Rofecoxib caused excess heart diseaseBMJ 2005; 330 doi: https://doi.org/10.1136/bmj.330.7485.212-a (Published 27 January 2005) Cite this as: BMJ 2005;330:212
All rapid responses
An earlier publication of Graham's paper, and the debate it would
have generated, may have saved many from the adverse effects of rofecoxib
(1). Peer-reviewed journals can play an important role in creating
awareness of drug adverse effects by encouraging debate on the possible
hazards of pharmaceutical products. White and colleagues in analyzing 10
trials involving 7934 patients with osteoarthritis or rheumatoid arthritis
suggested that valdecoxib, and the non-steroidal anti-inflammatory drugs
(NSAID), have no adverse cardiovascular effects, when in fact their data
actually show the opposite (2).
The data presented is clearer if the percentage incidence is
presented to three decimal places rather than rounded up to a single
decimal point as in the original paper. In considering all the 7934
patrients reviewed, the cardiovascular event rate with placebo is 0.175%,
that with NSAID is 0.575%, with valdecoxib 10mg is 0.324% and with
valdecoxib 40 mg is 0.562%. Amongst non-aspirin users, cardiovascular
event rate is 0% in placebo, 0.359% with NSAID, 0.151% with valdecoxib 10
mg, 0.224% with valdecoxib 20 mg, and 0.324% with valdecoxib 40 mg.
Thus, it is clear that the cardiovascular event rate with valdecoxib is
higher than in the placebo group, and probably increases the higher the
dose of drug used. Incidence from the valdecoxib 80 mg group may not be
reliable since much smaller number of patients were studied. The adverse
cardiovascular effect of valdecoxib 40 mg appears equivalent to that of
Because of its cardioprotective effect, therapy with low-dose aspirin
appears to abolish the adverse cardiovascular effect of the coxibs, making
the cardiovascular event rate of aspirin users equivalent whether the
patient is on placebo, valdecoxib or NSAID (3). The smaller number of
such patients also make these data less conclusive.
The mortality data confirms the suspicion that valdecoxib and the
NSAID do have adverse cardiovascular effects. There were 4 cardiovascular
deaths in the valdecoxib group, 3 cardiovascular deaths in the NSAID group
and none in the group on placebo. The adverse cardiovascular effect of the
coxibs may be due its inhibition of prostaglandin I2 formation, with
resulting unfavorable effects on platelet aggregation and endothelium
Given the influential role peer-reviewed journals have, the absence
of a feedback mechanism for debating published articles will add to the
problems highlighted by Fontanarosal et al and further delay recognizing
the hazards of pharmaceutical products (5).
1. 1. Graham D, Campen D, Hui M, Spence M, Cheetham C, Levy G, et al.
Risk of acute myocardial infarction and sudden cardiac death in patients
treated with cyclo-oxygenase-2 selective and non-selective non-steroidal
anti- inflammatory drugs: nested case-control study. Lancet
2005;365:Published online Jan 25, 2005.
2. White WB, Strand V, Roberts R, Whelton A. Effects of the
Cyclooxygenase-2 specific inhibitor Valdecoxib versus Nonsteroidal anti-
inflammatory agents and placebo on cardiovascular thrombotic events in
patients with arthritis. Am J Ther 2004; 11: 244-50.
3. Topol EJ, Falk GW. A coxib a day won’t keep the doctor away.
Lancet 2004; 364: 639-40.
4. FitzGerald GA. Coxibs and cardiovascular disease. N Engl J Med
2004; 351: 1709-11.
5.Fontanarosa PB, Rennie D, DeAngelis CD. Postmarketing surveillance-
Lack of vigilance, lack of trust. JAMA 2004; 292: 2647-50.
Competing interests: No competing interests
This is the response we sent to the Lancet concerning this study.
