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TIMI

A nti-Xa T herapy to L ower cardiovascular events in addition to A spirin with or without thienopyridine therapy in S ubjects with A cute C oronary S yndrome – Thrombolysis in Myocardial Infarction 46 Trial .

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TIMI

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  1. Anti-Xa Therapy to Lower cardiovascular events in addition to Aspirin with or without thienopyridine therapy in Subjects with Acute Coronary Syndrome – Thrombolysis in Myocardial Infarction 46 Trial C. Michael Gibson, Jessica L. Mega, Christopher J. Hammett, VasilHricak, PascualBordes, Adam Witkowski, Valentin Markov, Paul Burton, and Eugene Braunwald for the TIMI 46 Study Group ATLAS TIMI 46 Funded by a Research Grant from Johnson and Johnson and Bayer to Brigham & Women’s Hospital. Dr. Gibson has received honoraria & consulting fees from J&J and Bayer

  2. ATLAS TIMI RIVAROXABAN 46 Coagulation Cascade TF (Tissue Factor) XIa XI IX IXa VIIa + TF VII Extrinsic Pathway Intrinsic Pathway VIIIa X Xa Va IIa (Thrombin) II Rivaroxaban is a potent and selective oral direct factor Xa inhibitor which blocks initiation of the final common coagulation pathway Fibrinogen Fibrin Gibson CM, AHA 2008

  3. ATLAS TIMI GOALS of ATLAS ACS TIMI 46 46 Conduct a robust phase II dose ranging trial Primary Goal - Safety: • To identify tolerable doses of rivaroxaban in the treatment of ACS for evaluation in a large Phase III trial • Secondary Goal - Efficacy: • To explore efficacy of rivaroxaban at tolerable doses Gibson CM, AHA 2008

  4. ATLAS TIMI STUDY DESIGN 46 Recent ACS Patients Stabilized 1-7 Days Post-Index Event Aspirin 75-100 mg MD Decision to Treat with Clopidogrel NO YES N = 3,491 STRATUM 1 ASA Alone N=761 STRATUM 2 ASA + Clop. N=2,730 RIVA BID N=911 2.5 mg (76) 5 mg (430) 7.5 mg (178) 10 mg (227) PLACEBO N=253 5 mg (77) 10 mg (98) 20 mg (78) RIVA BID N=254 2.5 mg (77) 5 mg (97) 10 mg (80) RIVA QD N=254 5 mg (77) 10 mg (99) 20 mg (78) RIVA QD N=912 5 mg (78) 10 mg (430) 15 mg (178) 20 mg (226) PLACEBO N=907 5 mg (74) 10 mg (428) 15 mg (178) 20 mg (227) Treat for 6 Months Gibson CM, AHA 2008

  5. ATLAS TIMI SAFETY EVALUATION: EXPANDED TIMI BLEEDING CLASSIFICATION 46 Clinically Significant Bleeding - Any of the following: TIMI Major – Intracranial bleeding or clinically overt bleeding associated with a drop in Hgb of > 5g/dl or absolute drop in Hct of > 15% TIMI Minor - Clinically overt bleeding (including bleeding evident on imaging studies) associated with a fall in Hgb of > 3 gm/dL but < 5 gm/dL from baseline Bleeding Requiring Medical Attention – Bleeding requiring either medical attention, medical treatment, surgical treatment that does not meet the above criteria (e.g. a nosebleed) * A transfusion is counted as 1 g/dl or 3% Hct Gibson CM, AHA 2008

  6. ATLAS TIMI EFFICACY EVALUATION 46 Primary Efficacy Endpoint: • Death • MI • Stroke • Severe Recurrent Ischemia Requiring Revascularization • Secondary Efficacy Endpoint: • Death • MI • Stroke Gibson CM, AHA 2008

  7. KEY ENROLLMENT CRITERIA ATLAS TIMI 46 Inclusion Criteria • ACS sx > 10 min at rest within 7 days of randomization • STEMI or NSTEMI / UA with at least 1 of: • Elevated cardiac enzyme marker (CK-MB or Tn I or Tn T) •  1 mm ST-segment deviation • TIMI risk score 3 Exclusion Criteria • Tx with warfarin • GI bleeding within 6 mos. • Increased bleeding risk • H/o hemorrhagic stroke • Ischemic stroke or TIA within 30 days • Abciximabtx within 8 hrs, Eptifibatide or Tirofiban within 2 hrs ACS=Acute Coronary Syndrome; NSTEMI=Non-ST-Elevation Myocardial Infarction; STEMI=ST-Elevation Myocardial Infarction; TIMI=Thrombolysis In Myocardial Infarction; UA=Unstable Angina Gibson CM, AHA 2008

