Methods predicting risk of an adverse clinical outcome

• US 8,728,742 B2
• Filed: 03/16/2012
• Issued: 05/20/2014
• Est. Priority Date: 03/17/2011
• Status: Active Grant

• Current Assignee: Critical Care Diagnostics Inc.
• Original Assignee: Critical Care Diagnostics Inc.
• Inventors: Snider, James V.
• Primary Examiner(s): HOWARD, ZACHARY C
• Application Number:
  US13/422,574
• Publication Number:
  US 20120276551A1
• Time in Patent Office: 795 Days
• Field of Search: None
• US Class Current: 435/7.1
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07K 14/47 from mammals
• CPC Class Codes: C07K 14/4726 Lectins
• CPC Class Codes: C07K 14/715 for cytokines; for lymphokines; for interferons
• CPC Class Codes: G01N 2333/4724 Lectins
• CPC Class Codes: G01N 2333/7155 for interleukins [IL]
• CPC Class Codes: G01N 2800/32 Cardiovascular disorders
• CPC Class Codes: G01N 2800/325 Heart failure or cardiac arrest, e.g. cardiomyopathy, congestive heart failure
• CPC Class Codes: G01N 2800/50 Determining the risk of developing a disease
• CPC Class Codes: G01N 2800/52 Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
• CPC Class Codes: G01N 2800/54 Determining the risk of relapse
• CPC Class Codes: G01N 2800/56 Staging of a disease; Further complications associated with the disease
• CPC Class Codes: G01N 33/53 Immunoassay; Biospecific binding assay; Materials therefor
• CPC Class Codes: G01N 33/68 involving proteins, peptides or amino acids involving lipoproteins G01N33/92
• CPC Class Codes: G01N 33/6869 Interleukin
• CPC Class Codes: G01N 33/6893 related to diseases not provided for elsewhere

Abstract

Provided are methods for evaluating the risk of an adverse clinical outcome in a subject, deciding whether to discharge or continue treating a subject (e.g., on an inpatient basis), or to initiate or terminate treatment, selecting a subject for participation 5 in a clinical study, and selecting a therapeutic treatment for a subject that include determining a level of ST2 and a level of galectin-3 in a biological sample from the subject. Kits are also provided that contain an antibody that specifically binds to ST2, an antibody that specifically binds to galectin-3, and instructions for using the in the methods described.

Claims

1. A method for evaluating the risk of an adverse clinical outcome (ACO) in a subject having heart failure, the method comprising:

(a) performing an assay to determine a level of galectin-3 in a biological sample from a subject having heart failure,

(b) comparing the level of galectin-3 in the biological sample of (a) to a reference level of galectin-3;

(c) selecting a subject having an elevated level of galectin-3 in the biological sample of (a) as compared to the reference level of galectin-3;

(d) performing an assay to determine a level of soluble ST2 in a biological sample from the selected subject;

(e) comparing the level of soluble ST2 in the biological sample of (d) to a reference level of soluble ST2; and

(f) identifying a selected subject having an elevated level of soluble ST2 in the biological sample of (d) as compared to the reference level of soluble ST2 as having an increased risk of an ACO as compared to a subject having heart failure and an elevated level of galectin-3, who has a non-elevated level of soluble ST2, or identifying a selected subject having a non-elevated level of soluble ST2 in the biological sample of (d) as compared to the reference level of soluble ST2 as having a decreased risk of an ACO as compared to a subject having heart failure and an elevated level of galectin-3, who has an elevated level of soluble ST2.

2. The method of claim 1, wherein the ACO is a rehospitalization, recurrence of one or more physical symptoms associated with angina, cardiovascular disease, or heart failure, an increase in the severity of one or more physical symptoms associated with a disease state, an increase in the frequency of one or more physical symptoms associated with a disease state, mortality, admission to a health care facility, or organ transplant.