They may or
not accept to publish it, but they don't have online reactions. It may
BMJ readers, too. I hope this does not compromise the acceptability by the
Lancet, just in case. Please go to the Lancet and read Graham's full
Cardiovascular risks of rofecoxib and other NSAIDs
Patrick Blin, MD, PhD (1), Mathieu Molimard, MD, PhD (1), Annie
(1), Jacques Benichou, MD, PhD (2), Nicholas Moore, MD, PhD, FRCP (Edin)
(1) Department of Pharmacology, Université Victor Segalen Bordeaux 2,
Bordeaux, France; INSERM U657, Bordeaux, France; CHU de Bordeaux,
(2) INSERM U657, Rouen, France; Unité de Biostatistique, CHU de Rouen,
In their recent and excellent paper (1) Graham et al show an
adjusted odds ratio for the occurrence of myocardial infarction (MI) and
sudden cardiovascular death in current users of high-dose rofecoxib,
naproxen, and non-steroidal anti-inflammatory drugs (NSAIDs) other than
ibuprofen or celecoxib, and in recent (1 to 60 days) users of any NSAID,
compared to remote (>60 days) users of any NSAID (including rofecoxib
celecoxib). These results are rather surprising, because in most other
NSAIDs are generally cardioprotective (2) or have no effect on
mortality (3, 4, 5), or the risk of myocardial infarction increases after
withdrawal (6). However, these studies were comparative to no use rather
than remote use of NSAIDs. In Dr Graham’s study, the reference group is
group of remote users, ie, those patients who have not used the drugs
the last 60 days, and the risk of MI is increased in recent or current
use within the last 60 days. However, recent or current use may be
of regular or longer term use of NSAIDs which may select different
with more active disease, at higher risk of cardiovascular disease (7).
The main thrust of the paper, however, is the increased risk of
compared to celecoxib: rofecoxib is not different from the non-selective
NSAIDs, all of which are associated with a higher adjusted risk of MI than
celecoxib, a fact that the authors do not emphasize. So that the real
of this paper is a “protective” effect of celecoxib, rather than increased
with rofecoxib. Interestingly this only appears when the crude odds ratios
adjusted for cardiovascular risk (except for high-dose rofecoxib). The
elements in the cardiovascular risk adjustment are given in table 2 of the
paper. Some of these elements are indeed risk factors (previous history of
cardiovascular admission), others are described as indicative of risk, but
in fact use of cardiovascular drugs that are protective such as beta-
ACE inhibitors, lipid-lowering drugs, etc used in primary or secondary
prevention. Looking at table 2, there seems to be a higher use of these
protective drugs in the celecoxib group than in all the other groups.
the greater use of cardioprotective drugs explain the large change induced
this group by adjustment? The cardioprotective effect of celecoxib is
not generally admitted, and the recent Adenoma Prevention with Celecoxib
(APC) study, similar to the rofecoxib APPROVe study (8) also showed a dose
dependent increase in cardiovascular risk with celecoxib (9).
This does not explain the apparently higher risk associated with
high dose. However there were only 18 patients (10 cases and 8 controls)
with high-dose rofecoxib in the current use group, resulting in an
situation, where a single misclassified subject (in dose or group for
controls that were not clinically reviewed) might make these results non-
significant. Not that there could not be an increased risk with high-dose
rofecoxib, as suggested by other studies.
Finally the computation of an excess risk resulting in 88000 to
related to the use of rofecoxib extrapolated from data from clinical
ludicrous. The same type of extrapolation had been done for GI bleeding
when the COX2 inhibitors were put on the market (10-12). These
computation were wrong (13). The present one are probably wrong too. The
risks in continuous use clinical trials in selected patients or in
indications can hardly be applied indiscriminately to the intermittent use
in real life. Since they used data from clinical trials to compute excess
with rofecoxib, one can wonder why the authors did not also use the data
from the APC trial (9) to compute the excess risk with celecoxib. At the
the authors should have used data from their own study, which may be
construed as representative of real use and risks, as they did in a
version of the paper (14), where the computations gave “only” 27000
However, the data from their study indicate not only an increase risk with
rofecoxib rather than celecoxib, but also an increased risk with the non-
specific NSAIDs, which are much more widely used, so that the real message
should have been that the use of any NSAIDs (including rofecoxib) rather
celecoxib resulted in several hundred thousands or millions of excess
Without rejecting a possible cardiovascular risk with rofecoxib (for
there may be some strong arguments), obviously more studies are needed.
And risks or benefits found in studies in indications that have nothing to
with the common indications and usage patterns of NSAIDs (or for that
any other drug) should be extrapolated only with the greatest of caution.
