1、Use of Biomarkers in Patients with Acute Cardiovascular Disease,Allan 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 Coul
2、ter. He has been or presently is a consultant to Ortho Diagnostics, Sensera, Diadexus, Abbott, Hawaii Biotech and Tartagen.,CP1051812-1,Clinical Outcomes by Braunwald Class,Days,Days,Primary Unstable Angina Class B,Postinfarction Angina Class C,Accelerated Angina Class I,Subacute Angina at Rest Clas
3、s II,Acute Angina at Rest Class III,P,P,0.97,0.91,0.53,0.96,0.88,0.72,0.94,0.86,0.35,0.97,0.89,0.55,0.89,0.80,0.37,JACC 25:1286, 1995,ECG Risk Factors in Patients with ACS,Death or MI (%),Days,JACC 36(3):970-1062, 2000,ST elevation and depression,ST depression only,ST elevation only,T-wave inversion
4、 only,No ST or T-wave change,n=237,n=287,n=93,n=216,n=78,CP956024-12,Relationship of ECG Changes and FPA*,FPA (nM),*JACC 18:898-903, 1991,nl 1.5,Long-Term Prognostic Value of Elevated cTnI in Unstable Angina,% free from death and/or AMI,Time from admission (days),Normal cTnI,Log rank 6.63, P=0.01,El
5、evated cTnI,Circulation. 1997;95:2053-2059,Antman, 1998 1.1 (0.4-3.5) Benamer, 1998 13.7 (3.9-48.3) Brisisc, 1998 8.0 (0.9-65.1) Cin, 1996 17.9 (5.2-61.2) Galvani, 1997 6.6 (1.3-32.3) Hamm, 1992 11.7 (3.2-42.6) Luscher, 1997 2.5 (1.3-4.8) Ohman, 1996 4.7 (1.7-12.7) Olatidoye, 1998 156.1 (17.4-1,402)
6、 Ottani, 1997 6.6 (2.0-22.1) Rebuzzi, 1998 25.3 (5.2-123.2) Solymoss, 1997 2.4 (0.7-8.1) Stubbs, 1996 1.5 (0.5-4.2) Wu, 1995 31.5 (6.7-144.9) Antman, 1996 3.8 (1.8-8.03),Individual Studies of Patients with“Unstable Angina” Without ST Segment Elevation,Peto OR & 95% CI (fixed),Pooled OR P0.0001,0.2 0
7、.1 1 5 10 50,Favors lower risk,Favors higher risk,4.8 (3.6-6.5),Antman, 1996 3.82 (1.03-14.18) Benamer, 1998 13.68 (3.87-48.33) Brisisc, 1998 7.96 (0.97-65.25) Cin, 1996 17.91 (5.24-61.25) Galvani, 1997 6.55 (1.32-32.38) Hamm, 1992 11.71 (3.22-42.57) Luscher, 1997 5.93 (1.61-21.79) Olatidoye, 1998 1
8、56.17 (17.39-1,402.09) Rebuzzi, 1998 25.27 (5.18-123.23) Solymoss, 1997 4.93 (0.72-33.19) Wu, 1995 31.52 (6.89-144.19),Individual Studies of Patients with “Unstable Angina” and Normal CKMB Values,Peto OR & 95% CI (fixed),Pooled OR P0.0001,0.2 0.1 1 5 10 50,Favors lower risk,Favors higher risk,11.83
9、(7.56-18.51),cTnI in Patients with Unstable Angina,Mortality at 42 days (% of patients),CP886232- 7,NEJM 335:1342-1349, 1996,Cardiac Troponin I (ng/mL),831,174,148,134,50,67,1.0,1.8,3.5,3.9,6.2,7.8,Risk ratio,-,0.5-6.7,1.2-10.6,1.3-11.7,1.7-22.3,2.6-23.0,95% CI,Synergism of ECG and Elevated Troponin
