The Effect of Platelet Administration in Antiplatelet Associated Intracerebral Hemorrhage Caitlin Jenkins, PharmD PGY-1 Pharmacy Resident St. Joseph’s/Candler Health System Co-Investigator: Sabrina Croft, PharmD, BCPS Hannah Matson, PharmD Candidate Joseph Crosby, PhD, RPh Thank you for that introduction. Our purpose was to see what we were doing before the new guidelines and if it was safe and efficacious.

Disclosure Statement Disclosure statement: these individuals have the following to disclose concerning possible personal or financial relationships with commercial entities (or their competitors) that may be referenced in this presentation Caitlin Jenkins, PharmD: nothing to disclose Sabrina Croft, PharmD, BCPS: nothing to disclose Hannah Matson, PharmD Candidate: nothing to disclose Joseph Crosby, PhD, RPh: nothing to disclose

Background Intracerebral Hemorhage 10% of all CVAs are intracerebral hemorrhages (ICH) Overall CVA mortality has decreased by 35% No change in ICH mortality Of all strokes, 87% are ischemic and 10% are intracerebral hemorrhage (ICH) strokes, whereas 3% are subarachnoid hemorrhage (SAH) strokes. Thirty day mortality estimates have been reported to be approximately 40–50% in ICH and while the death rate of stroke overall (ischemic, ICH, and SAH) has decreased by 35% since 2001, there has been no change in ICH case fatality or long term mortality. Mozaffarian et.al. A Report From the American Heart Association. Circulation. 2015;131:e29-e322. Zahuranec et.al. Neurology. 2014;82:2180–2186.

Background Antiplatelet agents Used to prevent CVA and CAD Increases the risk for developing a hemorrhagic stroke Complicates outcomes after hemorrhagic stroke With the population trending towards longer life expectancy, we see more and more patients on medications for cardiovascular disease such as anticoagulants and antiplatelet agents. These agents, while used to prevent stroke as well as other cardiovascular complications, can increase the risk for developing a hemorrhagic stroke and can complicate outcomes when a patient presents with a hemorrhagic stroke, especially ICH since these medications can potentially cause hematoma volume expansion.10-12 A study by Hankey et.al. demonstrated that antiplatelet medication use increased a patient’s chance of having an ICH by 0.3 – 0.4% Franke et.al. Stroke J Cereb. 1990;21:726–30. Rosand et.al. Arch Intern Med. 2004;164:880–4. Flibotte et.al. Neurology. 2004;63:1059–64.

Background AHA/ASA Guidelines NCCS/SCCM Guidelines Neither recommend for or against the use of platelets in ICH for patient’s on antiplatelet medications NCCS/SCCM Guidelines Platelet transfusion is NOT recommended If neurosurgical procedure will not be performed If platelet function is within normal limits Prior to a neurosurgical procedure in patients exposed to NSAIDs or GP IIb/IIIa inhibitors Platelet transfusion is recommended Prior to a neurosurgical procedure in patients exposed to ASA or P2Y12 inhibitors American Heart Association/American Stroke Association Neurocritical Care Society/Society of Critical Care Medicine Currently, platelet administration to patients taking antiplatelet medications in the setting of ICH is controversial due to conflicting literature.15-17 Neither recommend for, nor recommend against……. NCCS/SCCM Guidelines: NOT recommended: Prior to a neurosurgical procedure in patients exposed to NSAIDs, or GP IIb/IIIa inhibitors (abciximab, eptifibatide, or tirofiban) Platelet transfusion is recommended: Prior to a neurosurgical procedure in patients exposed to ASA, clopidogrel, prasugrel, or ticagrelor Hemphill et.al. Stroke. 2015;46:2032-2060. Frontera et.al. Neurocrit Care 2016;24:6–46.

Background NCCS/SCCM Guidelines Initial dose of one single-donor apheresis unit of platelets Platelet testing suggested prior to repeat transfusion Repeat transfusion only for those with persistently abnormal platelet function tests and/or ongoing bleeding Desmopressin 0.4 mcg/kg IV x 1 dose Regardless of platelet transfusion Repeat transfusion only for those with persistently abnormal platelet function tests and/or ongoing bleeding Should receive a 0.4 mcg/kg IV dose of DDAVP in those patients undergoing a neurosurgical procedure and exposed to ASA, clopidogrel, prasugrel, or ticlopidine Frontera et.al. Neurocrit Care. 2016;24:6–46.

