C. Michael Gibson, MS, MD · 2019. 11. 18. · C.M. GibsonC.M. Gibson D. Vinerean D. Vinereanu H....
Transcript of C. Michael Gibson, MS, MD · 2019. 11. 18. · C.M. GibsonC.M. Gibson D. Vinerean D. Vinereanu H....
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AAntinti--XaXa TTherapy to herapy to LLower ower Cardiovascular Events in Cardiovascular Events in AAddition to Standard Therapy in ddition to Standard Therapy in pypySSubjects with ubjects with AAcute cute CCoronary oronary SSyndrome yndrome -- ThrombolysisThrombolysis in in
Myocardial Infarction 51 Trial (ATLAS ACS 2 Myocardial Infarction 51 Trial (ATLAS ACS 2 -- TIMI 51): TIMI 51): A Randomized DoubleA Randomized Double Blind Placebo Controlled Study to Evaluate the Efficacy and Safety ofBlind Placebo Controlled Study to Evaluate the Efficacy and Safety ofA Randomized, DoubleA Randomized, Double--Blind, Placebo Controlled Study to Evaluate the Efficacy and Safety of Blind, Placebo Controlled Study to Evaluate the Efficacy and Safety of
RivaroxabanRivaroxaban in Subjects with Acute Coronary Syndromein Subjects with Acute Coronary Syndrome
C. Michael Gibson, MS, MDC. Michael Gibson, MS, MDon behalf of the ATLAS ACS 2 TIMI 51 Investigatorson 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.
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BACKGROUNDBACKGROUNDTHROMBUS
ATLAS ACS-TIMI 46N =3,491
6 HR 0.69 (95% CI, 0.50 - 0.96)
0 03
5.5%Placebo4
,
4
roke
(%)
P = 0.03
3
ding
(%)
2
3.9%Rivaroxaban (combined)
eath
, MI,
or s
tr
1.51.8 1.82
MI M
ajor
Ble
ed
0
De
0.1
0.71
TIM
Days after randomization300
0
60 90 120 150 1800
Lancet 2009;374(9683):29-38.
Placebo 5 mg 10 mg 15 mg 20 mg
Rivaroxaban
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TRIAL ORGANIZATIONTRIAL ORGANIZATIONTrial Leadership: TIMI Study Group
Chairman: Eugene Braunwald, Principal Investigator: C. Michael GibsonI ti t J i M St ti ti i S bi M h Ch l C t tInvestigator: Jessica Mega, Statisticians: Sabina Murphy, Charles Contant
Executive CommitteeJean-Pierre Bassand, Deepak Bhatt, Christoph Bode, Keith Fox, Marc Cohen, Shinya Goto, David Schneider, Freek Verheugt
Sponsors: Johnson & Johnson and Bayer Health CareJ&J: Paul Burton, Peter DiBattiste, Alexei N. Plotnikov, Linda DeCaprio, Xiang Sun Bayer: Nancy Cook Bruns, Scott Berkowitz, Frank Misselwitz
Data Safety Monitoring BoardDouglas Weaver (Chair) , Christian Hamm, Judith S. Hochman, Jeffrey Anderson, g ( ) , , , y ,Hiroyuki Daida, Statistician: Allan Skene
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Recent ACS: STEMI, NSTEMI, UARecent ACS: STEMI, NSTEMI, UAStabilized 1Stabilized 1--7 Days Post7 Days Post--Index EventIndex 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
Stratified by Thienopyridine Use at MD Discretion
ASA 75 to 100 mg/day
Rivaroxaban5.0 mg BIDPlacebo
n=5 176
Rivaroxaban 2.5 mg BID
n=5,176n=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 CABGSAFETY: TIMI major bleeding not associated with CABGSAFETY: TIMI major bleeding not associated with CABGSAFETY: TIMI major bleeding not associated with CABG
