Intracoronary Compared with IntravenousBolus Abciximab ApplicationDuring PrimaryPercutaneous Coronary InterventionCardiac Magnetic Resonance Substudy of theAIDA STEMI trialHolger 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 abciximabDisclosuresFunding:Unrestricted grant by Lilly, GermanyUniversity of Leipzig – Heart CenterUniversity of Leipzig, Clinical Trial Centre Leipzig: supported by the FederalMinistry of Education and Research (BMBF) FKZ 01KN1102Potential Conflict of Interest:Research Funding:Terumo, Lilly. Maquet Cardiovascular, Teleflex MedicalConsulting:Maquet Cardiovascular, AvidalSpeaker Honoraria:Lilly, Astra Zeneca, Daiichi Sankyo, Boehringer Ingelheim, MaquetCardiovascular, Medicines Company
INTRODUCTION Randomized studies have consistently shownthat treatment with an adjunctive glycoproteinIIb/IIIa inhibitor improves coronarymicrocirculation and clinical outcome in high-riskST-segment elevation myocardial infarction(STEMI) patients undergoing primarypercutaneous coronary intervention (PCI). Intracoronary abciximab bolus administrationresults in higher local concentrations andincreased levels of platelet glycoprotein IIb/IIIareceptor occupancy compared with standardintravenous application
Abciximab IC versus IVNavarese et al. Platelets 2011;1-8BackgroundCICERO 2010CRYSTAL AMI 2010Dominguez-Rodriguez 2009EASY-MI 2010Iversen 2011Thiele 2008500022271252553185777100932632325521707733.7%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 ratioEvents Total Events Total Weight M-H, Fixed 95%Total (95%)Total events636 610 100.0% 0.43 (0.20;0.94)9 20Heterogeneity: Chi2 =1.88, df=3 (P=0.60);I2=0%Test for overall effect: Z=2.11 (P=0.03)30-day MortalityM-H, Fixed 95%Odds ratioFavors IC Favors IV0.01 0.1 1 10 100Favors IC Favors IVCICERO 2010EASY-MI 2010Iversen 2011Thiele 200830-day Myocardial Infarction305027153185774082263521707727.5%55.5%17.0%Study or SubgroupIntracoronary abciximab Intravenous abciximab Odds ratioEvents Total Events Total Weight M-H, Fixed 95%Total (95%)Total events636562 100.0% 0.54 (0.23;1.28)8 14Heterogeneity: 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 ratio0.01 0.1 1 10 1000.72 (0.16;3.27)Not estimable0.56 (0.18;1.75)0.19 (0.01;4.13)586CICERO 2010EASY-MI 2010Iversen 2011Thiele 200830-day Target Vessel Revascularization90702715318577100162263521707727.5%55.5%17.0%Study or SubgroupIntracoronary abciximab Intravenous abciximab Odds ratioEvents Total Events Total Weight M-H, Fixed 95%Total (95%)Total events 636562 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 ratioFavors IC Favors IV0.01 0.1 1 10 1000.87 (0.35;2.17)Not estimable0.38 (0.15;0.94)0.19 (0.01;4.13)586
The large, randomized AIDA STEMI (AbciximabIntracoronary versus intravenously DrugApplication in STEMI) multicenter trial,intracoronary abciximab application did notresult in a difference in major adverse cardiacevents (MACE) compared with the standardintravenous route , but the rate of newcongestive heart failure was significantly lowerand there was an observed benefit in the femalesubgroup.
