New Oral Anticoagulants:What we’ve all been waiting for!       Gerald A Soff, MD
Approach to Anticoagulation 1937: First use of heparin for treatment of venous  thrombosis:    – Murray, D. et al (1937) ...
Heparin: “An Indirect Anticoagulant”             Dependent of Antithrombin III•   Katzung BG et al. Basic & Clinical Pharm...
• Randomized, controlled study of anticoagulation versus no  treatment.• Med/Surg. patients with PE (based on history, phy...
Prothrombin Time Titration of Vitamin           K Antagonist.       Target PT ratio 2-3 X Control
Results   Group           Total         Deaths       Non-Fatal        Other                                From PE      re...
Warfarin        Why We Hate It!                        Maybe not so bad!Narrow Therapeutic Window            Tremendously ...
Ximelagatran: Caution Needed For New Drug Development!• A “new” oral direct thrombin inhibitor.   ASH Section devoted to ...
New Oral Anticoagulants: (Direct)•   http://cenblog.org/the-haystack/tag/bmy/, © 2011 American Chemical Society
Parameter              Dabigaran                    Rivaroxaban             Apixaban    Target                 Thrombin   ...
Drug        Trade Name    Manufacturer Apixaban      Eliquis ®   Pfizer/Bristol-Myers                                  Squ...
Development Strategies Clinical Trial Development   – Prophylaxis in high risk orthopedic patients   – Atrial fibrillatio...
ISTH Bleeding Definitions• Major Bleeding – Bleeding …   – with a fall in hemoglobin of ≥2 g/dL, or   – with transfusion o...
• “Indications and Usage: PRADAXA (dabigatran  etexilate mesylate) capsules is indicated to reduce  the risk of stroke and...
Dabigatran versus Warfarin in Patients             with Atrial Fibrillation:    Randomized Evaluation of Long-Term Anticoa...
Cumulative Hazard Rates for the Primary        Outcome of Stroke or Systemic Embolism.                                 Mon...
Efficacy Outcomes, According to             Treatment Group  Event      Dabigatran   Dabigatran   Warfarin    Relative    ...
Safety Outcomes, According to                Treatment Group Event     Dabigatran   Dabigatran   Warfarin   Relative Risk ...
RE-LY: Dabigatran versus Warfarin in     Patients with Atrial Fibrillation:• Dabigatran 150 mg bid: As safe as warfarin, m...
Dabigatran For Prevention Of VTE After   Major Orthopaedic Surgery: Phase III Studies     Study         Comparator        ...
Dabigatran For Prevention of VTE    After Major Orthopaedic SurgeryDVT, PE and all-cause                Enoxaparin        ...
The RECOVER Study:Dabigatran versus Warfarin in the Treatment   of Acute Venous Thromboembolism•   Randomized, double blin...
RECOVER Study: Cumulative Risk of  Recurrent VTE or Related Death Schulman S et al. NEJM 2009;361:2342-2352.
Cumulative Risks of a First Event of Major        Bleeding and of Any Bleeding Major Bleed: Hazard Ratio: 0.82 (95% CI, 0...
Dabigatran For VTE Treatment• “For the treatment of acute venous  thromboembolism, a fixed dose of dabigatran is as  effec...
Dabigatran Etexilate: PRADAXA ®• “Indicated to reduce the risk of stroke and systemic embolism  in patients with non-valvu...
Dabigatran Etexilate: PRADAXA ®1. Atrial Fibrillation:   – 150 mg bid: more effective than warfarin   – 75 mg bid for CrC...
RECORD Trials (REgulation of Coagulation in ORthopaedicsurgery to prevent Deep vein thrombosis and            pulmonary em...
Xarelto®/Rivaroxaban                Trial Information                          Drug Intervention           Elective   Tria...
Xarelto®/Rivaroxaban         RECORD Trial Efficacy Results            Composite of symptomatic VTE and all-cause mortality...
Xarelto®/Rivaroxaban:           RECORD Safety Outcomes                   Rivarox.   Enoxaparin   Odds Ratio vs      P valu...
Xarelto®/Rivaroxaban          RECORD Trials• Rivaroxaban 10 mg daily:• Consistently more effective than  Enoxaparin (40 mg...
ROCKET AF: Stroke Prevention in      Atrial Fibrillation• “Rivaroxaban Once-daily oral direct  Factor Xa inhibition Compar...
ROCKET AF: Study Design• Atrial Fibrillation With:   – At least 2 Risk Factors: CHF , Hypertension, Age 75,      Diabetes ...
ROCKET-AF: Primary Efficacy            Outcome       Rivaroxaban Warfari Hazard ratio p value                            (...
