<unk>  was generally well tolerated in the trial populations, but a small proportion (5–6%) developed elevated liver enzyme levels, which prompted the FDA to reject an initial application for approval in 2004. The further development was discontinued in 2006 following reports of hepatotoxicity. Subsequent analysis of Phase 2 clinical study data using extreme value modelling (see Extreme value theory) showed that the elevated liver enzyme levels observed in Phase 3 clinical studies could have been predicted; if this had been known at the time, it might have affected decisions on future development of the compound. A chemically different but pharmacologically similar substance, AZD-0837, was developed by Aztrazeneca for similar indications. It is a prodrug of a potent, competitive, reversible inhibitor of free and fibrin-bound thrombin called ARH0637. The development of AZD-0837 has been discontinued. Due to a limitation identified in long-term stability of the extended-release AZD-0837 drug product, a follow-up study from ASSURE on stroke prevention in patients with non-valvular atrial fibrillation, was prematurely closed in 2010 after 2 years. There was also a numerically higher mortality against warfarin. In a Phase 2 trial for AF the mean serum creatinine concentration increased by about 10% from baseline in patients treated with AZD-0837, which returned to baseline after cessation of therapy.
Ximelagatran
Avatrombopag
Apixaban
Lusutrombopag
Enoxaparin sodium
Palladin
Rivaroxaban
Dabigatran