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CP887679-0Use of Biomarkers in Patients with Acute Cardiovascular DiseaseAllan S.Jaffe,MD.*Consultant-Cardiology&Laboratory MedicineProfessor of MedicineMayo Clinic and Medical SchoolRochester,Minnesota*Dr.Jaffe is a consultant and receives research support from Roche,Dade Behring and Beckmann Coulter.He has been or presently is a consultant to Ortho Diagnostics,Sensera,Diadexus,Abbott,Hawaii Biotech and Tartagen.CP1051812-1Clinical Outcomes by Braunwald ClassClinical Outcomes by Braunwald ClassDaysDaysDaysDaysDaysDaysPrimary Unstable AnginaPrimary Unstable AnginaPrimary Unstable AnginaClass BClass BClass BPostinfarction AnginaPostinfarction AnginaPostinfarction AnginaClass CClass CClass CAccelerated AnginaAccelerated AnginaAccelerated AnginaClass IClass IClass ISubacute Angina at RestSubacute Angina at RestSubacute Angina at RestClass IIClass IIClass IIAcute Angina at RestAcute Angina at RestAcute Angina at RestClass IIIClass IIIClass IIIP PPP PPSurvivalSurvivalSurvivalInfarct freeInfarct freeInfarct freeInfarct free withoutInfarct free withoutInfarct free withoutinterventioninterventioninterventionJACC 25:1286,1995JACC 25:1286,1995JACC 25:1286,1995CP887679-2ECG Risk Factors in Patients with ACSDeath or MIDeath or MI(%)(%)DaysDaysJACC 36(3):970-1062,2000JACC 36(3):970-1062,2000ST elevation and depressionST elevation and depressionST depression onlyST depression onlyST elevation onlyST elevation onlyT-wave inversion onlyT-wave inversion onlyNo ST or T-wave changeNo ST or T-wave changen=237n=237n=287n=287n=93n=93n=216n=216n=78n=78CP956024-12CP887679-3Relationship of ECG Changes and FPA*FPAFPA(nM)(nM)*JACC 18:898-903,1991JACC 18:898-903,1991100CP887679-4Long-Term Prognostic Value of ElevatedcTnI in Unstable Angina%freefreefromfromdeathdeathand/orand/orAMIAMITime from admission(days)Time from admission(days)Normal cTnINormal cTnIElevated cTnIElevated cTnICirculation.1997;95:2053-2059 CP887679-5Antman,1998Antman,19981.1(0.4-3.5)1.1(0.4-3.5)Benamer,1998Benamer,199813.7(3.9-48.3)13.7(3.9-48.3)Brisisc,1998Brisisc,19988.0(0.9-65.1)8.0(0.9-65.1)Cin,1996Cin,199617.9(5.2-61.2)17.9(5.2-61.2)Galvani,1997Galvani,19976.6(1.3-32.3)6.6(1.3-32.3)Hamm,1992Hamm,199211.7(3.2-42.6)11.7(3.2-42.6)Luscher,1997Luscher,19972.5(1.3-4.8)2.5(1.3-4.8)Ohman,1996Ohman,19964.7(1.7-12.7)4.7(1.7-12.7)Olatidoye,1998Olatidoye,1998156.1(17.4-1,402)156.1(17.4-1,402)Ottani,1997Ottani,19976.6(2.0-22.1)6.6(2.0-22.1)Rebuzzi,1998Rebuzzi,199825.3(5.2-123.2)25.3(5.2-123.2)Solymoss,1997Solymoss,19972.4(0.7-8.1)2.4(0.7-8.1)Stubbs,1996Stubbs,19961.5(0.5-4.2)1.5(0.5-4.2)Wu,1995Wu,199531.5(6.7-144.9)31.5(6.7-144.9)Antman,1996Antman,19963.8(1.8-8.03)3.8(1.8-8.03)Individual Studies of Patients with“Unstable Angina”Individual Studies of Patients with“Unstable Angina”Without Without ST Segment ElevationST Segment ElevationPeto