ROCKET-AF: Safety Outcomes                 Rivaroxaban   Warfarin     Hazard ratio     P                  Event Rate   Eve...
EINSTEIN: Rivaroxaban For          Venous Thrombosis Treatment•   EINSTEIN-DVT and EINSTEIN-PE:     – Rivaroxaban 15 mg bi...
Cumulative Event Rates for the Primary     Efficacy Outcome in the DVT and PE Studies.                                    ...
Cumulative Event Rates for the Principal Safety           Outcome in the Acute DVT Study.The EINSTEIN Investigators. NEJM ...
EINSTEIN: Rivaroxaban For Venous      Blood Clot Treatment• Trend towards more effective than  heparin:warfarin, but stati...
EINSTEIN: Rivaroxaban For Venous        Blood Clot Treatment• “The reversibility of the drugs’ (warfarin) effects and the ...
MAGELLAN:       Prophylaxis in High Risk Medical Patients• Is 10 days of anticoagulation with rivaroxaban non-inferior to ...
MAGELLAN:Primary VTE efficacy endpoints:  – Day 10: Rivaroxaban vs Enoxaparin: (2.7% vs 2.7%)  – Day 35: extended thrombo...
ATLAS ACS 2 TIMI 51:                   Rivaroxaban vs Placebo• Tested 2.5 mg bid and 5 mg bid vs placebo• Patients were on...
Rivaroxaban: Xarelto®• 1.   Nonvalvular Atrial Fibrillation:   –   CrCl >50 mL/min: XARELTO® 20 mg PO daily with the eveni...
Rivaroxaban: Xarelto®• Drugs That Inhibit CYP3A4 Enzymes and Drug Transport  Systems:   – Avoid concomitant administration...
ApixabanAugust, 2010 August, 2011
ADVANCE:Apixaban versus Enoxaparin In High-Risk          Orthopedic Patients ADVANCE-3: THR    – Apixaban 2.5 mg orally b...
APIXABAN: ADVANCE-3 (THR)      Apixaban versus Enoxaparin In High-Risk                Orthopedic Patients                 ...
ARISTOTLE: Phase III trial or     Apixaban vs Warfarin in Atrial             FibrillationApixaban 5 mg twice dailyWarfar...
ARISTOTLE: Phase III trial or Apixaban        vs Warfarin in Atrial Fibrillation      End point       Apixaban   Warfarin ...
APPRAISE-1: Apixaban, in   combination with antiplatelet therapy     after acute coronary syndromes• Alexander J et al. N ...
Kaplan–Meier Curves for the Primary Efficacy Outcome.Alexander JH et al. N Engl J Med 2011;365:699-708.
Kaplan–Meier Curves for the Primary Safety Outcome.Alexander JH et al. N Engl J Med 2011;365:699-708.
Monitoring of Dabigatran:              Drug added to normal plasma                        EC                      PT      ...
Barriers To Broader Use Of New               Oral Anticoagulants:• “Fixed Dose,” but it is not yet known which dose we sho...
New Agents For DVT Treatment In                Cancer? Both Dabigatran and Rivaroxaban VTE Treatment studies showed  non-...
Correspondences on major bleeding  in community setting/trauma on           Dabigatran• “Lack of a readily available metho...
•   Reduction of Risk of Stroke and Systemic Embolism in Nonvalvular Atrial    Fibrillation:     – XARELTO® is indicated t...
RECORD4: Rivaroxaban For Thrombosis                     Prophylaxis in THR Patients                 12   Total VTE        ...
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new oral anticoagulants

  1. 1. New Oral Anticoagulants:What we’ve all been waiting for! Gerald A Soff, MD
  2. 2. Approach to Anticoagulation 1937: First use of heparin for treatment of venous thrombosis: – Murray, D. et al (1937) Surgery, 2, 163. – Crafoord, C. (1937) Acta Chir. Scand. 79, 407. 1947: First description of heparin followed by Vitamin K Antagonist (warfarin, dicoumarol) for pulmonary embolism . – 329 patients with pulmonary embolism treated, with only one death. – Allen, EV et al. (1947) Ann Intern Med 27:371.
  3. 3. Heparin: “An Indirect Anticoagulant” Dependent of Antithrombin III• Katzung BG et al. Basic & Clinical Pharmacology, 11th Edition, McGraw-Hill, 2009.
  4. 4. • Randomized, controlled study of anticoagulation versus no treatment.• Med/Surg. patients with PE (based on history, physical exam, pulmonary infarction on CXR, and right heart strain on EKG.• Treatment: – Heparin 10,000 units q 6 hours, for 6 doses without laboratory control. – Acenocoumarol (Nicoumalone) adjusted for Prothrombin Time• Barritt, D. W. and S. C. Jordan. Lancet 1(7138): 1309-1312, 1960.
