Biomarkers For Prediction Of Major Adverse Cardiac Events And Uses Thereof

• US 20110053179A1
• Filed: 08/30/2010
• Published: 03/03/2011
• Est. Priority Date: 08/31/2009
• Status: Active Grant

• Current Assignee: Abbott Laboratories
• Original Assignee: Abbott Laboratories
• Inventors: Hebbar, Sudarshan, Doss, Robert C., Keirans, Walter J., Datwyler, Saul A., Shih, Jessie W.
• Granted Patent: US 8,501,420 B2
• Time in Patent Office: Days
• US Class Current: 435/7.4
• CPC Class Codes: G01N 2800/324 Coronary artery diseases, e.g. angina pectoris, myocardial infarction
• CPC Class Codes: G01N 2800/50 Determining the risk of developing a disease
• CPC Class Codes: G01N 2800/60 Complex ways of combining multiple protein biomarkers for diagnosis
• CPC Class Codes: G01N 33/6887 from muscle, cartilage or connective tissue
• CPC Class Codes: G01N 33/6893 related to diseases not provided for elsewhere

Abstract

The present invention relates to combinations of biomarkers and levels thereof that may be used, for example, in the determination of risk associated with the occurrence of a major adverse cardiac event (MACE) in a patient.

Claims

1. A method of determining risk of experiencing a major adverse cardiac event (MACE), in a patient, within one year from presentation of at least one symptom of acute coronary syndrome (ACS) comprising the steps of:

a) obtaining a test sample from said patient;

b) determining the amount of at least three biomarkers selected from the group consisting of cardiac Troponin I (cTnI), pro-B-type natriuretic peptide (proBNP) or a cleavage product thereof, high sensitivity C reactive protein (hsCRP), myeloperoxidase (MPO), placental growth factor (PlGF), estimated glomerular filtration rate (eGFR), homocysteine (HCY), choline, ischemia modified albumin (IMA), soluble CD40 ligand (sCD40L) and lipoprotein-associated phospholipase A₂ (LpPLA2) in said test sample; and

c) comparing the amount of said at least three biomarkers to biomarker reference standards, wherein said risk is determined by results of said comparison.

2. The method of claim 1, wherein said at least three biomarkers are selected from the group consisting of proBNP or a cleavage product thereof, PlGF, eGRF and homocysteine.

3. The method of claim 1, wherein said at least three biomarkers are selected from the group consisting of proBNP or a cleavage product thereof, PlGF and eGFR.

4. The method of claim 1, wherein said at least three biomarkers are selected from the group consisting of cTnI, proBNP or a cleavage product thereof and PlGF.

5. The method of claim 1, wherein said at least three biomarkers are selected from the group consisting of cTnI, proBNP or a cleavage product thereof, choline and eGFR.

6. The method of claim 1, wherein said test sample is selected from the group consisting of blood, serum, and plasma.

7. The method of claim 1, wherein said cleavage product is BNP or NT-proBNP.

8. The method of claim 1, wherein said results are used to determine risk of experiencing a major adverse cardiac event within one year of presentation of at least one symptom of acute coronary syndrome subsequent to stress testing undergone by said patient.

9. The method of claim 1, wherein said major adverse cardiac event comprises at least one condition selected from the group consisting of a myocardial infarction, death, revascularization, repeat revascularization, stroke, heart failure and dysrhymias.

10. A method of determining risk of experiencing a major adverse cardiac event, in a patient, within one year from presentation of at least one symptom of ACS comprising the step of:

assessing the level of BNP in a test sample from said patient, wherein a BNP level less than or equal to approximately 150 pg/mL indicates that the level of PlGF in said test sample must be assessed and a BNP level greater than approximately 150 pg/mL indicates that the eGRF of said patient must be assessed, wherein if said PlGF level must be assessed, a PlGF level less than or equal to approximately 19.5 pg/mL indicates that the level of BNP in said test sample must be reassessed, wherein if said level of BNP must be reassessed, a BNP level less than or equal to approximately 65 pg/mL indicates said patient has a low risk of experiencing a major adverse cardiac event within one year from presentation of at least one symptom of ACS and a BNP level greater than approximately 65 pg/mL indicates said patient has a moderate risk of experiencing a major adverse cardiac event within one year from presentation of at least one symptom of ACS, and wherein if eGFR must be assessed, an eGFR level greater than approximately 68 mL/min/1.73 m² indicates said patient has a moderate risk of experiencing a major adverse cardiac event within one year from presentation of at least one symptom of ACS and an eGRF level less than or equal to approximately 68 mL/min/1.73 m² indicates said patient has a high risk of experiencing a major adverse cardiac event within one year from presentation of at least one symptom of ACS.

11. The method of claim 10, wherein a patient having a BNP level of less than or equal to approximately 150 pg/mL has an approximately 6.4% incidence of having a major adverse cardiac event within one year from presentation of at least one symptom of ACS.

12. The method of claim 10, wherein a patient having a BNP level greater than approximately 150 pg/mL has an approximately 27.6% incidence of having a major adverse cardiac event within one year from presentation of at least one symptom of ACS.

13. The method of claim 10, wherein a patient having a PlGF level less than or equal to approximately 19.5 pg/mL has an approximately 2.4% incidence of having a major adverse cardiac event within one year from presentation of at least one symptom of ACS.

14. The method of claim 10, wherein a patient having a PlGF value of greater than approximately 19.5 pg/mL has an approximately 14.5% incidence of having a major adverse cardiac event within one year from presentation of at least one symptom of ACS.