OR&95%CI(fixed)Peto OR&95%CI(fixed)0.20.11 51050FavorsFavorslower risklower riskFavorsFavorshigher riskhigher risk4.8(3.6-6.5)4.8(3.6-6.5)CP887679-6Antman,1996Antman,19963.82(1.03-14.18)3.82(1.03-14.18)Benamer,1998Benamer,199813.68(3.87-48.33)13.68(3.87-48.33)Brisisc,1998Brisisc,19987.96(0.97-65.25)7.96(0.97-65.25)Cin,1996Cin,199617.91(5.24-61.25)17.91(5.24-61.25)Galvani,1997Galvani,19976.55(1.32-32.38)6.55(1.32-32.38)Hamm,1992Hamm,199211.71(3.22-42.57)11.71(3.22-42.57)Luscher,1997Luscher,19975.93(1.61-21.79)5.93(1.61-21.79)Olatidoye,1998Olatidoye,1998156.17(17.39-1,402.09)156.17(17.39-1,402.09)Rebuzzi,1998Rebuzzi,199825.27(5.18-123.23)25.27(5.18-123.23)Solymoss,1997Solymoss,19974.93(0.72-33.19)4.93(0.72-33.19)Wu,1995Wu,199531.52(6.89-144.19)31.52(6.89-144.19)Individual Studies of Individual Studies of Patients with“Unstable Angina”and Normal Patients with“Unstable Angina”and Normal CKMB ValuesCKMB ValuesPeto OR&95%CI(fixed)Peto OR&95%CI(fixed)Pooled ORPooled OR0.20.11 51050FavorsFavorslower risklower riskFavorsFavorshigher riskhigher risk11.83(7.56-18.51)11.83(7.56-18.51)CP887679-7cTnI in Patients with Unstable AnginaMortality at 42 daysMortality at 42 days(%of patients)(%of patients)CP886232-7NEJM 335:1342-1349,1996NEJM 335:1342-1349,1996Cardiac Troponin I(ng/mL)Cardiac Troponin I(ng/mL)8311741481345067Risk ratio-95%CI CP887679-8Synergism of ECG and Elevated Troponins(PARAGON)CP1099500-8JACC 41:376,2003JACC 41:376,20036-6-momodeath/death/MI rateMI raten=262ST-depressionST-depressionn=125n=259n=174n=57n=82TroponinTroponinTroponin+Troponin+CP887679-9FRISC-II GUSTO IV(Death and MI)CP1142356-17James et al:Am J Med 115:181,2003James et al:Am J Med 115:181,200314141212101088664422000.01 0.01 g/Lg/LFRISC-IIFRISC-IIDeath and MI at 30 days(%)Death and MI at 30 days(%)0.03 0.03 g/Lg/LBelow cutoffBelow cutoffAbove cutoffAbove cutoff0.1 0.1 g/Lg/LCutoffCutoff0.01 0.01 g/Lg/LGUSTO-IVGUSTO-IV0.03 0.03 g/Lg/L0.1 0.1 g/Lg/LCutoffCutoff11118080171774743030616166665215211111114764762012013863862658093287464306441,992 5,1232,563 4,5523,446 3,679CP887679-10ABCDEGHTotal CV,%ACS180CentaurImmuno 1AccessAccess2VidasLiaisonRXL CSOpusImmuliteAlpha DxECiAIA 21IFCC Precision Study(Clinical Chem 2004)CP887679-11Rapid Troponin I AssayRapid Troponin I AssayOutcomes in Relation to Troponin Values:The Issue of Assay SensitivityCP1148152-9Int J Cardiol 93:113,2004Int J Cardiol 93:113,2004%NegNegDeathDeathMIMIDeath or MIDeath or MI569892130132205Troponin T(0.1 Troponin T(0.1 g/L)g/L)Troponin T(0.01 Troponin T(0.01 g/L)g/L)PosPos%4115113139862513619711636221301CP887679-12Correspondence Between Commercial Assays and Correspondence Between Commercial Assays and Western BlottingWestern BlottingAssay Positive WBDSA Negative WBDSA TotalBeckman 10%CV+17 20 37-11 106 117Roche 10%CV+16 8 24-12 118 130Beckman 99th%+20 38 58-8 88 96Roche 99th%+21 44 65-7 82 