Continuous Flow LVADs: A New Physiology Ulrich P. Jorde, MD Associate Professor of Medicine Medical Director, Mechanical Circulatory Support Programs Columbia University

Heartmate I 1 kilogram 2 valves Pulsatile - large abdominal pocket

First Generation LVADs Design Limitations due to perceived need for pulsatility Too big Pocket infection Too noisy

Does man need pulsatile flow ? Source: Any physiology textbook

HM II: Axial Flow pump 342 grams No valves No pulse No pocket

Survival HM II : 58% Survival HM I : 23 % Survival Med Rx: 8% ?!

Current 1-year success on HM II support awaiting HTX: 85% Absolute improvement of 17% over time WITHOUT change in pump technology This improvement is due to clinical experience with a new physiology, continous flow. When “n” is small, IME* is big (again) John R, Naka Y, Smedira SG, Starling R, Jorde U, Eckman P, Farrar D, Pagani F. JACC 5/2011 * IME = In My Experience

Case Presentation 69 year old man with h/o Afib / ICM. HM II implant 4 months prior Uncomplicated postoperative course CC: Melena Labs: Hgb 7.4 INR 1.8 plt 176 Dx: Upper GI bleed ?

Case Continued EGD: Negative Colonoscopy: Negative Hgb 8.4 after 2 Unit PRBC. INR 1.2 Dx: AV malformation ?

Capsule Study Why is he bleeding now? Are these AVMs new?

GI Bleeding and AVMs in Cardiovascular Disease Aortic Stenosis and Von Willebrand Factor Deficiency Sadler, NEJM 2003;394:4

Normal vessel Vascular Injury Platelet-Plug Von Willebrand factor (VWF) is a large multimeric glycoprotein that is synthesized in endothelial cells and megakaryocytes Normal vessel Vascular Injury Acts as a bridging molecule for platelet adhesion/ aggregation at vascular injury sites When the vessel wall is intact, plasma von Willebrand factor that is present in a coiled structure and platelets coexist in circulating blood with minimal interactions. von Willebrand factor and collagen fibrils localized in the subendothelial extracellular matrix. In the event of blood vessel damage, von Willebrand factor is released from the exposed subendothelial matrix, and uncoils, in order to facilitate adhesion of circulating platelets to the lesion in synergy with collagen. Once platelets are activated (represented by irregular margins), receptor IIb3 (as shown as yellow crosses) bind to von Willebrand factor This event, allows IIb3 to bind platelets to the vessel wall and to others platelets that eventually lead to platelet-plug formation mediated by von Willebrand factor. Platelet-Plug Mannucci P. N Engl J Med 2004;351:683-694

HM II Rotor Induces Shear Stress Geisen Eur J CTS 2008: vWF deficiency in HM II recipients

Normalization of vW Factors After Transplant In all 6 patients, who had VWF levels measured during HMII support and repeated after heart transplantation, there was normalization of the HMW vWF multimers levels Statistically significant elevation in the VWF:Ag and VWF:Rco. Uriel et al. JACC 2010 15

35/79 patients had bleed requiring > 1 unit blood transfusion after POD 7 Uriel et al. JACC 2010

High Incidence of Bleeding During HM II Support Recently our group reported high incidence of bleeding requiring transfusing during HM II support. With increase risk of bleeding among older patients reaching 66% of the patients. Uriel et al. JACC 2010

Anticoagulation Trial Protocol Heparin postop Coumadine (INR 2-3) ASA 81 Persantine 75 TID 5 % CUMC Protocol Change 2007 No heparin post-op 2010 INR goal 2 ASA 81 mg 2 %

Should we replace vWf at time of HTX (or other major procedures) ? Double-blind, placebo controlled Study of VWF versus Placebo in patients with HM II undergoing Cardiac transplant. Bleeding Clotting Sensitization Rejection

Less bleeding, more clotting ? Embolic event Bleeding Age /Low albumin vwF deficiency Anticoagulation Afib / Age / Female sex Infection Low INR Can change Fixed * * Generally speaking

Device Thrombosis: Definition * Device Thrombosis: Any obstructive thrombus in the device or its conduits associated with clinical symptoms of impaired pump performance (e.g. decreased pump flow, need to increase pump speed, increased power, hemolysis) or the need for thrombolytic or surgical intervention. In addition, pumps will be analyzed at Thoratec. Any severe thrombus scored as a level 3 thrombus (>50% obstruction) will be captured as an event. Hemolysis: Two consecutive plasma-free hemoglobin (PFHgb) values greater than 40 mg/dl within 24-hours of each other and an LDH value greater than 1,000 mg/dl within the same 24 - hour period. * Supplement to: Miller LW, Pagani FD, Russell SD, et al. Use of a continuous-flow device in patients awaiting heart transplantation. N Engl J Med 2007;357:885-96.

