GI Bleeding in the Era of Continuous- Flow Left ... · ©2017 MFMER | slide-1 GI Bleeding in the...

©2017 MFMER | slide-1

GI Bleeding in the Era of Continuous-Flow Left Ventricular Assist Devices

Patrick Wieruszewski, PharmD PGY1 Pharmacy Resident

Pharmacy Grand Rounds March 7, 2017


Objectives

• Discuss the history of left ventricular assist devices and the associated complications post-implantation

• Review the pathophysiology of gastrointestinal bleeding in patients with left ventricular assist devices

• Identify potential pharmacologic options for the treatment and prevention of gastrointestinal bleeding


Heart Failure in the United States

• 6.5 million affected and rising

• 250,000 with end-stage heart failure

• 1 million new cases annually

0

20

40

60

80

100

1 5 10

% M

ort

ality

Years After Diagnosis

Benjamin EJ et al. Circulation 2017;ahead of print.

Fosbol EL et al. Circ Heart Fail 2009;2(6):582-90.

Roger VL. Circ Res 2013;113(6):646-59.


Left Ventricular Assist Devices (LVADs) 1966 – First LVAD

(wean to recovery)

1970 – NIH LVAD working group formed

1978 – First LVAD implanted as BTT 1984 – First Successful

LVAD for BTT

1990s – Interest declined due to complications

DeBakey ME. Am J Cardiol 1971;27(1):3-11.

Stewart GC et al. Circulation 2012;125(10):1304-15.

NIH = National Institutes of Health

BTT = Bridge to Transplantation

Baylor Medicine, ca. 1966


REMATCH (2001)

0

0

Su

rviv

al

(pro

ba

bil

ity)

Months

0.2

0.6

0.4

0.8

1.0

6 12 18 24

Medical

therapy

LVAD

p = 0.09

Rose EA et al. N Eng J Med 2001;345(20):1435-43.


Continuous-Flow HeartMate II™

Rose EA et al. N Eng J Med 2001;345(20):1435-43.

Salughter MS et al. N Eng J Med 2009;361(23):2241-51.

Fang JC. N Eng J Med 2009;361(23):2282-5.

p = 0.008 (2009)

Pulsatile LVAD (2009)

Continuous LVAD (2009)

0

0

Su

rviv

al

(pro

ba

bil

ity)

Months

0.2

0.4

0.8

1.0

6 12 18 24

Medical therapy

(2001)

Pulsatile LVAD (2001)

p = 0.09 (2001)

0.6


Trends in Heart Transplantation

0

1000

2000

3000

4000

5000

6000

2006 2011 2016

# P

ati

en

ts

Year

Wait List Additions

#Transplanted

United Network for Organ Sharing 2017.

INTERMACS Statistical Report 2016.

LVAD Implants


Complications of Continuous-Flow LVADs

0

10

20

30

40

50

Inc

ide

nc

e (

%)

Starling RC et al. J Am Coll Cardiol 2011;57(19):1890-8.


0

10

20

30

40

50

Infection Bleeding Arrhythmias RespiratoryFailure

Incid

en

ce (

%)

Complications of Continuous-Flow LVADs

Starling RC et al. J Am Coll Cardiol 2011;57(19):1890-8.


Iatrogenic Anticoagulation

0

2

4

6

8

10

12

14

2004 2007 2010 2013

Pu

mp

Th

rom

bo

sis

at

1 y

ear

(%)

Year of Implantation

?

Stulak JM et al. N Eng J Med 2014;370(15):1467-8.

Meyer AL et al. J Thorac Cardiovasc Surg 2008;135(1):203-4.

