COX-2 Inhibitors

I believe that a couple candidates were asked in the last set of vivas about controversy surrounding COX-2 inhibitors. Here are some things to think about:

-The first controversy was with Rofecoxib (Vioxx) marketed by Merck & Co.
-Approved by the FDA in 1999 as an analgesic for treatment of osteoarthritis and various other acute pain conditions - by being a selective COX inhibitor, gastric side-effects e.g. ulceration were thought to be avoided.
-Over the next few years, concern grew about potential serious cardiovascular side-effects in patients who were taking rofecoxib.

-In 2001, the VIGOR study(Vioxx GI Outcomes Research) (Bombardier et al) was submitted to the FDA. It compared rofecoxib and naproxen, looking at efficacy and side effects over a one year period.
-They found a statistically significant 4-fold increased risk of acute MI in rofecoxib patients who were already at increased risk of cardiovascular disease, when compared to naproxen patients.
-The proposed mechanisms of cardiotoxicity included inhibition of PGI2 (prostacyclin), which is normally involved in vasodilatation & clot formation prevention, and possibly the production of cardiotoxic metabolites from rofecoxib itsself.
-There was further controversy between Merck & Co and the NEJM regarding certain data being withheld which resulted in lengthy legal proceedings.

-In 2002, warning labels were produced on rofecoxib packaging warning of the increased risk of CVS morbidity.
-Since then, further studies have demonstrated higher rates of CVS morbidity in Vioxx patients e.g. MI, CVA, arrhythmia, renovascular disease

-Rofecoxib was withdrawn in 2004 by Merck & Co.

The second controversy was with Valdecoxib (Bextra), manufactured by G.D.Searle & Company (now part of Pfizer) and approved by the FDA in 2001.
-Again, it was used to treat OA, RA, and painful menstruation.
-It was withdrawn in 2005 due to a perceived increased risk of MI & CVA. Also, Toxic Epidermal Necrolysis and Steven Johnson's Syndrome had been reported.

-So what has been learned from this:

Doctors must be selective when prescribing COX-2 inhibitors both in dose and duration, especially to those with an increased risk/previous history of cardiovascular disease.
New drugs with mechanisms of action similar to COX-2 inhibitors, including the COX-2 inhibitors themsselves will undergo much more extensive trials in the future, to try and avoid both the medical and financial problems associated with rofecoxib.