View
23
Download
0
Category
Preview:
DESCRIPTION
MULTI centre evaluation of S ingle high-dose bolus T iRofiban versus A bciximab with sirolimus eluting s TE nt or bare metal stent in acute myocardial infarction stud Y. - PowerPoint PPT Presentation
Citation preview
MULTIcentre evaluation of Single high-dose bolus TiRofiban versus Abciximab
with sirolimus eluting sTEnt or bare metal stent in acute myocardial infarction studY
MULTIcentre evaluation of Single high-dose bolus TiRofiban versus Abciximab
with sirolimus eluting sTEnt or bare metal stent in acute myocardial infarction studY
ClinicalTrials.gov number, NCT00229515
M. Valgimigli, MD, PhDOn behalf of Multistrategy Investigators
MULTIcentre evaluation of Single high-dose bolus TiRofiban versus Abciximab
with sirolimus eluting sTEnt or bare metal stent in acute myocardial infarction studY
MULTIcentre evaluation of Single high-dose bolus TiRofiban versus Abciximab
with sirolimus eluting sTEnt or bare metal stent in acute myocardial infarction studY
M. Valgimigli, MD, PhDOn behalf of Multistrategy Investigators
ClinicalTrials.gov number, NCT00229515
Potential Conflicts of interestPotential Conflicts of interest
Speaker’s bureau: Merck, Medicure
Research grant: Merck,
BackgroundBackground There is limited data on the comparison
between Abciximab vs. Tirofiban at high bolus dose (HDB: 25 g/kg over 3 min)
• 4 RCTs have so far contrasted these two drugs in 719 pts undergoing PCI of whom less than 300 were recruited in the setting of STEMI 1,2
The use of DES in the setting of STEMI is currently discouraged due to partially conflicting results on efficacy from MC-RCTs 3,4
and safety concerns from registries 5,6
1: Valgimigli et al. JAMA 2005; 2: Danzi et al. Am J Cardiol 2004; 3: Spaulding et al. NEJM 2006 4: Laarman et al. NEJM 2006; 5: Spertus et al. Circulation 2006; Steg PG et al. ESC 2007
INCLUSION CRITERIA:
• Chest pain for >30 min with ST-segment elevation ≥1 mm
in two or more contiguous leads, or with a new left
bundle-branch block• Admission either within 12 h
of symptom onset or between 12 and 24 h after
onset with evidence of continuing ischemia
EXCLUSION CRITERIA:
Those related to controindications to the use
of glycoprotein IIb/IIIa inhibitors
INCLUSION CRITERIA:
• Chest pain for >30 min with ST-segment elevation ≥1 mm
in two or more contiguous leads, or with a new left
bundle-branch block• Admission either within 12 h
of symptom onset or between 12 and 24 h after
onset with evidence of continuing ischemia
EXCLUSION CRITERIA:
Those related to controindications to the use
of glycoprotein IIb/IIIa inhibitors
Trial DesignTrial Design
Aspirin160-325 mg orally or 250 mg
intravenously, followed by 80-125 mg orally indefinitely
Clopidogrel300 mg orally and then 75 mg/day for
at least 3 months
Unfractioned Heparin
(40-70 U/kg)Target ACT of at least 200 secs
Aspirin160-325 mg orally or 250 mg
intravenously, followed by 80-125 mg orally indefinitely
Clopidogrel300 mg orally and then 75 mg/day for
at least 3 months
Unfractioned Heparin
(40-70 U/kg)Target ACT of at least 200 secs
No exclusion criteria based on:
• Haemodynamic Status
• Angiographic Findings
STEMI all-comer PatientsSTEMI all-comer Patients
Aspirin + Clopidogrel + UFHBefore Arterial Sheath
Insertion
Aspirin + Clopidogrel + UFHBefore Arterial Sheath
Insertion
Tirofiban*Tirofiban*Tirofiban*Tirofiban* AbciximabAbciximabAbciximabAbciximab
SESSESSESSES BMSBMSBMSBMS
Trial DesignTrial Design
SESSESSESSES BMSBMSBMSBMS
1:11:1
1:11:11:11:1
