Rofecoxib, a COX-2 Inhibitor, Lowers C-Reactive Protein and Interleukin-6 Levels in Patients With Acute Coronary Syndromes


      Patients with acute coronary syndromes (ACS) have high levels of inflammatory mediators such as C-reactive protein (CRP) and interleukin (IL)-6.


      To evaluate whether patients with ACS treated with rofecoxib, a COX-2 inhibitor, will have reduced CRP, IL-6, and soluble tumor necrotic factor receptor-1 (sTNF-R1) levels and improved endothelial function.

      Methods and results

      Thirty-four patients hospitalized with ACS were randomized to receive rofecoxib, 25 mg/d plus aspirin 100 mg/d, or placebo plus aspirin, 100 mg/d, for a period of 3 months. Blood samples for CRP, IL-6, and sTNF-R1 levels were drawn prior to randomization, and after 1 month and 3 months. CRP levels in the rofecoxib group (n = 18) were significantly lower both at 1 month and 3 months compared to the baseline levels (p < 0.02). IL-6 levels were significantly lower at 1 month (p < 0.02) in the rofecoxib group, but not at 3 months. There was no change in endothelial function or sTNF-R1 levels.


      Patients recovering from ACS had lower levels of CRP and IL-6 at 1 month and lower CRP levels at 3 months when treated with rofecoxib plus aspirin. Suppression of inflammatory processes may lead to retardation of coronary atherosclerosis and coronary events.

