New approaches to chronic anticoagulatio na

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  • Lewis et al examined data from the 2658 PCI-CURE patients to evaluate the benefit of clopidogrel according to the timing of PCI after randomization. Rates of outcome events (CV death or myocardial infarction) were lower in patients treated with clopidogrel than with placebo, irrespective of the timing of intervention. The lowest absolute event rates were seen in patients treated with clopidogrel who underwent PCI within 48 hours of randomization. Lewis BS, Mehta SR, Keith AA, et al. Benefit of clopidogrel according to timing of percutaneous coronary intervention in patients with acute coronary syndromes: further results from the Clopidogrel in Unstable angina to prevent Recurrent Events study. Am Heart J. 2005;150:1177-1184.
  • Lecture Notes Unfortunately, coronary angiography may underestimate the true incidence of thrombus. The impact of thrombolytic therapy on the true incidence of thrombus as assessed using direct visualization of thrombus via angioscopy is shown here. While the 30 day incidence of protruding thrombus was reduced from 70% to 30% in thrombolytic patients, all thrombolytic patients (n=40) had some form of thrombus (laminated shown here in red). Thus, thrombolysis reduces thrombus burden but thrombus remains, thrombolysis exposes underlying ulcerated lesions, and angioscopic evidence of plaque instability is more frequent in patients treated with thrombolysis. The high frequency of thrombotic lesions underscore the need for effective antithrombotic therapy following thrombolytic administration. Antithrombotic therapies in acute MI may therefore reduce the incidence of reocclusion or reinfarction. References 1. Van Belle et al. Circulation. 1998;97:26-33.
  • The ASPECT II study enrolled a broader population of pts including those within 8 wks of UA or Acute MI. Although the study planned to enroll 8700 pts enrollment was slow and was stopped after 999 pts were randomized to either ASA 80 mg, Coumadin (INR 3-4) , or a Combination of Coumadin (INR 2-2.5) + ASA 80 mg. ANIMATE As expected, and by design, the INR values were higher in the Coumadin alone group than in the combination therapy group but were in range in only 40-50 % of pts. ANIMATE Both OA arms showed significantly lower rates of D/MI/CVA than the ASA alone control arm. ANIMATE Although the rate of major bleeding was similarly low across all 3 grouprs those pts receiving OA had higher rates of txn and minor bleeds. ANIMATE Note also that the rate of discontinuation of treatement was 10% in the ASA alone arm but double that in the OA arms---a pattern seen in other trials.
  • There are many targets for novel anticoagulants in the coagulation pathway: Tissue factor pathway inhibitor (TFPI) bound to Factor Xa inactivates the tissue factor (TF)–Factor VIIa complex, preventing initiation of coagulation Activated protein C (APC) degrades Factors Va and VIIIa, and thrombomodulin (soluble; sTM) converts thrombin (Factor IIa) from a procoagulant to a potent activator of protein C Fondaparinux and idraparinux indirectly inhibit Factor Xa, requiring antithrombin (AT) as a cofactor Direct (AT-independent) inhibitors of Factor Xa include rivaroxaban (BAY 59­7939), LY517717, YM150 and DU-176b (all orally available), and DX-9065a (intravenous) Oral, direct thrombin inhibitors include ximelagatran (now withdrawn) and dabigatran Weitz JI & Bates SM. New anticoagulants. J Thromb Haemost 2005;3:1843–1853
  • Rivaroxaban is a novel, oral, direct Factor Xa inhibitor 1 Rivaroxaban has predictable dose-proportional pharmacokinetics and pharmacodynamics in healthy subjects, and showed no evidence of accumulation after multiple dosing 2 Studies in healthy subjects showed that rivaroxaban had no clinically relevant interactions with acetylsalicylic acid or naproxen. 3,4 Further studies demonstrated that the pharmacology of rivaroxaban was not affected by age, gender or weight to a clinically relevant degree, suggesting that fixed dosing should be possible for all patients 5,6 The phase II development programme of rivaroxaban involved four studies of rivaroxaban for the prevention of venous thromboembolism (VTE) after major orthopaedic surgery 7–10 All of the doses investigated in the three double-blind studies of rivaroxaban in this indication (5–60 mg), had similar efficacy compared with the low molecular weight heparin enoxaparin 8–10 There were dose–response relationships between rivaroxaban and major bleeding in all of the studies; however, there were no significant differences in the observed incidence of major bleeding between rivaroxaban and enoxaparin in any study 8–10 These findings suggest that rivaroxaban has a wide therapeutic window When efficacy and safety were considered together, rivaroxaban 10 mg once daily (od) was selected for further investigation in the RECORD programme 10 1. Perzborn E et al. J Thromb Haemost 2005;3:514–521. 2. Kubitza D et al. Eur J Clin Pharmacol 2005;61:873–880. 3. Kubitza D et al. J Clin Pharmacol 2006;46:981–990. 4. Kubitza D et al. Br J Clin Pharmacol 2007;63:469–476. 5. Kubitza D et al. J Clin Pharmacol 2007;47:218–226. 6. Kubitza D et al. Blood 2006;108:Abstract 905. 7. Eriksson BI et al. Thromb Res 2007;doi:10.1016/j.thromres.2006.12.025. 8. Eriksson BI et al. J Thromb Haemost 2006;4:121–128. 9. Turpie AG et al. J Thromb Haemost 2005;3:2479–2486. 10. Eriksson BI et al. Circulation 2006;114:2374–2381.
