Lessons from the withdrawal of rofecoxib
BMJ 2004; 329 doi: https://doi.org/10.1136/bmj.329.7471.867 (Published 14 October 2004) Cite this as: BMJ 2004;329:867All rapid responses
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The article seems to hint that the cardiovascular side-effects
reported with rofecoxib can be a class effect. Only time will tell if
this assumption is right or wrong .
I’d like to point out,however,that we already had examples in the
past of drugs withdrawn from the market due to adverse reactions not
shared by other compounds belonging to the same pharmacological class.
Years ago two H2-receptor antagonists, oxmetidine and niperotidine have
been found to induce acute liver injury and their use has been banned.
Nevertheless ranitidine and various other H2-blockers have continued to
be used by millions of individuals all over the world – and still are-
with no harm for the patients.
In August 2001 cerivastatin was removed from European and USA markets
because of a high risk of rhabdomyolysis , but other statins keep being
employed everywhere as a cholesterol-lowering agents , although,
obviously, under careful medical surveillamce.
It’s true that “absence of evidence is not evidence of absence”. On
the other hand everybody is presumed innocent until found guilty.
Competing interests:
None declared
Competing interests: No competing interests
The Lancet published the results of an unscientific meta-analysis of
rofecoxib studies online on November 5th 2004 [1]. I think that this cumulative
meta-analysis is highly flawed and I think that the authors misrepresent a number of facts.
The meta-analysis is essentially a review of all randomised controlled clinical
trials in adult patients with chronic musculoskeletal disorders that compared
rofecoxib with placebo or other NSIADs. The authors reviewed 63 reports, and 18
clinical trials (involving 25 273 patients). They specifically studied the
incidence of MI, and they concluded that the overall rate of MI was increased in
rofecoxib patients (combined relative risk of 2.24, based on 52 events in the
rofecoxib group compared to 12 in the control group). In particular, the authors
claimed that this increased RR was already apparent in 2000, when 14 347
patients had been randomised and 44 MI events had occurred in rofecoxib treated
patients (see figure 3 in the paper). However, the increased RR occurred suddenly in the year
2000 and it was due to the fact that the cumulative data was then being
driven by a comparison with naproxen as the control agent (large amount of data
derived from the VIGOR trial), rather than other NSIADS or a placebo (which mainly drove
the cumulative data until that point in time). The choice of a comparator is
critically important if the comparator agent is associated with a significantly
lower, or significantly higher, risk of MI than that found in rofecoxib treated patients. The authors concluded that by the end of the
year 2000, the cumulative evidence demonstrated that rofecoxib more than doubled
the risk of MI. Compared to what?
It may appear that the risk of MI was more than doubled compared to naproxen,
but it was not doubled relative to placebo and other NSIADs. In fact, the
authors published the comparative results in table 2 in their paper, and their
published results demonstrate that the RR of rofecoxib compared to placebo was 1.04, and
1.55 when compared to non-naproxen NSIADS. However, the lead author Jüni
apparently still made this statement as reported by Zosia Chustecka in a heartwire
report [2]-: "Jüni tells heartwire that the meta-analysis also shows that
this increased risk of MI with rofecoxib did not vary with controls (similar for
placebo, naproxen, or a nonnaproxen NSAID), did not vary with the daily dose of
rofecoxib used (12.5 mg, 25 mg, and 50 mg), and did not depend on length of
treatment (it was similar for trials of duration less than 6 months and those of
more than 6 months)". Why did Jüni claim that the increased risk of MI with
rofecoxib did not vary with controls when their own meta-analysis specifically
demonstrated that this statement was not true?
In fact, Jüni et al. comprehensively dealt with the issue of naproxen as a
comparator agent in their meta-analysis paper, and they specifically state-:
"The difference in coronary risk in the VIGOR trial has been widely interpreted
as being due to a cardioprotective effect of naproxen, rather than an adverse
effect of rofecoxib. We examined this hypothesis by stratifying results from
randomised trials according to the control intervention and found that the
increase in risk was indeed greater in trials comparing rofecoxib and naproxen,
but that this finding was probably attritutable to chance." Don't you think that
this conclusion is bizarre? Chance! I can understand a meta-analyst concluding
that a specific finding could be due to chance when it occurs once, or very
infrequently. However, Jüni's own meta-analysis paper reviewed a number of
naproxen studies (see figure 4) and they demonstrate a near-uniform result among
the 11 studies -- that naproxen is associated with a reduced risk of MI compared
to other controls. Therefore, using naproxen as a comparator agent presumably
inflates the estimated RR of iatrogenic MI due to rofecoxib, and makes the "apparent"
harmful effect greater than the likely "true" harmful effect.
