Basic & Clinical Pharmacology & Toxicology, 2014, 115, 179–184 Doi: 10.1111/bcpt.

12244

MiniReview

The Impact of NSAID Treatment on Cardiovascular Risk –

Insight from Danish Observational Data
Anne-Marie Schjerning Olsen1, Emil L. Fosbøl1,2,3 and Gunnar H. Gislason1,4,5
1
Department of Cardiology, Copenhagen University Hospital Gentofte, Hellerup, Denmark, 2Department of Cardiology, The Heart Centre,
Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark, 3Duke Clinical Research Institute, Duke University Medical Center,
Durham, NC, USA, 4Faculty of health and medical sciences, University of Copenhagen, Copenhagen, Denmark and 5The National Institute of
Public Health, University of Southern Denmark, Copenhagen, Denmark
(Received 14 January 2014; Accepted 13 March 2014)

Abstract: This MiniReview describes the present evidence for the relationship between cardiovascular risk and use of non-steroi-
dal anti-inflammatory drugs (NSAIDs) with special focus using Danish register-based data. NSAIDs are among the most widely
used drugs worldwide and mainly used for management of pain and inflammatory conditions. Through the past decade, much
attention has been given to the cardiovascular safety of these drugs, and several studies have shown increased risk of adverse
cardiovascular effects associated with NSAID use. Current guidelines discourage any use of NSAIDs in patients with cardiovas-
cular disease, yet over a period of 8–10 years, 35–44% of patients with myocardial infarction or heart failure were exposed to
NSAIDs in Denmark. Furthermore, NSAID use was associated with an increased risk of death or myocardial infarction by up to
5 times that of non-users. There was also a clear indication for a dose-related response in risk associated with NSAID therapy,
supporting a causal association. Notably, the cardiovascular risk associated with NSAID treatment was prevalent at start of treat-
ment, suggesting no safe treatment window for NSAIDs in patients with cardiovascular disease. Thus, evidence from observa-
tional studies is accumulating, suggesting that NSAIDs are a major public health concern due to the widespread use of these
drugs. Although it seems unlikely that we can completely avoid use of NSAIDs, even among high-risk patients, these results
highlight the importance of balancing the benefit versus the risk of treatment before initiating NSAID treatment.

Non-steroidal anti-inflammatory drugs (NSAIDs) are fre-
quently used for common conditions such as pain and inflam-
matory diseases. NSAID use and the cardiovascular safety
have been scrutinized during the last decade and studies have
related NSAID use with increased cardiovascular risk in
healthy individuals and in patients with established cardiovas-
cular disease [1–4].
The first non-selective NSAIDs were developed and mar-
keted in the 1950s, but aspirin had been known for about a
century before and was marketed in the late 1890s. Pharmaco-
logically, the NSAIDs have their effect through inhibition of
the cyclooxygenase (COX) enzyme and are effective analge-
sics; but unfortunately, the non-selective NSAIDs were found
to be associated with increased risk of gastrointestinal side
effects with continuous treatment [5–8]. In the late 1990s, the
selective COX-2 inhibitors were introduced as a new genera-
tion of anti-inflammatory drugs. Pharmacologically, the selec-
tive COX-2 inhibitors were characterized by selectively
inhibiting the COX-2 isoenzyme, and thereby, they were
expected to possess anti-inflammatory, analgesic and antipy-
retic activity but lack the gastrointestinal toxicity of NSAIDs
Author for correspondence: Anne-Marie Schjerning Olsen, Department
of Cardiology – post 635, Copenhagen University Hospital Gentofte,
Niels Andersens Vej 65, 2900 Hellerup, Denmark (fax +45 70201283,
e-mail amschjerning@gmail.com).
[7,9]. In 2000, the Vioxx Gastrointestinal Outcomes Research
(VIGOR) trial firstly reported an increased cardiovascular risk
with use of the selective COX-2 inhibitor rofecoxib. As the
release of the VIGOR trial, several studies have found similar
worrying results and even extended this to the traditional non-
selective NSAIDs as well [10–14].
Cardiovascular Risk Associated with Use of NSAIDs
Several studies have shown increased risk of adverse cardio-
vascular effects associated with NSAID use in healthy individ-
uals and in patients with established cardiovascular disease
[1–4].
Previously, it was thought that the cardiovascular risk-taking
NSAIDs was higher in patients with established cardiovascular
disease; however, recent data suggest that the risk might be
the same in healthy people [15,16]. We analysed the cause-
specific cardiovascular risk associated with NSAID in healthy
individuals [17]. In brief, we found that most NSAIDs were
associated with increased cardiovascular risk and in particular
that use of diclofenac and rofecoxib was associated with
increased risk of cardiovascular mortality and morbidity
(Fig. 1).
In two populations of patients with myocardial infarction
(MI) and chronic heart failure (HF), 34–36% received NSA-

