Chetan B. Patel, MD

Assistant Professor of Medicine

Duke Cardiac Transplantation and Mechanical Circulatory Support Program

LVAD Complications: Bleeding and Clotting

Duke Advanced Heart Failure SymposiumOctober 5th 2013

Disclosures

• Consultant for Thoratec Corp and Heartware Inc.

* Off label use of eptifibitide, tissue-plasminogen activator

LVAD therapy

• Improving survival• 15,000 Heartmate II devices have now been implanted worldwide• Impact of mechanical circulatory support on the natural history of

heart failure and vice versa• Effect of continuous flow on the human circulation

Kirklin JK, et al JHLT 2012; 31:117-26.

LVAD therapy: Challenges Ahead

Right Heart FailureTricuspid Regurgitation

Aortic Insufficiency

“Walking” Ventricular Tachycardia

Bleeding Thrombosis

LVAD therapy: Challenges Ahead

• Predictable: • Artificial (metal) surface in contact with human circulation• Moving Parts• Systemic Anticoagulation

• Unpredicted:• Impact of non-pulsatile flow on bleeding• Interaction between LVAD and the coagulation system

independent of anticoagulation

Anticoagulation Strategies for Continuous Flow LVADs

Historical Perspective

– Initial experience with early version of the HMII demonstrated high pump thrombosis rate (40%)

– Pump re-design and call for higher levels of anticoagulation (INR 2.5-3.5)

– Practice guidelines suggested INR 2.0-3.0

– Dual antiplatelet therapy

– Perioperative heparin

J Heart Lung Transplant 2010; 29:S1-S39

Early Bleeding/ThrombusHeartMate II Destination Therapy Trial

CF LVAD (n=133)

[211 pt-years] PF LVAD (n=59)

[41 pt-years]

Events/pt yr Events/pt yr Risk Ratio [95% Confidence

Interval] p-value

Pump Replacements 0.06 0.51

<0.001

Stroke 0.13 0.22 0.21

Ischemic 0.06 0.10 0.38

Hemorrhagic 0.07 0.12 0.33

Device-related infection 0.48 0.90 0.01

Local non-device infection 0.76 1.33 0.02

Sepsis 0.39 1.11 <0.001

Bleeding

Bleeding requiring PRBC 1.66 2.45 0.06

Bleeding requiring surgery 0.24 0.29 0.57

Other Neurological 0.17 0.29 0.14

Right Heart Failure

Extended Inotropes 0.14 0.46 <0.001

RVAD 0.02 0.07 0.12

Cardiac Arrhythmias 0.69 1.31 0.006

Respiratory Failure 0.31 0.80 <0.001

Renal Failure 0.10 0.34 <0.001

Hepatic Dysfunction 0.01 0.00

Device Thrombosis 0.02 0.00

Re-hospitalizations 2.64 4.25 0.02

0.0 0.5 1.0 1.5 2.0

Favors CF LVAD Favors PF LVAD

N Engl J Med 2009; 361: 2241-51

Early Bleeding/ThrombusHeartware HVAD Bridge to Transplant Study

Suarez J et al. Circ HF, 2011

Aaronson et al. Circulation, 2012

VAD Therapy goes Beyond The Surgery

• To date > 60 HMII devices in 2013

• >75 durable LVADs implanted

• Over 170 patients currently on device support

• Patient-pump exposure

Calendar 2011 Data from Annual Heart Report

Suarez J et al. Circ HF, 2011

Non-Surgical Bleeding after Continuous Flow Pump Support

• 33 pts Montefiore• 20 pts HMII• 13 other

(9 VentrAssist)• 8 GIB HMII

J Card Surg, 2010

Non-Surgical Bleeding

Texas Heart Institute• 172 HMII patients THI• 19% bleeding episode• Majority from AVMs

Demirozu et al. J Heart Lung Transplant 2011

• Association made between AVM formation and severe aortic stenosis- Heyde’s Syndrome• Associated with low pulse pressure

Aorta

Left

ventricle

CF LVAD Speed

mm

Hg

LVAD Physiology

Ao

valve

Increasing LVAD speed leads to decreased contribution of left heart and a narrow pulse pressure

Acquired Von Willebrand Disease

Bleeding after Continuous Flow Pump Support

37 CF VAD patients at Duke and University of Minnesota

Plasma collected and stained for HMW vWF

100% of patients demonstrated loss of HMW vWF

10/37 patients had bleeding complications

Corrects after cardiac transplantation

Crow et al. Ann Thoracic Surg, 2010Uriel et al. JACC, 2010

Increased intraluminal pressureLower pulse pressure;hypoperfusion

Angiodysplasia (Heyde’s Syndrome)