I think that Jüni's cumulative meta-analysis is highly flawed because it uses a
heterogeneous group of control population studies as a comparator. I think that a meta-analysis
of multiple clinical studies is only scientifically valid if the different
control population studies have relatively homogeneous results (similar baseline
risk of MI in the different control groups). I cannot understand why the Lancet decided to
rush such a flawed meta-analysis into publication when this particular issue has
already been discussed years ago.
The issue of whether the increased risk of
MI associated with rofecoxib is "real" or "apparent" was already discussed in
the mainstream medical literature a few years ago. In particular, the authors of a 2001 paper [3]
expressed serious concerns regarding the issue of whether the increased risk
of MI in rofecoxib treated patients is due to a direct harmful thrombotic effect
of rofecoxib, or whether the "apparent" harmful effect is due to a comparison
with naproxen, which may have a cardioprotective antithrombotic effect. The
authors concluded that they didn't have enough evidence to come to a definitive
conclusion, and they therefore used another ancillary comparative technique to
shed more light on this issue. They compared the risk of MI in rofecoxib treated
patients (who were at low risk of MI) to the risk of MI in placebo patients from
four aspirin primary prevention trials (who were presumed to have a similar low
risk of MI). They noted that rofecoxib treated patients had a higher risk of MI
(0.74%) compared to those placebo patients (0.52%). This fact suggested that the
increased risk of MI in rofecoxib treated patients could be "real" rather than
"apparent". However, the authors noted that there is no guarantee that the
rofexcoxib and placebo patients had the same baseline risk of MI (because they
were from totally different studies). They therefore suggested that a large
randomised trial should be performed in "higher-than-normal risk" MI patients
(eg. elderly OA patients who have a higher baseline risk of MI) in order to to
generate a stronger signal, and hopefully a definitive answer to this dilemma. I
think that this suggestion was very rational and an appropriate solution to this
dilemma. I think that Merck was highly delinquent because it did not perform
that
much-needed RCT during the past few years. I think that the FDA was also highly delinquent because it did
not insist that it be performed. And, finally, I think that the Lancet editor (and other
mainstream medical journal editors) were also highly delinquent because they did
not repeatedly insist, during the past four years, that this RCT be performed. I think that the available
evidence strongly suggests that the increased risk of MI in rofecoxib
patients may be "real", but the medical research community obviously missed a golden opportunity to prove that point
by performing a well-designed large randomised trial using an appropriate
homogeneous control group as the comparator group.
What particularly bothers me about this Lancet published meta-analysis is
that it obfuscates the issue as to whether rofecoxib significantly increases the
risk of an MI, and it does not shed any useful light on the issue. Sackett [4]
stated that confidence in a RCT's conclusion is directly proportional to the
trial's signal/noise ratio. An increase in a trial's signal, and/or a decrease
in a trial's noise, increases the trial's signal/noise ratio, thereby allowing
one to become increasingly confident in the scientific validity of the
trial's results. To maximise a RCT's signal, Sackett suggests that trial
designers should ensure that there is a combination of a high control event rate
and a large effect size. All the rofecoxib trials had a low baseline MI rate
(partly because high risk coronary patients were excluded from trial
participation + partly because most trials were of short duration) and this fact
significantly decreased each trial's potential signal, and therefore the trials'
signal/noise ratio. Theoretically, a cumulative meta-analysis could allow one to
increase the "overall" signal and thereby improve the "overall" signal/noise ratio
(according to Sackett, confidence in a RCT's results is inversely proportional
to the square root of the sample size, which means that the any gains in
confidence obtained by adding the results of multiple studies is not simply
proportional to the final sample size number).
