Relevance of achieved levels of markers of systemic inflammation following treatment

• US 20060115903A1
• Filed: 10/06/2005
• Published: 06/01/2006
• Est. Priority Date: 10/06/2004
• Status: Active Grant

• Current Assignee: Brigham and Women's Hospital Incorporated
• Original Assignee: Brigham and Women's Hospital Incorporated
• Inventors: Ridker, Paul
• Granted Patent: US 9,164,104 B2
• Time in Patent Office: Days
• US Class Current: 436/71
• CPC Class Codes: A61K 31/22 of acyclic acids, e.g. pravastatin
• CPC Class Codes: A61K 31/40 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: G01N 2333/4737 C-reactive protein
• CPC Class Codes: G01N 2800/32 Cardiovascular disorders
• CPC Class Codes: G01N 2800/324 Coronary artery diseases, e.g. angina pectoris, myocardial infarction
• 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 33/6863 Cytokines, i.e. immune system proteins modifying a biological response such as cell growth proliferation or differentiation, e.g. TNF, CNF, GM-CSF, lymphotoxin, MIF or their receptors
• CPC Class Codes: G01N 33/6893 related to diseases not provided for elsewhere
• CPC Class Codes: G01N 33/92 involving lipids, e.g. cholesterol , lipoproteins, or their receptors steroid hormones G01N33/743

Abstract

The invention involves, inter alia, the use of markers of systemic inflammation to determine whether or not an individual undergoing treatment with a cardiovascular agent to reduce the risk of a future cardiovascular event will benefit from continued treatment with the cardiovascular agent. Further, this invention describes the use of markers of systemic inflammation to evaluate the efficacy of treatment and to assist physicians in deciding on the course of a treatment in an individual at risk of future cardiovascular events.

Claims

1. A method for diagnosing a human subject, comprising:

(i) obtaining a level of a marker of systemic inflammation in a human subject undergoing therapy with a statin to reduce the risk of a future cardiovascular event, wherein the marker is selected from the group consisting of;

C-reactive protein (CRP), soluble intercellular adhesion molecule (sICAM-1), ICAM 3, BL-CAM, LFA-2, VCAM-1, NCAM, PECAM, fibrinogen, serum amyloid A (SAA), lipoprotein associated phospholipase A2 (LpPlA2), sCD40 ligand, myeloperoxidase, Interleukin-6 (IL-6), and Interleukin-8 (IL-8),

(ii) obtaining a level of low density lipoprotein cholesterol (LDLC) in the human subject,

(iii) comparing the level of the marker obtained in (i) to a predetermined value corresponding to a level of the marker in an apparently healthy control population, and

(iv) determining whether the level of the marker obtained in (i) is above a predetermined level, said determination being indicative of whether the patient would benefit from continued therapy with the statin or would benefit from a change in therapy with the statin, when the level of LDLC obtained in (ii) is below 70 mg/dL or is above 100 mg/dL.

2. The method of claim 1, wherein step (i) and step (ii) are repeated so as to monitor the human subject'"'"'s levels of the marker and LDLC over time.

7. The method of claim 1, wherein the marker of systemic inflammation is CRP.

3-6. -6. (canceled)

8-10. -10. (canceled)

11. A method for evaluating the efficacy of a therapy for reducing the risk of a future cardiovascular event comprising:

(i) obtaining a level of a marker of systemic inflammation in a human subject undergoing therapy with a statin to reduce the risk of a future cardiovascular event, wherein the marker is selected from the group consisting of;

C-reactive protein (CRP), soluble intercellular adhesion molecule (sICAM-1), ICAM 3, BL-CAM, LFA-2, VCAM-1, NCAM, PECAM, fibrinogen, serum amyloid A (SAA), lipoprotein associated phospholipase A2 (LpPlA2), sCD40 ligand, myeloperoxidase, Interleukin-6 (IL-6), and Interleukin-8 (IL-8),

(ii) obtaining a level of LDLC in said human subject,

(iii) comparing the level of the marker obtained in (i) to a predetermined value corresponding to a level of the marker in an apparently healthy control population, and

(iv) determining whether the level of the marker obtained in (i) is above a predetermined level said determination being indicative of whether the therapy is efficacious, when the level of LDLC obtained in (ii) is below 70 mg/dL or above 100 mg/dL.

17. The method of claim 11, wherein the marker of systemic inflammation is CRP.

12. The method of claim II wherein step (i) and step (ii) are repeated so as to monitor the human subject'"'"'s levels of the marker of systemic inflammation and LDLC over time.