  5. 5. Prothrombin Time Titration of Vitamin K Antagonist. Target PT ratio 2-3 X Control
  6. 6. Results Group Total Deaths Non-Fatal Other From PE recurrences Deaths Untreated 19 5 5 0 Treated 54 0 1 2Interim analysis resulted in early termination of untreatedgroup.Deaths in Treatment Arm: 1 death from aspiration pneumonia 1 death related to medication error. Patient received phenindione instead of Acenocoumarol and developed renal failure.Barritt, D. W. and S. C. Jordan (1960). Lancet 1(7138): 1309-1312.
  7. 7. Warfarin Why We Hate It! Maybe not so bad!Narrow Therapeutic Window Tremendously large experienceSensitive to changes in diet We know everything about it (Vitamin K- Dependent Factors: II, VII, IX, X, C, S)Slow to act, very long half-life Simple, standardized test for functional level (INR).Numerous drug interactions Reversal agents highly effective and readily available.Wide range in therapeutic doses, Virtually no side effects except for bleeding.difficult to predict.Treacherous to use in cancer Cheap!patients!
  8. 8. Ximelagatran: Caution Needed For New Drug Development!• A “new” oral direct thrombin inhibitor.  ASH Section devoted to it in 2005!• After marketing in Europe and other countries, severe hepatic dysfunction observed in 5-6%, including cases of fatal liver failure.• Withdrawn in 2006.
  9. 9. New Oral Anticoagulants: (Direct)• http://cenblog.org/the-haystack/tag/bmy/, © 2011 American Chemical Society
  10. 10. Parameter Dabigaran Rivaroxaban Apixaban Target Thrombin Factor Xa Factor Xa Oral bioavailability 6.5% 80% 66% Dosing Fixed, once or twice daily Fixed, once or twice Fixed, twice daily daily Pro-Drug Yes No No Half-life (h) 12–14 7–13 8–13 Routine coagulation No No No monitoring Renal clearance 80% 66%; half as inactive ∼25% drug Potential drug P-gp inhibitors, Inhibitors of CYP3A4 CYP3A4 inhibitors interactions (Rifampicin, quinidine, and P-gp amiodarone) Involvement of CYP No CYP3A4 CYP3A4 Clinical status FDA Approved FDA Approved Phase III• Cytochrome P450 3A4 P-gp: P-glycoprotein• Excerpt from Eriksson et al, 2011
  11. 11. Drug Trade Name Manufacturer Apixaban Eliquis ® Pfizer/Bristol-Myers SquibbRivaroxaban Xarelto ® Bayer/Johnson & Johnson (Janssen)Dabigatran Pradaxa ® Boehringer Ingelheim
  12. 12. Development Strategies Clinical Trial Development – Prophylaxis in high risk orthopedic patients – Atrial fibrillation – Treatment of venous thrombosis – Acute Coronary Syndrome Fixed dose No monitoring Statistics: non-inferiority versus superiority
  13. 13. ISTH Bleeding Definitions• Major Bleeding – Bleeding … – with a fall in hemoglobin of ≥2 g/dL, or – with transfusion of ≥2 units of PRBC or whole blood, or – that occurs in a critical location, i.e., intracranial, intraspinal, intraocular, retroperitoneal, intraarticular or pericardial, or – that causes death• Clinically Relevant Non-Major Bleeding – Bleeding – that does not meet criteria for major bleeding, and – that requires any medical or surgical intervention to treat the bleeding
  14. 14. • “Indications and Usage: PRADAXA (dabigatran etexilate mesylate) capsules is indicated to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation.”• Dabigatran etexilate is the prodrug of dabigatran, which reversibly inhibits the active site of thrombin.• Oral bioavailability is ∼6%.• DE is rapidly converted to dabigatran by esterases in the blood and liver with peak plasma concentrations achieved 2–3 h after oral administration.
  15. 15. Dabigatran versus Warfarin in Patients with Atrial Fibrillation: Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY)• Atrial fibrillation and a risk of stroke• Noninferiority trial, Randomized• Dabigatran: 110 mg or 150 mg twice daily (blinded to which dose)  (Orthopedic studies were once daily!)• Warfarin (unblinded) adjusted-dose.• Median follow-up period was 2.0 years.• The primary outcome was stroke or systemic embolism.• No mention of numbers of cancer patients in cohorts. – Connolly S, et al, NEJM 2009; 361:1139-1151
  16. 16. Cumulative Hazard Rates for the Primary Outcome of Stroke or Systemic Embolism. MonthsConnolly SJ et al. N Engl J Med 2009;361:1139-1151.
