Thank you Dr. Gordon for your article and thank you Dr. Safaa for sharing your thoughts.
I just wanted to add my thoughts regarding the long term use of selective COX-2 inhibitors. While the study results do emphasize the potential importance of the COX-2 pathway in those that benefit from aspirin, this doesn’t necessarily mean that selective COX-2 inhibitors will fair better than aspirin in prevention trials. Do selective COX-2 inhibitors produce stronger inhibition of the COX-2 pathway than aspirin or other NSAIDs? To my knowledge the anti-inflammatory effects are similar, suggesting that this may also be the case with regards to their effects in COX-2 overexpression.
Were selective COX-2 inhibitors used in Chan et al’s study? The authors mention that only 17 participants from both cohorts used selective COX-2 inhibitors and therefore, as Dr. Gordon, mentioned follow up data was not reported.
Selective COX-2 inhibitos are associated with reduced prostacyclin production by vascular endothelium with little inhibition of platelet thromboxane A2 production a pro-thrombotic agent. COX-2 inhibitors are associated with elevated blood pressure which could predispose to endothelial injury and explain the link with fatal cardiovascular ischemia.
Interestingly two of the main trials that incriminated selective COX-2 inhibitors (two from six trials) were the adenomatous polyp prevention trial (APC trial) and the previous spontaneous colonic polyps (PreSAP trial). The data-safety monitoring board discontinued the APC trial after observing a dose (800 mg vs 400 mg daily) related increased rate of cardiovascular events and a reported increase in the risk of death from cardiovascular causes. Later, a combined analysis of these two adenoma prevention trials confirmed a dose related risk of serious cardiovascular events.
In addition an indistinct subset of colorectal cancer patients have evidence of hypercoagulability. Effective identification of those at risk should be crucial before selective COX-2 inhibitors are used in colorectal prevention trials.
All this makes COX-2 less attractive and aspirin more attractive in the subset of individuals that are considered at risk of colorectal cancer or those with a history of colorectal cancer.
Another idea is the concomitant use of aspirin and selective COX-2 inhibitors, one drug could potentially offset the adverse effects of the other. So far there has been no data to support any benefit from the concomitant use.
1. FDA. Celecoxib (marketed as Celebrex) - Healthcare Professional Sheet text version. Accessed at http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm124655.htm. Accessed on September 24, 2009.
2. Solomon SD, Pfeffer MA, McMurray JJ et al. Effect of Celecoxib on Cardiovascular Events and Blood Pressure in Two Trials for the Prevention of Colorectal Adenomas. Circulation. 2006 Sep 5;114(10):1028-1035. Epub 2006 Aug 30.