Pharm
Dabigatran
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Dabigatran
, Pradaxa, Idarucizumab, Praxbind
Mechanism
Prodrug converted in liver to active drug
Oral
Direct Thrombin Inhibitor
Selectively and reversibly inhibits free and clot-bound thrombin
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%)
Contraindications
Mechanical
Prosthetic Heart Valve
s
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
Indications
Atrial Fibrillation
(non-valvular)
Poor INR control on
Warfarin
Barriers to INR monitoring
Warfarin Drug Interactions
Venous Thromboembolism
Requires initial 5-10 days of
Low Molecular Weight Heparin
(
LMWH
, e.g.
Enoxaparin
) or standard
Heparin
(2009) N Engl J Med 361:2342-52 [PubMed]
Precautions
Hemorrhage
Idarucizumab (Praxbind)
Monoclonal Antibody
antidote specific to Pradaxa (available in 2016)
Appears very effective in initial studies
Other reversal agents if Idarucizumab (Praxbind) is not available
See
Direct Thrombin Inhibitor
and
Anticoagulant Reversal
for other agents that may offer partial reversal
Prothrombin Complex Concentrate
may offer benefit in severe bleeding
Dialysis
is unlikely to be beneficial due to logistics of placing large bore filtered catheters in actively bleeding patients
Normal PTT level suggests Pradaxa is not therapeutic and not increasing bleeding risk
Bleeding typically stops spontaneously within 6-8 hours (but this is too long in exanguination)
Focused control of bleeding
Consider hematology
Consultation
Dosing
Standard dose: 150 mg twice daily
Same dose for
Atrial Fibrillation
and
Venous Thromboembolism
(initial, maintenance and recurrence prevention)
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
Creatinine Clearance
15-30 ml/minute
Contraindicated in
Creatinine Clearance
<15 ml/minute
Creatinine Clearance
30-50 ml/minute AND concurrent
Ketoconazole
or Dronedarone (Multaq)
This dose has not been studied
Precautions
Do not chew, break or open capsules
Shelf life on an open bottle of Pradaxa is only 60 days
Missed doses
Missing 2 or more doses (1 day) risks hyerpcoagulation and complications (contrast with 3 days for
Warfarin
)
Optimize pill taking reminders to avoid missed doses
If dose missed, take when remember unless within 6 hours of next dose
Transition from Pradaxa to
Warfarin
Creatinine Clearance
50 ml/min or greater
Start
Warfarin
and stop Pradaxa after
Warfarin
day 3
Creatinine Clearance
30-50 ml/min
Start
Warfarin
and stop Pradaxa after
Warfarin
day 2
Creatinine Clearance
15-30 ml/min
Start
Warfarin
and stop Pradaxa after
Warfarin
day 1
Dosing
Reversal Agent
See
Emergent Reversal of Anticoagulation
Idarucizumab (Praxbind)
Monoclonal Antibody
specific for Dabigatran with half-life of 1 hour, and renally excreted
Idarucizumab is highly effective in initial studies and FDA approval, but expensive ($3500 wholesale in 2016)
Complete Dabigatran reversal within minutes with effect lasting >24 hours, without
Hypercoagulable
adverse effects
Mild adverse effects (
Headache
, skin and infusion site irritation)
Gartland and Abboud (2020) Crit Dec Emerg Med 34(1):18
Buchheit (2016) Crit Pathw Cardiol 15(3):77-81 [PubMed]
Pollack (2015) N Engl J Med 373(6): 511-20 +PMID: 26095746 [PubMed]
Pollack (2017) N Engl J Med 377(5): 431-41 +PMID:28693366 [PubMed]
Labs
No routine labs needed (No monitoring of INR needed)
If bleeding, expect the following results:
PTT at 1-2 hours: 2x normal
PTT at 12 hours: 1.5x normal
PTT >2.5x normal suggests over-
Anticoagulation
PTT normal on Pradaxa suggests the patient is not anticoagulated
Thrombin Time
is most increased
PT/INR is variably affected
Efficacy
Slightly more effective than
Warfarin
in prevention against thrombotic events in
Atrial Fibrillation
Prevent 5 more strokes per 1000 patients per year than
Warfarin
Connolly (2009) N Engl J Med 361(12): 1139-51 [PubMed]
Appears as effective as
Warfarin
in
Venous Thromboembolism
(FDA approved)
As with
Warfarin
, requires initial 5-10 days of
Low Molecular Weight Heparin
(
LMWH
, e.g.
Enoxaparin
) or standard
Heparin
Disadvantages
Cost: $260/month (contrast with
Warfarin
which is $80/month with monitoring)
Twice daily dosing
Dyspepsia
is common
Not as effective as
Warfarin
in preventing
Myocardial Infarction
Warfarin
prevents 2 more
Myocardial Infarction
s per 1000 patients than Dabigatran
High renal elimination (80%)
Exercise
caution in
Chronic Kidney Disease
Safety
Fewer
Intracranial Bleeding
complications than with
Warfarin
(
Coumadin
)
More
Gastrointestinal Bleeding
complications than with
Coumadin
http://www.fda.gov/drugs/drugsafety/ucm396470.htm
Drug Interactions
P-Glycoprotein Inhibitor
s (decreases excretion with increased absorption and bleeding risk)
Simvastatin
Lovastatin
Does not appear to occur significantly with
Rosuvastatin
or
Atorvastatin
(2017) Presc Lett 24(2):12
Other
Anticoagulant
s and antiplatelet agents
Aspirin
and other antiplatelet agents
NSAID
s
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]
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