  • Two phase IIb, dose-finding studies of rivaroxaban for the treatment and secondary prevention of DVT were undertaken. 1,2 The studies enrolled >1150 patients with acute, symptomatic proximal DVT In ODIXa-DVT (bid study), the primary endpoint was an improvement in thrombus burden (assessed by ultrasound) without recurrent VTE (recurrent DVT, PE or VTE-related death), after 3 weeks’ treatment In EINSTEIN-DVT (od study), the primary endpoint was a deterioration in thrombus burden (on either CUS or PLS) with recurrent VTE, after 3 months’ treatment In ODIXa-DVT, the incidences of improved thrombus burden with the bid rivaroxaban doses after 3 weeks’ treatment were greater than with od rivaroxaban and standard therapy After 3 months’ treatment, all rivaroxaban doses and regimens, in both studies, had similar efficacy to standard therapy for the prevention of recurrent VTE Incidences of major bleeding with rivaroxaban were low in ODIXa-DVT (1.7–3.3% vs 0% with standard therapy) Incidences of clinically relevant bleeding (the composite of major and clinically relevant, non-major bleeding) with rivaroxaban were low in EINSTEIN-DVT and similar to standard therapy (2.2–6.0% vs 8.8% with standard therapy) The greater efficacy of bid rivaroxaban for thrombus regression early after DVT formation, relative to od rivaroxaban, suggest that a bid regimen may offer the optimum benefit to the patient in the first few weeks of treatment. Lower bleeding incidences with long-term od rivaroxaban, and improved compliance with od regimens, suggest that an od regimen would be the best choice for long-term treatment and secondary prevention of VTE. This approach is being investigated in phase III studies Agnelli G et al . Treatment of acute, symptomatic, proximal deep vein thrombosis with the oral, direct Factor Xa inhibitor rivaroxaban (BAY 59-7939) – the ODIXa-DVT dose-ranging study. Eur Heart J 2006;27(Abstract Supplement):761 Buller HR. Once-daily treatment with an oral, direct Factor Xa inhibitor – rivaroxaban (BAY 59-7939) – in patients with acute, symptomatic deep vein thrombosis. The EINSTEIN-DVT dose-finding study. Eur Heart J 2006;27(Abstract Supplement):761
  • summarizes main efficacy and safety results of trial. rivaroxaban regimen significantly superior to enoxaparin for: Prevention of total VTE, with an RRR of 78.9% Prevention of major VTE, with an RRR of 87.8% The incidence of major bleeding was very low and similar for both groups
  • Information for speakers: most of the following slides contain important notes to accompany the presentation
  • This slide summarizes the main efficacy and safety results of this trial Rivaroxaban was significantly superior to enoxaparin for the prevention of the composite of DVT, PE and all-cause mortality, with a RRR of 49% Rivaroxaban was significantly superior to enoxaparin for the prevention of major VTE, with a RRR of 62% The incidence of major bleeding was low and similar for both drugs
  • Results of in vitro studies have shown that rivaroxaban is a direct, specific, competitive Factor Xa inhibitor. 1 Studies in healthy subjects demonstrated that it has no direct effect on thrombin and does not require a cofactor 2 Rivaroxaban inhibits free and fibrin-bound Factor Xa activity, prothrombinase activity, and Factor Xa generated via the intrinsic or extrinsic coagulation pathway in human plasma 1,3 Rivaroxaban has potent anticoagulant effects, as demonstrated by its effects on global clotting tests (prothrombin time, activated partial thromboplastin time) 2,4 Rivaroxaban does not affect platelet aggregation 5–7 Recombinant FVIIa, given after the initiation of bleeding, partially reversed the anticoagulant effect of high-dose rivaroxaban 8 Perzborn E et al . In vitro and in vivo studies of the novel antithrombotic agent BAY 59­7939—an oral, direct Factor Xa inhibitor. J Thromb Haemost 2005;3:514–521 Kubitza D et al . Safety, pharmacodynamics, and pharmacokinetics of single doses of BAY 59­7939, an oral, direct Factor Xa inhibitor. Clin Pharmacol Ther 2005;78:412–421 Depasse F et al . Effect of BAY 59-7939 – a novel, oral, direct Factor Xa inhibitor – on clot-bound Factor Xa activity in vitro . J Thromb Haemost 2005;3(S1):Abstract P1104. Poster presentation at the International Society on Thrombosis and Haemostasis XXth Congress, Sydney, Australia, August 6–12, 2005 Kubitza D et al . Safety, pharmacodynamics and pharmacokinetics of BAY 59­7939 – an oral, direct Factor Xa inhibitor – after multiple dosing in healthy male subjects. Eur J Clin Pharmacol 2005;61:873–880 Perzborn E et al . Biochemical and pharmacologic properties of BAY 59-7939, an oral, direct Factor Xa inhibitor. Pathophysiol Haemost Thromb 2004;33(S2):Abstract PO079. Poster presentation at the 18th International Congress on Thrombosis, Ljubljana, Slovenia, June 20–24, 2004 Fareed J et al . Antithrombotic mechanism of action of BAY 59­7939 – a novel, oral, direct Factor Xa inhibitor. J Thromb Haemost 2005;3(S1):abstract P0518. Poster presentation at the XXth International Society on Thrombosis and Haemostasis Congress, Sydney, Australia, August 6–12, 2005 Kubitza D et al . Rivaroxaban (BAY 59‑7939) – an oral, direct Factor Xa inhibitor – has no clinically relevant interaction with naproxen. Br J Clin Pharmacol , 2007;63:469–474 Tinel H, Huetter J, Perzborn E. Partial reversal of the anticoagulant effect of high-dose rivaroxaban – an oral, direct Factor Xa inhibitor – by recombinant Factor VIIa in rats. Blood 2006;108(11):Abstract 915
