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was offered by acontinuous IV infusion 1 h prior to the induction ofthrombosis or cuticle incision.Antithrombotic studiesApixaban exhibited strong antithrombotic ALK Inhibitor activity in therabbit models of AV-ST, ECAT and DVT, which comparedwell with regular antithrombotic agents. For instance, apixaban, the direct FXa inhibitorrivaroxaban, the direct thrombin inhibitor dabigatran andthe oral anticoagulant warfarin showed comparable efficacy inthe prevention model of DVT. In the preventionmodel of ECAT, apixaban was as efficacious as theantiplatelet agent clopidogrel and warfarin. Doses and plasma concentrations of apixaban for 50%thrombus reduction ranged from 0.07 to 0.27 mg/kg/h and0.065 to 0.36 lM, respectively. The 1 mg/kg/h dose was connected with roughly 80% antithromboticefficacy in these models.
Interestingly, thepotency of apixaban in arterial and venous thrombosisprevention models was broadly equivalent. Apixaban alsoeffectively ALK Inhibitor inhibited the growth of a pre-formed intravascularthrombus CDK inhibitors in a therapy model of DVT, suggestingthat apixaban shows possible for the therapy of establishedthrombosis.Bleeding time studiesThe bleeding possible of apixaban was compared withthose of rivaroxaban, dabigatran and warfarin in the rabbitcuticle bleeding time model. At the highest effectivedoses studied, warfarin elevated bleeding timealmost six-fold, whereas apixaban, rivaroxaban and dabigatranprolonged bleeding time 1.13-, 1.9 and 4.4-fold,respectively. As shown in Fig. 3, the antithromboticefficacy and bleeding profiles of warfarin anddabigatran had been much less favorable than those of apixaban andrivaroxaban.
It need to be noted; nevertheless, that extrapolationof pre-clinical bleeding time data to humans requirescaution. Provoked bleeding measured in anaesthetizedhealthy animals could not directly translate into spontaneousbleeding observed in the clinical setting, where complicationsof cardiovascular disease and polypharmacy are oftenpresent. Nevertheless, PARP pre-clinical bleeding time studies arestill useful for producing hypotheses for clinical investigation,as an example by allowing the anti-haemostatic profilesof experimental agents to be ranked and comparedwith those of established agents such as warfarin. The preclinicalcomparison of these agents’ therapeutic windows,as summarized in Fig. 3, remains a hypothesis, and headto-head clinical studies are necessary to validate theseresults.
Combination therapyDual antiplatelet therapy with clopidogrel and aspirincurrently represents the regular of care for the reductionof CDK inhibitors atherothrombotic events in a broad selection of patients. Tounderstand the benefit-risk ratio of apixaban therapy incombination with regular antiplatelet therapy, apixabanwas evaluated in combination with clinically relevant dosesof aspirin and/or clopidogrel for the prevention of arterialthrombosis in rabbit models. These evaluationsshowed that the triple combination of apixaban, aspirin andclopidogrel resulted in improved antithrombotic activityversus mono-therapies, with out excessively increasingbleeding time in rabbits. Such data suggest that intensiveantithrombotic therapy with apixaban, aspirin and clopidogrelmay be a viable alternative for enhancing antithromboticefficacy with out unacceptable increases in bleeding.
This hypothesis was tested in a big phase III study,APPRAISE-2, in high-risk patients with recent ACS treatedwith apixaban or placebo furthermore to monoor dual antiplatelettherapy. Veryrecently, the trial was discontinued depending on ‘‘evidence ALK Inhibitor of aclinically significant increase in bleeding among patientsrandomized to apixaban, and this increase in bleeding wasnot offset by clinically meaningful reductions in ischemicevents’’. The investigators from the APPRAISE-2 trialwill continue to overview the accessible data to far better understandthe effects of apixaban in this ACS patient populationand will publish the results.As discussed above, the translatability of preclinicalbleeding models to safety in clinical settings requirescaution.
It appears that the preclinical CDK inhibitors cuticle bleedingeffect of apixaban in combination with dual antiplatelettherapy in rabbits does not translate directly into spontaneousbleeding observed in the APPRAISE-2 trial. Theunderlying causes for this disconnect usually are not known, butmay be related to species differences, bleeding time versusspontaneous bleeding, vascular bed differences, and thefact that unlike animal bleeding models, the APPRAISE-2patients had the highest tendency to bleed due to advancedage, diabetes, complications of cardiovascular disease,other comorbidities and the additive hazards of combinationantiplatelet therapy. Finally, the APPRAISE-2 findingdoes not mean that apixaban can't benefit otherpatient populations, as recent phase III clinical trials ofapixaban have demonstrated promising results in patientswith venous thromboembolismandatrial fibrillation.Ex vivo coagulation markersThe conventional clotting time tests for adjusting anticoagulantdoses of heparinand warfarina