GI Bleeding

Decrease in HMW multimers leading to impaired anticoagulation

Acquired vWD

vWF fragments Impaired platelet aggregation

Continuous Flow Device

Non-Surgical Bleeding after Continuous Flow Pump Support

N= 71 with 156 readmissions (4year) , 19% of all readmissions related to bleeding

N=83 with 224 readmissions ( 3 year) , 66 readmissions in 34 patients (30% overall) related to bleeding

Ann Thorac Surg 2013;95:1276–81)

J Am Coll Cardiol 2013;61:153–63

331 patients from a CF VAD BTT

trial

10 patients with thrombotic events

and 58 hemorrhagic events

Some centers reduced INR goal to

1.5-2.0 based on bleeding events

ASA 81 mg daily

No postoperative heparin

J Heart Lung Transplant 2009; 28:881-7

Suarez J et al. Circ HF 2011

Management of Gastrointestinal Bleeding in Axial Flow VADs

To do list:

Fix bleeding issues with LVAD therapy

The Other Side of the Bleeding-Clotting Quagmire

Romano et al. ISHLT 2011

• Event-free survival decreased with evidence of hemolysis

• Pump thrombus = Hemolysis?

What defines thrombosis?

Hemolysis DefinitionsINTERMACS: Plasma free Hgb > 40 mg/dl occurring > 72 hours post-implantHeartMate II DT Trial: 2 plasma free Hgb >40 mg/dl within 24 hours of each other and an LDH > 1000 mg/dl within the same 24-hour periodADVANCE: plasma free Hgb > 40 mg/dl

• Will add cine image of aortic outflow with possible thrombus at CT

Thrombosis is “invisible”

Managing Thrombotic Events

• Pump thrombosis may present with:

– Thromboembolism

– Hemolysis (LDH, haptoglobin, plasma free Hgb)

– Increasing power consumption with high flow rates

– Abrupt pump dysfunction (stoppage)

• Treatment will depend upon acuity, impact on patient, and pump performance

• Anticoagulation and antiplatelet therapy is device-specific

• Adopted a stepped approach to treatment of pump thrombosis• Enhanced anticoagulation• Targeting different

components of the coagulation cascade

Circ Heart Fail. 2012;5:e68-e70

Duke Experience with Lytic Therapy

Under Review, J Card Fail

TPA

Duke Experience with Lytic Therapy

Under Review, J Card Fail

Bleeding Thrombosis

LVAD therapy: Challenges Ahead

Stulak et al. J Heart Lung Transplant 2013, epub

Increased intraluminal pressureLower pulse pressure; hypoperfusion

Angiodysplasia (Heyde’s Syndrome)

GI Bleeding

Decrease in HMW multimers leading to impaired anticoagulation

Acquired vWD

vWF fragments Impaired platelet aggregation

Continuous Flow Device

Bleeding after Continuous Flow Pump Support

Challenges = Opportunities

• Novel anticoagulants

• Balance between antiplatelet therapy and anticoagulant

• Intermittent pulsatility

• Medical therapies to counteract acquired von-Willebrand’s disease

• Pump Redesign

• Novel biomarkers

Characteristic Total (N=49) Ischemic (N=33) Non-Ischemic (N=16)

Age, years 69.6 (54.0-73.6) 70.0 (64.3-74.1) 54.7 (41.7-72.5)

Male, % 71.4 78.8 56.3

BMI 31.1 (26.5-35.5) 28.7 (26.5-34.2) 34.4 (24.7-39.2)

Caucasian, % 71.4 84.9 43.8

Heartware Use, % 34.7 36.4 31.3

Ve-VO2 Slope 42 (35-47) 42 (36-47) 44 (31-47)

NT-proBNP, pg/mL 3287 (2007-4810) 3067 (2037-3927) 4758 (1977-5869)

Galectin-3, ng/mL 24.3 (16.3-35.0) 24.0 (20.1-32.3) 24.7 (14.8-38.0)

Copeptin, pmol/L 419 (374-550) 425 (374-550) 389 (378-514)

MR-proADM, nmol/L 210 (183-303) 206 (183-244) 231 (190-361)

Soluble ST2, ng/mL 61.2 (42.8-112.8) 56.5 (41.7-102.0) 67.5 (52.3-226.3)

Ahmad et al. AHA 2013

Summary

• LVAD therapy improves survival and quality of life in patients with advanced heart failure

• Continuous flow has provided a new set of challenges and unique physiology

• The bleeding-clotting paradigm problem has been an area of intense interest-associated with high readmission rates and morbidity

• Future work will focus on altering the impact of continuous flow on human circulation