Review

European Journal of Preventive

Cardiology

Non-steroidal anti-inflammatory 2020, Vol. 27(8) 850–867

! The European Society of
Cardiology 2019
drug effects on renal and Article reuse guidelines:
sagepub.com/journals-permissions
cardiovascular function: from DOI: 10.1177/2047487319848105
journals.sagepub.com/home/cpr
physiology to clinical practice

Aderville Cabassi1, Stefano Tedeschi1,2, Stefano Perlini3,

Ignazio Verzicco1, Riccardo Volpi1, Gianluca Gonzi4 and

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Stefano Del Canale5

Abstract
Excessive or inappropriate use of non-steroidal anti-inflammatory drugs can affect cardiovascular and renal function.
Non-steroidal anti-inflammatory drugs, both non-selective and selective cyclooxygenase 2 inhibitors, are among the most
widely used drugs, especially in the elderly, with multiple comorbidities. Exposition to a polypharmacy burden represents
a favourable substrate for the onset of non-steroidal anti-inflammatory drug-induced deleterious effects. Cardiovascular
and renal issues concerning the occurrence of myocardial infarction, atrial fibrillation, heart failure and arterial hyper-
tension, as well as acute or chronic kidney damage, become critical for clinicians in their daily practice. We discuss
current available knowledge regarding prostanoid physiology in vascular, cardiac and renal systems, pointing out potential
negative non-steroidal anti-inflammatory drug-related issues in clinical practice.

Keywords
Non-steroidal anti-inflammatory drugs, acute and chronic renal disease, atrial fibrillation, myocardial infarction, heart
failure, arterial hypertension
Received 22 December 2018; accepted 11 April 2019

Epidemiology of non-steroidal
anti-inflammatory drugs use and
potential risks
Non-steroidal anti-inflammatory drugs (NSAIDs) are
among the most used drugs in the world to treat a var-
iety of conditions including pain, rheumatoid arthritis,
osteoarthritis, musculoskeletal disorders. NSAID use is
reported to increase with age as many chronic pain
conditions, such as osteoarthritis, become more preva-
lent; overall, an estimated 10–40% of people aged over
65 years use prescribed or over-the-counter NSAIDs
daily.1 In the USA, NSAIDs reached 98 m prescriptions
in 2012 with more than 29 m adults being regular
users.2 In Sweden, NSAIDs are the most commonly
prescribed oral analgesics for musculoskeletal pain,
accounting for almost 80% of prescriptions over a
five-year period.3 In Italy, the 2017 OSMED report4
(which includes both doctors’ prescriptions and over-
the-counter NSAID consumption) refers to total
country NSAID sales of 175 m Euros (i.e. 2.89 Euros
per inhabitant); the number of sold defined daily doses/
1000 inhabitants/day in 2017 was 19.2 (slightly declin-
ing from 2013), much lower than those reported for
Northern European countries in 2016, where the
values were 74.3 in Iceland, 73.9 in Finland, 54.4 in
Sweden, 43.8 in Norway and 31.8 in Denmark.4,5
Moreover, according to the same Italian OSMED
report, NSAID consumption reached a prevalence of
1
Cardiorenal Research Unit, University of Parma, Parma, Italy
2
Cardiology Unit, Ospedale Vaio, Vaio-Fidenza, Parma, Italy
3
Unità di Medicina Interna, Università di Pavia, Vaio-Fidenza, Parma, Italy
4
Cardiology Unit, Azienda Ospedaliera-Universitaria di Parma, Italy
5
Parma Health Authority, Parma, Italy
Corresponding author:
Aderville Cabassi, Cardiorenal Research Unit, Clinica e Terapia Medica,
Department of Medicine and Surgery, DIMEC University of Parma, Via
Gramsci 14, 43126 Parma, Italy.
Email: aderville.cabassi@unipr.it
Cabassi et al. 851

33% for people > 65 years.4 Because chronic pain often
calls for prolonged use of NSAIDs, elderly people with
multiple comorbidities are exposed to a worrisome drug
burden (a phenomenon known as polypharmacy). The
latter, coupled with age-related progressive decline in
renal function makes the elderly more vulnerable to the
noxious effects of many drugs, especially NSAIDs.6
Their potential toxicity is further aggravated by the
fact that their use is often inappropriate, and without
real control by doctors. Patients themselves, motivated
by the efficacy and availability of these drugs, increase
the doses and prolong their use. Uncontrolled NSAID
(COX-1)-selective ketorolac caused the highest risk of
hospitalization among inappropriately prescribed
medications.9 The excessive or inappropriate use of
NSAIDs can affect cardiovascular and renal function
because of their specific effects on prostanoid synthe-
sis.10 Issues concerning cardiovascular, renal and
gastrointestinal safety are therefore critical for clin-
icians. Consequently, we decided first to review the
prostanoid physiology of vascular, cardiac and renal
systems to explain the effects of NSAIDs and their
potential deleterious mechanisms, and then to translate
the information to clinical conditions.

