New Drugs Antiplatelets-Antithrombotics - John Fanikos, RPh, MBA ...

Targeting Blood Clotting Factors: IIa vs XaProcoagulant•Fibrin Formation•Platelet Activation•Feedback activation•TAFI ActivationInflammation•P-Selectinexpression•Cell adhesion•ChemotaxisThrombinAnticoagulant•Protein C, SActivation•ProstacyclinformationCell Proliferation•Tissue Repair•Growth Factorsecretion•AngiogenesisFactor XCell Proliferation &Inflammation•Cytokine release•Smooth muscle cellproliferationProcoagulant•Thrombin Formation•PAI-1 ReleaseNew Oral Anticoagulants vs WarfarinDrugDabigatranRivaroxabanApixibanWarfarinTargetFactor IIa(Thrombin)Factor XaFactor XaVitamin KepoxidereductaseDosingFixed,Once orTwicedailyFixed,Oncedaily, orTwiceDailyFixed,TwicedailyVariable,OncedailyCoagulationMonitoringNoNoNoYesHalfLife(h)14-179.09-14Eikelboom JW et al. Circulation 2007;116:131-13340RenalClearance(%)10065250InteractionsProton PumpInhibitorsPotentCYP3A4inhibitorsPotentCYP3A4inhibitorsMultipledrugs,dietaryVitamin KDabigatran Etexilate: An Oral DirectThrombin Inhibitor• Specific, competitive, reversible univalentthrombin inhibitor• Inhibits free and fibrin-bound thrombinactivity• Pro-Drug rapidly converted to active form• Rapid onset within 2 hours• Low bioavailability, 3.5-5%• Half life 12-17 hours• Renal clearance as glucuronic acidconjugate• Cytochrome P450 system isoenzymes arenot involved with metabolism, noinduction or inhibition.• Prolongs aPTT in a non-linear fashion• Approved in Europe and Canada Baetz BE. Pharmacotherapy 2008.Perzborn E. J Thromb Haemost 2005.Kubitza D., J Clin Pharmacol 2007.Rendix,Pradaxa ®Eikelboom JE. Thromb Haemostasis 2009.RE-COVER Trial DesignObjectiveconfirmationof VTE72 hE RE= enrollmentR= randomizationSingledummyperiodWarfarinplaceboWarfarinInitial parenteraltherapyUntil INR ≥2.0 attwo consecutivemeasurements(8-11 days)Double-dummy periodDabigatran etexilate 150 mg bidWarfarin placeboDabigatran etexilate placebo bidWarfarin(INR 2.0–3.0)6 monthsEnd of treatment30 daysfollow upSchulman S et al. N Engl J Med2009:361:2342-52Cumulative Risk of Recurrent VenousThromboembolism and Related DeathCumulative Risk of First Event of MajorBleeding and of Any BleedingEstimated Cumulative Risk (%)Estimated Cumulative Risk (%)DabigatranWarfarin, any bleedingDabigatran, any bleedingWarfarin, MBEDabigatran, MBEWarfarin and any bleedingWarfarinDabigatran andany bleedingNo. at riskMonths Since RandomizationDabigatran andmajor bleedingWarfarin andmajor bleedingDabigatran was non-inferior to warfarin for prevention of recurrent or fatal VTE(P