multicentre evaluation of single high-dose bolus tirofiban versus abciximab with sirolimus eluting...

MULTIMULTIcentre evaluation of centre evaluation of SSingle high-ingle high-dose bolus dose bolus TTiRofiban versus iRofiban versus AAbciximab bciximab

with sirolimus eluting swith sirolimus eluting sTETEnt or bare metal nt or bare metal stent in acute myocardial infarction studstent in acute myocardial infarction studYY

MULTISTRATEGY

M. Valgimigli, MD, PhDOn behalf of Multistrategy Investigators

ClinicalTrials.gov number, NCT00229515

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

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


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


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)


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


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


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

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)


(CEC adjudicated)

No. at RiskAbciximab 372 351 343 331 325Tirofiban 372 355 350 342 336

8 Month Outcomes Death/MI (CEC adjudicated)



0 20 40 60 80 100 120 140 160 180 200 220 240 260

D ays after Random ization

20

15

10

5

0

Pro

bability o

f Death

or M

yoca

rdia

l Infa

rction

(%) Abcix im ab

Tirofiban


7.3%6.2%

8 Month Outcomes Target Vessel Revascularization

(CEC adjudicated)


(CEC adjudicated)

0 20 40 60 80 100 120 140 160 180 200 220 240 260

Days after Randomization

20

15

10

5

0

Pro

bab

ility of T

arget V

essel Revascu

larization (%

)

Abciximab

Tirofiban

P= 0.58 at Lo g-rank t est

7.3%

6.2%



(CEC adjudicated)


(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


20

15

10

5

0

Prim

ary E

nd P

oin

t (%)

Sirolim us-stent

U ncoated stent

7.8%

14.5%


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


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%


(CEC adjudicated)


(CEC adjudicated)

No. at RiskUncoated Stent 372 355 347 331 322Sirolimus-Stent 372 357 355 351 350



0 20 40 60 80 100 120 140 160 180 200 220 240 260


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%


*: % 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

multicentre evaluation of single high-dose bolus tirofiban versus abciximab with sirolimus eluting...

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