Management of Anticoagulation in LVAD Recipients

JoAnn Lindenfeld, MDProfessor of Medicine

Director, Advanced Heart Failure and Transplantation

Vanderbilt Heart and Vascular Institute

Anticoagulation for LVADs: Thrombosis is the Problem

• History of the Problem

• How do we think this happens?

• Potential Causes

• Focus on Under-anticoagulation

• Future Directions

• Those who do not remember history are doomed to repeat it• Voltaire

Occurrence of Confirmed Pump Thrombosis at 3 months after HeartMate II Implantation.

Starling RC et al. N Engl J Med 2014;370:33-40

Starling RC et al NEJM 2014;370:33-40

FDA approvesHVAD for BTTNov 2012

N = 837 patients and 895 devices between 2004 and mid-2013

FDA approvesHM II for DTJan 2010

FDA approvesHM II for BTTApril 2008

Confirmed pump thrombosis at 3 months increasedFrom 2.2% pre-March 2011 to 8.4% by January of 2013

And the median time to pump thrombosis decreasedFrom 18.6 months to 2.7 months

Anticoagulation for LVADs: Thrombosis is the Problem

• History of the Problem

• How do we think this happens?

• Potential Causes

• Focus on Under-anticoagulation

• Future Directions

• Those who do not remember history are doomed to repeat it• Voltaire

HeartMate II

Thrombus

0 1 2 3 6 9 12 24 36 Months post LVAD implant

LDH mg/dL

>1000

800

600

400

200

0No thrombus

Thrombus enlarges and is lysed by LVAD

“Second hit”Infection , lower RPM, etc

HVAD

Clinical Event

Enhanced Anticoagulation

Under-anticoagulation

LDH Values Rise Before Confirmed Pump Thrombosis.

Starling RC et al. N Engl J Med 2014;370:33-40

Event-free survival is markedly decreased after hemolysis onset

Cowger JA et al. Journal of Heart and Lung Transplantation, 2014;33: 35 - 43

Event-free survival (free of death, urgent UNOS 1A transplant for thrombosis, device exchange for thrombosis, or stroke/peripheral embolic event)

LVAD Thrombosis: A Piece of the Puzzle

• History of the Problem

• How do we think this happens?

• Potential Causes

• Focus on Under-anticoagulation

• Future Directions

• Those who do not remember history are doomed to repeat it• Voltaire

LVAD Thrombosis: Potential Causes• Under-anticoagulation• Decreased flow rates and bearing heating• Inflow cannula angulation• New materials in device• Infection• Hypertension• Space between rotor and housing• Right ventricular failure• Aortic valve pathology and aortic root thrombosis• Iron Deficiency• Erythropoiesis-Stimulating Agents(ESAs)• Blood type• Hypercoaguable states

Nassif ME et al. JACC: Heart Failure, 2015; 3: 146 - 153

Pump Thrombosis and Mortality Increase with the Use of Erythropoiesis-Stimulating Agents(ESAs)

Nassif ME et al. JACC: Heart Failure, 2015; 3: 146 - 153

HR =2.35 (1.38–4.00) p= 0.002

HR =1.62 (1.12–2.33) p= 0.01

Years

Years

Dentali F et al. Semin Thromb Hemost 2012; 38: 535-548

Non-O Blood Type Confers A 2-fold Risk of Deep Vein Thrombosis in the General Population

ABO Blood Group is a Major Determinant of VWF

• 70% of the variation in plasma VWF is genetically determined

• 30% of this genetically determined variation is ABO Blood Group

• VWF levels are 25% higher in Non-O blood groups

Franchini M, Makris M. Blood Transfus 2013; 11:164-5

Blood Group and Hypercoaguability --DVTCases (n=712) Controls (n=712) OR (95% CI)

O without FVL 177 (24.8) 328 (46.1) 1*

O and FVL 43 (6.0) 26 (3.7) 3.06 (1.82–5.16)Non-O without FVL

403 (56.6) 313 (44.0) 2.39 (1.89–3.02)

Non-O and FVL 89 (12.6) 45 (6.2) 3.67 (2.45–5.48)O without PTM 189 (26.5) 339 (47.6) 1*

O and PTM 31 (4.3) 15 (2.1) 3.71 (1.95–7.04)Non-O without PTM

445 (62.5) 349 (49.0) 2.29 (1.82–2.87)

Non-O and PTM 47 (6.7) 9 (1.3) 9.37 (4.49–10.5)O without deficiencies of AT, PC, PS

209 (29.5) 349 (49.1) 1*

O and deficiencies of AT, PT, PS

11 (1.5) 5 (0.7) 3.67 (1.26–10.7)

Non-O without deficiencies of AT, PC, PS

476 (66.8) 351 (49.3) 2.26 (1.82–2.82)

Non-O and deficiencies of AT, PC, PS

16 (2.2) 7 (0.9) 3.82 (1.54–9.43)

Prevalence of blood groups in various combinations with thrombophilic abnormalities in the study cases and controls (OR and 95% CI).