Clinical FU only Clinical FU only @@ 1, 4, 8 1, 4, 8 ms, 1yr and then yearly ms, 1yr and then yearly
up to 5up to 5
Clinical FU only Clinical FU only @@ 1, 4, 8 1, 4, 8 ms, 1yr and then yearly ms, 1yr and then yearly
up to 5up to 5
Coronary Angiography±PCIStenting was the default strategy in pts with a RVD≥ 2.5 mm at visual estimation
*: given as a bolus of 25 g/kg, followed by an 18-24 hour infusion at 0.15 g/kg/min
Study Primary EndpointsStudy Primary Endpoints
Pharmacology ArmPharmacology Arm
≥50% ST segment elevation resolution within 90’ after last balloon inflation @ tt-EKG
Non-inferiority basisNon-inferiority basis
Stent ArmStent Arm
Cumulative rate of MACE, defined as overall death, Reinfarction or TVR within 8 months
Superiority basisSuperiority basis
Valgimigli et al. Am Heart J. 2007 Jul;154(1):39-45
Assumed event ratesEndpoint Test Abciximab Tirofiban SES BMS
Power
≥50% N-Inf. 85% 85% ─ ─ 9%* >85%
STR
MACE Sup. ─ ─ 16% 27% ─ 80%
Study Primary EndpointsPower Analysis
Study Primary EndpointsPower Analysis
With 600 pts randomized and type I error set @2.5%With 600 pts randomized and type I error set @2.5%
*: ~50% of previously reported ≥50% STR between Abciximab vs. placebo in the ACE trial (Antoniucci et al. J Am Coll Cardiol 2003)
Study OrganizationStudy OrganizationSponsor: University of Ferrara, Italy
Data Management: Medical Trial Analysis, Switzerland
Site and data monitoring: Medical Trial Analysis, Italy ; Sermes C.R.O., Spain
Clinical Events Committee: P. Agostoni (Chair), Belgium, E. Meliga, The Netherlands.
ECG core lab: MTA, C. Arcozzi (Chair)
Angiographic core lab: MTA, P. Malagutti (Chair)
DSMB: P. Vranckx, (Chair), Belgium
G Campo Ferrara R Moreno Madrid
G Percoco Lagosanto T Piva Ancona
M Anselmi Verona I Sheiban Torino
L Bolognese Arezzo G Pasquetto Mirano
S Colangelo Torino F Prati Rome
N de Cesare Zingonia M Nazzaro Rome
A Rodriguez B. Aires J Fernández Huelva
M Ferrario Pavia J Mieres B Aires
MULTISTRATEGY P.I.s and Sites
MULTISTRATEGY P.I.s and Sites
745 Randomized745 Randomized
Abciximab andUncoated Stent
(n=186)
Abciximab andUncoated Stent
(n=186)
1:1:1:1
1030 Patients Assessed for Eligibility
285 Excluded• 153 Not Meeting Inclusion Criteria• 132 Refused to Participate
Abciximab andSirolimus-Stent
(n=187)
Abciximab andSirolimus-Stent
(n=187)
Tirofiban andUncoated Stent
(n=186)
Tirofiban andUncoated Stent
(n=186)
Tirofiban andSirolimus-Stent
(n=186)
Tirofiban andSirolimus-Stent
(n=186)
N=186 N=186 N=186 N=186 N=186 N=186 N=186 N=186
8 month Follow-up Study
N=179 N=182 N=184 N=177 N=179 N=182 N=184 N=177
ST Segment Resolution StudyST Segment Resolution Study
1 pt withdrew consent
99% received Abciximab97% received PCI90% received Abc+BMS99% qualified as STEMI3% non-interpretable ECG
100% received Abciximab99% received PCI87% received Abc+BMS100% qualified as STEMI2% non-interpretable ECG
100% received Tirofiban98% received PCI95% received Tir+BMS99% qualified as STEMI1% non-interpretable ECG
100% received Tirofiban98% received PCI89% received Abc+BMS99.5% qualified as STEMI4% non-interpretable ECG
72%
97%
100%
Abciximab Tirofiban P BMS SES BMS SES
Age (yr) 64.1 (55-74) 63.4 (55-70) 66.3 (57-75) 64.1 (54-74) 0.29
Male Sex (%) 73.1 72.6 79.5 78.5 0.26
BMI (kg/m2) 27 (25-29) 27 (25-29) 27 (24-29) 27 (24-29) 0.27
Diabetes (%) 12.4 14 17 14.5 0.26
Hypertension (%) 60.2 52.6 58 58 0.84
CrCl (ml/min) 78.8 79.8 78.6 81.3 0.78
Prior MI (%) 6.4 9.1 9.1 5.9 0.54
Prior PCI (%) 6.4 7.5 2.7 4.8 0.18
Prior CABG (%) 0.5 0.5 2.1 1 0.42
Prior CVA (%) 3.7 2.7 9.1 3.2 0.05
