New Evidence on COX2 and the heart

We have all heard of the COX2 controversy not so long ago, when the FDA asked MSD to withdraw their (then new) COX2 agent VIOXX from the shelves in USA, when they saw an increase rate of heart attacks in patients who were using VIOXX chronically for their joint pains. There was some suggestions on this in the VIGOR study. Post market surveillance by FDA also seemed to support this fear. Of course, in defense, MSD countered that there was although there was a trend, they explained that the population who were taking VIOXX were also the epopulation who were likely to have haert attacks, and so it may just be the population cohort. Clinical explanation were lacking to support the FDA. Pfizer, who also had two COX2 decided to voluntarily withdraw BEXTRA (another COX2) but continued to sell their CELEBRAX, saying that in their CLASS trial, they did not notice any increase in heart attacks. When we look at the CLASS study, those who were taking CELEBRAX were, fortunately for the patients also taking aspirin. This must have protected them, thereby counteracting the pro-thrombotic effects of the COX2. Many of us do believe that COX2 agents are pro-thrombotic. Well, we now have some evidence. Dr M Gnosh and investigators at the Connecticut Heart Center, studied the pro-thrombotic effects of COX2 in mice. Their findings were published in the latest on-line version of the J. of Experimental Medicine. They notice that mice given COX 2 had a reduction in PPAR delta, which in turn allowed a higher level of TF ( tissue factor ), which was pro-thrombotic, at the endothelial wall. Just to recollect that in normals, COX2 stimulates the endocannabinoid system to release PPAR delta, which in turn reduces TF on the endothelial wall, preventing platelet aggregation and thrombosis. With COX2 inhibitor use, the COX2 inhibitor reduces the PPAR delta release by their effects on the endo-cannabinoid system, thereby allowing greater release of TF on the endothelial wall, and so promoting thrombosis. TF inhibitors does reverse this effect. Obviously much more work needs to be done. If this piece of evidence is reproduced, then we would have a good explanation on what FDA is talking about. Alas, the FDA is proven correct on this one.

More on Vioxx

Vioxx is the first COX2 that was withdrawn from the US market in 2004, because of the reported increased incidence of CVS and cerebral events with the use of Vioxx. Almost 20 million patients worldwide, have been taking Vioxx and there are 7,000 lawsuits pending in USA and 11 other European countries, against MSD, the makers of Vioxx. So far, 11 or more suits have been settled, primarily in USA. 7 of the 11 that was decided by jury, were decided in favour of MSD. The legal liabilities for MSD, on this issue is a staggering USD 5BN, enough, I think to do MSD in.

With all these legal suits going on, 7,000 suits in USA tried to get the US courts to allow for a class action suit against MSD, obviously on the premise that the Vioxx cardiovascular side-effects is due to Vioxx, and not the individual patient subset, whereas, MSD is contending that the unfortunate patient CVS side-effects were due to the concomitant patient co-morbidities and not directly due to Vioxx. Believe me, the difference is so fine that perhaps only the lawyers can tell the difference. Be it as it may, the US court decided that the 7,000 odd suits cannot be lodge together as a class action. Thus making MSD very happy.

At the end of the day, and together with our previous postings, it does look like there is a problem with COX2 and the heart, but it may be a class effect, common to the other COX2 as well, perhaps to varying degree. For the many who need COX2, it may be wise to consider taking the COX2 that you like, with a small dose of aspirin (that is what I tell my patients), or go back to the COX1 inhibitor and use some PP inhibitor to help the stomach (like what I do, when I have to play golf). I am sure that moe news is yet to come. We have not heard the last word on this yet.