Journal Club

Dr Awadhesh Kumar Sharma

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, MDHenning 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, MDon behalf of the AIDA STEMI Investigators

Off-label use of IC abciximab

Disclosures

Funding:Unrestricted grant by Lilly, GermanyUniversity of Leipzig – Heart CenterUniversity 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 MedicalConsulting:Maquet Cardiovascular, AvidalSpeaker Honoraria:Lilly, Astra Zeneca, Daiichi Sankyo, Boehringer Ingelheim, Maquet Cardiovascular, Medicines Company

INTRODUCTION Randomized studies have consistently shown

that treatment with an adjunctive glycoprotein IIb/IIIa inhibitor improves coronary microcirculation and clinical outcome in high-risk ST-segment elevation myocardial infarction (STEMI) patients undergoing primary percutaneous coronary intervention (PCI).

Intracoronary abciximab bolus administration results in higher local concentrations and increased levels of platelet glycoprotein IIb/IIIa receptor occupancy compared with standard intravenous application

Abciximab IC versus IV

Navarese et al. Platelets 2011;1-8

Background

CICERO 2010CRYSTAL AMI 2010Dominguez-Rodriguez 2009EASY-MI 2010Iversen 2011Thiele 2008

500022

27125255318577

710093

26323255217077

33.7%7.4%

44.8%14.1%

0.690.29 (0.01;7.59)Not estimableNot estimable0.20 (0.04;0.92)0.66 (0.11;4.05)

Study or SubgroupIntracoronary abciximabIntravenous abciximab Odds ratio

Events Total Events Total Weight M-H, Fixed 95%

Total (95%)

Total events

636 610 100.0% 0.43 (0.20;0.94)9 20

Heterogeneity: Chi2 =1.88, df=3 (P=0.60);I2=0%Test for overall effect: Z=2.11 (P=0.03)

30-day Mortality

M-H, Fixed 95%Odds ratio

Favors IC Favors IV0.01 0.1 1 10 100

Favors IC Favors IV

CICERO 2010EASY-MI 2010Iversen 2011Thiele 2008

30-day Myocardial Infarction

3050

2715318577

4082

2635217077

27.5%

55.5%17.0%

Study or SubgroupIntracoronary abciximab Intravenous abciximab Odds ratio

Events Total Events Total Weight M-H, Fixed 95%

Total (95%)

Total events636

562 100.0% 0.54 (0.23;1.28)

8 14

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

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

M-H, Fixed 95%Odds ratio

0.01 0.1 1 10 100

0.72 (0.16;3.27)Not estimable0.56 (0.18;1.75)0.19 (0.01;4.13)

586

CICERO 2010EASY-MI 2010Iversen 2011Thiele 2008

30-day Target Vessel Revascularization

9070

2715318577

100162

2635217077

27.5%

55.5%17.0%

Study or SubgroupIntracoronary abciximab Intravenous abciximab Odds ratio

Events Total Events Total Weight M-H, Fixed 95%

Total (95%)Total events 636

562 100.0% 0.53 (0.29;0.99)

16 28Heterogeneity: Chi2 =2.58, df=2 (P=0.36);I2=2%

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

M-H, Fixed 95%Odds ratio

Favors IC Favors IV0.01 0.1 1 10 100

0.87 (0.35;2.17)Not estimable0.38 (0.15;0.94)0.19 (0.01;4.13)

586

The large, randomized AIDA STEMI (Abciximab Intracoronary versus intravenously Drug Application in STEMI) multicenter trial, intracoronary abciximab application did not result in a difference in major adverse cardiac events (MACE) compared with the standard intravenous route , but the rate of new congestive heart failure was significantly lower and there was an observed benefit in the female subgroup.

