Jared Ham, PharmD PGY1 Pharmacy Practice Resident Timing of thromboprophylactic therapy after repair of subarachnoid hemorrhage Jared Ham, PharmD PGY1 Pharmacy Practice Resident Palmetto Health Richland, Columbia, SC April 28, 2017

No disclosures to report Primary Investigator: Jared S. Ham, PharmD Co-Investigators: Erin D. Creech, PharmD, BCPS, BCCCP Cortney R. Dodson, PharmD, BCCCP Please note that this Power Point presentation is an educational tool that is general in nature. It is not intended to be an exhaustive review of the subject matter or the opinion of Palmetto Health. Materials presented in this presentation should not be considered a substitute for actual statutory or regulatory language. Always refer to your legal counsel and the current edition of a referenced statute, code and/or regulation for precise language.

Objective To describe the safety of early versus late initiation of thromboprophylactic therapy after surgical repair of aneurysmal subarachnoid hemorrhages

Palmetto Health Richland Columbia, SC 650-bed, multi-disciplinary, teaching hospital Level I trauma center 70+ adult ICU beds Medical ICU Surgical / Trauma ICU Cardiovascular ICU Neurosurgical ICU

Background Aneurysmal subarachnoid hemorrhage (SAH) has an estimated incidence of 33,000 cases per year in the United States and a mortality rate as high as 50% Treated rapidly with one of three surgical methods to stop brain bleeding Clipping Coil Pipeline embolization Patients often remain immobile or have limited movement post-op & are at an increased risk of developing a venous thromboembolism (VTE) Image from: https://goo.gl/VJJleJ Serrone JC, et al. World Neurosurg. 2013;80(6):859-863 Kshettry VR, et al. J Clin Neurosci. 2014;21(2):282-286. Nyquist P, et al. Crit Care Med. 2017. Epub Suarez JI, et al. N Engl J Med. 2006;354(4):387-396 Vespa P, et al. Neurocrit Care. 2011; 15(2):295-297

Guideline Recommendations American Heart Association/American Stroke Association: Not specific as to if or when thromboprophylaxis therapy (TPT) should be initiated after surgery Neurocritical Care Society/Society of Critical Care Medicine: Early use of sequential compression devices (SCDs) Initiation of chemical TPT after at SAH has been secured for ≥24 hours Nyquist P, et al. Crit Care Med. 2017. Epub Connolly ES, Jr., et al. Stroke. 2012;43(6):1711-1737 Vespa P, et al. Neurocrit Care. 2011; 15(2):295-297

Thromboprophylactic Therapy Use of chemical anticoagulation to prevent VTE is controversial as it may increase the risk of intracranial bleeding Commonly used agents include heparin and enoxaparin Vespa P, et al. Neurocrit Care. 2011; 15(2):295-297 Image from: https://goo.gl/7EfhI5

Study Primary Objective To evaluate the safety of early versus late initiation of TPT via the composite incidence of re-bleeding or hemorrhage expansion in patients with SAH after surgical repair

Secondary Objectives Secondary: Incidence of re-bleeding Incidence of hemorrhage expansion Development of VTE Death from hemorrhagic condition Discharge disposition In-hospital mortality Length of hospital stay among survivors Length of intensive care unit (ICU) stay among survivors Readmission to the ICU Development of heparin-induced thrombocytopenia Need to discontinue TPT

Primary Outcome Definition Radiological Negative Clinical Negative* No evidence of re-bleeding or hemorrhage expansion after initiation of TPT via: MRI CT CT-Angio No evidence of re-bleeding or hemorrhage expansion as noted in physician progress notes secondary to: Stable laboratory markers Mental status Patient function *Clinical negative markers were evaluated until discharge

Methods Single-center, retrospective, observational, IRB approved cohort study Patient lists were generated via ICD9/10 codes and charge data All patients identified were screened for inclusion Patient’s were grouped by time of TPT initiation as either: Early Initiated Therapy (EIT): ≤72 hours post surgical repair Late Initiated Therapy (LIT): >72 hours post surgical repair

