1. Evaluation of Optimal Time to Achieve Intensive Blood Pressure Control on Mortality in Patients with Intracerebral Hemorrhage
Bradley Smith, Pharm.D.
PGY1 Pharmacy Resident
St. Joseph’s/Candler Health System
Co-Investigators:
Allison Powell, Pharm.D., BCPS
Erica Merritt, Pharm.D., BCPS
Rachel Webb, Pharm.D., BCPS
Macey McDaniel, PharmD Candidate

2. 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:
Bradley Smith, Pharm.D.: nothing to disclose
Allison Powell, Pharm.D., BCPS: nothing to disclose
Erica Merritt, Pharm.D., BCPS: nothing to disclose
Rachel Webb, Pharm.D., BCPS: nothing to disclose
Macey McDaniel, Pharm.D. candidate: nothing to disclose

3. Background Intracerebral Hemorrhage (ICH)
2nd most common presentation of stroke
Characterized by marked elevations in blood pressure
Can lead to neurological deterioration and death
Affects ~200,000 patients in U.S. per year
~35-52% mortality at 30 days
Balami JS, et al. The Lancet Neurology. 2012;11(1):

4. Background Mainstay of therapy: hypertension control
A systolic blood pressure (SBP) goal of < 140 mmHg is recommended in
Patients with an initial SBP mmHg
No contraindication to intensive blood pressure control
Hemphill JC, et al. Stroke. 2015;46(7):

5. Background INTERACT-2 Large, multi-center study in patients with ICH
Intensive SBP control (< 140 mmHg) compared with guideline-directed therapy (< 180 mmHg)
Did not demonstrate significant reduction in death or severe disability at 90 days
Demonstrated significantly improved functional outcomes
All-cause mortality and nonfatal serious adverse events did not differ between groups
Anderson CS, et al. N Engl J Med. 2013;368(25):

6. Background Mohrien et al1 Ovesen et al2
Small, single-center study in patients with ICH
Comorbid conditions affect acute hypertensive control in patients with ICH
Ovesen et al2
Small, multicenter study in patients with ICH
Hematoma expansion occurs primarily within 7 to 8 hours of onset in patients with ICH
Mohrien KM, et al. Journal of Critical Care. 2015;30(2):
Ovesen C, et al. Stroke. 2015;45(4):

7. Purpose
To evaluate the optimal time to achieve intensive blood pressure control on mortality in patients with ICH

8. Study Objectives Primary Objective Secondary Objective
To evaluate the difference in mortality in ICH patients who achieved an intensive blood pressure control of SBP < 140 mmHg at 1, 6, or 24 hours
Secondary Objective
To evaluate the impact of intensive blood pressure control at 1, 6, or 24 hours on ICU length of stay (LOS), hospital LOS, and hematoma expansion at 24 hours

9. Study Measures Primary Measures Secondary Measures Hospital mortality
Achieved goal SBP at 1, 6, or 24 hours
Secondary Measures
ICU LOS (days)
Hospital LOS (days)
Hematoma expansion at 24 hours

10. Study Center St. Joseph’s/Candler Health System
Community health system with 714 inpatient beds divided between two anchor hospitals
St. Joseph’s: 32-bed adult ED, certified stroke center
Candler: 40-bed adult ED, certified stroke center

11. Methodology Design: Single-center, retrospective chart review
Population:
Adult patients treated in the ED
Treated between October 1, 2011 to September 30, 2016
Diagnosed with ICH

12. Methodology Inclusion Criteria Exclusion Criteria
Males or non-pregnant females ≥ 18 years old
Diagnosed with concomitant subarachnoid hemorrhage
Diagnosis of ICH confirmed with CT scan or MRI in the emergency department
Surgical hematoma removal
SBP > 150 mmHg on presentation
Glasgow Coma Score (GCS) < 5 on presentation
Expired within 24 hours of presentation
Made DNR or comfort care only within 24 hours of presentation

13. Statistical Analysis
Fisher’s exact tests were used to analyze categorical data
One-way ANOVA was used for continuous variables
A p-value of < 0.05 was considered statistically significant
To evaluate our data…

14. 406 patients screened 354 patients excluded* 52 patients included
Patient Selection
406 patients screened
354 patients excluded*
52 patients included
*Reasons for exclusion:
216 Direct hospital admissions
74 SBP < 150 on presentation
31 GCS < 5 on presentation
22 Made DNR within 24 hours
The most common reason for exclusion included treatment for less than 6 months.

