ADD-ONS / MEDICATION / ANTICOAGULANTS

Dabigatran (Pradaxa)

Created 19/10/2022, last revision 25/10/2022

Dabigatran (PRADAXA) is an oral anticoagulant drug used to treat and prevent VTE and stroke in people with nonvalvular atrial fibrillation (NVAF) through direct thrombin inhibition. It is used as an alternative to warfarin, which does not require laboratory monitoring or dietary restrictions. Dabigatran belongs to a group of drugs called direct oral anticoagulants (DOACs)

Indication

  • Primary and secondary stroke prevention in non-valvular atrial fibrillation (NVAF) – RE-LY trial
  • Treatment and prevention of deep vein thrombosis (DVT) and pulmonary embolism (PE) (RECOVER, RECOVER II, RE-SONATE, RE-MEDY trials)
  • VTE prevention in the knee and hip surgery

Contraindications

  • hypersensitivity to the medicinal substance or any of the excipients
  • pregnancy and breastfeeding
  • severe renal impairment Cockcroft-Gault formula!
    • adults: creatinine clearance <30 mL/min (0.5 mL/s) 
    • pediatric patients: creatinine clearance <50 mL/min/1.72 m2
  • clinically significant active bleeding
  • lesions or conditions considered a significant risk factor for major bleeding
    • current or recent gastrointestinal ulcerations, presence of malignant tumors
    • recent brain or spinal injury, a recent surgical procedure in the brain, spine, or eye
    • recent intracranial hemorrhage, known presence or suspected esophageal varices, arteriovenous malformations, vascular aneurysms, or severe
      intraspinal or intracerebral vascular anomalies
  • spontaneous or pharmacological (concomitant anticoagulants) disorder of hemostasis
  • liver disease – all DOACs are contraindicated in patients with liver disease associated with coagulopathy and clinically apparent risk of bleeding
  • concomitant therapy (especially potent P-glycoprotein inhibitors – see interactions below):
    • dronedarone (Multaq)
    • rifampicin
    • ketoconazole, itraconazole
    • cyclosporine
    • tacrolimus
  • mechanical heart valves requiring VKAs

Mechanism of action

  • Direct Thrombin Inhibitor (DTI) with a favorable safety profile without hepatotoxicity
  • it reversibly binds to the active site on the thrombin molecule, preventing thrombin-mediated activation of coagulation factors
Direct anticoagulants
They inactivate the coagulation factors present in the plasma
Indirect anticoagulants
They affect coagulation factors by reducing their liver production
Direct thrombin/factor Xa inhibitors
These drugs are bound to thrombin/factor Xa and thereby block their function
Indirect thrombin/factor Xa inhibitors
These drugs act through the activation of antithrombin
  • vitamin K antagonists (VKAs)
    • warfarin (coumadin)
  • xabans (free and clot-bound factor Xa inhibitors)
    • apixaban
    • rivaroxaban
    • edoxaban
    • betrixaban
  • hirudin (direct thrombin inhibitor – DTI)

Pharmacokinetics and pharmacodynamics

  • dabigatran is a prodrug – after absorption in the digestive tract, it transforms by enzymatic transformation into an active metabolite
  • fasting or post-meal administration is possible
  • rapid onset of action (peak in 2-3 hours after administration)
  • half-life approximately 8h after a single dose and increases to 14-17h after repeated administration
    • the effect can extend up to 30 hours in renal insufficiency!
    • higher risk of bleeding with dTT > 200ng/mL detected 10-16h after previous dose
  • there is a relationship between dabigatran plasma concentration and the anticoagulant effect
  • the kidneys excrete 80% of the drug ⇒ increased plasma concentrations in renal insufficiency
  • prolongs APTT, but this effect is not dose- or effect-dependent (APTT is not equivalent to dabigatran serum concentration)

Interactions

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Dosing

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Monitoring

  • clinical monitoring usual for all anticoagulated patients (apixaban is no “shoot and forget” drug)
  • specific laboratory monitoring can be done in selected cases

→ monitoring of patients treated with DOACs

Complications, adverse events

  • in routine clinical practice, according to the GLORIA-AF registry, the annual risk of major bleeding is 1.12% and life-threatening bleeding 0.54%
  • dabigatran has fewer IC bleeds, but more GI bleeds compared to warfarin (especially in patients >75 years of age  [Desai, 2016]
  • after the acute bleeding has been solved:
    • exclude any source of bleeding (intestinal polyp, peptic ulcer, etc.), particularly with repeated bleeding
    • exclude overdose – check renal functions, interactions, and other factors, check specific lab tests (peak and end of dose levels ) ; adjust the dose if required
    • consider reduced dose or switch to another drug
Hemorrhagic complications (RE-LY)
dabigatran 110mg
n=6015
dabigatran 150mg
n=6076
warfarin
n=6022
Major bleeding
322 (2.7%/rok)
375 (3.11%/rok)
397 (3.36%/rok)
Intracranial bleeding
(ICH, SAH, SDH)
27 (0.23%/rok)
36 (0,3%/rok)
87  (0,74%/rok)
life-threatening bleeding
145 (1.22%/rok)
175 (1.45%/rok)
212 (1,8%/rok)
GI bleeding
133 (1.12%) 182 (1.51%) 120 (1.01%)
Other adverse events
Dabigatran
110 mg (%)
Dabigatran
150 mg (%)
Warfarin
  dyspepsia
11,8
1,3
5,8
  dyspnoea
9,3
9,5
9,7
dizziness
 8,1
 8,3
9,4
 peripheral edema
7,9
7,9
7,8
fatigue
6,6
6,6
6,2
cough
5,7
5,7
6
back pain
 5,2
6,2
 5,9
joint pain
 4,5
 5,5
 5,7
diarrhea
 6,3
 6,5
 5,7

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