Background The PATCH trial was a multicenter, randomized, open-label parallel trial designed to determine the efficacy and safety of platelet transfusion in nonsurgical patients in the setting of antiplatelet associated ICH The primary measure was difference in functional outcome at 3 months after randomization scored with the modified Rankin Scale (mRS) score Higher in the platelet transfusion group than in standard care group (OR 2.22; 95% CI 1.20–4.09; p=0.0108) PATCH is the first randomized trial to investigate the effects of platelet transfusion on acute intracerebral hemorrhage after the use of antiplatelet therapy 19% in patch trial were excluded 40 out of 97 (42%) participants who received platelet transfusion had a serious adverse event, as did 28 out of 93 (29%) who received standard care 24 (25%) participants assigned to platelet transfusion and 15 (16%) assigned to standard care died while in hospital Safety outcomes in the intention-to-treat population did not differ between groups ODDs shifted towards death or disability with platelet administration – platelet group higher odds/worse outcomes Baharoglu et.al. Lancet 2016; 387: 2605–13.

Background mRS Score No symptoms at all 1 No symptoms at all 1 No significant disability despite symptoms 2 Slight disability 3 Moderate disability 4 Moderately severe disability 5 Severe disability 6 Dead 0 = no symptoms 1 = able to carry out all usual duties and activities 2 = unable to carry out all previous activities, but able to look after own affairs without assistance 3 = requiring some help, but able to walk without assistance 4 = unable to walk without assistance and unable to attend to own bodily needs without assistance 5 = bedridden, incontinent and requiring constant nursing care and attention 6 = dead

Purpose To evaluate the effect of platelet transfusion on patient outcomes in nonsurgical patients taking antiplatelet medications prior to ICH 9

Study Objectives Primary Objective Secondary Objectives mRS score at discharge Secondary Objectives Hospital mortality Critical care unit mortality Critical care unit length of stay (LOS) Hospital LOS Hematoma expansion 24 hours after admission Safety of platelet transfusion To evaluate the effect of platelet transfusion ….. in patients taking antiplatelet medications prior to ICH

Study Center St. Joseph’s/Candler Health System Community health system with 714 inpatient beds divided between two anchor hospitals Candler: 20-bed adult medical/surgical ICU, certified stroke center St. Joseph’s: 10-bed adult medical/surgical ICU, 16-bed cardiovascular unit, 12-bed neuro ICU, and certified stroke center

Methods Study design Population Retrospective, observational investigation Population Adult patients admitted to a critical care unit at St. Joseph’s/Candler Health System from January 1, 2010 to December 31, 2015 that were on antiplatelet medication prior to admission and were admitted for ICH

Methods Inclusion criteria: Males and non-pregnant females of at least 18 years of age with non-traumatic ICH On antiplatelet medication for at least 7 days prior to admission Glasgow Coma Scale (GCS) score of 8 – 15 at the time of admission mRS score of 0 – 1 at the time of admission

Methods Exclusion criteria: Transferred into a critical care unit from an outside hospital when no information was available within 24 hours of transfer Evidence of epi/subdural hematoma on CT An underlying aneurysm or arteriovenous malformation Planned surgical evacuation of ICH within 24 hours of admission Previous adverse reaction to platelet transfusion Known use of vitamin K antagonist (unless international normalized ratio ≤1.3) or history of coagulopathy Known use of direct oral anticoagulants Known use of heparin, low molecular weight heparin, or fondaparinux Known thrombocytopenia (<100 cells × 10⁹/L) Apparent imminent death

Methods Outcome variables Primary Secondary mRS score at discharge Hospital mortality Critical care unit mortality Critical care unit LOS (days) Hospital LOS (days) Hematoma expansion within 24 hours Safety of platelet transfusion

Methods Data analysis Mann Whitney U tests for ordinal data modified Rankin Scale score Fisher’s exact tests for categorical data Hospital mortality and critical care unit mortality Student t-tests for continuous variables Hospital LOS, critical care unit LOS, and hematoma expansion p<0.05 was statistically significant

Patient Selection 17 526 Patients Evaluated 29 Patients Included 5 Platelet Group 24 Control Group 497 Patients Excluded N=351, not on antiplatelet; N=9, apparent imminent death within 24 hours; N=2, AVM or aneurysm; N=12, mRS > 1 at admission; N=26, no follow-up CT; N=95, on anticoagulant with INR ≥ 1.3; N=2, ICH related to trauma; 17

Demographics and Clinical Characteristics Results Demographics and Clinical Characteristics Control (n=24) Platelets (n=5) P-value Age, years ± SD 69 ± 5.42 70 ± 15.91 0.429 Male, n (%) 12 (50) 3 (60) 0.535 HTN, n (%) 21 (87.5) 5 (100) 0.554 Ischemic Stroke, n (%) 9 (37.5) 0.131 ICH, n (%) 2 (8.33) 1 (20) 0.446 Statin Use, n (%) 38% african american 18