10、s (PARAGON),CP1099500-8,JACC 41:376, 2003,6-mo death/ MI rate,n=262,ST-depression,P=0.20,n=125,n=259,n=174,n=57,n=82,P=0.13,P=0.15,FRISC-II GUSTO IV (Death and MI),CP1142356-17,James et al: Am J Med 115:181, 2003,14 12 10 8 6 4 2 0,0.01 g/L,FRISC-II,Death and MI at 30 days (%),0.03 g/L,P=0.04,0.1 g/
11、L,P=0.01,P=0.15,Cutoff,0.01 g/L,GUSTO-IV,0.03 g/L,P0.001,0.1 g/L,P0.001,P0.001,Cutoff,11,80,17,74,30,61,66,521,111,476,201,386,265,809,328,746,430,644,1,992,5,123,2,563,4,552,3,446,3,679,0.0,10.0,20.0,30.0,40.0,50.0,60.0,A,B,C,D,E,G,H,Total CV, %,ACS180,Centaur,Immuno 1,Access,Access2,Vidas,Liaison,
12、RXL,CS,Opus,Immulite,Alpha Dx,ECi,AIA 21,IFCC Precision Study (Clinical Chem 2004),OR 4.55; 2.66-7.78,Rapid Troponin I Assay,Outcomes in Relation to Troponin Values: The Issue of Assay Sensitivity,CP1148152-9,Int J Cardiol 93:113, 2004,%,Neg,Death,MI,Death or MI,56,98,92,130,132,205,Troponin T (0.1
13、g/L),Troponin T (0.01 g/L),OR 1.80; 1.30-2.54,1.82; 1.38-2.40,1.64; 1.31-2.06,OR 3.20; 2.22-4.59,2.26; 1.79-2.85,1.47; 1.12-1.93,3.42; 2.57-5.98,4.29; 3.02-6.09,Pos,%,%,41,15,113,139,86,25,136,197,116,36,221,301,Correspondence Between Commercial Assays and Western Blotting,Assay Positive WBDSA Negat
14、ive WBDSA Total,Beckman 10% CV+ 17 20 37- 11 106 117 Roche 10% CV+ 16 8 24- 12 118 130 Beckman 99th% + 20 38 58 - 8 88 96 Roche 99th% + 21 44 65- 7 82 89,Myeloperoxidase Predictions of Events When cTNT “Negative”,CP1131968-3,NEJM 349:1600, 2003,Odds ratio,Odds ratio,Revascularization Myeloperoxidase
15、 quartile 2 Myeloperoxidase quartile 3 Myeloperoxidase quartile 4 Major adverse cardiac events Myeloperoxidase quartile 2 Myeloperoxidase quartile 3 Myeloperoxidase quartile 4,30 Days,6 Months,Prognostic Effects of MPO at 72 Hours,CP1132618-7,Death, MI (%),Circulation 108:1443, 2003,Before PCI,Adjus
16、ted hazard ratio 2.04 (0.65-6.42),Adjusted hazard ratio 3.07 (1.21-4.26),MPO high,MPO low,After PCI,Hours,cTnI Negative ACS?,Circulation 107:533, 2003,CP1104508-19,Sensitivity of cTnI, CK-MB, and Myoglobin with Sensitive Contemporary Assays,AHJ 148:577, 2004,TnI (0.1 g/L) CK-MB (3.5 g/L) Myo (98/56
17、g/L),CP1176222-2,0 min,30 min,60 min,90 min Sensitivity,2 hr,3 hr,6 hr,6 hr Specificity,TnI (0.4 g/L) TnI (0.1 g/L) TnI (0.07 g/L),cTnT and Angiographic Measures,CP1179389-5,TnT (0.01),Prog Cardiovasc Dis 47(3), 2004,P0.001,Stenosis (%),TnT (0.01),P=0.02,Thrombus (%),P=0.03,TFG 0/1 (%),P0.001,TMPG 0
18、/1 (%),JACC 36(3):970- 1062, 2000,Medical and Interventional Response to GP IIb/IIIa Agents in Troponin Positive Patients,+24h,+48h,+24h,+48h,+72h,n=1,265,OR=0.37,P=0.032,CAPTURE,2.8%,1.3%,n=9,461,OR=0.72,P=0.003,PURSUIT,n=1,570,OR=0.45,P=0.016,PRISM-PLUS,n=12,296,OR=0.66,P=0.001,All,n=1,239,OR=0.46
