Primary Cause of Death within 3 months Table 3 After Pump Exchange or After Primary Implant*death due to Thrombus Primary Cause of Death n % n % Circulatory Failure21734.7% 533.3% Multisystem Organ Failure11418.2% 640.0% CNS Event 8814.1% 213.3% Infection 51 8.1% 1 6.7% Respiratory Failure 48 7.7% 1 6.7% Device Malfunction 11 1.8% 0 0.0% * Censored at devices exchange CNS, central nervous system

17. INTERMACS: HeartMate II Pump Analysis Implants: April 2008 – December 2012, n=6910 Follow-up: Through June 2013 17 Months post Implant Event: Time to first Infection % Freedom from Infection p =.008 n=6910, events=3206 n=337, events=131 Figure 9

18. INTERMACS: HeartMate II Pump Analysis Implants: April 2008 – December 2012, n=6910 Follow-up: Through June 2013 18 Months post Implant Event: Time to first CVA % Freedom from CVA p <.0001 n=6910, events=619 n=337, events=37 Figure 10 CVA, cerebrovascular accident

19. 19 INTERMACS: HeartMate II Pump Analysis Implants: April 2008 – December 2012, n=6910 Follow-up: Through June 2013 Main Event n=337: Exchanges due to Thrombus Median Visual Analog Scale (VAS) 1 st Operation (n) 181 119 90 53 36 21 12 5 2 2 2 1 2 nd Operation (n) 23 86 72 29 17 6 4 2 1 1 ---- ---- 2 nd Operation (exchanges due to thrombus) Median p value.05.72.83.79.61.31.53 --- ---- ---- ----- ----- Figure 12 1st Operation (prior to exchange)

20. 20 INTERMACS: HeartMate II Pump Analysis Implants: April 2008 – December 2012, n=6910 Follow-up: Through June 2013 Median INR – 1month post implant forward INR Post Implant Follow-up by Quarter/Year Figure 14 INR, International normalized ratio

21. 21 INTERMACS: HeartMate II Pump Analysis Implants: April 2008 – December 2012, n=6910 Follow-up: Through June 2013 Median INR – 1month post implant forward % of Patients Post Implant Follow-up by Quarter/Year p(overall) =.22 Figure 15 INR, International normalized ratio; pts, patients

22. Limitations Pump Design/Production Intermacs can not give granular data on subtle differences/changes in clinical practice/patient selection overtime that may affect outcome –Implantation techniques ie inflow angles –Intensity of anticoagulation; compulsive f/u –heparin bridging; –Pump speed vs AV opening –BP management 22

23. Changes Over Time GI bleeding –decrease in anticoagulation goals –Elimination of heparin bridging –Decrease rpms to allow AV opening 23 Pump Design/Production –2011 changes in outflow graft ; bend relief software changes –2011 Marked ramp up in production

24. Summary 6 fold Increase in Pump Exchange or death due to thrombosis in 2011 to 6% from 1% in 2009 Early Hazard of Pump thrombosis in first 3 months after 2011 not seen prior to 2011 Overall survival not changed (I yr 80%) BUT if you have a pump exchanged for thrombosis your survival is decrease (1 yr 70%) and your chance of stroke or infection is increased 24

25. Summary Risk factors for early Pump thrombosis is predominantly Pt year (2011) and early LDH rise after implant; other risk factors younger age; white; large BMI; LVEF > 20% 25

26. Conclusions (personal not intermacs) Most important change post 2011 is not increase rate of thrombosis but new early hazard of thrombosis< 3 months; – different than late thrombosis –Whatever is happening is happening in the OR or early postop –Importance of HMII inflow cannulae ventricular alignment; bridging heparin –Early LDH rise not seen prior to 2011—causative or result of early thrombus? Great variations of incidence of thrombosis between sites ( 1% to >20%) –Detailed statistical review of different site practices (consortium of high and low incident sites) is needed to determine subtle difference in operative/implantation and pt care practices that may elucidate important risk factors for thrombosis –Will allow hypothesis generation to validate in prospective study (PREVENT) Therapeutic window for HMII is more narrow now than prior to 2011 –Multifactorial etiology- pump; implantation; pump management (anticoagulation, speed); patient; patient care ?Anticoagulation goals in high thrombosis incident sites higher now than prior to 2011 Importance of pump flow pass the bearing to dissipate heat—rpms > 9000 if possible Continued Thoratec review of manufacturing practices and changes made in pump in 2011 26