Very Low Concentrations of Troponin I Or T for Assessing a Cardiovascular Risk with Respect to the Administration of Anti-Inflammatory Drugs
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(19) & (11) EP 2 133 696 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 16.12.2009 Bulletin 2009/51 G01N 33/68 (2006.01) (21) Application number: 08010524.0 (22) Date of filing: 10.06.2008 (84) Designated Contracting States: (72) Inventor: Spanuth, Eberhardt AT BE BG CH CY CZ DE DK EE ES FI FR GB GR 69221 Dossenheim (DE) HR HU IE IS IT LI LT LU LV MC MT NL NO PL PT RO SE SI SK TR (74) Representative: Prüfer & Partner GbR Designated Extension States: European Patent Attorneys AL BA MK RS Sohnckestrasse 12 81479 München (DE) (71) Applicant: Spanuth, Eberhardt 69221 Dossenheim (DE) (54) Very low concentrations of troponin I or T for assessing a cardiovascular risk with respect to the administration of anti-inflammatory drugs (57) The present invention relates to a method for ponin I or T diagnosing the risk of a patient to suffer from a cardio- b) diagnosing the risk of the patient by comparing the vascular complication as a consequence of administra- measured level to known leves associate with different tion of a COX-2 inhibiting compound, comprising the grades of risk in a patient. steps of a) measuring the level of very low concentrations of tro- EP 2 133 696 A1 Printed by Jouve, 75001 PARIS (FR) 1 EP 2 133 696 A1 2 Description Mukherjee D, Nissen SE, Topol EJ. Risk of cardiovascu- lar events associated with selective COX-2 Inhibitors. JA- [0001] The present invention relates to the use of very MA 2001; 286: 954-959.). low concentrations of troponin I or T for assessing the [0006] Cardiovascular complications, such as acute cardiovascular risk of a patient with respect to the admin- 5 myocardial infarction or stroke, may lead to serious istration of an anti-inflammatory drug, particularly health problems and even death. Therefore, many pa- NSAIDs (non-steroidal anti-inflammatory drugs) or ster- tients who would strongly benefit from treatment with se- oids, more particularly selective Cox-2 inhibitors. lective Cox-2 inhibitors are not treated as it is unknown [0002] An aim of modem medicine is to provide per- whether treatment may result in a cardiovascular com- sonalized or individualized treatment regimens. Those 10 plication. are treatment regimens which take into account a pa- [0007] Cardiovascular problems or risks can remain tient’s individual needs or risks. Of particular importance asymptomatic for long periods of time. Therefore, reliable is the cardiovascular risk or complication, particularly an diagnosis of the presence of a cardiovascular risk is more unrecognized cardiovascular risk or complication. difficult and error-prone than generally believed. In par- [0003] Selective Cox-2 inhibitors are widely used po- 15 ticular, general practitioners and non-cardiologists often tent anti-inflammatory drugs. Compared to many other are not able to identify a previously unrecognized cardi- anti-inflammatory drugs, they appear to cause less gas- ovascular problem. trointestinal side-effects, such as gastrointestinal bleeds [0008] According to the state of the art, it is only pos- or ulcers. Therefore, for many patients treatment with sible to exclude patients with cardiovascular symptoms selective Cox-2 inhibitors is the treatment of choice. 20 or a known history of heart disease or hypertension from [0004] However, it has been noted, that selective Cox- treatment with selective Cox-2 inhibitors. 2 inhibitors can lead to cardiovascular complications, [0009] This risk management is insufficient, as also possibly followed by cardiac decompensation and even asymptomatic patients may develop a cardiovascular death. Rofecoxib (VIOXX™), a selective Cox-2 inhibitor, complication due to an unrecognized predisposition, e.g. was removed from the market voluntarily by the manu- 25 the presence of an arterial plaque. As mentioned earlier, facturing company, Merck, after a 3.9 times rise in the only patients without any recognisable cardiovascular rate of serious thromboembolic incidents had led to pre- risk were included in the APPROVE study, yet treatment mature discontinuation of the APPROVE study (Adeno- led to cardiovascular complications in several patients. matous Polyp Prevention On Vioxx). Only patients with- [0010] This does not only apply with respect to selec- out any recognisable cardiovascular risk were included 30 tive Cox-2 inhibitors, but also with respect to other class- in that study for the secondary prevention of colon ade- es of anti-inflammatory drugs, e.g. being inhibitors of nomas. Even in the early post-observation phase higher Cox-2 and other target (e.g. Cox-1), and which may blood pressure levels had been noticed with 25 mg ro- cause cardiovascular complications. Examples for these fecoxib than with a placebo. 