Intracoronary Compared with Intravenous Bolus Abciximab Application
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Intracoronary Compared with Intravenous Bolus Abciximab Application During Primary Percutaneous Coronary Intervention Cardiac Magnetic Resonance Substudy of the AIDA STEMI trial. Holger Thiele, MD; Jochen Wöhrle, MD; Henning Suenkel, BSc; Josephine Meissner, MD; Sebastian Kerber, MD;

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Holger Thiele, MD; Jochen Wöhrle, MD;

Henning Suenkel, BSc; Josephine Meissner, MD; Sebastian Kerber, MD;

Bernward Lauer, MD; Matthias Pauschinger, MD; Ralf Birkemeyer, MD; Christoph Axthelm, MD;

Rainer Zimmermann, MD; Petra Neuhaus, PhD; Oana Brosteanu, PhD; Steffen Desch, MD;

Matthias Gutberlet, MD; Gerhard Schuler, MD; Ingo Eitel, MD

on behalf of the AIDA STEMI Investigators


Disclosures Application

Off-label use of IC abciximab

Funding:

Unrestricted grant by Lilly, Germany

University of Leipzig – Heart Center

University of Leipzig, Clinical Trial Centre Leipzig: supported by the Federal Ministry of Education and Research (BMBF) FKZ 01KN1102

  • Potential Conflict of Interest:

  • Research Funding:

    • Terumo, Lilly. Maquet Cardiovascular, Teleflex Medical

    • Consulting:Maquet Cardiovascular, Avidal

    • Speaker Honoraria:

    • Lilly, Astra Zeneca, Daiichi Sankyo, Boehringer Ingelheim, Maquet Cardiovascular, Medicines Company


Gp iib iiia ic versus iv
GP IIb/IIIa IC versus IV Application

IPA Periphery (20 μmol/L ADP)

GpIIb/IIIa Receptor-Blockade

110

110

P=0.67

100

100

P=0.013

P=0.995

P<0.001

P=0.001

90

90

80

80

70

70

60

60

%IPA

% Receptor-Blockade

50

50

40

40

30

30

20

20

10

10

0

0

15 min

post Bolus

60 min

post Bolus

Bolus 1

Bolus 2

30 min

post Bolus

Baseline

Bolus 1

Bolus 2

Peripheral blood

Blood coronary sinus

IC Eptifibatide n=21

IV Eptifibatide n=19

Background

2 x Bolus within 10 min. 180 μg/kg eptifibatide IC versus IV, subsequently

2 μg/kg-1 .min-1 continuous infusion i.v. for 18 h

Deibele et al. Circulation 2010;121:784-791


Abciximab ic versus iv

30-day Mortality Application

Intracoronary abciximab

Intravenous abciximab

Odds ratio

Odds ratio

Events

Total

Events

Total

Weight

Study or Subgroup

M-H, Fixed 95%

M-H, Fixed 95%

CICERO 2010

CRYSTAL AMI 2010

Dominguez-Rodriguez 2009

EASY-MI 2010

Iversen 2011

Thiele 2008

5

0

0

0

2

2

263

23

25

52

170

77

33.7%

7.4%

44.8%

14.1%

0.69

0.29 (0.01;7.59)

Not estimable

Not estimable

0.20 (0.04;0.92)

0.66 (0.11;4.05)

271

25

25

53

185

77

7

1

0

0

9

3

Total (95%)

636

610

0.43 (0.20;0.94)

100.0%

9

20

Total events

Heterogeneity: Chi2 =1.88, df=3 (P=0.60);I2=0%

0.01 0.1 1 10 100

Test for overall effect: Z=2.11 (P=0.03)

Favors IV

Favors IC

30-day Myocardial Infarction

Intracoronary abciximab

Intravenous abciximab

Odds ratio

Odds ratio

Study or Subgroup

M-H, Fixed 95%

M-H, Fixed 95%

Events

Total

Events

Total

Weight

3

0

5

0

271

53

185

77

4

0

8

2

263

52

170

77

27.5%

55.5%

17.0%

0.72 (0.16;3.27)

