The era where warfarin is to be slowly phased-out, and no more annoying blood tests, could be here with the availability of dabigatran (Pradaxa®, Boehringer Ingelheim). Dabigatran is a competitive, direct thrombin inhibitor and is indicated to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation and following major lower limb orthopaedic surgery (hip/knee replacement). Dabigatran prevents the development of thrombi, with its active moieties inhibiting both free and clot-bound thrombin and thrombin-induced platelet aggregation.

As it is a relatively new medicine, caution should be taken regarding its adverse effects and considering that the pharmacokinetics show an absolute bioavailability of 3% to 7% following oral administration, meaning some patients get double the effective dose. Its oral bioavailability also increases by 75% when the pellets are taken without the capsule shell compared to the intact capsule formation, which is a concern for patients with trouble swallowing or administering via a nasogastric tube.

Dabigatran’s primary elimination is via renal clearance, with its pharmacokinetic parameters such as half-life increasing with renal function impairment as well as co-administration with selected P-glycoprotein inhibitors or inducers (e.g. calcium channel blockers, immunosuppressants, macrolides) due to the fact that conversion of dabigatran, a pro-drug substrate of this transporter, into the active moiety will be affected.

Table 1. Selected drug interactions with Dabigatran. 

Medications Effects
Rifampicin Decreased efficacy of dabigatran
Anticoagulants, Aspirin, Amiodarone, Azoles, Clopidogrel, Macrolides, NSAIDs, Verapamil, Quinidine Increased bleeding risk
Hydrocortisone, Immunosuppressants, Protease inhibitors, Progesterone May increase bleeding risk (P-gp inhibitor)
Carbamazepine, St John’s Wort Use with caution – unknown effects (P-gp inducer)

 

All medicines with anti-coagulation properties/increased bleeding risk (including herbal medicines e.g. fish oil, garlic, ginger, ginseng, ginkgo, dong guai, baical skullcap) should be used with caution in combination with dabigatran.

Dabigatran’s safety profile has been compared favourably to enoxaparin. Dosing guidelines have recently been amended to consider creatinine clearance (CrCl) where:

  • CrCl > 30ml/min, recommended dose is 110mg or 150mg twice a day,
  • CrCl < 30ml/min, dabigatran is contraindicated.

Currently noted adverse reactions for dabigatran are dyspepsia (abdominal pain/discomfort), anaemia, nausea, gastrointestinal ulceration/haemorrhage, bleeding, epistaxis, diarrhoea, gastritis, haemorrhoids, abnormal liver function tests, and allergic reactions. Other high risk factors for bleeding include patients who are above 75 years of age, and those with moderate kidney impairment.

Dabigatran is contraindicated in patients with prosthetic heart valves, acute haemorrhage, cerebrovascular haemorrhage, anaemia, and severe renal disease; and should also to be avoided in patients who are pregnant or lactating.

There is no specific antidote for dabigatran at this stage, and Boehringer Ingelheim recommend their CARE guide in managing bleeding cases as follows:

  • Cease dabigatran
  • Assess source of bleeding
  • Replace blood volume
  • Employ dialysis and/or consider coagulation factors if severe or life threatening.

The Queensland Health Guideline for Managing Patients on Dabigatran (Pradaxa®) assists health professionals with managing patients who are converting from dabigatran to warfarin:

Table 2. Schedule for conversion from dabigatran to warfarin with a high risk of thrombosis. 

Creatinine clearance (CrCl) Initiate warfarin
50mL/min ≤ 3 days before discontinuing dabigatran
31-50mL/min 2 days before discontinuing dabigatran
< 30mL/min Dabigatran is contraindicated
Discontinue immediately and start warfarin

 

As with all of the fairly new medicines, everyone should be looking out for and reporting adverse reactions to dabigatran when this medicine is being used.

The take home messages for patients are similar to most anti-coagulants as well. If a dose is missed, take it, but do not double up within six hours of the next dose, just miss it. Watch out for signs of bruising or bleeding, and do not stop this medicine without informing the doctor. Do not chew, break, or open the capsules, but swallow it whole, and always inform the healthcare professional(s) if there are any concerning issues.

Interesting points to consider:

  • INR test is relatively insensitive to the activity of dabigatran, and if switching over from warfarin, only start dabigatran after INR<2. If switching over from a parenteral anti-coagulant, start dabigatran at the time of discontinuation of the parenteral drug.
  • Special note for dabigatran bottled pack (instead of the blister pack), dabigatran should be discarded four months after opening due to its deterioration on exposure to humidity.
  • Dabigatran should be discontinued at least 24 hours prior to surgery, although high risk and major surgery patients are recommended to discontinue it 2-4 days before.
  • Significant reduction in the risk of stroke and systemic embolism, including haemorrhagic strokes, has been shown with 150mg dabigatran twice a day dose compared to warfarin.
  • Significantly fewer major bleeding events occur with the 110mg dabigatran twice a day dose, but a higher incidence of ischemic stroke when compared to the 150mg dose, and at similar rates to warfarin.
  • Significantly lower life threatening and intracranial bleeding occurs with both doses of dabigatran when compared to warfarin.
  • Significant reduction in vascular mortality with the 150mg dabigatran twice a day dose when compared to warfarin.

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