1. Restarting Long-Term Anticoagulation Therapy After an Intracranial Hemorrhage
Judith Misas, Pharm.D. Candidate
PGY1 Residency Interview
February 2018

2. Objective
Discuss the controversy of restarting anticoagulation therapy after intracranial hemorrhage and their potential impact on patient care
Evaluate guideline recommendations and discuss areas for improvement
Review evidence-based literature to direct best-practice

3. Patient Case
JP, a 68 year old female (weight = 66 kg, height = 5’5’’), presented to the ED with slurred speech, and left sided weakness.
Past medical History: Nonvalvular A-fib, HTN
Home medications:
Xarelto 20 mg daily
Metoprolol tartrate 25 mg twice a day
Lisinopril 20 mg daily
Social history: No illicit drugs, no alcohol consumption, not a smoker
Lab: Hgb: 11.6, INR: 1.2, Plt: 245, K: 3.7, Scr: 1.0, CrCl: 56 ml/min
Vitals: 158/83, 108 beats/min, 18 breaths/min, 36 °F
Imaging:
Brain CT: Intraparenchymal hemorrhage, no midline shift

4. Drug Information Rivaroxaban (Xarelto) Mechanism of Action
Direct Factor Xa inhibitor blocking thrombin production
Indications:
Non-valvular atrial fibrillation: 20 mg daily with food
DVT/PE treatment: Initiate 15 mg twice a day with food for 3 weeks, then 20 mg daily with food
Post-op DVT prophylaxis:
Knee replacement: 10 mg daily for 12 days
Hip replacement: 10 mg daily for 35 days
Renal/Hepatic adjustment:
For non-valvular atrial fibrillation, CrCl > ml/min: 15 mg once daily with food
For every other indications, avoid use in CrCl < 30 ml/min
Pharmacokinetics:
Half life: 7-12 hours
Time to peak: 2-4 hours

5. Drug Information Metoprolol Mechanism of Action Indications:
Beta 1 adrenergic receptor inhibitor, does not affect beta 2 adrenergic receptors
Indications:
Hypertension/verticular rate control:
IV: 2.5 to 5 mg every 2 to 5 minutes (maximum total dose: 15 mg)
Maintenance: Oral (metoprolol tartrate): 25 to 100 mg twice daily; Oral (metoprolol succinate): 50 to 400 mg once daily
Myocardial Infarction:
IV: 5 mg every 5 minutes in the early treatment of ST elevation myocardial infarction
Oral: 25 to 50 mg (metoprolol tartrate) every 6 to 12 hours; or to daily metoprolol succinate and increase as tolerated to a maximum dose of 200 mg/day
Renal/Hepatic adjustment:
No dose adjustment necessary
Pharmacokinetics:
Half life: 3-7 hours in adults
Time to peak: IV: 20 minutes, PO: 6-12 hours

6. Drug Information Lisinopril Mechanism of Action Indications:
Prevents conversion of angiotensin I to angiotensin II, a potent vasoconstrictor
Indications:
Hypertension:
Oral: Initial: 5 to 10 mg once daily. Maintenance: 10 to 40 mg once daily.
Heart failure:
Oral: Initial: 2.5 to 5 mg once daily; Target dose: 20 to 40 mg once daily
Myocardial Infarction:
Oral: 5 mg immediately, then 5 mg at 24 hours, 10 mg at 48 hours, and then 10 mg once
Renal/Hepatic adjustment:
CrCl >30 mL/minute: No dosage adjustment necessary.
CrCl 10 to 30 mL/minute: Initial: 5 mg once daily (maximum: 40 mg/day)
CrCl <10 mL/minute: Initial: 2.5 mg once daily (maximum: 40 mg/day)
Hemodialysis: Initial: 2.5 mg once daily (dialyzable) (maximum: 40 mg/day)
Pharmacokinetics:
Half life: 12 hours
Time to peak: 7 hours

7. Treatment/Follow up DVT Prophylaxis: SCDs Medications:
Nicardipine drip ( mg/hr): 5 mg/hr
Titrate and maintain SBP less than 140
Metoprolol (Lopressor) 5 mg IV Q6
Lisinopril 20 mg QD
Famotidine 20 mg IV BID
Follow up: Patient’s intracranial bleeding stops, and after several days, patient is stable, weaned off of oxygen, tolerating food, and being transferred to stepdown unit

8. Dilemma: Should we resume anticoagulation? If so, when?
What medication therapy should we resume?

9. Should we resume anticoagulation?
Guideline states:
Anticoagulation after nonlobar ICH and antiplatelet monotherapy after any ICH might be considered, particularly when there are strong indications for these agents (Class IIb; Level of Evidence B)
Survey says:
Proportion of respondents suggesting OAC anticoagulant resumption varied from 30% (for cerebral amyloid angiopathy = lobar) to 98% (for traumatic ICH)
Nonlobar intracranial hemorrhage
Lobar intracranial hemorrhage

