CP887679- 1

Use of Biomarkers in Patients with Acute Use of Biomarkers in Patients with Acute Cardiovascular DiseaseCardiovascular Disease

Allan S. Jaffe, MD.*Allan S. Jaffe, MD.*Consultant - Cardiology & Laboratory Consultant - Cardiology & Laboratory

Medicine MedicineProfessor of MedicineProfessor of MedicineMayo Clinic and Medical SchoolMayo Clinic and Medical SchoolRochester, MinnesotaRochester, 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.

CP1051812-1

Clinical Outcomes by Braunwald ClassClinical Outcomes by Braunwald Class

0.0

0.5

1.0

0 30 60 90 120 150 180

DaysDaysDaysDays

DaysDaysDaysDaysPrimary Unstable AnginaPrimary Unstable Angina

Class BClass BPrimary Unstable AnginaPrimary Unstable Angina

Class BClass BPostinfarction AnginaPostinfarction Angina

Class CClass CPostinfarction AnginaPostinfarction Angina

Class CClass C

Accelerated AnginaAccelerated AnginaClass IClass I

Accelerated AnginaAccelerated AnginaClass IClass I

Subacute Angina at RestSubacute Angina at RestClass IIClass II

Subacute Angina at RestSubacute Angina at RestClass IIClass II

Acute Angina at RestAcute Angina at RestClass IIIClass III

Acute Angina at RestAcute Angina at RestClass IIIClass III

PPPP

PPPP

SurvivalSurvival

Infarct freeInfarct free

Infarct free withoutInfarct free withoutinterventionintervention

SurvivalSurvival

Infarct freeInfarct free

Infarct free withoutInfarct free withoutinterventionintervention

0.970.970.970.97

0.910.910.910.91

0.530.530.530.53

0.960.960.960.96

0.880.880.880.88

0.720.720.720.72

0.940.940.940.94

0.860.860.860.86

0.350.350.350.35

0.970.970.970.97

0.890.890.890.89

0.550.550.550.55

0.890.890.890.89

0.800.800.800.80

0.370.370.370.37

JACC 25:1286, 1995JACC 25:1286, 1995JACC 25:1286, 1995JACC 25:1286, 1995

CP887679- 3

ECG Risk Factors in Patients with ACSECG Risk Factors in Patients with ACS

Death or MIDeath or MI(%)(%)

DaysDaysJACC 36(3):970-1062, 2000JACC 36(3):970-1062, 2000

ST elevation and depressionST elevation and depression

ST depression onlyST depression only

ST elevation onlyST elevation only

T-wave inversion onlyT-wave inversion only

No ST or T-wave changeNo ST or T-wave change n=237n=237

n=287n=287

n=93n=93

n=216n=216

n=78n=78

CP956024-12

0

10

20

30

0 60 120 180 240 300 360

CP887679- 4

0

10

20

30

ST-segment shift T-wave change

Relationship of ECG Changes and FPA*Relationship of ECG Changes and FPA*

FPAFPA(nM)(nM)

**JACC 18:898-903, 1991JACC 18:898-903, 1991

100

nl <1.5nl <1.5

CP887679- 5

0.5

0.6

0.7

0.8

0.9

1.0

0 60 120 180 240 300 360

Long-Term Prognostic Value of ElevatedLong-Term Prognostic Value of ElevatedcTnI in Unstable AnginacTnI in Unstable Angina

% % freefreefromfromdeathdeathand/orand/or

AMIAMI

Time from admission (days)Time from admission (days)

Normal cTnINormal cTnI

Log rank 6.63, P=0.01Log rank 6.63, P=0.01

Elevated cTnIElevated cTnI

Circulation. 1997;95:2053-2059

CP887679- 6

Antman, 1998Antman, 1998 1.1 (0.4-3.5)1.1 (0.4-3.5)

Benamer, 1998Benamer, 1998 13.7 (3.9-48.3)13.7 (3.9-48.3)

Brisisc, 1998Brisisc, 1998 8.0 (0.9-65.1)8.0 (0.9-65.1)

Cin, 1996Cin, 1996 17.9 (5.2-61.2)17.9 (5.2-61.2)

Galvani, 1997Galvani, 1997 6.6 (1.3-32.3)6.6 (1.3-32.3)

Hamm, 1992Hamm, 1992 11.7 (3.2-42.6)11.7 (3.2-42.6)

Luscher, 1997Luscher, 1997 2.5 (1.3-4.8)2.5 (1.3-4.8)

Ohman, 1996Ohman, 1996 4.7 (1.7-12.7)4.7 (1.7-12.7)

Olatidoye, 1998Olatidoye, 1998 156.1 (17.4-1,402)156.1 (17.4-1,402)

Ottani, 1997Ottani, 1997 6.6 (2.0-22.1)6.6 (2.0-22.1)

Rebuzzi, 1998Rebuzzi, 1998 25.3 (5.2-123.2)25.3 (5.2-123.2)

Solymoss, 1997Solymoss, 1997 2.4 (0.7-8.1)2.4 (0.7-8.1)

Stubbs, 1996Stubbs, 1996 1.5 (0.5-4.2)1.5 (0.5-4.2)

Wu, 1995Wu, 1995 31.5 (6.7-144.9)31.5 (6.7-144.9)

Antman, 1996Antman, 1996 3.8 (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 Elevation

Peto OR & 95% CI (fixed)Peto OR & 95% CI (fixed)

Pooled OR P<0.0001Pooled OR P<0.0001

0.2 0.1 1 5 10 50

FavorsFavorslower risklower risk

FavorsFavorshigher riskhigher risk

4.8 (3.6-6.5)4.8 (3.6-6.5)

