1. Thrombosis Management in Cardiology: The relevance of direct Factor Xa inhibition Prevention and Treatment of Venous Thromboembolism Alexander G G Turpie Professor of Medicine McMaster University Hamilton ON Canada

2. 2 2 1.Goldhaber SZ Am Coll Cardiol. 1992;19:246-247 2.Heit JA,et al ASH Annual Meeting Abstracts 2005;106:910 3.Cohen AT, et al. Thromb Haemost 2007;98:756−64 4.Cohen AT. Poster ISPOR 8th, 2005  3 rd most common cardiovascular disease world-wide after ischaemic heart disease and stroke 1  Causes ~300,000 deaths in the United States and over 500,000 deaths in Europe per year 2,3  In the EU, more than twice as many people die from VTE than from AIDS, breast cancer, prostate cancer and transportation accidents combined 3  3.1 billion Euros per year total estimated costs for VTE-associated care 4 VTE is a Serious Disease that Affects Hundreds of Thousands People each Year

3. 3 Known Consequences of VTE  Increased future risk of recurrent VTE  3-10% recurrent VTE at 1-year 1  Chronic post-thrombotic syndrome (PTS)  Fatal Pulmonary Embolism (PE)  Chronic thromboembolic pulmonary hypertension  Markedly increased risk of disability and reduced quality of life for the patient  Costs of investigating and treating add considerable healthcare costs 1,3 3 1.Kearon C. Circulation. 2003;107(23 Suppl 1):I22  I30. 2.Cohen AT, et al. Thromb Haemost 2007;98:756–764. 3.Ginsberg JS, et al. Arch Intern Med. 2000;160:669  672. Pulmonary embolus Deep Venous Thromboembolism (DVT)

4. 4 PTS is a Relatively Common but Serious Complication  PTS occurs in nearly one-third of pts within 5 years of initial DVT 1  DVT-induced valvular incompetence leads to lower limb hypertension 2  PTS is characterized by 3 :  Pain  Odema  Hyperpigmentation  Eczema  Varicose collateral veins  Severe PTS can lead to intractable, painful venous leg ulcers requiring ongoing nursing and medical care 4 4 © Diepgen TL, et al. Dermatology Online Atlas (Reprinted with permission). 1.Prandoni P, et al. Ann Intern Med. 1996;125:1–7. 2.Kahn SR, et al. Arch Intern Med. 2004;164:17–26. 3. Kahn SR. J Thromb Thrombolysis. 2006; 21(1) 41-48. 4. Kahn SR, et al. J Gen Intern Med. 2000;15:425–429.

5. 5 Desired Characteristics of New Oral Anticoagulants for VTE Treatment  Simplify VTE treatment strategies: one oral anticoagulant for the entire duration of treatment / secondary prevention  Eliminate the need for bridging / switching from a parenteral to an oral anticoagulant  Reduce the length of hospital stay/facilitate earlier hospital discharge  Offer healthcare savings through an improved benefit–risk profile

6. 6 6 Prothrombin FibrinFibrinogen Thrombin Dabigatran and others Factor Xa Rivaroxaban Apixaban, Endoxaban and others Factor X Prothrombinase- complex Phospholipids Factor Va – Factor Xa Ca 2+ Factor IX Factor IXa Factor VIIa Tissue factor Phospholipids Ca 2+ Factor IXa Factor VIIIa Phospholipids Ca 2+ Initiation phase Propagation phase = thrombin-generation phase Thrombin phase New Drugs in Phase III Development Directly Targeting Coagulation Factors Adapted from: Kubitza & Haas. Expert Opin Investig Drugs 2006

