October 29, 2018

Mitigating Risk of Intracranial Hemorrhage while using Blood Thinners

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By Hope Quattlebaum, PharmD candidate and Lisa C Hutchison, PharmD, MPH
Donald W. Reynolds Institute on Aging at UAMS



Blood thinners, such as novel oral anticoagulant agents (NOACs), reduce the risk of developing an emboli (clot) in conditions such as atrial fibrillation (afib), deep venous thrombosis (DVT), and other cardiovascular conditions. The NOACs include apixaban (Eliquis), rivaroxaban (Xarelto), dabigatran (Pradaxa), and edoxaban (Savaysa).  Using blood thinners prevent clots of all kinds, even ‘good’ clots. When ‘good’ clots are inhibited serious bleeding can occur, such as intracranial hemorrhage (ICH).

Clinicians sometimes mitigate risk by choosing to use aspirin in place of a NOAC since it is thought to have a lower risk of ICH. However, studies show that apixaban 5 mg twice daily did not increase ICH compared to aspirin therapy in afib patients6. Based on this, apixaban is a better choice than aspirin since it poses no additional risk and is more effective. However, it was not known if this conclusion could be applied to other disease states.  A meta-analysis published in 2018 attempted to answer this question.

The meta-analysis included five major randomized controlled trials (RCTs) with the purpose to assess the risk of ICH with NOACS versus aspirin in all indications5. The researchers looked for RCTs that compared apixaban and rivaroxaban to aspirin for 3 or more months. The primary endpoint was rates of ICH in NOACs versus aspirin. The table provides information on the age, disease state and comparison groups in each of the five studies.

Trial name Mean age (years) Disease state Treatment groups
AVERROES6, 2014 70 Atrial fibrillation 5mg apixaban twice daily v. aspirin 81-324 mg
NAVIGATE ESUS1, 2018 67 Embolic stroke of undetermined source 15 mg rivaroxaban once daily v. aspirin 100mg
EINSTEIN CHOICE4, 2017 58.5 Venous thromboembolism 20mg or 10 mg daily rivaroxaban v. aspirin 100mg
COMPASS2, 2017 68.2 Stable cardiovascular disease 5 mg rivaroxaban twice daily v. aspirin 100 mg
COMPASS3, 2017 67.8 Stable peripheral or carotid artery disease 5 mg rivaroxaban twice daily v. aspirin 100 mg


After pooling evidence, the researchers determined that the risk of ICH with rivaroxaban 10-20mg daily is 3.31 times higher than aspirin. Lower doses, 10 mg daily or 5 mg twice daily, were not associated with higher risk of ICH. Apixaban did not show an increased risk. Researchers calculated that 15-20 mg rivaroxaban can cause an additional 3 hemorrhages per 1000 patients compared to aspirin or apixaban. Evaluation of the secondary endpoint showed that rivaroxaban 15-20 mg increased the rate of fatal bleeding by 2.37 times compared to aspirin and apixaban 5mg twice daily. Also, the same dose is associated with 2.64 times higher risk for major bleeding compared to aspirin, while apixaban showed no increase in risk.

This meta-analysis provides substantial evidence that rivaroxaban at higher doses (15-20 mg daily) increases risk of ICH and fatal bleeding in many patients needing anti-thrombotic therapy. These doses are equivalent to those recommended in afib, DVT treatment, but higher than the recommended dose for DVT prevention, 10 mg daily.  Apixaban 5 mg twice daily and rivaroxaban 10mg were not associated with these increased risks. Unfortunately, no direct comparisons could be made between aspirin and dabigatran or edoxaban.




1 Hart RG, Sharma M, Mundl H, et al; NAVIGATE ESUS Investigators. Rivaroxaban for stroke prevention after embolic stroke of undetermined source. N Engl J Med. 2018;378(23):2191-2201. doi: 10.1056/NEJMoa1802686
2 Eikelboom JW, Connolly SJ, Bosch J, et al; COMPASS Investigators. Rivaroxaban with or without aspirin in stable cardiovascular disease. N Engl J Med. 2017;377(14):1319-1330. doi:10.1056/NEJMoa1709118
3 Anand SS, Bosch J, Eikelboom JW, et al; COMPASS Investigators. Rivaroxaban with or without aspirin in patients with stable peripheral or carotid artery disease: an international, randomised, double-blind, placebo-controlled trial. Lancet. 2017;S0140-6736(17)32409-1.
4 Weitz JI, Lensing AWA, Prins MH, et al; EINSTEIN CHOICE Investigators. Rivaroxaban or aspirin for extended treatment of venous thromboembolism. N Engl J Med. 2017;376(13): 1211-1222. doi:10.1056/NEJMoa1700518
5 Huang W, Singer DE, Wu Y, et al. Association of Intracranial Hemorrhage Risk With Non–Vitamin K Antagonist Oral Anticoagulant Use vs Aspirin Use: A Systematic Review and Meta-Analysis. JAMA Neurol. Published online August 13, 2018. doi:10.1001/jamaneurol.2018.2215
6 Connolly, S. J., Eikelboom, J., Joyner, C, et al; AVERROES Steering Committee and Investigators. Apixaban in patients with atrial fibrillation. N Engl J Med. 2011; 364(9), 806-817.