CP887679- 7

Antman, 1996Antman, 1996 3.82 (1.03-14.18)3.82 (1.03-14.18)

Benamer, 1998Benamer, 1998 13.68 (3.87-48.33)13.68 (3.87-48.33)

Brisisc, 1998Brisisc, 1998 7.96 (0.97-65.25)7.96 (0.97-65.25)

Cin, 1996Cin, 1996 17.91 (5.24-61.25)17.91 (5.24-61.25)

Galvani, 1997Galvani, 1997 6.55 (1.32-32.38)6.55 (1.32-32.38)

Hamm, 1992Hamm, 1992 11.71 (3.22-42.57)11.71 (3.22-42.57)

Luscher, 1997Luscher, 1997 5.93 (1.61-21.79)5.93 (1.61-21.79)

Olatidoye, 1998Olatidoye, 1998 156.17 (17.39-1,402.09)156.17 (17.39-1,402.09)

Rebuzzi, 1998Rebuzzi, 1998 25.27 (5.18-123.23)25.27 (5.18-123.23)

Solymoss, 1997Solymoss, 1997 4.93 (0.72-33.19)4.93 (0.72-33.19)

Wu, 1995Wu, 1995 31.52 (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 Values

Peto OR & 95% CI (fixed)Peto OR & 95% CI (fixed)

Pooled ORPooled ORP<0.0001P<0.0001

0.2 0.1 1 5 10 50

FavorsFavorslower risklower risk

FavorsFavorshigher riskhigher risk

11.83 (7.56-18.51)11.83 (7.56-18.51)

CP887679- 8

cTnI in Patients with Unstable AnginacTnI in Patients with Unstable AnginaM

ort

alit

y at

42

day

sM

ort

alit

y at

42

day

s(%

of

pat

ien

ts)

(% o

f p

atie

nts

)

CP886232- 8NEJM 335:1342-1349, 1996NEJM 335:1342-1349, 1996

Cardiac Troponin I (ng/mL)Cardiac Troponin I (ng/mL)

1

1.7

3.43.7

6

7.5

0

1

2

3

4

5

6

7

8

0 to <0.4 0.4 to <1.0 1.0 to <2.0 2.0 to <5.0 5.0 to <9.0 9

831 174 148 134 50 67

1.0 1.8 3.5 3.9 6.2 7.8Risk ratio--- 0.5-6.7 1.2-10.6 1.3-11.7 1.7-22.3 2.6-23.095% CI

CP887679- 9

Synergism of ECG and Elevated Troponins Synergism of ECG and Elevated Troponins (PARAGON)(PARAGON)

CP1099500-8JACC 41:376, 2003JACC 41:376, 2003

0

5

10

15

20

25

30

No 1 mm 2 mm

6-modeath/MI rate

6-modeath/MI rate

n=262

ST-depressionST-depression

P=0.20P=0.20

n=125 n=259

n=174n=57

n=82

P=0.13P=0.13

P=0.15P=0.15Troponin–Troponin+Troponin–Troponin+

CP887679- 10

FRISC-II – GUSTO IV (Death and MI)FRISC-II – GUSTO IV (Death and MI)

CP1142356-17James et al: Am J Med 115:181, 2003James et al: Am J Med 115:181, 2003

14

12

10

8

6

4

2

0

14

12

10

8

6

4

2

00.01 µg/L0.01 µg/L

FRISC-IIFRISC-II

De

ath

an

d M

I at

30 d

ays

(%

)D

ea

th a

nd

MI a

t 30

day

s (

%)

0.03 µg/L0.03 µg/L

P=0.04P=0.04

Below cutoff Above cutoffBelow cutoff Above cutoff

0.1 µg/L0.1 µg/L

P=0.01P=0.01 P=0.15P=0.15

CutoffCutoff

0.01 µg/L0.01 µg/L

GUSTO-IVGUSTO-IV

0.03 µg/L0.03 µg/L

P<0.001P<0.001

0.1 µg/L0.1 µg/L

P<0.001P<0.001 P<0.001P<0.001

CutoffCutoff

1111

8080

1717

7474

3030

6161

6666

521521

111111

476476

201201

386386

265 809 328 746 430 644 1,992 5,123 2,563 4,552 3,446 3,679

CP887679- 11

0.0

10.0

20.0

30.0

40.0

50.0

60.0

A B C D E G H

To

tal C

V,

%

ACS180

Centaur

Immuno 1

Access

Access2

Vidas

Liaison

RXL

CS

Opus

Immulite

Alpha Dx

ECi

AIA 21

IFCC Precision Study(Clinical Chem 2004)

CP887679- 12CP1148152-7

cTnI Positives and cTnT Levels: An assay ComparisoncTnI Positives and cTnT Levels: An assay Comparison

Int J Cardiol 93:113, 2004Int J Cardiol 93:113, 2004

Positive R-TnI(%)

Positive R-TnI(%)

TnT levels (g/L)TnT levels (g/L)

R-TnI pos

R-TnI neg

R-TnI pos

R-TnI neg

0.01 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 >

1,2171,217653653

171171

7272 46461414

1919 161611

77 44 2525

212212264264

285285

245245 178178167167

128128 9292 6565 5454 4304308282

-100

-80

-60

-40

-20

0

20

40

60

80

100

CP887679- 13

0369

12

0369

12

0369

12

OR 4.55; 2.66-7.78

Rapid Troponin I AssayRapid Troponin I Assay

Outcomes in Relation to Troponin Values: The Outcomes in Relation to Troponin Values: The Issue of Assay SensitivityIssue of Assay Sensitivity