The Abciximab Intracoronary versus intravenously DrugApplication in ST-Elevation Myocardial Infarction(AIDA STEMI) trial
Methodology• Primary Study Endpoint:Composite of all-cause death, reinfarction, new congestive heartfailure 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-releaseThiele et al. Circulation 2008;118:49-57Thiele et al. Am Heart J 2010;159:547-554Methods
1032 patients randomizedto IC abciximab1002 patients PCI started995 patients abciximabbolus given; PCIcompleted935 patients with 90 dayfollow-upStudy Design, Flow, and Compliance2065 patients with suspected STEMI- STEMI with symptoms <12 h- Planned primary PCI- no contraindication for abciximab8 technical PCI-problems7 exclusion criteria detectedUFH 50-70 IU/kgAspirin 500 mg, Clopidogrel 600 mg/Prasugrel 60 mgAbciximab bolus 0.25 mg/kg plus 12 h infusion 0.125 µg/kg/min1033 patients randomizedto IV abciximab1001 patients PCI started993 patients abciximabbolus given; PCIcompleted932 patients with 90 dayfollow-up64 withdrawal informed consent32 lost to follow-up25 incomplete information62 patients not PCI eligible:- 46 STEMI not confirmed- 13 emergency CABG- 3 exclusion criteria
Primary Outcome and ComponentsIC IV OR 95% CI PDeath/Reinfarction/newCHFn/total n (%) 65/935 (7.0) 71/932 (7.6) 0.91 0.91-1.28 0.58DeathOveralln/total n (%) 42/935 (4.5) 34/932 (3.6) 1.24 0.78-1.97 0.36Cardiac 35 33Non-cardiac 7 1Reinfarctionn/total n (%) 17/935 (1.8) 17/932 (1.8) 1.0 0.51-1.96 0.99New CHFn/total n (%) 22/935 (2.4) 38/935 (4.1) 0.57 0.33-0.97 0.04Results
Summary + Conclusions• This randomized, multi-center, large-scale trialinvolving more than 2000 STEMI patientsundergoing primary PCI showed that IC abciximabbolus administration is safe.• The IC bolus administration of abciximab does notadd a benefit in comparison to the standard IVbolus with respect to the combined primary studyendpoint consisting of death, reinfarction, or newcongestive heart failure within 90 days.• The IC route might be related to reduced rates ofnew congestive heart failure.
Combined Clinical EndpointTime from randomization [days]Cumulativeeventfreesurvivalfromdeath,reinfarctionandcongestiveheartfailure[%]p=0.54Intracoronary AbciximabIntravenous AbciximabThiele et al. Lancet 2012;379:923-31Background
Congestive Heart Failurep=0.03Intracoronary AbciximabIntravenous AbciximabTime from randomization [days]Cumulativeeventfreesurvivalofcongestiveheartfailure[%]Thiele et al. Lancet 2012;379:923-31Background
AIDA-STEMI CMR Substudy• CMR enables investigation of mechanistic andpathophysiological effects of intracoronary +intravenous abciximab application on myocardialdamage and reperfusion injury.• To determine potential benefits of intracoronaryabciximab application on infarct size, myocardialsalvage, microvascular obstruction and ventricularfunction to further evaluate the benefit with respectto congestive heart failure.Thiele et al. Am Heart J 2010;159:547-554
Study Organization and Study SitesDSMB:Uwe ZeymerHans-Richard ArntzChristoph BodeKarl WegscheiderSteering Committee:Holger ThieleJochen WöhrleOana BrosteanuGerhard SchulerCRO:Clinical Trial Center LeipzigInvestigator Initiated TrialMethods22 study sites in Germany8 CMR study sitesCMR core laboratory:Ingo Eitel (Coordinator)Josephine MeissnerHenning SünkelHolger Thiele
Patient characteristics Patients in the 2 groups had similar baselinecharacteristics except for hypertension andprevious bypass surgery. All other prescribed drugs and study procedureswere similar for both groups
CMR RESULTSThe median time between the index eventand CMR was 3 days (IQR: 2 to 4 days) for both groups
Clinical outcome and relationship of CMRmarkers andclinical outcome At 12-month follow-up, there were 13 deaths(3.3%) in the intracoronary and 8 (2.0%) in theintravenous abciximab groups (hazard ratio:1.69; 95% confidence interval: 0.69 to 4.11; p=0.25). There were also no significant differences in theoccurrence 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; hazardratio: 0.84; 95% confidence interval: 0.48to 1.46; p= 0.53)Patients in whom MACE occurred hadsignificantly larger infarcts, less myocardialsalvage, and more pronounced LVdysfunction
Intramyocardial hemorrhage and MO asmarkers of severe reperfusion injury weremore frequent in patients with MACEwithout reaching statistical significance.
Summary + Conclusions• This largest multicenter CMR study in STEMI patients todate demonstrates that IC as compared to IV abciximabdid not result in a difference in myocardial damageand/or reperfusion injury.• The results of the AIDA STEMI CMR substudy thereforeconfirm the lack of difference in the combined endpointof death, reinfarction or congestive heart failure of theAIDA STEMI trial.