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use, mainly fuelled by the over-the-counter market and
widespread advertising, is a worldwide problem exacer-
bated by varying prescription rules which can under-
rate true NSAID consumption. NSAID-related adverse
effects are among the leading causes of hospital admis-
sion, especially in the elderly, and rank among the top
drugs causing adverse effects.7 We recently reported, in
a study conducted in a large population of elderly
patients (n ¼ 80,229) in Emilia Romagna, a Northern
region of Italy, that prolonged use of NSAIDs (more
than 15 days) was the most common inappropriately
prescribed class of medications. Specific interventions
focused on the appropriateness of prescriptions in the
elderly by general practitioners halved the inappropri-
ate use of NSAIDs.8 After 10 years (2003–2013) of fol-
lowing a cohort of elderly patients who resided in
Northern Italy, we found that cyclooxygenase-1
Physiology of prostanoids: how do they
interfere with cardiovascular and renal
function?
Prostanoids, including prostaglandins (PGs) and
thromboxanes (TXs), are derivative product of C20
unsaturated fatty acids metabolism, mainly arachidonic
acid (C20:4(-6)), the most abundant precursor in
(C20:4(o-6)) humans with 5 cis- and 13 trans- double-
bond prostanoids relevant in human species (Figure
1).10 Arachidonic acid is released from cell membrane
phospholipids after ester bond cleavage is performed by
the enzymes of the phospholipase A2 family. Once the
ester bond between arachidonic acid and the membrane
is hydrolysed, arachidonic acid is metabolised by pros-
taglandin G/H synthase (PGHS), the key enzyme

Membrane phospholipids

Phospholipase A 2
H3C

Arachidonic Acid
NSAIDs or X HO
Cyclooxygenase 1 and 2
COX 2 inhibitor PGH2
O

PGG 2
synthase

PGH2
PGD2 PGE2 PGF2 PGI2 TxA 2
synthase isomerases synthase synthase synthase
PGD2 PGE2 PGF2 PGI2 TxA2

DP1 DP2 EP1 EP2 EP3 EP4 FP IP TP

Gαs Gαi Gαq Gαs Gαi/s/q Gαs Gαq Gαs Gαi/s/q

cAMP cAMP [Ca++] cAMP cAMP cAMP [Ca++] cAMP cAMP

[Ca++] [Ca++] [Ca++]

PGs and Tx receptors: green boxes indicate «relaxant», red boxes «constrictive» receptors.

