The correct answer is: C) 4-factor prothrombin complex concentrate (PCC) or activated PCC (aPCC).

A recent meta-analysis showed that treatment with a higher dose of a new oral anticoagulant (NOAC) significantly reduced stroke or systemic embolic events (SEEs) by 19%, compared with warfarin; this benefit was mainly driven by a decrease in hemorrhagic stroke, which was reduced by half (Table 1).¹

These observations suggest that each year approximately 0.4% of patients with non-valvular AF who are receiving NOACs can be expected to experience a hemorrhagic stroke.

How to Manage NOACs in the Acute Phase of an Intracranial Hemorrhage

The goal of the emergency treatment is to normalize the coagulation. This can be particularly challenging in patients treated with NOACs due to the current absence of specific antidotes, although development of reversal agents are in late phases of clinical testing.

First, a prompt interruption of anticoagulation is required; time, given the relatively short plasma half life of the NOACs (11-13 hours for rivaroxaban 20 mg in patients with renal impairment), is the best antidote for non-cerebral bleeding.² However, in patients with hemorrhagic stroke, a quicker normalization of coagulation is required to avoid expansion of the hematoma, which is associated with a mortality of around 50%.

Vitamin K is not helpful to reverse the anticoagulant effect of NOACs because, unlike vitamin K antagonists (VKAs) that reduce the circulating levels of the vitamin K-dependent clotting factors (Factors II, VII, IX, X) by inhibiting their production, these agents directly antagonize the action of normal levels of circulating activated Factor II (dabigatran) or activated Factor X (rivaroxaban, apixaban, edoxaban).

In the case of NOACs, fresh frozen plasma (FFP) will not be of help to reverse anticoagulation because the plasma abundance of the drug inhibits newly administered coagulation factors as well. However, FFP may be indicated to expand plasma volume in patients who require massive transfusion of red blood cells. Unlike patients who received fibrinolytic therapy and shortly thereafter develop intracranial bleeding, this patient would not be expected to have a low fibrinogen level since rivaroxaban acts by inhibiting factor Xa and does not deplete fibrinogen.

Dialysis is helpful to rapidly clear dabigatran from the circulation as it is not highly protein bound, and would be a reasonable choice in patients with a life-threatening bleed who have acute anuric renal failure shortly after a dose of dabigatran. However, rivaroxaban is highly protein bound (92-95%)³, and, thus, dialysis is not likely to be effective to remove it from the circulation.

Most of the available data in support of the different reversal strategies of NOACs come from studies in animals, in healthy subjects, and in vitro:

• In mice, prothrombin complex concentrate (PCC), a concentrate of coagulation factors II (VII), IX, and X, has been shown to reduce expansion of dabigatran-induced hematoma.⁴
  
  
• In healthy volunteers, administration of 50 U/kg of PCC completely reversed rivaroxaban-induced prolongation of the prothrombin time, but had no effect on dabigatran-induced prolongation of coagulation tests, in particular of thrombin time and ecarin clotting time.⁵
  
  
• In vitro testing, using blood samples from volunteers taking NOACs, showed that aPCC (similar to PCC but with activated Factor VIIa) corrected more coagulation parameters than PCC alone.⁶

Based on these experimental data, the administration of PCC (starting at dose of 25 U/kg) or aPCC (50 IE/kg, with a maximum of 200 IE/kg/day) can be considered in patients with life-threatening bleeding. PCC and aPCC could overcome the anticoagulant effect induced by direct thrombin and factor Xa inhibitors by providing coagulation factors in high concentration and thus enhancing thrombin generation.

Should NOACs be Restarted After an ICH? And if Yes, When?

Once the hemorrhagic stroke has occurred, another dilemma facing clinicians is the decision whether and when to resume anticoagulation, which is associated with worse intracranial hemorrhage (ICH) outcomes and increased risk of recurrence. Randomized clinical trials are needed for both vitamin VKAs and NOACs. Ultimately, the decision will depend on the estimated risk of recurrent ICH and the risk of thromboembolism. The most consistently identified risk factors for recurrent ICH are lobar location, often associated with cerebral amyloid angiopathy, older age, carriership of the apolipoprotein E2 or 4 alleles and greater number of microbleeds on T2-weighted gradient-echo magnetic resonance imaging, markers of more severe underlying vasculopathy. Long-term anticoagulation should be avoided after spontaneous lobar ICH⁷ (risk of recurrence 15% per year⁸). The risk/benefit ratio of anticoagulation is more reasonable in patients with deep hemispheric ICH, where the risk of recurrence is lower (2% per year). In these patients, anticoagulation may be considered; however, the optimal timing for resumption has yet to be defined. In patients treated with warfarin, the combined risk of recurrent ICH or ischemic stroke reached a nadir when warfarin was resumed after approximately 10 to 30 weeks. For this, to date, a reasonable recommendation regarding time to resumption of anticoagulation therapy would be after 10 weeks.⁹ Non-pharmacological prevention strategies such as ablation or occlusion of the atrial appendage should be considered in patients for whom anticoagulation resumption is contraindicated.

References

1. Ruff CT, Giugliano RP, Braunwald E, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet 2014;383:955-62.
2. Heidbuchel H, Verhamme P, Alings M, et al. European Heart Rhythm Association Practical Guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation. Europace 2013;15:625-51.
3. Bayer Pharma AG. Xarelto (Rivaroxaban) Summary of Product Characteristics (Xarelto website). 2011. Available at: http://www.xarelto.com/html/downloads/Xarelto_Summary_of_Product_Characteristics_Dec2011.pdf. Accessed 5/12/2012.
4. Zhou W, Schwarting S, Illanes S, Liesz A, Middelhoff M, Zorn M et al. Hemostatic therapy in experimental intracerebral hemorrhage associated with the direct thrombin inhibitor dabigatran. Stroke 2011;42:3594-9.
5. Eerenberg ES, Kamphuisen PW, Sijpkens MK, et al. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation 2011;124:1573-9.
6. Marlu R, Hodaj E, Paris A, Albaladejo P, Crackowski JL, Pernod G. Effect of nonspecific reversal agents on anticoagulant activity of dabigatran and rivaroxaban. A randomised crossover ex vivo study in healthy volunteers. Thromb Haemos 2012;108:217–24.
7. Morgenstern LB, Hemphill JC, Anderson C, et al. Guidelines for the management of spontaneous intracerebral hemorrhage. A guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2010;41:2108-29.
8. Eckman MH, Rosand J, Knudsen KA, Singer DE, Greenberg SM. Can patients be anticoagulated after intracerebral haemorrhage? A decision analysis. Stroke 2003; 34:1710-16.
9. Majeed A, Kim YK, Roberts RS, et al. Optimal timing of resumption of warfarin after intracerebral haemorrhage. Stroke 2010;41:2860-66.