      Key words


      ACS (acute coronary syndromes), CAD (coronary artery disease), CRP (C-reactive protein), HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A), IL (interleukin), LDL (low-density lipoprotein), MI (myocardial infarction), NSAID (nonsteroidal anti-inflammatory drug), sTNF-R1 (soluble tumor necrosis factor receptor-1), TNF (tumor necrosis factor)
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        • Berk B
        • Weintraub W
        • Alexander W
        Elevation of C- reactive protein in “active” coronary artery disease.
        Am J Cardiol. 1990; 65: 168-172
        • Rifai N
        • Joubran R
        • Yu H
        • et al.
        Inflammatory markers in men with angiographically documented coronary heart disease.
        Clin Chem. 1999; 45: 1967-1973
        • Ikonomidis I
        • Andreotti F
        • Economou E
        • et al.
        Increased proinflammatory cytokines in patients with chronic stable angina and their reduction by aspirin.
        Circulation. 1999; 100: 793-798
        • Biasucci L
        • Vitelli A
        • Liuzzo G
        • et al.
        Elevated levels of interleukin-6 in unstable angina.
        Circulation. 1996; 94: 874-877
        • Liuzzo G
        • Biasucci LM
        • Gallimore JR
        • et al.
        The prognostic value of C-reactive protein and serum amyloid A in severe unstable angina.
        N Engl J Med. 1994; 331: 417-424
        • Haverkate F
        • Thompson S
        • Pyke S
        • et al.
        Production of C-reactive protein and risk of coronary events in stable and unstable angina.
        Lancet. 1997; 349: 462-466
        • Verheggen P
        • Maat M
        • Cats V
        • et al.
        Inflammatory status as a main determinant of outcome in patients with unstable angina, independent of coagulation activation, and endothelial cell function.
        Eur Heart J. 1999; 20: 567-574
        • Heeschen C
        • Hamm C
        • Bruemmer J
        • et al.
        Predictive value of C-reactive protein and troponin T in patients with unstable angina: a comparative analysis.
        J Am Coll Cardiol. 2000; 35: 1535-1542
        • Biasucci L
        • Liuzzo G
        • Fantuzzi G
        • et al.
        Increasing levels of interleukin (IL)1Ra and IL-6 during the first 2 days of hospitalization in unstable angina are associated with increased risk of in-hospital coronary events.
        Circulation. 1999; 99: 2079-2084
        • Kuller L
        • Tracy R
        • Shaten J
        • et al.
        Relation of C-reactive protein and coronary heart disease in the MRFIT nested case-control study.
        Am J Epidemiol. 1996; 144: 537-547
        • Ridker P
        • Cushman M
        • Stampfer M
        • et al.
        Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men.
        N Engl J Med. 1997; 336: 973-979
        • Koening W
        • Sund M
        • Fröhlich M
        • et al.
        C-reactive protein, a sensitive marker of inflammation, predicts future risk of coronary heart disease in initially healthy middle-aged men.
        Circulation. 1999; 99: 237-242
        • Ridker P
        • Rifai N
        • Stampfer M
        • et al.
        Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men.
        Circulation. 2000; 101: 1767-1772
        • Ridker P
        • Hennekens C
        • Buring J
        • et al.
        C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women.
        N Engl J Med. 2000; 342: 836-843
        • Ridker PM
        • Buring JE
        • Cook NR
        • et al.
        C-reactive protein, the metabolic syndrome, and risk of incident cardiovascular events: an 8-year follow-up of 14,719 initially healthy American women.
        Circulation. 2003; 107: 391-397
        • Zwaka T
        • Hombach V
        • Torzewski J
        C-reactive protein-mediated low-density lipoprotein uptake by macrophages.
        Circulation. 2001; 103: 194-197
        • Pasceri V
        • Willerson J
        • Yeh E
        Direct proinflammatory effect of C-reactive protein on human endothelial cells.
        Circulation. 2000; 102: 2165-2168
        • Devaraj S
        • Xu DY
        • Jialal I
        C-reactive protein increases plasminogen activator inhibitor-1 expression and activity in human aortic endothelial cells: implications for the metabolic syndrome and atherothrombosis.
        Circulation. 2003; 107: 398-404
        • van Deventer SJH
        • Buller HR
        • ten Cate JW
        • et al.
        Experimental endotoxemia in humans: analysis of cytoline release and coagulation, fibrinolytic and complement pathways.
        Blood. 1990; 76: 2520-2526
        • Ng SB
        • Tan YN
        • Guy GR
        Differential induction of the interleukin-6 gene by tumor necrosis factor and interleukin-1.
        J Biol Chem. 1994; 269: 19021-19027
        • Sanceau J
        • Kaiso T
        • Hirano T
        • et al.
        Triggering of the human interleukin-6 gene by interferon-γ and tumor necrosis factor-α in monocyte cells involves cooperation between interferon regulatory factor-1, NFκB and SP1 transcription factors.
        J Biol Chem. 1995; 270: 27920-27931
        • Baumann H
        • Gauldie J
        Regulation of hepatic acute phase plasma protein genes by hepatocyte stimulating factors and other mediators of inflammation.
        Mol Biol Med. 1990; 7: 147-159
        • Heinrich PC
        • Castell JV
        • Andus T
        Interleukin-6 and the acute phase response.
        Biochem J. 1990; 265: 621-636
        • Seino Y
        • Ikeda U
        • Ikeda M
        • et al.
        Interleukin-6 gene transcripts are expressed in human atherosclerotic lesion.
        Cytokine. 1994; 6: 87-91
        • Rus HG
        • Vlaicu R
        • Niculescu F
