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-1
Objectives Discuss the history of left ventricular assist devices and the associated complications postimplantation 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-2
% Mortality Heart Failure in the United States 6.5 million affected and rising 250,000 with end-stage heart failure 1 million new cases annually 100 80 60 40 20 0 1 5 10 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-3
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 Baylor Medicine, ca. 1966 NIH = National Institutes of Health BTT = Bridge to Transplantation 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. 2017 MFMER slide-4
Survival (probability) REMATCH (2001) 1.0 0.8 0.6 LVAD 0.4 0.2 Medical therapy p = 0.09 0 0 6 12 18 24 Months Rose EA et al. N Eng J Med 2001;345(20):1435-43. 2017 MFMER slide-5
Survival (probability) Continuous-Flow HeartMate II 1.0 0.8 Continuous LVAD (2009) 0.6 0.4 0.2 Medical therapy (2001) Pulsatile LVAD (2009) Pulsatile LVAD (2001) p = 0.008 (2009) p = 0.09 (2001) 0 0 6 12 18 24 Months 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. 2017 MFMER slide-6
# Patients Trends in Heart Transplantation 6000 Wait List Additions 5000 4000 #Transplanted LVAD Implants 3000 2000 1000 0 2006 2011 2016 Year United Network for Organ Sharing 2017. INTERMACS Statistical Report 2016. 2017 MFMER slide-7
Incidence (%) Complications of Continuous-Flow LVADs 50 40 30 20 10 0 Starling RC et al. J Am Coll Cardiol 2011;57(19):1890-8. 2017 MFMER slide-8
Incidence (%) Complications of Continuous-Flow LVADs 50 40 30 20 10 0 Infection Bleeding Arrhythmias Respiratory Failure Starling RC et al. J Am Coll Cardiol 2011;57(19):1890-8. 2017 MFMER slide-9
Pump Thrombosis at 1 year (%) Iatrogenic Anticoagulation 14 12 10 8 HeartMate II 6 4 2? 0 2004 2007 2010 2013 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. 2017 MFMER slide-10
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 PT = Pump thrombosis GIB = GI Bleed Lopilato AC et al. Artif Organs 2015;39(11):939-44. 2017 MFMER slide-11
% patients 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 60 40 20 0 p <0.001 p = 0.004 p = 0.01 18 4 44 0 GIB GIAD Thrombotic event 17 8 LVAD Control GIB = GI Bleed GIAD = GI angiodysplasia Shrode CW et al. Clin Gastroenterol Hepatol 2014;12(9):1461-7. 2017 MFMER slide-12
Acquired von Willebrand Syndrome vwf multimer deficiency Shear stress vwf = von Willebrand Factor vwf deformation Impaired plateletmediated homeostasis Proteolysis (ADAMTS13) Nascimbene A et al. Blood 2016;127(25):3133-41. Crow S et al. Ann Thorac Surg 2010;90:1263-9. 2017 MFMER slide-13
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-14
Proportion of patients (%) Proportion of causes (%) Hospital Readmissions 115 CF-LVADs, follow-up ~1.5 years 29% with 1 readmission 15% with 2 readmissions 29% with >2 readmissions 35 30 25 20 15 10 5 0 40 35 30 25 20 15 10 5 0 Bleeding Cardiac Infection Thrombosis Biliary Pump related Other Elective CF-LVAD = Continuous-flow LVAD Hasin T et al. J Am Coll Cardiol 2013;61(2):153-63. 2017 MFMER slide-15
# procedures per event prbcs per event Morbidity and Mortality Deaths related to LVAD GIB are rare Morbidity is significant 3 12 10 2 8 6 1 4 2 0 Kushiner et al. Stern et al. Marsano et al. 0 Morgan et al. Kushnir et al. Stern et al. Marsano et al. prbc = packed red blood cells GIB = GI Bleed 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-16
% patients Diagnostic Evaluation Clinical suspicion Bleeding source identified in only ~50% 30 20 10 0 Etiology AVM Ulcer Polyp Erosion Hemorrhoid Diverticula Cushing K et al. Dig Dis Sci 2016;61:1440-7. 2017 MFMER slide-17
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-18
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-19
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-20
Danazol in LVADs 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 Schettle et al. (n = 19) Before Danazol After Danazol 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 HM = HeartMate II GIB = GI Bleed prbc = packed red cells EGD = esophagogastroduodenoscopy AVM = ateriovenous malformation 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. 2017 MFMER slide-21
Plasma levels of VEGF (pg/ml) Thalidomide Mechanism Anti-angiogenic Inhibits VEGF 140 120 100 80 60 40 20 p < 0.001 Treatment considerations Prothrombotic Bone marrow suppression Fluid retention Neuropathy Teratogenic Thalomid REMS Special handling 0 Pre-thalidomide Post-thalidomide VEGF = vascular endothelial growth factor REMS = Risk evaluation and mitigation strategies Bauditz J et al. World J Gastroenterol 2007;13(45):5979-84. Ge ZZ et al. Gastroenterology 2011;141(5):1629-37. 2017 MFMER slide-22
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-23
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-24
Octreotide in LVADs Hayes et al. (2010) 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 Aggarwal et al. (2012) 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 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-25
Octreotide in LVADs Loyaga- Rendon et al. (2015) 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 Malhorta et al. (2017) 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 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-26
Other Potential Options Doxycycline von Willebrand factor concentrate Hormones Anti-fibrinolytics Desmopressin Angiotensin II antagonizers 2017 MFMER slide-27
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-28
Clinical Vignette Admission history since LVAD implant 1 st admission EGD with APC for angioectasias 2 nd 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-29
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-30
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-31
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-32
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-33
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-34
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-35
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 2017 MFMER slide-36
Questions & Discussion 2017 MFMER slide-37
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-38