16 additional cardiovascular other classes of anti-inflammatory drugs include non-se- incidents per 1,000 treated patients (myocardial infarc- 35 lective Cox-2 inhibitors (compounds inhibiting Cox-1 and tion, stroke) with 25 mg rofecoxib compared with a pla- Cox-2). Even though the risk of leading to cardiovascular cebo (Topol EJ. Failing the public health--rofecoxib, Mer- complications is not as high as for selective Cox-2 inhib- ck, and the FDA. N Engl J Med 2004; 351: 1707-9) were itors, there may be cases where a possible cardiovascu- noticed after 18 months of follow-up. An increased car- lar complication has to be taken into account. diovascular risk has also been suspected in other studies 40 [0011] For example, cardiovascular side-effects are al- (VIGOR) and has been supported by data from a recent so suspected for other anti-inflammatory drugs, in par- meta-analysis (Bombardier C, Laine L, Reicin A, Shapiro ticular other NSAIDs or steroids. D, Burgos-Vargas R, Davis B, Day R, Ferraz MB, Hawkey [0012] WO 2006/077265 discloses a method for diag- CJ, Hochberg MC, Kvien TK, Schnitzer TJ; VIGOR Study nosing the risk of a patient to suffer from a cardiovascular Group. Comparison of upper gastrointestinal toxicity of 45 complication as a consequence of administration of a rofecoxib and naproxen in patients with rheumatoid ar- Cox-2 inhibiting compound, comprising the steps of a) thritis. VIGOR Study Group. N Engl J Med 2000; 343: measuring the level of a cardiac hormone, b) diagnosing 1520-8; Jüni P, Nartey L, Reichenbach S, Sterchi R, Di- the risk of the patient by comparing the measured level eppe PA, Egger M. Risk of cardiovascular events and to known levels associated with different grades of risk rofecoxib: cumulative meta-analysis. Lancet 2004; online 50 in a patient. ahead). [0013] In some cases, so-called molecular markers [0005] Similar cardiovascular side-effects are sus- permit to establish rapid and sufficiently accurate diag- pected within the scope of a class effect for other selec- nosis of the pathological state of a subject. A prominent tive cyclooxygenase (COX)-2 inhibitors such as celecox- example is troponin T and/or troponin I for the diagnosis ib (Celebrex™, Pfizer), lumiracoxib (Prexige™, Novartis) 55 of MI, as mentioned beforehand, or natriuretic peptides, and parecoxib, a pro-drug of valdecoxib, although at a in particular BNP and NT-proBNP for various non- lower incidence rate (Fitzgerald GA. Coxibs and cardio- ischemic heart diseases, e.g. heart failure. Blood levels vascular disease. N Engl J Med 2004; 351: 1709-1711. of cardiac troponins are sensitive and specific markers 2 3 EP 2 133 696 A1 4 of myocardial injury that are routinely used for the diag- In particular, the diagnostic means should be reliable and nosis of acute myocardial infarction. With regard for the suited for use by general practitioners and non-cardiol- determination of troponin, as an example of an ischemic ogists. marker, reference is made to Katus et al. (Mol Cell Cardiol [0016] The object of the invention is attained by a meth- 1989; 21:1349-53), Hamm et al. (NEJM 1992; 327: 5 od for diagnosing the risk of a patient to suffer from a 146-50), Ohmann et al. (NEJM 1996; 335: 1333-34), cardiovascular complication ("cardiovascular risk") as a Christenson et al. (ClinChem 1998; 44: 494-501), and to consequence of administration of an anti-inflammatory EP-A-0 394 819. Particularly preferred test for detection drug, particularly an NSAID, steroid, or a selective Cox- of troponin T are elektrochemiluminescence immu- 2 inhibitor, comprising the steps of noassays and for detection of troponin I fluorescence po- 10 larization immunoassays, respectively, reference is a) measuring the level of Very low concentrations of made to James et al. (ClinChem 2006; 52: 6832-37), and troponin I or T, numerous other publications. Troponin levels may also be elevated in some patients b) diagnosing the risk of the patient by comparing with heart failure, but blood levels are shown to be much 15 the measured level to known levels associated with lower compared with patients with acute myocardial inf- different grades of risk in a patient. arction when currently available assays are used. [0014] Recently, previously undetectable very low [0017] The object of the invention is furthermore at- concentrations of troponin I measured by the second- tained by a method for diagnosing the cardiovascular risk generation Stratus CS® with reagents provided by Dade 20 of a patient who is a candidate for administration of a Behring suggest that troponin values below the 99th per- compound having Cox-2 inhibiting properties, compris- centile could contain diagnostic information in patients ing the steps of with heart diseases. The limit of detection for this assay is 0.02 Pg/L, the 99th percentile is 0.07 Pg/L, and the a) measuring, preferably in vitro, the level of Very lowest concentration with a CV <10% has been reported 25 low concentrations of troponin I or T, as both 0.06 Pg/L and 0.10 Pg/L, respectively.