7. 7 Rivaroxaban Proven VTE Prevention in Adult Patients Undergoing THR and TKR Eriksson BI et al. N Engl J Med 2008; 358:2765–2775 Kakkar AK et al. Lancet 2008; 372:31–39 Lassen MR et al. N Engl J Med 2008; 358:2776–2786 Turpie AGG et al. Lancet 2009; 373:1673–1680 THR*: Oral rivaroxaban superior to sc enoxaparin in VTE prevention THR: Oral rivaroxaban long-term superior to enoxaparin short-term in VTE prevention TKR*: Oral rivaroxaban superior to sc enoxaparin in VTE prevention TKR: Oral rivaroxaban superior to bid sc enoxaparin in VTE prevention 7 *THR: Total Hip Replacement, TKR: Total Knee Replacement

8. 8 1. Eriksson et al. New Engl J Med 2008; 2. Kakkar et al. Lancet 2008; 3. Lassen et al. New Engl J Med 2008; 4. Turpie et al. Lancet 2009 Enoxaparin Rivaroxaban 10 mg od Mandatory bilateral venography Mandatory bilateral venography R 6–8 hours post-surgery in all RECORD studies Day 1 Double blind Last dose, day before venography Study Rivaroxaban therapy Dose Duration Enoxaparin therapy Dose Duration THR10 mg od5 weeks40 mg od5 weeks 1 THR10 mg od5 weeks40 mg od2 weeks *2 TKR10 mg od2 weeks40 mg od2 weeks 3 TKR10 mg od2 weeks30 mg bid2 weeks 4 * Followed by oral placebo for 3 weeks RECORD1–3: Evening before surgery RECORD4: 12–24 hours post-surgery RECORD Phase III Programme: Study Design SURGERYSURGERY FOLLOWUPFOLLOWUP 8

9. 9 Pooled analysis: Time points Rivaroxaban Follow-up Enoxaparin Follow-up Rivaroxaban Enoxaparin Follow-up Rivaroxaban Follow up by: 30–35 days after last dose Day 12 (10–14) Day 1Day 35 (31–39) Enoxaparin Placebo Follow-up Day 12 (10–14) Hip 1 Hip 2 Knee 4 Total study duration pool Day 12±2 active treatment pool Total treatment duration pool Rivaroxaban Enoxaparin Follow-up Knee 3 9 1.Eriksson et al. New Engl J Med 2008; 2.Kakkar et al. Lancet 2008; 3.Lassen et al. New Engl J Med 2008; 4. Turpie et al. Lancet 2009

10. 10 RECORD1–4* Pooled Analysis: Summary 1.3% 0.6% 0.4% RRR 58% ‡ p<0.001 p=0.076 (NS) Endpoints in total treatment duration pool # 0.2% p-values analysed using a Cox regression model; safety population, n=12,383; *RECORD2 compared extended-duration (35±4 days) rivaroxaban with short-duration (12±2 days) enoxaparin; # 5 weeks in RECORD1 and RECORD2 (includes placebo-controlled period in RECORD2) and 2 weeks in RECORD3 and RECORD4; ‡ Homogeneity test, p=0.313; ¶ Homogeneity test, p=0.431 0 0.5 1.0 1.5 2.0 2.5 Major bleedingSymptomatic VTE and all-cause mortality 0.5% 0.3% 0.2% RRR 52% ¶ p=0.001 p=0.175 (NS) Endpoints in day 12±2 active treatment pool 1.0% Major bleedingSymptomatic VTE and all-cause mortality Enoxaparin regimens Rivaroxaban regimens Incidence (%) 10 Turpie et al. Oral presentation at the XXII Congress of the ISTH. Boston, MA, USA. July 11–16, 2009. Turpie et al. Blood 2008;112(11):Abstract 36.

11. 11 RECORD1–4*: PE and all-cause mortality # HR = 0.61 (95% CI: 0.39–0.98) p=0.039 0 0.5 1.0 2.0 1.5 Day 1 = day of surgery 47 events 29 events Enoxaparin regimens Rivaroxaban regimens Time-to-event relative to surgery (days) 010203040506070 Cumulative event rate (%) *RECORD2 compared extended-duration (35±4 days) rivaroxaban with short-duration (12±2 days) enoxaparin # Post-hoc analysis; safety population, n=12,383 Turpie et al. Blood (ASH Annual Meeting Abstracts) 2008 11 Total study duration pool