Not estimable

0.56 (0.18;1.75)

0.19 (0.01;4.13)

CICERO 2010

EASY-MI 2010

Iversen 2011

Thiele 2008

Total (95%)

586

0.54 (0.23;1.28)

562

100.0%

636

14

Total events

8

Heterogeneity: Chi2 =0.58, df=2 (P=0.75);I2=0%

0.01 0.1 1 10 100

Test for overall effect: Z=1.39 (P=0.17)

Favors IC

Favors IV

30-day Target Vessel Revascularization

Intracoronary abciximab

Intravenous abciximab

Odds ratio

Odds ratio

Study or Subgroup

M-H, Fixed 95%

M-H, Fixed 95%

Events

Total

Events

Total

Weight

9

0

7

0

CICERO 2010

EASY-MI 2010

Iversen 2011

Thiele 2008

10

0

16

2

263

52

170

77

0.87 (0.35;2.17)

Not estimable

0.38 (0.15;0.94)

0.19 (0.01;4.13)

271

53

185

77

27.5%

55.5%

17.0%

562

100.0%

0.53 (0.29;0.99)

Total (95%)

586

636

Total events

16

28

Heterogeneity: Chi2 =2.58, df=2 (P=0.36);I2=2%

Test for overall effect: Z=2.00 (P=0.05)

0.01 0.1 1 10 100

Favors IC

Favors IV

Background

Abciximab IC versus IV

Navarese et al. Platelets 2011;1-8


Study design flow and compliance

Follow-up Application

Background

Study Design, Flow, and Compliance

2065 patients with suspected STEMI willing to participate

Randomised (n=2065)

Allocation

  • Intravenous abciximab (n=1033)

  • Received intervention (n=993)

  • Did not receive intervention (n=40)

    • STEMI not confirmed, no abciximab bolus (n=23)

    • emergency CABG, no abciximab bolus (n=8)

    • exclusion criteria detected before or during PCI, no abciximab bolus (n=5)

    • technical problems with PCI, no abciximab bolus (n=4)

  • Intracoronary abciximab (n=1032)

  • Received intervention (n=995)

  • Did not receive intervention (n=37)

    • STEMI not confirmed, no abciximab bolus (n=23)

    • emergency CABG, no abciximab bolus (n=5)

    • exclusion criteria detected before or during PCI, no abciximab bolus (n=5)

    • technical problems with PCI, no abciximab bolus (n=4)

  • Lost to follow-up (n=101)

    • Withdrew informed consent (n=31)

    • Lost to follow-up (n=15)

    • Incomplete documentation (n=15)

    • Premature study termination before receiving abciximab bolus (n=40 – see description above)

  • Lost to follow-up (n=97)

    • Withdrew informed consent (n=33)

    • Lost to follow-up (n=17)

    • Incomplete documentation (n=10)

    • Premature study termination before receiving abciximab bolus (n=37 – see description above)

Primary endpoint

analysis

Analyzed at 90-day follow-up (n=935)

Analyzed at 90-day follow-up (n=932)

Thiele et al. Lancet 2012;379:923-31


Combined clinical endpoint

Background Application

Combined Clinical Endpoint

p=0.54

Cumulative event free survival from death, reinfarction and

congestive heart failure [%]

Intracoronary Abciximab

Intravenous Abciximab

Time from randomization [days]

Thiele et al. Lancet 2012;379:923-31


Congestive heart failure

Background Application

Congestive Heart Failure

p=0.03

Intracoronary Abciximab

Intravenous Abciximab

Cumulative event free survival of congestive heart failure [%]

Time from randomization [days]

Thiele et al. Lancet 2012;379:923-31


Aida stemi cmr substudy
AIDA STEMI CMR Substudy Application

  • CMR enables investigation of mechanistic and pathophysiological effects of intracoronary + intravenous abciximab application on myocardial damage and reperfusion injury.