89CP887679-13MyeloperoxidaseMyeloperoxidasePredictions of Events When cTNT“Negative”Predictions of Events When cTNT“Negative”CP1131968-3NEJM 349:1600,2003NEJM 349:1600,2003Odds ratioOdds ratioOdds ratioOdds ratioRevascularizationRevascularizationMyeloperoxidase quartile 2Myeloperoxidase quartile 2Myeloperoxidase quartile 3Myeloperoxidase quartile 3Myeloperoxidase quartile 4Myeloperoxidase quartile 4Major adverse cardiac eventsMajor adverse cardiac eventsMyeloperoxidase quartile 2Myeloperoxidase quartile 2Myeloperoxidase quartile 3Myeloperoxidase quartile 3Myeloperoxidase quartile 4Myeloperoxidase quartile 430 Days30 Days6 Months6 MonthsUnadjustedUnadjustedAdjustedAdjustedCP887679-14Prognostic Effects of MPO at 72 HoursPrognostic Effects of MPO at 72 HoursCP1132618-7Death,Death,Death,MIMIMI(%)(%)(%)Circulation 108:1443,2003Circulation 108:1443,2003Before PCIBefore PCIBefore PCIAdjusted hazard ratioAdjusted hazard ratioAdjusted hazard ratio2.04(0.65-6.42)2.04(0.65-6.42)2.04(0.65-6.42)Adjusted hazard ratioAdjusted hazard ratioAdjusted hazard ratio3.07(1.21-4.26)3.07(1.21-4.26)3.07(1.21-4.26)MPO highMPO highMPO highMPO lowMPO lowMPO lowAfter PCIAfter PCIAfter PCIHoursHoursHoursCP887679-15cTnI Negative ACS?Circulation 107:533,2003Circulation 107:533,2003Circulation 107:533,2003CP1104508-19CP887679-16Sensitivity of cTnI,CK-MB,and Myoglobin with Sensitive Sensitivity of cTnI,CK-MB,and Myoglobin with Sensitive Contemporary AssaysContemporary AssaysAHJ 148:577,2004AHJ 148:577,2004TnI(0.1 g/L)TnI(0.1 g/L)CK-MB(3.5 g/L)CK-MB(3.5 g/L)Myo(98/56 g/L)Myo(98/56 g/L)CP1176222-20 min30 min60 min90 minSensitivity2 hr3 hr6 hr6 hrSpecificity TnI(0.4 g/L)TnI(0.4 g/L)TnI(0.1 g/L)TnI(0.1 g/L)TnI(0.07 g/L)TnI(0.07 g/L)CP887679-17cTnT and Angiographic MeasuresCP1179389-5TnT(0.01)TnT(0.01)TnT(0.01)Thrombus(%)Thrombus(%)TFG 0/1(%)TFG 0/1(%)TMPG 0/1(%)TMPG 0/1(%)CP887679-18JACC 36(3):970-JACC 36(3):970-1062,20001062,2000Medical and Interventional Response to GP IIb/IIIa Agents in Medical and Interventional Response to GP IIb/IIIa Agents in Troponin Positive PatientsTroponin Positive Patients+24h+24h+48h+48h +24h+24h+48h+48h +72h+72hn=1,265n=1,265CAPTURECAPTURE2.8%2.8%1.3%1.3%n=9,461n=9,461PURSUITPURSUITn=1,570n=1,570PRISM-PLUSPRISM-PLUSn=12,296n=12,296AllAlln=1,239n=1,239n=1,228n=1,228n=287n=287n=2,754n=2,7545.8%5.8%2.8%2.8%10.3%10.3%7.6%7.6%8.0%8.0%2.9%2.9%8.0%8.0%4.9%4.9%4.4%4.4%3.2%3.2%3.8%3.8%1.8%1.8%4.3%4.3%3.9%3.9%Death or MIDeath or MI(%)(%)Start GP IIb/IIIa inhibitor/placeboStart GP IIb/IIIa inhibitor/placeboPercutaneous coronary interventionPercutaneous coronary interventionCP956024-13CP887679-19LMW Heparin vs VF Heparin in TIMI 11BLMW Heparin vs VF Heparin in TIMI 11BJ Am Coll Cardiol 36:1812,2000J Am Coll Cardiol 36:1812,2000CP1008642-5Clinical events at 14 days(%)Clinical events at 14 days(%)CKMB negative patientsCKMB negative patientsEnoxaparinEnoxaparinUFHUFH6 