A nti nti- -Xa Xa T herapy to herapy to L ower ower Cardiovascular Events in Cardiovascular Events in A ddition to Standard Therapy in ddition to Standard Therapy in py py S ubjects with ubjects with A cute cute C oronary oronary S yndrome yndrome - - Thrombolysis Thrombolysis in in Myocardial Infarction 51 Trial (ATLAS ACS 2 - Myocardial Infarction 51 Trial (ATLAS ACS 2 - TIMI 51): TIMI 51): A Randomized Double A Randomized Double Blind Placebo Controlled Study to Evaluate the Efficacy and Safety of A Randomized, Double A Randomized, Double-Blind, Placebo Controlled Study to Evaluate the Efficacy and Safety of Blind Placebo Controlled Study to Evaluate the Efficacy and Safety of Blind, Placebo Controlled Study to Evaluate the Efficacy and Safety of Rivaroxaban in Subjects with Acute Coronary Syndrome Rivaroxaban in Subjects with Acute Coronary Syndrome C. Michael Gibson, MS, MD C. Michael Gibson, MS, MD on behalf of the ATLAS ACS 2 TIMI 51 Investigators on behalf of the ATLAS ACS 2 TIMI 51 Investigators Funded by a research grant from Johnson and Johnson and Bayer to Brigham & Women’s 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. Hospital. Dr. Gibson has received honoraria & consulting fees from J&J and Bayer.
BACKGROUND BACKGROUND THROMBUS ATLAS ACS-TIMI 46 N =3,491 , Placebo 4 6 HR 0.69 5.5% (95% CI, 0.50 - 0.96) P = 0.03 0 03 3 roke (%) ding (%) 4 MI Major Bleed eath, MI, or str 3.9% 2 1.8 1.8 Rivaroxaban 1.5 (combined) 2 TIM De 1 0.7 0.1 0 0 0 Placebo 5 mg 90 120 150 180 10 mg 15 mg 20 mg 0 30 60 Days after randomization Rivaroxaban Lancet 2009;374(9683):29-38.
TRIAL ORGANIZATION TRIAL ORGANIZATION Trial Leadership: TIMI Study Group Chairman: Eugene Braunwald, Principal Investigator: C. Michael Gibson I Investigator: Jessica Mega, Statisticians: Sabina Murphy, Charles Contant ti t J i M St ti ti i S bi M h Ch l C t t Executive Committee Jean-Pierre Bassand, Deepak Bhatt, Christoph Bode, Keith Fox, Marc Cohen, Shinya Goto, David Schneider, Freek Verheugt Sponsors: Johnson & Johnson and Bayer Health Care J&J: Paul Burton, Peter DiBattiste, Alexei N. Plotnikov, Linda DeCaprio, Xiang Sun Bayer: Nancy Cook Bruns, Scott Berkowitz, Frank Misselwitz Data Safety Monitoring Board Douglas Weaver (Chair) , Christian Hamm, Judith S. Hochman, Jeffrey Anderson, g ( ) , , , y , Hiroyuki Daida, Statistician: Allan Skene
Recent ACS: STEMI, NSTEMI, UA Recent ACS: STEMI, NSTEMI, UA Stabilized 1 Stabilized 1- -7 Days Post 7 Days Post- -Index Event Index Event Exclusions: increased bleeding risk, warfarin use, ICH, Exclusions: increased bleeding risk, warfarin use, ICH, prior stroke if on ASA + thienopyridine prior stroke if on ASA + thienopyridine ASA 75 to 100 mg/day Stratified by Thienopyridine Use at MD Discretion Rivaroxaban Rivaroxaban Placebo 5.0 mg BID 2.5 mg BID n=5 176 n=5,176 