Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials
BMJ 2006; 332 doi: https://doi.org/10.1136/bmj.332.7553.1302 (Published 01 June 2006) Cite this as: BMJ 2006;332:1302
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Ibuprofen is reported to be associated with an elevated risk of
vascular events, compared to placebo. However, the 95% confidence interval
for the rate ratio, as stated in the paper, is 0.96 to 2.37, hence
includes 1 (no difference).
Furthermore, the comparison of traditional NSAIDs versus placebo was
partly based on indirect evidence, and may be biased in many ways. It is
surprsing that the authors do not seem to take this into account when
drawing their potentially far-reaching conclusion.
Competing interests:
I was involved in studies funded by GlaxoSmithKlein and ARTU Biologicals, but none of these involved NSAIDs or COX 2 inhibitors
Competing interests: No competing interests
Editor - The systematic review by Kearney PM at al (1) evaluated
trials that compared selective COX 2 inhibitors with placebo or with
traditional non-steroid anti-inflammatory drugs (NSAIDs) and concluded
that Coxibs increase moderately the risk of vascular events.
However, on celecoxib the conclusion was somehow different. The authors
after evaluating 41 (from 45 eligible) trials of at least 4 weeks duration
stated that there was a weak trend towards an increased incidence of
serious vascular events with higher daily doses and that the result was
mainly determined by the results of the Adenoma Prevention with Celecoxib
trial (2).
However another recent systematic review on celecoxib by Caldwell et
al (3) reached a different result. The authors included in their meta-
analysis clinical trials that compared celecoxib with placebo or NSAIDs.
Of 48 eligible trials there were 42 exclusions because trials had duration
of less than 6 weeks or did not report major cardiovascular events or
because of some were replication of other trials. The remaining six trials
included in the meta-analysis involved patients who were affected by wide
range of diseases (osteoarthritis, rheumatoid arthritis, Alzheimer's
disease, and prevention of adenomas). The review concludes that use of
celecoxib was associated with a 2.26 (1.0 – 5.1) increased risk of
myocardial infarction when compared with placebo, and a 1.88 (1.15 to
3.08) increased risk of myocardial infarction when compared with all
comparator treatment arms including placebo.
Both reviews acknowledged that the respective trials were not powered
or designed to identify serious cardiovascular events associated with anti
-inflammatory drug use. Nevertheless the different conclusions between
the two meta-analysis on celecoxib may have some explanations . One can be
the inclusion criteria. Caldwell et al (5), for example, were interested
in trials of 6 weeks duration which might have missed at least other 5
trials of 4 weeks duration that were considered by Kearney’s review.
Conversely they seem to have applied a more methodological rigor that
brought to the inclusion of such few trials but probably conveying results
with reduced heterogeneity within trials .
We believe that on celecoxib the results of Caldwell’s systematic
review are more consistent.
Reference
1. Kearney PM, Baigent C, Godwin J, et al. Do selective cyclo-
oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory
drugs increase the risk of atherothrombosis? Meta-analysis of randomised
trials. BMJ 2006; 332:1302-1308
2. Solomon SD, McMurray JJ, Pfeffer MA, et al. Adenoma Prevention
with Celecoxib (APC) Study Investigators. Cardiovascular risk associated
with celecoxib in a clinical trial for colorectal adenoma prevention. N
Engl J Med 2005; 352:1071 -80
3. Caldwell B, Aldington S, Weatherall M, et al. Risk of
cardiovascular events and celecoxib: a systematic review and meta-
analysis. J R Soc Med 2006; 99:132-140
Competing interests:
None declared
Competing interests: No competing interests
The report by Patricia Kearney et. al., BMJ 3 June 2006, gives
support to the letter in relation to the study by Julia Hippisley-Cox et
al, BMJ 3 December 2005, who revised the gastrointestinal risks.
In the meantime, a clear picture is evolving, which shows that, as
predicted by Paracelsus five hundred years ago, the risks and benefits are
determined by their doses and potencies, more than by their selectivity to
the Cox enzymes, with the particular exception of low dose aspirin, which
permanently inhibits the platelets function without affecting the
endothelial prostacycline, producing the useful antithrombotic effect. But
in higher doses, aspirin is also toxic.
