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(Chest. 2004;125:1610-1615.)
© 2004 American College of Chest Physicians

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

Daniel Monakier, MD; Michal Mates, MD; Marc W. Klutstein, MD; Jonathan A. Balkin, MBBS; Bernard Rudensky, MD; David Meerkin, MBBS and Dan Tzivoni, MD

* From the Departments of Cardiology (Drs. Monakier, Klutstein, Balkin, Meerkin, and Tzivoni) and Internal Medicine (Dr. Mates), and Laboratory of Clinical Immunology (Dr. Rudensky), Shaare Zedek Medical Center, Jerusalem, Israel.

Correspondence to: Dan Tzivoni, MD, Director, Department of Cardiology, Jesselson Heart Center, Shaare Zedek Medical Center, 12 Hans Beyth St, PO Box 3235, 91031 Jerusalem, Israel; e-mail: cardio{at}szmc.org.il


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Background: Patients with acute coronary syndromes (ACS) have high levels of inflammatory mediators such as C-reactive protein (CRP) and interleukin (IL)-6.

Aim: 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.

Conclusion: 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: acute coronary syndromes • COX-2 inhibitor • C-reactive protein • endothelial function • interleukin-6 • rofecoxib


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
High levels of inflammatory mediators such as interleukin (IL)-6, serum amyloid A, and especially C-reactive protein (CRP) were found in patients with coronary artery disease (CAD),1234 and their presence was predictive of cardiovascular events in patients with stable and unstable angina,56789 as well as in healthy men10111213 and women.1415 Data suggest that CRP may play a direct role in the progression and activation of atherosclerosis. This effect may be due to its ability to enhance macrophage uptake of low-density lipoprotein (LDL) cholesterol and formation of foam cells, inducing the expression of adhesion molecules in human endothelial cells,1617 as well as increasing plasminogen activator inhibitor-1 expression.18

IL-6 is a proinflammatory cytokine produced in the vascular wall and smooth-muscle cells in response to several factors,192021 and is a primary determinant of hepatic CRP production.2223 IL-6 gene transcripts are expressed in human atherosclerotic lesions.2425 Elevated levels of IL-6 have been reported in patients with acute coronary syndromes (ACS),2627 and its presence is associated with higher cardiac event rates in both patients with ACS28 and normal individuals.13

The active inflammatory process plays a major role in plaque destabilization leading to ACS; and, recently, evidence for enhanced acute-phase responsiveness in patients with unstable angina has been demonstrated.29 Treatment with aspirin1130 and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins)313233 has been shown to reduce levels of CRP both in primary and secondary prevention trials, suggesting that they possess anti-inflammatory properties in addition to their antiplatelet (aspirin) or lipid-lowering effect (statins). This may contribute to retardation of atherosclerosis and reduction in frequency of cardiac events.

Endothelial dysfunction is well documented in patients with CAD, and has been associated with high CRP levels.34 Recently, improvement in endothelial function was reported by Chenevard et al35 in patients with stable CAD treated with aspirin plus celecoxib, 200 mg bid, for 2 weeks. This treatment was associated with reduction in CRP levels as well as oxidized LDL. Soluble tumor necrosis factor receptor 1 (sTNFR-1) was found to be the best predictor for mortality in a study of patients with congestive heart failure36; however, treatment with tumor necrosis factor (TNF) antagonists showed no benefit. TNF-{alpha} has less variability than other inflammatory markers, reflecting a more chronic inflammatory process. Although elevated levels of soluble TNF receptor 2 were found in patients with documented CAD,37 the level of TNF receptor 1 in patients with ACS is not yet known.