Event driven trial with 1,002 primary efficacy events
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NATIONAL LEAD INVESTIGATORSRUSSIA (1756)RUSSIA (1756) ARGENTINA (404)ARGENTINA (404) CHILE (213)CHILE (213) TURKEY (119)TURKEY (119)
M. Ruda M. Ruda M. Amuchastegui M. Amuchastegui R. CorbalanR. Corbalan Z. YigitZ. YigitINDIA (1469)INDIA (1469) JAPAN (400)JAPAN (400) FRANCE (213)FRANCE (213) SERBIA (117)SERBIA (117)
V ChopraV Chopra S GotoS Goto G MontalescotG Montalescot Z VasiljevicZ VasiljevicV. ChopraV. Chopra S. GotoS. Goto G. Montalescot G. Montalescot Z. VasiljevicZ. VasiljevicPOLAND (1062)POLAND (1062) NETHERLANDS (377)NETHERLANDS (377) CANADA (190)CANADA (190) PORTUGAL (115)PORTUGAL (115)
M. Tendera M. Tendera T. Oude Ophuis T. Oude Ophuis M. van HessenM. van Hessen
M. Le May M. Le May P. Theroux P. Theroux
J. MoraisJ. Morais
CHINA (901)CHINA (901) ISRAEL (353)ISRAEL (353) SLOVAKIA (178)SLOVAKIA (178) LATVIA (100)LATVIA (100)R GR G S M i lS M i l T D iT D i A E liA E liR. Gao R. Gao S. Meisel S. Meisel T. Duris T. Duris A. ErglisA. Erglis
BULGARIA (792)BULGARIA (792) GERMANY (332)GERMANY (332) LITHUANIA (177)LITHUANIA (177) DENMARK (99)DENMARK (99)
N. Gotcheva N. Gotcheva E. GiannitsisE. Giannitsis
H. Katus H. Katus B. PetrauskieneB. Petrauskiene S. Eggert JensenS. Eggert JensenUNITED STATES (684)UNITED STATES (684) ROMANIA (304)ROMANIA (304) TUNISIA (177)TUNISIA (177) NEW ZEALAND (98)NEW ZEALAND (98)
C.M. GibsonC.M. Gibson D. VinereanuD. Vinereanu H. HaoualaH. Haouala H. WhiteH. WhiteUKRAINE (629)UKRAINE (629) COLOMBIA (269)COLOMBIA (269) BELGIUM (173)BELGIUM (173) MALAYSIA (97)MALAYSIA (97)A. ParkhomenkoA. Parkhomenko R. BoteroR. Botero F. Van de WerfF. Van de Werf K. Hian SimK. Hian Sim
BRAZIL (529)BRAZIL (529) MEXICO (254)MEXICO (254) EGYPT (159)EGYPT (159) GREECE (69)GREECE (69)J. NicolauJ. Nicolau G. LlamasG. Llamas A. MowafyA. Mowafy
AUSTRALIA (510)AUSTRALIA (510) UNITED KINGDOM (254)UNITED KINGDOM (254)KOREA, REPUBLIC OF KOREA, REPUBLIC OF
(150)(150) CROATIA (62)CROATIA (62)P. Aylward P. Aylward I. SquireI. Squire K. SeungK. Seung M. BergovecM. Bergovec
CZECH REPUBLIC (485)CZECH REPUBLIC (485) ITALY (235)ITALY (235) SWEDEN (144)SWEDEN (144) MOROCCO (57)MOROCCO (57)P. Widimsky P. Widimsky D. ArdissinoD. Ardissino M. DellborgM. Dellborg
44 Countries44 Countries 766 Sites766 Sites
yy ggHUNGARY (412)HUNGARY (412) SPAIN (230)SPAIN (230) THAILAND (140)THAILAND (140) PHILIPPINES (38)PHILIPPINES (38)
R. Kiss R. Kiss A. BetriuA. Betriu P. SritaraP. Sritara
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BASELINE CHARACTERISTICSPlacebo Rivaroxaban
2.5 mg BIDRivaroxaban5.0 mg BID
Age, mean (SD) 61.5 (± 9.4) 61.8 (± 9.2) 61.9 (± 9.0)
Sex, male (%) 75.0 74.9 74.2
SPIT
AL
Prior MI, (%) 27.3 26.3 27.1
Diabetes, (%) 31.8 32.3 31.8PRE
HO
STEMI, (%) 50.9 50.3 49.9
NSTEMI, (%) 25.6 25.5 25.8
AL
UA, (%) 23.6 24.2 24.3
Revasc at Index, (%) 60.7 60.4 60.4HOSP
ITA
ASA+Thienopyridine, (%) 93.1 93.3 93.3