Over 20 years ago, a report from England demonstrated that all NSAIDs
could produce some deaths per million of prescriptions. The least potent,
like Ibuprofen, produced the lowest risk of death: 1.5; with increasing
risk depending of increasing potency: Naproxen 4.6, Diclofenac 5.3,
Piroxicam 7.0, and Indometacin 7.1. The most potent, Meloxicam, did not
exist then. It would be useful to have data on its toxicity.
The experience with the cardiovascular risk of the new Cox-2
inhibitors follows a similar pattern. The most potent, like Rofecoxib and
Valdecoxib, are already retired. We have no data from the following in
potency, Etoricoxib, although it is known to worsen hypertension. The
least potent, like Celecoxib (still in use), and Lumiracoxib, help us to
understand that the class effect is not only of Cox-2, but of Cox
inhibitors in general.
The odds ratios for adverse effects oscillate, depending on the
endpoint (cardiovascular or gastrointestinal), the reference parameters
and the dose, from the most to the least potent and toxic, as follows:
Rofecoxib (1.32 to 3.58, in 12 studies), Valdecoxib (3 fold, 1 study),
Diclofenac (1.55, 1 study), Other NSAIDs (1.16 to 2.06, 3 studies), Other
Cox-2 (1.45, 1 study), Naproxen (1.14 to 1.5, 3 studies), Ibuprofen (1.09
to 1.24, 2 studies), Celecoxib (0.43 to 1.26 in 6 studies, in 3 of them
approximates 1.25), Lumiracoxib (1.14, ns, in one study). The study by
Kearney et. al. adds important data.
As end results, the patients show benefits in their suffering and
quality of life, but pay with an increased risk in other important aspects
that could eventually shorten their lifespan.
At the other hand, the continuous suffering of pain or inflammation
could also shorten their lifespan through the associated stress and
cardiovascular or gastrointestinal pathophysiological adverse reactions to
the disease mechanisms.We doctors must explain to our patients and they
decide.
We should recommend the less potent, less toxic, like Acetaminophen,
Celecoxib or Ibuprofen, (these two have similar odds ratios of toxicity),
in the lowest dose, for the shortest time, and also care for better
protection of the cardiovascular risk factors, like hypertension or
hyperlipidemia, or the gastrointestinal adverse effects.
Competing interests:
None declared
Competing interests: No competing interests
Dear Editor,
Recently a study by Lévesque et al suggests that the risk of
myocardial infarction(MI) was highest following first-time use of
rofecoxib in elderly population(1).This risk did not increase with the
length of treatment and returned to baseline shortly after treatment was
discontinued. Among elderly users of predominantly low doses of these
agents, short-term use of rofecoxib is not without risk, and that risk of
MI is not restricted to continuous users nor accentuated with longer-term
use.Hence, it is also important to identify those most susceptible to
cardiotoxicity mediated by COX-2 inhibitor therapy and to investigate
whether an early risk is present for celecoxib and in other populations.
Reference:
(1)Lévesque LE, Brophy JM, Zhang B. Time variations in the risk of
myocardial infarction among elderly users of COX-2 inhibitors.
CMAJ2006;174(11):1563-9.
Competing interests:
None declared
Competing interests: No competing interests
Kearney et al. (p. 1302-8) show that the evident cardiovascular (CV) risk of using a COX-2 inhibitor falls into the same range that Yussuf et al. found for the known harmful life-style factors (1). Yussuf et al. also reported that the risk-increasing and the risk-decreasing lifestyle factors, which their major study quantified, appear to be non-interactive. I pointed shortly thereafter (2) the reasonable expectation, on the basis of Yussuf’s work, that the addition of one or more of the known CV risk-decreasing factors could offset the risk of commencing to take a COX-2 inhibitor. Thus, smoking cessation, or starting a diet rich in fruits & vegetables might allow one to incur the risk of using a COX-2 inhibitor with ~no net gain in overall CV risk. The key assumption in such 'risk-swapping' is that the risks and benefits involved are additive, as Yussuf et al. concluded was the case. If so, it opens the door to a new way to manage therapeutic risk.