Several studies3839 reported a correlation between the COX-2 enzyme activity and atherosclerotic plaques. Overexpression of functionally coupled cyclooxygenase-2 and prostaglandin-E synthase was found in carotid artery atherosclerotic plaques of patients with recent transient ischemic attack or stroke. The author concludes that, "the current available COX-2 inhibitors might provide a novel form of therapy for plaque stabilization of patients with atherosclerotic disease and prevention of acute ischemic syndromes."40 In a study by Altman et al,41 the use of aspirin plus meloxican, a COX-2 inhibitor, for 30 days in patients with ACS without ST-segment elevation was associated with lower rate of recurrent angina, myocardial infarction (MI), or death. An interesting experiment by Saito et al42 showed better cardiac function in rats that received a selective COX-2 inhibitor after ligation of the left coronary artery in contrast to the control group. Recently, a concern was raised regarding the safety of the COX-2 inhibitors. In the Vioxx Gastrointestinal Outcomes Research study,43 the rate of MI was higher in patients with rheumatoid arthritis treated with rofecoxib as compared to those treated with naproxen. This was primarily seen in the population with the highest risk for MI that had indication for antiplatelet therapy. However, in that study no aspirin was administered. In a retrospective cohort study, Ray et al44 found that users of high-dose rofecoxib (50 mg/d) were 1.7 times more likely than nonusers to have coronary heart disease, while no increased risk was observed in users of rofecoxib at doses of <= 25 mg. In an analysis45 of 23 studies with > 28,000 patients, there was no excess of cardiovascular events in patients treated with rofecoxib compared to placebo or non-naproxen nonsteroidal anti-inflammatory drugs (NSAIDs). The differences observed with naproxen were most likely due to its antiplatelet effect. Rofecoxib, which is a specific inhibitor of the COX-2 enzyme, has less GI side effects than the nonspecific NSAIDs434647; therefore, we considered it to be safe for our study population.

The purpose of our study was to prospectively evaluate the influence of a COX-2 inhibitor (rofecoxib) on levels of inflammatory markers (CRP, IL-6, sTNF-R1), and on endothelial function in patients recovering from non–ST-segment elevation ACS.


   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
This was a prospective, randomized, double-blind, placebo-controlled study. Patients hospitalized for non–ST-segment elevation ACS were randomized to receive either rofecoxib, 25 mg/d, plus 100 mg of aspirin, or placebo plus 100 mg of aspirin for a period of 3 months. Regarding the randomization of the patients, a tablet of rofecoxib, 25 mg, or a placebo tablet was put into a nontransparent capsule. The hospital pharmacist distributed the medications in separate dark boxes. The boxes were distributed to the patients by the research coordinator of the study, without knowing the content of the boxes. Patients were randomized into two equiprobable groups via a common pseudorandom number generator. In this specific case, a discrete uniform distribution of the 10 digits (0–9) was used, with odd numbers allocating patients to group A, and even numbers allocating patients to group B. A Fisher exact test was used as a quality control tool for verifying that the observed allocation follows the above-mentioned distribution. Compliance was monitored by tablet counts.

Patients hospitalized for a non–ST-segment elevation ACS were included in the study. This was defined as rest angina with ST-T abnormalities in the presence or absence of elevated creatine phosphokinase or troponins. ST-segment elevation on hospital admission, infectious or other inflammatory disease, serum creatinine > 1.5 mg/dL, active peptic ulcer, history of GI bleeding, uncontrolled hypertension, asthma, allergy to NSAIDs, and congestive heart failure were considered exclusion criteria. The study was approved by the hospital ethics committee, and written informed consent was obtained from each patient prior to enrollment.

Laboratory Tests
Blood samples of inflammatory markers, biochemistry, and lipid profile were drawn at hospital admission and again at 1 month and 3 months. The baseline samples were obtained prior to any invasive procedure, at an average of 24 h after the index anginal episode. CRP levels were determined by nephelometry, using a high-sensitivity assay (Dade Behring Marburg GmbH; Marburg, Germany), and IL-6 and sTNF-R1 by enzyme-linked immunosorbent assay (R&D Systems; Minneapolis, MN). Endothelial function was evaluated noninvasively using high-frequency ultrasound of the brachial artery, assessing blood flow response to hyperemia (endothelium-dependent vasodilatation) and nitroglycerin spray (endothelium-independent vasodilatation).48

