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

RE-VOLUTION - Trial ProgramPrimary VTE Prevention(completed)Acute VTETreatmentSecondary VTEPreventionSecondary Preventionin ACS—Phase IIStroke Prevention inAtrial FibrillationMore than 34,000 patients involvedRivaroxaban: An Oral Direct Factor XaInhibitorXarelto ®• Direct, specific, competitive FactorXa inhibitor• Inhibits free and fibrin-bound FactorXa activity and prothrombinaseactivity• Does not directly inhibit thrombin,but inhibits thrombin generation viadirect inhibition of Factor Xa activity• Rapid onset within 2-4 hours• High bioavailability of > 80%• No observed effects on agonistinducedplatelet aggregation• Does not require a cofactor such asantithrombin• No dosage adjustment for gender,age, extreme body weightPerzborn E. J Thromb Haemost 2005.• No interaction with aspirin,enoxaparin, digoxin,Kubitza D., J Clin Pharmacol 2007.naproxen, ranitidine, or antacidsEikelboom JE. Thromb Haemostasis 2009• Approved in Europe and CanadaGulseth GP. Am Soc Health-Syst Pharm 2008RECORD Phase III Trials: VTE ProphylaxisHIP replacementRivaroxaban 10 mg odfor 31–39 daysvsenoxaparin 40 mg odfor 5 weeksN=4,541HIP replacementRivaroxaban 10 mg odfor 31–39 daysvsenoxaparin 40 mg odfor 10–14 days thenoral placeboN=2,509 Same efficacy and safety outcomes Same independent, blinded committee adjudicated all outcomes 12,729 patients randomizedKNEE replacementRivaroxaban 10 mg odfor 10–14 daysvsenoxaparin 40 mg odfor 10–14 daysN=2,531KNEE replacementRivaroxaban 10 mg odfor 10–14 daysvsenoxaparin 30 mg bidfor 10–14 daysN=3,148IncidenceRECORD1RECORD2RRR 70%4%Prevention of VTE in THARRR 79% Extended prophylaxis with10%5 weeks of Rxrivaroxaban vs. short-termterm8%3%prophylaxis with enoxaparinRRR 88%6%RRR 88%2%4%RRR 80%1%2%0%0%Total VTE Major VTE Symptomatic Major BleedingTotal VTE Major VTE Symptomatic Major BleedingVTEVTEEriksson et al., N Engl J Med 2008Enoxaparin 40 mg QDKakkar et al., Lancet 2008;372:31–39RECORD3Rivaroxaban 10 mg QDRECORD4Prevention of VTE in TKAVTE Prevention TKARRR 49% 2 weeks of RxRRR 31%rivaroxaban daily vs20%11%enoxaparin bid for 2weeks15%8%6%10%4%RRR 62%5%RRR 65%2%0%0%Total VTE Major VTE Symptomatic Major BleedingTotal VTE Major VTE Symptomatic Major BleedingVTEVTELassen et al. N Engl J Med 2008Turpie AGG, et al. EFORT 2008. Abstract F85.EINSTEIN-EXTENSION STUDYRivaroxaban Clinical Development ProgramRivaroxaban 20mg Once DailyPlacebo(n = 594)P-Value(95% CI)(n= 602)Mean Duration 190 Days 190 Days NSRecurrent DVT, 8 (1.3%) 42 (7.1%) P11,000 patientsHip replacement or kneereplacementVs standard prophylaxis(enoxaparin)Vs standard prophylaxis(enoxaparin)~14,000 patientsNon-inferiority vs standardtherapy (warfarin)~7,500 patientsVs standard therapy~3,500 patientsNotesApproved inCanada; EUpending; FDAAdvisoryCommitteeMarch ‘09Late start201020102012Buller H. For the EINSTEIN Investigators Presented at American Society ofHematology Meeting, New Orleans Dec 2009.ATLAS ACS TIMI-51