  8. ATLAS TIMI NATIONAL LEAD INVESTIGATORS 46 27 Countries 297 Sites Gibson CM, AHA 2008

  9. ATLAS BASELINE CHARACTERISTICS TIMI 46 Gibson CM, AHA 2008

  10. PRIMARY SAFETY ENDPOINT:CLINICALLY SIGNIFICANT BLEEDING ATLAS TIMI 46 (= TIMI Major, TIMI Minor, Bleed Req. Med. Attn.) HR 5.1 15.3% 15 Total Daily Dose: Rivaroxaban 20 mg ---- Rivaroxaban 15 mg ---- Rivaroxaban 10 mg ---- Rivaroxaban 5 mg ---- Placebo --- (3.4-7.4) 3.6 12.7% (2.3-5.6) 3.4 10.9% 10 (2.3-4.9) Clinically Significant Bleeding (%) 6.1% 2.2 5 (1.25-3.91) 3.3% *p<0.01 for placebo Vs Riva 5mg. p<0.001 for Riva 10,15,20mg vs placebo 0 180 90 120 150 60 0 30 Days After Start of Treatment Kaplan-Meier estimates for cumulative events, HR(CI), for bleeding rates during the 180 day period ; HR=Hazard Ratio; CI=Confidence Interval Gibson CM, AHA 2008

  11. SAFETY ENDPOINTS:TIMI Major, TIMI Minor and Bleeding Req. Med. Attn. P trend<0.001 Rate (%) 10 5 20 5 Plac Plac 20 5 20 Plac 10 10 Med Attention TIMI Major TIMI Minor P trend<0.0001 Rate (%) 10 Plac Plac Plac 5 15 20 10 5 20 10 15 5 15 20 TIMI Major TIMI Minor Med Attention Raw Event rates for TIMI Major & TIMI Minor in ASA Alone & ASA+CLOP arm. Raw event rates for Med Attention in ASA alone. Kaplan-Meier estimate bleeding rate for medical attention in ASA+CLOP arm during 180 day period. P trend=p value for dose response over actual dose values. Gibson CM, AHA 2008

  12. SAFETY EVALUATION: LIVER FUNCTION TEST ABNORMALITIESFirst Elevation of ALT (SGPT) to > 3 X ULN ATLAS TIMI 46 5 All Placebo (n = 1133) 4.5% 4 3.7% 3 All Rivaroxaban (n = 2270) HR 0.83 (0.58-1.18)p = NS First Elevation of ALT (SGOT) to > 3 X ULN (%) 2 1 Three cases of ALT>3X ULN & Total Bili >2X ULN, all on placebo 0 180 90 120 150 60 0 30 Days After Start of Treatment Kaplan-Meier estimates for cumulative events ,HR(CI), for rates of liver function test abnormalities during the 180 day period;HR=Hazard Ratio; CI=Confidence Interval; SGPT = Serum glutamate pyruvatetransaminase; ALT = Alaninetransaminase; Bili=Bilirubin; ULN= Upper Limit of Normal; Gibson CM, AHA 2008

  13. PRIMARY EFFICACY ENDPOINT: Death / MI / Stroke / Severe Ischemia Req. Revascularization ATLAS TIMI 46 8 All Placebo (n = 1160) 7.0% 6 5.6% 4 Death / MI / Stroke / Severe Ischemia Req. Revasc. (%) HR 0.79 (0.60-1.05)p = 0.10 All Rivaroxaban (n = 2331) 2 0 180 90 120 150 60 0 30 Days After Randomization Cumulative Kaplan-Meier estimates of HR and the rates of key study end points during the 180 day period; Death=All Cause Death ; HR=Hazard Ratio; MI=Myocardial Infarction; Gibson CM, AHA 2008

