You are here
Rofecoxib Shows No Effect on Markers of Cardiovascular Disease
“I was surprised that rofecoxib had no effect, as I had originally hypothesized that it would both improve endothelial dysfunction and reduce signs of inflammation,” said Lawrence M. Title, MD at the Queen Elizabeth II Health Sciences Centre in Halifax, Nova Scotia, Canada. “I was more surprised that we saw no effect on the markers of inflammation, including high-sensitivity C-reactive protein (CRP), given that rofecoxib is an anti-inflammatory drug,” he added.
The researchers note that all the participants in the study were getting low-dose aspirin and many of the patients were also receiving cholesterol-lowering drugs, including statins, and ACE inhibitors to treat their coronary artery disease; so it is possible that rofecoxib had no incremental effect on top of this standard therapy. In addition, the patients were stable, which means their markers of inflammation may not have been high at the beginning of the study. Dr. Title also said it is important to note that this study measured test results and not actual clinical outcomes.
“The lack of effect on flow-mediated dilation (a measure of blood vessel function) and inflammatory markers, suggest that it is unlikely that rofecoxib will have any favorable ‘protective’ effects on the artery wall as add-on therapy and therefore, may not provide any cardiac protection for stable patients with coronary heart disease. However, because we were only measuring what are called “surrogate” endpoints such as flow-mediated dilation and C-reactive protein levels, rather than looking at clinical endpoints (such as heart attack or death,) we cannot be sure that our findings can be extrapolated to the clinical setting. The only way to answer whether rofecoxib has any protective or deleterious clinical effects on coronary artery disease patients would be to perform a large-scale (thousands of patients) randomized clinical trial,” Dr. Title said.
The researchers enrolled 60 patients with coronary artery disease who had undergone cardiac catheterization at the Queen Elizabeth II Health Sciences Centre. The participants were typical of patients with angina (chest pain) or a history of heart attack. The patients were randomly assigned to receive either a placebo pill or rofecoxib (25 mg/day) for an 8-week period. The dose was chosen because it appears to inhibit COX-2 without interfering with the anti-clotting benefits of aspirin. With ultrasound, the researchers watched how the brachial artery in the arm responded when a blood pressure cuff was used to increase blood flow in the arm, as well as when the participants were given nitroglycerin pills. Blood samples were analyzed to measure levels of cholesterol and markers of inflammation, including C-reactive protein (CRP), sICAM-1, and soluble interleukin-6 receptor (sIL-6r). There were no significant changes in either the placebo or rofecoxib groups.
Cyclooxygenase-2 (COX-2) is an enzyme that is found in atherosclerotic blood vessels, but not in normal arteries. This may suggest that COX-2 is responsible for the development of atherosclerotic plaque. However, COX-2 also has protective effects by producing prostacyclin which helps prevent clot formation in the arteries that may cause heart attacks. Thus, there is controversy whether drugs like rofecoxib, which block the effects of COX-2, may have protective or deleterious effects in heart patients. Of note, a recent study of arthritis patients (VIoxx Gastrointestinal Outcomes Research or VIGOR) linked rofecoxib to higher rates of heart attacks, although other studies have not seen an increased risk. In contrast to Dr. Title’s study, a recent trial of another COX-2 inhibitor (celecoxib, brand name Celebrex) in 14 patients with coronary artery disease indicated improved blood vessel function and a decline in C-reactive protein levels, when given on top of aspirin, statins, and ACE inhibitors. However, without a head to head study, one cannot directly compare the effects of rofecoxib and celecoxib on blood vessel function and inflammation.
In an editorial in the journal, Subodh Verma, MD, PhD, and Paul E. Szmitko, BSC at Toronto General Hospital, University of Toronto in Toronto, Canada, wrote that this study is “a very important addition to the clinical data on coxibs and cardiovascular risk.” They emphasized the importance of the finding that rofecoxib does not impair endothelial function, which is a key pathophysiological indicator of vascular risk. However, the editorial authors also sounded a note of caution in interpreting the results.
“Although these data suggest that in patients with known atherosclerosis there may be no detrimental effect of rofecoxib therapy on endothelial function and inflammatory profile, a number of important points need to be considered in evaluating these data,” they wrote.
Their editorial pointed out that the results of this study are different than those of some other recent studies and that the high proportion of patients who were also being treated with aspirin, cholesterol and blood pressure drugs may have affected the results. The authors noted that the common use of these other medicines reflects the real-life scenario.
Jeffrey L. Anderson, MD at LDS Hospital and the University of Utah in Salt Lake City, who was not involved with this study, said the results indicating rofecoxib had no effect on the factors being measured are of interest in light of the debate about the potential impact of COX-2 inhibition on coronary risk.
“To me, this is reassuring that, if needed for analgesia, COX-2 inhibitors can be given ‘safely’ (although this needs to be confirmed by outcome trials), but it also suggests that COX-2 inhibitors don't add anything (at a mechanistic or intermediary endpoint level) to aspirin alone and shouldn't be given pending additional evidence for coronary protection,” Dr. Anderson said.
Source: American College of Cardiology