© 2014 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society)
180 ANNE-MARIE SCHJERNING OLSEN ET AL.
Fig. 1. Case crossover analysis. The estimates and surrounding error bars (representing the 95% confidence intervals) illustrate the association
between use of NSAIDs and the listed end-points for any use of the specific drugs. (With permission from [17], fig. 3).
IDs after discharge from the hospital [3,18]. The data suggest
an increased risk of death and re-MI associated with NSAID
use compared with non-users. Furthermore, a dose-related
excess mortality associated with the use of NSAIDs was
observed. Several studies have demonstrated increased risk of
overall death and MI associated with some NSAIDs
[1,5,10,13,18–22], whereas only few studies have examined
the specific cardiovascular risk of each NSAID [2,17]. Dic-
lofenac and rofecoxib were here found to be associated with
increased risk of cardiovascular mortality and morbidity,
whereas ibuprofen was found to be associated with an
increased risk of stroke [2,17,23]. The NSAID with the lowest
associated cardiovascular risk has in several studies been
reported to be naproxen [1,24]. Conversely, naproxen has been
found to be associated with higher risk of gastrointestinal
bleeding than rofecoxib, and gastrointestinal bleeding among
patients with MI is known to be associated with poor progno-
sis [6,16].
The Impact of Duration of NSAID Treatment
The American Heart Association published in 2007 a focused
update discouraging the use of NSAIDs in patients with estab-
lished cardiovascular disease [25]. NSAID use is to be
restricted to patients, where no other appropriate alternative is
available, and only in lowest dose and shortest period judged
necessarily. Despite this, many patients with cardiovascular
disease receive NSAIDs. In the period from 1997 to 2009,
more than 40% of all Danish post-MI patients claimed at least
one prescription for NSAIDs. Same high number was seen in
HF patients, where 36% claimed at least one prescription from
1997 to 2006 [3]. Previously, use of NSAIDs was thought to
be risk neutral in short treatment periods and in low doses,
which may explain why NSAIDs are still used in patients with
heart disease. However, recent studies have suggested that
© 2014 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society)
MiniReview
there is no safe treatment window taking NSAIDs as cardio-
vascular patient. So far, only two randomized studies have
been specifically designed to determine the cardiovascular
safety of NSAID treatment [12,26,27]. In 2005, Nussmeier
et al.[12] conducted a randomized trial designed to investigate
the cardiovascular safety according to the duration of NSAID
treatment looking at the risk of the selective COX-2 inhibitor
valdecoxib in patients undergoing coronary artery bypass sur-
gery. They found increased cardiovascular risk after only
10 days of treatment with the selective COX-2 inhibitors val-
decoxib and its intravenous pro-drug parecoxib. In the
APPROVE study, participants were followed for adverse
events while on treatment and during the following 14 days.
The study demonstrated that use of rofecoxib was associated
with increased rates of APTC events (combined incidence of
non-fatal myocardial infarction, non-fatal stroke and death
from cardiovascular, haemorrhagic and unknown causes (Anti-
platelet Trialists’ Collaboration [APTC] combined end-point).
Study data were compatible with an early increase in risk that
persists for 1 year after stopping treatment [27]. In 2006, Lev-
esque et al.[28] additionally found increased risk of MI after
only 9 days of treatment with the selective COX-2 inhibitor
rofecoxib, in a population-based cohort study of elderly sub-
jects initiating NSAID therapy. In 2011, we analysed the risk
of death and re-MI according to treatment duration in post-MI
patients [29]. We looked at all Danish patients having a first-
time MI in the period of 1997–2006 and found an increased
cardiovascular risk with the selective COX-2 inhibitor rofecox-
ib after only 7 days of treatment (fig. 2). Particularly worrying
was that the risk of death and re-MI associated with treatment
with the commonly used non-selective NSAID diclofenac was
increased immediately after the start of treatment and persisted
thereafter. Our results might suggest that diclofenac was asso-
ciated with even higher risk of death and re-MI already at the
