Predicting risk of major adverse cardiac events

• US 9,965,593 B2
• Filed: 04/03/2014
• Issued: 05/08/2018
• Est. Priority Date: 04/18/2008
• Status: Active Grant

• Current Assignee: Critical Care Diagnostics Inc.
• Original Assignee: Critical Care Diagnostics Inc.
• Inventors: Snider, James V., Heyman, Eugene R.
• Primary Examiner(s): Zeman, Mary K
• Application Number:
  US14/244,526
• Publication Number:
  US 20150081224A1
• Time in Patent Office: 1,496 Days
• CPC Class Codes: C12Q 1/6883 for diseases caused by alterations of genetic material
• CPC Class Codes: C12Q 2600/158 Expression markers
• CPC Class Codes: G01N 2333/58 Atrial natriuretic factor complex; Atriopeptin; Atrial natriuretic peptide [ANP]; Brain natriuretic peptide [BNP, proBNP]; Cardionatrin; Cardiodilatin
• CPC Class Codes: G01N 2333/7155 for interleukins [IL]
• CPC Class Codes: G01N 2800/32 Cardiovascular disorders
• CPC Class Codes: G01N 2800/50 Determining the risk of developing a disease
• CPC Class Codes: G01N 33/6869 Interleukin
• CPC Class Codes: G01N 33/6893 related to diseases not provided for elsewhere
• CPC Class Codes: G01N 33/74 involving hormones or other non-cytokine intercellular protein regulatory factors such as growth factors, including receptors to hormones and growth factors
• CPC Class Codes: G16H 50/20 for computer-aided diagnosis, e.g. based on medical expert systems
• CPC Class Codes: G16H 50/30 for calculating health indices; for individual health risk assessment

Abstract

Measurement of circulating ST2 and natriuretic peptide (e.g., NT-proBNP) concentrations is useful for the prognostic evaluation of subjects, in particular for the prediction of adverse clinical outcomes, e.g., mortality, transplantation, and heart failure.

Claims

1. A method of treating a subject, the method comprising:

(a) determining a first level of soluble ST2 in a biological sample comprising serum, blood, or plasma that is obtained from a subject at a first time point (ST2 T0) using an immunoassay comprising a monoclonal antibody that binds specifically to soluble ST2;

(b) initiating administration of outpatient treatment to the subject at the first time point;

(c) determining a second level of soluble ST2 in a biological sample comprising serum, blood, or plasma that is obtained from the subject at a second time point (ST2 T1) using the immunoassay comprising the monoclonal antibody that binds specifically to soluble ST2;

(d) determining a third level of soluble ST2 in a biological sample comprising serum, blood, or plasma that is obtained from the subject at a third time point (ST2 T2) using the immunoassay comprising the monoclonal antibody that binds specifically to soluble ST2;

(e) determining a level of a natriuretic peptide (NP) in a biological sample comprising serum, blood, or plasma that is obtained from the subject at the second time point (NP T1) using an immunoassay comprising a monoclonal antibody that binds specifically to the NP;

(f) determining a level of the NP in a biological sample comprising serum, blood, or plasma that is obtained from the subject at the third time point (NP T2) using the immunoassay comprising the monoclonal antibody that binds specifically to the NP;

(g) determining a first MACE risk score (MACERS) for the subject based upon, at least in part, the ratio of ST2 T1 to ST2 T0, in addition to a weighted natural logarithm of NP T1 according to the following formula;

First MACERS=(ST2T1/ST2T0)+α

ln(NP T1), wherein α

is a weighting factor;

(h) determining a second MACE risk score (MACERS) for a subject based upon, at least in part, the ratio of ST2 T2 to ST2 T0, in addition to a weighted natural logarithm of NP T2 according to the following formula;

Second MACERS=(ST2T2/ST2T0)+α

ln(NP T2), wherein α

is a weighting factor;

(i) selecting a subject having a second MACERS that is equal to or elevated as compared to the first MACERS; and

(j) administering inpatient treatment to the selected subject.

2. The method of claim 1, wherein the NP is N-terminal pro-BNP (NT-proBNP).

3. The method of claim 1, wherein the weighting factor α

is about 0.33.

4. The method of claim 1, wherein the first time point is within 1-7 days of the onset of symptoms in the subject.

5. The method of claim 1, wherein the second time point is 2-14 days after the first time point.

6. The method of claim 1, wherein the subject has been diagnosed with heart failure.

15. The method of claim 1, wherein the subject has a BMI of 25-29.

16. The method of claim 1, wherein the subject has a BMI of ≥

30.

17. The method of claim 1, wherein the subject has renal insufficency.

7. A method of evaluating a subject'"'"'s condition over time and treating the subject, the method comprising:

(a) determining a first level of soluble ST2 in a biological sample comprising serum, blood, or plasma that is obtained from a subject at a first time point (ST2 T0) using an immunoassay comprising a monoclonal antibody that binds specifically to soluble ST2;

(b) determining a second level of soluble ST2 in a biological sample comprising serum, blood, or plasma that is obtained from the subject at a second time point (ST2 T1) using the immunoassay comprising the monoclonal antibody that binds specifically to soluble ST2;

(c) determining a third level of soluble ST2 in a biological sample comprising serum, blood, or plasma that is obtained from the subject at a third time point (ST2 T2) using the immunoassay comprising the monoclonal antibody that binds specifically to soluble ST2;

(d) determining a level of a natriuretic peptide (NP) in a biological sample comprising serum, blood, or plasma that is obtained from the subject at the second time point (NP T1) using an immunoassay comprising a monoclonal antibody that binds specifically to the NP;

(e) determining a level of the NP in a biological sample comprising serum, blood, or plasma that is obtained from the subject at the third time point (NP T2) using the immunoassay comprising the monoclonal antibody that binds specifically to the NP;

(f) determining a first MACE risk score (MACERS) for a subject based upon, at least in part, the ratio of ST2 T1 to ST2 T0, in addition to a weighted natural logarithm of NP T1 according to the following formula;

First MACERS=(ST2T1/ST2T0) +α

ln(NP T1 ), wherein α

is a weighting factor;

(g) determining a second MACERS for a subject based upon, at least in part, the ratio of ST2 T2 to ST2 T0, in addition to a weighted natural logarithm of NP T2 according to the following formula;

Second MACERS=(ST2T2/ST2T0) +α

ln(NP T2), wherein α

is a weighting factor;

(h) identifying a subject having a second MACERS that is increased as compared to the first MACERS, and determining that the identified subject'"'"'s condition is declining; and

(i) initiating inpatient treatment of the identified subject.

8. The method of claim 7, wherein the weighting factor α

is about 0.33.

9. The method of claim 7, wherein the first time point is within 1-7 days of the onset of symptoms in the subject.

10. The method of claim 7, wherein the second time point is 2-14 days after the first time point.

11. The method of claim 7, wherein the subject has been diagnosed with heart failure.

12. The method of claim 7, wherein the subject has a BMI of 25-29.

13. The method of claim 7, wherein the subject has a BMI of ≥

30.

14. The method of claim 7, wherein the subject has renal insufficiency.