  14. SECONDARY EFFICACY ENDPOINT: Incidence of Death / MI / Stroke ATLAS TIMI 46 6 All Placebo (n = 1160) 5.5% P = 0.028 4 3.9% Death / MI / Stroke (%) HR 0.69 (0.50-0.96) P=0.028 2 All Rivaroxaban (n = 2331) ARR = 1.6% NNT = 63 0 180 0 90 120 150 60 30 Days After Randomization Kaplan-Meier estimates for cumulative events ,HR(CI), for rates of key study end points during the 180 day period; Death=All Cause Death; HR=Hazard Ratio; CI=Confidence Interval; MI=Myocardial Infarction; NNT=Number Needed to Treat per 6 months to prevent 1 event; ARR=Absolute Risk Reduction Gibson CM, AHA 2008

  15. SECONDARY EFFICACY ENDPOINT: Incidence of Death / MI / Stroke ATLAS TIMI 46 Stratum 2: ASA + Clop. Stratum 1: ASA Alone HR 1.24 4.7 11.9 P trend = 0.01 P trend = 0.72 3.8 HR 0.67 HR 0.79 HR 0.70 HR O.71 HR 0.58 8.0 3.0 Death / MI / Stroke (%) * Death / MI / Stroke (%) 7.0 2.7 2.7 HR 0.37 4.7 n=453 n=907 n=154 n=860 n=356 n=158 n=253 n=154 n=196 TDD * Kaplan-Meier estimates for cumulative events, HR, for rates of key study end points during the 180 day period; P trend=p value for dose response over actual dose values Death=All Cause Death; HR=Hazard Ratio; MI=Myocardial Infarction. Note change in axis right hand panel. Gibson CM, AHA 2008

  16. ATLAS TIMI SUMMARY- SAFETY 46 • There was increased bleeding associated with higher doses of rivaroxaban. • Most bleeding was bleeding requiring medical attention, rather than TIMI major or TIMI minor bleeding • No evidence of drug induced liver injury Gibson CM, AHA 2008

  17. ATLAS TIMI SUMMARY-EFFICACY 46 1o Endpoint: 21% RRR (HR 0.79, p=0.10) in death, MI, stroke, or severe recurrent ischemia requiring revascularization 2o Endpoint: 31% RRR in the risk of death, MI, or stroke (HR 0.69, p=0.028) Gibson CM, AHA 2008

  18. ATLAS TIMI SELECTION OF DOSES FOR PHASE III 46 Based upon: • Efficacy at lower doses of rivaroxaban • Graded increase in bleeding at higher doses of rivaroxaban • A trend for BID doses of rivaroxaban to be safer and more efficacious than QD dosing of rivaroxaban in ACS • Two low doses, 2.5 mg BID and 5 mg BID, have been selected for the Phase III trial Gibson CM, AHA 2008

  19. ATLAS 1 Outcomes in Doses to be Taken Forward in Phase 3 Trial ATLAS TIMI 46 Stratum 1: ASA Alone Stratum 2: ASA + Clop. 5% 15% Placebo Placebo Riva 2.5 & 5.0 mg BID Riva 2.5 & 5.0 mg BID 11.9% 4% 12% 3.8% Death, MI, Stroke HR=0.54 (0.27-1.08) Death, MI, Stroke HR=0.55 (0.27-1.11) 3% 9% P=0.08 P=0.09 6.6% 2.0% 6% 2% 1.2% TIMI Major Bleed 3% 1% TIMI Major Bleed 1.2% p=0.03 p=0.17 0.2% 0% 0% 0.0% 180 90 180 90 0 0 * If fewer than 5 events were present in a cell, raw event rates are reported and a Fisher’s exact test was used, otherwise Kaplan-Meier(KM) estimates and a Hazard Ratio(HR) with confidene interval are provided for 180 day period. Raw event rates were reported for TIMI Major Bleed . KM estimates of HR and rates of secondary efficacy endpoints are provided. Death=All Cause Death; MI=Myocardial Infarction Note change in right hand panel. Gibson CM, AHA 2008

  20. PHASE III DESIGN ATLAS 2 TIMI Recent ACS Patients (Event driven trial: 13,500 to16,000 pts) Stabilized 1-7 Days Post-Index Event 51 Stratified by Thienopyridine use PLACEBO RIVAROXABAN 2.5 mg BID RIVAROXABAN 5.0 mg BID Study is event driven---expected duration is 33 months PRIMARY EFFICACY ENDPOINT: CV Death, MI, Stroke Gibson CM, AHA 2008

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