Probably not but .....

I wish I had "the" answer for this one but I don't think anyone is currently smart enough to answer this nor is there enough good evidence to answer it. Let me try to give you some objective info to help you in this situation.

Some background - Coxibs (celecoxib, valdecoxib, rofecoxib) have been aggressively marketed directly to consumers and healthcare providers in the United States. These agents have rapidly dominated the prescription-drug market for NSAIDs, accounting for worldwide sales of roughly $10 billion. For example, Vioxx® alone was a $2.5 BILLION a year product for the manufacturer.

In September of this year, rofecoxib [Vioxx®] was voluntarily pulled from the market because of an increased risk of myocardial infarction when the drug was used for 18 months or greater (there was no greater risk when used < 18 months). More recently, valdecoxib[Bextra®] received a "black box" warning for its' package labeling regarding the incidence of Stevens-Johnson syndrome and contraindicating it's use in post-CABG patients. Late last month, the National Cancer Institute (NCI) stopped drug administration in a celecoxib[Celebrex®] arm of a colon polyp prevention trial because of a higher than expected incidence of cardiovascular (CV) events in the celecoxib group. FDA will continue to evaluate all available data regarding CV and other risks of celecoxib in order to determine whether additional regulatory action is needed. Many providers and hospitals are trying to figure out what to do in the interim.

Pharmacology

Basic physiology shows thromboxane A2 (TXA) and prostaglandin I2 (PGI) to be balanced in vivo. TXA, produced largely by COX1, causes platelet aggregation, vasoconstriction, and vascular proliferation. PGI, originally thought to be produced only by COX1, inhibits platelet aggregation, causes vasodilatation, and prevents the proliferation of vascular smooth-muscle cells. The "mix" of TXA and PGI in vivo should maintain a balance. Think of it like warm water. You can make the warm water hotter by increasing the hot water flow or decreasing the cold water flow.

More recent evidence shows COX2 in the vascular endothelium is a dominant source of PGI. The relative imbalance of TXA and PGI in the vascular in patients taking COX2s could explain the apparent increased incidence of thrombosis seen with these agents.

Literature

There are no published, randomized, controlled trials designed to look specifically at these adverse events in relation to the COX2s. All the information is from retrospective analyses or series of anecdotal reports.

We cannot account for other biases or confounders which may have predisposed patients to these CV side effects (remember, UGDP and sulfonylureas?). Having said that, all currently available COX2s (as well as Vioxx®) have been at least associated with an increased risk of thrombosis and cardiovascular events although a direct cause and effect relationship hasn't been proven. The VIGOR (rofecoxib vs naproxen) trial showed a five-fold increase in the incidence of myocardial infarction. A retrospective look at the CLASS study(celecoxib vs naproxen) revealed signs of increased cardiovascular risk. The recent NCI trial showed an increased risk of cardiovascular events in the celecoxib group (2.5 times greater risk vs placebo in the 200mg BID group and a 3.9 times greater risk in the 400mg BID group). The FDA required a "black box" warning for valdecoxib after finding a greater incidence of Stevens Johnson syndrome (87 reported cases to the FDA) and a 2 times greater risk (vs placebo) of thrombosis in post-CABG patients on valdecoxib (2% for IV valdecoxib/parecoxib, 1% for oral valdecoxib, and 0.5 for placebo).

Some people may be on a baby aspirin (81 mg) a day for cardiovascular protection in addition to a COX2. Remember, as little as 30-50mg of aspirin knocks out COX1 and hence kills the safety benefit of the COX2s. I'd suggest you think of it this way - the GI risk of baby aspirin + COX2 = GI risk of a traditional or non-selective NSAID (Thanks to Dr Jay Higgs for this analogy!).

The only studied COX2 with an outcome benefit was Vioxx®. The other studies looked at endoscopoic erosions and the correlations between endoscopic erosions and serious GI events (defined above) is fair at best. The reduction in serious GI complications was reduced from 1.8% in the control group to 1.3% in the rofecoxib group (an absolute risk reduction of 0.5%).

The question we need to ask with these agents as well as any other prescribing decisions should be, "Is the incremental benefit (in this case a 0.5% reduction in GI complications)worth the incremental cost (usually > $1.00 per dose increase over non-selective NSAIDS)"? And IF we choose to prescribe a COX2 for this GI safety benefit, are we willing (is the patient willing?) to accept what appears to be an increased risk of serious cardiovascular adverse events? We need to educate our patients on their choices as well as their risks and benefits.

There are NO published, randomized, clinical trials showing an efficacy benefit for any of the COX2s. Of course, there may be individual patients who do better on a COX2 vice a non-selective NSAIDs but these anecdoctal reports (n=1 studies) cannot be extrapolated to the population at large. The COX2 niche seemed to be their safety benefit. And now their safety seems to be in question. What do we do?

Suggestions?

In light of the latest information about both Bextra® (valdecoxib) and Celebrex® (celecoxib), I would encourage all providers to carefully evaluate the patient's overall risk factors for serious cardiovascular events prior to deciding whether to place patients on either of these drugs.  Neither Bextra® nor Celebrex® should be used as first line agents for patients who have no risk for serious GI adverse events, and who have not been tried on other equally efficacious, yet significantly less costly therapeutic agents which could  include (but are not limited to) meloxicam (Mobic®), ibuprofen, salsalate, acetaminophen, or other formulary medications. The FDA is planning on convening an "expert panel" in February of this year to review the available evidence and make some recommendations.

References

- DOD-MMQC-04-1332, dated 14 December 2004

- FDA Statement on the Halting of a Clinical Trial of the Cox-2 Inhibitor Celebrex, dated 17 December 2004
(http://www.fda.gov/bbs/topics/news/2004/NEW01144.html)

- Fitzgerald G. Coxibs and cardiovascular disease. NEJM. 2004;351-1709-10.

- FDA Alert for Practitioners, Celebrex® (celecoxib), dated 17 December 2004

- Ray WA, Griffin MR, Stein CM. Cardiovascular Toxicity of Valdecoxib. NEJM. 2004;351:2767.

- FitzGerald GA, Patrono C. The coxibs, selective inhibitors of cyclooxygenase-2. N Engl J Med 2001;345:433-42.

- Bombardier C,  Laine  L, Reicin A, et  al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. NEJM. 2000; 343:1520-8.

- FitzGerald G. A., Patrono C. Drug Therapy: The Coxibs, Selective Inhibitors of Cyclooxygenase-2 <http://content.nejm.org/cgi/content/short/345/6/433> . NEJM. 2001; 345:433-442.

- Silverstein et al. CLASS - Celecoxib Long-term arthritis safety study. JAMA. 2000;284:1247-55.

This Pearl is meant for academic and educational purposes only. This Pearl is meant to raise important points regarding the safe and cost-effective pharmacotherapy of patients. It is not meant to be the definitive reference for the treatment or prophylaxis of various diseases. Although every effort is taken to ensure this Pearl is correct and factual, errors may occur. The Pharmacoeconomic Center assumes no liability for incorrect information or harm that may occur from the use of the information included in this Pearl.