However, that basic assumption is only valid if the different trials use the same
control agent (or a similar control agent that results in a similar control
event rate). That basic assumption certainly doesn't apply to the rofecoxib studies
included in Jüni's meta-analysis,
which used different control agents (placebo, naproxen and non-naproxen NSIADS)
with varying control event rates. Therefore, a cumulative meta-analysis of heterogenous rofecoxib studies
doesn't increase the signal/noise ratio. In fact, it decreases the signal/noise
ratio by significantly increasing the noise level. Publication of this
cumulative meta-analysis is therefore antithetical to the basic principle of EBM
science -- because it is likely to obscure, rather than illuminate, the truth.
Jeff Mann.
References:
1. Peter Jüni, Linda Nartey,
Stephan Reichenbach, Rebekka Sterchi, Paul A Dieppe, Matthias Egger. Risk of
cardiovascular events and rofexcoxib: cumulative meta-analysis. Lancet.
November 5th 2004. Published online at
http://www.lancet.com
2. Heartwire report published November 4th.
Available in the heartwire section of theheart.org.
3. Mukherjee D, Nissen SE, Topol EJ. Risk of
cardiovascular events associated with selective COX-2 inhibitors. JAMA
2001; 286:954–59.
4. 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
Competing interests:
None declared
Competing interests: No competing interests
Dieppe et al, comments some lessons from the withdrawal of rofecoxib
[1]. We are agree about the recommendations proposed, specially with the
need to determine the cardiovascular risk for other COX-2 selective
inhibitors, because this adverse drug reaction must be a class effect but
with a different risk for each drug.
For example, more than twenty years ago the risk of upper
gastrointestinal bleeding was associated with aspirin and other non-
steroidal anti-inflammatory drugs, but a study published in 1991 was the
first to demonstrate a different risk for individual drugs [2]. Something
similar could be happening now.
Certainly in the VIGOR Study [3] the incidence of myocardial
infarctions were less common in the naproxen group (0.1%) than in the
rofecoxib group (0.4%), meaning a relative risk of 0.2 (CI95%= 0.1 to
0.7). Although it is true that in the CLASS study (celecoxib vs
diclofenac/ibuprofen) the rates of myocardial infarction were similar
between groups (0.25% vs 0.27%) in this trial patients taking aspirin were
included (20.9% vs 20.4%) [4]. Then, the pharmacodynamic weakness of
celecoxib (COX-2 do not inhibit platelet aggregation) was avoided.
The promotion of rofecoxib was also questioned before [5],
nevertheless in the last years this drug was worldwide used by a lot of
people. Now, the voluntary withdrawal from the market [6] seems ethical,
but it is? How many deaths could be attributed to the cardiovascular
adverse drug reaction? Now, maybe a domino effect of withdrawals will
never be, but it is clear that COX-2 inhibitors do not have to be used as
first line drugs, because other non-steroidal anti-inflammatory drugs with
the same efficacy, cheaper, and probably with a better safety profile are
available in the market.
Moreover, we do not know about another serious adverse drug reactions
of low frequency related to Cox-2 inhibitors. For example, recently an
acute temporary visual impairment was probably associated with the use of
celecoxib and rofecoxib, because the inhibition of synthesis of
prostacyclin and other compounds could affect the retinal blood flow [7].
In the ethics perspective, the clinical research aims to benefit
individual participants and patient groups through the identification and
testing of improved therapeutic treatments and to benefit society by
making these treatments available. But the potential risk of harm to
participants has led to widespread agreement that sound ethical standards
must be observed in clinical research, irrespective of the geographic and
economic setting in which it is undertaken. The rofecoxib incident lead us
to think that sometimes nobody remember the lessons form other drugs such
as mibefradil [8], troglitazone [9], phenylpropanolamine [10] or the
stilbestrol [11] and thalidomide [12] tragedies.
Clinical research sponsored or undertaken by developed countries in
developing countries also rises fundamental questions about distributive
justice [13]. Moreover, in these countries some unethical trials could be
performed [14] because many professionals do not have the experience or
the knowledge, the regulatory authorities do not have a legislative
background similar to FDA or EMEA, the health systems have limited
resources, and the pharmaceutical prices could affect the access to drugs.