Data Collected Baseline data collected includes: Age Sex Race Ethnicity Admitting service Coagulopathy Hypertension Use of dual anti-platelet therapy (DAPT) Anticoagulant use Smoking status BMI Creatinine clearance Glasgow Coma Score (GCS) or other neurological scale TPT used

Inclusion & Exclusion Criteria Inclusion Criteria Exclusion Criteria Adult patients (≥18 years old) Admitted to Palmetto Health Richland from June 1, 2012 to October 1, 2016  Diagnosis of SAH Surgical repair via either clip, pipeline embolization, or coil method ≥1 post-op dose of prophylactic enoxaparin or heparin Traumatic SAH Lack of follow-up radiological scans after initiation of enoxaparin therapy despite suspected re-bleeding or hemorrhage expansion noted in physician notes Transfer to another institution within 72 hours of surgical repair Therapeutic anticoagulation

Statistical Analyses Primary Endpoint: Secondary Endpoints: Initial analysis computed the proportions of patients in each group that met the composite endpoint Logistic regression with the composite endpoint as the outcome variable, group (EIT vs. LIT) as the major predictor, and each baseline characteristic as candidate covariates Secondary Endpoints: Logistic regression for dichotomous variables Wilcoxon Rank Sum Tests for continuous variables

Patient Screening 202 individual patient encounters identified for screening 95 patients met inclusion criteria Early Initiated TPT: 75 Patients 107 Patients were excluded from analysis -No repair of aneurysm/SAH: 83 -Traumatic SAH: 10 -Lack of follow up documentation/imaging: 10 -No TPT after repair: 3 -Therapeutic anticoagulation: 1 Late Initiated TPT: 20 Patients

Baseline Characteristic Patient Demographics Baseline Characteristic EIT, n=75 LIT, n=20 P Value Age, median (IQR) 55 (46-64.5) 52 (43-59.5) 0.59 Male, n (%) 20 (26.7%) 6 (30%) 0.78 Admission to Neurosurgery Service, n (%) 41 (54.7%) 12 (60%) - Caucasian, n (%) 34 (45.3%) 9 (45%) 0.81 BMI, median (IQR) 29.5 (25.6-33.4) 27.6 (25.7-31.7) 0.52 GCS, median (IQR) 15 (14-15) 14.5 (10.5-15) 0.19 Creatinine Clearance, median (IQR) 99.2 (71.9-122.5) 97.6 (75.4-118.9) 0.70

Patient Demographics Continued Baseline Characteristic EIT, n=75 LIT, n=20 P Value Hypertension, n (%) 45 (60%), 3 unknown 6 (30%), 2 unknown 0.03 Coagulopathy, n (%) 3 (4%) 0 (0%) >0.99 Smoker, n (%) 29 (38.7%), 6 unknown 9 (45%), 4 unknown 0.40 Use of home anticoagulant, n (%) 4 (5.3%), 2 unknown 0 (0%), Use of DAPT, n (%) 4 (5.3%), 1 (5%),

Population Data Total Population, n=95 Time to Surgery in hours (Median, IQR) 20.9 (12.6-36.8) Time to TPT initiation post-op in hours (Median, IQR) 44.5 (23-64.3) TPT started <24h post-op, n (%) 25 (33.3%) TPT started <18h post-op, n(%) 4 (4.2%) Enoxaparin Use 92 (97%)

Results: Primary Endpoint Endpoints EIT, n=75 LIT, n=20 P Value Composite Primary, n (%) 3 (4%) 1 (5%) >0.999 Re-bleeding, n 2 (2.7%) X Hemorrhage expansion, n 1 (1.3%) 0 (0%) Time to TPT, median (IQR) 29.6 (21.7-49.6) 113.8 (92.6-194.3)

