Dabigatran

See Also

Indications

Atrial Fibrillation (non-valvular)
1. Poor INR control on Warfarin
2. Barriers to INR monitoring
3. Warfarin Drug Interactions
Venous Thromboembolism Treatment or prophylaxis
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]
Heparin Induced Thrombocytopenia (HIT)
1. Off-label use

Contraindications

Mechanical Prosthetic Heart Valves
1. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm332949.htm
Active pathologic bleeding
Creatinine Clearance <30 ml/min
Creatinine Clearance <50 ml/min AND concurrent P-Glycoprotein Inhibitor

Mechanism

Prodrug converted in liver to active drug
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

Oral Bioavailability: 3 to 7%
Onset: 1 hour post-ingestion (and therapeutic levels within 2 hours of first dose)
Half-Life: 12-17 hours
Primarily renal excretion (80%)

Precautions
Hemorrhage

See Emergent Reversal of Anticoagulation
Idarucizumab (Praxbind)
1. Monoclonal Antibody antidote specific to Dabigatran (available in 2016)
2. Appears very effective with rapid activity in initial studies
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. Hemodialysis does remove Dabigatran
  1. However Hemodialysis is unlikely to be practical
  2. Logistics of placing large bore filtered catheters in actively bleeding patients
4. Normal PTT level suggests Dabigatran is not therapeutic and not increasing bleeding risk
5. Consider Activated Charcoal if Dabigatran Overdose and taken within 2-4 hours of presentation
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

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
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
VTE Prophylaxis following hip or knee surgery
1. Avoid if GFR <30 ml/min (or with strong P-Glycoprotein Inhibitor AND GFR <50 ml/min)
2. Start 220 mg orally daily on postoperative day 1
  1. May give a first dose of 110 mg one to four hours after surgery
3. Continue for 28 to 35 days after hip surgery (or 10 days after knee surgery)
Precautions
1. Do not chew, break or open capsules
2. Shelf life on an open bottle of Pradaxa is only 60 days
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
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

Labs

No routine labs needed (No monitoring of INR needed)
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

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]
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

Unknown safety in pregnancy
Unknown safety in Lactation
Fewer Intracranial Bleeding complications than with Warfarin (Coumadin)
More Gastrointestinal Bleeding complications than with Coumadin
1. http://www.fda.gov/drugs/drugsafety/ucm396470.htm

Drug Interactions

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
Other Anticoagulants and antiplatelet agents
1. Aspirin and other antiplatelet agents
2. NSAIDs

Reources

Dabigatran (DailyMed)
1. https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=ba74e3cd-b06f-4145-b284-5fd6b84ff3c9

References

(2014) Presc Lett 21(11): 61
(2011) Prescr Lett 18(12):67
(2012) Prescr Lett 19(3):13
Lemkin (2013) Crit Dec Emerg Med 27(4): 2-9
(2009) N Engl J Med 361:1139-51 [PubMed]
Wilbur (2017) Am Fam Physician 95(5): 295-302 [PubMed]