  • The primary efficacy endpoint was the incidence of the composite of any deep vein thrombosis (DVT) (as detected by mandatory bilateral venography), non-fatal pulmonary embolism (PE) and all-cause mortality by day 13 +4 (total VTE) The main secondary efficacy endpoint was major VTE – the composite of proximal DVT, non-fatal PE and VTE-related death Further efficacy endpoints included the incidence of DVT, symptomatic VTE and events occurring during the follow-up period
  • The main safety endpoint was the incidence of major bleeding events beginning after the first blinded dose of study medication and up to 2 days after the last dose Major bleeding included Fatal bleeding Bleeding into a critical organ Bleeding that required re-operation Clinically overt extra-surgical-site bleeding associated with a fall in haemoglobin of ≥2 g/dl or requiring the infusion of >2 units of blood or packed cells Other safety endpoints included Any on-treatment bleeding Any on-treatment, non-major bleeding (any on-treatment bleeding event not adjudicated as major bleeding) Haemorrhagic wound complications (the composite of excessive wound hematoma and surgical-site bleeding) Further safety endpoints also included liver enzyme monitoring and cardiovascular adverse events occurring during and after therapy
  • Rivaroxaban has a wide therapeutic window When efficacy and safety are considered together, this study suggests that 10 mg once daily is the optimum dose of Rivaroxaban
  • In the post-surgical setting, after short-term use

Transcript

  • 1. ht tp: //t opw orldofhealt h.blogspot .com/2011/10/blood-clots-complicat ion-informat ion.html
  • 2. Anticoagulation: The Art of Balance Both efficacy and safety are important, imbalance in efficacy and safety may result in patient harm
  • 3. 1. Safety versus Efficacy2. Thrombosis = Clotting + Coagulation3. AntiThrombotics That Have Changed Clinical Practice a) Anticoagulants b) Antiplatelets c) Anticlotting4. AntiCoagulants a) Aspirin b) Warfarin5. AntiPlatelets a) Clopidogrel b) Ticragrelor c) Bivalrudin6. AntiClotting a) Dabigatran b) Apixiban c) Rivaroxaban
  • 4. Optimal SafetyThrombosis and Efficacy Bleeding Dose (concentration) of Anticoagulant
  • 5. TF (Tissue Factor) XI XIaIntrinsic Pathway IX IXa VIIa + TF VII VIIIa Extrinsic Pathway X Xa Intrinsic or Extrinsic pathway activation leads to thrombin Va formation via the final common II IIa (Thrombin) coagulation pathway Fibrinogen Fibrin
  • 6. Anticoagulants Low-molecular-weight heparinAntiplatelet Drugs Thienopyridines Glycoprotein IIb/IIIa InhibitorsAnticlotting Drugs ht tp: //ww w.google.com/imgres?hl=en&safe=off&client =firefox-a&rls=org.mozilla: en-US: official&biw=1183&bih=571&tbm=isch&t bnid=gJfy0XT2Af0GTM :&imgrefurl=ht t p: //w w w.jeffersonhospit al.org/diseases-conditions/pulmonary-embolism.aspx%3Fdisease%3D77f678e3-7667-4203-9c6d-a5d898b5334c&docid=eYaTKeFWNC0-1M &imgurl=ht t p://w ww .jeffersonhospit al.org/images/st aywell/es_2396.gif&w =530&h=530&ei=U -26T-mgJob68gTl_sHW Ag&zoom=1&iact =hc&vpx=344&vpy=186&dur=1656&hovh=224&hovw =224&t x=81&ty=245&sig=114822581881067850021&page=4&t bnh=126&t bnw =125&st art =61&ndsp=25&ved=1t :429,r: 14,s: 61,i: 242
  • 7. <48 hrs after rand PCI ≥ 48 hrs from rand and PCI after hospital during initial hosp discharge 0.20 0.20 0.20Cumulative Hazard Rates Death / MI Denotes median Time to PCI ASA ASA 0.15 0.15 0.15 ASA 0.10 0.10 0.10 ASA + Clopidogrel ASA + Clopidogrel 0.05 0.05 0.05 ASA + Clopidogrel RR:0.53 (0.27-1.06) RR:0.72 (0.51-1.01) RR:0.70 (0.48-1.02) 0.0 0.0 0.0 0 100 200 300 0 100 200 300 0 100 200 300 Days of Follow-up Days of Follow-up Days of Follow-up Lewis BS, et al. Am Heart J. 2005;150:1177-1184.
  • 8.  Angioscopic findings 100% 83% suggestive of plaque 79% 80% instability are extremely 70% 71% frequent (75% to 80% of 60% the study population) as is the presence of clots ub m r h T y poc o gn A n o 40% even in the absence of clinical symptoms. 20% % s i  Only 16% of clot seen 0% on angio < 8 Days 8<& 10 < & > 15 Days (n=18) < 10 Days < 15 Days (n=14) o (n=10) (n=14) Days after lysis or medical therapy Van Belle et al. Circulation. 1998;97:26- 33.