6P=0.006P=0.0066 60 04 46 69 9171710101111404021212828P=0.007P=0.007cTnI NegativecTnI Negativen=179n=179cTnI PositivecTnI Positiven=180n=180CP887679-20TACTICS(TIMI 18)CP1036852-9ConservativeConservativeInvasiveInvasiveNo.No.treatmenttreatmenttreatmenttreatmentPrimary endpointPrimary endpoint0.1 ng/mL0.1 ng/mL734734 4.3 4.36.66.60.1-0.40.1-0.418118116.516.54.44.40.4-1.50.4-65 yr old65 yr old 6,208 6,20815.315.313.313.3ST-segment deviationST-segment deviation 6,275 6,27514.314.311.511.5No ST-segment deviationNo ST-segment deviation 6,287 6,287 8.6 8.6 7.0 7.0Enzymes elevated at entryEnzymes elevated at entry 3,176 3,17613.013.010.710.7Enzymes not elevated at entryEnzymes not elevated at entry 9,386 9,38610.910.9 8.8 8.8DiabetesDiabetes 2,840 2,84016.716.714.214.2No diabetesNo diabetes 9,722 9,722 9.9 9.9 7.9 7.9Low riskLow risk 4,187 4,187 6.7 6.7 5.1 5.1Intermediate riskIntermediate risk 4,185 4,185 9.4 9.4 6.5 6.5High riskHigh risk 4,184 4,18418.018.016.316.3History of revascularizationHistory of revascularization 2,246 2,24614.414.4 8.4 8.4No history of revascularizationNo history of revascularization10,31610,31610.710.7 9.5 9.5Revascularization after randomization Revascularization after randomization 4,577 4,57713.913.911.511.5No revascularization after randomization No revascularization after randomization 7,985 7,98510.010.0 8.1 8.1Relative risk(95%CI)Relative risk(95%CI)ClopidogrelClopidogrelbetterbetterPlaceboPlacebobetterbetterNEJM 345:494,2001NEJM 345:494,2001CP887679-23CP1189452-44 4 peptides related with each other regarding peptides related with each other regarding biochemistry and physiological functionbiochemistry and physiological function Atrial Atrial natriureticnatriureticpeptide(ANP)peptide(ANP)Brain(or B type)Brain(or B type)natriureticnatriuretic peptide peptide(BNP)(BNP)C-type C-type natriureticnatriuretic peptide peptide(CNP)(CNP)UrodilatinUrodilatin,a slightly extended form of ANP,a slightly extended form of ANPH H2 2N NCOOHCOOHCOOHCFCDRISGLCCNatriuretic Peptide Family CP887679-24 Common 17-amino acidCommon 17-amino acidring structurering structure Ring structure highlyRing structure highlyconservedconserved 11/17 amino acids11/17 amino acidsare homologousare homologous Ring structure essentialRing structure essentialfor physiological activityfor physiological activityH H2 2N NCOOHCOOHCOOHCFCDRISGLCCCP1189452-5Natriuretic Peptide FamilyBiochemistryCP887679-25CardiomyocyteBloodBloodproBNPproBNP(108 aa)(108 aa)BNP-32(proBNP 77-108)BNP-32(proBNP 77-108)BNP-32BNP-32Physiologically active formPhysiologically active formNT-proBNP 1-76NT-proBNP 1-76SecretionSecretionLV stretchLV stretchWall tensionWall tensionPre-proBNP(134 aa)Pre-proBNP(134 aa)Signal peptide(26 aa)Signal peptide(26 aa)proBNPproBNPSerin proteaseSerin protease(Corin?)