19、,P=0.009,n=1,228,OR=0.71,P=0.105,n=287,OR=0.35,P=0.062,n=2,754,OR=0.59,P=0.001,5.8%,2.8%,10.3%,7.6%,8.0%,2.9%,8.0%,4.9%,4.4%,3.2%,3.8%,1.8%,4.3%,3.9%,Death or MI (%),Start GP IIb/IIIa inhibitor/placebo,Percutaneous coronary intervention,CP956024-13,LMW Heparin vs VF Heparin in TIMI 11B,J Am Coll Car
20、diol 36:1812, 2000,CP1008642-5,TACTICS (TIMI 18),CP1036852-9,Conservative Invasive No. treatment treatment Primary endpoint 0.1 ng/mL 734 4.3 6.6 0.1 - 0.4 181 16.5 4.4 0.4 - 1.5 213 17.6 5.4 1.5 693 15.6 8.8 Death or MI 0.1 ng/mL 734 1.9 3.0 0.1 - 0.4 181 12.1 4.4 0.4 - 1.5 213 11.8 2.7 1.5 693 10.
21、0 5.9,Cardiac troponin I,JAMA 286:2405, 2001,Favors invasive treatment,Favors Conservative treatment,Odds ratio,Relation Between Creatinine Clearance, Troponin T, and Outcomes,CURE Rates and Relative Risks of First Primary Outcome,CP1019654-1,NEJM 345:494, 2001,CP1189452-4,4 peptides related with ea
22、ch other regarding biochemistry and physiological function Atrial natriuretic peptide (ANP) Brain (or B type) natriuretic peptide (BNP) C-type natriuretic peptide (CNP) Urodilatin, a slightly extended form of ANP,Natriuretic Peptide Family,Common 17-amino acid ring structure Ring structure highly co
23、nserved 11/17 amino acids are homologous Ring structure essential for physiological activity,CP1189452-5,Natriuretic Peptide Family Biochemistry,Cardiomyocyte,Blood,proBNP (108 aa) BNP-32 (proBNP 77-108),BNP-32 Physiologically active form,NT-proBNP 1-76,Secretion LV stretch Wall tension,Pre-proBNP (
24、134 aa),Signal peptide (26 aa),proBNP,Serin protease (Corin?),Mair: Scand J Clin Lab Invest, 1999,CP1189452-10,CP1189452-20,97.5% percentile (pg/mL),30 30-39 40-49 50-59 60,Age groups,Age-Specific Reference Range for NT-proBNP,AHJ 149(4), April 2005,pg/mL,NT-proBNP,pg/mL,BNP,Weight categories (BMI),
25、Weight categories (BMI),25,25-29.9,30,25,25-29.9,30,P0.001,P0.001,Values of BNP and NTproBNP by Weight,CP1189452-21,38 4,BNP concentration (pg/mL),Diagnosis,n=139,1,076 138,No CHF,CP1189452-25,n=97,CHF,LV dysfunction No acute CHF,n=14,141 31,BNP Levels of Patients Diagnosed Without CHF, with Baselin
26、e Left Ventricular Dysfunction, and with CHF,BNP Levels in Heart Failure,Median BNP level (pg/mL),CP1189452-26,BNP Levels in Normal Subjects and Inpatients with Heart Failure,Normal,I,II,III,IV,Class,CP1189452-27,ED Probability of CHF Recorded,P0.0001 from clinical judgment to combined,McCullough PA
27、 et al: Circulation 106:416, 2002,Diagnostic accuracy (%),Clinical judgment,BNP,Combined,70 72 74 76 78 80 82,74.0,81.2,81.5,n=1,538,BNP Study Primary End Point,n=1,586; 50% CHF; 56% male; 6417 yo; 41% COPD; 30% Hx CHF,CP1189452-28,BNP (pg/mL) Sens Spec PPV NPV50 97 62 71 95 100 90 76 79 89 150 85 8