12. 12 RECORD1–4*: Composite of Death, MI, Stroke, Symptomatic VTE, and Major Bleeding # *RECORD2 compared extended-duration (35±4 days) rivaroxaban with short-duration (12±2 days) enoxaparin # Post-hoc analysis; safety population, n=12,383 HR = 0.69 (95% CI: 0.53–0.89) p=0.004 Total study duration pool Cumulative event rate (%) 010203040506070 0.5 1.0 2.0 1.5 2.5 3.0 Day 1 = day of surgery 139 events 96 events Time-to-event relative to surgery (days) Enoxaparin regimens Rivaroxaban regimens 0 12 Turpie et al. Oral presentation at the XXII Congress of the ISTH. Boston, MA, USA. July 11–16, 2009. Turpie et al. Blood 2008;112(11):Abstract 36.

13. VTE prevention in hospitalized medically ill patients http://clinicaltrials.gov/ct2/show/NCT00571649?term=rivaroxaban&rank=9

14. MAGELLAN: Study Design Enoxaparin 40 mg once daily for 10 days Patients hospitalized for acute medical illness with decreased level of mobility Rivaroxaban 10 mg once daily for 35 days Day 1 R N = 8000 Follow-up Day 10Day 90 Day 35 End of treatment Oral placebo for 25 days Randomization Primary efficacy endpoint  Composite of asymptomatic proximal DVT detected by bilateral ultrasound, symptomatic DVT, non-fatal PE and VTE-related death. Primary safety endpoint  Major bleeding and clinically relevant non-major bleeding

15. 15 VTE – Phases of the Disease and Conventional Treatment with Anticoagulants Phases of the disease Long-term Types and intensity of conventional anticoagulation treatment Initial, parenteral therapeutic dose anticoagulation Early maintenance anticoagulation / Secondary prevention Long-term maintenance anti- coagulation / Secondary prevention UFH, LMWH, Fondaparinux VKA INR 2.0-3.0 VKA INR 2.0-3.0 or 1.5-2.0 At least 5 days At least 3 months > 3 months / years/ indefinite* *With re-assessment of the individual benefit–risk at periodic intervals. Kearon C, et al. Chest. 2008;133;454-545. ESC Textbook of Cardiovascular Medicin 2nd Edition 2009; Chapter 37 Schellong S, Bounameaux H, Büller HR pp 1348-1349 Intermediate Acute

16. 16 VTE Treatment: Clinical Studies 1 Phase IIPhase III Rivaroxaban Oral direct FXa inhibitor EINSTEIN DVT Rivaroxaban vs LMWH/UFH followed by VKA 1 ODIXa DVT Rivaroxaban vs enoxaparin followed by VKA 2 EINSTEIN DVT/PE 4 Rivaroxaban for 3, 6 or 12 months vs enoxaparin for > 5 days followed by VKA for 3, 6, or 12 months EINSTEIN EXT 4 Pre-treatment with rivaroxaban or VKA for 6 or 12 months followed by rivaroxaban or placebo for 6 or 12 months Dabigatran Oral direct thrombin inhibitor RE-COVER 4 & RE-COVER II 4 5-10 days pre-treatment with LMWH bridging to dabigatran or VKA for 6 months RE-MEDY 4 3-6 months treatment with approved anticoagulant; switch to dabigatran or warfarin RE-SONATE 4 6-18 months VKA treatment followed by 6 months dabigatran or placebo Apixaban Oral direct FXa inhibitor Botticelli-DVT Apixaban vs LMWH or fondaparinux followed by VKA 3 AMPLIFY 4 Apixaban 10 mg bid followed by 5 mg bid for 6 months vs enoxaparin followed by warfarin AMPLIFY-EXT 4 Apixaban 2.5 mg bid or 5 mg bid for extended 12 months period vs placebo 1. Büller HR et al. Blood 2008;112:2242–2247 2. Agnelli GA et al. Circulation 2007;116:180–187 3. Büller HR et al. J Thromb Haem 2008;6:1313–1318 4. www.clinicaltrials.gov