Anyway, the rofecoxib withdrawal remember us some rational drug use
statements: “a new drug do not have to be always the best”, “an expensive
drug is not always more efficacious”, and “the absence of evidence about
insecurity does not means evidence of safety”. Again, the patient´s health
was affected. The pharmaceutical company only loss money.
Juan Carlos Maldonado, MD.
Clinical research, Pharmacology Unit. Biomedical Center, Central
University of Ecuador.
Edmundo Estévez, MD, MSc.
Director, Biomedical Center and Secretary, Bioethical Committee.
Central University of Ecuador.
REFERENCES:
1- Dieppe PA, Ebrahim S, Martin RM, Jüni P. Lessons from the
withdrawal of rofecoxib. BMJ 2004; 329: 867-8.
2- Laporte JR, Carné X, Vidal X, Moreno V, Juan J. Upper
gastrointestinal bleeding in relation to previous use of analgesics and
non-steroidal anti-inflammatory drugs. Lancet 1991; 337: 85-9.
3- Bombardier C, Laine L, Reicin A, et al., for the VIGOR Study
Group. N Engl J Med 2000; 343: 1520-8.
4- Silverstein FE, Faich G, Goldstein JL, et al. Gastrointestinal
toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for
osteoarthritis and reumatoid arthritis. The CLASS Study: a randomized
controlled trial. JAMA 2000; 284: 1247-55.
5- Josefson D. FDA warns Merck over its promotion of rofecoxib. BMJ
2001; 323: 767.
6- Singh D. Merck withdraws arthritis drug worldwide. BMJ 2004; 329:
816.
7- Coulter DM, Clark DWJ, Savage RL. Celecoxib, rofecoxib, and acute
temporary visual impairment. BMJ 2003; 327: 1214-5.
8- Po ALW, Zhang WY. What lessons can be learn from withdrawal of
mibefradil from the market? Lancet 1998; 351: 1829-30.
9- Wise J. Diabetes drug withdrawn after reports of hepatic events.
BMJ 1997; 315: 1559.
10- Kernan WN, Viscoli CM, Brass LM, et al. Phenylpropanolamine and
the risk of hemorrhagic stroke. N Engl J Med 2000; 343: 1826-32.
11- Herbst AL, Ulfeder H, Poskanzer DC. Adenocarcinoma of the vagina:
association of maternal stilbestrol therapy with tumor appearance in young
women. N Engl J Med 1971; 284: 878-81.
12- Lenz W. Thalidomide and congenital abnormalities. Lancet 1962; 1:
45.
13- Lansang MA, Crawley FP. The ethics of international biomedical
research. BMJ 2000; 321: 777-8.
14- Charatan F. Surfactant trial in Latin American infants
criticized. BMJ 2001; 322: 575.
Competing interests:
None declared
Competing interests: No competing interests
Sir,
In their editorial following the withdrawal of rofecoxib, Dieppe and
collaborators are advocating for a series of measures before definite
licensing of a drug. We have been confronted with several experiences at
the General Direction of Health of France regarding this issue, and would
like to add to the debate by bringing some more perspectives. Dieppe and
collaborators are suggesting that new drugs to be used on a large scale
should undergo a 'phase introduction' before definite licensing is
granted. This objective is, we believe, one of the main measures to be
taken by regulators in the near future because it is by definition
impossible to obtain before marketing a sufficient database to be able to
assess with accuracy all drug-related risks and benefits. However, we do
not believe that the "large scale randomized trials" asked for by Dieppe
and collaborators would be the only solution. From the information
available to date, we do not believe either, as suggested by Dieppe and
colleagues, that more transparency on data was the problem at hand in this
instance. In effect, to take the example of the rofecoxib, cardiovascular
risks, were suggested very soon from the Vigor study, as Dieppe recalls
and this did not resulted in, nor justify, stopping the marketing of the
drug. And a large scale randomized trial was indeed conducted, which led
to the withdrawal of the drug, but it was conducted on patients who were
not fully representatives of those usually treated with the drug.