CP1148152-9

Int J Cardiol 93:113, 2004Int J Cardiol 93:113, 2004

%%

NegNeg

DeathDeath MIMI Death or MIDeath or MI

56 98 92 130 132 205

Troponin T (0.1 g/L)Troponin T (0.1 g/L)

Troponin T (0.01 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

PosPos

%%

%%

41

15

113

139

86

25

136

197

116

36

221

301

CP887679- 14

Correspondence Between Commercial Assays and Correspondence Between Commercial Assays and Western BlottingWestern Blotting

Assay Positive WBDSA Negative 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

CP887679- 15

MyeloperoxidaseMyeloperoxidasePredictions of Events When cTNT “Negative”Predictions of Events When cTNT “Negative”

CP1131968-3

NEJM 349:1600, 2003NEJM 349:1600, 2003

0 1 2 3 4 5 6 7 8 9 10 0 1 2 3 4 5 6 7 8 9 10

Odds ratioOdds ratio Odds ratioOdds ratio

Revascularization

Myeloperoxidase quartile 2

Myeloperoxidase quartile 3

Myeloperoxidase quartile 4

Major adverse cardiac events

Myeloperoxidase quartile 2

Myeloperoxidase quartile 3

Myeloperoxidase quartile 4

Revascularization

Myeloperoxidase quartile 2

Myeloperoxidase quartile 3

Myeloperoxidase quartile 4

Major adverse cardiac events

Myeloperoxidase quartile 2

Myeloperoxidase quartile 3

Myeloperoxidase quartile 4

30 Days30 Days 6 Months6 Months

UnadjustedUnadjusted AdjustedAdjusted

CP887679- 16

Prognostic Effects of MPO at 72 HoursPrognostic Effects of MPO at 72 Hours

CP1132618-7

Death,Death,MIMI(%)(%)

Death,Death,MIMI(%)(%)

Circulation 108:1443, 2003Circulation 108:1443, 2003

0

5

10

15

0 24 48 72

Before PCIBefore PCIBefore PCIBefore PCI

Adjusted hazard ratioAdjusted hazard ratio2.04 (0.65-6.42)2.04 (0.65-6.42)

Adjusted hazard ratioAdjusted hazard ratio2.04 (0.65-6.42)2.04 (0.65-6.42) Adjusted hazard ratioAdjusted hazard ratio

3.07 (1.21-4.26)3.07 (1.21-4.26)Adjusted hazard ratioAdjusted hazard ratio

3.07 (1.21-4.26)3.07 (1.21-4.26)

MPO highMPO highMPO highMPO high

MPO lowMPO lowMPO lowMPO low

After PCIAfter PCIAfter PCIAfter PCIHoursHoursHoursHours

CP887679- 17

cTnI Negative ACS?cTnI Negative ACS?

Circulation 107:533, 2003Circulation 107:533, 2003Circulation 107:533, 2003Circulation 107:533, 2003

CP1104508-19

CP887679- 18

Sensitivity of cTnI, CK-MB, and Myoglobin with Sensitive Sensitivity of cTnI, CK-MB, and Myoglobin with Sensitive Contemporary AssaysContemporary Assays

0

20

40

60

80

100

AHJ 148:577, 2004AHJ 148:577, 2004

TnI (0.1 µg/L) CK-MB (3.5 µg/L) Myo (98/56 µg/L)TnI (0.1 µg/L) CK-MB (3.5 µg/L) Myo (98/56 µg/L)

CP1176222-2

0

20

40

60

80

100

0 min 30 min 60 min 90 minSensitivity

2 hr 3 hr 6 hr 6 hrSpecificity

TnI (0.4 µg/L) TnI (0.1 µg/L) TnI (0.07 µg/L)TnI (0.4 µg/L) TnI (0.1 µg/L) TnI (0.07 µg/L)

CP887679- 19

100

80

60

40

20

0

Sensitivity of Admission Values By Time from Sensitivity of Admission Values By Time from Onset of SymptomsOnset of Symptoms

CP1176222-4AHJ 148:578, 2004AHJ 148:578, 2004

TnI0.07 µg/L

TnI0.1 µg/L

TnI0.4 µg/L

CK-MB Myoglobin

8684

64

36

68

53

67

57

100

86

<4 hours (n=58)

>4 hours (n=118)

CP887679- 20

cTnT and Angiographic MeasurescTnT and Angiographic Measures

CP1179389-5

TnT (<0.01)TnT (<0.01)Prog Cardiovasc Dis 47(3), 2004Prog Cardiovasc Dis 47(3), 2004

64.8

72.0

60

62

64

66

68

70

72

74P<0.001P<0.001

Stenosis (%)Stenosis (%)

TnT (>0.01)TnT (>0.01)

29.3

42.5

0

10

20

30

40

50P=0.02P=0.02

Thrombus (%)Thrombus (%)

7.0

15.6

0

5

10

15

20P=0.03P=0.03

TFG 0/1 (%)TFG 0/1 (%)

42.1

58.1

0

10

20

30

40

50

60

70P<0.001P<0.001

TMPG 0/1 (%)TMPG 0/1 (%)

CP887679- 21

02468

10

02468

10

JACC 36(3):970-JACC 36(3):970-1062, 20001062, 2000

Medical and Interventional Response to GP IIb/IIIa Agents in Medical and Interventional Response to GP IIb/IIIa Agents in Troponin Positive PatientsTroponin Positive Patients

