Is Merck gearing up for "son of Vioxx"?

The editorial commentary by David Graham in the October 4,2006 issue of the Journal of the American Medical Association ("COX-2 Inhibitors,other NSAIDs and cardiovascular Risk,The seduction of Common Sense" vol. 296,no 13 p 1653) is very critical in regard to both Merck and the FDA. If Dr. Graham's analysis is correct Merck is already cooking the books to get a Vioxx like drug approved by the FDA. Admittedly, this is Dr. Graham's analysis of the pre-approval activities of Merck and their version of those activities is likely to differ significantly from his comments and for those we will have to wait a while.

Here is what he said- Merck has announced they will proceed to get approval for etoricoxib,a new COX-2 inhibitor. They will rely , in part, on the results of the MEDAL trial in which etoricoxib was compared with diclofenac and found to demonstrate that the cardiovascular event risk was the same with either medication using a "noninferiority study" design, which according to Graham, is "especially poor" at identifying risk between drugs. Further, the comparator drug was diclofenac which apparently has been associated with an increased risk of c-v events. By inference, he argues etoricoxib must also increase c-v risk.

Graham then says;

"This veiled and misleading ambiguity has much in common with the stratagems used by VIGOR and APPROVe,where the true results were opposite to those claimed and promoted."

There are two articles regarding COX-2 inhibitors in the same issue, one of which demonstrates an increased risk of cardiovascular events with diclofenac.One is a meta-analysis of randomized clinical trials (RCTs) dealing with renal effects and cardiac rhythm problems and the other a systematic analysis of observational studies. It is the latter which provides the following:

The relative risks (RR) of cardiovascular events is elevated with lower and higher doses of celecoxib-1.33 for the 25 mg/day dose and 1.64 for the greater than 25 mg /day dose.

The highest RR reported is with diclofenac at 1.50 while no increased risk is noted with naproxen and ibuprofen but idomethacin's RR is increased at 1.36.(Ref.Cardiovascular Risk and Inhibition of Cyclooxygenase,McGettigen P and Henry,D JAMA vol 296,no 13,p 1633)

The authors make an important comment :

"Typically, in pharmacoepidemiological studies there is reluctance to accept as causal RR estimates much below 2" This is because this type of study is subject to various biases but, predictably, the authors still believe the demonstrated association "are real". (When do authors not believe what they find is true?)

Here is a related quote form David Sackett et al in their second edition of "Evidence Based Medicine" (Churchhill Livingstone reprinted 2001, p.163)

"How Big should relative risk and odds ratios be before we should be impressed by them? ....We might not want to label an odds ratio from a case-control study as impressive unless it is greater than 4...in cohort studies..we might regard a relative risk of greater than 3 as convincing for more serious adverse events"

This systematic analysis utilized data from both case control and cohort studies so somewhere between 3 and 4 might be the threshold for concern according to the Canadian gurus of Evidence based medicine and these were all under 2.

Even though one can argue about causality and relative risk level this issue of JAMA will do little to encourage the use of COX-2 drugs. Graham's suggestion of using naproxen (or ibuprofen) plus a proton pump inhibitor (PPI) as an alternative makes sense and is what I was recommending for the last several years.