Cardiovascular Risk of NSAIDs: Time to Translate Knowledge into Practice
and High-Income Coun-
tries. PLoS Med 10(2): e1001388.
Cardiovascular Risk of NSAIDs: Time to Translate Knowledge into Practice
K. Srinath Reddy 0
Ambuj Roy 0
0 1 Public Health Foundation of India , ISID Campus, Vasant Kunj, New Delhi , India , 2 Department of Cardiology, Cardio Thoracic Centre, All India Institute of Medical Sciences , Ansari Nagar, New Delhi , India
Clinical use of non-steroidal
anti-inflammatory drugs (NSAIDs) carries
cardiovascular risk, which acquires implications for
public health against the backdrop of rising
chronic disease rates in low- and
middleincome countries (LMICs). New evidence
from an international study conducted by
Patricia McGettigan and David Henry and
published this week in PLOS Medicine 
sheds light on how emerging evidence
about NSAID risk is poorly translated into
practice and sales in countries around the
world, raising questions about the use and
promotion of potentially harmful drugs.
NSAIDs are extensively prescribed for
pain management in patients with
osteoarthritis and several other painful conditions.
The large number of drugs in this group is
broadly divided into nonselective
cyclooxygenase (COX) inhibitors and selective
COX inhibitors. This classification is based
on the selective inhibition of COX-2
enzyme, which is primarily responsible for
the generation of inflammatory mediators.
The emergence of selective COX-2
inhibitors in the 1990s was widely welcomed by
physicians, as these drugs were expected to
reduce the adverse gastrointestinal effects
associated with inhibition of COX-1.
However, the enthusiasm evaporated when
it was discovered that rofecoxib (Vioxx), an
early and aggressively marketed molecule
of this drug class, increased the risk of
serious cardiovascular events [2,3].
Subsequently, several systematic reviews and
meta-analyses showed that other NSAIDs
too were associated with adverse
cardiovascular events .
The adverse cardiovascular profile of
NSAIDs includes risk of atherothrombotic
events like myocardial infarction (MI) and
stroke, which can be fatal. The increased
cardiovascular risk has been observed both
in people with a prior high risk of
cardiovascular disease and in previously
healthy individuals , and this risk
appears to be dose dependent . What
The Perspective section is for experts to discuss the
clinical practice or public health implications of a
published study that is freely available online.
Linked Research Article
This Perspective discusses the
following new study published in
Patricia McGettigan and David Henry
find that, although some
non-steroidal anti-inflammatory drugs (NSAIDs)
such as diclofenac are known to
increase cardiovascular risk,
diclofenac is included on 74 countries
essential medicine lists and was the
most commonly used NSAID in the
15 countries they evaluated.
is intriguing, however, is that the increase in
cardiovascular risk has been variable with
the different molecules. Apart from
rofecoxib, diclofenac is the agent most
associated with an increased risk of
cardiovascular events: a 40%60% higher relative risk
of serious cardiovascular events, compared
to non-use of NSAIDs, has been reported
[46,9]. This is a rate equivalent to or
possibly higher than that of rofecoxib, now
withdrawn from the market. In contrast,
another traditional NSAID, naproxen, has
been found to be relatively benign, with a
cardiovascular risk that was observed to be
neutral or much lower than that of
The reason for this variability in
cardiovascular risk among the non-selective
NSAIDs is not completely understood, but
mechanistic research suggests it could be
related to the extent of COX-2 inhibition
by drugs that do not block COX-1
completely . The higher the level of
COX-2 inhibition and the lower the level of
COX-1 inhibition, the greater appears to
be the risk of thrombotic cardiovascular
events like fatal or non-fatal MI and stroke.
This probably explains the low
cardiovascular risk of naproxen, which completely
blocks COX-1 and thus has anti-platelet
effects that reduce cardiovascular events.
When COX-1 inhibition is incomplete
(,95%), enough thromboxane A2 (TxA2)
is generated for platelet activation . The
inhibition of COX-2 reduces the
generation of vaso-protective prostacyclin (PGI2),
a prostaglandin that guards against
thrombogenesis, atherogenesis, and high blood
pressure . The inhibition of COX-2,
coupled with an incomplete inhibition of
COX-1, provides a potent thrombogenic
stimulus by altering the PGI2-TxA2
balance. While both diclofenac and naproxen
are non-selective, the differences in the
COX-1 and COX-2 inhibition each drug
achieves may explain the variability in their
cardiovascular risk profiles.