Systolic Pres (mmHg) 135 130 135 135 0.85
Heart Rate (bpm) 75 75 74 74.5 0.70
LVEF (%) 45 45 45 45 0.78
Killip class >1 (%) 16.1 19.3 15.6 12.3 0.38
Symptoms to H (min) 105 90 107 100 0.47
Door to balloon (min) 97 91.5 100 95 0.78
Abciximab Tirofiban P BMS SES BMS SES
Age (yr) 64.1 (55-74) 63.4 (55-70) 66.3 (57-75) 64.1 (54-74) 0.29
Male Sex (%) 73.1 72.6 79.5 78.5 0.26
BMI (kg/m2) 27 (25-29) 27 (25-29) 27 (24-29) 27 (24-29) 0.27
Diabetes (%) 12.4 14 17 14.5 0.26
Hypertension (%) 60.2 52.6 58 58 0.84
CrCl (ml/min) 78.8 79.8 78.6 81.3 0.78
Prior MI (%) 6.4 9.1 9.1 5.9 0.54
Prior PCI (%) 6.4 7.5 2.7 4.8 0.18
Prior CABG (%) 0.5 0.5 2.1 1 0.42
Prior CVA (%) 3.7 2.7 9.1 3.2 0.05
Systolic Pres (mmHg) 135 130 135 135 0.85
Heart Rate (bpm) 75 75 74 74.5 0.70
LVEF (%) 45 45 45 45 0.78
Killip class >1 (%) 16.1 19.3 15.6 12.3 0.38
Symptoms to H (min) 105 90 107 100 0.47
Door to balloon (min) 97 91.5 100 95 0.78
Baseline CharacteristicsBaseline Characteristics
Abciximab Tirofiban P BMS SES BMS SES
1-VD 40.3 45.7 45.2 48.4 0.72
2-VD 36.6 34.9 32.8 32.2 0.73
3-VD 20.4 18.3 21.5 17.7 0.78
LAD-culprit 43.4 45.9 41.8 43.1 0.88
RCA-culprit 35.1 39.3 42.9 40.3 0.48
LMCA-culprit 1.6 1.6 0 0.5 0.14
SVG-culprit 0 0 1.1 0 0.13
Interventions 96.8 98.4 97.8 98.7 0.67
De Novo culprit 96.8 95.7 97.3 96.8 0.79
No. Stents 1 1 1 1 0.47
Stent Length 20 23 19 23 0.18
Max Stent Size 3.07±0.4 3.05±0.4 3.14±0.5 3.05±0.5 0.06
Stent post-dil 18.9 21.6 20.3 21.7 0.91
Max Pressure 14.1±4.3 14.6±3.6 13.6±4.4 14.7±3.6 0.039
GP2b/3a infusion 12 (12-12) 12 (12-12) 24 (16-24) 24 (17-24) <0.001
ACT at peak 225 250 229 231 0.87
(191-307) (250-303) (194-284) (188-286)
Abciximab Tirofiban P BMS SES BMS SES
1-VD 40.3 45.7 45.2 48.4 0.72
2-VD 36.6 34.9 32.8 32.2 0.73
3-VD 20.4 18.3 21.5 17.7 0.78
LAD-culprit 43.4 45.9 41.8 43.1 0.88
RCA-culprit 35.1 39.3 42.9 40.3 0.48
LMCA-culprit 1.6 1.6 0 0.5 0.14
SVG-culprit 0 0 1.1 0 0.13
Interventions 96.8 98.4 97.8 98.7 0.67
De Novo culprit 96.8 95.7 97.3 96.8 0.79
No. Stents 1 1 1 1 0.47
Stent Length 20 23 19 23 0.18
Max Stent Size 3.07±0.4 3.05±0.4 3.14±0.5 3.05±0.5 0.06
Stent post-dil 18.9 21.6 20.3 21.7 0.91
Max Pressure 14.1±4.3 14.6±3.6 13.6±4.4 14.7±3.6 0.039
GP2b/3a infusion 12 (12-12) 12 (12-12) 24 (16-24) 24 (17-24) <0.001
ACT at peak 225 250 229 231 0.87
(191-307) (250-303) (194-284) (188-286)
Baseline CharacteristicsBaseline Characteristics
Abciximab Tirofiban P BMS SES BMS SES
RVD (mm) before PCI 2.81 2.88 2.90 2.85
0.43 2.52-3.16 2.55-3.14 2.58-3.23 2.61-3.06
after PCI 2.87 2.91 2.90 2.86 0.79
2.57-3.24 2.62-3.17 2.58-3.26 2.61-3.14
MLD (mm) before PCI 0 0 0 0 0.34
0-0.77 0-0.56 0-0.73 0-1.00
after PCI 2.68 2.66 2.65 2.61 0.64
2.34-2.96 2.42-2.91 2.41-3.00 2.42-2.91 % stenosis
before PCI 100 100 100 100 0.57
71-100 79-100 76.5-100 70-100
after PCI 6.5 7 6 8 0.89 2-13 2-13 1-13 2-13.5
Abciximab Tirofiban P BMS SES BMS SES
RVD (mm) before PCI 2.81 2.88 2.90 2.85
0.43 2.52-3.16 2.55-3.14 2.58-3.23 2.61-3.06
after PCI 2.87 2.91 2.90 2.86 0.79
2.57-3.24 2.62-3.17 2.58-3.26 2.61-3.14
MLD (mm) before PCI 0 0 0 0 0.34
0-0.77 0-0.56 0-0.73 0-1.00
after PCI 2.68 2.66 2.65 2.61 0.64
2.34-2.96 2.42-2.91 2.41-3.00 2.42-2.91 % stenosis
before PCI 100 100 100 100 0.57
71-100 79-100 76.5-100 70-100
after PCI 6.5 7 6 8 0.89 2-13 2-13 1-13 2-13.5
QCA AnalysisQCA Analysis
ST Segment ResolutionRationale for choosing this endpoint
in STEMI
ST Segment ResolutionRationale for choosing this endpoint
in STEMI
Circulation 2004;110(21):e506-10.Jama 2005;293(9):1063-72. Eur Heart J. 2007 Jun;28(12):1433-9.