        Interleukin-6 and interleukin-8 protein and gene expression in human arterial atherosclerotic wall.
        Atherosclerosis. 1996; 127: 263-271
        • Miyao Y
        • Yasue H
        • Ogawa H
        • et al.
        Elevated plasma interleukin-6 levels in patients with acute myocardial infarction.
        Am Heart J. 1993; 126: 1299-1304
        • Guillen I
        • Blanes M
        • Gomez-Lechon MJ
        • et al.
        Cytokine signaling during myocardial infarction: sequential appearance of IL-1β and IL-6.
        Am J Physiol. 1995; 269: R229-R235
        • Biasucci LM
        • Liuzzo G
        • Fantuzzi G
        • et al.
        Increasing levels of interleukin (IL)-1Ra and IL-6 during the first 2 days of hospitalization in unstable angina are associated with increased risk of in-hospital coronary events.
        Circulation. 1999; 99: 2079-2084
        • Liuzzo G
        • Angiolillo D
        • Buffon A
        • et al.
        Enhanced response of blood monocytes toin vitrolipopolysaccharide challenge in patients with recurrent unstable angina.
        Circulation. 2001; 103: 2236-2241
        • Kennon S
        • Price C
        • Mills P
        • et al.
        The effect of aspirin on C-reactive protein as a marker of risk in unstable angina.
        J Am Coll Cardiol. 2001; 37: 1266-1270
        • Ridker P
        • Rifai N
        • Pfeffer M
        • et al.
        Long-term effects of pravastatin on plasma concentration of C-reactive protein.
        Circulation. 1999; 100: 230-235
        • Ridker P
        • Rifai N
        • Lowenthal S
        Rapid reduction in C-reactive protein with cerivastatin among 785 patients with primary hypercholesterolemia.
        Circulation. 2001; 103: 1191-1193
        • Albert MA
        • Danielson E
        • Rifai N
        • et al.
        Effect of statin therapy on C-reactive protein levels: the pravastatin inflammation/CRP evaluation (PRINCE); a randomized trial and cohort study.
        JAMA. 2001; 286: 91-93
        • Fichtlscherer S
        • Rosenberger G
        • Walter D
        • et al.
        Elevated C-reactive protein levels and impaired endothelial vasoreactivity in patients with coronary artery disease.
        Circulation. 2000; 102: 1000-1006
        • Chenevard R
        • Hurlimann D
        • Bechir M
        • et al.
        Selective COX-2 inhibition improves endothelial function in coronary artery disease.
        Circulation. 2003; 107: 405-409
        • Rauchhaus M
        • Doehner W
        • Francis D
        • et al.
        Plasma cytokine parameters and mortality in patients with chronic heart failure.
        Circulation. 2000; 102: 3060-3067
        • Porsch-Oezcueruemez M
        • Kunz D
        • Kloer HU
        • et al.
        Evaluation of serum levels of solubilized adhesion molecules receptors in coronary heart disease.
        J Am Coll Cardiol. 1999; 34: 1995-2001
        • Stemme V
        • Swdenborg J
        • Claesson H
        • et al.
        Expression of cyclo-oxygenase-2 in human atherosclerotic carotid arteries.
        Eur J Vasc Endovasc Surg. 2000; 20: 146-152
        • Belton O
        • Byrne D
        • Kearney D
        • et al.
        Cyclooxygenase-1 and -2-dependent prostacyclin formation in patients with atherosclerosis.
        Circulation. 2000; 102: 840-845
        • Cipollone F
        • Prontera C
        • Pini B
        • et al.
        Overexpression of functionally coupled cyclooxygenase-2 and prostaglandin E synthase in symptomatic atherosclerotic plaques as a basis of prostaglandin E2-dependent plaque instability.
        Circulation. 2001; 104: 921-927
        • Altman R
        • Luciardi HL
        • Muntaner J
        • et al.
        Efficacy assessment of meloxicam, a preferential cyclooxygenase-2 inhibitor, in acute coronary syndromes without ST-segment elevation.
        Circulation. 2002; 106: 191-195
        • Saito T
        • Rodger IW
        • Hu F
        • et al.
        Inhibition of cyclooxygenase-2 improves cardiac function in myocardial infarction.
        Biochem Biophys Res Commun. 2000; 273: 772-775
        • Bombardier C
        • Laine L
        • Reicin A
        • et al.
        Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis.
        N Engl J Med. 2000; 343: 1520-1528
        • Ray WA
        • Stein CM
        • Daugherty JR
        • et al.
        COX-2 selective non-steroidal anti-inflammatory drugs and risk of serious coronary heart disease.
        Lancet. 2002; 360: 1071-1073
        • Konstam MA
        • Weir MR
        • Reicin A
        • et al.
        Cardiovascular thrombotic events in controlled, clinical trials of rofecoxib.
        Circulation. 2001; 104: r15-r23
        • Laine L
        • Harper S
        • Simon T
        • et al.
        A randomized trial comparing the effect of rofecoxib, a cyclooxygenase 2-specific inhibitor, with that of ibuprofen on the gastroduodenal mucosa of patients with osteoarthriris.
        Gastroenterology. 1999; 117: 776-783
        • Langman M
        • Jensen D
        • Watson D
        • et al.
        Adverse upper gastrointestinal effects of rofecoxib compared with NSAIDs.
        JAMA. 1999; 282: 1929-1933
        • Celermajer D
        • Sorensen K
        • Gooch V
        • et al.
        Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis.
        Lancet. 1992; 340: 1111-1115
        • Biasucci L
        • Liuzzo G
        • Grillo R
        • et al.
        Elevated levels of C-reactive protein at discharge in patients with unstable angina predict recurrent instability.
        Circulation. 1999; 99: 855-860
        • Ridker P
        • Rifai N
        • Pfeffer M
        • et al.
        Elevation of tumor necrosis factor-α and increased risk of recurrent coronary events after myocardial infarction.
        Circulation. 2000; 101: 2149-2153