Direct thrombin inhibitors

Direct thrombin inhibitors (DTIs)

Dabigatran etexilate (Pradaxa®) is the only direct thrombin inhibitor clinically available for oral administration. The active compound dabigatran is hardly absorbed from the gastrointestinal tract. However, prodrug dabigatran etexilate had been identified as a substrate for the P-glycoprotein transporter.

Dabigatran is a potent, synthetic, reversible, non-peptide thrombin inhibitor. The inhibition of thrombin results in decreased formation of fibrin and reduces thrombin-stimulated platelet aggregation and thus prevents the formation of thrombi. Dabigatran inhibits both free and fibrin-bound forms of thrombin, as well as thrombin induced platelet aggregation. Other more traditional anticoagulants (coumarins, low molecular weight heparin (LMWH), unfractioned heparin (UFH), fondaparinux, and hirudins (parenterally administered direct thrombin inhibitors)) and their targets are also indicated in the graphic.

Dabigatran etexilate is administered orally. The anticoagulant effect is predictable and depends on the dose.

Monitoring by laboratory tests (analogous to INR) is not required in routine situations. No pharmacokinetic drug-drug interactions are currently known.

The main toxic effect of the drug known so far is bleeding, in common with other anticoagulants. The frequency of severe bleeding compared with bleeding caused by warfarin is still an issue of discussion. Gastrointestinal problems (nausea, vomiting and constipation) and vascular problems (edema and deep vein thrombosis) have been described. Compared with coumarin, dabigatran etexilate is 10-30 times more expensive.

Dabigatran etexilate is registered for the prevention of thromboembolic events in patients who received hip or knee surgery. The indication is limited, but might be extended in the future, for example to prevent stroke and thromboembolic events in general. Recent studies have compared the effects of warfarin and dabigatran in patients with atrial fibrillation and acute venous thromboembolism, however these results are still under debate.

EPAR of dabigatran.