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STATISTICAL ANALYSISSTATISTICAL ANALYSISPrePre--specified Primary Efficacy Analysisspecified Primary Efficacy Analysisp y y yp y y y
Rivaroxaban(2.5 mg BID and 5 mg BID)
vs.Placebo
If
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PRIMARY EFFICACY ENDPOINT: PRIMARY EFFICACY ENDPOINT: CVCV Death / MI / StrokeDeath / MI / Stroke
10.7%10.7%(%)
(%) PlaceboPlacebo
2 Yr KM Estimate
8.9%8.9%
Inci
denc
e
Inci
denc
e
RivaroxabanRivaroxaban(b th d )(b th d )
HR 0.84 HR 0.84 (0.74(0.74--0.96)0.96)
0 0080 008um
ulat
ive
Ium
ulat
ive
I
(both doses)(both doses) mITT mITT p = 0.008p = 0.008ITT ITT p = 0.002p = 0.002
ARR 1.8%ARR 1.8%timat
ed C
utim
ated
Cu
Months After RandomizationMonths After Randomization
NNT = 56NNT = 56Est
Est
N t Ri k Months After RandomizationMonths After Randomization51135113 43074307 34703470 26642664 18311831 10791079 4214211022910229 85028502 67536753 51375137 35543554 20842084 831831
PlaceboPlaceboRivaroxabanRivaroxaban
No. at Risk
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.
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STENT THROMBOSIS ARC Definite / Probable / Possible
2 Y KM E ti t
2.9%2.9%
ce (%
)ce
(%)
PlaceboPlacebo
2 Yr KM Estimate
2.3%2.3%
e In
cide
nce
Inci
denc
HR 0.69HR 0.69umul
ativ
eum
ulat
ive
RivaroxabanRivaroxaban(both doses)(both doses)
(0.51(0.51-- 0.93)0.93)
mITTmITT p = 0.016p = 0.016mat
ed C
um
ated
Cu
ITT ITT p = 0.008p = 0.008Esti
Esti
ARC Definite/probable: HR=0.65, mITT p=0.017, ITT p=0.012
Months After RandomizationMonths After Randomization
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EFFICACY ENDPOINTS:EFFICACY ENDPOINTS:Low Dose 5.0 mg BIDLow Dose 5.0 mg BIDgg
Cardiovascular DeathCV Death / MI / Stroke
10
ence
(%)
Placebo
8.8%
10.7% HR 0.94
mITTp=0.63 4.0%
4.1%PlaceboHR 0.85
mITTp=0.028
ulat
ive
Inci
de ITTp=0.57
ITTp=0.010
5
mat
ed C
umu
Rivaroxaban5 mg BID
Rivaroxaban5 mg BID
0
Estim
0 24 0 24
g
NNT=53
1 Months024
Months0 24
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EFFICACY ENDPOINTS:EFFICACY ENDPOINTS:Very Low Dose 2.5 mg BIDVery Low Dose 2.5 mg BID
All Cause DeathCardiovascular DeathCV Death / MI / Stroke
ce (%
) HR 0.84
mITT
HR 0.66
mITT10.7%Placebo
4.5%4.1%
Placebo HR 0.68
mITT0 002
Placebo12%5% 5%
ativ
e in
cide
n p=0.020ITT
p=0.007
p=0.002ITT
p=0.005
9.1%
2.9%2.7%
p=0.002ITT
p=0.004
Rivaroxaban2 5 mg BIDate
d C
umul
a
Rivaroxaban2 5 mg BID
Rivaroxaban2 5 mg BID
0 24
2.5 mg BID
0 24Months
Estim
a
0 24Months Months
2.5 mg BID2.5 mg BIDNNT = 63NNT = 71NNT = 63
12 12 12Months Months Months
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EFFICACY ENDPOINTS:EFFICACY ENDPOINTS:Very Low Dose 2.5 mg BIDVery Low Dose 2.5 mg BID
P ti t T t d ith ASA Thi idiP ti t T t d ith ASA Thi idi
All Cause DeathCardiovascular DeathCV Death / MI / Stroke
Patients Treated with ASA + Thienopyridine Patients Treated with ASA + Thienopyridine
Placebo
nce
(%)
HR 0.85
mITT p=0.039
HR 0.62
mITTp
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PRIMARY EFFICACY SUBGROUP RESULTSHR (95% CI) Pinteraction
All Rivaroxaban vs. Placebo