  • 9. Rates of Recurrent MI Rothberg et al. Ann. Int. Med. 2005;143:241-250
  • 10. 999 Pts within 8 wks of UA or Acute MIRx : ASA 80 mg; Coumadin (INR 3-4); or Combination: ( INR 2-2.5)+ ASA 80 mg Efficacy Safety 30 Major BleedDeath,MI,CVA Tranfusion 20 Minor Bleed 15 % 10 8 5 1 1 1 1 2 1 0 ASA Coumadin Combo Rate of Discontinuation 10% 19% 20% van Es et al Lancet 360:109,2002
  • 11. ht tp: //ww w.google.com/imgres?hl=en&safe=off&client =firefox-a&hs=sXf&sa=X&rls=org.mozilla:en-US:official&biw=1183&bih=571&tbm=isch&prmd=imvns&t bnid=ZRdea8IELC7UVM : &imgrefurl=ht t p: //w ww .nat ure.com/nature/journal/v415/n6868/fig_t ab/415219a_F1.ht ml&docid=s21WGM BaFAYw KM &imgurl=ht t p://w ww .nat ure.com/nat ure/journal/v415/n6868/images/415219a-f1.2.jpg&w =600&h=660&ei=yPK6T6_nI Yn49QTemsCt Cg&zoom=1&iact =hc&vpx=94&vpy=113&dur=1294&hovh=235&hovw =214&t x=100&ty=255&sig=114822581881067850021&page=2&t bnh=131&t bnw =119&st art =9&ndsp=24&ved=1t : 429,r:6,s: 9,i: 176
  • 12. 1
  • 13.  ⇒ Effective  Rapid onset and offset of action ⇒ Safe  Predictable PK and PD  Wide therapeutic window ⇒ Easy  No need for monitoring  Oral, preferably once daily  Fixed doses  Low propensity for food and drug interactions
  • 14. ht tp: //ww w.google.com/imgres?st art =125&hl=en&safe=off&client =firefox-a&rls=org.mozilla: en-U S: official&biw =1183&bih=571&t bm=isch&tbnid=Z_zA8sipt nXY0M: &imgrefurl=ht t p://w ww .dailymail.co.uk/t ravel/art icle-1267969/DVT-t est -developed-air-passengers.ht ml&docid=Ux38QVoRbKiY5M &imgurl=ht t p://i.dailymail.co.uk/i/pix/2010/04/21/article-0-053BFF6A0000044D-401_468x307.jpg&w=468&h=307&ei=2uq6T-LGC5Sy8QTt 5sDW Cg&zoom=1&iact =hc&vpx=478&vpy=17&dur=1028&hovh=182&hovw =277&t x=124&ty=201&sig=114822581881067850021&page=6&t bnh=127&t bnw =174&ndsp=27&ved=1t : 429,r:3,s: 125,i: 119 ht tp: //ww w.google.com/imgres?st art =291&hl=en&safe=off&client =firefox-a&rls=org.mozilla: en-U S:official&biw =1183&bih=571&t bm=isch&tbnid=gt NkHJpv_qW DBM : &imgrefurl=ht t p://ww w .ahealthyclick.com/a-z-healt h/dvt /sympt oms-of-blood-clot -in-leg.html/&docid=g2nyoJLv3Rg_PM &imgurl=ht t p: //w ww .ahealt hyclick.com/w p-cont ent /uploads/2012/05/Sympt oms-Of-Blood-Clot -In-Leg.jpg&w=300&h=300&ei=Gey6T5-cDomi9QSBw ZnACg&zoom=1&iact =hc&vpx=192&vpy=54&dur=1258&hovh=225&hovw =225&t x=121&ty=248&sig=114822581881067850021&page=12&t bnh=125&t bnw =120&ndsp=29&ved=1t : 429,r:1,s: 291,i: 7 ht tp: //ww w.google.com/imgres?st art =76&hl=en&safe=off&client =firefox-a&rls=org.mozilla:en-US:official&biw =1183&bih=571&t bm=isch&t bnid=XBRJeGnnxq27JM: &imgrefurl=ht t p://lungcancer.about.com/od/livingwit hlungcancer/t p/cancert ravel.ht m&docid=PmNgnFhkM FU3zM &imgurl=ht t p: //0.t qn.com/d/lungcancer/1/0/O/1/-/-/dvt .jpg&w=306&h=226&ei=2uq6T-LGC5Sy8QTt 5sDW Cg&zoom=1&iact =hc&vpx=729&vpy=199&dur=2487&hovh=180&hovw =244&t x=49&ty=198&sig=114822581881067850021&page=4&t bnh=123&t bnw =183&ndsp=25&ved=1t: 429,r: 23,s: 76,i:54 ht t p://ww w.google.com/imgres?st art =140&hl=en&safe=off&client =firefox-a&rls=org.mozilla: en-U S:official&biw =1183&bih=571&t bm=isch&t bnid=w u2zoLJ9JnzkTM : &imgrefurl=ht t ps: //new sline.llnl.gov/_rev02/art icles/2010/mar/03.12.10-dvt .php&docid=5vdchuOgF-dPNM&imgurl=htt ps://new sline.llnl.gov/_rev02/art icles/2010/mar/images/031210_images/blood-clot1.jpg&w =500&h=375&ei=R--6T8CULYGm8QSP8di6Cg&zoom=1&iact =hc&vpx=456&vpy=6&dur=859&hovh=194&hovw=259&t x=87&t y=220&sig=114822581881067850021&page=7&t bnh=138&t bnw =212&ndsp=25&ved=1t : 429,r: 3,s: 140,i: 121ht tp: //ww w.google.com/imgres?st art =365&num=10&hl=en&safe=off&client =firefox-a&rls=org.mozilla:en-US:official&biw =1183&bih=571&tbm=isch&t bnid=bHJjrI vqumE_VM :&imgrefurl=ht tp://surgicaldiary.com/80-fact s-about -deep-venous-t hrombosis/&docid=2Akfme1Ohgat2M &imgurl=ht t p://surgicaldiary.com/images/80-fact s-about -deep-venous-t hrombosis-big.jpg&w =455&h=800&ei=Gfi6T5eW Oo2i8QS0_uH ZCg&zoom=1&iact =hc&vpx=692&vpy =125&dur=1141&hovh=298&hovw =169&tx=62&t y=321&sig=114822581881067850021&page=15&t bnh=131&tbnw =75&ndsp=28&ved=1t: 429,r:25,s:365,i: 227 =118&hl=en&safe=images&client =firefox-a&hs=lIL&sa=X&rls=org.mozilla: en-U S: official&biw =1183&bih=571&t bm=isch&prmd=imvnsu&t bnid=YuH ibcDzM 3FyDM : &imgrefurl=ht t p: //w ww .fut urit y.org/health-medicine/diabet es-causes-drop-in-test ost erone/&docid=EZhkAP6dBFmOXM &imgurl=ht t p: //fut urit y.org/w p-content /uploads/2010/05/t