Statistical Analysis
Statistical analysis of CRP, IL-6, sTNF-R1 levels and endothelial function was performed by the Wilcoxon test, comparing the 1-month and 3-month results to the baseline values of each group.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Thirty-four patients participated in the study, and all completed at least 1 month of treatment; 18 patients received rofecoxib, and 16 patients received placebo. Of the 23 patients who completed 3 months of treatment, 12 patients received rofecoxib and 11 patients received placebo. Most of the patients who did not complete the 3-month follow-up were excluded, mainly due to the development of infections and inflammatory conditions that could potentially elevate the inflammatory markers studied. There were no significant differences in baseline clinical characteristics between the two groups (Table 1 ). All patients in the rofecoxib group and 14 of the 16 patients in the placebo group were treated with aspirin prior to hospitalization, and most were receiving HMG-CoA reductase inhibitors. Most patients had proven CAD either by angiography or having a history of MI. There were no significant differences in baseline laboratory values between the groups (Table 2 ).


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  		Table 1. Baseline Characteristics*

 

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  		Table 2. Laboratory Baseline Values*

 
Baseline CRP levels in the rofecoxib group ranged from 0.04 to 13.6 mg/dL (mean, 1.33 ± 3.09 mg/dL); in the placebo group, baseline CRP levels ranged from 0.06 to 3.14 mg/dL (mean, 0.64 ± 0.76 mg/dL). In an intention-to-treat analysis, CRP levels were significantly reduced at 1 month by 0.84 mg/dL in the rofecoxib group compared to its baseline values and by 1.3 mg/dL after 3 months (p < 0.02; Fig 1 ). No significant change of CRP level was detected in the placebo group. After excluding the poorly compliant patients (n = 3) from the analysis, a more significant reduction in CRP levels both at 1 month and 3 months was noted (p < 0.004 and p < 0.02, respectively). CRP reduction was also significant (p < 0.03 at 1 month and 3 months) after excluding one patient with a very high baseline CRP level (13.6 mg/dL) in the rofecoxib group (n = 17 and n = 11 at 1 month and 3 months, respectively).



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  		Figure 1. Changes in CRP levels (milligrams per deciliter) in the rofecoxib and placebo groups at 1 month and 3 months, compared to baseline values.

 
IL-6
Baseline IL-6 levels in the rofecoxib group ranged from 0.96 to 6.7 pg/dL (mean, 3.57 ± 2.07 pg/dL); in the placebo group, baseline IL-6 levels ranged from 0.12 to 6.7 mg/dL (mean, 3.02 ± 2.10 pg/dL). In an intention-to-treat analysis, IL-6 levels were significantly reduced at 1 month in the rofecoxib group (p = 0.01) but not at 3 months (p = 0.13) when compared to baseline. There were no significant changes in IL-6 levels in the placebo group (Fig 2 ). When poorly compliant patients were excluded from analysis in the rofecoxib group, there was a very significant reduction of IL-6 level at 1 month (p < 0.002) and a borderline reduction at 3 months (p = 0.067).



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  		Figure 2. Changes in IL-6 levels in the rofecoxib and placebo groups at 1 month and 3 months, compared to baseline values.

 
sTNF-R1
Analysis of sTNF-R1 serum levels showed no significant change from baseline to 1-month and 3-month values in the rofecoxib or the placebo groups. Results were within normal range (820 to 990 pg/mL) in all but one patient.

Endothelial Function
Assessment of endothelial function was performed on 22 patients who were nonsmokers: 12 patients in the rofecoxib group, and 10 patients in the placebo group. No change in brachial artery vascular reactivity was detected between baseline measurements and those at 1 month or 3 months in the rofecoxib or the placebo groups.

Safety and Tolerability
During the 3 months of treatment, there were no significant side effects. One placebo-treated patient had a suspected allergic reaction. Three patients had acute MIs: two patients in the placebo group, and one patient in the rofecoxib group. Two further patients were hospitalized for unstable angina, both from the placebo group. Three patients underwent revascularization, all in the rofecoxib group.