3. The method of claim 2, wherein the rehospitalization or admission is for cardiovascular disease.

4. The method of claim 2, wherein the mortality is mortality due to cardiovascular disease.

5. The method of claim 1, wherein the risk of an ACO is within 1 year.

6. The method of claim 5, wherein the risk of an ACO is within 30 days.

7. The method of claim 1, wherein the sample comprises serum, blood, or plasma.

8. The method of claim 7, wherein the sample is serum.

9. The method of claim 1, wherein the biological sample of (a) and the biological sample of (d) are obtained from the subject at the same time.

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

30, or renal insufficiency.

11. The method of claim 1, wherein the reference level of soluble ST2 is a level of soluble ST2 in a subject that does not have high risk cardiovascular disease.

12. The method of claim 1, wherein the reference level of galectin-3 is a level of galectin-3 in a subject that does not have high risk cardiovascular disease.

13. The method of claim 1, wherein the reference level of soluble ST2 or the reference level of galectin-3 is a threshold level of soluble ST2 or galectin-3.

14. The method of claim 1, wherein the method further comprises determining the level of one or more additional markers in the subject.

15. The method of claim 14, wherein the one or more additional markers are selected from the group consisting of:

proANP, NT-proANP, ANP, proBNP, NT-proBNP, BNP, troponin, CRP, creatinine, Blood Urea Nitrogen (BUN), liver function enzymes, albumin, and bacterial endotoxin.

16. The method of claim 1, wherein the subject is human.

17. The method of claim 1, wherein a selected subject is identified as having an increased risk of an ACO as compared to a subject having heart failure and an elevated level of galectin-3, who has a non-elevated level of soluble ST2.

18. The method of claim 1, wherein a selected subject is identified as having a decreased risk of an ACO as compared to a subject having heart failure and an elevated level of galectin-3, who has an elevated level of soluble ST2.

19. A method for deciding whether to discharge or continue treating a subject having heart failure on an inpatient basis, comprising the steps of:

(a) performing an assay to determine a level of galectin-3 in a biological sample from a subject having heart failure;

(b) comparing the level of galectin-3 in the biological sample of (a) to a reference level of galectin-3;

(c) selecting a subject who has an elevated level of galectin-3 in the biological sample of (a) as compared to the reference level of galectin-3;

(d) performing an assay to determine a level of soluble ST2 in a biological sample from the selected subject;

(e) comparing the level of soluble ST2 in the biological sample of (d) to a reference level of soluble ST2; and

(f) determining that a selected subject having an elevated level of soluble ST2 in the biological sample of (d) as compared to the reference level of soluble ST2 should receive continued treatment on an inpatient basis, or that a selected subject having a non-elevated level of soluble ST2 in the biological sample of (d) as compared to the reference level of soluble ST2 should be discharged from inpatient treatment.

20. A method of selecting a subject having heart failure for participation in a clinical study of a treatment for heart failure, comprising the steps of:

(a) performing an assay to determine a level of galectin-3 in a biological sample from a subject having heart failure;

(b) comparing the level of galectin-3 in the biological sample of (a) to a reference level of galectin-3;

(c) identifying a subject having an elevated level of galectin-3 in the biological sample of (a) as compared to the reference level of galectin-3;

(d) performing an assay to determine a level of soluble ST2 in a biological sample from the identified subject;

(e) comparing the level of soluble ST2 in the biological sample of (d) to a reference level of soluble ST2; and

(f) selecting an identified subject having an elevated level of soluble ST2 in the biological sample of (d) as compared to the reference level of soluble ST2 for participation in a clinical study of a treatment for heart failure.

21. A method for selecting a therapeutic treatment for a subject having heart failure comprising the steps of:

(a) performing an assay to determine a level of galectin-3 in a biological sample from a subject having heart failure;

(b) comparing the level of galectin-3 in the biological sample of (a) to a reference level of galectin-3;

(c) identifying a subject having an elevated level of galectin-3 in the biological sample of (a) as compared to the reference level of galectin-3;

(d) performing an assay to determine the level of soluble ST2 in a biological sample from the identified subject;

(e) comparing the level of soluble ST2 in the biological sample of (d) to a reference level of soluble ST2; and

(f) selecting inpatient treatment for an identified subject having an elevated level of soluble ST2 in the biological sample of (d) as compared to the reference level of soluble ST2, or selecting outpatient treatment for an identified subject having a non-elevated level of soluble ST2 in the biological sample of (d) as compared to the reference level of soluble ST2.