ASAASA + thienopyridine 0.86 (0.75 -0.98)
0.340.69 (0.45 -1.05)
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SAFETY ENDPOINTST t t E t N CABG TIMI M j Bl di *
AnalysisPlacebo 2.5 mg
Rivaroxaban5.0 mg
Rivaroxaban
Treatment-Emergent Non CABG TIMI Major Bleeding*
2 Yr KM Estimate 0.6% 1.8%HR 3.46
2.4%HR 4.47
p 3X ULNALT > 3X ULN 1 6% 1 3% 1 4%
Liver Function Test (ALT > 3xULN) ##p 3X ULNALT > 3X ULN 1.6% 1.3%p=NS
1.4%p=NS
There was no excess of either combined ALT > 3x ULN and Total Bilirubin > 2x ULN cases among patients treated with Rivaroxaban, or SAEs.
11--1010 Days After Last Days After Last DoseDose
1.8% 1.4% 2.2%
Post-Treatment CVD / MI / Stroke##
DoseDose p=NS p=NS
*: First occurrence of Non-CABG TIMI major bleeding events occurred between first dose to 2 days post last dose as adjudicated by the CEC across thienopyridine use strata; Two year Kaplan-Meier estimates, HR and 95% confidence interval estimates from Cox model stratified by thienopyridine are provided; Stratified log-rank p-values are provided; #: Raw percentage of subjects with abnormal value measured between first dose to 2 days post last dose among subjects with normal baseline measurement; ##: Raw percentage.
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TREATMENTTREATMENT--EMERGENT EMERGENT FATAL BLEEDS AND ICHFATAL BLEEDS AND ICH
1.2Placebop=NS for Riva vs Placebo p=0.009 for Riva vs Placebo
0 8
1 2.5 mg Rivaroxaban5.0 mg Rivaroxaban
p=NS for Riva 5 vs Placebop=NS for Riva 2.5 vs Placebop=0.044 for Riva 2.5 vs 5
p= 0.005 Riva 5 vs PlaceboP=0.037 for Riva 2.5 vs Placebop=0.44 for Riva 2.5 vs 5
00
0.7
0.6
0.8
p=NS for all
nt (%
)
0.2 0.20 10 1
0.4
0 1
0.4
0.20 2
0.4comparisons
Per
cen
0.10.1 0.1
0
0.2
Fatal ICH Fatal ICH
n=4 n=5 n=8n=9 n=6 n=15 n=5 n=18n=14
Fatal ICH Fatal ICH
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SUMMARYSUMMARY
•• Rivaroxaban reduced the risk of cardiovascular death, Rivaroxaban reduced the risk of cardiovascular death, myocardial infarction, or stroke in patients across themyocardial infarction, or stroke in patients across themyocardial infarction, or stroke in patients across the myocardial infarction, or stroke in patients across the spectrum of ACS.spectrum of ACS.
• Rates of major bleeding and ICH were higher with rivaroxaban; however, there was no excess risk of fatal ICH or fatal bleeding with rivaroxaban compared to placeboor fatal bleeding with rivaroxaban compared to placebo (particularly with 2.5 mg BID).
• One death would be prevented if 56 patients on antiplatelet therapies were treated for two years with rivaroxaban 2.5 mg BID.
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CONCLUSIONCONCLUSION
• Very low dose anticoagulation with rivaroxaban (2 5 mg BID) in addition torivaroxaban (2.5 mg BID), in addition to antiplatelet therapies, represents an effective strategy to reduce cardiovasculareffective strategy to reduce cardiovascular events in patients with a recent ACS.
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The full article is available online at www.nejm.org.