Conflict of interest: the authors are involved in a 46000 patient
study of the
usage patterns and risks associated with COX2-selective inhibitors and
NSAIDs in France, the results of which should be available within a few
months. This study, financed by Merck & Co and Pfizer, Inc, is done at
behest of the French authorities under the control of an independent
scientific committee. The authors have no financial benefit from this
its results or any other involving these drugs. Some of the authors have
working on issues related to NSAIDs safety for years, and have formed a
number of opinions they may tend to favour, possibly, which could skew
1. Graham D, Campen D, Hui M, Spence M, Cheetham C, Levy G, et al.
of acute myocardial infarction and sudden cardiac death in patients
with cyclo-oxygenase-2 selective and non-selective non-steroidal anti-
inflammatory drugs: nested case-control study. Lancet 2005;365:Published
online Jan 25, 2005.
2. Kimmel SE, Berlin JA, Reilly M, Jaskowiak J, Kishel L, Chittams J, et
effects of nonselective non-aspirin non-steroidal anti-inflammatory
medications on the risk of nonfatal myocardial infarction and their
with aspirin. J Am Coll Cardiol 2004;43(6):985-90.
3. Garcia Rodriguez LA, Varas-Lorenzo C, Maguire A, Gonzalez-Perez A.
Nonsteroidal antiinflammatory drugs and the risk of myocardial infarction
the general population. Circulation 2004;109(24):3000-6.
4. Mamdani M, Rochon P, Juurlink DN, Anderson GM, Kopp A, Naglie G, et
al. Effect of selective cyclooxygenase 2 inhibitors and naproxen on short-
term risk of acute myocardial infarction in the elderly. Arch Intern Med
5. Ray WA, Stein CM, Hall K, Daugherty JR, Griffin MR. Non-steroidal anti-
inflammatory drugs and risk of serious coronary heart disease: an
observational cohort study. Lancet 2002;359(9301):118-23.
6. Fischer LM, Schlienger RG, Matter CM, Jick H, Meier CR. Discontinuation
of nonsteroidal anti-inflammatory drug therapy and risk of acute
infarction. Arch Intern Med 2004;164(22):2472-6.
7. Nissen SE, Tuzcu EM, Schoenhagen P, Crowe T, Sasiela WJ, Tsai J, et al.
Statin therapy, LDL cholesterol, C-reactive protein, and coronary artery
disease. N Engl J Med 2005;352(1):29-38.
8. FDA. Vioxx (Rofecoxib) information. http://www.fda.gov/cder/drug/
infopage/vioxx/default.htm (accessed Feb1, 2005). 2004.
9. FDA. Celebrex (celecoxib) information. http://www.fda.gov/cder/drug/
infopage/celebrex/default.htm (accessed Feb1, 2005). 2004.
10. Singh G. Recent considerations in nonsteroidal anti-inflammatory drug
gastropathy. Am J Med 1998;105(1B):31S-38S.
11. Tramer MR, Moore RA, Reynolds DJ, McQuay HJ. Quantitative estimation
of rare adverse events which follow a biological progression: a new model
applied to chronic NSAID use. Pain 2000;85(1-2):169-82.
12. Wolfe MM, Lichtenstein DR, Singh G. Gastrointestinal toxicity of
nonsteroidal antiinflammatory drugs. N Engl J Med 1999;340(24):1888-99.
13. Moore N. Comment on 'Quantitative estimation of rare adverse events
which follow a biological progression: a new model applied to chronic
use' Tramer et al., Pain 2000;85:169-182. Pain 2001;91(3):401-2.
14. Graham D. Risk of Acute Myocardial Infarction and Sudden Cardiac
Death in Patients Treated with COX-2 Selective and Non-Selective NSAIDs.
December 2, 2004.
we are presently doing a
46000 patient study of the
usage patterns of rofecoxib,
celecoxib, and NSAIDs, and
hope to have results by next
may, which we will of course
consider superior to all other
Competing interests: No competing interests
We learn that naproxen use has a 14% increased risk of coronary heart
disease compared with other non-steroidal anti-inflammatory drugs.
The Lancet article's authors merely talk about naproxen's "lack of
protective effect". Aren't they being a little timid? Is 14% a low enough
figure to ignore, as everyone seems to be doing? At what point do we/our
patients start to panic and stockholders hastily review their portfolios:-
Competing interests: No competing interests
With the reports attributing Rofecoxib with increased cardiovascular
risks, the question that "are other COX 2 inhibitors safe enough?" abounds
The question is pertinent as the other congeners namely Valdecoxib,
Valacoxib, Nimesulide are still flourishing around the world. Definitive
trials are required to vindicate this group of drugs lest COX 2 inhibitors
would only be known for their side effects.
Till that very time should we refrain from the use of these drugs?
Competing interests: No competing interests