gi bleeding in the era of continuous- flow left ... · ©2017 mfmer | slide-1 gi bleeding in the...
TRANSCRIPT
©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
©2017 MFMER | slide-2
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
©2017 MFMER | slide-3
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.
©2017 MFMER | slide-4
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
©2017 MFMER | slide-5
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.
©2017 MFMER | slide-6
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
©2017 MFMER | slide-7
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
©2017 MFMER | slide-8
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.
©2017 MFMER | slide-9
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.
©2017 MFMER | slide-10
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™
©2017 MFMER | slide-11
“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
©2017 MFMER | slide-12
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
©2017 MFMER | slide-13
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.
©2017 MFMER | slide-14
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.
©2017 MFMER | slide-15
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
©2017 MFMER | slide-16
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.
©2017 MFMER | slide-17
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
©2017 MFMER | slide-18
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
©2017 MFMER | slide-19
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
©2017 MFMER | slide-20
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.
©2017 MFMER | slide-21
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
©2017 MFMER | slide-22
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.
• Treatment considerations
• 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
©2017 MFMER | slide-23
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.
©2017 MFMER | slide-24
Octreotide
• Somatostatin analog
• ↓splanchnic blood flow
• Inhibits angiogenesis
• Improves platelet aggregation
• Treatment considerations
• Relatively benign
• GI disturbances
• Increased blood pressure
• Impairment of glucose homeostasis
Malhorta R et al. ASAIO J 2017;ahead of print.
©2017 MFMER | slide-25
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.
©2017 MFMER | slide-26
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.
©2017 MFMER | slide-27
Other Potential Options
• Doxycycline
• von Willebrand factor concentrate
• Hormones
• Anti-fibrinolytics
• Desmopressin
• Angiotensin II antagonizers
©2017 MFMER | slide-28
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
©2017 MFMER | slide-29
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
©2017 MFMER | slide-30
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
©2017 MFMER | slide-31
Diagnostic Evaluation
• 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
©2017 MFMER | slide-32
Question 2
• What is the likely etiology of gastrointestinal bleeding in this patient?
A. Peptic ulcer
B. Hemorrhoid
C. Arteriovenous malformation
D. Rectal ulcer
©2017 MFMER | slide-33
Diagnostic Evaluation
• 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
©2017 MFMER | slide-34
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
©2017 MFMER | slide-35
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
©2017 MFMER | slide-36
“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