References:
1. Yussuf S. et al. Lancet 2004;364:937-52
2. Urquhart J. Pharmacoepidemiol Drug Safety 2005;14:145-7
Competing interests:
None
Competing interests: No competing interests
Selective and non-selective NSAIDs: Balancing cardiovascular and gastrointestinal risks
The meta-analysis reported by Kearney et al (1) revealed that
selective cyclooxygenase-2 (COX-2) inhibitors and high-dose regimens of
some traditional nonsteroidal anti-inflammatory drugs (NSAIDs) are
associated with a similar moderate increase in risk of cardiovascular
events.
The topic of increased cardiovascular risk with NSAIDs is attracting
much interest and two other meta-analyses have also been reported
recently(2,3). Similar to Kearney et al, we have noted that traditional
NSAIDs were associated with an increased risk of acute myocardial
infarction (2). McGettigan et al also noted that the risk of serious
cardiovascular events was increased with rofecoxib, a selective COX-2
inhibitor, and some older traditional NSAIDs (3). These findings are
consistent with a recent statement from the European Agency for the
Evaluation of Medical Products (EMEA). After reviewing new thrombotic
cardiovascular safety data, the EMEA concluded that NSAIDs may be
associated with a small increase in risk for thrombotic events, but the
overall benefit–risk profile for these drugs remains “favourable”. The
agency also reiterated previous advice that NSAIDs should be administered
at the lowest effective dose for the shortest possible duration.
There have been concerns among physicians that the risk of heart
attack and stroke may be increased significantly more with selective COX-2
inhibitors compared with traditional NSAIDs, which has not been borne out
by recent evidence (1-3). Consequently, several patients, including those
at high risk of serious GI bleeds, have switched from selective COX-2
inhibitors to traditional NSAIDs, leaving many without appropriate
gastroprotective strategies (4) and placing them at an increased risk of
gastrointestinal complications. Gastroprotective strategies, such as
selective COX-2 inhibitors and concomitant use of proton-pump inhibitors,
can greatly reduce the risk of upper gastrointestinal complications (5),
without significantly altering the risk of thrombotic cardiovascular
complications as compared with traditional non-selective NSAIDs.
Following Kearney’s observations, perhaps the whole benefit–risk
profile of selective COX-2 inhibitors and traditional NSAIDs should be re-
considered, including both cardiovascular and gastrointestinal risks. In
addition, the benefit–risk profile of all NSAIDs should be considered
against the underlying risk factors for individual patients.
References
1. Kearney PM, Baigent C, Godwin J, Halls H, Emberson JR, Patrono C.
Do selective COX-2 inhibitors and traditional NSAIDs increase the risk of
atherothrombosis? Meta-analysis of randomised trials. BMJ 2006;332:1302–8.
2. Singh G, Wu O, Langhorne P, Madhok R. Risk of acute myocardial
infarction with non-selective non-steroidal anti-inflammatory drugs: a
meta-analysis. Arthritis Res Ther 2006a Sep 22;8:R153 [Epub ahead of
print].
3. McGettigan P, Henry D. Cardiovascular risk and inhibition of
cyclooxygenase: a systematic review of the observational studies of
selective and nonselective inhibitors of cyclooxygenase 2. JAMA
2006;296:1633–44.
4. Singh G, Wang H, Tanaka E, Mithal A, Gerson L, Triadafilopoulos G.
Gastroprotection Gap: A rising and dangerous omission for elderly users of
NSAIDs with arthritis. Gastroenterology 2006b;130(Suppl. 2):A-82 (Abstract
564).
5. Schnitzer TJ, Burmester GR, Mysler E, Hochberg MC, Doherty M,
Ehrsam E, et al; TARGET Study Group. Comparison of lumiracoxib with
naproxen and ibuprofen in the Therapeutic Arthritis Research and
Gastrointestinal Event Trial (TARGET), reduction in ulcer complications:
randomised controlled trial. Lancet 2004;
364:665–74.
Competing interests:
Gurkirpal Singh: Grants - Pfizer, Novartis, Altana Pharma, Astra Zeneca; Speaker - Pfizer
Rajan Madhok: None
George Triadafilopoulos: Consultant and Speaker - Pfizer, Altana, Astra-Zeneca
Competing interests: No competing interests