(Corin?)Mair:Scand J Clin Lab Invest,1999Mair:Scand J Clin Lab Invest,1999CP1189452-10CP887679-26CP1189452-2097.5%97.5%percentilepercentile(pg/mL)(pg/mL)303030-3930-3940-4940-4950-5950-59 6060Age groupsAge groupsMalesMalesFemalesFemalesAge-Specific Reference Rangefor NT-proBNPCP887679-27AHJ 149(4),April 2005AHJ 149(4),April 2005pg/mLpg/mLpg/mLNT-proBNPNT-proBNPNT-proBNPpg/mLpg/mLpg/mLBNPBNPBNPWeight categories(BMI)Weight categories(BMI)Weight categories(BMI)Weight categories(BMI)Weight categories(BMI)Weight categories(BMI)252525 303030 252525 303030 Values of BNP and NTproBNP by WeightCP1189452-21CP887679-2838 438 4BNPBNPconcentrationconcentration(pg/mL)(pg/mL)DiagnosisDiagnosisn=139n=1391,076 1381,076 138No CHFNo CHFCP1189452-25n=97n=97CHFCHFLV dysfunctionLV dysfunctionNo acute CHFNo acute CHFn=14n=14141 31141 31BNP Levels of Patients Diagnosed Without CHF,with BNP Levels of Patients Diagnosed Without CHF,with Baseline Left Ventricular Dysfunction,and with CHFBaseline Left Ventricular Dysfunction,and with CHFCP887679-29BNP Levels in Heart FailureMedianMedianBNP BNP levellevel(pg/mL)(pg/mL)CP1189452-26BNP Levels in Normal Subjects and InpatientsBNP Levels in Normal Subjects and Inpatientswith Heart Failurewith Heart FailureNormalNormalI III IIIIIIIIIVIVClassClassCP887679-30CP1189452-27ED Probability of CHF RecordedED Probability of CHF RecordedP0.0001 from clinical judgment to combinedP0.0001 from clinical judgment to combinedMcCullough PA et al:Circulation 106:416,2002McCullough PA et al:Circulation 106:416,2002Diagnostic accuracy(%)Diagnostic accuracy(%)ClinicalClinicaljudgmentjudgmentBNPBNPCombinedCombined7070727274747676787880808282n=1,538n=1,538BNP Study Primary End PointCP887679-31n=1,586;n=1,586;50%CHF;56%male;50%CHF;56%male;6417 yo;41%COPD;6417 yo;41%COPD;30%Hx CHF30%Hx CHFCP1189452-28 BNPBNP(pg/mL)(pg/mL)SensSensSpecSpecPPVPPVNPVNPV 50 50979762627171959510010090907676797989891501508585838383838585Breathing Not Proper(BNP)Multicenter TrialCP887679-32AJC 95,April 15,2005AJC 95,April 15,2005OptimalOptimal cut-point cut-point SensSens SpecSpec PPVPPV NPVNPV AccuracyAccuracy(%)(%)(%)(%)(%)(%)(%)(%)(%)(%)(%)(%)Rule-in cutpointsRule-in cutpointsAll pt(n=599)All pt(n=599)9009009090858576769494878750 yr old50 yr old45045093939595676799999595n=144n=144 50 yr old50 yr old90090091918080777792928585n=455n=455Rule-out ptRule-out ptAll pt(n=599)All pt(n=599)300 30099996868626299998383CP1189452-30Optimal NT-proBNP Cutpoints for Acute Congestive Heart FailureCP887679-33McCullough PA et al for the BNP Multinational Study Investigators:McCullough PA et al for the BNP Multinational Study Investigators:J Am Coll Cardiol 41:278A,2003J Am Coll Cardiol 41:278A,2003Application of BNP Testing in CHF“Grey Zone”BNPGrey Zone”BNPBNP(pg/mL)BNP(pg/mL)“Grey Zone”BNPGrey Zone”BNP100-500 pg/mL100-500 pg/mL26.4%26.4%of all casesof all cases16.5%16.5%CHFCHF7.9%7.9%No CHFNo