therapy to lower cardiovascular events in additi抗xa因子治疗同时降低心血管事件课件

A Anti-Xa nti-Xa T Therapy to herapy to L Lower cardiovascular events in addition to ower cardiovascular events in addition to A Aspirin with or without thienopyridine therapy in spirin with or without thienopyridine therapy in S Subjects ubjects with with A Acute cute C Coronary oronary S Syndrome Thrombolysis in yndrome Thrombolysis in Myocardial Infarction 46 Trial Myocardial Infarction 46 Trial C. Michael Gibson, Jessica L. Mega, Christopher J. C. Michael Gibson, Jessica L. Mega, Christopher J. Hammett, Vasil Hricak, Pascual Bordes, Adam Hammett, Vasil Hricak, Pascual Bordes, Adam Witkowski, Valentin Markov, Paul Burton, Witkowski, Valentin Markov, Paul Burton, and Eugene Braunwald for the TIMI 46 Study Groupand Eugene Braunwald for the TIMI 46 Study Group Funded by a Research Grant from Johnson and Johnson and Bayer to Brigham NSTEMI=Non-ST-Elevation Myocardial Infarction; STEMI=ST- ACS=Acute Coronary Syndrome; NSTEMI=Non-ST-Elevation Myocardial Infarction; STEMI=ST- Elevation Myocardial Infarction; TIMI=Thrombolysis In Myocardial Infarction; UA=Unstable AnginaElevation Myocardial Infarction; TIMI=Thrombolysis In Myocardial Infarction; UA=Unstable AnginaGibson CM, AHA 2008 27 Countries 27 Countries297 Sites297 Sites NATIONAL LEAD INVESTIGATORSNATIONAL LEAD INVESTIGATORS Poland (502) M. Tendera Slovakia (119) T. Duris France (49) J. Bassand Russia (430) M. Ruda Spain (103) A. Betriu Korea (47) K. Seung United States (401) C.M. Gibson Israel (99) B. Lewis Sweden (47) M. Dellborg Bulgaria (259) N. Gotcheva Canada (91) P. Theroux Brazil (37) J. Nicolau Australia (207) P. Aylward United Kingdom (91) R. Wilcox Hungary (37) E. Ostor Czech Republic (180) P. Widimsky Germany (93) H. Katus Norway (22) D. Atar New Zealand (149) H. White Netherlands (89) F. Verheugt South Africa (18) A. Dalby Ukraine (161) A. Parkhomenko Belgium (77) F. Van de Werf Finland (16) M. Syvanne Italy (138) D. Ardissino Denmark (64) P. Grande China (4) R. Gao Gibson CM, AHA 2008 BASELINE CHARACTERISTICS Stratum 1 (ASA Alone) (N = 761) Stratum 2 (ASA + Clopidogrel) (N = 2730) Age (yr) (Mean SD)60.0 9.256.7 9.5 Diabetes20.6%18.9% Prior MI27.7%19.2% CrCl 3 X ULN (%)First Elevation of ALT (SGOT) to 3 X ULN (%) Kaplan-Meier estimates for cumulative events ,HR(CI), for rates of liver function test abnormalities during the 180 day 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 pyruvate transaminase; ALT = Alanine period;HR=Hazard Ratio; CI=Confidence Interval; SGPT = Serum glutamate pyruvate transaminase; ALT = Alanine transaminase; Bili=Bilirubin; ULN= Upper Limit of Normal;transaminase; Bili=Bilirubin; ULN= Upper Limit of Normal; 0 0 0 0 303060609090120120150150180180 SAFETY EVALUATION: LIVER FUNCTION TEST SAFETY EVALUATION: LIVER FUNCTION TEST ABNORMALITIESABNORMALITIES First Elevation of ALT (SGPT) to 3 X ULNFirst Elevation of ALT (SGPT) to 3 X ULN 5 5 Three cases of ALT3X ULN 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; Death=All Cause Death ; HR=Hazard Ratio; MI=Myocardial Infarction; 0 0 0 0 303060609090120120150150180180 Gibson CM, AHA 2008 Days After RandomizationDays After Randomization ARR = 1.6% ARR = 1.6% NNT = 63 NNT = 63 5.5% 3.9% 2 2 4 4 6 6 Death / MI / Stroke (%)Death / MI / Stroke (%) Kaplan-Meier estimates for cumulative events ,HR(CI), for rates of key study end points during the 180 day period; 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 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 Reductionto Treat per 6 months to prevent 1 event; ARR=Absolute Risk Reduction 0 0 0 0 303060609090120120150150180180 SECONDARY EFFICACY ENDPOINT: SECONDARY EFFICACY ENDPOINT: Incidence of Death / MI / StrokeIncidence of Death / MI / Stroke All RivaroxabanAll Rivaroxaban (n = 2331)(n = 2331) All PlaceboAll Placebo (n = 1160)(n = 1160) HR 0.69 HR 0.69 (0.50-0.96)(0.50-0.96) P=0.028P=0.028 P = 0.028P = 0.028 Gibson CM, AHA 2008 SECONDARY EFFICACY ENDPOINT: SECONDARY EFFICACY ENDPOINT: Incidence of Death / MI / StrokeIncidence of Death / MI / Stroke Death / MI / Stroke (%)Death / MI / Stroke (%) Death / MI / Stroke (%) *Death / MI / Stroke (%) * Stratum 1: ASA AloneStratum 1: ASA AloneStratum 2: ASA + Clop.Stratum 2: ASA + Clop. TDD n=253n=154n=196n=158 n=907n=154n=860n=356n=453 11.9 8.0 7.0 4.7 3.8 2.72.7 4.7 3.0 P trend = 0.01P trend = 0.72 HR 0.67 HR 0.58 HR 0.37 HR 0.70 HR O.71 HR 1.24 HR 0.79 * Kaplan-Meier estimates for cumulative events, HR, for rates of key study end points during the 180 day period; * 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 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. Death=All Cause Death; HR=Hazard Ratio; MI=Myocardial Infarction. Note change in axis right hand panel. Gibson CM, AHA 2008 SUMMARY- SAFETYSUMMARY- SAFETY There was increased bleeding associated with There was increased bleeding associated with higher doses of rivaroxaban.higher doses of rivaroxaban. No evidence of drug induced liver injury Most bleeding was bleeding requiring medical attention, rather than TIMI major or TIMI minor bleeding Gibson CM, AHA 2008 SUMMARY-EFFICACYSUMMARY-EFFICACY 2 2o o Endpoint Endpoint: : 31% RRR in the risk of death, MI, or stroke (HR 0.69, 31% RRR in the risk of death, MI, or stroke (HR 0.69, p=0.028)p=0.028) 1 1o o Endpoint Endpoint: : 21% RRR (HR 0.79, p=0.10) in death, MI, stroke, or 21% RRR (HR 0.79, p=0.10) in death, MI, stroke, or severe recurrent ischemia requiring revascularization severe recurrent ischemia requiring revascularization Gibson CM, AHA 2008 SELECTION OF DOSES FOR PHASE III Based upon: 1. Efficacy at lower doses of rivaroxaban 2. Graded increase in bleeding at higher doses of rivaroxaban 3. 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 ATLAS 1 Outcomes i