1. 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

2. No disclosures to report
Primary Investigator:
Jared S. Ham, PharmD
Co-Investigators:
Erin D. Creech, PharmD, BCPS, BCCCP
Cortney R. Dodson, PharmD, BCCCP
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3. Objective
To describe the safety of early versus late initiation of thromboprophylactic therapy after surgical repair of aneurysmal subarachnoid hemorrhages

4. 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

5. 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:
Serrone JC, et al. World Neurosurg. 2013;80(6):
Kshettry VR, et al. J Clin Neurosci. 2014;21(2):
Nyquist P, et al. Crit Care Med Epub
Suarez JI, et al. N Engl J Med. 2006;354(4):
Vespa P, et al. Neurocrit Care. 2011; 15(2):

6. 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 Epub
Connolly ES, Jr., et al. Stroke. 2012;43(6):
Vespa P, et al. Neurocrit Care. 2011; 15(2):

7. 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):
Image from:

8. 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

9. 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

10. 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

11. 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

12. 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

13. Inclusion & Exclusion Criteria
Inclusion Criteria
Exclusion Criteria
Adult patients (≥18 years old)
Admitted to Palmetto Health Richland from June 1, 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

14. 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

15. 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

16. Baseline Characteristic
Patient Demographics
Baseline Characteristic
EIT, n=75
LIT, n=20
P Value
Age, median (IQR)
55 ( )
52 ( )
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 ( )
27.6 ( )
0.52
GCS, median (IQR)
15 (14-15)
14.5 ( )
0.19
Creatinine Clearance, median (IQR)
99.2 ( )
97.6 ( )
0.70

17. 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%),

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

19. 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 ( )
113.8 ( )

20. 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 ( )
13.5 ( )
0.329
Length of stay among survivors, median (IQR)
17.1 ( )
21.7 ( )
0.248
Mortality: Each of the patients who passed away were very symptomatic GCS (3-6) or had higher grade bleeds HHS 3

21. 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

22. 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

23. 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 ( )
Length of stay among survivors, median (IQR)
16 ( )
17.6 ( )

24. 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

25. 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

26. 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

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

28. Self Assessment QuestionNO
Did the initiation of early thromboprophylactic therapy lead to more adverse events?

29. 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

30. 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

31. TPT Used