17. 17 Dabigatran Study Programme Confirmed symptomatic DVT or PE completing 6 to18 months VKA Dabigatran Etexilate 150 mg BID Placebo/warfarin Day 1 R N=1448 RE-SONATE/REMEDY Treatment period of 6 months Symptomatic VTE RE-COVER R N=2,564 Parenteral Anticoagulant Day 1Day 5-10 VKA target INR 2.5 (INR range 2–3) Symptomatic VTE RE-COVER II RE-COVER Pre-defined treatment period of 6 months N=2,554 Dabigatran Etexilate 150 mg BID 17 1. RECOVER Study Information. Trial ID: NCT00291330 Available at http://clinicaltrial.gov/ct2/show/NCT00291330 Accessed 15 November 2009 2. RECOVER Study Information. Trial ID: NCT00680186 Available at http://clinicaltrial.gov/ct2/show/NCT00680186 Accessed 15 November 2009 3. RESONATE Study Information. Trial ID: NCT00558259 Available at http://clinicaltrial.gov/ct2/show/NCT00558259. Accessed 15 November 2009 Parenteral Anticoagulant

18. 18 EventsDabigatran (n=1274)Warfarin (n=1265) Hazard ratios and confidence intervals Recurrent VTE (%)30 (2.4) 27 (2.2) Risk difference = 0.4% 95% CI; -0.8 to 1.5 p<0.0001 for prespecified non-inferiority Recurrent VTE to the end of follow-up period (%) 34 (2.7)32 (2.5) HR = 1.05 95% CI; 0.065 to 1.70 Major bleeding (%)20 (1.6)24 (1.9) HR = 0.82 95% CI; 0.45 to 1.48 Any bleeding (%)207 (16.2)280 (22.1) HR = 0.71 95% CI; 0.59 to 0.85 RE-COVER: Study Results Source – ASH 2009 Abstract

19. 19 Rivaroxaban: VTE Treatment Studies Phase IIPhase III Finished  ODIXa-DVT  EINSTEIN-DVT  EINSTEIN EXT Ongoing  EINSTEIN DVT  EINSTEIN PE http://clinicaltrials.gov 19

20. 20 Day 1Days 5–7Day 21Day 84Day 114 ODIXa-DVT 1 R Enoxaparin (1 mg/kg) VKA 10 mg bid 20 mg bid 40 mg od 30 mg bid DOUBLE BLIND OPEN LABEL 613 patients randomized INR 2–3 Rivaroxaban CCUS FOLLOW-UP CCUS+ PLS CCUS and PLS EINSTEIN-DVT 2 Rivaroxaban CUS+ PLS R LMWH/heparin VKA 20 mg od 30 mg od 40 mg od CUS and PLS FOLLOW-UP DOUBLE BLIND OPEN LABEL 543 patients randomized INR 2–3 Day 1Days 5–7Day 21Day 84Day 114 Phase II Study Designs: ODIXa-DVT and EINSTEIN-DVT Agnelli et al. Circulation 2007; Büller et al. Blood 2008

21. 21 Phase II: ODIXa-DVT and EINSTEIN-DVT: Efficacy Outcome 1,2 21 ODIXa-DVT 1 : Rivaroxaban showed similar efficacy to standard therapy Rivaroxaban total daily dose (mg) LMWH/VKA Rate of thrombus regression without recurrent VTE (%) 80 70 60 50 40 30 20 10 0 6040200 bid rivaroxaban doses od rivaroxaban dose EINSTEIN-DVT 2 : Rivaroxaban showed similar efficacy to standard therapy Rate of deterioration (%) Rivaroxaban total daily dose (mg) LMWH/VKA 103040 20 18 16 14 12 10 8 6 4 2 0 20 Recurrent DVT or PE, VTE-related death, and deterioration in CUS or PLS Agnelli et al (ESC Annual Meeting, Poster presentation) 2006; Buller et al (ESC Annual Meeting, Oral Presentation) 2006: Agnelli et al. Circulation 2007; Büller et al. Blood 2008