The Abciximab Intracoronary versus intravenously Drug Application in ST-Elevation Myocardial Infarction

(AIDA STEMI) trial

Methodology• Primary Study Endpoint:

Composite of all-cause death, reinfarction, new congestive heart failure at 90 days after randomization

• Secondary Study Endpoints: - Time to occurrence of combined clinical endpoint- TIMI-flow post PCI- ST-segment resolution- Infarct size by AUC of CK-release

Thiele et al. Circulation 2008;118:49-57Thiele et al. Am Heart J 2010;159:547-554

Methods

1032 patients randomized to IC abciximab

1002 patients PCI started

995 patients abciximab bolus given; PCI

completed

935 patients with 90 day follow-up

Study Design, Flow, and Compliance2065 patients with suspected STEMI

- STEMI with symptoms <12 h - Planned primary PCI

- no contraindication for abciximab

8 technical PCI-problems7 exclusion criteria detected

UFH 50-70 IU/kgAspirin 500 mg, Clopidogrel 600 mg/Prasugrel 60 mg

Abciximab bolus 0.25 mg/kg plus 12 h infusion 0.125 µg/kg/min

1033 patients randomized to IV abciximab

1001 patients PCI started

993 patients abciximab bolus given; PCI

completed

932 patients with 90 day follow-up

64 withdrawal informed consent32 lost to follow-up25 incomplete information

62 patients not PCI eligible:- 46 STEMI not

confirmed- 13 emergency

CABG- 3 exclusion

criteria

Primary Outcome and Components

IC IV OR 95% CI P

Death/Reinfarction/new CHF

n/total n (%) 65/935 (7.0) 71/932 (7.6) 0.91 0.91-1.28 0.58

Death

Overalln/total n (%) 42/935 (4.5) 34/932 (3.6) 1.24 0.78-1.97 0.36

Cardiac 35 33

Non-cardiac 7 1

Reinfarction

n/total n (%) 17/935 (1.8) 17/932 (1.8) 1.0 0.51-1.96 0.99

New CHF

n/total n (%) 22/935 (2.4) 38/935 (4.1) 0.57 0.33-0.97 0.04

Results

Summary + Conclusions• This randomized, multi-center, large-scale trial

involving more than 2000 STEMI patients undergoing primary PCI showed that IC abciximab bolus administration is safe.

• The IC bolus administration of abciximab does not add a benefit in comparison to the standard IV bolus with respect to the combined primary study endpoint consisting of death, reinfarction, or new congestive heart failure within 90 days.

• The IC route might be related to reduced rates of new congestive heart failure.

Combined Clinical Endpoint

Time from randomization [days]

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p=0.54

Intracoronary Abciximab

Intravenous Abciximab

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

Background

Congestive Heart Failure

p=0.03

Intracoronary Abciximab

Intravenous Abciximab

Time from randomization [days]

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

Background

AIDA-STEMI CMR Substudy

• 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

Study Organization and Study Sites

DSMB:Uwe ZeymerHans-Richard ArntzChristoph BodeKarl WegscheiderSteering Committee:Holger ThieleJochen WöhrleOana BrosteanuGerhard Schuler

CRO:Clinical Trial Center Leipzig

Investigator Initiated Trial

Methods

22 study sites in Germany8 CMR study sitesCMR core laboratory:Ingo Eitel (Coordinator)Josephine MeissnerHenning SünkelHolger Thiele

RESULTS

Patient characteristics

Patients in the 2 groups had similar baseline characteristics except for hypertension and previous bypass surgery.

All other prescribed drugs and study procedures were similar for both groups

CMR RESULTS

The median time between the index eventand CMR was 3 days (IQR: 2 to 4 days) for both groups

Clinical outcome and relationship of CMR markers and

clinical outcome

At 12-month follow-up, there were 13 deaths (3.3%) in the intracoronary and 8 (2.0%) in the intravenous abciximab groups (hazard ratio: 1.69; 95% confidence interval: 0.69 to 4.11; p= 0.25).

There were also no significant differences in the occurrence of nonfatal re-infarctions (p = 0.54) and congestive heart failure (p = 0.11).

Consequently, MACE at 12-month follow-up were similar (intracoronary 24 [6.2%] vs. intravenous 29 [7.3%] events; hazard ratio: 0.84; 95% confidence interval: 0.48 to 1.46; p= 0.53)

Patients in whom MACE occurred had significantly larger infarcts, less myocardial salvage, and more pronounced LV dysfunction

Intramyocardial hemorrhage and MO as markers of severe reperfusion injury were more frequent in patients with MACE without reaching statistical significance.

Summary + Conclusions

• 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.

THANKS