Comparative efficacy and safety of the novel oral anticoagulants dabigatran, rivaroxaban and apixaban in preclinical and clinical development

Abstract

Therapeutic oral anticoagulation is still commonly achieved by administration of warfarin or other vitamin K antagonists that are associated with an untoward pharmacokinetic / pharmacodynamic (PK/PD) profile leading to a high incidence of bleeding complications or therapeutic failure. Hence, there is an unmet medical need of novel easy-to-use oral anticoagulants with improved efficacy and safety. Recent developments include the identification of non-peptidic small-molecules that selectively inhibit certain serine proteases within the coagulation cascade. Of these, the thrombin inhibitor dabigatran and factor Xa inhibitor rivaroxaban have recently been licensed for thromboprophylaxis after orthopaedic surgery mainly in Europe. In addition, the factor Xa inhibitor apixaban is in late-stage clinical development. Each drug is prescribed at fixed doses without the need of anticoagulant monitoring. Phase III trials in orthopaedic patients essentially resulted in non-inferior efficacy of dabigatran and superior efficacy of rivaroxaban over enoxaparin without any marked differences of drug safety, while apixaban data is still controversial. However, alterations of rivaroxaban and apixaban pharmacokinetics upon interactions with inhibitors and inducers of CYP3A4 or P-glycoprotein may complicate the use of these compounds in daily practice, whereas dabigatran elimination largely depends on renal function. Hence, this review reports PK/PD, efficacy and safety data of dabigatran, rivaroxaban and apixaban throughout preclinical and clinical development.

Coagulation-induced shedding of platelet glycoprotein VI mediated by factor Xa

“…Rivaroxaban and dabigatran are both promising oral drugs with predictable and reliable pharmacokinetic and pharmacodynamic profiles that have recently gained approval from European drug agencies for venous thromboembolism prophylaxis in orthopedic surgery. [52][53][54] Dabigatran may be safer or more efficacious than warfarin in patients with atrial fibrillation. 30 Our findings have potential impact where anticoagulants targeting FXa or FIIa or both are used for short-or long-term clinical use, that is, in orthopedic surgery or in atherothrombotic diseases related to myocardial infarction or ischemic stroke.…”

Efficacy and safety of novel anticoagulants compared with established agents

“…In the orthopedic VTE prevention studies, there was no incidence of isolated liver enzyme elevations associated with either dabigatran dose as compared with enoxaparin [Ufer, 2010]. Benign elevations were noted in transaminase values.…”

New antithrombotic therapies and complementary and alternative medicine (CAM): Chartering into unknown territory

“…Rivaroxaban is metabolised by CYP3A4 in the CYP450 system with 70% of the drug excreted in the urine and the remaining 30% excreted through the faeces [1,38]. Rivaroxaban does interact with the CY450 system with specific interactions with CYP3A4 and CYP2J2 [40]. Similar to dabigatran, rivaroxaban is a substrate for P-gp efflux transport, but unlike dabigatran it is metabolised in the liver [1,38].…”