02468

10

02468

10

+24h+24h +48h+48h+24h+24h +48h+48h +72h+72h

n=1,265n=1,265OR=0.37OR=0.37P=0.032P=0.032

CAPTURECAPTURE

2.8%2.8%1.3%1.3%

n=9,461n=9,461OR=0.72OR=0.72P=0.003P=0.003

PURSUITPURSUIT

n=1,570n=1,570OR=0.45OR=0.45P=0.016P=0.016

PRISM-PLUSPRISM-PLUS

n=12,296n=12,296OR=0.66OR=0.66P=0.001P=0.001

AllAll

n=1,239n=1,239OR=0.46OR=0.46P=0.009P=0.009

n=1,228n=1,228OR=0.71OR=0.71P=0.105P=0.105

n=287n=287OR=0.35OR=0.35P=0.062P=0.062

n=2,754n=2,754OR=0.59OR=0.59P=0.001P=0.001

5.8%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/placebo Percutaneous coronary interventionPercutaneous coronary interventionCP956024-13

CP887679- 22

LMW Heparin vs VF Heparin in TIMI 11BLMW Heparin vs VF Heparin in TIMI 11B

J Am Coll Cardiol 36:1812, 2000J Am Coll Cardiol 36:1812, 2000 CP1008642-5

0

10

20

30

40

50

D/MI UR D/MI/UR D/MI UR D/MI/UR

Cli

nic

al e

ven

ts a

t 14

day

s (%

)C

lin

ical

eve

nts

at

14 d

ays

(%)

CK

MB

neg

ativ

e p

atie

nts

CK

MB

neg

ativ

e p

atie

nts EnoxaparinEnoxaparin

UFHUFH

66

P=0.006P=0.006

66

0044

6699

1717

1010 1111

4040

2121

2828

P=0.007P=0.007

cTnI NegativecTnI Negativen=179n=179

cTnI PositivecTnI Positiven=180n=180

CP887679- 23

TACTICS (TIMI 18)TACTICS (TIMI 18)

CP1036852-9

Conservative InvasiveNo. treatment treatment

Primary endpoint<0.1 ng/mL 734 4.3 6.60.1 - <0.4 181 16.5 4.40.4 - <1.5 213 17.6 5.41.5 693 15.6 8.8

Death or MI<0.1 ng/mL 734 1.9 3.00.1 - <0.4 181 12.1 4.40.4 - <1.5 213 11.8 2.71.5 693 10.0 5.9

Conservative InvasiveNo. treatment treatment

Primary endpoint<0.1 ng/mL 734 4.3 6.60.1 - <0.4 181 16.5 4.40.4 - <1.5 213 17.6 5.41.5 693 15.6 8.8

Death or MI<0.1 ng/mL 734 1.9 3.00.1 - <0.4 181 12.1 4.40.4 - <1.5 213 11.8 2.71.5 693 10.0 5.9

Cardiac troponin ICardiac troponin I

JAMA 286:2405, 2001JAMA 286:2405, 2001

0.010.01 0.10.1 1.01.0 1010

Favors invasive

treatment

Favors invasive

treatment

Favors Favors Conservative Conservative

treatmenttreatment

Favors Favors Conservative Conservative

treatmenttreatment

Odds ratioOdds ratio

CP887679- 24

Relation Between Creatinine Clearance,Relation Between Creatinine Clearance,Troponin T, and OutcomesTroponin T, and Outcomes

Troponin T LevelTroponin T Level(mcg per Liter)(mcg per Liter)

Creatinine ClearanceCreatinine Clearance(ml per minute)(ml per minute)

0.000-0.0100.000-0.010

0.011-0.1140.011-0.114

0.015-0.4630.015-0.463

0.465-17.300.465-17.30 > 98.6> 98.677.0-98.577.0-98.5

58.4-76.958.4-76.94.7-58.34.7-58.3

Death or MI %Death or MI %2525

2020

1515

1010

55

00

2525

2020

1515

1010

55

00

CP887679- 25

CURECURERates and Relative Risks of First Primary OutcomeRates and Relative Risks of First Primary Outcome

CP1019654-1

Pt with event (%)Pt with event (%)Patients

Characteristic (no.) Placebo ClopidogrelOverall 12,562 11.4 9.3Associated MI 3,283 13.7 11.3No associated MI 9,279 10.6 8.6Male 7,726 11.9 9.1Female 4,836 10.7 9.565 yr old 6,354 7.6 5.4>65 yr old 6,208 15.3 13.3ST-segment deviation 6,275 14.3 11.5No ST-segment deviation 6,287 8.6 7.0Enzymes elevated at entry 3,176 13.0 10.7Enzymes not elevated at entry 9,386 10.9 8.8Diabetes 2,840 16.7 14.2No diabetes 9,722 9.9 7.9Low risk 4,187 6.7 5.1Intermediate risk 4,185 9.4 6.5High risk 4,184 18.0 16.3History of revascularization 2,246 14.4 8.4No history of revascularization 10,316 10.7 9.5Revascularization after randomization 4,577 13.9 11.5No revascularization after randomization 7,985 10.0 8.1

PatientsCharacteristic (no.) Placebo ClopidogrelOverall 12,562 11.4 9.3Associated MI 3,283 13.7 11.3No associated MI 9,279 10.6 8.6Male 7,726 11.9 9.1Female 4,836 10.7 9.565 yr old 6,354 7.6 5.4>65 yr old 6,208 15.3 13.3ST-segment deviation 6,275 14.3 11.5No ST-segment deviation 6,287 8.6 7.0Enzymes elevated at entry 3,176 13.0 10.7Enzymes not elevated at entry 9,386 10.9 8.8Diabetes 2,840 16.7 14.2No diabetes 9,722 9.9 7.9Low risk 4,187 6.7 5.1Intermediate risk 4,185 9.4 6.5High risk 4,184 18.0 16.3History of revascularization 2,246 14.4 8.4No history of revascularization 10,316 10.7 9.5Revascularization after randomization 4,577 13.9 11.5No revascularization after randomization 7,985 10.0 8.1