beginning of the treatment course in comparison with the
MiniReview NSAID TREATMENT AND CARDIOVASCULAR RISK
selective COX-2 inhibitor rofecoxib, which was withdrawn
from the market in 2004. In more studies, diclofenac has been
found to have as high a risk as rofecoxib [15]. Ibuprofen was
associated with an increased risk of both end-points after
7 days of treatment; the risk was markedly lower compared
with diclofenac and rofecoxib. Lowest risk was found during
naproxen treatment. In 2012, long-term cardiovascular risk
with use of NSAID in post-MI patients was reported [30]. It
was demonstrated that the risk of death and of a composite
end-point of coronary death or non-fatal recurrent MI in post-
MI patients receiving NSAIDs may be independent of the time
elapsed after their first MI, suggesting that the relative risk
may be independent (fig. 3). It is known that cardiovascular
mortality and morbidity are complications after MI and that
the cardiovascular risk is most eminent soon after the MI but
declines as time passes and eventually corresponds to the risk
of the background population [31]. Knowledge about the car-
diovascular safety of NSAIDs in the years following MI is
limited, and we therefore looked at all patients in Denmark
having a first-time MI, analyzing the cardiovascular risk up to
5 years after their MI. From our results, the relative risk of
NSAID use was associated with persistently increased cardio-
vascular risk throughout all 5 years after discharge from hos-
pital after the first MI. However, the absolute difference
among users and non-users for combined CHD and MI was
about 3% and for mortality even smaller. Further investiga-
tions are needed to clarify whether long-term caution in using
these agents after MI should be recommended. We suggested
a persistent focus on the risk of NSAIDs among patients who
have experienced MI. Our non-randomized results suggest that
there seems to be no safe treatment window taking NSAID in
patients with established cardiovascular disease.
Fig. 2. Time-dependent Cox proportional hazard analysis of risk of death/re-MI according to duration of NSAID treatment in patients with prior
myocardial infarction. (With permission from [29], Fig. 6).
© 2014 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society)
181
Biological Mechanism
Hypertension, heart failure, renal failure and increased ten-
dency for thrombosis are some of the proposed biological
mechanisms of the increased cardiovascular risk associated
with use of most NSAIDs, but a thorough explanation is still
awaited [9,25,32–35]. NSAIDs are known to inhibit the cyclo-
oxygenase (COX) enzymes, which are involved in the produc-
tion of prostaglandins [9,33,36,37]. The two major
cyclooxygenase isoenzymes are COX-1 and COX-2, which
both form prostaglandin H2 from arachiodonic acid, which is
further catalysed producing bioactive lipids (prostanoids) such
as prostacyclin, thromboxane A2, and prostaglandins D2, E2
and F2. The COX isoenzymes are present in various tissues
throughout the human body and hence also influence the hae-
mostasis differently through prostanoids [38,39]. Platelets play
an important role in the cardiovascular haemostasis and
express only COX-1, whereas endothelial cells express both
COX-1 and COX-2. COX-1 produces thromboxane A2
(TXA2), which stimulates platelet aggregation, vasoconstric-
tion and increases vascular and cardiac remodelling, and
COX-2 is involved in the synthesis of prostacyclin, which is a
potent vasodilator that inhibits platelet function and promotes
renal sodium excretion. An observed shift in the prothrombot-
ic/antithrombotic balance on endothelial surfaces towards
thrombosis and an association between the degree of COX-2
inhibition and the tendency for thrombosis of the drugs has
led to the simplified hypothesis that the more COX-2 inhibi-
tion the drug exerts relative to COX-1 inhibition, the higher
the risk of cardiovascular events [9,25,33,36,40,41]. The non-
selective NSAIDs have also been associated with increased
cardiovascular risk, and therefore, this theory of balanced ver-
182 ANNE-MARIE SCHJERNING OLSEN ET AL.
Fig. 3. Time-dependent Cox proportional hazard analysis of the risk
of coronary death or non-fatal myocardial infarction (MI) according to
the time of NSAID treatment among patients with prior MI. (With
permission from [30], Fig. 2).
sus unbalanced COX inhibition is now debatable. Other
mechanisms may explain the associated cardiovascular risks
