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The new england journal of medicine COX-2 Inhibitors — A Lesson in Unexpected Problems
This issue of the Journal contains three articles of their major side effects, gastrointestinal bleed-about the adverse cardiovascular effects of agents ing. Although the basic science was logical, the ac-that selectively inhibit one form of prostaglandin tual proof of enhanced safety turned out to be moreendoperoxide synthase, commonly known as cy- elusive. When the first two drugs in this class wereclooxygenase-2 (COX-2).1-3 This is part of a long approved by the Food and Drug Administration inbench-to-bedside story with an adverse outcome 1999, the lack of evidence of a clear benefit with re-that was not widely anticipated at its start. Unfortu- spect to gastrointestinal safety prevented the manu-nately, as the evidence began to suggest unexpect- facturers from making the very claim that had beened toxicity of this group of agents, the same zeal that the reason for developing these agents in the firsthad driven the clinical investigation to show their place. Two large studies of the drugs were publishedgastrointestinal safety was not evidenced by stud- in 2000. In the Celecoxib Long-Term Arthritis Safetyies designed to show their cardiovascular safety.
Study (CLASS), the apparent gastrointestinal pro- In 1987, evidence emerged4 that there were prob- tective effect of celecoxib noted at the 6-month ably two enzymes — cyclooxygenase-1 (COX-1) and analysis5 had evaporated at the 12-month analysis.6COX-2 — with the capacity to catalyze the transfor- Some have speculated that this lack of a demonstra-mation of arachidonic acid to prostaglandin H ; ble benefit might have been due to the fact that pa- this is the step committing the substrate arachidon- tients were allowed to continue the use of low-doseic acid to emerge as a member of the prostaglan- aspirin. In contrast, the Vioxx Gastrointestinal Out-din–thromboxane family. This family contains many comes Research (VIGOR) study7 prohibited the usemolecular entities, including molecules with both of low-dose aspirin and demonstrated a reduced in-prothrombotic (thromboxane A ) and antithrom- cidence of gastrointestinal lesions after long-term botic (prostacyclin) properties. Within a few years, it use of rofecoxib, as compared with naproxen.
had been established that COX-2 was selectively An unexpected problem arose. In the VIGOR expressed in tissues that had been exposed to cer- study, there was a higher incidence of myocardial in-tain inflammatory mediators and that it was pos- farction in the rofecoxib group than in the controlsible to selectively inhibit COX-2. As the science group treated with naproxen. Because the studyadvanced, it seemed likely that the adverse gastro- lacked a placebo group, it was unclear whether theintestinal effects of common pain relievers whose effect was due to an increased cardiovascular riskmechanism of action was cyclooxygenase inhibi- with rofecoxib or a protective effect of naproxen, ortion were attributable to the inhibition of COX-1. whether this was merely a chance finding. At theThe idea emerged that selective inhibitors of COX-2 time, the science was not sufficiently advanced tocould relieve pain without gastrointestinal side ef- give the adverse cardiovascular effects clear biolog-fects; if true, this would be a major advance.
ic plausibility; however, preliminary evidence pub- A number of pharmaceutical companies devel- lished near the time of completion of the trial sup- oped and tested selective inhibitors of COX-2 with ported the plausibility of COX-2–induced adversethe idea of developing agents for the relief of in- cardiovascular events by suggesting that COX-2 in-flammatory pain that would be as effective as non- hibitors reduced the production of the antithrom-steroidal antiinflammatory drugs but without one botic product, prostacyclin, without changing the Downloaded from www.nejm.org on February 19, 2005 . For personal use only. No other uses without permission. Copyright 2005 Massachusetts Medical Society. All rights reserved. production of the prothrombotic product, throm- tion of a new drug into the market. In contrast, theboxane.8 Unfortunately, no randomized, controlled detection of an increased incidence of a commontrials were initiated to address primarily the ques- event, such as heart attack or stroke, is much moretion of cardiovascular toxicity. Instead, efficacy trials difficult. The uncomfortable conundrum is that thedesigned to investigate the prevention of recurrent latter has a much bigger impact on the public healthcolonic polyps and the management of postopera- than the former. Because epidemiologic studies withtive pain were launched, with monitoring of cardio- cardiovascular end points are subject to major con-vascular events for safety. From early on both drugs founding, ascertainment of the true risk associatedwere marketed intensively, with massive direct-to- with treatment requires randomized controlled tri-consumer advertising. Before withdrawal, the com- als specifically designed to look for such a risk.