Relative risk (95% CI)Relative risk (95% CI)

0.4 0.6 0.8 1 1.2Clopidogrel

betterClopidogrel

betterPlacebobetter

Placebobetter

NEJM 345:494, 2001NEJM 345:494, 2001

CP887679- 26CP1189452-4

4 peptides related with each other regarding biochemistry and physiological function

• Atrial natriureticpeptide (ANP)

• Brain (or B type)natriuretic peptide(BNP)

• C-type natriuretic peptide(CNP)

• Urodilatin, a slightly extended form of ANP

4 peptides related with each other regarding biochemistry and physiological function

• Atrial natriureticpeptide (ANP)

• Brain (or B type)natriuretic peptide(BNP)

• C-type natriuretic peptide(CNP)

• Urodilatin, a slightly extended form of ANP

HH22

NN——COOHCOOH——COOHCOOH

CF

C

D R I

S

GL

CC

Natriuretic Peptide FamilyNatriuretic Peptide Family

Natriuretic Peptide FamilyNatriuretic Peptide Family

CP887679- 27

• Common 17-amino acidring structure

• Ring structure highlyconserved

• 11/17 amino acidsare homologous

• Ring structure essentialfor physiological activity

• Common 17-amino acidring structure

• Ring structure highlyconserved

• 11/17 amino acidsare homologous

• Ring structure essentialfor physiological activity

HH22

NN——COOHCOOH——COOHCOOH

CF

C

D R I

S

GL

CC

CP1189452-5

Natriuretic Peptide FamilyNatriuretic Peptide FamilyBiochemistryBiochemistry

Natriuretic Peptide FamilyNatriuretic Peptide FamilyBiochemistryBiochemistry

CP887679- 28

CardiomyocyteCardiomyocyteCardiomyocyteCardiomyocyte

BloodBloodBloodBlood

proBNP (108 aa)BNP-32 (proBNP 77-108) proBNP (108 aa)BNP-32 (proBNP 77-108)

BNP-32Physiologically active form

BNP-32Physiologically active form

NT-proBNP 1-76NT-proBNP 1-76

SecretionLV stretch

Wall tension

SecretionLV stretch

Wall tension

Pre-proBNP (134 aa)Pre-proBNP (134 aa)

Signal peptide (26 aa)Signal peptide (26 aa)

proBNPproBNP

Serin protease(Corin?)

Serin protease(Corin?)

Mair: Scand J Clin Lab Invest, 1999Mair: Scand J Clin Lab Invest, 1999

CP1189452-10

CP887679- 29

0

50

100

150

200

250

50 60 70 80

BNP Values by Age and GenderBNP Values by Age and Gender

JACC 40:978, 2002JACC 40:978, 2002

Age (yr)Age (yr)

Bio

site

® B

NP

(p

g/m

L)

Bio

site

® B

NP

(p

g/m

L)

Sh

ion

og

i® B

NP

(p

g/m

L)

Sh

ion

og

i® B

NP

(p

g/m

L)

CP1189452-19

MalesMales

Age (yr)Age (yr)

FemalesFemales

CP887679- 30CP1189452-20

0

100

200

300

400

97.5%percentile(pg/mL)

97.5%percentile(pg/mL)

<30 30-39 40-49 50-59 60<30 30-39 40-49 50-59 60

Age groupsAge groups

MalesMales

FemalesFemales

Age-Specific Reference RangeAge-Specific Reference Rangefor NT-proBNPfor NT-proBNP

Age-Specific Reference RangeAge-Specific Reference Rangefor NT-proBNPfor NT-proBNP

CP887679- 31

0

5,000

10,000

15,000

20,000

25,000

30,000

0

500

1,000

1,500

2,000

2,500

3,000

3,500

AHJ 149(4), April 2005AHJ 149(4), April 2005

pg

/mL

pg

/mL

pg

/mL

pg

/mL

NT-proBNPNT-proBNPNT-proBNPNT-proBNP

pg

/mL

pg

/mL

pg

/mL

pg

/mL

BNPBNPBNPBNP

Weight categories (BMI)Weight categories (BMI)Weight categories (BMI)Weight categories (BMI) Weight categories (BMI)Weight categories (BMI)Weight categories (BMI)Weight categories (BMI)

25 25 25 25 25-29.9 25-29.9 25-29.9 25-29.9 30 30 30 30 25 25 25 25 25-29.9 25-29.9 25-29.9 25-29.9 30 30 30 30

P<0.001 P<0.001 P<0.001 P<0.001 P<0.001 P<0.001 P<0.001 P<0.001

Values of BNP and NTproBNP by WeightValues of BNP and NTproBNP by WeightValues of BNP and NTproBNP by WeightValues of BNP and NTproBNP by Weight

CP1189452-21

CP887679- 32

Influence of multiple sampling on BNP and NT-proBNP RCVs; the RCVs for BNP, NT-Influence of multiple sampling on BNP and NT-proBNP RCVs; the RCVs for BNP, NT-proBNP, and BNP >350 ng/L are shown separately, as derived from singleton, duplicate, proBNP, and BNP >350 ng/L are shown separately, as derived from singleton, duplicate, and triplicate sampling with each sample analyzed in singleton, for estimating the and triplicate sampling with each sample analyzed in singleton, for estimating the homeostatic setpoints of the 2 serial resultshomeostatic setpoints of the 2 serial results