  • To determine potential benefits of intracoronary abciximab application on infarct size, myocardial salvage, microvascular obstruction and ventricular function to further evaluate the benefit with respect to congestive heart failure.

Thiele et al. Am Heart J 2010;159:547-554


CMR Prognostic Implications Application

Prognostic relevance

validated

Prognostic relevance

validated

Prognostic relevance

partly validated

Prognostic relevance

validated

Prognostic relevance

partly validated

Prognostic relevance

Hemorrhage

Myocardial salvage

Microvascular obstruction

Infarct size

LV Volumes +

Ejection fraction

Desch et al. Trials 2011:12:e204-215


Methods Application

Study Organization and Study Sites

Investigator Initiated Trial

22 study sites in Germany

8 CMR study sites

CMR core laboratory:Ingo Eitel (Coordinator)

Josephine Meissner

Henning Sünkel

Holger Thiele

DSMB:Uwe Zeymer

Hans-Richard Arntz

Christoph BodeKarl Wegscheider

Steering Committee:

Holger Thiele

Jochen Wöhrle

Oana Brosteanu

Gerhard Schuler

CRO:

Clinical Trial Center Leipzig


CMR Protocol Application

Contrast-Injection 1,5 mmol/kg/BW Bolus Gd i.v.

Area at risk +

Hemorrhage

late MO + Infarct size

EF, EDV, ESV

Methods

35

40

0

5

10

15

20

25

30

Time (min)

Delayed enhancement 4CH + 2CH + SA

T2

SA

Function 4CH+2 CH

FunctionShort axes

Survey

Thiele et al. Am Heart J 2010;159:547-554


Cmr image analysis

Methods Application

CMR Image Analysis

  • Core laboratory assessed by blinded observers:

  • Edema

  • Hemorrhage

  • Endocardial contours

  • Epicardial contours

  • Infarct

  • Microvascular obstruction

Area at risk = Volume Edema/Volume LV mass

%Infarct Size = Volume Infarct/Volume LV mass

%MO = MO-Volume/Volume LV mass

%Hemorrhage = T2 hypointense core/Volume LV mass

Myocardial salvage = Edema-Infarct Size

Myocardial salvage index = Edema-Infarct Size/Edema

Thiele et al. JACC 2010; 2010;55:2201-2209

Eitel et al. JACC 2010; 55:2470–2479


Study design flow and compliance1

Methods Application

401 assigned to intravenous

abciximab

Incomplete CMR scan

- Scan terminated n=3

- T2 poor image quality n=40

- DE poor image quality n=10

Analyzed CMR data

- LV function n=401

- T2-weighted imaging n=361

- DE imaging n=391

- MO n=390

- Hypointense core/Hemorrhage n=353

Study Design, Flow, and Compliance

2065 patients enrolled and randomly assigned

No CMR (n=1270)

795 patients underwent CMR

394 assignedtointracoronary

abciximab

Incomplete CMR scan

- Scan terminated n=4

- T2 poor image quality n=39

- DE poor image quality n=7

Analyzed CMR data

- LV function n=394

- T2-weighted imaging n=355

- DE imaging n=387

- MO n=384

- Hypointense core/Hemorrhage n=346


Patient characteristics

Results Application

Patient Characteristics


Study procedures and medications

Results Application

Study Procedures and Medications


Area at risk infarct size

Infarct size Application

50

Median [IQR]

16% [9, 25]

Median [IQR]

17% [8, 25]

40

p=0.52

30

Infarct size, %LV

20

10

0

IC abciximab

N=385

IV abciximab

N=389

Results

Area at Risk + Infarct Size

Area at risk

Median [IQR]

35% [25, 48]

Median [IQR]