  17. 17. Efficacy Outcomes, According to Treatment Group Event Dabigatran Dabigatran Warfarin Relative Relative Relative 110 mg bid 150 mg bid (n=6022) Risk Risk Risk (n=6015) (n=6076) DE 110 vs W DE 150 vs DE 150 vs W DE 110Stroke or 1.53 1.11 1.69 0.91 0.66 0.73Systemic ( p<0.001 for (p<0.001) (p=0.005)Embolism Non-inferior) MI 0.72 0.74 0.53 1.35 1.38 1.02 (p 0.07) (p 0.048) (p 0.88)Death from 2.43 2.28 2.69 0.90 0.85 0.94 Vascular (p 0.21) (p 0.04) (p 0.44) CausesDeath from 3.75 3.64 4.13 0.91 0.88 0.97any cause (p 0.13) (p 0.051) (0.66)Events are %/yr  Connolly SJ et al. NEJM 2009;361:1139-1151.p are superiority unless noted as non-inferiority
  18. 18. Safety Outcomes, According to Treatment Group Event Dabigatran Dabigatran Warfarin Relative Risk Relative Risk Relative Risk 110 mg bid 150 mg bid (n=6022) DE 110 vs W DE 150 vs W DE 150 vs (n=6015) (n=6076) D110 Major 2.71 3.11 3.36 0.80 0.93 1.16Bleeding (p 0.003) (p 0.31) (p 0.052) Minor 13.16 14.84 16.37 0.79 0.91 1.16Bleeding (p<0.001) (p 0.005) (p<0.001) All 14.62 16.42 18.15 0.78 0.91 1.16Bleeding (p<0.001) (p 0.002) (p<0.001) Events are %/yr p are superiority unless noted as non-inferiorityConnolly SJ et al. NEJM 2009;
  19. 19. RE-LY: Dabigatran versus Warfarin in Patients with Atrial Fibrillation:• Dabigatran 150 mg bid: As safe as warfarin, more effective.• Dabigatran 110 mg bid: Safer than warfarin, as effective. – Connolly SJ et al. NEJM 2009;361:1139-1151.• FDA Approved 150 mg and 75 mg doses for non-valvular atrial fibrillation?• “Ultimately, the FDAs decision to approve only the 150-mg strength was based on our inability to identify any subgroup in which use of the lower dose would not represent a substantial disadvantage” – Beasley et al. NEJM 364:1788-1790, 2011
  20. 20. Dabigatran For Prevention Of VTE After Major Orthopaedic Surgery: Phase III Studies Study Comparator Time to 1st Treatment administration of duration dabigatran RE-NOVATE Enoxaparin 1–4 hours 28–35 days (THR) 40 mg qd, starting post-surgery evening before surgery RE- Enoxaparin 6–12 hours post- 12–15 days MOBILIZE 30 mg bid, starting 12– surgery (TKR) 24 hours post-surgery RE-MODEL Enoxaparin 1–4 hours 6–10 days (TKR) 40 mg qd, starting post-surgery evening before surgery Dabigatran 150 and 220 mg daily were investigated in all three studies. Eriksson et al. Blood 2006; Friedman et al. J Thromb Haemost 2007; Eriksson et al. J Thromb Haemost 2007.
  21. 21. Dabigatran For Prevention of VTE After Major Orthopaedic SurgeryDVT, PE and all-cause Enoxaparin Dabigatran Dabigatranmortality (%) (150 mg qd) (220 mg qd)RE-NOVATE (THR) 6.7% 8.6% 6.0% (Enox 40 mg qd) p<0.0001* p<0.0001*RE-MOBILIZE (TKR) 25.3% 33.7% 31.1% p=0.02† (Enox 30 mg bid) p=0.0009†RE-MODEL (TKR) 37.7% 40.5% 36.4% (Enox 40 mg qd) 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 enoxaparinEriksson et al. Blood 2006; Friedman et al. J Thromb Haemost 2007;Eriksson et al. JTH, 2007
  22. 22. The RECOVER Study:Dabigatran versus Warfarin in the Treatment of Acute Venous Thromboembolism• Randomized, double blind study• Initial treatment: – “Approved parenteral anticoagulant (generally unfractionated heparin administered intravenously or low-molecular-weight heparin administered subcutaneously).” – Given for at least 5 days.• Dabigatran 150 bid (n=1273) or warfarin (n=1266)• Analysis at 6 months.• Cancer: – Dabigatran: n=64 (5.0%), warfarin: n=57 (4.5%)• Schulman S et al, NEJM 2009; 361:2342-2352
  23. 23. RECOVER Study: Cumulative Risk of Recurrent VTE or Related Death Schulman S et al. NEJM 2009;361:2342-2352.