15. Demographics Study Group N = 52 Age- yr ± SD 78.8 ± 11.8
Male sex- no. (%)
31 (59.6)
Caucasian race- no. (%)
26 (50.0)
African American race- no. (%)
Pertinent past medical history- no. (%)
HTN
46 (88.5)
CVA/TIA
9 (17.3)
ICH
4 (7.7)
Home Medications- no. (%)
Antihypertensives
39 (75.0)
Anticoagulants
10 (19.2)
Mean SBP on presentation- mmHg ± SD
187.1 ± 26.1
Of note, there was a statistically significant difference in age. Although cumbersome, physicians can directly monitor the safety and efficacy of warfarin via INR levels. This may increase the comfort of prescribing warfarin in the elderly population who may have more co-morbidities compared to the younger patient population. All other demographics were similar between both groups.

16. Antihypertensive Agents Used
Patients Receiving [N=52, n(%)]*
Nicardipine
32 (61.5)
Labetalol
29 (55.8)
Hydralazine
10 (19.2)
Amlodipine
6 (11.5)
Enalaprilat
4 (7.7)
These are some of the risk factors listed in the NCCN guidelines that could be easily evaluated in a retrospective, chart review. Of note, there was no statistically significant differences in these risk factors.
It appears that patients that required more monitoring due to compliance, non-adherence to diet, and other complications were referred to the pharmacist-driven anticoagulation clinic. There is no standardized referral process in place regarding new coumadin therapy initiation. It is dependent on the preference of the physician.
TTR was defined as the INR value reported at a visit no more than once per month. The goal was to avoid collecting INR values that reflected interventions to warfarin from previous non-therapeutic level.
*Average agents used per patient = 1.9

17. Primary Measures 34% 22% N = 52 p = 0.6100 N = 48 p = 0.1899 N = 31
1.) This slide characterizes the overall percentage of time within therapeutic range for patients taking warfarin.
2. TTR was defined as the INR value reported at a visit no more than once per month. The goal was to avoid collecting INR values that reflected interventions to warfarin from previous non-therapeutic level.
3.) Our TTR was 44% which is below the reported TTR of 58% in the EINSTEIN trial and 61% in the AMPLIFY trial. In our study, patients that were outside of the therapeutic range were more likely to be below at 34% which increases the risk of recurrent VTE and reduces the risk of bleeding.
It appears that patients that required more monitoring due to compliance, non-adherence to diet, and other complications were referred to the pharmacist-driven anticoagulation clinic. There is no standardized referral process in place regarding new warfarin therapy initiation. It is dependent on the preference of the physician.
N = 52
p =
N = 48
p =
N = 31
p =
N = 21

18. Secondary Measures ICU LOS (days ± SD) Hospital LOS Achieved
Not Achieved
p-value
Goal 1 hr [N=52, n(%)]
4.5 ± 3.0
[4(7.7)]
6.2 ± 6.0 [48(92.3)]
0.5799
5.0 ± 3.2 [4(7.7)]
13.8 ± 11.0 [48(92.3)]
0.1201
Goal 6 hr [N=48, n(%)]
5.1 ± 4.2 [17(35.4)]
6.7 ± 6.6 [31(64.6)]
0.3717
12.3 ± 8.3 [17(35.4)]
14.6 ± 12.1 [31(64.6)]
0.4891
Goal 24hr [N=31, n(%)]
5.5 ± 5.2 [10(32.3)]
7.3 ± 7.2 [21(67.7)]
0.4864
14.2 ± 12.9 [10(32.3)]
14.8 ± 11.8 [21(67.7)]
0.8986
Looking at our primary outcome, the utilization of anticoagulants.
SOC utilization: 69%
NOAC utilization: 31%

19. Secondary Measures Hematoma Expansion @ 24 hours (%) Expansion
No Expansion
p-value
Achieved Goal 1 hr [N=4]
50.0
1.0000
Achieved Goal 6 hr [N=17]
11.8
88.2
<0.0001
Achieved Goal 24 hr [N=10]
40.0
60.0
0.3833
Never Achieved [N=21]
19.0
81.0
0.0001
Although not statistically significant, NOACs seems to be associated with reduced VTE and increased bleeding risk. However, this finding may be explained by the higher sub-therapeutic levels in patients using warfarin.

20. Secondary Measures Hematoma Expansion @ 24 hours (%) Expansion
No Expansion
p-value
Achieved Goal 1 hr [N=4]
50.0
1.0000
Achieved Goal 6 hr [N=17]
11.8
88.2
<0.0001
Achieved Goal 24 hr [N=10]
40.0
60.0
0.3833
Never Achieved [N=21]
19.0
81.0
0.0001
Although not statistically significant, NOACs seems to be associated with reduced VTE and increased bleeding risk. However, this finding may be explained by the higher sub-therapeutic levels in patients using warfarin.

