Rapid Responses to:

NEWS: Jeanne Lenzer FDA advisers warn: COX 2 inhibitors increase risk of heart attack and stroke BMJ 2005; 330: 440 [Full text]

Rapid Responses: Submit a response to this article

Rapid Responses published:

Opportunity missed to make COX-2 inhibitors safer: lower, effective doses ignored.

Jay S. Cohen   (28 February 2005)

Questioning the scientific validity of the COX-2 inhibitor RCTs

Jeffrey Mann   (29 March 2005)

Opportunity missed to make COX-2 inhibitors safer: lower, effective doses ignored. 28 February 2005
Jay S. Cohen, physician Del Mar, CA, USA 92014 Send response to journal: Re: Opportunity missed to make COX-2 inhibitors safer: lower, effective doses ignored.	To the BMJ Editor: It is unfortunate that recent regulatory committees, while discussing many pressing issues involving COX-2 inhibitors (1), did not also seize the opportunity to consider the use of lower, safer doses of these drugs. Few healthcare professionals realize that even at their lowest recommended doses, celecoxib (Celebrex) and valdecoxib (Bextra) are still very powerful medications. Indeed, the manufacturer compares the efficacy for pain relief of celecoxib 200 mg/day and valdecoxib 10 mg/day to that of naproxen 500 mg twice-daily. However, Naproxen 500 mg BID is the highest of four commonly available dosages in the U.S. that include: 375 mg BID; 250 mg BID; 200 mg BID (over-the-counter). Many patients get ample relief with these lower doses, even with the OTC dosage. If these lower dosages of naproxen work, why aren't celecoxib and valdecoxib produced at similarly reduced dosages? Regulatory authorities advise that all anti-inflammatory drugs should be used at the lowest dosage required by each patient, because the gastrointestinal, renal and, now, cardiovascular toxicities of these drugs are dose-related. It is possible to follow this sound advice with naproxen, ibuprofen, and diclofenac, but not with celecoxib or valdecoxib. Instead, for osteoarthritis, the recommended dosages of celecoxib and valdecoxib are one-size-fits-all. These dosages of celecoxib and valdecoxib have not been linked to increased cardiovascular events -- yet -- but this does not mean that safety has been established. Much study still must be done, especially in at-risk populations such as the elderly. In the meantime, every medically sound step toward greater safety should be considered. During their pre-marketing research, effectiveness was seen with lower doses of celecoxib and valdecoxib. For example in a large study conducted by the Mayo Clinic of people with severe osteoarthritis, 50 mg twice-daily of celecoxib (one-half the recommended dosage) provided significant pain relief on all efficacy measures in comparison to placebo. Equally important, the lower dosage caused fewer adverse effects than higher dosages, and no renal toxicity was seen with the lower dosage (2). With valdecoxib, randomized, placebo-controlled studies showed that 5 and 2.5 mg -- one-half and one-quarter lower, respectively, than the recommended dosage -- were effective for osteoarthritis (3-5). Nevertheless, despite these findings, these lower, effective dosages of celecoxib and valdecoxib have never been marketed in the U.S. When powerful new drugs are marketed in very limited or one-size-fits -all sizes that ignore the pharmacologic principle of individual variation, problems are inevitable. Drugs that do not allow doctors to select dosages based on variables such as a patient's age, weight, state of health, use of other medications, or a history suggestive of a poor metabolizer, make it impossible to avoid the overmedication of some patients. Drugs that do not allow doctors to seek the lowest rather than highest effective dosage place patients at unnecessary risk of adverse events. Until manufacturers are required to market drugs at the full range of safe and effective dosages, the list of serious new medication toxicities will continue to lengthen. We should remember that many drugs withdrawn in recent years were one-size-fits-all: terfenadine, astemizole, fenfluramine, d-fenfluramine, alosetron (now back at a lower dosage). The fact is that most adverse effects are dose-related (6), and individual variation and outliers must taken into account or more problems will ensue. Already, new toxicities are identified in more than 50 percent of new drugs after they are marketed (7). This is a record we must and can improve. We must never forget that the substances we prescribe can have powerful effects on sensitive human systems and that the best dosage of any medication is the least amount needed to accomplish the goal. We can start by requiring the manufacturer of celecoxib and valdecoxib to undertake the actions necessary to market lower, safer, proven-effective dosages of these drugs. Jay S. Cohen, M.D. Associate Professor (voluntary) Departments of Family and Preventive Medicine and of Psychiatry, University of California, San Diego References 1. FDA advisors warn: COX-2 inhibitors increase risk of heart attack and stroke. BMJ 2004;330:bmj.com. 2. Bensen, WG, Fiechtner, JJ, McMillen, JI, et al. Treatment of osteoarthritis with celecoxib: a randomized controlled trial. Mayo Clinic Proceedings 1999;74(11):1095?105. 