estost erone_1.jpg&w=425&h=290&ei=I Pm6T5OJMYSc9gTwoe2qCg&zoom=1&iact =hc&vpx=462&vpy=135&dur=1171&hovh=185&hovw =272&t x=103&ty=211&sig=116047331458444575597&page=6&t bnh=121&t bnw =165&ndsp=25&ved=1t : 429,r: 15,s: 118,i: 92 ht t p://ww w.google.com/imgres?hl=en&safe=off&client =firefox-a&rls=org.mozilla: en-US: official&biw=1183&bih=571&t bm=isch&t bnid=jV3q_mW ORlxFcM: &imgrefurl=ht t p: //w ww .indiahospit alt our.com/vascular/pulmonary-embolism-t reatment -surgery-india.ht ml&docid=gA95nFjmNM CU tM &imgurl=ht t p: //w ww .indiahospit alt our.com/images/innerpage/vascular/Pulmonary-Embolism1.jpg&w =318&h=306&ei=U-26T-mgJob68gTl_sH W Ag&zoom=1&iact=hc&vpx=90&vpy=188&dur=951&hovh=220&hovw=229&t x=117&t y=242&sig=114822581881067850021&page=4&tbnh=126&t bnw=129&start =61&ndsp=25&ved=1t: 429,r: 12,s:61,i
  • 15. ORAL PARENTERAL TF/VIIa TFPI (tifacogin) TTP889 X IX Rivaroxaban IXa APC (drotrecogin alfa) Apixaban VIIIa sTM (ART-123) LY517717 Va YM150 AT Fondaparinux DU-176b Xa Idraparinux Betrixaban TAK 442 II DX-9065a Dabigatran IIa Fibrinogen Fibrinapted from Weitz & Bates, J Thromb Haemost 2007
  • 16. TissueXIIa factor XIa VIIa IXa Xa II ×Factor IIa (thrombin) Dabigatran
  • 17.  Dabigatran doses of 150 and 220 mg once daily (od) were investigated in all three studies Study Type of Comparator Number of Time to 1st Treatment surgery patients administration duration of dabigatran RE-MODEL TKR Enoxaparin 2010 1–4 hours 6–10 days 40 mg od, starting post-surgery evening before surgery RE-MOBILIZE TKR Enoxaparin 2615 6–12 hours 12–15 days 30 mg bid, starting post-surgery 12–24 hours post- surgery RE-NOVATE THR Enoxaparin 3494 1–4 hours 28–35 days 40 mg od, starting post-surgery evening before surgeryTKR: total knee replacement; THR: total hip replacementEriksson et al. Blood 2006; Friedman et al. J Thromb Haemost 2007; Eriksson et al. J Thromb Haemost 2007
  • 18. Enoxaparin Dabigatran Dabigatran (150 mg) (220 mg) DVT, PE and all-cause mortality (%) RE-NOVATE 6.7 8.6 6.0 p<0.0001* p<0.0001* RE-MOBILIZE 25.3 33.7 31.1 p=0.0009 † p=0.02† RE-MODEL 37.7 40.5 36.4 p=0.0005* p=0.0345* Major bleeding (%) RE-NOVATE 1.6 1.3 2.0 RE-MOBILIZE 1.4 0.6 0.6 RE-MODEL 1.3 1.3 1.5*Non-inferior to enoxaparin; †inferior to enoxaparinEriksson et al. Blood 2006; Friedman et al. J Thromb Haemost 2007; Eriksson et al. J Thromb Haemost 2007
  • 19. TissueXIIa factor × XIa VIIa IXa Rivaroxaban Xa Apixaban YM150 DU-176b LY517717 Factor II Betrixaban (prothrombin) TAK 442 Fibrinogen Fibrin clot
  • 20.  Oral, direct, selective factor Xa O inhibitor  Produces concentration-dependent N NH2 anticoagulation N  No formation of reactive intermediates O O N  No organ toxicity or LFT abnormalities in chronic toxicology studies  Low likelihood of drug interactions or QTc prolongation  Good oral bioavailability N O  No food effect  Balanced elimination (~25% renal)  Half-life ~12 hrsHe et al., ASH, 2006, Lassen, et al ASH, 2006
  • 21.  Apixaban od and bid (total daily doses 5-20mg) were assessed relative to enoxaparin and warfarin, in 1,217 patients Total VTE and All-Cause Mortality (%) Total VTE and All-Cause Mortality (%) Major Bleeding (%) Major Bleeding (%) 30 26.6 30 25 25Percent Percent 20 20 15.6 15 15 10.6 10 8.6 10 6.8 5 5 3.0 1.3 1.6 0 0 0 0 Enoxaparin Enoxaparin 5mg 10mg20mg Warfarin (INR (30mg bid) 5mg 10mg20mg Warfarin (INR (30mg bid) Apixaban 1.8-3.0) Apixaban 1.8-3.0) (Total Daily Dose) (Total Daily Dose) Lassen et al. Blood 2006
  • 22.  Apixaban bid (5 and 10mg) and od (20mg) were assessed relative to low molecular weight heparin (LMWH) or fondaparinux followed by VKA, in 520 patients Composite of Symptomatic Composite of Symptomatic Recurrent VTE and Deterioration Recurrent VTE and Deterioration Major Bleeding (%) Major Bleeding (%) of Thrombotic Burden (%) of Thrombotic Burden (%) 10 10 8 8 6.0 6 5.6 6 PercentPercent 4.2 4 4 2.6 2 2 0.8 0.8 0 0 0 0 5mg 10mg 20mg LMWH/ 5mg 10mg 20mg LMWH/ fondaparinux fondaparinux bid bid bid + VKA bid bid bid + VKA Apixaban Apixaban Büller, Eur Heart J 2006