Influence of multiple sampling on BNP and NT-proBNP RCVs; the RCVs for BNP, NT-Influence of multiple sampling on BNP and NT-proBNP RCVs; the RCVs for BNP, NT-proBNP, and BNP >350 ng/L are shown separately, as derived from singleton, duplicate, proBNP, and BNP >350 ng/L are shown separately, as derived from singleton, duplicate, and triplicate sampling with each sample analyzed in singleton, for estimating the and triplicate sampling with each sample analyzed in singleton, for estimating the homeostatic setpoints of the 2 serial resultshomeostatic setpoints of the 2 serial results

Week-to-week

RCV (%)

Week-to-week

RCV (%)

Patient samples (no.)Patient samples (no.)

BNPNT-proBNPBNP >350 ng/L

BNPNT-proBNPBNP >350 ng/L

CP1189452-22

Clin Chem 50:2054, 2004Clin Chem 50:2054, 2004Clin Chem 50:2054, 2004Clin Chem 50:2054, 2004

5757

8282

6868

113113

9898

69698787

64645454

Multiple SamplingMultiple Sampling

11 22 33

CP887679- 33

38 ± 438 ± 4

BNPconcentration

(pg/mL)

BNPconcentration

(pg/mL)

DiagnosisDiagnosis

n=139n=139

1,076 ± 1381,076 ± 138

No CHFNo CHF

CP1189452-25

n=97n=97CHFCHFLV dysfunction

No acute CHFLV dysfunctionNo acute CHF

n=14n=14

141 ± 31141 ± 31

BNP 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 CHF

BNP 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 CHF

0

200

400

600

800

1,000

1,200

1,400

CP887679- 34

12.395.4

221.5

459.1

1006.3

0

200

400

600

800

1,000

1,200

BNP Levels in Heart FailureBNP Levels in Heart Failure

MedianBNP level

(pg/mL)

MedianBNP level

(pg/mL)

CP1189452-26

BNP Levels in Normal Subjects and Inpatientswith Heart Failure

BNP Levels in Normal Subjects and Inpatientswith Heart Failure

NormalNormal II IIII IIIIII IVIV

ClassClass

CP887679- 35CP1189452-27

ED Probability of CHF RecordedED Probability of CHF Recorded

P<0.0001 from clinical judgment to combinedP<0.0001 from clinical judgment to combinedMcCullough PA et al: Circulation 106:416, 2002McCullough PA et al: Circulation 106:416, 2002

Diagnostic accuracy (%)Diagnostic accuracy (%)

Clinicaljudgment

Clinicaljudgment

BNPBNP

CombinedCombined

70 72 74 76 78 80 8270 72 74 76 78 80 82

74.0

81.2

81.5

n=1,538n=1,538

BNP Study Primary End PointBNP Study Primary End PointBNP Study Primary End PointBNP Study Primary End Point

CP887679- 36

n=1,586; 50% CHF; 56% male;64±17 yo; 41% COPD; 30% Hx CHF

n=1,586; 50% CHF; 56% male;64±17 yo; 41% COPD; 30% Hx CHF

CP1189452-28

BNP(pg/mL) Sens Spec PPV NPV

50 97 62 7195

100 90 76 7989

150 85 83 8385

BNP(pg/mL) Sens Spec PPV NPV

50 97 62 7195

100 90 76 7989

150 85 83 8385

AUC = 0.91AUC = 0.91

Breathing Not Proper (BNP)Breathing Not Proper (BNP)Multicenter TrialMulticenter Trial

Breathing Not Proper (BNP)Breathing Not Proper (BNP)Multicenter TrialMulticenter Trial

CP887679- 37

0.0

0.2

0.4

0.6

0.8

1.0

0.0 0.2 0.4 0.6 0.8 1.0

Sen

siti

vity

Sen

siti

vity

(tru

e-p

osi

tive

s)(t

rue-

po

siti

ves)

Sen

siti

vity

Sen

siti

vity

(tru

e-p

osi

tive

s)(t

rue-

po

siti

ves)

1-1-specificity (false-positives)specificity (false-positives)1-1-specificity (false-positives)specificity (false-positives)AJC 95, April 15, 2005AJC 95, April 15, 2005

Area underArea underthe curvethe curve

CombinedCombined 0.960.96NT-proBNPNT-proBNP 0.940.94Clinical judgmentClinical judgment 0.900.90

Area underArea underthe curvethe curve

CombinedCombined 0.960.96NT-proBNPNT-proBNP 0.940.94Clinical judgmentClinical judgment 0.900.90

ModalityModalityModalityModality

NT-proBNP and Clinical Judgment of the Diagnosis NT-proBNP and Clinical Judgment of the Diagnosis of CHFof CHF

NT-proBNP and Clinical Judgment of the Diagnosis NT-proBNP and Clinical Judgment of the Diagnosis of CHFof CHF

CP1189452-29

CP887679- 38AJC 95, April 15, 2005AJC 95, April 15, 2005

Optimal cut-point Sens Spec PPV NPV Accuracy

(%) (%) (%) (%) (%) (%)

Rule-in cutpoints

All pt (n=599) 900 90 85 76 94 87

<50 yr old 450 93 95 67 99 95n=144

50 yr old 900 91 80 77 92 85n=455

Rule-out pt

All pt (n=599) 300 99 68 62 99 83

Optimal cut-point Sens Spec PPV NPV Accuracy

(%) (%) (%) (%) (%) (%)