  24. 24. Cumulative Risks of a First Event of Major Bleeding and of Any Bleeding Major Bleed: Hazard Ratio: 0.82 (95% CI, 0.45 to 1.48; P=0.38) Any Bleeding: Hazard Ratio: 0.71 (95% CI, 0.59 to 0.85, p<0.001) Schulman S et al. NEJM 2009;361:2342-2352.
  25. 25. Dabigatran For VTE Treatment• “For the treatment of acute venous thromboembolism, a fixed dose of dabigatran is as effective as warfarin, has a safety profile that is similar to that of warfarin, and does not require laboratory monitoring.” – Schulman S et al. NEJM 2009;361:2342-2352.• Not yet FDA approved for VTE treatment!• Study did not evaluate/validate its use for initial anticoagulation treatment.
  26. 26. Dabigatran Etexilate: PRADAXA ®• “Indicated to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation.”• Dosing: The recommended dose: PRADAXA 150 mg twice daily.• For patients with low creatinine clearance – CrCl 15-30 mL/min, dose is PRADAXA 75mg twice daily – CrCl <15 mL/min or on dialysis, dose cannot be provided• “Effect of P-gp Inducers and Inhibitors on PRADAXA Exposure” – P-gp inducers (e.g., rifampin) reduces dabigatran exposure and should generally be avoided. – P-gp inhibitors ketoconazole, verapamil, amiodarone, quinidine, and clarithromycin, do not require dose adjustments.
  27. 27. Dabigatran Etexilate: PRADAXA ®1. Atrial Fibrillation: – 150 mg bid: more effective than warfarin – 75 mg bid for CrCl 15-30 mL/min2. VTE Treatment: (Not approved) – Dabigatran 150 bid as effective as warfarin, and trend towards reduced bleeding3. High Risk Orthopedic Surgery: : (Not approved) – Dabigatran 150 and 220 mg daily not safer and trend towards higher thrombosis rates.
  28. 28. RECORD Trials (REgulation of Coagulation in ORthopaedicsurgery to prevent Deep vein thrombosis and pulmonary embolism)
  29. 29. Xarelto®/Rivaroxaban Trial Information Drug Intervention Elective Trial Rivaroxaba Enoxapari Duration of Treatment Surgery OR n nRECORD 1 THA 10mg PO QD 40mg SQ QD Both: 35 ± 4 days Rivaroxaban: 35 ± 4 10mg PO QDRECORD 2 THA 40mg SQ QD days Enoxaparin: 13 ± 2 days Rivaroxaban: 12 ±2RECORD 3 TKA 10mg PO QD 40mg SQ QD days Enoxaparin: 13 ± 2 days 10mg PO QD 30mg SQRECORD 4 TKA Both: 12 ± 2 days q12hTurpie AG, et al. Thrombo Haemost. 2011;105(3):444-53.
  30. 30. Xarelto®/Rivaroxaban RECORD Trial Efficacy Results Composite of symptomatic VTE and all-cause mortality Rivaro. Enoxaparin Odds ratio vs (%) (%) Enox. (95% CL) Pooled Data 0.5 1.0 0.48 (0.30-0.76) * RECORD 1 0.3 0.4 0.88 (0.27-2.78) RECORD 2 0.2 0.4 0.40 (0.04-2.45) RECORD 3 0.7 2.1 0.31 (0.12-0.70) RECORD 4 0.8 1.4 0.56 (0.25-1.2) * p=0.001 Turpie AG, et al. Thrombo Haemost. 2011;105(3):444-53.
  31. 31. Xarelto®/Rivaroxaban: RECORD Safety Outcomes Rivarox. Enoxaparin Odds Ratio vs P value (%) (%) Enox. (95% CL) Day 12 +/- 2Major Bleeding 0.3 0.2 1.62 (0.77-3.53) 0.23 Major + non- 2.8 2.5 1.17 (0.93-1.46) 0.19major clinically relevant Any 6.6 6.2 1.07 (0.92-1.24) 0.38 Turpie AG, et al. Thrombo Haemost. 2011;105(3):444- 53.
  32. 32. Xarelto®/Rivaroxaban RECORD Trials• Rivaroxaban 10 mg daily:• Consistently more effective than Enoxaparin (40 mg daily or 30 mg bid) for high risk orthopedic patients.• Safety comparable with Enoxaparin.
  33. 33. ROCKET AF: Stroke Prevention in Atrial Fibrillation• “Rivaroxaban Once-daily oral direct Factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation.” – Patel MR, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883-91.