  • 23. Agent DisadvantagesHeparin • Parenteral administration • Risk of heparin-induced thrombocytopenia (HIT) • Narrow therapeutic window (low bioavailability, short half-life)Warfarin • Requires frequent monitoring due to: – Narrow therapeutic window – Unpredictable pharmacology – Multiple drug–drug and food–drug interactions – Increased risk of major and minor bleedsLMWH • Parenteral administration • Risk of heparin-induced thrombocytopenia (HIT)Indirect Xa • Parenteral administrationInhibitor • Long half-life(e.g. fondaparinux) • Limitations related to special patient populationsDirect • Parenteral administrationThrombin • Current applications limited to cardiovascularInhibitors management Albans S et al. Eur J Clin Invest 2005;35(Suppl 1):12-20.
  • 24.  Predictable O Cl pharmacology O S O N N H N O O Rivaroxaban® – rivaroxaban  High bioavailability  Low risk of drug–drug interactions  Fixed dose  No requirement for monitoringPerzborn et al. 2005; Kubitza et al. 2005; 2006; 2007; Roehrig et al, 2005
  • 25.  Direct, specific, competitive Factor Xa inhibitor Inhibits free and fibrin-bound Factor Xa activity, and prothrombinase activity Does not directly inhibit thrombin, but inhibits thrombin generation via inhibition of Factor Xa activity Does not affect agonist-induced platelet aggregation, and therefore has no direct effect on primary hemostasis Does not require a cofactor No interaction with aspirin, enoxaparin, digoxin, naproxen, ranitidine, or antacids Perzborn et al., J Thromb Haemost 2005; ICT 2004; Depasse et al., ISTH 2005; Kubitza et al., J Clin Pharmacol 200; ASH 2005; Fareed et al., ISTH 2005
  • 26. XIa TF (Tissue Factor) XIIntrinsic Pathway IX IXa VIIa + TF VII Extrinsic Pathway VIIIa X XaIf either Intrinsic or Extrinsicpathway is activated, Rivaroxaban Vablocks the final common II IIa (Thrombin)coagulation pathway leading tothrombin formation by blockingFactor Xa Fibrinogen Fibrin
  • 27.  Two large, phase II studies of rivaroxaban for 3 mo for treatment and long-term secondary VTE prevention: › ODIXa-DVT : Rivaroxaban 10–30 mg bid and 40 mg od › EINSTEIN DVT : Rivaroxaban 20–40 mg od › LMWH followed by VKA comparator in both studiesAgnelli et al. Circulation 2007; Büller. Eur Heart J 2006
  • 28. Oral rivaroxaban compared with subcutaneous enoxaparin forextended thromboprophylaxis after total hip arthroplasty
  • 29. 5 Rivaroxaban 10 mg once daily Total VTE Enoxaparin 40 mg once daily 4 RRR 70%Incidence (%) 3 Major VTE RRR 88% 2 Symptomatic VTE 1 Major bleeding 3.7% 1.1% 2.0% 0.2% 0.5% 0.1% 0.3% 0.3% 0
  • 30. Extended thromboprophylaxis withrivaroxaban compared with short-term thromboprophylaxis with LMWH after total hip arthroplasty
  • 31. 10 Total VTE Rivaroxaban 10 mg once daily Enoxaparin 40 mg once daily 8Incidence (%) 6 Major VTE 4 Symptomatic RRR 78.9% VTE 2 Major bleeding RRR 87.8% RRR 80.1% 9.3% 2.0% 5.1% 0.6% 1.2% 0.2% 0.1% 0.1% 0
  • 32. Rivaroxaban – an oral, direct Factor Xa inhibitor –for the prevention of venous thromboembolism intotal knee arthroplasty surgery
  • 33. Total VTE 20 RRR 49% Enoxaparin 40 mg od Rivaroxaban 10 15 mg odIncidence (%) 10 Major VTE 5 Symptomatic VTE Major bleeding RRR 62% RRR 65% NS 18.9% 9.6% 2.6% 1.0% 2.0% 0.7% 0.5% 0.6% 0
  • 34. 70 Rivaroxaban 1.25 mg (n=8) Rivaroxaban 5 mg (n=6) 60 Rivaroxaban 10 mg (n=8) 50 Anti-Xa Activity Rivaroxaban 20 mg (n=7) % Inhibition of Factor Xa Rivaroxaban 40 mg (n=8) 40 Rivaroxaban 80 mg (n=6) Placebo (n=25) 30 20 10 0 -10 0 2 4 6 8 10 12 14 16 18 20 22 24 Time (hours) ► All once-daily dosage regimens demonstrated Xa inhibition for out to 24 hours ► These results provided foundation for selection ofKubitza, et al. Clin Pharmacol Ther 2005;78(4):412-21. once-daily dosing regimen for Phase III programs
  • 35.  Specific, competitive, direct FXa inhibitor  Inhibits free and clot- associated FXa activity, 100 and prothrombinase Inhibition of Factor Xa activity (%) activity 80  Inhibits thrombin generation via inhibition of FXa activity 60 ◦ Prolongs time to thrombin 40 generation ◦ Inhibits peak thrombin 20 Free FXa generation Prothrombinase activity Clot-associated FXa ◦ Reduces the total amount 0 of thrombin generated 0.01 0.1 1 10 100 1000 Rivaroxaban (nM)  Does not require a cofactorPerzborn et al. J Thromb Haemost 2005; ICT 2004; Depasse et al. ISTH 2005; Kubitza et al. Clin Pharmacol Ther2005; Br J Clin Pharmacol, 2007; Graff et al. In press
  • 36. • Dose peaks in 2.5–4 hrs, t1/2=5-9 hrs (11-13 hrs in elderly)• One dose will be selected for clinical use• No monitoring required given consistent dose response• Dual modes of excretion •Renal (66%), no excess bleeding associated with CrCl •Fecal/biliary (28%)• Minimal drug/drug interactions, no major circulatingmetabolites, no drug accumulation Kubitza et al., Eur J Clin Pharmacol 2005; Eriksson et al., J Thromb Haemost 2006; Turpie et al., J Thromb Haemost 2005; Kubitza et al., ISTH 2005; Kubitza et al., ASH 2005; Kubitza et al., J Clin Pharmacol 2006