28、3 83 85,AUC = 0.91,Breathing Not Proper (BNP) Multicenter Trial,AJC 95, April 15, 2005,Optimal cut-point Sens Spec PPV NPV Accuracy (%) (%) (%) (%) (%) (%) Rule-in cutpointsAll pt (n=599) 900 90 85 76 94 8750 yr old 450 93 95 67 99 95 n=14450 yr old 900 91 80 77 92 85 n=455 Rule-out ptAll pt (n=599)
29、 300 99 68 62 99 83,CP1189452-30,Optimal NT-proBNP Cutpoints for Acute Congestive Heart Failure,McCullough PA et al for the BNP Multinational Study Investigators: J Am Coll Cardiol 41:278A, 2003,Application of BNP Testing in CHF,“Grey Zone” BNP,BNP (pg/mL),“Grey Zone” BNP 100-500 pg/mL,26.4% of all
30、cases,16.5% CHF,7.9% No CHF,0,100,200,300,400,500,600,700,800,900,1,000,1,100,1,200,1,300,CP1189452-31,CP1189452-32,pg/mL Coronary pulmonale 200-500 Primary pulmonary 300-500 hypertension Acute pulmonary 150-500 embolism,BNP Elevations Right-Sided Coronary Heart Failure,CP1189452-33,Acute or chronic
31、 systolic or diastolic HF LV hypertrophy Inflammatory cardiac diseases Systemic arterial hypertension with LVH Pulmonary hypertension Acute or chronic renal failure Ascitic liver cirrhosis Endocrine disorders (eg, hyper-aldosteronism, Cushings syndrome),When Can Non-CHF Patients Present with BNP Ele
32、vations?,CP1189452-34,Well HF patients Acute mitral regurgitation Pulmonary edema 1 hour old Other cases “up-stream” from left ventricle Mitral stenosis Atrial myoxma,When Will CHF Present Without BNP Elevations?,P 0.0001,P = 0.9,Baseline BNP & Clinical Outcomes,P 0.0001,P = 0.9,Death,MI,N = 1356,N
33、= 320,Morrow DA JACC 2004,CP1173030-6,Relationship of NT-proBNP and cTnT,*P0.01 vs NT-proBNP 250 ng/L Circulation 110:3206, 2004,*,*,Death/MI at 6 months,Test for interaction: P=NS,%,BNP neg BNP cut point = 80 pg/mL,CP1189452-45,CONS,INV,BNP pos (19% BNP pos),n= 681 685 156 164,Morrow DA: JACC, 2004
34、,Baseline BNP: CONS vs INV Strategy,Beta-Blocker Therapy and BNP Levels,Luchner A et al: JACC 32:1839, 1998,pg/ mL,pmol/ mL,ANP 32%,BNP 89%,cGMP 18%,n=592,n=80,P0.01,P0.01,P0.01,No b-blocker (n=592) b-blocker (n=80),CP1189452-59,Outcomes by Number of Positive Outcomes TACTICS-TIMI 18,CP1143360-10,Ci
35、rc 109:584, 2004,Death or MI (%),P=NS,Positive markers (no.),P=NS,P=NS,2.9,4.4,6.2,6.5,12.1,13.3,Death or MI by Multimarker Approach,Odds of Positive Marker TACTICS-TIMI 18,CP1143360-7,Circ 109:583, 2004,T18 Tnl T11 Tnl Combined T18 TnT T11 TnT Combined T18 BNP T16 BNP Combined T18 CRP T11 CRP Combined,Male more likely,Female more likely,0 0.5 1 1.5 2,
