Presentation on theme: "The SELECT-ACS Trial Jean-Claude Tardif MD Montreal Heart Institute"— Presentation transcript:
1 The SELECT-ACS Trial Jean-Claude Tardif MD Montreal Heart Institute Effects of the P-selectin antagonist inclacumabon myocardial damage after PCI for NSTEMIJean-Claude Tardif MDMontreal Heart InstituteUniversity of Montrealon behalf of the SELECT-ACS steering committee
2 The SELECT-ACS trialBackgroundMyocardial damage is common after PCI, due in part to inflammation and platelet activation.P-selectin, a cell adhesion molecule expressed on activated endothelial cells and platelets, plays a critical role in leukocyte and platelet rolling.Animal studies have suggested that inhibition of P-selectin decreases neutrophil and platelet adhesion, macrophage accumulation and neointimal formation after injury.
3 Inclacumab Fully human recombinant monoclonal IgG4 antibody The SELECT-ACS trialInclacumabFully human recombinant monoclonal IgG4 antibodyMutated Fc portion, elimination of effector functions by IgG4 conversion and L235E mutationHigh selectivity (3000 fold) for P-selectin vs E- and L-selectinNo adverse findings in non-clinical safety profilingAnti-inflammatory + antithrombotic effects: in vitro assays, ex vivo human flow system, in vivo inflammation modelReduction in CD11b expression on neutrophils
4 The SELECT-ACS trialStudy objectiveTo determine the efficacy of inclacumab in reducing myocardial damage during percutaneous coronary intervention (PCI) in patients with non-ST elevation MI (NSTEMI)
5 Study design The SELECT-ACS trial Placebo (1 infusion) • years• NSTEMI• TnI or CK-MB above99th percentile• Scheduled for cathand ad hoc PCIPlacebo (1 infusion)RandomizationInclacumab 5 mg/kg (1 infusion)Inclacumab 20 mg/kg (1 infusion)Coronary angioAd hoc PCITnI + CK-MB8, 16, 24 hoursSafety visits30 and 120 daysScreeningNSTEMIStudy drug infusion1-24 hrs pre-PCI
6 Exclusion criteria PCI within past 72 hours, recent thrombolysis The SELECT-ACS trialExclusion criteriaPCI within past 72 hours, recent thrombolysisRecent cerebral vascular disease or strokeBleeding disorders, blood dyscrasiaSevere uncontrolled hypertensionPrior CABG surgeryActive or chronic infectionSevere inflammatory or auto-immune diseaseUncontrolled diabetesHepatic failure, severe renal failure
7 Efficacy and safety endpoints The SELECT-ACS trialEfficacy and safety endpointsPrimary efficacy endpointChange in troponin I at 16 and 24 hours post-PCISecondary efficacy endpointsPeak troponin I (TnI) post-PCIArea under the curve for TnI over 24 hoursChange in TnI at 8 hours post-PCIChanges in CK-MB at 8, 16 and 24 hrs post-PCISafety analysis (in all patients who received infusion)AEs, lab results, physical exam, vital signs, ECG
8 Patient flow The SELECT-ACS trial Placebo n=175 1-24 hrs pre-cath 14 pts did not receivestudy drug190 pts excluded:normal arteries (n=85), CABG (n=58)medical therapy (n=18), other (n=29)Placebo n=1751-24 hrs pre-cathInclacumab 5 mg/kg n=1791-24 hrs pre-cathCoronaryangiographyPCIn=340Randomization (n=544)Inclacumab 20 mg/kg n=1761-24 hrs pre-cath18 pts excluded:no baseline or post-baseline TnISafety Population120-day follow-upn=530Efficacy Populationn=322
11 Change in troponin I at 24 hours The SELECT-ACS trialChange in troponin I at 24 hoursTroponin I (TnI)Placebon=115Inclacumab5 mg/kgn=9520 mg/kgn=112Baseline geometric meanI.Q.R.1.030.710.8224 hours post-PCI1.761.210.99Change from baseline157.7%55.5%19.1%Placebo-adjusted change295% C.I.p-value---1.4%(-26.7, 32.7)0.93-24.4%(-43.1, 0.4)0.051Adjusted geometric mean %change (based on repeated ANCOVA model).2Placebo-adjusted geometric mean %change obtained by exponentiating thedelta adjusted mean from repeated ANCOVA, then subtracting 1 and X100.
