The
bottom line
The results of a meta-analysis
in the BMJ support previous studies,
which have shown that selective COX-2
inhibitors and traditional NSAIDs
cause a small absolute increase in
the risk of cardiovascular (CV) events.
Naproxen may confer slightly less
CV risk than other NSAIDs but until
this is confirmed with further evidence,
naproxen should continue to be prescribed
with the same precautions as other
NSAIDs.
Should
this change practice?
In
addition to the increased CV risk,
traditional NSAIDs and selective COX-2
inhibitors increase the risk of gastrointestinal
(GI) complications, hypertension,
heart failure and renal failure.
The
following steps are appropriate for
people with osteoarthritis or musculoskeletal
pain, particularly if they are elderly:
-
Before using any
NSAID consider other interventions:
paracetamol and non-drug interventions
should be tried first and will
work for many
-
If NSAIDs are required, use the
lowest effective dose, for the
shortest possible length of time.
Consider the overall safety profile
of NSAIDs (in particular GI safety)
and risk factors for individual
patients. Low-dose ibuprofen should
normally be considered before
naproxen or diclofenac
-
Consider
gastroprotection with traditional
NSAIDs in those at high risk of
upper GI complications (e.g. aged
65 or over, history of GI or CV
disease). Options include misoprostol
and proton-pump inhibitors.
Selective COX-2 inhibitors
do not have good evidence to support
the belief that they reduce NSAID-associated
dyspepsia or serious upper GI complications,
compared with other NSAIDs. The Committee
on Safety of Medicines has also warned
about their use in people with existing
CV disease and CV risk factors.
|
Source 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;332:1302-8
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The objective
of this study1
was to assess the effects of selective cyclo-oxygenase-2
(COX-2) inhibitors and traditional (non-selective)
non-steroidal anti-inflammatory drugs (NSAIDs)
on the risk of vascular events. The authors
performed a meta-analysis of randomised
controlled trials (RCTs) that compared selective
COX-2 inhibitors with placebo or traditional
NSAIDs, with a minimum of four weeks treatment,
and recorded serious vascular events (stroke,
vascular death and myocardial infarction
[MI]). Studies for review were identified
from a search of Medline and Embase (January
1996 to April 2005), Food and Drug Administration
records, and data on file from the manufacturers’
databases (Novartis, Pfizer, and Merck).
No indication was provided as to whether
or not allocation was concealed in the studies.
The meta-analysis
included 138 RCTs, involving a total of
145,373 people; demographics such as age,
gender, etc., were not stated. Selective
COX-2 inhibitors included rofecoxib, celecoxib,
etoricoxib▼, lumiracoxib▼
or valdecoxib. Traditional NSAIDs included
naproxen (42 trials), ibuprofen (24 trials),
diclofenac (26 trials), as well as nabumetone,
indometacin, loxoprofen and, ketoprofen
(7 trials in total).
Comparisons
of the effects on vascular events were made
between selective COX-2 inhibitors and placebo,
between selective COX-2 inhibitors and traditional
NSAIDs, and between individual NSAIDs and
placebo. Selective COX-2 inhibitors were
also compared separately with naproxen and
non-naproxen traditional NSAIDs, on the
basis that naproxen might have aspirin-like
antiplatelet effects.
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Selective COX-2 inhibitors
were associated with a significantly increased
incidence of serious vascular events compared
with placebo, which was mainly attributed
to an increased risk of myocardial infarction
(see Table),
with little apparent difference in other
vascular outcomes.
When selective COX-2 inhibitors
were compared with traditional NSAIDs, there
was a significantly increased risk versus
naproxen, but not versus other traditional
NSAIDs or NSAIDs as a whole (see Table).
Less
robust methodology was used to compare the
CV risks of NSAIDs with placebo (it included
indirect estimates of vascular risk from
trials of selective COX-2 inhibitors versus
placebo and selective COX-2 inhibitors versus
traditional NSAIDs), and results of these
analyses should be interpreted cautiously.