HeartMate II™


“Clotters” vs. “Bleeders”

Characteristic* PT

(n = 8)

No PT

(n = 56)

p-value

GIB

(n = 15)

No GIB

(n = 49)

p-value

Age, mean 55.6 56.4 0.87 58.3 55.7 0.50

Female 4 (50) 9 (16) 0.03 5 (33) 8 (16) 0.15

Prior VTE 1 (13) 7 (13) 1.00 1 (7) 7 (14) 0.44

Prior GIB 0 (0) 3 (5) 0.50 0 (0) 3 (6) 0.33

INR, mean 2.1 2.24 0.24 2.21 2.27 0.67

Antiplatelet 1 (13) 28 (50) 0.05 7 (47) 23 (47) 0.99

*n (%) unless otherwise noted

Lopilato AC et al. Artif Organs 2015;39(11):939-44. PT = Pump thrombosis

GIB = GI Bleed


More at Play?

LVAD

(n = 159)

Control

(n = 159)

p-value

Age (y) 55±13 64±15 <0.001

Male 121 (76%) 90 (57%) <0.001

INR at GIB 2.3±1.3 3.3±2.2 NS

Shrode CW et al. Clin Gastroenterol Hepatol 2014;12(9):1461-7.

GIB = GI Bleed

GIAD = GI angiodysplasia

18

44

17

4 0

8

0

20

40

60

GIB GIAD Thromboticevent

% p

ati

en

ts

LVAD

Control

p <0.001 p = 0.004 p = 0.01


Acquired von Willebrand Syndrome

Shear stress

Proteolysis

(ADAMTS13)

vWF deformation

vWF multimer

deficiency

vWF = von Willebrand Factor

Impaired platelet-mediated

homeostasis

Nascimbene A et al. Blood 2016;127(25):3133-41.

Crow S et al. Ann Thorac Surg 2010;90:1263-9.


Arteriovenous Malformations

Pseudo-Heyde

Syndrome • Narrow pulse pressure

• ↓Intraluminal pressure

• Mucosal vein dilation

BLEEDING

• vWF deficiency

• Anticoagulation

• Stress

Mayo Foundation for Medical Education and Research

Heyde EC et al. N Eng J Med 1958;259:941.

Cushing K et al. Dig Dis Sci 2016;61:1440-7.


Hospital Readmissions

0

5

10

15

20

25

30

35

Pro

po

rtio

n o

f p

ati

en

ts (

%)

0

5

10

15

20

25

30

35

40

Pro

po

rtio

n o

f cau

ses (

%)

Bleeding

Cardiac

Infection

Thrombosis

Biliary

Pump related

Other

Elective

• 115 CF-LVADs, follow-up ~1.5 years

• 29% with 1 readmission

• 15% with 2 readmissions

• 29% with >2 readmissions

Hasin T et al. J Am Coll Cardiol 2013;61(2):153-63. CF-LVAD = Continuous-flow LVAD


Morbidity and Mortality

• Deaths related to LVAD GIB are rare

• Morbidity is significant

0

2

4

6

8

10

12

Morganet al.

Kushniret al.

Stern etal.

Marsanoet al.

pR

BC

s p

er

even

t

pRBC = packed red blood cells

GIB = GI Bleed

0

1

2

3

Kushiner et al. Stern et al. Marsano et al.

# p

roc

ed

ure

s p

er

eve

nt

Kushnir VM et al. Gastrointest Endosc 2012;75:973-9.

Stern DR et al. J Card Surg 2010;25:352-6.

Marsano J et al. Dig Dis Sci 2015;60:1859-67.

Morgan JA et al. J Heart Lung Transplant 2012;31:715-8.


Diagnostic Evaluation

• Clinical suspicion

• Bleeding source identified in only ~50%

Cushing K et al. Dig Dis Sci 2016;61:1440-7.