Primary Outcome Results are not statistically significant. Mann-Whitney U test results: p-value =0.271 Control (n=24) 0=0, 1=3, 2=0, 3=1, 4=12, 5=5, 6=3 Platelets (n=5) 0=0, 1=1, 2=0, 3=0, 4=1, 5=2, 6=1 19

Results Secondary Outcomes Control (n=24) Platelets (n=5) P-value Hospital Mortality, n (%) 3 (12.5) 1 (20) 0.553 ICU Mortality, n (%) ICU LOS, days ± SD 6.5 ± 2.56 7 ± 9.79 0.437 Hospital LOS, days ± SD 11.7 ± 4.50 8.2 ± 9.96 0.248 Hematoma Expansion, cm ± SD 0.35 ± 0.270 0.41 ± 0.747 0.425 Infusion Related Reactions, n – 20

Discussion Platelets were administered to 17% of patients in the study Of the five patients that received platelets, none had any serious adverse reactions to the transfusion 54% of patients that were on antiplatelets were excluded due to concurrent use with anticoagulants with INR ≥ 1.3 40 (42%) participants who received platelet transfusion had a serious adverse event, as did 28 (29%) who received standard care Only 19% of patch excluded 21

Limitations Small, retrospective cohort nature limits external validity Inconsistent documentation led to potential bias for the available data reviewed 67% of patients screened were excluded due to lack of home antiplatelet use See trend? 22

Conclusions Platelet transfusion appears to make no difference in the outcome of discharge mRS scores or any other secondary outcome PATCH showed worse outcomes in all outcomes except for infusion related reactions 23

Acknowledgements Sabrina Croft, PharmD, BCPS Hannah Matson, PharmD Candidate Joseph Crosby, PhD, RPh I would like to thank my colleagues for their contributions to this study.

Self Assessment Purpose: Self Assessment Question: To evaluate the effect of platelet transfusion on patient outcomes in nonsurgical patients taking antiplatelet medications prior to ICH Self Assessment Question: For which antiplatelet medications is it recommended that patients receive platelet transfusion prior to surgery for ICH management?

Self Assessment For which antiplatelet medications is it recommended that patients receive platelet transfusion prior to surgery for ICH management? Aspirin or P2Y12 inhibitors

References Mozaffarian D, Benjamin EJ, Go AS, et.al. on behalf of the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart Disease and Stroke Statistics—2015 Update: A Report From the American Heart Association. Circulation. 2015;131:e29-e322. Zahuranec DB, Lisabeth LD, Sánchez BN, et.al. Intracerebral hemorrhage mortality is not changing despite declining incidence. Neurology. 2014;82:2180–2186. Franke CL, de Jonge J, van Swieten JC, Op de Coul AA, van Gijn J. Intracerebral hematomas during anticoagulant treatment. Stroke J Cereb. 1990;21:726–30. Rosand J, Eckman MH, Knudsen KA, Singer DE, Greenberg SM. The effect of warfarin and intensity of anticoagulation on outcome of intracerebral hemorrhage. Arch Intern Med. 2004;164:880–4. Flibotte JJ, Hagan N, O’Donnell J, Greenberg SM, Rosand J. Warfarin, hematoma expansion, and outcome of intracerebral hemorrhage. Neurology. 2004;63:1059–64. Hemphill III JC, Greenberg SM, Anderson CS, et.al. Guidelines for the Management of Spontaneous Intracerebral Hemorrhage: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke. 2015;46:2032-2060. Frontera JA, Lewin III JJ, Rabinstein AA, et.al. Guideline for Reversal of Antithrombotics in Intracranial Hemorrhage: A Statement for Healthcare Professionals from the Neurocritical Care Society and Society of Critical Care Medicine. Neurocrit Care 2016;24:6–46. Baharoglu MI, Cordonnier C, Salman RAS, et.al. Platelet transfusion versus standard care after acute stroke due to spontaneous cerebral haemorrhage associated with antiplatelet therapy (PATCH): a randomised, open-label, phase 3 trial Lancet 2016; 387: 2605–13.

The Effect of Platelet Administration in Antiplatelet Associated Intracerebral Hemorrhage Caitlin Jenkins, PharmD PGY-1 Pharmacy Resident St. Joseph’s/Candler Health System Co-Investigator: Sabrina Croft, PharmD, BCPS Hannah Matson, PharmD Candidate Joseph Crosby, PhD, RPh FFP = all coagulation factors and labile factors (5 and 8) Feiba = non-activated factors 2, 9, and 10, and activated 7 Cryoprecipitate = fibrinogen, factor 8 concentrate, factor 8 vWF, platelets, and fibronectin 28