15. The method of claim 10, wherein a patient having an eGFR of greater than approximately 68 mL/min/1.73 m² has an approximately 14.3% incidence of having a major adverse cardiac event within one year from presentation of at least one symptom of ACS.

16. The method of claim 10, wherein a patient having an eGFR of less than or equal to 68 mL/min/1.73 m² has an approximately 36.5% incidence of having a major adverse cardiac event within one year from presentation of at least one symptom of ACS.

17. The method of claim 10, wherein a patient having a BNP level of less than or equal to approximately 65 pg/mL, has a less than approximately 1% incidence of having a major adverse cardiac event within one year from presentation of at least one symptom of ACS.

18. The method of claim 10, wherein a patient having a BNP level of greater than approximately 65 pg/mL has an approximately 12.1% incidence of having a major adverse cardiac event within one year from presentation of at least one symptom of ACS.

19. A method of determining incidence of experiencing a major adverse cardiac event, in a patient, within one year from presentation of at least one symptom of ACS comprising the step of:

assessing the level of BNP in a test sample from said patient, wherein a BNP level less than or equal to approximately 150 pg/mL indicates that the level of PlGF in said test sample must be assessed and a BNP level greater than approximately 150 pg/mL indicates that the eGRF of said patient must be assessed, wherein if said PlGF level must be assessed, a PlGF level less than or equal to approximately 19.5 pg/mL indicates that the level of HCY in said test sample must be assessed and a PlGF level greater than 19.5 indicates said patient has a moderate risk of experiencing a major adverse cardiac event within one year from presentation of at least one symptom of ACS, wherein if said eGFR must be assessed, an eGFR greater than approximately 68 mL/min/1.73 m² indicates said patient has a moderate risk of experiencing a major adverse cardiac event within one year from presentation of at least one symptom of ACS and an eGRF level less than or equal to approximately 68 mL/min/1.73 m² indicates said patient has a high risk of experiencing a major adverse cardiac event within one year from presentation of at least one symptom of ACS, and wherein if said HCY level must be assessed, a HCY level less than or equal to approximately 12.5 mmol/L indicates said patient has a low risk of experiencing a major adverse cardiac event within one year from presentation of at least one symptom of ACS and a HCY level greater than approximately 12.5 mmol/L indicates said patient has a moderate risk of experiencing a major adverse cardiac event within one year from presentation of at least one symptom of ACS.

20. The method of claim 19, wherein a patient having a BNP level greater than approximately 150 pg/mL has an approximately 27.6% incidence of having a major adverse cardiac event within one year from presentation of at least one symptom of ACS.

21. The method of claim 19, wherein a patient having a BNP level of less than or equal to approximately 150 pg/mL has an approximately 6.4% incidence of having a major adverse cardiac event within one year from presentation of at least one symptom of ACS.

22. The method of claim 19, wherein a patient having a PlGF value of greater than approximately 19.5 pg/mL has an approximately 14.5% incidence of having a major adverse cardiac event within one year from presentation of at least one symptom of ACS.

23. The method of claim 19, wherein a patient having a PlGF level less than or equal to approximately 19.5 pg/mL has an approximately 2.4% incidence of having a major adverse cardiac event within one year from presentation of at least one symptom of ACS.

24. The method of claim 19, wherein a patient having an eGFR of greater than approximately 68 mL/min/1.73 m², has an approximately 14.3% incidence of having a major adverse cardiac event within one year from presentation of at least one symptom of ACS.

25. The method of claim 19, wherein a patient having an eGFR level of less than or equal to approximately 68 mL/min/1.73 m² has an approximately 36.5% incidence of having a major adverse cardiac event within one year from presentation of at least one symptom of ACS.

26. The method of claim 19, wherein a patient having a HCY level of less than or equal to 12.5 μ

mol/L has a less than approximately 1% incidence of having a major adverse cardiac event within one year from presentation of at least one symptom of ACS.

27. The method of claim 19, wherein a patient having a HCY level of greater than approximately 12.5 μ

mol/L has an approximately 10% incidence of having a major adverse cardiac event within one year from presentation of at least one symptom of ACS.

28. A method of determining risk of experiencing a major adverse cardiac event, in a patient with diagnosed, chronic kidney disease, within one year from presentation of at least one symptom of ACS comprising the steps of:

determining whether said patient has a cardiac Troponin I level less than or equal to approximately 0.015 ng/mL; and

assessing the level of BNP in a test sample from said patient, if said patient has a cardiac Troponin I level less than or equal to approximately 0.015 ng/mL, wherein a BNP level less than or equal to approximately 150 pg/mL indicates that the level of PlGF in said test sample must be assessed and a BNP level greater than approximately 150 pg/mL indicates that the eGRF of said patient must be assessed, wherein if said PlGF level must be assessed, a PlGF level less than or equal to approximately 19.5 pg/mL indicates that the level of BNP in said test sample must be reassessed, wherein if said level of BNP must be reassessed, a BNP level less than or equal to approximately 65 pg/mL indicates said patient has a low risk of experiencing a major adverse cardiac event within one year from presentation of at least one symptom of ACS and a BNP level greater than approximately 65 pg/mL indicates said patient has a moderate risk of experiencing a major adverse cardiac event within one year from presentation of at least one symptom of ACS, and wherein if eGFR must be assessed, an eGFR level greater than approximately 68 mL/min/1.73 m² indicates said patient has a moderate risk of experiencing a major adverse cardiac event within one year from presentation of at least one symptom of ACS and an eGRF level less than or equal to approximately 68 mL/min/1.73 m² indicates said patient has a high risk of experiencing a major adverse cardiac event within one year from presentation of at least one symptom of ACS.