Compared with placebo, there was a significant
increase in the incidence of serious vascular
events for diclofenac (rate ratio [RR] 1.63,
95%CI 1.12 to 2.37) but not for naproxen
(RR 0.92, 95%CI 0.67 to 1.26) or ibuprofen
(RR 1.51; 95%CI 0.96 to 2.37). The authors
postulated that higher doses of ibuprofen
(800mg three times a day) and diclofenac
(75mg twice a day) were associated with
increased risk of vascular events. This
assertion appeared as headlines in the media,
despite the absence of data in the paper
to support this.
Dose
used
The
data from placebo-controlled trials were
inadequate to allow assessment of whether
the CV risks of selective COX-2 inhibitors
are dose dependent. Although there was a
weak trend (P=0.03) towards larger risks
with higher doses of celecoxib, the results
were driven by one trial. Further research
is required before any firm conclusions
can be drawn.
Duration
of treatment
Only
9 of the 121 placebo-controlled trials included
were for 12 months or longer. Two-thirds
of vascular events occurred in these 9 studies,
and the RR for vascular events was 1.45
(95%CI 1.12 to 1.89; P=0.005) with an absolute
rate increase (ARI) of 0.3% per year (number
needed to harm [NNH]=333).
Concomitant
use of aspirin
84
of the placebo-controlled studies allowed
concomitant use of low-dose aspirin for
cardioprotection (presumably 300mg per day
or less). There were no indications that
the CV effects of selective COX-2 inhibitors
differed among aspirin users and non-users.
Table:
The risk of a serious vascular event with
selective COX-2 inhibitors compared with
traditional NSAIDs1
enlarge
image
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The main limitation of this
study is the relatively small number of
vascular events that are included. As these
data are derived from RCTs designed to examine
other safety issues, such as the effects
on the GI tract, or to look at the efficacy
of these agents in pain control, this is
not surprising.
It is difficult to assess
the reliability of the conclusions drawn,
as many details of the methodologies used
and important information, particularly
with regard to the comparison of traditional
NSAIDs with placebo, appears to be missing.
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This study adds weight to
previous analyses of the CV effects of selective
COX-2 inhibitors and traditional NSAIDs.
Selective COX-2 inhibitors
are associated with a small increase in
the risk of vascular events, e.g. MI and
stroke. Hence, the Committee on Safety of
Medicines (CSM) advises that these drugs
should be avoided in patients with established
CV disease, and used cautiously in those
with CV risk factors.2
Following a European regulatory
review of the CV safety of NSAIDs in 2005,3
the CSM concluded that the evidence was
insufficient to make firm conclusions regarding
the CV safety of naproxen, ibuprofen and
diclofenac relative to one another or selective
COX-2 inhibitors. However there were suggestions
that naproxen had a lower thrombotic risk
than selective COX-2 inhibitors. The present
study is consistent with this, and suggests
that the CV risk may be lower with naproxen
than with diclofenac or ibuprofen. However,
further studies are needed to confirm this
and naproxen should continue to be prescribed
with the same precautions as other NSAIDs.
At the time, the CSM suggested
that any CV risk of traditional NSAIDs was
likely to be small and associated with continuous
long-term treatment and higher doses. They
stated that switching treatment between
NSAIDs was not justified on the available
evidence.3
As the analysis of traditional NSAIDs versus
placebo in this study is based largely on
indirect comparisons, this advice still
seems appropriate. Prescribers and patients
should still be conscious of the need for
caution with all NSAIDs. Adverse GI events
with traditional NSAIDs are well recognised.