of NSAIDs, as prostacyclin has been found to act as a
restraint on many prothrombotic stimuli (e.g. collagen, throm-
bin, adenosine diphosphate, adrenaline, serotonin and TxA2)
[33,34]. Furthermore, ibuprofen might interact with aspirin,
preventing aspirin to bind in the COX-1 pathway in the
platelets. In contrast to aspirin, ibuprofen does not block irre-
versibly and thereby only partially protects against thrombosis
[42]. Focus has primarily been on the increased thromboem-
bolic risk, but NSAIDs have also been found to influence
renal function and the regulation of fluid balance, causing
fluid retention and worsening of HF, in addition to promoting
increased risk of hypertension and destabilization of blood
pressure [43].
Treatment Recommendations
It is of great concern that despite guidelines discouraging use
of NSAIDs in cardiovascular patients, NSAID use still
remains high in the general population [44]. In Denmark, the
remaining high use is in particular due to increased use of
OTC use of ibuprofen [45]. The associated cardiovascular risk
is a major public health challenge, not at least as recent meta-
analyses including all the prior randomized clinical trials have
© 2014 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society)
MiniReview
reported similar increased cardiovascular risk associated with
the more traditional non-selective NSAID diclofenac and ibu-
profen as rofecoxib as the prior observational studies [16].
These drugs are in some countries available as over-the-coun-
ter (OTC) drugs in supermarkets and at petrol stations without
any expert advice on use and potential side effects, which
leaves a misleading impression that these drugs are risk-free
alternatives [1,9,11,15,17,25,40,46–49]. In a newly published
paper, diclofenac was found to be the most commonly sold
NSAIDs in 15 countries [44]. Because of the wide availability
and use of NSAIDs, awareness of their proper use, dose,
potential side effects and possible safe periods for NSAID
treatment is warranted among health care providers as well as
in the general population. We believe as long as the area
remains unregulated, nothing is changing. We encourage The
US Food and Drug Association (FDA) and the European
Medicine Agency (EMA) to reconsider recommendations for
NSAID use, especially among vulnerable patient groups such
as those with ischaemic heart disease. Until such reconsidera-
tions are made, we advise that physicians consider alternatives
to NSAID therapy on the basis of individual patient character-
istics according to the stepwise approach from AHA to the
treatment of musculoskeletal pain in cardiovascular patients,
starting with non-pharmacological treatments, such as physical
therapy and exercise, weight loss to reduce stress on joints,
and heat or cold therapy. If this does not provide enough pain
relief, acetaminophen, aspirin and even short-term use of nar-
cotic analgesics are recommended as first-line drugs; NSAIDs
with the lowest COX-2 selectivity (naproxen 500 mg or ibu-
profen 1200 mg) should be used next, and the more selective
COX-2 inhibitors are at the bottom of the list, to be used only
as a last resort.
Conclusion
This MiniReview examined the impact of NSAID utilization
on cardiovascular risk. It is concluded that most NSAIDs are
associated with an increased cardiovascular risk, both in
healthy people and among patients with known cardiovascular
disease. The selective COX-2 inhibitor rofecoxib was with-
drawn from the market due to its cardiovascular risk; however,
this MiniReview suggests that the very commonly used
NSAID, diclofenac, has at least as high a cardiovascular risk
as rofecoxib. This is worrying as diclofenac is one of the most
commonly sold NSAIDs and even available as OTC without
any expert advice about interaction and side effects. Addition-
ally, this MiniReview concludes that there seems to be no safe
therapeutic window in patients with established cardiovascular
disease when taking NSAIDs. Further studies are warranted to
evaluate the cardiovascular safety of NSAIDs. At this point,
the overall evidence suggests advising caution in using NSA-
IDs at all times in particular in patients with known cardiovas-
cular disease.
Conflict of Interest
The authors state that there are no conflicts of interest to
disclose.
MiniReview NSAID TREATMENT AND CARDIOVASCULAR RISK
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