What is the drug of choice for intracranial (IC) bleeding?

Management of Intracranial Bleeding: Drug Selection Based on Etiology

The "drug of choice" for intracranial bleeding depends entirely on the underlying cause—there is no single universal agent, but rather specific reversal agents matched to the causative anticoagulant or antiplatelet therapy, with immediate discontinuation of all antithrombotic agents being the first critical step. 1, 2

Immediate Actions for All Intracranial Hemorrhages

• Discontinue all anticoagulants and antiplatelet agents immediately without waiting for laboratory confirmation, as time to reversal directly impacts mortality and hematoma expansion 2, 1
• Target correction of coagulopathy within 4 hours of admission 2

Specific Reversal Agents by Causative Drug

Warfarin-Associated ICH (INR ≥1.4)

• Administer 4-factor prothrombin complex concentrate (PCC) 25-50 IU/kg IV based on weight and INR PLUS vitamin K 10 mg IV immediately 3, 2
• This combination is superior to fresh frozen plasma and achieves faster, more complete reversal 3, 2
• Vitamin K must be given regardless of PCC administration to prevent INR rebound at 12-24 hours 3
• For INR 1.3-2.0, use lower PCC dose of 10-20 IU/kg to limit venous thromboembolism risk 3

Direct Oral Anticoagulants (DOACs)

For dabigatran:

• Administer idarucizumab 5g IV as first-line treatment 2

For factor Xa inhibitors (apixaban, rivaroxaban, edoxaban):

• Administer andexanet alfa as the specific reversal agent, with dosing based on timing and dose of last DOAC intake 2, 3
• Andexanet alfa reduced anti-factor Xa activity with 79% achieving hemostatic efficacy (defined as <35% hematoma volume increase at 12 hours) 3
• Alternative: 4-factor PCC can be used if andexanet alfa is unavailable, though data comparing outcomes are limited 3

Unfractionated Heparin

• Administer protamine sulfate 1 mg IV for every 100 units of heparin given in the previous 2-3 hours (maximum single dose 50 mg) 2, 4

Low Molecular Weight Heparin (Enoxaparin)

For therapeutic-dose LMWH:

• Administer protamine 1 mg IV per 1 mg enoxaparin (maximum 50 mg single dose) if dosed within 8 hours 2, 4
• Use 0.5 mg IV per 1 mg enoxaparin if dosed within 8-12 hours 2, 4
• If life-threatening bleeding persists or renal insufficiency present, consider redosing protamine at 0.5 mg per 100 anti-Xa units 4

For prophylactic-dose LMWH:

• Routine reversal is NOT recommended unless aPTT is significantly prolonged 4

Thrombolytic Agents

• Administer cryoprecipitate 10 units IV as first-line reversal for thrombolytic-related ICH within 24 hours of administration 2

Antiplatelet Agents (Aspirin, Clopidogrel)

• Discontinue immediately when ICH is present or suspected 1
• Platelet transfusion is NOT recommended for antiplatelet-associated ICH in patients who will not undergo neurosurgical procedures, regardless of hemorrhage volume or neurologic examination 1
• If neurosurgical intervention is required, platelet transfusion may be considered, ideally with platelet function testing prior to transfusion 1
• One single donor apheresis unit of platelets is the suggested initial dose if transfusion is deemed necessary 1

Pentasaccharides (Fondaparinux)

• Administer activated PCC (aPCC) 20 U/kg IV or recombinant factor VIIa 90 μg/kg IV 2
• Do not use protamine—it is ineffective for these agents 4

Supportive Medical Management

Beyond reversal agents, supportive care includes:

• Blood pressure control: Target systolic BP <140 mmHg promptly and precisely 5, 3
• Osmotic agents (mannitol and glycerol) for increased intracranial pressure management 6
• External ventricular drainage with intraventricular fibrinolysis for intraventricular hemorrhage 5

Critical Pitfalls to Avoid

• Never delay reversal while waiting for laboratory confirmation—reversal decisions should be based on bleeding severity and medication history 2
• Do not use recombinant factor VIIa routinely—it reduces hematoma expansion but does not improve outcome and increases thromboembolic complications 7
• Do not transfuse platelets empirically for antiplatelet-associated hemorrhage unless neurosurgery is planned 1
• Do not restart antithrombotics before repeat imaging confirms hemorrhage stability—premature resumption increases rebleeding risk 4
• The risk of thromboembolism within 30 days after reversal is 7-12%, but immediate mortality risk from ongoing bleeding typically outweighs thrombotic risk 2

Note on Nimodipine

Nimodipine is FDA-approved for subarachnoid hemorrhage from ruptured intracranial aneurysms to reduce ischemic deficits, not for acute hemostasis in intracerebral hemorrhage 8