The divergent results of previous studies relating hsCRP to colorectal adenoma or cancer may be related to the timing at which hsCRP was measured (11
). Specifically, positive studies may reflect hsCRP elevations associated with occult disease, including adenoma (11
). In support of this explanation, cross-sectional data measuring hsCRP at the time of colonoscopy have shown a modest association with prevalent adenoma (24
), whereas a prospective study of incident adenoma and a cross-sectional study measuring hsCRP several years before diagnosis of adenoma showed inverse or no association (26
). In our study, because we examined hsCRP levels among individuals within 6 months of a clearing colonoscopy and endpoints were ascertained at protocol-defined surveillance colonoscopies, our results more closely reflect the association between hsCRP and incident neoplasia. Our findings are largely consistent with those of the similarly-designed Aspirin Polyp Prevention Study (PPS) (37
). However, the results from both the APC and Aspirin PPS trials do not exclude a potential association between hsCRP and the initial development of adenoma rather than recurrence. A limitation of our study is that we only had a single baseline measure of hsCRP and we could not correlate change in hsCRP with celecoxib treatment. However, celecoxib treatment reduced adenoma recurrence irrespective of baseline levels of hsCRP. Taken together with data from the Aspirin PPS which did measure hsCRP levels at baseline and at year 3, our findings support the conclusion that hsCRP does not mediate the chemopreventive effect of aspirin or celecoxib (37
Among individuals with high hsCRP levels (>3 mg/L), celecoxib treatment was associated with a 3-fold higher risk of an adverse cardiovascular event; in contrast, among those with low hsCRP (
3 mg/L), celecoxib treatment was not associated with higher risk. Although a formal test for interaction was not significant, this is likely due to the limited number of adverse cardiovascular events. These findings are consistent with emerging data that individuals can be stratified for celecoxib cardiovascular toxicity according to baseline cardiovascular risk. A prior pooled analysis of 6 placebo-controlled trials of celecoxib observed that patients with high baseline cardiovascular risk scores had the greatest risk of celecoxib-related adverse events (38
). Similarly, a five-year safety analysis of an extension of the APC trial showed a significant interaction between a baseline history of atherosclerotic heart disease and risk of celecoxib-associated cardiovascular events (33
). Further studies are needed to determine if baseline hsCRP alone can be used to identify patients for whom long-term use of celecoxib is relatively safe.
In the APC trial, patients were randomized to either 200-mg-bid or 400-mg-bid doses of celecoxib. Thus, it is unclear if baseline hsCRP may also predict risk of cardiovascular events among patients who take celecoxib once daily. In a parallel randomized placebo-controlled trial, treatment with 400-mg of daily celecoxib was associated with an overall non-significant increase in risk of cardiovascular events (RR 1.30; 95% CI, 0.65–2.62) (5
). Thus, it is possible that use of a once daily dosing of celecoxib among patients with low hsCRP may be a particularly effective strategy to minimize cardiovascular risk.
Lastly, in our analysis, we did observe a non-significant increase in risk of renal and hypertensive events in the subgroup of patients with low hsCRP randomized to 200-mg-bid. In contrast, there was no association among those randomized to 400-mg-bid. Based on this lack of a dose-response it is unlikely that there is a unique biological interaction between celecoxib and low baseline inflammatory state and renal or hypertensive events. Nonetheless, larger studies with a greater number of such endpoints are needed to make definitive conclusions.
In this large, randomized, placebo-controlled trial, baseline hsCRP was not associated with overall risk of adenoma recurrence or celecoxib chemopreventative benefit after three years of treatment. However, individuals with high hsCRP appeared to have the greatest risk of celecoxib-related cardiovascular toxicity. Further studies are needed to determine the role of hsCRP in relation to other markers of cardiovascular risk to evaluate the risk-benefit profile of celecoxib treatment for a range of clinical indications.