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Alexander GG Turpie

Comparison of rivaroxaban – an oral, direct Factor Xa inhibitor – and subcutaneous enoxaparin for thromboprophylaxis after total knee replacement. Alexander GG Turpie

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Alexander GG Turpie

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  1. Comparison of rivaroxaban – an oral, direct Factor Xa inhibitor – and subcutaneous enoxaparin for thromboprophylaxis after total knee replacement Alexander GG Turpie On behalf of Kenneth A Bauer, Scott D Berkowitz, Fred D Cushner, Bruce L Davidson, Michael Gent, Louis M Kwong, Michael R Lassen, Paul A Lotke, Frank Misselwitz, William D Fisher and the RECORD4 Study Investigators

  2. Disclosures for Alexander GG Turpie

  3. Rivaroxaban Rivaroxaban: an oral, direct Factor Xa inhibitor • Once daily • Predictable pharmacokinetics and pharmacodynamics • High oral bioavailability • Rapid onset of action • Fixed dose • No requirement for coagulation monitoring Rivaroxaban binds directly to the active site of Factor Xa (Ki 0.4 nM) Roehrig et al., 2005; Perzborn et al., 2005; Kubitza et al., 2005; 2006; 2007

  4. RECORD: phase III program • Rivaroxaban 10 mg od was compared with enoxaparin in 12,729 patients worldwide

  5. S U R G E R Y RECORD4: study design Double blind F Mandatory bilateral venography Rivaroxaban 10 mg od orally O L 6–8 hours post wound closure or adequate hemostasis L R O W 12–24 hours post wound closure or adequate hemostasis U Enoxaparin 30 mg q12h sc P Day 42+5 Day 1 Day 13±2 Last dose, 1 daybefore venography

  6. Enrolment: 131 sites worldwide Pakistan 1.2% India 15.7% Sri Lanka 1.7% Israel 2.0% United States 49.0% Bulgaria 1.4% Poland 7.8% Lithuania 2.0% Sweden 1.1% Denmark 2.2% Mexico 6.1% US and Canada = 58.8% Canada 9.8%

  7. Study flow Enoxaparin Rivaroxaban Enrolled (N=3418) Randomized (n=3148) 1564 1584 Safety population 1508 1526 mITT population for major VTE* 1122 1112 mITT population for primary efficacy(superiority analysis) 959 965 PP population for primary efficacy†(non-inferiority analysis) 878 864 *Patients may be valid for major VTE analysis if only proximal veins were assessed†Patients could have more than one protocol violation

  8. Patient demographics *Mean values

  9. Efficacy endpoints Primary • Total VTE: any DVT, non-fatal PE, and all-cause mortality up to day 13±4 Secondary • Major VTE: proximal DVT, non-fatal PE, and VTE-related death • DVT: any, proximal, and distal • Symptomatic VTE

  10. Safety endpoints Main • Major bleeding starting after the first blinded dose and up to 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 levels All endpoints were adjudicated centrally by independent, blinded committees *Up to 2 days after last dose of study medication

  11. RRR* = 31.4% ARD† = –3.19% (–5.67, –0.71) p=0.012 14 12 10 8 Incidence (%) 6 4 10.1% 6.9% 2 0 Enoxaparin30 mg q12h97/959 Rivaroxaban10 mg once daily67/965 Primary efficacy endpoint: total VTE *Relative risk reduction based on raw incidences; †absolute weighted risk difference (with 95% CI); mITT population, n=1924

  12. Secondary efficacy endpoints Symptomatic VTE Major VTE 5 5 4 4 ARD = –0.80% (–1.82, 0.22) p=0.124 3 3 ARD = –0.47% (–1.16, 0.23) p=0.187 Incidence (%) Incidence (%) 2 2 1 1 2.0% 1.2% 0.7% 1.2% 0 0 Enoxaparin30 mg q12h 22/1112 Rivaroxaban10 mg once daily 13/1122 Enoxaparin30 mg q12h 18/1508 Rivaroxaban10 mg once daily 11/1526 ARD, absolute weighted risk difference (with 95% CI)

  13. Major bleeding 5 4 p=0.110 3 Incidence (%) 2 0.7% 0.3% 1 0 Enoxaparin30 mg q12h4/1508 Rivaroxaban10 mg once daily10/1526 On-treatment major bleeding; safety population, n=3034

  14. Safety: components of bleeding On-treatment bleeding; *1 patient had fatal post-operative upper GI bleed and a fall in hemogloblin leading to transfusion; † 1intraspinal and 1 intracranial bleed with enoxaparin, 1 retroperitoneal bleed with rivaroxaban; ‡1 subject received only placebo and no active enoxaparin;§all 4 patients had a fall in hemogloblin leading to transfusion; safety population, n=3034

  15. Adverse events *Events occurring more than 1 day after the last intake of study drug during follow-up; safety population

  16. Liver function tests: on-treatment abnormalities Safety population, n=3034; ALT, alanine transaminase; ULN, upper limit of normal; TB, total bilirubin;

  17. RECORD4: summary Total VTE 12 Enoxaparin 30 mg q12h Rivaroxaban 10 mg once daily 10 8 Incidence (%) 6 SymptomaticVTE 4 Major VTE Major bleeding 2 0.7% 0.3% 2.0% 1.2% 10.1% 6.9% 1.2% 0.7% 0 p=0.124 p=0.187 p=0.110 RRR 31% p=0.012 All p-values based on absolute weighted risk differences

  18. RECORD4: conclusions Rivaroxaban demonstrated: • Superior efficacy for the primary endpoint (total VTE) • Low rate of major and symptomatic VTE events • Similar safety profile to enoxaparin • No statistically significant difference in major bleeding • Cardiovascular adverse events low and balanced between groups • No difference in the frequency of abnormal LFTs

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