n=5,176 n=5,174 PRIMARY ENDPOINTS: PRIMARY ENDPOINTS: EFFICACY: CV Death, MI, Stroke EFFICACY: CV Death, MI, Stroke (Ischemic, Hemorrhagic, or Uncertain Origin) (Ischemic, Hemorrhagic, or Uncertain Origin) SAFETY: TIMI major bleeding not associated with CABG SAFETY: TIMI major bleeding not associated with CABG SAFETY: TIMI major bleeding not associated with CABG SAFETY: TIMI major bleeding not associated with CABG Event driven trial with 1,002 primary efficacy events
NATIONAL LEAD INVESTIGATORS RUSSIA (1756) RUSSIA (1756) ARGENTINA (404) ARGENTINA (404) CHILE (213) CHILE (213) TURKEY (119) TURKEY (119) M. Ruda M. Ruda M. Amuchastegui M. Amuchastegui R. Corbalan R. Corbalan Z. Yigit Z. Yigit INDIA (1469) INDIA (1469) JAPAN (400) JAPAN (400) FRANCE (213) FRANCE (213) SERBIA (117) SERBIA (117) V. Chopra V. Chopra V Chopra V Chopra S Goto S Goto S. Goto S. Goto G. Montalescot G Montalescot G. Montalescot G Montalescot Z Z Z. Vasiljevic Z. Vasiljevic Vasiljevic Vasiljevic POLAND (1062) POLAND (1062) NETHERLANDS (377) NETHERLANDS (377) CANADA (190) CANADA (190) PORTUGAL (115) PORTUGAL (115) M. Tendera M. Tendera J. Morais J. Morais T. Oude Ophuis T. Oude Ophuis M. Le May M. Le May M. van Hessen M. van Hessen P. Theroux P. Theroux CHINA (901) CHINA (901) ISRAEL (353) ISRAEL (353) SLOVAKIA (178) SLOVAKIA (178) LATVIA (100) LATVIA (100) R G R G R. Gao R. Gao S M i S M i S. Meisel S. Meisel l l T. Duris T. Duris T D T D i i A E A E A. Erglis A. Erglis li li BULGARIA (792) BULGARIA (792) GERMANY (332) GERMANY (332) LITHUANIA (177) LITHUANIA (177) DENMARK (99) DENMARK (99) E. Giannitsis E. Giannitsis N. Gotcheva N. Gotcheva H. Katus H. Katus B. Petrauskiene B. Petrauskiene S. Eggert Jensen S. Eggert Jensen UNITED STATES (684) UNITED STATES (684) ROMANIA (304) ROMANIA (304) TUNISIA (177) TUNISIA (177) NEW ZEALAND (98) NEW ZEALAND (98) C.M. Gibson C.M. Gibson D. Vinereanu D. Vinereanu H. Haouala H. Haouala H. White H. White UKRAINE (629) UKRAINE (629) COLOMBIA (269) COLOMBIA (269) BELGIUM (173) BELGIUM (173) MALAYSIA (97) MALAYSIA (97) A. Parkhomenko A. Parkhomenko R. Botero R. Botero F. Van de Werf F. Van de Werf K. Hian Sim K. Hian Sim BRAZIL (529) BRAZIL (529) MEXICO (254) MEXICO (254) EGYPT (159) EGYPT (159) GREECE (69) GREECE (69) J. Nicolau J. Nicolau G. Llamas G. Llamas A. Mowafy A. Mowafy KOREA, REPUBLIC OF KOREA, REPUBLIC OF AUSTRALIA (510) AUSTRALIA (510) UNITED KINGDOM (254) UNITED KINGDOM (254) (150) (150) CROATIA (62) CROATIA (62) P. Aylward P. Aylward I. Squire I. Squire K. Seung K. Seung M. Bergovec M. Bergovec CZECH REPUBLIC (485) CZECH REPUBLIC (485) ITALY (235) ITALY (235) SWEDEN (144) SWEDEN (144) MOROCCO (57) MOROCCO (57) P. Widimsky P. Widimsky y D. Ardissino D. Ardissino M. Dellborg M. Dellborg g HUNGARY (412) HUNGARY (412) SPAIN (230) SPAIN (230) THAILAND (140) THAILAND (140) PHILIPPINES (38) PHILIPPINES (38) R. Kiss R. Kiss A. Betriu A. Betriu P. Sritara P. Sritara 44 Countries 44 Countries 766 Sites 766 Sites