The main problem with drugs is that randomized trials, and many
classical epidemiology studies, conducted before or after marketing mainly
for etiologic purposes, are unlikely to represent fairly the broad
experience of drug utilisation in the real life. The issue is not only
whether a drug could be associated with an unknown adverse event but also
whether its overall impact on the public health is beneficial or not in
the real life. This depends largely on the way it is used in practice,
what patients are switched to it, what are the other therapeutic options
and their drawbacks, what are the common co-prescriptions and of what co-
morbidities do the patients prescribed the drug suffer.
We have requested in France that whenever a drug is likely to be used
on a large scale, pharmaceutical companies should organize a post-
marketing study of the "public health impact" (PHI) of the drug. This PHI
assessment goes far beyond single endpoints as is the case in trials and
classical epidemiologic (etiologic) research. This is now requested,
before reimbursement is granted, within the framework of a formal
agreement signed in May 2003 between our Health Product Economic Committee
(CEPS) and the Association of Drug Enterprises (LEEM),. What is required
is that large scale epidemiologic evaluations are conducted that measure
the potential shifts in the disease-related morbidity and mortality at the
population level, as well as risk assessment evaluation and the
utilization of other concerned drugs. Our first very example of this new
policy was actually to ask for an independent, large scale cohort study of
35000 patients treated with rofecoxib, cerecoxib or classical NSAIDs
(Moore and collaborators). Concerned companies participated willingly in
this study. Unfortunately, due to the delay in having this policy approved
by all parties and implemented, full results are not yet available in this
case (preliminary results will be soon published however), but for future
drugs, they should hopefully be obtained in a more timely fashioned. More
than 50 such studies are in effect now signed between pharmaceutical firms
and the French authorities.
Some of these agreements have included the limitation of the size of
the population for which the drug should be reimbursed, as a mean for a
stepwise introduction of the drug pursuing similar goals as those
advocated above. However, the policy is only one year on its wheels and
will have to be evaluated for its efficiency in the future.
The present drug-decision system is in effect presenting with a
serious gap. It is schematically divided in two steps: evaluation of
efficacy and tolerance mainly through randomized trials on the one hand
and pharmacovigilance reporting of rare adverse events on the other hand.
Yet, the true impact of drugs on the public health is not fully evaluated.
Billions of dollars are spent and hundred millions of patients are exposed
to many classes of drugs worldwide without a full measure, if any in some
cases, of their impact of the incidence and prevalence of diseases
afterwards. In order to estimate how many myocardial infarctions have been
prevented by statins or GI bleeding by coxibs, one is left with mainly
modelling from the results of randomized trials, which barely represent
the real life experience. In this situation, one single drug may, such as
in the case of rofecoxib, easily appear as the "usual suspect" or
"scapegoat" following the result of this or that study, but this leaves
unanswered the question of what is really happening with the other ones,
and how is the public health "better" protected now?
We suggest that an international task force is organized to define
the objectives, methodologies and guidelines for the assessment of the
Public Health Impact of Drugs and to promote it consistently towards
regulatory bodies and health insurances, be they public or private.
Elements of the evaluation required are listed in table 1
Table 1 Elements of the Public Health Impact Assessment of Drugs
required by the General Health Directorate of France (2003)
• Description of the treated population and comparison with the
target population for the drug. Identification, within the population of
treated patients, of the fraction who was actually poorly controlled with
previous therapies
• Measure of the impact of the introduction of the new drug on the
incidence and prevalence of complications of the treated disease at the
population level, including associated morbidity and mortality
• Measure of the impact of comparative new other drugs in the same
population
• Evaluation of the impact of the introduction of the new drug on the
health system (medical and hospital services, use of diagnostic
procedures and other treatments, including other drugs.
Lucien Abenhaim, MD, MSc, PhD
Former General Director of Health of France (1999-2003)
Professor of Public Health, University of Paris V France
Full Professor of Epidemiology and Biostatistics, McGill University (PT)
Competing interests:
Participation or consulting for studies funded by Roche, United Therapeutics, Negma and Astra-Zeneca. None on NSAIDs or coxibs
Competing interests: No competing interests
Dr Cracknell is right to draw attention to the use of the black
triangle symbol to indicate that a drug is newly marketed, or being used
with a novel method of delivery, or in a new patient population with a new
indication, or as a combination product.