35% [26, 48]

p=0.97

Area at risk, %LV

IC abciximab

N=344

IV abciximab

N=354


Myocardial salvage index

Results Application

Myocardial Salvage Index

Median [IQR]

52 [35, 69]

Median [IQR]

50 [29, 69]

p=0.25

Myocardial salvage index

IC abciximab

N=342

IV abciximab

N=352


Reperfusion injury

Hemorrhage Application

p=0.19

37%

32%

Presence Hemorrhage, %

IC abciximab

N=346

IV abciximab

N=353

Results

Reperfusion Injury

Microvascular obstruction

p=0.19

52%

47%

Presence MO, %

IC abciximab

N=384

IV abciximab

N=390


Cmr lv ejection fraction

Results Application

CMR – LV Ejection Fraction

Median [IQR]

51% [43, 58]

Median [IQR]

50% [42, 58]

p=0.95

LV ejection fraction, %

IC abciximab

N=342

IV abciximab

N=352


Results Application

Infarct Size - Subgroups

Mean

Difference

(95% CI)

Infarct size (%LV)

Baseline variable

N

Mean

Difference

(95% CI)

p-value

for

interaction

IC

abciximab

IV

abciximab

All Patients

Male sex

Female sex

Age < 75 years

Age ≥ 75 years

Anterior MI

Non-anterior MI

Killip-class II to IV

Killip-class I

TIMI flow post PCI 0 to II

TIMI-flow post PCI III

Symptom onset-randomization < 3 h

Symptom onset-randomization 3-6 h

Symptom onset-randomization > 6h

Thrombectomy

No thrombectomy

Prasugrel

No prasugrel

774

586

188

656

118

353

388

91

683

89

685

334

296

136

187

587

173

419

18 (13)

18 (13)

18 (12)

18 (13)

18 (12)

21 (14)

15 (10)

28 (16)

16 (11)

24 (14)

17 (12)

17 (13)

19 (13)

18 (12)

20 (12)

17 (13)

18 (13)

19 (13)

18 (13)

18 (12)

19 (12)

18 (12)

21 (12)

21 (14)

15 (10)

25 (13)

17 (12)

19 (9)

18 (13)

15 (12)

20 (13)

20 (12)

19 (13)

18 (12)

17 (11)

19 (13)

-0.2 (-2.9;1.5)

0.1 (-2.0;2.1)

-1.4 (-4.9;2.1)

0.2 (-1.7;2.1)

-3.1 (-7.6;1.3)

0.1 (-2.8;3.0)

-0.7 (-2.7;1.3)

3.0 (-3.1;9.0)

-0.9 (-2.8; 0.8)

4.4 (-0.5;9.3)

-0.9 (-2,8;1.0)

2.0 (-0.7;4.6)

-1.6 (-4.5;1.3)

-1.2 (-5.3;2.8)

1.4 (-2.2;5.0)

-0.8 (-2.9;1.2)

0.6 (-3.0;4.3)

0.2 (-2.2;2.7)

0.52

0.49

0.46

0.11

0.79

0.42

0.50

0.71

0.96

0.50

0.85

0.37

0.60

0.47

0.78

0.84

0.89

-6 -4 -2 0 2 4 6

IV better

IC better



Cmr and outcome
CMR and Outcome Application

Results


Summary conclusions
Summary + Conclusions Application

  • This largest multicenter CMR study in STEMI patients to date demonstrates that IC as compared to IV abciximab did not result in a difference in myocardial damage and/or reperfusion injury.

  • The results of the AIDA STEMI CMR substudy therefore confirm the lack of difference in the combined endpoint of death, reinfarction or congestive heart failure of the AIDA STEMI trial.


Acknowledgement Application

AIDA STEMI Investigators from 22 sites in Germany

Steering Committee

Clinical Trial Center

at University Leipzig

ECG Core Lab

MRI Core Lab

Sponsors

Study Sites

DSMB

CEC


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