  34. 34. ROCKET AF: Study Design• Atrial Fibrillation With: – At least 2 Risk Factors: CHF , Hypertension, Age 75, Diabetes – OR Stroke, TIA or Systemic embolus• Treatment Arms: – Rivroxaban: 20 mg daily • (15 mg for Cr Cl 30-49 ml/min) – Warfarin: INR target (2 – 3)• Primary Endpoint: Stroke or non-CNS Systemic Embolism.• Note! Rivaroxaban dose higher than Orthopedic prophylaxis studies (20 mg vs 10 mg).  Patel MR, et al NEJM 365:883-91, 2011.
  35. 35. ROCKET-AF: Primary Efficacy Outcome Rivaroxaban Warfari Hazard ratio p value (n=7081) n (95% CI) (n=7090) Primary end point, 1.70 2.15 0.79 0.015 (superiority) (0.65-0.95) Vascular death, 3.11 3.63 0.86 0.034 stroke, embolism (0.74-0.99) Hemorrhagic stroke 0.26 0.44 0.59 0.024 (0.37-0.93) Ischemic stroke 1.34 1.42 0.94 0.581 (0.75-1.17) Unknown stroke 0.06 0.10 0.65 0.366 (0.25-1.67) Primary Endpoint: Stroke or non-CNS Systemic Embolism. Event Rates are per 100 patient-years. Patel MR, et al NEJM 365:883-91, 2011.
  36. 36. ROCKET-AF: Safety Outcomes Rivaroxaban Warfarin Hazard ratio P Event Rate Event Rate (95% CI) valueAll Clinically 1.03Relevant 14.91 14.52 0.442Bleeds (0.96, 1.11) 1.04Major Bleeds 3.60 3.45 0.576 (0.90, 1.20)Non-major 1.04Clinically 11.80 11.37 0.345Relevant (0.96, 1.13)Bleeding 0.24 0.48 0.50 0.003causing death (0.31-0.79)Intracranial 0.49 0.74 0.67 0.019hemorrhage (0.47-0.94)
  37. 37. EINSTEIN: Rivaroxaban For Venous Thrombosis Treatment• EINSTEIN-DVT and EINSTEIN-PE: – Rivaroxaban 15 mg bid for 3 weeks followed by 20 mg once-daily – Enoxaparin 1 mg/kg twice-daily (> 5 days), plus vitamin K antagonist (INR 2.0-3.0) – (Allowed up to 48 hours of IV heparin, LMWH, Fondaparinux before enrollment.)• EINSTEIN Extension: – Rivaroxaban 20 mg once-daily versus placebo in patients who have already completed 6 or 12 months of Rivaroxaban or a vitamin K antagonist.• Primary Endpoint: Symptomatic, recurrent VTE• Principle Safety Endpoint: Major bleeding and clinically relevant non-major bleeding. – Active cancer: Rivaroxaban, n=118 (6.8%), Control, n=89 (5.2%)
  38. 38. Cumulative Event Rates for the Primary Efficacy Outcome in the DVT and PE Studies. P<0.001 for Acute noninferiorit Treatmen y t Extended P<0.001 Treatment for superiorit yThe EINSTEIN Investigators. NEJM 2010;363:2499-2510.
  39. 39. Cumulative Event Rates for the Principal Safety Outcome in the Acute DVT Study.The EINSTEIN Investigators. NEJM 2010;363:2499-2510.
  40. 40. EINSTEIN: Rivaroxaban For Venous Blood Clot Treatment• Trend towards more effective than heparin:warfarin, but statistically noninferior.• As safe as heparin:warfarin.• “A unique aspect of the Acute DVT Study is the use of rivaroxaban as a single agent, replacing both low-molecular-weight heparin and a vitamin K antagonist in the treatment of DVT.” – The EINSTEIN Investigators. N Engl J Med 2010;363:2499-2510.
  41. 41. EINSTEIN: Rivaroxaban For Venous Blood Clot Treatment• “The reversibility of the drugs’ (warfarin) effects and the ability to measure the anticoagulant effect in specific situations will continue to be highly desirable features and will help to allay physicians concerns.”• “If these novel, breakthrough, oral anticoagulant drugs prove to be effective across the broad spectrum of patients in routine care and are conscientiously priced, the worldwide impact will be huge.” – Edtorial accompanying The Einstein Report. – Elaine M. Hylek, N Engl J Med 2010; 363:2559-2561
  42. 42. MAGELLAN: Prophylaxis in High Risk Medical Patients• Is 10 days of anticoagulation with rivaroxaban non-inferior to enoxaparin?• Is 35 days of anticoagulation with rivaroxaban superior to enoxaparin followed by placebo?• Rivaroxaban compared with enoxaparin for the prevention of venous thromboembolism in acutely ill medical patients.• Rivaroxaban 10 mg po qd compared with Enoxaparin 40 mg qd X 10 +/-4 days.• Rivaroxaban 10 mg po qd compared with placebo X 35 +/- 4 days.