Is this Device Thrombosis ?

A Case of Device Thrombosis ? 52 yo woman HM II 24 months ago (2nd device, failed explant; initially nl LVEF deteriorated over 8 weeks) Chronic Driveline Infection Surveillance LDH 1700 (Plasma free Hgb 20 mg/dl) . INR 2.2 (ASA 81/ Coumadin). Power 6 PI 4 TTE ?

Device Thrombosis Role of Ramp Study Speed optimization Examine interaction of pump,LV cavity and valvular function during different flow conditions. Optimize LVEDD / RV function Optimize AV opening Optimize MR 2. R/o Device thrombosis Examine flow through device Does LVEDD decrease appropriately ?

Ramp Study (Goal Speed: AV opening, no MR) Therapeutic Anticoagulation ! R/o LV clot ! R/o AV clot ! Parasternal long axis view Drop Speed to 8000 Acquire LVEDD, MR, AI, AV opening Increase speed every 2 min Assess BP LVEDD, MR, AI, AV at each stage Stop if: Suction or VT LVEDD < 3 cm 12000 rpm

Suspicious (? diagnostic) Ramp Test Elevated LDH =1710 and High plasma free Hgb = 20.2

Is this Device Thrombosis ? LDH 1700 to 3000 Scr 1.1 to 2.3

The Uriel Threshold

Test at time of Suspicion versus Test done Predischarge for Speed Optimization LDH 1700 LDH 320 LDH 400

Device Thrombosis We will see it more often in DT patients - longer support times - need to hold anticoagulation - comorbidities (infection) set up prothrombotic state Need to develop early detection & management algorythms

Aortic Insufficiency in HM II

AI due to Constant Aortic Root Pressure > 80 mmHg ?

Mechanism of AI Development Aortic Insufficiency develops in HM II. Why ? Picture Courtesy of Hiroo Takayama, MD

Commissural Fusion and AI in HM I Patient Connally, Frazier et al Journal of Heart and Lung Transplantation 2003; 22: 1291-1295

Degrees of AV Fusion Jorde et al. Columbia continuous flow pumps AI prospective study

De novo AI during HM II Support: 25% @ 1 Year (n=140 , Columbia) Mechanistic observations AI present if: Ao root large AV does not open AV closed AV opens AI 66% 8% J Heart Lung Transplant Oct 2010

Mechanism of AI Development Aortic valve does not open Aortic valve leaflet fusion occurs Aortic Insufficiency Solution: Maintain device speed in a range where AV opens intermittently Ramp Study for Device Optimization at Time of Discharge

Heartware: Has the future arrived ?

Heartware 91% 6 months survival in BTT trial Easier implant ? No sternotomy ? Less bleeding ? Interference with ICD leads ? vW deficiency : Yes ! Thrombus formation

Understanding complications translates into better outcomes ! Criteria for DT: - Class IIIb/IV systolic CHF - Failing OMM (45 /60 days) - No irreversible endorgan dysfunction (i.e. HD) - Motivated patient who can manage device. Park SJ, Milano C, Tatooles AJ et al. AHA 2010

VAD Volume Growth @ Columbia 11 long term VADs in Jan 2012 HM II DT approval 10% DT 50% DT 2016 100 Long Term 80% DT 2006 2007 2008 2009 2010 2011* projected

Continuous-Flow LVAD Destination Therapy Versus Orthotopic Heart Transplantation in Patients above 65 Years of Age DT patients - Not OHT candidate - Median age 73 yrs - LVEF 15% - CI 1.8 l/min - 58% inotrop S. Melnitchouk, U. Jorde, H. Takayama, N. Uriel, P. Colombo, J. Yang, D. Mancini, Y. Naka. ISHLT 2011

Device of the Future Current actual pumps already adequate ? Driveline needs to go (No infection, no prothrombotic state, less emboli) Smart software permitting AV opening and rpm increase with exercise Smaller, lighter batteries – cellphone charger

Thank you ! Yoshifumi Naka, MD LVAD Team Columbia