ST segment resolution correlates with infarct size and infarct transmurality
as assessed at MRI or SPECT
ST segment resolution has strong and independent prognostic implications in terms of both death or the composite of death or MI
Interventions in STEMI which improve ST segment resolution have a consistent effect on outcomes and viceversa
Lancet 1997;350(9078):615-9
N Engl J Med. 2008 Feb 7;358(6):557-67 J Am Coll Cardiol 2003;42(11):1879-85 Jama 2005;293(9):1063-72.
ST Segment ResolutionInternal Validity Assessment of the
Chosen 1° Endpoint
ST Segment ResolutionInternal Validity Assessment of the
Chosen 1° Endpoint
P=0.023 at Log Rank test
ST-Res ≥50%
ST-Res <50%
0 20 40 60 80 100 120 140 160 180 200 220 240 260
Days after Random ization
88
90
92
94
96
98
100
Death
/M
I Fre
e S
urv
ival (%
)
ST Segment ElevationST Segment Elevation
P=0.78
P=0.62
ST segment(mm)
Number of ECG leads with ST
0
10
20
Unit
sAbciximab Tirofiban
Primary Endpoint ≥50% ST segment resolution
Primary Endpoint ≥50% ST segment resolution
Abciximab Tirofiban
0
10
20
30
40
50
60
70
80
90
100
H0: 85%83.6% 85.3%
P<0.001 for non-inferiority*
*: at ITT and PP Analysis (Heterogeneity: 2 6.22, P=0.718)
Tirofiban BetterTirofiban Better Abciximab BetterAbciximab Better
11 0.90.9 0.80.8 0.70.7 0.60.6 0.50.51.11.11.21.21.31.31.41.41.51.5
Pre
spec
ifie
d N
on
-in
feri
ori
ty L
imit
Overall
< 65 yr≥ 65 yr
MaleFemale
DiabetesNo Diabetes
Killip class 1Killip class ≥2
Single-vessel diseaseDouble-vessel diseaseTriple-vessel disease
Anterior Myocardial infarctionNon Anterior Myocardial infarction
Time to Tx ≤ 4 hrTime to Tx > 4 hr
Creatinine Clearance ≥ 60 ml/minCreatinine Clearance < 60 ml/min
RISK RATIO (95% CI) PRIMARY END POINTTirofiban Abciximab
%85.3 83.6
86.6 84.684.5 82.3
86.0 81.982.4 88.5
84.6 80.085.2 84.2
86.5 84.977.0 78.9
85.2 85.887.2 86.784.2 72.8
79.6 71.989.4 92.1
84.7 88.486.0 82.0
85.6 85.185.8 76.3
P-VALUE
0.74
0.57
0.860.890.10
0.110.26
0.950.37
0.890.11
0.55
0.550.55
0.53
Non-inferiority Superiority
0.001
Bare Metal StentSirolimus-Eluting Stent 85.9 84.6 0.74
84.8 82.7 0.59
1° Endpoint: ≥50% ST segment resolution1° Endpoint: ≥50% ST segment resolutionSubgroup AnalysisSubgroup Analysis
0.0020.003
<0.0010.37
0.059<0.001
<0.0010.22
0.0020.003
0.020.01
0.002
<0.0010.01
0.0040.002
0.001<0.001
Perce
ntile
0102030405060708090
Percentage o f ST segm ent reso lution at 90 '
100
90
80
70
60
50
40
30
Tirofi ban Abcixim ab
100
85 .3%
83 .6%
ECG AnalysisCore Lab Evaluation
ECG AnalysisCore Lab Evaluation
N=722N=722
30-Day Outcomes Efficacy Endpoints
(CEC adjudicated)
30-Day Outcomes Efficacy Endpoints
(CEC adjudicated)
-0,5
1
2,5
4
MACEMACE Death/MIDeath/MI uTVRuTVR DefiniteDefinite Def/ProbDef/Prob
Stent Thrombosis (ARC)
