Pharmacotherapy

The pharmacotherapy for hemorrhagic stroke aims to provide supportive care, prevent complications, and manage underlying conditions. As a clinical pharmacist preparing for board certification, it is essential to have a comprehensive understanding of the pharmacological interventions used in the management of hemorrhagic stroke. Here are the key pharmacotherapy considerations:

• Blood Pressure Management:
  • Goal SBP 130-150 mmHg is reasonable for most patients with ICH if tolerated. More intensive reduction to SBP <130 mmHg may be harmful.
  • Intravenous agents like nicardipine, labetalol, or clevidipine are preferred for acute reduction in first 24 hours.
  • Caution with excessive BP lowering in patients with very high baseline SBP or large ICH.
  • Initial blood pressure control is crucial to prevent hematoma expansion and minimize the risk of rebleeding.
  • Antihypertensive agents commonly used in hemorrhagic stroke include:
    • Nicardipine:
      • Intravenous calcium channel blocker.
      • Initial dose: 5 mg/hour IV infusion.
      • Titrate by 2.5 mg/hour every 5-15 minutes to achieve target blood pressure.
      • Maximum dose: 15 mg/hour.
    • Labetalol:
      • Non-selective beta-blocker with alpha-blocking properties.
      • Initial dose: 10-20 mg IV over 1-2 minutes.
      • May repeat every 10-20 minutes if necessary.
    • Clevidipine:
      • Intravenous dihydropyridine calcium channel blocker.
      • Initial dose: 1-2 mg/hour IV infusion.
      • Titrate by doubling the dose every 2-5 minutes to achieve target blood pressure.
      • Maximum dose: 21 mg/hour.
    • Oral agents like captopril, labetalol, or nimodipine can be used for BP maintenance after the first day.
    • Caution with excessive reduction in patients with very high baseline SBP or large ICH to avoid hypoperfusion.
    • Minimize SBP fluctuations and achieve smooth sustained control.

• Anticoagulation Reversal
  • Patients on anticoagulant therapy like warfarin or DOACs are at high risk of hematoma expansion. Rapid reversal is critical but should not delay other acute ICH care.

Warfarin Reversal

• 4-factor PCC is preferred over FFP for warfarin reversal. Provides faster increase in factor levels.
• Dose is 25-50 IU/kg or fixed 1500 IU for ICH. Maximum dose not established.
• Always give 5-10 mg IV vitamin K regardless of PCC use to sustain effect.
• Monitor INR to guide dosing. Target INR <1.3.
• Adverse effects like DVT/PE are rare if appropriate dosing used.

Dabigatran Reversal

• Idarucizumab 5 g IV (two 2.5 g boluses) effectively binds dabigatran and reverses anticoagulation.
• Normalization of dilute thrombin time or ecarin clotting time confirms reversal.
• No need to wait for coagulation test results if recent dabigatran ingestion.
• Adverse effects are rarely reported. Hypersensitivity is possible.

Factor Xa Inhibitors

• Andexanet alfa preferred for reversal of apixaban, rivaroxaban, edoxaban.
• IV bolus followed by 2 hour infusion. Dose per specific Xa inhibitor and timing since last dose.
• 4-factor PCC reasonable option if andexanet unavailable. Dose 50 IU/kg.
• aPCC also suggested but less evidence than 4-factor PCC.
• Monitor anti-Xa levels. Target <0.1 IU/mL for apixaban, <0.2 IU/mL for rivaroxaban.
• Thrombosis risk 5-10%. Higher with andexanet compared to PCC.

Heparin Reversal

• For UFH, 1 mg IV protamine sulfate reverses 100 units of heparin. Maximum 50 mg over 10 minutes.
• For LMWH, 1 mg protamine per 1 mg enoxaparin. Only partial reversal.
• Monitor aPTT. Target 40-60 seconds.

• Seizure Prophylaxis:
  • Seizure activity can exacerbate brain injury; therefore, prophylactic antiepileptic drugs (AEDs) may be administered.
  • In patients with spontaneous ICH, impaired consciousness, and confirmed electrographic seizures, antiseizure drugs should be administered to reduce morbidity
    • In patients with spontaneous ICH without evidence of seizures, prophylactic antiseizure medication is not beneficial to improve functional outcomes, long-term seizure control, or mortality.
  • Commonly used AEDs for seizure treatment include
    • Phenytoin:
      • Loading dose: 15-20 mg/kg IV at a rate of 50 mg/minute.
      • Maintenance dose: 300-400 mg/day in divided doses.
    • Levetiracetam:
      • Loading dose: 1000-3000 mg IV over 15 minutes.
      • Maintenance dose: 1000 mg twice daily or 500 mg twice daily in renal impairment.
    • Phenobarbital:
      • Loading dose: 10-20 mg/kg IV at a rate of 1 mg/kg/minute.
      • Maintenance dose: 1-3 mg/kg/day in divided doses.

• Prevention of Complications:
  • Thromboembolic Prophylaxis:
    • Subcutaneous heparin or low-molecular-weight heparin should be initiated to prevent deep vein thrombosis and pulmonary embolism in patients with reduced mobility.
    • Dosage and frequency depend on the specific agent used and patient characteristics. Consult guidelines for appropriate dosing.
  • Acid Suppression:
    • Proton pump inhibitors (PPIs) such as pantoprazole or omeprazole may be prescribed to prevent stress ulcers and gastrointestinal bleeding.
    • Dosage and frequency depend on the specific PPI used. Consider renal and hepatic function when determining dosing.
  • Glycemic Control:
    • Maintaining optimal blood glucose levels is crucial in reducing the risk of secondary brain injury.
    • Regular blood glucose monitoring and insulin therapy may be initiated to achieve tight glycemic control.
• Underlying Condition Management:
  • If an underlying condition, such as an arteriovenous malformation (AVM), is identified as the cause of the hemorrhage, referral to neurosurgery for further evaluation and potential intervention is necessary.
  • Management of comorbidities, including hypertension, diabetes, and dyslipidemia, is essential to optimize long-term outcomes and reduce the risk of recurrent strokes.
  • Refer to specific guidelines and consult with the healthcare team for detailed drug selection, dosing, and monitoring considerations.