Rule-in cutpoints

All pt (n=599) 900 90 85 76 94 87

<50 yr old 450 93 95 67 99 95n=144

50 yr old 900 91 80 77 92 85n=455

Rule-out pt

All pt (n=599) 300 99 68 62 99 83

CP1189452-30

Optimal NT-proBNP Cutpoints for Acute Optimal NT-proBNP Cutpoints for Acute Congestive Heart FailureCongestive Heart Failure

Optimal NT-proBNP Cutpoints for Acute Optimal NT-proBNP Cutpoints for Acute Congestive Heart FailureCongestive Heart Failure

CP887679- 39

McCullough PA et al for the BNP Multinational Study Investigators: J Am Coll Cardiol 41:278A, 2003McCullough PA et al for the BNP Multinational Study Investigators: J Am Coll Cardiol 41:278A, 2003

Application of BNP Testing in CHFApplication of BNP Testing in CHF

0

100

200

300

400 “Grey Zone” BNP“Grey Zone” BNP

BNP (pg/mL)BNP (pg/mL)

“Grey Zone” BNP100-500 pg/mL

“Grey Zone” BNP100-500 pg/mL 26.4% of all cases26.4% of all cases

16.5%CHF

16.5%CHF

7.9%No CHF

7.9%No CHF

00 100100 200200 300300 400400 500500 600600 700700 800800 900900 1,0001,000 1,1001,100 1,2001,200 1,3001,300

CP1189452-31

CP887679- 40CP1189452-32

pg/mL

Coronary pulmonale 200-500

Primary pulmonary300-500 hypertension

Acute pulmonary 150-500 embolism

pg/mL

Coronary pulmonale 200-500

Primary pulmonary300-500 hypertension

Acute pulmonary 150-500 embolism

BNP ElevationsBNP ElevationsRight-Sided Coronary Heart FailureRight-Sided Coronary Heart Failure

BNP ElevationsBNP ElevationsRight-Sided Coronary Heart FailureRight-Sided Coronary Heart Failure

CP887679- 41CP1189452-33

• Acute or chronic 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, Cushing’s syndrome)

• Acute or chronic 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, Cushing’s syndrome)

When Can Non-CHF Patients Present with When Can Non-CHF Patients Present with BNP Elevations?BNP Elevations?

When Can Non-CHF Patients Present with When Can Non-CHF Patients Present with BNP Elevations?BNP Elevations?

CP887679- 42CP1189452-34

• Well HF patients

• Acute mitral regurgitation

• Pulmonary edema <1 hour old

• Other cases “up-stream” fromleft ventricle

Mitral stenosisAtrial myoxma

• Well HF patients

• Acute mitral regurgitation

• Pulmonary edema <1 hour old

• Other cases “up-stream” fromleft ventricle

Mitral stenosisAtrial myoxma

When Will CHF PresentWhen Will CHF PresentWithout BNP Elevations?Without BNP Elevations?When Will CHF PresentWhen Will CHF Present

Without BNP Elevations?Without BNP Elevations?

CP887679- 43

Circulation 108:278, 2003Circulation 108:278, 2003Circulation 108:278, 2003Circulation 108:278, 2003

0

4

8

12

16

20

0 120 240 360

CumulativeCumulativeprobabilityprobability

of deathof death(%)(%)

CumulativeCumulativeprobabilityprobability

of deathof death(%)(%)

DaysDaysDaysDays

>1,869 >1,869 ng/Lng/L>1,869 >1,869 ng/Lng/L

P<0.001P<0.001P<0.001P<0.001669-1,869 669-1,869 ng/Lng/L669-1,869 669-1,869 ng/Lng/L

238-668 238-668 ng/Lng/L238-668 238-668 ng/Lng/L

237 237 ng/Lng/L237 237 ng/Lng/L

CP1189452-43

Survival – GUSTO IV ACSSurvival – GUSTO IV ACSSurvival – GUSTO IV ACSSurvival – GUSTO IV ACS

CP887679- 44

11 22 33 44

in risk

Inclusion

Day 2

6 weeks

3 months

6 months

in risk

Inclusion

Day 2

6 weeks

3 months

6 months

JACC 45(4), 2005JACC 45(4), 2005

1.36 (1.04-1.76)1.36 (1.04-1.76)

1.83 (1.23-2.72)1.83 (1.23-2.72)

1.89 (1.14-3.14)1.89 (1.14-3.14)

1.29 (0.99-1.67)1.29 (0.99-1.67)

1.46 (1.06-2.03)1.46 (1.06-2.03)

CP1189452-44

Odds Ratio for Events by TimeOdds Ratio for Events by TimeOdds Ratio for Events by TimeOdds Ratio for Events by Time

<URL URL <HC HC

1.8 5.0 2.5 7.9

2.0 5.3 3.3 7.2

0.6 3.8 1.9 6.4

0.5 3.4 1.2 8.5

0.2 2.1 0.7 5.5

<URL URL <HC HC

1.8 5.0 2.5 7.9

2.0 5.3 3.3 7.2

0.6 3.8 1.9 6.4

0.5 3.4 1.2 8.5

0.2 2.1 0.7 5.5

in risk in risk

CP887679- 45

1.21.8

5.0

8.4

0

1

2

3

4

5

6

7

8

9

10

30 Days 6 Months

%

P < 0.0001 P = 0.9

Baseline BNP & Clinical Outcomes

P < 0.0001 P = 0.9

Death MI

3.8

5.2

4.1

5.3

0

1

2

3

4

5

6

7

8

9

10

30 Days 6 Months

%

BNP <= 80

BNP > 80

N = 1356N = 320

Morrow DA JACC 2004

CP887679- 46

0

1

2

3

4

5

6

0 10 20 30

CP1173030-5Circulation 110:3206, 2004Circulation 110:3206, 2004

Death and AMI by NTproBNP LevelsDeath and AMI by NTproBNP Levels

30-day follow-up30-day follow-up

Ev

ent

rate

at

30 d

ays

(%

)E

ven

t ra

te a

t 30

day

s (

%)