  • 37. Rivaroxaban: Anti-Thrombotic Efficacy 100 *P<0.05 ; **P<0.01 ** • Arterial thrombosis 80Thrombus reduction (%) rabbit arteriovenous shunt model * 60 • Rivaroxaban dose- dependently prevented arterial thrombosis 40 20 0 0.3 1.0 3.0 Rivaroxaban (mg/kg) p.o.
  • 38. Primary  Total venous thromboembolism (VTE): any deep vein thrombosis (DVT), non-fatal pulmonary embolism (PE), and all-cause mortality Secondary  Major VTE: proximal DVT, non-fatal PE, and VTE-related death  DVT: any, proximal, distal  Symptomatic VTEAll endpoints were adjudicated centrally by independent, blinded committees
  • 39. Rivaroxaban Safety: Bleeding Time Tail Transection Bleeding Time in Rats X-fold prolongation of Compound bleeding time at ED50 (control =1)Rivaroxaban [po] 1.8Enoxaparin [sc] 2.2Ximelagatran [po] 3.7Dabigatran [po] 4.9Warfarin [po] > 6.3 Bleeding time comparable to enoxaparin Lower compared to thrombin inhibitors orwarfarin
  • 40. Main  Major bleeding starting after the first blinded dose and ≤2 days after last dose ◦ Bleeding that was fatal, into a critical organ or required re-operation ◦ Extra-surgical-site bleeding associated with a drop in hemoglobin ≥2 g/dL or requiring transfusion of ≥2 units blood Other  Any bleeding on treatment*  Non-major bleeding*  Hemorrhagic wound complications*  Cardiovascular adverse events  Liver enzyme levelsAll endpoints were adjudicated centrally by independent, blinded committees*Up to 2 days after last dose of study medication
  • 41. Rivaroxaban: Bleeding Time with Combination Therapy Tail Transection Bleeding Time in Rats X-fold prolongationCompounds of bleeding timeClopidogrel 1 mg/kg [po] 2.1 +/- 0.3Aspirin 3 mg/kg [po]Clopidogrel 1 mg/kg [po]Aspirin 3 mg/kg [po] 2.5 +/- 1 +Rivaroxaban 0.1 mg/kg [iv] Similiar Bleeding Times
  • 42. DVT, PE, and all-cause mortality Major, post-operative bleeding 30Incidence rate % 20 10 0 0 5 10 15 20 25 30 35 40 Enoxaparin 40 mg Total daily dose (mg) of Rivaroxaban Eriksson et al., Circulation 2006
  • 43.  Rivaroxaban was well tolerated, with similar incidence of AEs as enoxaparin  Rivaroxaban did not affect ECG parameters  Rivaroxaban did not have any substance-specific effects on laboratory parameters (except for clotting tests)  LFT increases with BAY 59-7939 did not exceed the level observed with enoxaparin › There was no dose-dependent increase in transaminase levelsLiver functiontest (LFT) Rivaroxaban Enox 5 mg 10 mg 20 mg 30 mg 40 mg 40 mgALT > 3× ULN 5/119 6/133 4/133 7*/129 5/127 10/140% 4.2 4.5 3.0 5.4 3.9 7.1 *One patient had ALT >3× ULN and bilirubin >2× ULN (occurring before first intake of study drug)
  • 44. Phase II Phase IIIVTE prevention after major  ODIXa-HIP1orthopaedic surgery  ODIXa-HIP2  ODIXa-KNEE  RECORD1  ODIXa-OD-HIP  RECORD2  RECORD3  RECORD4VTE prevention inhospitalized medically illpatientsVTE treatment  ODIXa-DVT  EINSTEIN-DVT  EINSTEIN-DVT  EINSTEIN-PE  EINSTEIN-EXTStroke prevention in atrialfibrillation Japanese Phase III studySecondary prevention ofacute coronary syndromes ~8,000 >42,000
  • 45. Rivaroxaban CM Gibson 2007
  • 46. Safety RivaroxabanEfficacy Ease CM Gibson 2007
  • 47.  Is a selective, reversible, active-site directed Factor Xa inhibitor that inhibits coagulation triggered by both the collagen (intrinsic) and tissue factor (extrinsic) pathways Reduces thrombus formation in both venous and arterial thrombosis models Has a bleeding risk comparable to Enoxaparin, and lower compared to thrombin inhibitors and Warfarin, in preclinical in vivo models CM Gibson 2007
  • 48.  Reaches Peak (Cmax)) in 2.5–4 hours; half-life of 5–9 hours at steady state (little longer in older) Dual modes of excretion: Renal (66%) & Faecal / biliary (28%) No substantial accumulation after multiple dosing, few drug interactions Dose dependent prolongation of prothrombin time CM Gibson 2007
  • 49. • Ongoing evaluation in acute and chronic settings for Target Enrollment Phase II-III prevention and treatment of multiple venous and 35,000 - 40,000 arterial indications CM Gibson 2007