  43. 43. MAGELLAN:Primary VTE efficacy endpoints: – Day 10: Rivaroxaban vs Enoxaparin: (2.7% vs 2.7%) – Day 35: extended thromboprophylaxis – Rivaroxaban vs Enoxaparin (4.4% vs 5.7%).Overall bleeding rates: – Rivaroxaban higher: – Day 10: Rivaroxaban (2.8%) vs Enoxaparin (1.2%) – Day 35, Rivaroxaban (4.1%) vs Enoxaparin (1.7%) p<0.0001. – Rates of other adverse events, including liver and cardiovascular events, were similar in both arms
  44. 44. ATLAS ACS 2 TIMI 51: Rivaroxaban vs Placebo• Tested 2.5 mg bid and 5 mg bid vs placebo• Patients were on ASA and 93% also on clopidogrel End point Riva 2.5 mg Placebo HR (95% CI) p bid (%) (%) CV 0.84 (0.72-0.97 death/MI/strok 9.1 10.7 0.02 ) e 0. 66 (0.51- CV death 2.7 4.1 0.002 0.86) All-cause 0.68 (0.53-0. 2.9 4.5 0.002 death 87) Major non- CABG 1.8 0.6 3.46 (2.08-5.77) 0.001 bleeding ICH 0.4 0.2 2.83 (1.02-7.86) 0.04 Fatal bleeding 0.1 0.2 0.67 (0.24-1.89) 0.45
  45. 45. Rivaroxaban: Xarelto®• 1. Nonvalvular Atrial Fibrillation: – CrCl >50 mL/min: XARELTO® 20 mg PO daily with the evening meal. – CrCl 15 to 50 mL/min: 15 mg PO daily with the evening meal.• 2. Prophylaxis of Deep Vein Thrombosis: – 10 mg PO daily with or without food. – Initial dose > 6 to 10 hours after surgery once hemostasis has been established. – THR: 35 days is recommended. – TKR: 12 days is recommended.• 3. VTE Treatment (Not Approved) – Rivaroxaban 15 mg bid for 3 weeks followed by 20 mg once-daily• 4. Acute Coronary Syndrome (Not Approved) – Rivaroxaban 2.5 mg bid with antiplatelet agents.
  46. 46. Rivaroxaban: Xarelto®• Drugs That Inhibit CYP3A4 Enzymes and Drug Transport Systems: – Avoid concomitant administration with combined P-gp and strong CYP3A4 inhibitors, which cause significant increases in rivaroxaban exposure.• Drug-Disease Interactions With Drugs That Inhibit CYP3A4 Enzymes and Drug Transport Systems: – Use only if benefit justifies risk in patients with renal impairment with concomitant use of P-gp and weak or moderate CYP3A4 inhibitors due to potentially significant increase in rivaroxaban exposure.• Drugs That Induce CYP3A4 Enzymes and Drug Transport Systems: – Avoid P-gp and strong CYP3A4 inducers due to decreases in rivaroxaban exposure.
  47. 47. ApixabanAugust, 2010 August, 2011
  48. 48. ADVANCE:Apixaban versus Enoxaparin In High-Risk Orthopedic Patients ADVANCE-3: THR – Apixaban 2.5 mg orally bid – Initiated 12 to 24 hours after wound closure. – Enoxaparin at a dose of 40 mg q 24 hours. – Initiated 12 hours before surgery. – Prophylaxis was continued for 35 days after surgery, Primary efficacy outcome: Composite of All DVT, PE, or death from any cause during the treatment period.
  49. 49. APIXABAN: ADVANCE-3 (THR) Apixaban versus Enoxaparin In High-Risk Orthopedic Patients Apixaban Enoxaparin Relative (2.5 mg bid) (40 mg qd) Risk Primary Endpoint 1.4% (n=27) 3.9% (n=74) 0.36, P<0.001 Symptomatic deep- <0.1% (n=1) 0.2% (n=5) vein thrombosis All Bleeding 4.8% (n=129) 5.0% (n=134) (Major and Minor) Major Bleeding 0.8% 0.7% (95% CI: 0.5 to 1.3) (95% CI: 0.4 to 1.1)Treatment was for 35 daysThe primary Endpoint: Composite of asymptomatic or symptomatic DVT, PE,or death from any cause during the treatment period.Lassen et al, NEJM, 363;26, 2010.
  50. 50. ARISTOTLE: Phase III trial or Apixaban vs Warfarin in Atrial FibrillationApixaban 5 mg twice dailyWarfarin (target INR 2.0 to 3.0)Atrial fibrillation and at least one additional risk factor for stroke. (n=18,201 patients).Primary outcome: Ischemic or hemorrhagic stroke or systemic embolism.Designed to test for noninferiority. – Granger et al. N Engl J Med 2011;365:981- 92.