13-16. -16. (canceled)

18-20. -20. (canceled)

21. A method for diagnosing a patient, comprising:

(i) obtaining a level of a marker of systemic inflammation in a human subject undergoing therapy with a therapeutic agent other than a statin to reduce the risk of a future cardiovascular event, wherein the marker is selected from the group consisting of;

C-reactive protein (CRP), soluble intercellular adhesion molecule (sICAM-1), ICAM 3, BL-CAM, LFA-2, VCAM-1, NCAM, PECAM, fibrinogen, serum amyloid A (SAA), lipoprotein associated phospholipase A2 (LpPlA2), sCD40 ligand, myeloperoxidase, Interleukin-6 (IL-6), and Interleukin-8 (IL-8),

(ii) comparing the level of the marker obtained in (i) to a predetermined value corresponding to a level of the marker in an apparently healthy control population, and

(iii) determining whether the level of the marker obtained in (i) is above the predetermined level, said determination being indicative of whether the patient would benefit from continued therapy with the agent or would benefit from a change in therapy with the agent.

22. The method of claim 21, wherein step (i) is repeated so as to monitor the human subject'"'"'s level of the marker over time.

27. The method of claim 21, wherein the marker of systemic inflammation is CRP.

23-26. -26. (canceled)

28-31. -31. (canceled)

32. A method for evaluating the efficacy of a therapy with a therapeutic agent other than a statin for reducing the risk of a future cardiovascular event comprising:

(i) obtaining a level of a marker of systemic inflammation in a human subject undergoing the therapy to reduce the risk of a future adverse cardiovascular event, wherein the marker is selected from the group consisting of;

C-reactive protein (CRP), soluble intercellular adhesion molecule (sICAM-1), ICAM 3, BL-CAM, LFA-2, VCAM-1, NCAM, PECAM, fibrinogen, serum amyloid A (SAA), lipoprotein associated phospholipase A2 (LpPlA2), sCD40 ligand, myeloperoxidase, Interleukin-6 (IL-6), and Interleukin-8 (IL-8),

(ii) comparing the level of the marker obtained in (i) to a predetermined value corresponding to a level of the marker in an apparently healthy control population, and

(iii) determining whether the level of the marker obtained in (i) is above the predetermined level, said determination being indicative of whether the therapy is efficacious.

33. The method of claim 32, wherein step (i) is repeated so as to monitor the human subject'"'"'s level of the marker over time.

38. The method of claim 32, wherein the marker of systemic inflammation is CRP.

42. The method of claim 32, further comprising measuring a level of a lipid in the human subject, said level of lipid being further indicative of whether the therapy is efficacious.

34-37. -37. (canceled)

39-41. -41. (canceled)

43. A method for deciding on the course of a therapy in a human subject, comprising:

(i) obtaining a level of a marker of systemic inflammation in a human subject undergoing a therapy to reduce the risk of a future adverse cardiovascular event, wherein the marker of systemic inflammation is selected from the group consisting of;

C-reactive protein (CRP), soluble intercellular adhesion molecule (sICAM-1), ICAM 3, BL-CAM, LFA-2, VCAM-1, NCAM, PECAM, fibrinogen, serum amyloid A (SAA), lipoprotein associated phospholipase A2 (LpPlA2), sCD40 ligand, myeloperoxidase, Interleukin-6 (IL-6), and Interleukin-8 (IL-8),

(ii) comparing the level of the marker obtained in (i) to a predetermined value corresponding to a level of the marker in an apparently healthy control population,

(iii) determining whether the level of the marker obtained in (i) is above the predetermined level, and

(iv) deciding on the course of the therapy based on such determination.

44. The method of claim 43, wherein step (i) is repeated so as to monitor the human subject'"'"'s level of the marker over time.

49. The method of claim 43, wherein the marker of systemic inflammation is CRP.

53. The method of claim 43, further comprising measuring a level of a lipid in the human subject, wherein said deciding is also based upon the lipid level measured in the human subject.

45-48. -48. (canceled)

50-52. -52. (canceled)

54. A method for treating a human subject with an elevated level of a marker of systemic inflammation comprising:

(i) treating the human subject with a first therapy for reducing the risk of a cardiovascular event,

(ii) obtaining a level of the marker of systemic inflammation in the human subject,

(iii) comparing the level of the marker obtained in (ii) to a predetermined value corresponding to a level of the marker in an apparently healthy control population, and, if the predetermined level of the marker is not reached,

(iv) treating the human subject with a second therapy for reducing the risk of a cardiovascular event, and repeating (ii) and (iii) until the predetermined level of the marker is reached.

55. The method of claim 54, wherein the marker of systemic inflammation is selected from the group consisting of:

C-reactive protein (CRP), soluble intercellular adhesion molecule (sICAM-1), ICAM 3, BL-CAM, LFA-2, VCAM-1, NCAM, PECAM, fibrinogen, serum amyloid A (SAA), lipoprotein associated phospholipase A2 (LpPlA2), sCD40 ligand, myeloperoxidase, Interleukin-6 (IL-6), and Interleukin-8 (IL-8).

56. The method of claim 54, wherein the marker of systemic inflammation is CRP.

57-59. -59. (canceled)