However, Vioxx was not a black triangle drug when it was withdrawn
(it having been first marketed in August 1999) and reporters should remain
vigilant in reporting their SUSPISCIONS of serious adverse reactions to
any drug irrespective of how long it has been marketed.
An electronic Yellow Card is available at www.yellowcard.gov.uk
Competing interests:
West Midlands Centre for Adverse Drug Reaction Reporting
Competing interests: No competing interests
The warning signals were there from the beginning over cardiovascular
adverse effects from Vioxx, for those willing to see them. Why then were
GPs and consultants keen to use Vioxx and other COX-2s with such
enthusiasm? I believe there were several reasons from very effective
marketing by the drug companies, uncritical appraisal of the evidence by
clinicians, pressure to prescribe from arthritis charities, and the effect
of NICE guidelines. As a GP I certainly felt pressure from secondary care
to prescribe COX-2s in preference to NSAIDs especially in the elderly (on
the presumption this was safer). This episode should act as an
important reminder to treat all new drugs with great caution, and drug
company claims with great scepticism, until their risks and benefits over
existing treatments are fully known. The black triangle is there for a
reason.
Competing interests:
None declared
Competing interests: No competing interests
The BMJ has published an editorial on lessons from the withdrawal of
rofecoxib.(1) So where does the BMJ place the editorial? On the page
opposite to a full-page advertisement for celecoxib! Whether accidental or
deliberate, the advertising executives at Pfizer (the manufacturers of
celecoxib) are probably extremely pleased with this situation.
Is it not time for the BMJ to consider adopting the policy of the New
England Journal of Medicine – “main content uninterrupted by commercial
advertising"?(2)
Faiyaz Mohammed
Specialist Registrar – Gastroenterology
Wythenshawe Hospital, Manchester
M23 9LT
1 Dieppe P, Ebrahim S, Martin R, Juni P. Lessons from the withdrawal
of rofecoxib. BMJ 2004; 329:867-8
2 Drazen J.M, Anderson K.R, Curfman G.D. A New Look – Form Follows
Function. N Engl J Med 2003; 348:66, Jan2, 2003
Competing interests:
None declared
Competing interests: No competing interests
Dear Sir,
Rofecoxib (Vioxx) which was first marketed in the UK in 1999 was
recalled worldwide on 30th of September, 2004.. In the UK some 400,000
patients have been taking this for various conditions , mainly
osteoarthritis, rheumatoid arthritis and other rheumatic as well as non
rheumatic conditions. This withdrawal, which was entirely voluntary by the
pharmaceutical company (Merck, Sharp & Dohme), was a consequence of
long term trial results which showed higher cardiovascular risks compared
with placebo after continued use for 18 months, and concerns expressed
recently (1,2). An advisory letter had been sent by the Medicines and
Healthcare Products Regulatory Agency with advice to discontinue this drug
for patients who had been prescribed this and to arrange
replacement/alternative medication. It was made clear by the agency that
this specific advice was relating to Rofecoxib alone and not for other Cox
II inhibitors. It is understood that switching to an alternative should
happen within a 28 day period.
As most hospital rheumatology departments are not computerised, as is
the case in general practice, it was felt that hospital clinicians such as
rheumatologists will not be in a position to advice patients immediately
on this issue.
We reviewed our patients attending the rheumatology clinics with
regard to use of Rofecoxib and whether they were still on this medication
over the 2 week period following its voluntary withdrawal. Of consecutive
75 patients seen with the age range from 24-80 (predominantly female), 12
patients were prescribed Rofecoxib and all had discontinued this
medication within the first few days on advice either from their general
practitioner (3), from pharmacists (3), on hearing about this via the
media (3), advice from the clinic (2) or advice from a friend (1). Of
these 12 patients, only one actually rang our department to get further
advice on hearing about this on the media.
Of the 12 who were on Rofecoxib, 6 were advised to replace with
another coxib ( Celecoxib 1,Valdecoxib 2, and Etoricoxib 3). In the
remaining 6 patients, no further coxib or non steroidals were prescribed
and they were advised to rely on simple analgesics only . Therefore,
continuation of a non steroidal was not deemed essential in this half of
the total 12 patients who were on Rofecoxib.