0

10

20

30

AVM Ulcer Polyp Erosion Hemorrhoid Diverticula

% p

ati

en

ts Etiology


Treatment Approach

• Resuscitation

• Transfusions

• Reversal typically avoided

• Local intervention during scoping

• Pump speed reduction

• Empiric proton pump inhibitors

• Adjustment of anticoagulation program

• Pharmacologic therapy for recurrence


Anticoagulation Program

• Patient specific

• No standardized, validated approach developed

• ↓Anticoagulant

• INR 2.0-3.0

• INR 2.0-2.5

• INR 1.8-2.2

• d/c warfarin

• ↓Antiplatelet

• Aspirin 325mg

• Aspirin 81mg

• d/c aspirin


Danazol

• Synthetic androgen

• Progestin-like effects

• Inhibits IL-1 and TNF-α

• Vascular stability

• Treatment considerations

• Thromboembolic events

• Hepatotoxic

• Intracranial hypertension

• Teratogenic

Mori H et al. Am J Reprod Immunol 1990;24(2):45-50.


Danazol in LVADs

Before

Danazol

After

Danazol

Schettle et al. (n = 19)

Mean pRBCs (n) 8.1 2.8

Mean hospitalizations (n) 3.3 1.2

Falls et al. (n = 5)

Mean time between

hospitalizations (m)

1.5 4.4

Schettle et al. J Heart Lung Transplant 2014;33(5):549-550.

Schettle et al. J Heart Lung Transplant 2016;35(4S):S83.

Falls et al. J Heart Lung Transplant 2016;35(4S):S240.

59 y/o male s/p HMII™

9 hospitalizations

for GIB

40 pRBCs

7 EGDs

8 other scopes

(AVMs)

Danazol 200mg twice daily x 49

days

No GIB x 9 months

HM = HeartMate II™

GIB = GI Bleed

pRBC = packed red cells

EGD = esophagogastroduodenoscopy

AVM = ateriovenous malformation


Thalidomide

• Mechanism

• Anti-angiogenic

• Inhibits VEGF

Bauditz J et al. World J Gastroenterol 2007;13(45):5979-84.

Ge ZZ et al. Gastroenterology 2011;141(5):1629-37.


• Prothrombotic

• Bone marrow suppression

• Fluid retention

• Neuropathy

• Teratogenic

• Thalomid® REMS

• Special handling

0

20

40

60

80

100

120

140

Pre-thalidomide Post-thalidomide

Pla

sm

a le

ve

ls o

f V

EG

F

(pg

/mL

)

p < 0.001

VEGF = vascular endothelial growth factor

REMS = Risk evaluation and mitigation strategies


Thalidomide in LVADs

Patient Age # episodes Documented AVM GIB Effect Other outcome

1 66 4 Yes No recurrence -

2 65 4 Yes No recurrence -

3 62 4 Yes No recurrence Discontinued (AE)

4 63 2 Yes No recurrence Discontinued (AE)

5 67 3 No No recurrence Dose reduction (AE)

6 29 3 No Reduced bleeding Transplanted

7 61 3 Yes No recurrence Transplanted

8 35 2 Yes Reduced bleeding Expired

9 65 4 Yes - Expired

10 66 1 No No recurrence Discontinued (AE)*

11 52 1 No No recurrence Discontinued (AE)

12 67 1 No No recurrence -

13 55 3 No No recurrence -

*recurrent GIB after discontinuation

AVM = arteriovenous malformation

AE = adverse event

Ray R et al. ASAIO J 2014;60:482-3.

Ray R et al. J Heart Lung Transplant 2015;34(1):132-4.

Chan LL et al. Heart Lung Circ 2017; ahead of print.


Octreotide

• Somatostatin analog

• ↓splanchnic blood flow

• Inhibits angiogenesis

• Improves platelet aggregation


• Relatively benign

• GI disturbances

• Increased blood pressure

• Impairment of glucose homeostasis

Malhorta R et al. ASAIO J 2017;ahead of print.


Octreotide in LVADs

• Retrospective analysis of CF-LVADs (n = 5 received octreotide)

• Averaged 2 prior GIB events

• Received 25mcg/min infusion, 100mcg SQ BID or 10mg IM q4weeks

• “GI bleeding was successfully treated”

Hayes et al.