BASELINE CHARACTERISTICS Placebo Rivaroxaban Rivaroxaban 2.5 mg BID 5.0 mg BID Age, mean (SD) 61.5 (± 9.4) 61.8 (± 9.2) 61.9 (± 9.0) SPITAL Sex, male (%) 75.0 74.9 74.2 PRE HO Prior MI, (%) 27.3 26.3 27.1 Diabetes, (%) 31.8 32.3 31.8 STEMI, (%) 50.9 50.3 49.9 NSTEMI, (%) 25.6 25.5 25.8 AL HOSPITA UA, (%) 23.6 24.2 24.3 Revasc at Index, (%) 60.7 60.4 60.4 ASA+Thienopyridine, (%) 93.1 93.3 93.3
STATISTICAL ANALYSIS STATISTICAL ANALYSIS Pre Pre- -specified Primary Efficacy Analysis specified Primary Efficacy Analysis p p y y y y y y Rivaroxaban (2.5 mg BID and 5 mg BID) vs. Placebo If <0.05, then proceed Rivaroxaban Rivaroxaban 2.5 mg BID 5 mg BID vs. vs. Placebo Placebo • The primary method of analysis was a log rank test stratified by thienopyridine p y y g y py use in the mITT population with confirmation in an ITT analysis
PRIMARY EFFICACY ENDPOINT: PRIMARY EFFICACY ENDPOINT: CV CV Death / MI / Stroke Death / MI / Stroke 2 Yr KM Estimate (%) (%) Placebo Placebo 10.7% 10.7% Incidence Incidence 8.9% 8.9% umulative I umulative I HR 0.84 HR 0.84 (0.74 (0.74- -0.96) 0.96) Rivaroxaban Rivaroxaban timated Cu timated Cu (b th d (both doses) (both doses) (b th d ) ) mITT p = 0.008 p = 0.008 0 008 0 008 mITT ITT p = 0.002 p = 0.002 ITT ARR 1.8% ARR 1.8% Est Est NNT = 56 NNT = 56 Months After Randomization Months After Randomization Months After Randomization Months After Randomization No. at Risk N t Ri k 5113 5113 Placebo Placebo 4307 4307 3470 3470 2664 2664 1831 1831 1079 1079 421 421 Rivaroxaban Rivaroxaban 10229 10229 8502 8502 6753 6753 5137 5137 3554 3554 2084 2084 831 831 HR and 95% confidence interval estimates from Cox model stratified by thienopyridine use are provided per mITT approach; Stratified log-rank p-values are provided for both mITT and ITT approaches.
STENT THROMBOSIS ARC Definite / Probable / Possible 2 Y KM E ti 2 Yr KM Estimate t 2.9% 2.9% ce (%) ce (%) Placebo Placebo e Incidenc e Incidenc 2.3% 2.3% umulative umulative HR 0.69 HR 0.69 mated Cu mated Cu (0.51 (0.51- - 0.93) 0.93) Rivaroxaban Rivaroxaban (both doses) (both doses) mITT p = 0.016 p = 0.016 mITT Esti Esti ITT p = 0.008 p = 0.008 ITT ARC Definite/probable: HR=0.65, mITT p=0.017, ITT p=0.012 Months After Randomization Months After Randomization
EFFICACY ENDPOINTS: EFFICACY ENDPOINTS: Low Dose 5.0 mg BID Low Dose 5.0 mg BID g CV Death / MI / Stroke Cardiovascular Death Placebo 10.7% HR 0.85 HR 0.94 Placebo ence (%) 4.1% 10 mITT mITT 4.0% 8.8% p=0.028 p=0.63 ulative Incide ITT ITT p=0.010 p=0.57 mated Cumu 5 Rivaroxaban Rivaroxaban 5 mg BID 5 mg BID g Estim NNT=53 0 24 24 24 24 0 0 0 0 1 Months Months
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