22. 22 EINSTEIN Phase III: Study Designs Confirmed symptomatic DVT or PE completing 6 or 12 months of rivaroxaban or VKA Rivaroxaban 20 mg od Placebo Day 1 R N=1,147 EINSTEIN EXT: Treatment period of 6 or 12 months 30-day observation period 15 mg bid Objectively confirmed DVT without symptomatic PE R N=3,465 Rivaroxaban Day 1Day 21 Enoxaparin 1.0 mg/kg bid for at least 5 days, plus VKA to start <48 hrs, target INR 2.5 (INR range 2–3) Objectively confirmed PE with or without symptomatic DVT EINSTEIN DVT/PE: Pre-defined treatment period of 3, 6, or 12 months 20 mg od N=3,300 30-day observation period Rivaroxaban 22 EINSTEIN DVT, PE, Extension Evaluation Study Information available at: http://clinicaltrials.gov. Accessed 15 November 2009

23. 23 Primary and Secondary Outcome Measures of EINSTEIN DVT and EINSTEIN PE Evaluation  Primary outcome measures 1,2  Symptomatic recurrent VTE, i.e., the composite of (recurrent) DVT or fatal or non-fatal PE  Principal safety outcome 1,2  Combination of major and clinically relevant non-major bleeding  Secondary outcome measures 1,2  All-cause mortality  Vascular events EINSTEIN DVT, PE Evaluation Study Information available at http://clinicaltrials.gov, Accessed 15 November 2009.http://clinicaltrials.gov 23

24. Study design Confirmed symptomatic DVT or PE completing 6 or 12 months of rivaroxaban or VKA in EINSTEIN VTE program Rivaroxaban 20 mg od Placebo Day 1 R N=1,197 Treatment period of 6 or 12 months 30-day observational period Confirmed symptomatic DVT or PE completing 6 or 12 months of VKA ~53% ~47% Randomized, double-blind, placebo-controlled, event-driven (n=30), superiority study EINSTEIN Extension Trial ID: NCT00439725

25. 25 EINSTEIN Extension: Study Results EventsRivaroxaban (n=594)Placebo (n=602) Recurrent VTE (%)*8 (1.3) 42 (7.1) HR = 0.184 RRR = 82% P < 0.0001 Major bleeding (%)4 (0.7)0)P = 0.11 *Some patients experienced more than one event

26. Major outcomes Primary efficacy outcome*  Symptomatic recurrent VTE, i.e. composite of recurrent DVT, non- fatal PE, or fatal PE, or unexplained death where PE cannot be excluded Principal safety outcome*  Major bleeding, defined as overt bleeding associated with:  A fall in hemoglobin of 2 g/dL or more, or  A transfusion of 2 or more units of packed red blood cells or whole blood, or  Occurrence at a critical site: intracranial, intraspinal, intraocular, pericardial, intra-articular, intramuscular with compartment syndrome, retroperitoneal, or  Death *Adjudicated by the Central Independent Adjudication Committee

27. Patient flow  Mean duration of therapy  Before study entry: placebo 249 days; rivaroxaban 248 days  During study: placebo 190 days; rivaroxaban 190 days  Last patient enrolled  Treated for at least 3 months Safety population ITT population for primary efficacy Placebo 595 594 590 602 598 Rivaroxaban Randomized (n=1,197)

28. Patient characteristics ITT population; *index event not confirmed in all patients Placebo (n=594) Rivaroxaban (n=602) Males (%) 5759 Age, mean (years) 58 Body mass index, mean (kg/m 2 ) 28 Creatinine clearance (mL/min) <5049(8%)37(6%) 50–<80121(20%)134(22%) ≥80373(63%)371(62%) Index event* DVT350(59%)376(63%) PE with or without DVT233(39%)213(35%) Risk factors Patients with idiopathic DVT/PE358(60%)344(57%) Patients with risk factors236(40%)258(43%)