CHF001001002002003003004004005005006006007007008008009009001,0001,0001,1001,1001,2001,2001,3001,300CP1189452-31CP887679-34CP1189452-32pg/mLpg/mLCoronary pulmonaleCoronary pulmonale200-500200-500Primary pulmonaryPrimary pulmonary300-500 300-500 hypertensionhypertensionAcute pulmonaryAcute pulmonary150-500 150-500 embolismembolismBNP ElevationsRight-Sided Coronary Heart FailureCP887679-35CP1189452-33 Acute or chronic systolic or diastolic HFAcute or chronic systolic or diastolic HF LV hypertrophyLV hypertrophy Inflammatory cardiac diseasesInflammatory cardiac diseases Systemic arterial hypertension with LVHSystemic arterial hypertension with LVH Pulmonary hypertensionPulmonary hypertension Acute or chronic renal failureAcute or chronic renal failure AsciticAscitic liver cirrhosis liver cirrhosis Endocrine disorders(Endocrine disorders(egeg,hyper-,hyper-aldosteronismaldosteronism,Cushings syndrome),Cushings syndrome)When Can Non-CHF Patients Present with BNP Elevations?CP887679-36CP1189452-34 Well HF patientsWell HF patients Acute Acute mitralmitral regurgitation regurgitation Pulmonary edema 1 hour oldPulmonary edema 1 hour old Other cases“up-stream”fromOther cases“up-stream”fromleft ventricleleft ventricleMitralMitral stenosisstenosisAtrial Atrial myoxmamyoxmaWhen Will CHF PresentWithout BNP Elevations?CP887679-37Baseline BNP&Clinical Outcomes DeathMIN=1356N=320Morrow DA JACC 2004 CP887679-38CP1173030-6Relationship of NT-proBNP and cTnTRelationship of NT-proBNP and cTnT*P0.01 vs NT-proBNP 250 ng/LP250 ng/L250 ng/L0.1 g/LNT-proBNPNT-proBNPTroponin TTroponin TDeath,myocardial infarction(%)Death,myocardial infarction(%)*CP887679-39Death/MI at 6 monthsDeath/MI at 6 monthsTest for interaction:Test for interaction:P=NSP=NS%BNP negBNP negBNP cut point=80 pg/mLBNP cut point=80 pg/mLCP1189452-45CONSCONSINVINVBNP posBNP pos(19%BNP pos)(19%BNP pos)n=681685156164 Morrow DA:JACC,2004Morrow DA:JACC,2004Baseline BNP:CONS vs INV StrategyCP887679-40Beta-Blocker Therapy and BNP LevelsLuchner A et al:JACC 32:1839,1998Luchner A et al:JACC 32:1839,1998pg/pg/mLmLpmol/pmol/mLmLANPANP 32%32%BNPBNP 89%89%cGMPcGMP 18%18%n=592n=80No No b bb b-blocker(n=592)-blocker(n=592)b bb b-blocker(n=80)-blocker(n=80)CP1189452-59CP887679-41Outcomes by Number of Positive OutcomesTACTICS-TIMI 18CP1143360-10Circ 109:584,2004Circ 109:584,2004DeathDeathor MIor MI(%)(%)FemaleFemaleMaleMaleP=NSP=NSPositive markers(no.)Positive markers(no.)P=NSP=NSP=NSP=NSDeath or MI by Multimarker ApproachDeath or MI by Multimarker ApproachCP887679-42Odds of Positive MarkerTACTICS-TIMI 18TACTICS-TIMI 18CP1143360-7Circ 109:583,2004Circ 109:583,2004T18 TnlT18 TnlT11 TnlT11 TnlCombinedCombinedT18 TnTT18 TnTT11 TnTT11 TnTCombinedCombinedT18 BNPT18 BNPT16 BNPT16 BNPCombinedCombinedT18 CRPT18 CRPT11 CRPT11 CRPCombinedCombinedMale more likelyMale more likelyFemale more likelyFemale more likely000.50.5111.51.522
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