bined yearly sales of COX-2 inhibitors exceeded When the CLASS and VIGOR trials were started, the cardiovascular adverse events were not fore- In September 2004, Merck withdrew rofecoxib seen. However, when these clinical trials showed from the market because its trial, designed to test an increased risk of myocardial infarction, rather
the hypothesis that COX-2 inhibitors could prevent than consider this finding a major danger signal,
recurrent colonic polyps, showed increased car- the manufacturers designed trials to show efficacy
diovascular toxicity (one of the articles in this is- for other indications and enhanced the cardiovas-
sue of the Journal presents the cardiovascular data cular safety monitoring in these subsequent trials.
from this study3). The National Cancer Institute It is a sobering thought that although the number
stopped a similar trial of celecoxib when an inde- of deaths and cardiovascular events attributable to
pendent panel of cardiovascular experts reviewed COX-2 inhibitors remains in dispute, had trials de-
the data and also found a greater risk of cardiovas- signed to test the question of cardiovascular toxici-
cular events among patients treated with celecoxib; ty directly been launched in 1999 and executed with
the data on cardiovascular events from that trial are urgency, substantial morbidity and perhaps a sub-
reported in this issue of the Journal.1 Also reported stantial number of deaths could have been prevent-
in this issue are the cardiovascular toxicity data from ed. As we apply new science to develop new medi-
a trial of another COX-2 inhibitor, valdecoxib (and cines, we must not forget that our first job is to do
its intravenous prodrug, parecoxib).2 This trial, no harm.
which examined pain relief in patients recovering
from coronary-artery bypass surgery, showed an in- 1. Solomon SD, McMurray JJV, Pfeffer MA, et al. Cardiovascular
risk associated with celecoxib in a clinical trial for colorectal adeno- creased incidence of cardiovascular end points at ma prevention. N Engl J Med 2005;352.
30 days among patients who had received a total of 2. Nussmeier NA, Whelton AA, Brown MT, et al. Cardiovascular
only 10 days of COX-2 inhibition.
complications of the COX-2 inhibitors parecoxib and valdecoxib af-ter cardiac surgery. N Engl J Med 2005;352.
Taken together, these three large, randomized, 3. Bresalier RS, Sandler RS, Quan H, et al. Cardiovascular events
controlled trials designed to test the efficacy of associated with rofecoxib in a colorectal adenoma chemopreventiondifferent COX-2 inhibitors for a variety of indica- trial. N Engl J Med 2005;352.
Tanaka Y, Ward SL, Smith WL. Immunochemical and kinetic ev- tions confirmed the cardiovascular toxicity that idence for two different prostaglandin H-prostaglandin E isomeras-had been suggested five years earlier. Since three es in sheep vesicular gland microsomes. J Biol Chem 1987;262:different COX-2 inhibitors were all found to be as- 1374-81.
Silverstein FE, Faich G, Goldstein JL, et al. Gastrointestinal tox- sociated with cardiovascular complications, it ap- icity with celecoxib vs nonsteroidal anti-inflammatory drugs for os-pears that this is a class effect. Because there are teoarthritis and rheumatoid arthritis: the CLASS Study: a random-well-established options for treatment of all the ized controlled trial. JAMA 2000;284:1247-55.
Mukherjee D, Nissen SE, Topol EJ. Risk of cardiovascular events approved indications for these drugs, it is reason- associated with selective COX-2 inhibitors. JAMA 2001;286:954-9.
able to ask whether the use of the drugs can now be 7. Bombardier C, Laine L, Reicin A, et al. Comparison of upper
justified.
gastrointestinal toxicity of rofecoxib and naproxen in patients withrheumatoid arthritis. N Engl J Med 2000;343:1520-8.
There is a lesson from all this. The spontaneous 8. McAdam BF, Catella-Lawson F, Mardini IA, Kapoor S, Lawson
reporting systems we have in place to track adverse JA, FitzGerald GA. Systemic biosynthesis of prostacyclin by cyclo-drug reactions make it possible to detect an in- oxygenase (COX)-2: the human pharmacology of a selective inhibi- tor of COX-2. Proc Natl Acad Sci U S A 1999;96:272-7. [Erratum, creased incidence of rare events, such as fulminant Proc Natl Acad Sci U S A 1999;96:5890.]liver failure or rhabdomyolysis, after the introduc- Copyright 2005 Massachusetts Medical Society. Downloaded from www.nejm.org on February 19, 2005 . For personal use only. No other uses without permission. Copyright 2005 Massachusetts Medical Society. All rights reserved.

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