22. The method of claim 21, wherein the outpatient treatment comprises administration of a therapeutic agent selected from the group consisting of:

nitrates, calcium channel blockers, diuretics, thrombolytic agents, digitalis, renin-angiotensin-aldosterone system (RAAS) modulating agents, and cholesterol-lowering agents.

23. The method of claim 22, wherein the cholesterol-lowering agent is a statin.

24. The method of claim 21, wherein inpatient treatment is selected for an identified subject having an elevated level of soluble ST2 as compared to the reference level of soluble ST2.

25. The method of claim 21, wherein outpatient treatment is selected for an identified subject having a non-elevated level of soluble ST2 as compared to the reference level of soluble ST2.

26. The method of claim 25, wherein the outpatient treatment comprises administration of a therapeutic agent selected from the group consisting of:

nitrates, calcium channel blockers, diuretics, thrombolytic agents, digitalis, renin-angiotensin-aldosterone system (RAAS) modulating agents, and cholesterol-lowering agents.

27. A method for evaluating the risk of an adverse clinical outcome (ACO) in a subject having heart failure, the method comprising:

(a) selecting a subject having heart failure and an elevated level of galectin-3 as compared to the reference level of galectin-3;

(d) performing an assay to determine a level of soluble ST2 in a biological sample from the selected subject;

(e) comparing the level of soluble ST2 in the biological sample to a reference level of soluble ST2; and

(f) identifying a selected subject having an elevated level of soluble ST2 in the biological sample as compared to the reference level of soluble ST2 as having an increased risk of an ACO as compared to a subject having heart failure and an elevated level of galectin-3, who has a non-elevated level of soluble ST2;

or identifying a selected subject having a non-elevated level of soluble ST2 in the biological sample as compared to the reference level of soluble ST2 as having a reduced risk of an ACO as compared to a subject having heart failure and an elevated level of galectin-3, who has an elevated level of soluble ST2.

28. The method of claim 27, wherein a selected subject is identified as having an increased risk of an ACO as compared to a subject having heart failure and an elevated level of galectin-3, who has a non-elevated level of soluble ST2.

29. The method of claim 27, wherein a selected subject is identified as having a decreased risk of an ACO as compared to a subject having heart failure and an elevated level of galectin-3, who has an elevated level of soluble ST2.

30. A method for selecting a therapeutic treatment for a subject having heart failure comprising the steps of:

(a) identifying a subject having an heart failure and an elevated level of galectin-3 as compared to the reference level of galectin-3 ;

(b) performing an assay to determine the level of soluble ST2 in a biological sample from the identified subject;

(c) comparing the level of soluble ST2 in the biological sample to a reference level of soluble ST2; and

(d) selecting inpatient treatment for an identified subject having an elevated level of soluble ST2 in the biological sample as compared to the reference level of soluble ST2, or selecting outpatient treatment for an identified subject having a non-elevated level of soluble ST2 in the biological sample as compared to the reference level of soluble ST2.

31. The method of claim 30, wherein inpatient treatment is selected for an identified subject having an elevated level of soluble ST2 as compared to the reference level of soluble ST2.

32. The method of claim 30, wherein outpatient treatment is selected for an identified subject having a non-elevated level of soluble ST2 as compared to the reference level of soluble ST2.

33. The method of claim 32, wherein the outpatient treatment comprises administration of a therapeutic agent selected from the group consisting of:

nitrates, calcium channel blockers, diuretics, thrombolytic agents, digitalis, renin-angiotensin-aldosterone system (RAAS) modulating agents, and cholesterol-lowering agents.