29. Primary efficacy outcome and individual components Placebo (n=594) Rivaroxaban (n=602) Symptomatic recurrent VTE*427.1%81.3% Recurrent DVT315.2%50.8% Non-fatal PE132.2%20.3% Fatal PE10.2%0 Unexplained death (where PE cannot be excluded) 010.2% ITT population; *some patients experienced more than one event

30. Number of subjects at risk Rivaroxaban6025905835735525034821711381321149281 Placebo5945825705545214674441641381331109385 ITT population Primary efficacy outcome analysis (time to first event) 10 9 8 7 6 5 4 3 2 1 0 Cumulative event rate (%) 0306090120150180210240270300330360 Time to event (days) Rivaroxaban (n=602) Placebo (n=594) HR=0.184; p<0.0001 RRR=82% Number needed to treat to prevent 1 primary efficacy outcome: 15

31. Placebo (n=590) Rivaroxaban (n=598) Major bleeding 0 4 (0.7%)* Bleeding contributing to death00 Bleeding in a critical site00 Associated with fall in hemoglobin  2 g/dL and/or transfusion Gastrointestinal bleeding03 (0.5%) Menorrhagia01 (0.2%) Principal safety outcome: major bleeding  Number needed to harm: approximately 139 *p=0.11 Safety population

32. Placebo (n=590) Rivaroxaban (n=598) Clinically relevant non-major bleeding7 (1.2%)32 (5.4%)* Urogenital/uterus2 (0.3%)12 (2.0%) Nasal1 (0.2%)8 (1.3%) Rectal/anal2 (0.3%)6 (1.0%) Skin2 (0.3%)4 (0.7%) Ear01 (0.2%) Gastrointestinal01 (0.2%) Surgical site01 (0.2%) Other outcomes Safety population; some patients experienced more than one event *p<0.01

33. Placebo (n=594) Rivaroxaban (n=602) Cardiovascular outcomes 4 (0.7%) STEMI 01 (0.2%) Unstable angina 1 (0.2%)3 (0.5%) Transient ischemic attack 1 (0.2%)0 Ischemic stroke 1 (0.2%)0 Non-CNS systemic embolism 1 (0.2%)0 ITT population Other outcomes Total mortality2 (0.3%)1 (0.2%) PE1 (0.2%) Cancer1 (0.2%) Unexplained death including where PE cannot be excluded 01 (0.2%)

34. ALT >3 x ULN (single measurement) Continued Improved n=1n=6 ALT >3 x ULN (3 measurements) Continued Improved n=1 Allopurinol/statins/ multiple drugs n=1 Hepatic steatosis, 8-year history of ALT  ALT >3 x ULN (single measurement) Discontinued Improved n=1 Unexplained n=3 1 liver hemangioma/ hepatic steatosis 2 unexplained ALT >8 x ULN (2 measurements) Discontinued Improved 0n=1 Alcohol abuse/ allopurinol/ hepatitis A Asymptomatic ALT rises, study treatment, clinical history, and concomitant medication Observation/ frequency Treatment/ outcome PlaceboRivaroxaban Liver failure/ death00 ALT >3x ULN + bilirubin >2x ULN 00 Safety population

35. 35 Summary  VTE is a serious and potentially life-threatening condition  Current standard of treatment usually requires initial parenteral LMWH/UFH or fondaparinux followed by an oral VKA  For many patients with VTE, secondary prevention with VKA is not extended beyond 6 months since risk of VTE may be outweighed by risk of major bleeding 1  Patients with VTE have a major risk of recurrent VTE that may persist for years 2,3  New oral anticoagulants may have the potential to improve benefit- risk and simplify acute VTE treatment and secondary prevention 35 1. Schulman S: N Engl J Med 2003 Oct 30; 349(18):1713-21 2. Prandoni P, Lensing AWA, Cogo A, et al. Ann Intern Med 1996; 125: 1–7. 3. Heit JA, Mohr DN, Silverstein MD, et al. Arch Intern Med 2000; 160: 761–768.