21. Discussion
Achieving intensive blood pressure control at 1, 6, or 24 hours did not show improved hospital mortality
Achieving target SBP at 1, 6, or 24 hours did not have a significant impact on ICU or hospital LOS
Patients who achieved target SBP at 6 hours had a significantly lower rate of hematoma expansion (p < )
Patients who never achieved SBP < 140 mmHg had a significantly lower rate of hematoma expansion (p = )
Speaking Points:
1. The use of NOACs accounted for 31% of prescribed anticoagulants in oncology patients
2. Although not statistically significant, there may be a trend towards reduced VTE recurrence in the NOAC group with equivalent bleeding risk. However, the increased rates of recurrent VTE in the standard of care group may be caused by the percentage of time spent below the therapeutic range. These findings are in contrast with the current literature that found both a reduced rate of VTE and bleeding risk in the NOAC group.
3. Time in therapeutic range is likely representative of true clinical practice in this patient population.

22. Limitations
Small, retrospective cohort nature limits external validity
Inconsistent documentation led to potential bias for the available data reviewed
Lack of standardized SBP goals led to potential bias
No patients were able to maintain intensive blood pressure control across all 3 observed intervals
Speaking Points:
The small, retrospective cohort nature limits the external validity of the results and precludes the ability to establish causal relationships.
Inconsistent documentation led to potential bias for the available data reviewed.
Calculation of time in therapeutic range was subjected to selection bias in patients receiving warfarin therapy.
There was no consistent criteria for indefinite anticoagulation as determined by the medical oncologists.

23. Conclusions Further studies warranted
Patients who achieved goal SBP < 140 mmHg at 1, 6, or 24 hours did not show improved hospital mortality
Achieving target SBP < 140 mmHg did not have a significant impact on ICU or hospital LOS
Data also suggests that achieving goal SBP < 140 mmHg within 6 hours may prevent hematoma expansion
Further studies warranted
Speaking Points:
Overall, this analysis found no statistical difference in recurrent VTE or bleeding risk with the use of NOACs compared to the standard of care. Therefore, this pilot study indicates that the use of NOACS may be a safe and effective alternative for the management of chronic VTE in oncology patients.
However, further testing in a prospective trial is warranted to definitively recommend NOAC use.

24. Objective and Self Assessment
Demonstrate if more rapid achievement of systolic blood pressure < 140 mmHg reduces hospital mortality in patients with ICH
Self Assessment:
What is the current guideline recommended goal blood pressure in patients with ICH?
Answer:
SBP less than 140 mmHg is a safe and effective goal for patients with initial SBP between 150 and 220 mmHg
To review, what is the current accepted standard of care for the chronic management of VTE in oncology patients?

25. Acknowledgements Allison Powell, PharmD, BCPS
Erica Merritt, PharmD, BCPS
Rachel Webb, PharmD, BCPS
Macey McDaniel, PharmD Candidate

26. References
Balami JS, Buchan AM. Complications of intracerebral haemorrhage. The Lancet Neurology. 2012;11(1):
Hemphill JC, Greenberg SM, Anderson CS, et al. Guidelines for the Management of Spontaneous Intracerebral Hemorrhage. Stroke. 2015;46(7):
Anderson CS, Heeley E, Huang Y, et al. Rapid Blood-Pressure Lowering in Patients with Acute Intracerebral Hemorrhage. New England Journal of Medicine N Engl J Med. 2013;368(25):
Mohrien, KM, Elijovich E, Venable GT, et al. Intensive Blood Pressure Control during the Hyperacute Phase of Intracerebral Hemorrhage in Patients at Risk for Resistant Hypertension: A Retrospective Cohort Study. Journal of Critical Care (2015);30(2):
Ovesen C., Christensen AF, Krieger DW, et al. Time Course of Early Postadmission Hematoma Expansion in Spontaneous Intracerebral Hemorrhage. Stroke (2014);45(4):
Thank you for your time and attentino. At this time, I would like to open the floor to questions.

27. Evaluation of Optimal Time to Achieve Intensive Blood Pressure Control on Mortality in Patients with Intracerebral Hemorrhage
Bradley Smith, Pharm.D.
PGY1 Pharmacy Resident
St. Joseph’s/Candler Health System
Co-Investigators:
Allison Powell, Pharm.D., BCPS
Erica Merritt, Pharm.D., BCPS
Rachel Webb, Pharm.D., BCPS
Macey McDaniel, PharmD Candidate