The relative risk of hospitalisation for
an acute GI event for a person in their
70s is 1.20 (95%CI 1.09 to 1.32) compared
to someone in their 50s, whereas for someone
aged 80 years or older the relative risk
is 1.61 (95%CI 1.46 to 1.78). Renal adverse
events may be more insidious in onset and
less dramatic, but the RR of hospitalisation
for an acute renal event due to NSAIDs for
someone in their 70s is 4.70 (95%CI 3.49
to 6.33), and for someone aged 80 or older
the RR is 8.79 (95%CI 6.55 to 11.8).4
In addition, traditional
NSAIDs increase blood pressure by an average
of 5mmHg,5
and the CSM has issued a warning about etoricoxib
and its effect on blood pressure.2
NSAIDs increase the risk of heart failure
in patients with a history of hypertension,
diabetes or renal failure.6
Despite some reduction in
the number of items of NSAIDs prescribed
in late 2004 and early 2005 following the
withdrawal of rofecoxib and the publication
of the CSM advice, about 4.5million NSAID
items are still being prescribed in primary
care in England each quarter (see Figure).7
For
people with osteoarthritis or musculoskeletal
pain, the following steps are appropriate,
particularly if they are elderly:
-
Before using any NSAID consider
other interventions: paracetamol
and non-drug interventions should
be tried first and will work for
many8
-
If NSAIDs are required, use the
lowest effective dose, for the
shortest possible length of time.3,8
Consider the overall safety profile
of NSAIDs (in particular GI safety)
and risk factors for individual
patients.3
Low-dose ibuprofen should normally
be considered before naproxen
or diclofenac8
-
Consider
gastroprotection with traditional
NSAIDs in those at high risk of
upper gastrointestinal (GI) complications
(e.g. aged 65 or over, history
of GI or CV disease). Options
include misoprostol and proton-pump
inhibitors.9
Selective
COX-2 inhibitors do not have good
evidence to support the belief that
they reduce NSAID-associated dyspepsia
or serious upper GI complications,
such as perforated ulcer or bleeding,
compared with traditional NSAIDs.9,10
|
Figure: Prescribing
trends for NSAIDs in England (2000—2005)7
enlarge
image
Back
to top
- 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;332:1302-8
- Duff G, Chairman, Committee
on Safety of Medicines. Updated advice on the
safety of selective cox-2 inhibitors. Letter
to healthcare professionals. February 2005.
Accessed from www.mhra.
gov.uk on 14/06/06
- Duff G, Chairman, Committee
on Safety of Medicines. Cardiovascular safety
of NSAIDs - review of the evidence. Letter to
healthcare professionals. August 2005. Accessed
from www.mhra.gov.uk
on 14/06/06
- Dieppe
P, Bartlett C, Davey P, et al. Balancing
benefits and harms: the example of non-steroidal
anti-inflammatory drugs. BMJ 2004;329:31-4
- Johnson
AG, Nguyen TV, Day RO. Do non-steroidal
anti-inflammatory drugs affect blood pressure?
A meta-analysis. Ann Int Med 1994;121:289-300
- Garcia
Rodriguez LA, Hernandez-Diaz S. Non-steroidal
anti-inflammatory drugs as a trigger of
clinical heart failure. Epidemiology 2003,14:240-6
- Personal
communication. NHS Business Services Authority.
June 2006
- National
Prescribing Centre. The withdrawal of
co-proxamol: alternative analgesics for
mild to moderate pain. MeReC Bulletin
2006;16:13-6
- National
Prescribing Centre. NSAIDs and gastroprotection.
MeReC Briefing 2002;20:1-8
- Committee for Proprietary
Medicinal Products (CPMP) opinion following
an article 31 referral for all medicinal products
containing celecoxib, etoricoxib, parecoxib,
rofecoxib or valdecoxib. 30 April 2004. Accessed
from http://www.emea.eu.int/htms/human/
referral/referral.htm on 15/06/06
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Institute for Health and Clinical Excellence
(NICE) is associated with MeReC Publications
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inform decisions on service organisation
and delivery. This publication represents
the views of the authors and not necessarily
those of the Institute.
©National
Prescribing Centre 2006, The Infirmary,
70 Pembroke Place, Liverpool, L69 3GF
Telephone: 0151 794 8146 Fax: 0151 794 8139
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