   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The main findings of this study were that treatment with rofecoxib, a COX-2 inhibitor, in patients hospitalized for ACS was associated with significant reduction of CRP and IL-6 levels. The reduction in both CRP and IL-6 levels was observed after 1 month of treatment and persisted for 3 months. The treatment was well tolerated. The reduction in CRP and IL-6 was observed in patients already receiving medical treatment, as all patients were treated with aspirin and most were receiving HMG-CoA reductase inhibitors.

Biasucci et al49 showed that 49% of patients who were hospitalized for unstable angina had high CRP levels at discharge, and 42% of them had persistence of elevated CRP levels for >= 3 months. Patients with elevation of CRP on hospital discharge had an increased incidence of recurrence of instability or MI compared to those with lower CRP levels at discharge.

Data suggest that CRP may be not only a marker, but may have a direct role in the process of atherosclerosis. Zwaka et al16 demonstrated that CRP mediated the uptake of LDL cholesterol by macrophages, and Pasceri et al17 demonstrated a direct proinflammatory effect of CRP, inducing the expression of adhesion molecules in human endothelial cells. Therefore, therapy that reduces CRP levels in patients with ACS may directly suppress the atherosclerotic process and reduce event rates.

In our study, as previously noted, all patients were additionally treated with 100 mg of aspirin, as COX-2 inhibitors have no antiplatelet effect. No change in sTNF-R1 levels was observed during the study. In both groups, levels were within normal range, and there were no significant changes noted between baseline, 1 month, and 3 months in either group. Therefore, sTNF-R1 levels, unlike TNF-{alpha}50 and soluble TNF receptor 2,37 probably do not reflect the inflammatory process in patients with non–ST-segment elevation ACS.

Endothelial function did not change during the course of this study in either group. This is in contrast to a previous study34 in which patients with CAD and high levels of CRP had impaired endothelial function, while reduction in CRP was associated with improvement in function. The lack of improvement in endothelial function in patients treated with rofecoxib in spite of reduction in CRP may be due to the small number of patients in each group and the short follow-up period.

The major limitations of the study are the small number of patients studied, and the high dropout rate at the 3-month follow-up (six patients in the rofecoxib group, and five patients in the placebo group). Patients were excluded because of various reasons: rehospitalization because of acute MI (n = 3), unstable angina (n = 2), and infection or inflammatory conditions requiring anti-inflammatory treatment (n = 6). In spite of the relatively small number of patients studied, even the intention-to-treat analysis showed a significant reduction of CRP and IL-6 in the rofecoxib group after 1 month and 3 months of treatment, and there was no significant change in the placebo group.

We conclude that in patients hospitalized for non–ST-segment elevation ACS, treatment with a COX-2 inhibitor NSAID in combination with aspirin is associated with lower levels of CRP and IL-6 at 1-month and 3-month follow-up periods. The reduced level of inflammatory markers may translate into reduction of acute coronary events. This has to be evaluated in large-scale studies and for a longer follow-up period.