  51. 51. ARISTOTLE: Phase III trial or Apixaban vs Warfarin in Atrial Fibrillation End point Apixaban Warfarin HR (95% CI) p (%/year) (%/year) Stroke or 1.27 1.60 0.79 (0.66-0.95) 0.01 systemic embolism* Major bleeding 2.13 3.09 0.69 (0.60-0.80) <0.001 All-cause 3.52 3.94 0.89 (0.80-0.99) 0.047 mortality Hemorrhagic 0.24 0.47 0.51 (0.35-0.75) <0.001 stroke Ischemic/uncer 0.97 1.05 0.92 (0.74-1.13) 0.42 tain stroke Apixaban 5 mg twice daily Granger et al. N Engl J Med 2011;365:981-92.
  52. 52. APPRAISE-1: Apixaban, in combination with antiplatelet therapy after acute coronary syndromes• Alexander J et al. N Engl J Med. 2011 Aug 25;365(8):699- 708• Apixaban tested at 2.5 mg bid and 10 mg qd.• Acute coronary syndrome (myocardial infarction, with or without ST-segment elevation, or unstable angina) within the previous 7 days• Apixaban or placebo in addition to mono or dual antiplatelet therapy.
  53. 53. Kaplan–Meier Curves for the Primary Efficacy Outcome.Alexander JH et al. N Engl J Med 2011;365:699-708.
  54. 54. Kaplan–Meier Curves for the Primary Safety Outcome.Alexander JH et al. N Engl J Med 2011;365:699-708.
  55. 55. Monitoring of Dabigatran: Drug added to normal plasma EC PT T TT aPT T• Peak plasma level is ~180 ng/ml. – van Ryn et al. Thromb Haemost 2010; 103: 1116–1127
  56. 56. Barriers To Broader Use Of New Oral Anticoagulants:• “Fixed Dose,” but it is not yet known which dose we should be using. – And like LMWH, it is highly unlikely that doses will not need to be titrated in select high-risk populations, such as cancer, moderate liver/renal dysfunction, thrombocytopenia, chemotherapy, etc.• No established assay for plasma levels. – Assay will be essential for cancer patients, who are at risk for organ dysfunction, thrombocytopenia, as well as drug interactions.• Limited data on drug interactions.• Limited knowledge about dosing in mild-moderate organ dysfunction, obesity, thrombocytopenia, etc.• No reversal agent!
  57. 57. New Agents For DVT Treatment In Cancer? Both Dabigatran and Rivaroxaban VTE Treatment studies showed non-inferiority to warfarin. In cancer, warfarin is known not to be optimal (Lee et al. CLOT Study, NEJM, 2003). Need to demonstrate non-inferiority to LMWH in cancer population. Studies included only 4-6% cancer patients and no subgroup analysis was provided. Patients with liver disease, or renal insufficiency, or life-expectancy <6 months were excluded. NO MONITORING, NO REVERSAL AGENTS!
  58. 58. Correspondences on major bleeding in community setting/trauma on Dabigatran• “Lack of a readily available method to determine the degree of anticoagulation”• “Currently, the only reversal option for dabigatran is emergency dialysis (as suggested in a single line in the package insert)”.• “Recently, we have cared for several injured patients receiving dabigatran, all of whom had poor outcomes. Although the results of conventional coagulation studies were normal, the values obtained on rapid thromboelastography (rTEG) at the time of admission were grossly abnormal.”• Cotton BA et al., N Engl J Med 2011; 365:2039-2040 (Letter)
  59. 59. • Reduction of Risk of Stroke and Systemic Embolism in Nonvalvular Atrial Fibrillation: – XARELTO® is indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. – There are limited data on the relative effectiveness of XARELTO® and warfarin in reducing the risk of stroke and systemic embolism when warfarin therapy is well controlled.• Prophylaxis of Deep Vein Thrombosis: – XARELTO® is indicated for the prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE) in patients undergoing knee or hip replacement surgery.
  60. 60. RECORD4: Rivaroxaban For Thrombosis Prophylaxis in THR Patients 12 Total VTE Enoxaparin 30 mg q12h, 10-14 days 10.1% 10 Rivaroxaban 10 mg qd 10-14 days Incidence (%) 8 6.9% Efficacy: Non-inferiority of rivaroxaban 6 4 Major VTE Symptomatic Major 2.0% VTE bleeding 2 1.2% 1.2% 0.7% 0.7% 0.3% 0 RRR 31% p=0.124 p=0.187 p=0.124 p=0.012Redrawn from Turpie AG et al. Lancet 373, 1673-80, 2009.

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