10. When should we resume anticoagulation?
Guidelines states:
The optimal timing to resume oral anticoagulation after anticoagulant-related ICH is uncertain.
Avoidance of oral anticoagulation for at least 4 weeks, in patients without mechanical heart valves, might decrease the risk of ICH recurrence (Class IIb; Level of Evidence B).
European Guideline (2017) states 4-8 weeks for patients who were on anticoagulation prior to ICH for NVAF
Survey says:
Timing of resumption: 21.4% preferred to re-start OACs after 1-3 weeks of incident ICH, while 25.3% opted to start after 1-3 months.
Neurosurgery respondents preferred earlier OAC resumption compared to stroke neurologists or thrombosis experts

11. What medication therapy should we resume?
Guideline states:
The usefulness of dabigatran, rivaroxaban, or apixaban in patients with atrial fibrillation and past ICH to decrease the risk of recurrence is uncertain (Class IIb; Level of Evidence C).
Survey says
Xu Y, Shoamanesh, et al. (2018) Oral anticoagulant re-initiation following intracerebral hemorrhage in non-valvular atrial fibrillation: Global survey of the practices of neurologists, neurosurgeons and thrombosis experts. PLoS ONE 13(1): e

12. Cohort Study from Denmark
Nielsen PB, et al. (2015):
The event rates for ischemic stroke/SE in patients treated with anticoagulation vs no antithrombotic treatment were 5.3 vs 10.4 at 1 year of follow-up (adjusted HR: 0.59, 95% CI ), while for antiplatelet therapy, 10.3 (adjusted HR: 0.98, 95% CI )

13. Cohort Study from Denmark
Nielsen PB (2015) in Denmark (n = 719):
For all-cause mortality, the event rates were for patients treated with anticoagulation vs 19.1 for no antithrombotic treatment (adjusted HR: , 95% CI ), and 19.5 for antiplatelet therapy (adjusted HR: , 95% CI ).
The median time until resumption was 31 days (range 18–65)
Nielsen, Peter Brønnum, et al. “Restarting Anticoagulant Treatment After Intracranial Haemorrhage in Patients With Atrial Fibrillation and the Impact on Recurrent Stroke, Mortality and Bleeding: A Nationwide Cohort Study.” Circulation, American Heart Association, Inc., 9 June 2015.

14. Most Recent Finding
Biffi A., et al (2017) conducted a meta-analysis from 3 sources: Multicenter RETRACE study (n = 542), a U.S.-based single-center ICH study (n = 261), and the Ethnic/Racial Variations of Intracerebral Hemorrhage study (n = 209):
It was found that resuming anticoagulation was associated with decreased ischemic stroke risk after lobar and nonlobar ICH, but not with increased ICH recurrence risk
Biffi, A., et al. (2017), Oral Anticoagulation and Functional Outcome after Intracerebral Hemorrhage. Ann Neurol., 82: 755–765. doi: /ana.25079

15. Patient Case JP continues to improve and finally gets discharged
Blood pressure well controlled under 130/80 with medication
Lifestyle modifications implemented
Patient is resumed on her medications:
Xarelto 20 mg daily (within 4-8 weeks)
Metoprolol (Lopressor) 25 mg twice a day
Lisinopril 20 mg daily

16. Take Home Points
Main concern with restarting anticoagulation is recurrence of ICH
We need more randomized trials
APACHE-AF (Phase II randomized trial-apixaban vs aspirin vs no antithrombotic after ICH) currently recruiting patients, trial starts March 2018
But in the meantime …
Patients with high-risk thromboembolism should be on anticoagulation
Per guidelines, wait 4 weeks before resuming … The “when” is still controversial and patient-specific
NOACs has less risk for intracranial bleed than warfarin

17. Reference
Biffi, A., Kuramatsu, J. B., Leasure, A., Kamel, H., Kourkoulis, C., Schwab, K., Ayres, A. M., Elm, J., Gurol, M. E., Greenberg, S. M., Viswanathan, A., Anderson, C. D., Schwab, S., Rosand, J., Testai, F. D., Woo, D., Huttner, H. B. and Sheth, K. N. (2017), Oral Anticoagulation and Functional Outcome after Intracerebral Hemorrhage. Ann Neurol., 82: 755–765. doi: /ana.25079
Hemphill, J. Claude, et al. “Guidelines for the Management of Spontaneous Intracerebral Hemorrhage.” Stroke, American Heart Association, Inc., 1 July 2015,
H. Heidbuchel, P. Verhamme, M. Alings, M. Antz, H.C. Diener, W. Hacke, et al.Updated European Heart Rhythm Association practical guide on the use of non- vitamin K antagonist anticoagulants in patients with non-valvular atrial fibrillationEuropace, 17 (2015), pp
Nielsen, Peter Brønnum, et al. “Restarting Anticoagulant Treatment After Intracranial Haemorrhage in Patients With Atrial Fibrillation and the Impact on Recurrent Stroke, Mortality and Bleeding: A Nationwide Cohort Study.” Circulation, American Heart Association, Inc., 9 June 2015.
Xu Y, Shoamanesh, et al. (2018) Oral anticoagulant re-initiation following intracerebral hemorrhage in non-valvular atrial fibrillation: Global survey of the practices of neurologists, neurosurgeons and thrombosis experts. PLoS ONE 13(1): e

18. Website

19. Questions?