(2010)

• Retrospective analysis of CF-LVADs (n = 13 received octreotide)

• Dosing not reported (SQ or continuous infusions used)

• No differences noted in mortality, rebleeding, length of stay, or usage of pRBCs, FFP, Cryo, platelets

Aggarwal et al.

(2012)

Hayes HM et al. Artif Organs 2010;34(9):703-6.

Aggarwal A et al. Ann Thorac Surg 2012;93(5):1534-40.


Octreotide in LVADs

• Case series (n = 7)

• Averaged 3 prior GIB admissions (14 pRBCs)

• Received 50mcg SQ BID or LAR 20mg IM q4weeks

• Non-significant reduction in hospitalization, pRBCs, and diagnostic procedures

• Safety: abdominal cramps, diarrhea

Loyaga-Rendon

et al. (2015)

• Prospective analysis (n = 10)

• Only 3 patients with prior GIB

• Received LAR 20mg IM q4weeks x 28 weeks

• No recurrent GIB at 28 weeks

• Possible VEGF benefits

• Safety: no adverse effects reported

Malhorta et al.

(2017)

Loyaga-Rendon RY et al. ASAIO J 2015;61(1):107-9.

Malhorta R et al. ASAIO J 2017;ahead of print.


Other Potential Options

• Doxycycline

• von Willebrand factor concentrate

• Hormones

• Anti-fibrinolytics

• Desmopressin

• Angiotensin II antagonizers


Clinical Vignette

• 64 y/o male with history notable for end-stage ischemic cardiomyopathy s/p HeartMate II implantation as DT 60 days prior now presents with melanotic stools, coffee ground emesis, and syncopal event this morning

• EMS – Hemodynamically stable, Hgb 8, INR 1.8

• Transfused 2 pRBCs


Clinical Vignette

• Admission history since LVAD implant

• 1st admission – EGD with APC for angioectasias

• 2nd admission – EGD with APC and clipping for AVM in the gastric antrum

• INR goal adjusted to 2.0-2.5

• Current anticoagulation program

• Warfarin, adjusted to INR goal 2.0-2.5

• Aspirin 325mg daily


Question 1

• What factors are probably contributing to gastrointestinal bleeding in this patient?

A. Older age

B. Anticoagulation

C. LVAD

D. Previous GI bleeding

E. All of the above



• Repeat blood draw reveals Hgb 9.9, INR 2.0

• Hemodynamically stable

• Interrogation of LVAD reveals normal functioning, with no power spikes

• GI bleed team consulted and patient taken to EGD suite


Question 2

• What is the likely etiology of gastrointestinal bleeding in this patient?

A. Peptic ulcer

B. Hemorrhoid

C. Arteriovenous malformation

D. Rectal ulcer



• Findings on EGD

• Altered blood/coffee ground-like material in the gastric antrum, gastric fundus, and gastric body

• One bleeding angioectasia found in the stomach

• Treated with APC and clips placed


Question 3

• Based on the presentation, how would you approach the future prevention of GI bleeding in this patient?

A. Discontinue warfarin

B. Danazol 200 mg BID

C. Octreotide LAR 20mg IM q4weeks

D. Change warfarin to apixaban


Conclusions

• LVADs provide survival benefit but increase the risk of GI bleeding

• GI bleeding in LVADs is multifactorial and complex

• While limited prospective data exist, there are emerging therapies that have prevented GI bleeding in patients with LVADs


“If you can think of how much love there would be in hundreds of hearts, then that is how much love there is in a plastic heart”

Michael E DeBakey, MD ca. 1966


Questions & Discussion


GI Bleeding in the Era of Continuous-Flow Left Ventricular Assist Devices

Patrick Wieruszewski, PharmD PGY1 Pharmacy Resident

Pharmacy Grand Rounds March 7, 2017

GI Bleeding in the Era of Continuous- Flow Left ... · ©2017 MFMER | slide-1 GI Bleeding in the...

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