30-day follow-up30-day follow-up

DeathDeath Myocardial infarctionMyocardial infarction

0

1

2

3

4

5

0 10 20 30

Odds ratio6.0 [2.7-13.5]Odds ratio

6.0 [2.7-13.5]

NT-proBNP lowNT-proBNP low

NT-proBNP highNT-proBNP high

Odds ratio2.6 [1.5-4.5]Odds ratio2.6 [1.5-4.5]

NT-proBNP lowNT-proBNP low

NT-proBNP highNT-proBNP high

CP887679- 47CP1173030-6

Relationship of NT-proBNP and cTnTRelationship of NT-proBNP and cTnT

*P<0.01 vs NT-proBNP ≤250 ng/LCirculation 110:3206, 2004*P<0.01 vs NT-proBNP ≤250 ng/LCirculation 110:3206, 2004

0

2

4

6

8

10

12

14

16 15.1

7.2

9.1

7.1

5.6

1.3

>250 ng/L ≤250 ng/L <0.01 μg/L0.01 - 0.1 μg/L

>0.1 μg/L

NT-proBNPNT-proBNP Troponin TTroponin TDea

th, m

yoca

rdia

l in

farc

tio

n (

%)

Dea

th, m

yoca

rdia

l in

farc

tio

n (

%)

**

**

CP887679- 48

7.5

12.2

5.5

11.6

0

2

4

6

8

10

12

14 Death/MI at 6 monthsDeath/MI at 6 monthsTest for interaction:

P=NSTest for interaction:

P=NS

%%

BNP negBNP cut point = 80 pg/mL

BNP negBNP cut point = 80 pg/mL

CP1189452-45

CONSCONSINVINV

BNP pos(19% BNP pos)

BNP pos(19% BNP pos)

n= 681 685 156 164

Morrow DA: JACC, 2004Morrow DA: JACC, 2004

Baseline BNP: CONS vs INV StrategyBaseline BNP: CONS vs INV StrategyBaseline BNP: CONS vs INV StrategyBaseline BNP: CONS vs INV Strategy

CP887679- 49

0

20

40

60

80

0

1

2

3

4

5

Beta-Blocker Therapy and BNP LevelsBeta-Blocker Therapy and BNP Levels

Luchner A et al: JACC 32:1839, 1998Luchner A et al: JACC 32:1839, 1998

pg/mLpg/mL

pmol/mL

pmol/mL

ANP 32%ANP 32%

BNP 89%BNP 89%

cGMP 18%cGMP 18%

n=592

n=80

P<0.01P<0.01

P<0.01P<0.01

P<0.01P<0.01

No -blocker (n=592)

-blocker (n=80)

No -blocker (n=592)

-blocker (n=80)

CP1189452-59

CP887679- 50

0

5

10

15

0 1 2 or 3

Outcomes by Number of Positive OutcomesOutcomes by Number of Positive OutcomesTACTICS-TIMI 18TACTICS-TIMI 18

CP1143360-10Circ 109:584, 2004Circ 109:584, 2004

Deathor MI(%)

Deathor MI(%)

FemaleMaleFemaleMale

P=NSP=NS

Positive markers (no.)Positive markers (no.)

P=NSP=NS

P=NSP=NS

2.92.9

4.44.4

6.26.2 6.56.5

12.112.113.313.3

Death or MI by Multimarker ApproachDeath or MI by Multimarker Approach

CP887679- 51

Odds of Positive MarkerOdds of Positive MarkerTACTICS-TIMI 18TACTICS-TIMI 18

CP1143360-7Circ 109:583, 2004Circ 109:583, 2004

T18 TnlT11 TnlCombined

T18 TnTT11 TnTCombined

T18 BNPT16 BNPCombined

T18 CRPT11 CRPCombined

T18 TnlT11 TnlCombined

T18 TnTT11 TnTCombined

T18 BNPT16 BNPCombined

T18 CRPT11 CRPCombined

Male more likelyMale more likely Female more likelyFemale more likely0 0.5 1 1.5 20 0.5 1 1.5 2

CP887679- 52

Outcomes by GenderOutcomes by GenderTACTICS-TIMI 18TACTICS-TIMI 18

CP1143360-11Circ 109:584, 2004Circ 109:584, 2004

Any MarkerPositive (n=442)

Any MarkerPositive (n=442)

WomenWomenNo Marker

Positive (n=173)No Marker

Positive (n=173)

MenMen

%%

InvasiveInvasive InvasiveInvasiveConser-vative

Conser-vative

Conser-vative

Conser-vative

3030

2020

1010

00

P=0.03P=0.03

P=0.02P=0.02

RehospRehosp

Death/MIDeath/MI

Any MarkerPositive (n=885)

Any MarkerPositive (n=885)

No MarkerPositive (n=297)

No MarkerPositive (n=297)

InvasiveInvasive InvasiveInvasiveConser-vative

Conser-vative

Conser-vative

Conser-vative

P=0.002P=0.002

P=NSP=NSP=0.07P=0.07

P=NSP=NS

P=NSP=NSP=NSP=NS