What Did the Authors Find?
McGettigan and Henry report new
evidence regarding the use of NSAIDs
in 15 countries representing high-,
medium-, and low-income countries. They
reviewed published evidence regarding the
cardiovascular risk profiles of different
NSAIDs, confirming that diclofenac is
associated with a substantially higher
cardiovascular risk than naproxen. Using IMS
Health 2011 data, they found that
diclofenac had a median of 3-fold higher sales (or
prescribing, in the case of England and
Canada) than naproxen in the 15 countries
studied. The preference for diclofenac over
naproxen was seen across high-, middle-,
and low-income countries, despite the fact
that both drugs have been available in
generic form for several years and the
information related to their comparative
cardiovascular risk profilewhere risks
associated with diclofenac far outweighs
that of naproxenhas been known for
nearly a decade. They observe that
diclofenac continues to figure in the essential
medicines lists (EMLs) of 74 countries,
while naproxen features in only 27. Their
results are striking, and suggest that
immediate action is warranted.
It is worth considering how national
EMLs are established. Countries develop
their national EMLs by setting up
committees comprising national experts,
usually linked to government-run medical
institutions , and their
recommendations vary in quality. The list prepared by
the World Health Organization (WHO)
has influence on the national lists but does
not have overriding power . Although
the WHO EML contains neither
diclofenac nor naproxen, McGettigan and Henry
reasonably question why WHO has not
provided information on the safety of these
drugs, which could inform and influence
India, the second most populous
country and not included in the 15 countries
McGettigan and Henry studied,
exemplifies this disconnect between available
evidence versus recommendations and
practice. Diclofenac features in Indias
current National List of Essential
Medicines, while naproxen does not. In 2008,
the sales of diclofenac were 11.3 times
higher than naproxen in financial terms
and 9.4 times higher in terms of the
number of tablets sold (unpublished data;
extracted from Intercontinental Marketing
Services Health Database, India, 2008).
How Can Such Non-Evidence
Based Practice Be Addressed?
It is mainly the responsibility of national
health agencies and drug regulatory
authorities to strongly caution against the
adverse cardiovascular effects of diclofenac
and other NSAIDs with poor risk profiles
and/or mandate their withdrawal from the
market. We believe there is a strong case for
removing diclofenac from national EMLs,
and that WHO should explain not just
what should be included in the EML, but
also explain why other NSAIDs (such as
diclofenac) are not being included, making
the risk estimate explicit. The dangers are
especially high in countries where
over-thecounter sale of diclofenac is permitted.
At the same time, practicing physicians
have a duty to regularly update their
knowledge on the drugs they frequently
prescribe. While there is usually a time lag
between scientific publications and
translation of that knowledge into improved
practice patterns, the internet should
hasten the diffusion of knowledge.
Cardiologists and neurologists too should play a
greater role by becoming better informed
of the adverse effects, disseminating
evidence-based recommendations on the risks
associated with different NSAIDs to other
physicians, and strongly advocating for
stricter regulation of NSAIDs with a
harmful cardiovascular profile.
LMICs are currently experiencing a
rapid health transition with escalating
rates of cardiovascular mortality [13,14].
The dangers of retaining potentially
harmful drugs on EMLs are especially
high in these countries, where standard
treatment guidelines are scarce and
continuing education of physicians is usually
not mandated. It is not just the case of
diclofenac versus naproxen that is at
stake. It is the broader challenge of
ensuring that everyone responsible for
the safety of patients makes informed
decisions in an appropriate and timely
manner. If we do not collectively rise to
that challenge, no NSAID can relieve the
pain of that failure.
Wrote the first draft of the manuscript: KSR
AR. Contributed to the writing of the
manuscript: KSR AR. ICMJE criteria for authorship
read and met: KSR AR. Agree with manuscript
results and conclusions: KSR AR.
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