Lewin- Reversal agents in ICH, What you need to know!

Clinical Pearls (Summary assisted by by Dr. Faith Armstrong)

Quick pearls:

• Antithrombotic ICH is expected to become more common and antithrombotic-associate ICH has a higher risk of hematoma expansion, higher mortality, and worse outcome
• Most of our epidemiologic data is specific to warfarin
• Rates of ICH with novel AC are lower, but we don’t have very effective methods of reversal

Specific agents:

• Vitamin K Antagonists (i.e. Warfarin): inhibits vitamin K oxide reductase, therefore inhibition of Facts II, VII, IX, and X
  • Doubles risk of IPH, causing 12-14% of all IPH (with risk increasing with INR lvl!)
  • Antidotes:
    • Vitamin K
      • It can take up to 24 hours to decrease INR with Vit K alone
        • Vit K in addition to PCC or FFP is needed to provide long-lasting INR correction
      • Low risk of anaphylaxis which can be mitigated by diluting it and infusing over 10-15 minutes
      • Recommended dose is 10mg (unless re-anticoagulation is needed rapidly for whatever reason, in which a lower dose would be beneficial); IV route is preferred
    • Factor replacement

• PCC
  • Pros: lower volume, fast reconstitution, more rapid INR correction, lower infection risk
  • Cons: expensive, not widely available, some must be re-dosed
• FFP
  • Pros: widely available, less expensive
  • Cons: needs to be thawed/matched, slower correction, risk of TRALI/TACO
• Two RCTs: no difference in thrombosis rates (3-8%)
• INCH trial: new 2016 study showing PCC is much more rapid and effective
  • Less hematoma expansion with PCC which stopped the study!
• Ideal Strategy
• Give PCC (rather than FFP) for INR correction WITH vit K 10mg IV
  • Suggest PCC4, but low quality evidence
  • PCC dosing should be weight-based & vary according to admission INR and type of PCC used
• Repeat INR testing 15-60 min post-PCC and every 6-8h for 24h
• Subsequent tx should be guided by INR (high risk for DIC with re-dosing)
• Direct Inhibitors: Bind to and directly inhibit Factors (Factor Xa inhibitor- Rivaroxiban/Apixaban/Edoxaban) and Thrombin (Factor IIa inhibitor- Dabigatran)

• Dabigatran (thrombin inhibitor)
  • New FDA approved agent: Idarucizumab (monoclonal antibody)
    • RRT will remove the drug as well, but drug levels will rebound
  • Ideal Strategy
    • Assess time of last ingestion (T1/2 ~12 hrs), renal function, medication interactions
      • Reversal should be guided by bleeding and not lab testing
    • Activated charcoal (50g) to intubated patients with ICH and/or those at low risk for aspiration who present <2h post-ingestion
    • CRRT is usefel due to low MW and low protein bound status
    • Administer Idarucizumab (5g IV two divided doses) if dabigatran was administered within a period of 3-5 half lives and no renal failure OR if there is renal insufficiency leading to continued drug exposure
• Rivaroxiban/Apixaban/Edoxaban (Factor Xa inhibitors)
  • Potential reversal options:
    • Activated charcoal within 2h of intake
    • Animal studies showing partial correction of lab abnormalities with PCC, aPCC, rFVIIa
    • Upcoming reversal agents in clinical trials (Andexanet-recombinant Xa, Aripazine)
  • Ideal Strategy
    • Discontinue agent
    • Activated charcoal as above
    • PCC4 (50 U/kg) or aPCC (50 U/kg) if ICH occurred within 3-5 half lives OR in context of liver failure (based on very limited data)
    • Await trial results for novel reversal agents
• UFH:
  • Protamine for UFH reversal (1mg neutralizes 80-120 units of heparin)
    • Dose according to amount of heparin received in the past 2-3 hours with 1mg/100 U heparin received (max single dose of 50mg)
• LMWH:
  • Protamine with dose based on timing of last LMWH dose
    • If LMWH w/in 8h: 1mg protamine/1mg LMWH received
    • If LMWH w/in 8-12h: 0.5mg Protamine/1mg LMWH received
  • If Protamine contraindicated, can use rFVIIa (90mcg/kg IV)
  • Andexanet? Stay tuned…..
• Pentasaccharides (Fondaparinux, Idraparinux)
  • Protamine ineffective
  • aPCC (20 IU/kg) for reversal
    • If not available then rFVIIa (90mcg/kg)
• Thrombolytics
  • Alteplase, Reteplase, and Tenecteplase bind preferentially to fibrin-bound plasminogen
    • Urokinase and Streptokinase bind equally to free and fibrin-bound plasminogen
  • Will cause a reduction in Fibrinogen (may be a marker of bleeding risk) and anti-platelet effects for ~ 12 hours
  • Antidotes:
    • Cryoprecipitate
      • Fibrinogen, FVIII, FXIII, fibronectin, vWF
      • Target fibrinogen >100 mg/dL
    • Antifibrinolytics
      • Bind to and inactivate plasmin and plasminogen preventing fibrinolysis
      • Amiocaproic acid & Tranexamic acid (TXA)
  • Ideal Strategy
    • Cryoprecipitate (10 units) who have received a thrombolytic agent in past 24h
      • Check fibrinogen levels after administration for goal >100
    • If cryo contraindicated or not available, TXA (10-15mg/kg over 20 min) or amiocaproic acid (4-5g IV) may be used
• Antiplatelets
  • Ideal Strategy
    • No routine platelet transfusions unless undergoing a neurosurgical procedure
  • PATCH trial:
    • Pts on anti-platelet therapy with an acute CVA
    • Odds of death was higher in patients who received platelets!
  • Desmopressin
    • No benefit found in case series, however very little harm