  • 50. Alexander W. American College of Cardiology, 59th Annual Scientific Session. P & T. 2010;35:291-4.Benjamin EJ, Wolf PA, D’Agostino RB et al. Impact of atrial fibrillation on the risk of death: the Framingham Heart Study. Circulation. 1998;98:946-52.Connolly SJ, Eikelboom J, Joyner C et al. Apixaban in patients with atrial fibrillation. N Engl J Med. 2011;364:806-17.Connolly SJ, Ezekowitz MD, Yusuf S et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:1139-51.Dulli DA, Stanko H, Levine RL. Atrial fibrillation is associated with severe ischemic stroke. Neuroepidemiology. 2003;22:118-23.Feinberg WM, Blackshear JL, Laupacis A et al. Prevalence, age distribution, and gender of patients with atrial fibrillation: analysis and implications. Arch Intern Med.1995;155:469-73.Flaker GC, Belew K, Beckman K et al. Asymptomatic atrial fibrillation: demographic features and prognostic information from the Atrial Fibrillation Follow-up InvestigaRhythm Management (AFFIRM) study. Am Heart J. 2005;149:657-63.Fuster V, Rydén LE, Cannom DS et al. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation : a report of the American College ofCardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committeefor Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients with Atrial Fibrillation). Circulation. 2006;114:e257-e354.Gage BF, Waterman AD, Shannon W et al.. Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAM2001;285:2864-70.Go AS, Hylek EM, Borowsky LH et al. Warfarin use among ambulatory patients with nonvalvular atrial fibrillation: the AnTicoagulation and Risk Factors in Atrial Fibrillatio(ATRIA) study. Ann Intern Med. 1999;131:927-34.Go AS, Hylek EM, Phillips KA et al. Prevalence of diagnosed atrial fibrillation in adults:national implications for rhythm management and stroke prevention: theAnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) study. JAMA. 2001;285:2370-5. Lip GY, Frison L, Halperin JL et al. Comparative validation of a novel risk score for predicting bleeding risk in anticoagulated patients with atrial fibrillation: the HAS-BL(Hypertension, AbnormalRenal/Liver Function, Stroke, Bleeding History of Predisposition, Labile INR, Elderly, Drugs/Alcohol Concomitantly) score. J Am Coll Cardiol 2011;57:173-80. Nutescu E, Chuatrisorn I, Hellenbart E. Drug and dietary interactions of warfarin and novel oral anticoagulants: an update. J Thromb Thrombolysis. 2011 Feb 27 [Epubof print].Lip GY, Nieuwlaat R, Pisters R et al. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based appthe euro heart survey on atrial fibrillation. Chest 2010;137:263-72.Preventing Stroke in Atrial Fibrillation: Overview of New and Emerging Antithrombotic Agents and Roles for PharmacistLloyd-Jones DM, Wang TJ, Leip EP et al. Lifetime risk for development of atrial fibrillation: the Framingham Heart Study. Circulation 2004;110:1042-6.Lopes RD, Alexander JH, Al-Khatib SM et al. Apixaban for reduction in stroke and other ThromboemboLic events in atrial fibrillation (ARISTOTLE) trial: design and rationHeart J. 2010;159:331-9.ROCKET AF Study Investigators. Rivaroxaban – once daily, oral, direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and EmbolismAtrial Fibrillation: rationale and design of the ROCKET AF study. Am Heart J. 2010;159:340-7.Roger VL, Go AS, Lloyd-Jones DM et al. Heart disease and stroke statistics 2011 update: a report from the American Heart Association. Circulation. 2011; 123:e18-e20Ruff CT, Giugliano RP, Antman EM et al. Evaluation of the novel factor Xa inhibitor edoxaban compared with warfarin in patients with atrial fibrillation: design and ratfor the Effective aNticoaGulation with factor xA next GEneration in Atrial Fibrillation-Thrombolysis in Myocardial Infarction study 48 (ENGAGE AF-TIMI 48). Am Heart J.2010;160:635-41.Singer DE, Albers GW, Dalen JE et al. Antithrombotic therapy in atrial fibrillation. Chest. 2008;133(6 Suppl):546S-92S.Stangier J. Clinical pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor dabigatran etexilate. Clin Pharmacokinetic 2008;47:285-95.The AMADEUS Investigators. Comparison of idraparinux with vitamin K antagonists for prevention of thromboembolism in patients with atrial fibrillation: a randomizedlabel, non-inferiority trial. Lancet. 2008;371:315-21.Ufer M. Comparative efficacy and safety of the novel oral anticoagulants dabigatran, rivaroxaban and apixaban in preclinical and clinical development. Thromb H2010; 103: 572–85.van Ryn J, Stangier J, Haertter S et al. Dabigatran etexilate - a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of