Pharm

Dabigatran

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Dabigatran, Pradaxa, Idarucizumab, Praxbind

  • Mechanism
  1. Prodrug converted in liver to active drug
  2. Oral Direct Thrombin Inhibitor
    1. Selectively and reversibly inhibits free and clot-bound thrombin
    2. Prevents conversion of Fibrinogen to fibrin (which in turn prevents clot)
  • Pharmacokinetics
  1. Oral bioavailability: 3 to 7%
  2. Onset: 1 hour post-ingestion (and therapeutic levels within 2 hours of first dose)
  3. Half-life: 12-17 hours
  4. Primarily renal excretion (80%)
  • Contraindications
  1. Mechanical Prosthetic Heart Valves
    1. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm332949.htm
  2. Active pathologic bleeding
  3. Creatinine Clearance <30 ml/min
  4. Creatinine Clearance <50 ml/min AND concurrent P-Glycoprotein Inhibitor
  • Indications
  1. Atrial Fibrillation (non-valvular)
    1. Poor INR control on Warfarin
    2. Barriers to INR monitoring
    3. Warfarin Drug Interactions
  2. Venous Thromboembolism
    1. Requires initial 5-10 days of Low Molecular Weight Heparin (LMWH, e.g. Enoxaparin) or standard Heparin
    2. (2009) N Engl J Med 361:2342-52 [PubMed]
  1. Idarucizumab (Praxbind)
    1. Monoclonal Antibody antidote specific to Pradaxa (available in 2016)
    2. Appears very effective in initial studies
  2. Other reversal agents if Idarucizumab (Praxbind) is not available
    1. See Direct Thrombin Inhibitor and Anticoagulant Reversal for other agents that may offer partial reversal
    2. Prothrombin Complex Concentrate may offer benefit in severe bleeding
    3. Dialysis is unlikely to be beneficial due to logistics of placing large bore filtered catheters in actively bleeding patients
    4. Normal PTT level suggests Pradaxa is not therapeutic and not increasing bleeding risk
  3. Bleeding typically stops spontaneously within 6-8 hours (but this is too long in exanguination)
    1. Focused control of bleeding
    2. Consider hematology Consultation
  • Dosing
  1. Standard dose: 150 mg twice daily
    1. Same dose for Atrial Fibrillation and Venous Thromboembolism (initial, maintenance and recurrence prevention)
    2. VTE requires concurrent initial 5-10 days of Low Molecular Weight Heparin (LMWH, e.g. Enoxaparin) or standard Heparin
  2. Half-dose: 75 mg twice daily Indications
    1. Creatinine Clearance 15-30 ml/minute
      1. Contraindicated in Creatinine Clearance <15 ml/minute
    2. Creatinine Clearance 30-50 ml/minute AND concurrent Ketoconazole or Dronedarone (Multaq)
    3. This dose has not been studied
  3. Precautions
    1. Do not chew, break or open capsules
    2. Shelf life on an open bottle of Pradaxa is only 60 days
  4. Missed doses
    1. Missing 2 or more doses (1 day) risks hyerpcoagulation and complications (contrast with 3 days for Warfarin)
    2. Optimize pill taking reminders to avoid missed doses
    3. If dose missed, take when remember unless within 6 hours of next dose
  5. Transition from Pradaxa to Warfarin
    1. Creatinine Clearance 50 ml/min or greater
      1. Start Warfarin and stop Pradaxa after Warfarin day 3
    2. Creatinine Clearance 30-50 ml/min
      1. Start Warfarin and stop Pradaxa after Warfarin day 2
    3. Creatinine Clearance 15-30 ml/min
      1. Start Warfarin and stop Pradaxa after Warfarin day 1
  • Dosing
  • Reversal Agent
  1. See Emergent Reversal of Anticoagulation
  2. Idarucizumab (Praxbind)
    1. Monoclonal Antibody specific for Dabigatran
    2. Idarucizumab is highly effective in initial studies and FDA approval
    3. Complete Dabigatran reversal within minutes with effect lasting >24 hours
    4. Pollack (2015) N Engl J Med 373(6): 511-20 +PMID: 26095746 [PubMed]
    5. Pollack (2017) N Engl J Med 377(5): 431-41 +PMID:28693366 [PubMed]
  • Labs
  1. No routine labs needed (No monitoring of INR needed)
  2. If bleeding, expect the following results:
    1. PTT at 1-2 hours: 2x normal
    2. PTT at 12 hours: 1.5x normal
    3. PTT >2.5x normal suggests over-Anticoagulation
    4. PTT normal on Pradaxa suggests the patient is not anticoagulated
    5. Thrombin Time is most increased
    6. PT/INR is variably affected
  • Efficacy
  1. Slightly more effective than Warfarin in prevention against thrombotic events in Atrial Fibrillation
    1. Prevent 5 more strokes per 1000 patients per year than Warfarin
    2. Connolly (2009) N Engl J Med 361(12): 1139-51 [PubMed]
  2. Appears as effective as Warfarin in Venous Thromboembolism (FDA approved)
    1. As with Warfarin, requires initial 5-10 days of Low Molecular Weight Heparin (LMWH, e.g. Enoxaparin) or standard Heparin
  • Disadvantages
  1. Cost: $260/month (contrast with Warfarin which is $80/month with monitoring)
  2. Twice daily dosing
  3. Dyspepsia is common
  4. Not as effective as Warfarin in preventing Myocardial Infarction
    1. Warfarin prevents 2 more Myocardial Infarctions per 1000 patients than Dabigatran
  5. High renal elimination (80%)
    1. Exercise caution in Chronic Kidney Disease
  • Safety
  1. Fewer intracranial bleeding complications than with Warfarin (Coumadin)
  2. More Gastrointestinal Bleeding complications than with Coumadin
    1. http://www.fda.gov/drugs/drugsafety/ucm396470.htm
  • Drug Interactions
  1. P-Glycoprotein Inhibitors (decreases excretion with increased absorption and bleeding risk)
    1. Simvastatin
    2. Lovastatin
    3. Does not appear to occur significantly with Rosuvastatin or Atorvastatin
    4. (2017) Presc Lett 24(2):12
  2. Other Anticoagulants and antiplatelet agents
    1. Aspirin and other antiplatelet agents
    2. NSAIDs
  • References
  1. (2014) Presc Lett 21(11): 61
  2. (2011) Prescr Lett 18(12):67
  3. (2012) Prescr Lett 19(3):13
  4. Lemkin (2013) Crit Dec Emerg Med 27(4): 2-9
  5. (2009) N Engl J Med 361:1139-51 [PubMed]
  6. Wilbur (2017) Am Fam Physician 95(5): 295-302 [PubMed]