12 Change in troponin I at 16 hours The SELECT-ACS trialChange in troponin I at 16 hoursTroponin I (TnI)Placebon=115Inclacumab5 mg/kgn=9520 mg/kgn=112Baseline geometric meanI.Q.R.1.030.710.8216 hours post-PCI1.741.301.09Change from baseline177.4%71.3%37.6Placebo-adjusted change295% C.I.p-value---3.4%(-27.2, 28.2)0.81-22.4%(-40.8, 1.7)0.071Adjusted geometric mean %change (based on repeated ANCOVA model).2Placebo-adjusted geometric mean %change obtained by exponentiating thedelta adjusted mean from repeated ANCOVA, then subtracting 1 and X100.
13 Change in peak troponin I and AUC The SELECT-ACS trialChange in peak troponin I and AUCTroponin I (TnI)Placebon=115Inclacumab5 mg/kgn=9520 mg/kgn=112Peak TnI geometric mean2.091.561.34Placebo-adjusted change195% C.I.p-value---1.5%(-26.3, 31.6)0.92-23.8%(-42.2, 0.5)0.05Area under the curve40.3728.8726.35Placebo-adjusted change-27.2%(-54.8, 17.2)0.19-33.9%(-58.1, 4.3)0.081Placebo-adjusted geometric mean %change obtained by exponentiating thedelta adjusted mean from repeated ANCOVA, then subtracting 1 and X100.
14 Percent change in troponin I over time The SELECT-ACS trialPercent change in troponin I over timeChange at 24 hrs with inclacumab 20 mg/kg vs pbo:diabetics -33.2%, non-diabetics -31.6% (p=0.03)
15 Change in CK-MB at 24 hours The SELECT-ACS trialChange in CK-MB at 24 hoursCK-MBPlacebon=115Inclacumab5 mg/kgn=9520 mg/kgn=112Baseline geometric meanI.Q.R.9.467.547.9724 hours post-PCI8.076.575.83Change from baseline1-15.0%-19.0%-29.8Placebo-adjusted change295% C.I.p-value---4.7%(-22.3, 16.9)0.64-17.4%(-32.1, 0.4)0.061 Adjusted geometric mean %change (based on repeated ANCOVA model).2 Placebo-adjusted geometric mean %change obtained by exponentiating thedelta adjusted mean from repeated ANCOVA, then subtracting 1 and X100.
16 Percent change in CK-MB over time The SELECT-ACS trialPercent change in CK-MB over timeIncidence of CK-MB increases >3 X ULN:placebo 18.3%, inclacumab 20 mg/kg 8.9% (p=0.05)
17 Plasma soluble P-selectin level after PCI The SELECT-ACS trialPlasma soluble P-selectin level after PCIPlacebo-adjusted GM percent change:-22.0% with inclacumab 20 mg/kg (p<0.01)
18 Safety summary The SELECT-ACS trial Inclacumab Placebo (n = 175) 5 mg/kg(n = 179)20 mg/kg(n = 176)n%n%n%Serious adverse eventsAdverse eventsInfectionBleeding up to 120 daysAll-cause death*Non-fatal MIStrokeHospitalization for ACSResuscitated cardiac arrestRevascularization procedures32106219212018.360.612.05.14311119114123124.062.010.66.145112197212225.663.610.84.0*Some peri-PCI MIs were reported as non-fatal MIs according to investigator’s judgement
19 The SELECT-ACS trialLimitationsEfficacy analyses were conducted in patients who received the infusion, underwent PCI and had TnI levels available at baseline and follow-up.Several results were of borderline statistical significance.Study not powered for evaluation of clinical endpoints.While TnI and CK-MB are reliable biomarkers of myocardial damage, the clinical significance of post-PCI elevations remains open to debate.
20 The SELECT-ACS trialConclusionsThe consistency of our data suggests that the P-selectin antagonist inclacumab reduces myocardial damage after PCI in patients with NSTEMI.Further clinical investigation will be required to determine the clinical value (benefit or harm) of inclacumab in patients presenting with myocardial infarction whether or not they undergo PCI.