Spiezia L et al. Blood Transfus 2013; 11:250-3

FVL Factor V LeidenPTM Prothrombin mutationAT AntithrombinFC Factor CFS Factor S

LVAD Thrombosis: A Piece of the Puzzle

• History of the Problem

• How do we think this happens?

• Potential Causes

• Focus on Under-anticoagulation

• Future Directions

• Those who do not remember history are doomed to repeat it• Voltaire

LVAD Thrombosis: Potential Causes Under-anticoagulation • Lower PTT targets

• Lower INR targets• Reduced post-operative bridging• Reduced late bridging• More bleeding• Aortic valve pathology (lowering RPM)• Interference from serum free

hemoglobin and bilirubin• Use of the aPTT

LVAD Thrombosis: Potential CausesEvidence: GI Bleeding is Associated with subsequent TE Events

Variable <50 years 50–70 years >70 yearsGI bleeding 8% 34% 50%TE events 20% 4% 37%Risk of GI bleed predicting TE eventa

7.3 [0.9–57] 6.8 [4–11.7] 14.5 [5.4–39]

p-value 0.058 <0.001 <0.001

Events and Risk Separated by Patient Age GI, gastrointestinal; TE, thromboembolic event.

N = 389

Stulak JM et al. J Heart Lung Tx 2014; 33:60-64

Proportion of patients with indicated INR levels by year--INTERMACS

Kirklin JK et al. Journal of Heart and Lung Transplantation, 2014; 33 12 - 22

LVAD Thrombosis: Potential Causes Under-anticoagulation

• Lower PTT targets• Lower INR targets• Reduced post-operative bridging• Reduced late bridging• More bleeding• Aortic valve pathology (lowering RPM)• Use of the aPTT

The Coagulation Cascade

1.21.110.90.80.70.60.50.40.30.20.100.0

30.0

60.0

90.0

120.0

150.0

180.0

210.0

240.0

270.0

1.21.110.90.80.70.60.50.40.30.20.100.0

30.0

60.0

90.0

120.0

150.0

aPTT

(sec

)

Anti-Xa Levels (U/ml)

aPTT

(sec

)

Anti-Xa Levels (U/ml)

LVAD n = 19

ADHF n = 10

McIlvennan C et al. J Heart Lung Tx In Press

Simultaneous Measurements of aPTT and anti-Xa levels in Patients 6 hours after Stable Heparin Dosing

In LVAD patients if aPTT is therapeutic anti-Xa is therapeutic in 9% but in ADHF patients it is therapeutic in 71%

Kearon C et al. Arch Int Med 1998;158:1140-3

Heparin <0.05 U/mL

Heparin <0.05 U/mL

Heparin <0.05 U/mL

Heparin <0.15- 2.5 U/mL

As the INR increases with Warfarin the PTT increases

n = 77 samples in 24 patients

Kearon C et al. Arch Int Med 1998;158:1140-3

As the INR increases with Warfarin the PTT increases

n = 77 samples in 24 patients

So as the INR increases from 1 to 2 on stable heparin a PTT of 70 sec is really 54 sec

On average for every increase of 1 in the INR the PTT increases by 16 seconds

Arch Intern Med. 1998;158(10):1140-1143.

As the INR increases with Warfarin the PTT increases

• Thus one would expect to see heparin doses being decreased as the INR increases

• Mungall and Floyd (J Clin Pharm 1989) reported that the dose of heparin required to achieve a therapeutic level decreased from 1899 to 1000 U/hr after warfarin was started

A Larger Study Confirms These Findings

Adayta S et al. JACC-HF; 2015

Functions of von Willebrand Factor

• Bridging molecule at sites of vascular injury for normal platelet adhesion

• Under high shear stress promotes platelet aggregation

• Acts as a carrier for Factor VII increasing the half-life 5 fold

Brinkhous KM et al. PNAS 1985;82:8752; De Meyer SF et al. Blood 2009;113:5049

Price E A et al. Ann Pharmacother 2013;47:151-158

An elevated PTT to anti-Xa predicts a poor outcome but only in patients not on warfarin

Management of Anticoagulation in LVAD Recipients: Future directions• Poor relationship of aPTT and anti-Xa with coumadin

confirmed

• Evaluate role of anti-platelet agents

• Check Factor VIII and vWF to see how affects this relationship

• Consider other factors such as blood type, genetic and acquired hypercoagulable states

• • Consider scores for thrombosis and bleeding risks