Stent Thrombosis (ARC)
P=0.85P=0.85P=0.98P=0.98
P=0.59P=0.59
P=0.56P=0.56
P=0.22P=0.22
Abciximab Tirofiban
4%
1%
2.5%
30-Day Outcomes Safety Endpoints
(DSMB adjudicated)
30-Day Outcomes Safety Endpoints
(DSMB adjudicated)
- 2
0
2
4
6
8
MajorMajor MinorMinor RBC Tranfusion
RBC Tranfusion
SevereSevere AnyAny
Thrombocytopenia Thrombocytopenia
P=0.44P=0.44
P=0.40P=0.40
P=0.82P=0.82P=0.03P=0.03
P=0.004P=0.004
Abciximab Tirofiban
TIMI-BleedingTIMI-Bleeding
2%
6%
4%
8%
0%
0 20 40 60 80 100 120 140 160 180 200 220 240 260
D ays after Random ization
20
15
10
5
0
Majo
r Adve
rse C
ard
iova
scula
r Eve
nts (%
)
Abcix im ab
Tirofiban
P= 0 .30 at Log-rank test
12.4%
9.8%
8 Month Outcomes MACE
(CEC adjudicated)
8 Month Outcomes MACE
(CEC adjudicated)
No. at RiskAbciximab 372 351 343 331 325Tirofiban 372 355 350 342 336
Primary Endpoint 8-month MACE
(CEC adjudicated)
Primary Endpoint 8-month MACE
(CEC adjudicated)
No. at RiskUncoated Stent 372 351 342 326 318Sirolimus-Stent 372 355 351 347 343
0 20 40 60 80 100 120 140 160 180 200 220 240 260
Days after Random ization
20
15
10
5
0
Prim
ary E
nd P
oin
t (%)
Sirolim us-stent
U ncoated stent
7.8%
14.5%
P= 0 .0039 at Log-rank test
Adjusted HR: 0.53 (97.5%CI: 0.33-0.83); p=0.006
0 20 40 60 80 100 120 140 160 180 200 220 240 260
Days after Random ization
20
15
10
5
0
Pro
bability o
f Targ
et Vessel
Reva
scula
rizatio
n (%
)
U ncoated stent
Sirolim us-stentP= 0.0002 at Log- rank test
10.2%
3.2%
8 Month Outcomes Target Vessel Revascularization
(CEC adjudicated)
8 Month Outcomes Target Vessel Revascularization
(CEC adjudicated)
No. at RiskUncoated Stent 372 355 347 331 322Sirolimus-Stent 372 357 355 351 350
8 Month Outcomes Death/MI (CEC adjudicated)
8 Month Outcomes Death/MI (CEC adjudicated)
0 20 40 60 80 100 120 140 160 180 200 220 240 260
Days after Random ization
20
15
10
5
0
Pro
bability o
f Dea
th o
r Myo
card
ial
Infa
rction (%
)
U ncoated stent
Sirolim us-stent
5.9%
7.5%
P= 0 .37 at Log-rank test
*: % SES patients taking dual antiplatelet treatment
82%*82%*82%*82%*
39%*39%*39%*39%*
32%*32%*32%*32%*
Uncoated Stent Sirolimus Stent
- 1, 5
0
1, 5
3
4 , 5
6
DefiniteDefinite Definite/ProbableDefinite/ProbableDefinite/ProbablePossible
Definite/ProbablePossible
ARC Stent Thrombosis (CEC adjudicated)
ARC Stent Thrombosis (CEC adjudicated)
P=0.65P=0.65
P=0.31P=0.31P=0.45P=0.45
0%
1.5%
3%
4.5%
6%
SummarySummary
Our study provides evidence that in a broad population of largely unselected patients undergoing angioplasty for ST-elevation myocardial infarction:
Tirofiban enables non-inferior STR within 90’ after intervention and similar outcomes at 8 months than Abciximab
The MACE rate was approximately halved by the use of SES compared to BMS
Recommended