Why COX-2 inhibitors such as Vioxx can cause heart attacks and strokes

New research reveals why COX-2 inhibitors such as Vioxx can cause heart attacks and strokes.

Researchers believe that their findings, published in the December issue of the Federation of American Societies for Experimental Biology (FASEB) journal, could enable the development of improved therapies which do not have these side-effects.

COX-2 inhibitors are primarily used to treat pain in conditions such as arthritis. They work by blocking the COX-2 enzyme, which is expressed at sites of inflammation and underlies the production of hormones called prostaglandins which swell the joints and cause the feeling of pain.

The new study, by researchers from Imperial College London and Queen Mary's School of Medicine and Dentistry, reveals that although COX-2 inhibitors target only COX-2, they also inhibit the enzyme COX-1 within the endothelial cells that line all blood vessels.

COX-1 in these cells makes prostacyclin, which thins the blood. Where this is inhibited there is a greater chance of blood clotting, which, if the drugs are used regularly, may increase the risk of heart attacks and strokes.

Prior to the study, many in the scientific community believed that the side effects of COX-2 inhibitors were caused by inhibiting COX-2 in the endothelium and that this was reducing the production of blood-thinning agents.

The researchers found no evidence for the existence of COX-2 in the endothelium, meaning that scientists can now work on developing therapies which still target COX-2 but which do not have the adverse affect on COX-1 in endothelial cells.

The researchers found that the COX-2 inhibitors only had a significant adverse effect on COX-1 in the endothelium and not on COX-1 in other areas such as platelets in the blood. This leads them to believe that there is something about the cellular environment in the endothelium that makes COX-1 in that area vulnerable to the COX-2 inhibitors.

Professor Jane Mitchell, one of the authors of the study from the National Heart and Lung Institute at Imperial College London, said: "COX-2 inhibitors can have great benefits for patients suffering from conditions such as arthritis. However, the problem is that their use appears associated with an increased risk of heart attacks. Our new research is exciting because it means we can work on developing better COX-2 inhibitors that don't pose the same risks in terms of heart attacks and strokes."

Professor Tim Warner, from the William Harvey Research Institute at Queen Mary University of London, added: "Our research is crucially important as COX-2 inhibitors are part of the nonsteroid class of drugs that are taken worldwide by many hundreds of millions of patients. It is essential that we have a true understanding of their sites of action so that we can produce new safe and effective drugs for years to come. This research will help us define such new drugs."

The researchers reached their conclusions after analysing donated human blood vessels, blood and cells. This research was funded by the British Heart Foundation, the Spanish Government and a European Community FP6 grant.