Results: Secondary Endpoints EIT, n=75 LIT, n=20 P Value In-Hospital Mortality, n (%) 5 (6.7%) 0 (0%) 0.58 Discharge to Skilled Nursing Facility, n (%) 17 (24.3%) 4 (20%) 0.538 ICU Readmission, n (%) 8 (10.7%) 0.453 Development of VTE, n (%) 1 (1.3%) 1 (5%) 0.378 Development of HIT, n (%) >0.999 Need to D/C TPT, n (%) 7 (9.3%) 2 (10%) ICU Length of stay among survivors, median (IQR) 12.2 (8.6- 17.9) 13.5 (11-19.8) 0.329 Length of stay among survivors, median (IQR) 17.1 (13.6- 23.5) 21.7 (14.7-26.7) 0.248 Mortality: Each of the patients who passed away were very symptomatic GCS (3-6) or had higher grade bleeds HHS 3

Primary Endpoint Patients Study ID Age Admission GCS HHS Re-bleeding or hemorrhage expansion Highest SBP & DBP in previous 24 hours Time to TPT Start (hours) Time to Primary from TPT Start (hours) 11 50 15 X Expansion 138/77 28.2 16 40 68 3 5 Re-bleed 179/138 442.8 118 69 52 2 186/123 25 261 76 67 6 185/92 49.3

Time to TPT Start (hours) Time to Death from TPT Start (hours) Mortality Patients Study ID Age Admission GCS HHS Primary Endpoint Death 2/2 Hemorrhagic Condition Time to TPT Start (hours) Time to Death from TPT Start (hours) 21 66 3 X No Yes 51.3 15.4 37 43 43.9 24.8 44 57 13 69 8.5 52 15 2 25 26.1 76 67 6 49.3 4.7

48hr Redistribution Endpoints TPT within 48hr, n=51 TPT >48hr, n=44 In-Hospital Mortality, n (%) 2 (3.9%) 3(6.8%) Discharge to Skilled Nursing Facility, n (%) 11 (21.6%) 10 (22.7%) ICU Readmission, n (%) 6 (11.8%) 6 (13.6%) Development of VTE, n (%) 1 (2%) 1 (2.3%) Development of HIT, n (%) 0 (0%) Need to D/C TPT, n (%) 5 (9.8%) 4 (9.1%) ICU Length of stay among survivors, median (IQR) 10.9 (8.2-18) 14 (11-18.1) Length of stay among survivors, median (IQR) 16 (12.3- 22.4) 17.6 (14.3-26.1)

Limitations Single center Retrospective, observational in nature Lack of generalizability Retrospective, observational in nature Limited sample size Unequal distribution of patients among groups Selection bias LIT with worse baseline function

Conclusions EIT did not significantly increase the risk of re-bleeding or hemorrhage expansion as compared to LIT There were no statistically significant differences in any outcome between the two groups, however mortality was numerically higher in the EIT group Further studies are needed to more clearly define optimal timing of TPT

Future Direction Completion of a second study evaluating the efficacy of early vs late VTE prophylaxis in this patient population After completion of this study the creation of an institutional guideline regarding timing of TPT initiation

Self Assessment Question Yes or No Did the initiation of early thromboprophylactic therapy lead to more adverse events?

Self Assessment Question NO Did the initiation of early thromboprophylactic therapy lead to more adverse events?

Jared Ham, PharmD PGY1 Pharmacy Practice Resident Timing of thromboprophylactic therapy after repair of subarachnoid hemorrhage Jared Ham, PharmD PGY1 Pharmacy Practice Resident Palmetto Health Richland, Columbia, SC April 28, 2017

TPT Definition TPT for this study was defined as: Heparin 5,000 units every 8 hours Heparin 5,000 units every 12 hours Enoxaparin 30mg daily Enoxaparin 40 mg daily Enoxaparin 30mg twice daily If BMI >30, Enoxaparin 40mg twice daily

TPT Used