3. Kivitz, A, Eisen, G, Zhao, WW, Bevirt, T, Recker, DP. Randomized placebo-controlled trial comparing efficacy and safety of valdecoxib with naproxen in patients with osteoarthritis. Journal of Family Practice 2002;51(6):530-7. 4. Makarowski, W, Zhao, WW, Bevirt, T, Recker, DP. Efficacy and safety of the COX-2 specific inhibitor valdecoxib in the management of osteoarthritis of the hip: a randomized, double-blind, placebo-controlled comparison with naproxen. Osteoarthritis & Cartilage 2002;10(4):290- 6. 5. Ormrod, D, Wellington, K, Wagstaff, AJ. Valdecoxib. Drugs 2002;62(14):2059-71. 6. Lazarou, J, Pomeranz, BH, Corey, PN. Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies. JAMA 1998;279(15):1200-5. 7. Moore, TJ, Psaty, BM, Furberg, CD. Time to act on drug safety. JAMA 1998;279(19):1571-3. Competing interests: None declared
Questioning the scientific validity of the COX-2 inhibitor RCTs 29 March 2005
Jeffrey Mann, Retired physician Salt Lake City, UT 84103 Send response to journal: Re: Questioning the scientific validity of the COX-2 inhibitor RCTs	Questioning the scientific validity of the COX-2 inhibitor trials. The subject of "increased cardiovascular risks associated with COX-2 inhibitor drugs" has been in the headlines in the past few months. The controversy first reached a fever pitch when Merck suddenly withdrew rofecoxib from the market in September 2004 because the APPROVE trial demonstrated that the drug was associated with an increased risk of adverse cardiovascular events. I was surprised by Merck's decision to abruptly withdraw the drug from the market, simply because a single RCT had demonstrated that rofecoxib was associated with a significantly increased risk of adverse cardiovascular events, and I was looking forward to reviewing the quality of the scientific evidence for myself. However, I had to wait many months before the official APPROVE study report was finally published in the NEJM [1]. I expected the APPROVe trial to have a very strong signal and a high signal/noise ratio, which would consequently provide the public with unequivocal scientific evidence that rofecoxib was definitely associated with an increased risk of adverse cardiovascular events. However, after reading the official report in the NEJM [1], I surprisingly discovered that the APPROVe trial had a low signal/noise ratio, due to the fact that chance events apparently caused the placebo group to have a disproportionately low control event rate in the last 18 months of the trial. It was only in the last 18 months of the trial that the APPROVe trial's signal became readily apparent, and a major portion of the signal was primarily due to the low control event rate in the placebo group (comparator group). I suspect that the placebo group's low control event rate in the last 18 months of the APPROVe trial is mainly due to random chance events, and I believe that this chance event phenomenon represents noise. Sackett stated [2] that one cannot have confidence in the conclusions of a RCT if the randomised trial has a low signal/noise ratio. If my suspicions are correct, then the APPROVE may have such a low signal/noise ratio that it cannot provide the public with scientifically valid evidence, and it may still be an open question whether COX-2 inhibitor drugs are associated with an increased risk of adverse cardiovascular events. I subsequently reviewed a number of COX-2 inhibitor trials that supposedly demonstrate that these drugs are associated with an increased risk of adverse cardiovascular events. I discovered that all these trials are characterised by a low control event rate, a small signal, and a high level of potential noise. From my perspective, that combination means that all these trials have a low signal/noise ratio, and one cannot therefore have confidence in their final conclusions. I have discussed all these issues in a critical essay which is freely available online [3]. My final conclusion is that one cannot expect a RCT to yield scientifically valid evidentiary conclusions if the RCT has a low control event rate, a small signal and a large amount of noise. If you agree with my position, then you may also question the scientific validity of the RCT evidence that COX-2 inhibitors are definitely associated with an increased risk of adverse cardiovascular events. Jeff Mann, MD. References: 1. Bresalier RS, Sandler RS, Quan H, Bolognese JA, Oxenius B, Horgan K, Lines C, Riddell R, Morton D, Lanas A, Konstam MA, Baron JA. Cardiovascular Events Associated with Rofecoxib in a Colorectal Adenoma Chemoprevention Trial. NEJM March 17th 2005. Vol 352. p1092-1102. 2. Sackett, David L. Why randomized controlled trials fail but needn't: 2. Failure to employ physiological statistics, or the only formula a clinician-trialist is ever likely to need (or understand!) CMAJ 165(9):1226-1237, October 30, 2001. Available online at http://www.cmaj.ca/cgi/content/full/165/9/1226 3. Mann J. Questioning the scientific validity of the COX-2 inhibitor RCTs showing an increased risk of adverse cardiovascular events. Available at http://jeffmann.net/soapbox/vioxx-cox2critique.htm An adobe PDF version, for printing purposes, is available at http://jeffmann.net/soapbox/vioxx-cox2critiqueadobe.pdf Competing interests: None declared