Impact of prolonged cyclooxygenase-2 inhibition on inflammatory markers and endothelial function in patients with ischemic heart disease and raised C-reactive protein: a randomized placebo-controlled study.
BACKGROUND
The impact of cyclooxygenase (COX)-2 antagonist treatment on acute coronary risk is controversial. We investigated the effect of prolonged COX-2 inhibition on inflammatory profile and endothelial function in patients with ischemic heart disease and high serum C-reactive protein (CRP) values.


RESULTS
In a double-blind study, 35 stable subjects on low-dose aspirin with > or =2 previous acute coronary events and 2 of 2 screening CRP values >2.0 mg/L were randomized to the COX-2 inhibitor rofecoxib (25 mg) or placebo daily for 6 months. Serum CRP, interleukin-6 (IL-6), P-selectin, matrix metalloproteinase-9 (MMP-9), and brachial artery endothelial function were evaluated. In the placebo group, CRP (median) was 3.16 mg/L (25% and 75% quartiles, 1.90 and 5.78 mg/L) at baseline and 4.22 mg/L (25% and 75% quartiles, 2.04 and 6.25 mg/L) at 6 months; in the rofecoxib group, CRP was 3.45 mg/L (25% and 75% quartiles, 2.08 and 5.78 mg/L) at baseline and 1.41 mg/L (25% and 75% quartiles, 1.17 and 4.81 mg/L) at 6 months (P=0.03). Rofecoxib compared with placebo also lowered IL-6 at 6 months (P=0.0002). There was a significant off-drug effect on CRP and IL-6 levels in the rofecoxib group 3 months after treatment (P=0.005 and P=0.009, respectively). Rofecoxib did not significantly affect P-selectin, MMP-9, and brachial artery vasoreactivity.


CONCLUSIONS
Prolonged COX-2 inhibition attenuates CRP and IL-6, does not modify P-selectin and MMP-9, and has no deleterious effect on endothelial function in stable patients with a history of recurrent acute coronary events and raised CRP. These results strengthen the rationale for evaluating the clinical benefit of COX-2 inhibition in patients with ischemic heart disease.
Bogaty
Peter
P
Quebec Heart Institute/Laval Hospital, Laval University, 2725 Chemin Ste-Foy, Quebec City, Quebec, Canada G1V 4G5. peter.Bogaty@med.ulaval.ca
Brophy
James M
JM
Noel
Martin
M
Boyer
Luce
L
Simard
Serge
S
Bertrand
Fernand
F
Dagenais
Gilles R
GR
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D000925:Anticoagulants / Q000008:administration & dosage / Q000627:therapeutic use; D001241:Aspirin / Q000008:administration & dosage / Q000627:therapeutic use; D015415:Biomarkers; D001916:Brachial Artery / Q000187:drug effects; D002097:C-Reactive Protein / Q000032:analysis*; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D004311:Double-Blind Method; D004347:Drug Interactions; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000503:physiopathology; D005260:Female; D006801:Humans; D007249:Inflammation / Q000097:blood* / Q000188:drug therapy / Q000201:enzymology; D015850:Interleukin-6 / Q000097:blood; D007783:Lactones / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000097:blood; D008565:Membrane Proteins; D008875:Middle Aged; D017202:Myocardial Ischemia / Q000097:blood* / Q000201:enzymology; D019007:P-Selectin / Q000097:blood; D011451:Prostaglandin-Endoperoxide Synthases / Q000502:physiology; D013450:Sulfones / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D014664:Vasodilation / Q000187:drug effects
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000925:Anticoagulants; D015415:Biomarkers; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D015850:Interleukin-6; D007783:Lactones; D008565:Membrane Proteins; D019007:P-Selectin; D013450:Sulfones; C116926:rofecoxib; D002097:C-Reactive Protein; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D020780:Matrix Metalloproteinase 9; D001241:Aspirin