It is to be noted that the cardiovascular safety concerns are related
only to Rofecoxib and not generalised to other cyclo-oxygenase selective
inhibitors, although in time other drugs of the same class may show
problems in due course, and practitioners should be vigilant about this.
There are lessons to be learned from this even (3). It had also
highlighted issues concerning computerised data record keeping, or the
lack of it in hospital specialist departments and at least in this regard
general practice is better equipped to deal with emergency situations of
this nature. Our local Primary Care Trust had advised all general
practices in the area to contact patients on this drug to discontinue it
immediately. This action would not be possible in most rheumatology
departments in the country for lack of computerised or electronic records.
Communications to patients from general practices in our experience
appears to be very effective in that we received one recorded call only in
our area from a concerned patient and enquiry with our local chemists
revealed hardly any enquiries from concerned patients.
Yours sincerely
B Pal
Consultant Rheumatologist
H Reddy
Specialist Registrar in Rheumatology
S Shetty
Specialist Registrar in Rheumatology
A Alexander
Hospital Practitioner in Rheumatology
Reference:
1.Mukherjee D, Nissen S E, Topol E J. Risk of cardiovascular events
associated with selective COX 2 inhibitors. JAMA 2001;286:954-9.
2.Juni P,Dieppe P.Older people should NOT be prescribed ‘coxibs’ in
place of conventional NSAIDs.Age Ageing 2004;33:100-4.
3.Dieppe P, Ebrahim S, Martin R M, Juni P. Lessons from withdrawal of
rofecoxib.BMJ,2004;329:867-8.
Competing interests:
None declared
Competing interests: No competing interests
I do wonder about the role of NICE in the spread of rofecoxib use in
the UK. As a GP who could remember Opren I did not use rofecoxib at all
until their guidelines were issued.
Competing interests:
None declared
Competing interests: No competing interests
Risk reduction in patients taking NSAIDS and COX-2 inhibitors
As a surgeon with a large oesophageal practice I am deeply concerned
that the recent scare and confusion around COX-2 inhibitors, as referred
to in ‘Lessons from the withdrawal of rofecoxib’ (BMJ 2004; 329:867-868),
will increase the already alarming proportion of patients taking anti-
inflammatories who suffer oesophageal, gastric and duodenal ulceration –
with potentially fatal consequences.
Prescriptions of traditional non-steroidal anti-inflammatory drugs
(NSAIDs) will undoubtedly continue to rise and my worry is that this will
be done without enough consideration given to their side effect profile -
it is already well documented that an estimated 30% of regular users
develop peptic ulcers1.
Currently the debate as to whether it is appropriate to switch to
another COX-2 inhibitor or switch to the older NSAIDs remains unresolved.
Regardless of which side of the fence anyone sits, as a surgeon, I would
strongly urge clinicians to protect their patients against the gastro-
intestinal side effects associated with NSAIDs and also COX-2 inhibitors.
This can be achieved effectively and simply by considering concomitant
proton pump inhibitor (PPI) prescribing - particularly for those at high
risk (those with a history of peptic ulcer and / or older than 60 years).
Most PPIs are licensed for the prevention of gastro-intestinal ulcers
and healing in those taking NSAID’s but only esomeprazole has data for
concomitant use with COX-2 inhibitors2, on the basis of which it has
recently been approved for use with this class of drugs.
Reference:
1. Laine L. The gastrointestinal effects of nonselective NSAIDs and COX-2-
selective inhibitors. Semin Arthritis Rheum 2002; 32 Suppl 1; 25-32.
2. Schieman JMet al. Esomeprazole prevents gastric and duodenal ulcers in
at-risk patients on continuous non-selective or COX-2-selective NSAID
therapy. Gastroenterology 2004;126(4 Suppl 2):A-82, Abs 638.
Competing interests:
I have been involved in Multi Centre studies sponsored by AstraZeneca and have received honoraria for lecturing at sponsored medical meetings.
Competing interests: No competing interests