   Footnotes
 
Abbreviations: 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

Received for publication April 7, 2003. Accepted for publication October 30, 2003.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Berk, B, Weintraub, W, Alexander, W (1990) Elevation of C- reactive protein in "active" coronary artery disease. Am J Cardiol 65,168-172[CrossRef][ISI][Medline]
  2. Rifai, N, Joubran, R, Yu, H, et al Inflammatory markers in men with angiographically documented coronary heart disease. Clin Chem 1999;45,1967-1973[Abstract/Free Full Text]
  3. 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[ISI][Medline]
  4. Biasucci, L, Vitelli, A, Liuzzo, G, et al Elevated levels of interleukin-6 in unstable angina. Circulation 1996;94,874-877[ISI][Medline]
  5. 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[Abstract/Free Full Text]
  6. 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[CrossRef][ISI][Medline]
  7. 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[Abstract/Free Full Text]
  8. 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[Abstract/Free Full Text]
  9. 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[ISI][Medline]
  10. 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[Abstract/Free Full Text]
  11. 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[Abstract/Free Full Text]
  12. 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[ISI][Medline]
  13. 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[ISI][Medline]
  14. 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[Abstract/Free Full Text]
  15. 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[CrossRef][ISI][Medline]
  16. Zwaka, T, Hombach, V, Torzewski, J C-reactive protein-mediated low-density lipoprotein uptake by macrophages. Circulation 2001;103,194-197
  17. Pasceri, V, Willerson, J, Yeh, E Direct proinflammatory effect of C-reactive protein on human endothelial cells. Circulation 2000;102,2165-2168[Abstract/Free Full Text]
  18. 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[CrossRef][ISI][Medline]
  19. 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[Abstract/Free Full Text]
  20. 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[Abstract/Free Full Text]
  21. Sanceau, J, Kaiso, T, Hirano, T, et al Triggering of the human interleukin-6 gene by interferon-{gamma} and tumor necrosis factor-{alpha} in monocyte cells involves cooperation between interferon regulatory factor-1, NF{kappa}B and SP1 transcription factors. J Biol Chem 1995;270,27920-27931[Abstract/Free Full Text]
  22. 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[ISI][Medline]
  23. Heinrich, PC, Castell, JV, Andus, T Interleukin-6 and the acute phase response. Biochem J 1990;265,621-636[ISI][Medline]
  24. Seino, Y, Ikeda, U, Ikeda, M, et al Interleukin-6 gene transcripts are expressed in human atherosclerotic lesion. Cytokine 1994;6,87-91[CrossRef][ISI][Medline]
  25. 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[CrossRef][ISI][Medline]
  26. 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[CrossRef][ISI][Medline]
  27. Guillen, I, Blanes, M, Gomez-Lechon, MJ, et al Cytokine signaling during myocardial infarction: sequential appearance of IL-1ß and IL-6. Am J Physiol 1995;269,R229-R235
  28. 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[ISI][Medline]
  29. Liuzzo, G, Angiolillo, D, Buffon, A, et al Enhanced response of blood monocytes to in vitro lipopolysaccharide challenge in patients with recurrent unstable angina. Circulation 2001;103,2236-2241[ISI][Medline]
  30. 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[Abstract/Free Full Text]
  31. 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[ISI][Medline]
  32. 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[ISI][Medline]
  33. 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[Free Full Text]
  34. 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[Abstract/Free Full Text]
  35. Chenevard, R, Hurlimann, D, Bechir, M, et al Selective COX-2 inhibition improves endothelial function in coronary artery disease. Circulation 2003;107,405-409[Medline]
  36. Rauchhaus, M, Doehner, W, Francis, D, et al Plasma cytokine parameters and mortality in patients with chronic heart failure. Circulation 2000;102,3060-3067[Abstract/Free Full Text]
  37. 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[Abstract/Free Full Text]
  38. 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[CrossRef][ISI][Medline]
  39. Belton, O, Byrne, D, Kearney, D, et al Cyclooxygenase-1 and -2-dependent prostacyclin formation in patients with atherosclerosis. Circulation 2000;102,840-845[Abstract/Free Full Text]
  40. 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[Abstract/Free Full Text]
  41. 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[CrossRef][ISI][Medline]
  42. 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[CrossRef][ISI][Medline]
  43. 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[Abstract/Free Full Text]
  44. 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[CrossRef][ISI][Medline]
  45. Konstam, MA, Weir, MR, Reicin, A, et al Cardiovascular thrombotic events in controlled, clinical trials of rofecoxib. Circulation 2001;104,r15-r23
  46. 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[CrossRef][ISI][Medline]
  47. Langman, M, Jensen, D, Watson, D, et al Adverse upper gastrointestinal effects of rofecoxib compared with NSAIDs. JAMA 1999;282,1929-1933[Abstract/Free Full Text]
  48. 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[CrossRef][ISI][Medline]
  49. 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[ISI][Medline]
  50. Ridker, P, Rifai, N, Pfeffer, M, et al Elevation of tumor necrosis factor-{alpha} and increased risk of recurrent coronary events after myocardial infarction. Circulation 2000;101,2149-2153[ISI][Medline]



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