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

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

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

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 > 15-50 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

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

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

Treatment/Follow up DVT Prophylaxis: SCDs Medications: Nicardipine drip (2.5 - 15 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

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

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

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

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): e0191137. https://doi.org/10.1371/journal.pone.0191137

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 0.33-1.03), while for antiplatelet therapy, 10.3 (adjusted HR: 0.98, 95% CI 0.65-1.49)

Cohort Study from Denmark Nielsen PB (2015) in Denmark (n = 719): For all-cause mortality, the event rates were 9.7 for patients treated with anticoagulation vs 19.1 for no antithrombotic treatment (adjusted HR: 0.55, 95% CI 0.37-0.82), and 19.5 for antiplatelet therapy (adjusted HR: 0.90, 95% CI 0.67-1.21). 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.

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:10.1002/ana.25079

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

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

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:10.1002/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. 1467-1507 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): e0191137.

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