By Robert A. Greenwald, M.D.
Posted: Tuesday, April 5, 2005
ARTICLES
Publication Date: April 5, 2005
This reflection was written before the FDA request, in the second week of April, for the withdrawal of Bextra and new warning label for Celebrex but is made all the more timely by recent events:
COX-2 inhibitors such as Vioxx have become the targets of Congressional hearings and a proposed post-approval drug monitoring body, but in all the hype about their hoped-for benefits and hubbub over their newfound side effects, it's easy to forget that these drugs do, after all, have important benefits -- and that we were on the verge of finding new and even more important uses for the drugs when the controversy over them arose, potentially squelching valuable research.
The "law of unintended consequences," well known to social scientists, states that the actions of people, and especially of governments, often have unplanned effects that are not necessarily beneficial. The recent actions of the FDA and the pharmaceutical industry regarding the COX-2 inhibitors (Vioxx, Celebrex, and Bextra) are a prime example.
COX-2 refers to an enzyme that participates in inflammation and pain of the sort that might be endured by patients with rheumatoid or osteoarthritis. The COX-2 selective drugs interfere with the action of this enzyme but spare a similar enzyme that protects the stomach, thereby lessening the risk of stomach-related side effects which might be seen with older, conventional arthritis drugs. (Both COX-2 drugs and the older non-selective drugs are referred to as non-steroidal anti-inflammatory drugs, or NSAIDs.) The COX-2 drugs were developed primarily for treatment of subjects at high risk for stomach problems, including the elderly, smokers, and patients with a history of gastrointestinal problems such as ulcers. However, they rapidly became much more widely used, largely due to aggressive marketing by their manufacturers. Now the concept has been called into question by the finding that in some studies using these agents, an increase in cardiac and/or cerebrovascular (stroke) events was observed. Vioxx was temporarily withdrawn, and the usage of Celebrex and Bextra plummeted.
Several other promising lines of research were underway at the time of these events: studies to determine if COX-2 drugs would either benefit or prevent Alzheimer's disease, studies to see if these agents would prevent colon polyps from turning into cancer, and ironically, the concept that a COX-2 drug might prevent rather than cause heart disease. As an unintended consequence, these and other lines of investigation, which might potentially benefit many thousands (or millions) of people, may be curtailed.
Alzheimer?s Disease (AD): One of the methods used to clarify how a chronic disease develops is to study a large number of patients, collecting extensive information about their backgrounds, including detailed drug histories. About 15 years ago, studies of AD suggested that patients who had taken NSAIDs were protected against AD, i.e., their risk was lower. At first this effect was attributed to a general anti-inflammatory action, but in subsequent test tube and animal experiments, NSAIDs were shown to prevent the formation of a substance called amyloid which is present in large amounts in the brains of persons with AD and which is believed to cause many of the mental changes that occur in that condition.
This has led to the design of large-scale clinical trials in which it was planned to administer an NSAID to a population at risk to determine if a preventive effect could be demonstrated. Since it is the elderly who are at risk for both AD and gastrointestinal side effects, and since COX-2 activity is enhanced in brain tissue from AD patients, a COX-2 inhibitor drug would be the obvious choice of NSAID for such a study, even though several small-scale clinical trials have so far been negative. It hardly seems likely now that a major trial will take place. In fact, on December 20, 2004, the NIH announced that their ADAPT study (AD Anti-inflammatory Prevention Trial) using Celebrex had also been suspended.
Colon cancer: The situation with colorectal cancer (CRC) is similar: epidemiologic, test tube, and animal studies all suggest that preventive treatment with an NSAID, especially a COX-2 selective NSAID, might prevent CRC. The discovery was based on the chance observation of a subject who suffered from a familial disorder of frequent colon polyp formation with a high risk of cancer. The patient had been given an old NSAID called sulindac, and his doctor noted that the number of polyps had dramatically decreased. This led to many studies involving NSAID administration to subjects with both familial and sporadic colon polyps, with many of the studies utilizing Celebrex. The rationale for such an approach was enhanced by test tube and animal experiments showing that COX-2 was important in development of CRC. Celebrex had been FDA-approved for prevention of colon polyps in people with familial polyposis since 1999. Vioxx (Merck's COX-2 drug) was being evaluated for this usage when it was withdrawn -- but the preliminary results showed that it too was effective in chemoprevention of colorectal polyps. The COX-2 hypothesis of cancer causation is not limited to CRC: it might also be applicable to many other cancers. Surely the new findings on heart disease will seriously impede the search for a cancer-preventative role for the COX-2 drugs.
C-reactive protein (CRP): CRP has been in the news for the last few years because of statistical and epidemiologic studies showing that a high CRP level in the blood is a possible predictor of heart disease. CRP is elevated as a result of inflammation of any sort, from periodontal (gum) disease to severe arthritis. It has been surmised, without any proof, that reducing CRP might help prevent heart disease. Most patients with cardiac risk factors should, of course, be doing all they can to lower their cholesterol, stop smoking, lose weight, and get more exercise. The major quandary is, would taking an anti-inflammatory drug that is known to lower CRP yield any further benefit regarding cardiac disease? The COX-2 agents surely lower CRP, as do all NSAIDs. But how can it be true that the COX-2 agents increase the risk of heart disease while lowering one of the known risk factors for heart disease? A quandary for risk/benefit evaluation!
Conclusion: Aggressive marketing by the manufacturers of the COX-2 drugs backfired into the current controversy. The drugs were originally intended only for high-risk populations, e.g., the elderly, those with prior gastrointestinal events, etc. A forty-year old male with a tennis elbow and no ulcer history was not the target population for these drugs. Over-enthusiasm for prescribing the COX-2 drugs has now backlashed into over-avoidance. Had the COX-2 agents been restricted to the populations for which they were originally intended, they might still be enjoying widespread use, and their potential for other, lifesaving indications would still be under exploration, and not on the shelf. Let us hope the recent FDA decision to keep the drugs on the market enables their most beneficial uses to continue, including any yet to be discovered.
Robert A. Greenwald, M.D., is Professor of Medicine at Albert Einstein College of Medicine.
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