Figure 1. Pathways in biosynthesis of prostanoids from arachidonic acid to prostaglandins (PGs) and thromboxane (TX) generation
and receptor signalling. cAMP: cyclic adenosin monophosphate; COX: cycloxygenase; DP, EP, FP, IP, TP are PGs and Tx receptors; Gai/
s/q are G protein coupled receptor subunits; NSAID: non-steroidal anti-inflammatory drug.
852
involved in PG and TX synthesis and commonly
known as COX. COX has both cyclooxygenase and
hydroperoxidase activity, with PGH2 as the reaction
end-product. PGH2 is further converted by specific
PG synthases to specific and biologically active PGs
or to TXA2 through TX synthase. As many prostanoids
(PGI2 – usually referred to as prostacyclin, PGH2 and
TXA2) are chemically unstable molecules that are
degraded to inactive products within a few minutes,
they are expected to act locally and play a paracrine
role. Prostanoids exert their effects through five main
subtypes of receptors: EP1, EP2, EP3 and EP4 for PGE2,
DP1 and DP2 for PGD2, and FP, IP and TP receptors
for PGF2a, PGI2 and TXA2 respectively (Figure 1). In
humans, alternative splicing leads to an additional eight
EP3 receptor isoforms, two TP isoforms (TPa, TPb),
and some other FP isoforms.11 Human PG receptors
are dependent on G-protein activation and are grouped
in G-protein-dependent cAMP and/or calcium signal-
ling receptors. In fact, they can be coupled to either
Gas (EP2, EP4, IP and DP1) that elevates intracellular
levels of cAMP, or Gaq (EP1, EP3 and FP) that
increases calcium intracellular levels, or Gas-proteins
(EP3, DP2 and TP) that can both increase or decrease
levels of cAMP and calcium.10,11 PG receptor signalling
involves both a cAMP-protein kinase A dependent
mechanism and independent mechanisms; the latter
are represented by the exchange proteins directly acti-
vated by cAMP (Epac1 and 2), which participate in
cardiovascular functions, regulating calcium handling
and vascular tone.12 In the PG and TX biosynthetic
cascade, two COX isoforms have been described in
humans, with a 60% homology in amino acid sequence;
COX-1 (PGHS-1) is typically considered the constitu-
tive, housekeeping and almost ubiquitously expressed
isoform, responsible for prostanoid production in most
tissues.13 COX-1 is the major source of TXA2 in both
endothelial and activated platelets and represents a
target for acetylation and inhibition by low dose acet-
ylsalicylate. COX-2 (PGHS-2) has long been believed to
be the inducible isoform, expressed at the site of inflam-
mation, infection or cancer.14 However, recent gene
expression studies in mice demonstrated a constitutive
expression of COX-2 in tissues such as brain, gut,
thymus and kidney.15 The constitutive expression of
COX-2 in kidneys is regulated by transcriptional fac-
tors unrelated to inflammation, supporting a physio-
logical role for this enzyme. In human pathological
conditions, such as arterial hypertension, diabetes or
heart failure (HF), COX-2 expression increases in
both renal cortex and medulla.16 COX-2 is responsible
for PGI2 generation in humans.17 Yet, other reports
based on immunohistochemistry and bioluminescent
imaging point to COX-1 as a principal source of
PGI2 in physiological conditions in human aortic
European Journal of Preventive Cardiology 27(8)
endothelial cells.18 Further studies are needed to clarify
their specific physiological role in PGI2 generation.
Vascular system
The effects of PGs and TXs on vascular tone and func-
tion, including platelet activation and aggregation, are
probably the most studied in prostanoid research. Given
the premise that most of the seminal information and
scientific advances on cardiovascular and renal effects of
prostanoids derive from experiments in mice that repre-
sent the animal model most used in knockout gene
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investigation, the observation of their characteristics,
although not directly transferable to humans, clearly
contributes to the understanding of human physiology.
Protein coding gene regions in humans and mice are
85% identical with a range between 60–99% homology.
Amino acid homology between human and mouse PGs
and TXs receptors ranges between 71–88%, with IP and
TP receptor sharing 79 and 74% of the sequence,
respectively.11 PGI2 and TXA2 have opposing effects
on both platelets and blood vessels, with the former
being an endogenous anticoagulant agent as shown in
knock-out mice (IP –/–) for its receptor, and the latter
having vasoconstrictive and pro-thrombotic effects. IP
–/– mice have normal development and show throm-
botic diathesis when early endothelial damage
occurs.19 TP knock-out mice were prone to bleed due
to a reduced ability to activate platelets in the case of
balloon catheter-induced injury.20 A possible explan-
ation for the PGI2 anticoagulant effect came from the
observation of its ability to stimulate thombomodulin in
endothelial cells, eventually promoting C-protein activ-
ity. However, in this study, some of the pro-thrombotic
and vascular effects of IP deletion were completely abro-
gated by TP deletion, suggesting that PGI2 acts mainly
as a modulator of the pro-thrombotic and vasocon-
strictive action of TXA2.21 PGE2 is also involved in
platelet aggregation, facilitating activation through the
EP3 receptor.22 Aside from a modulatory effect on plate-
let activity, prostanoids are also implicated in athero-
sclerosis development. Indeed, apoE-deficient mice, a
model of atherogenesis, crossbred with IP –/– or TP
–/– mice showing distinctive vascular patterns. ApoE
–/– TP –/– and apoE –/– IP –/– mice show, respectively,
a delay or an acceleration in atherogenesis. ApoE –/– IP
–/– mice have a more vulnerable plaque profile (due to
partial endothelial disruption) and a greater expression
of adhesion molecules like ICAM-1, promoting macro-
phage migration.23 Prostanoids play an important role
in endothelial-mediated vascular tone: in this regard
COX-2 seems to be of major relevance, as COX-2 –/–
mice, albeit showing normal constitutive PG synthesis,
evidence both a hypertensive pattern and an enhanced
pressor effect after angiotensin II infusion.24 In human
Cabassi et al.
coronary arteries from diabetic patients, COX-2 over-
expression has been proposed as a relevant compensa-
tory mechanism to preserve coronary flow under
conditions of impaired nitric oxide-dependent vascular
control through increased PGI2 production.25 PGI2 and
TXA2 show opposite effects on vascular tone regulation,
determining vasodilator and vasoconstrictive action
respectively.10 NSAIDs inhibit COX isoforms differ-
ently and reduce PG and TX synthesis (Figure 1).16,26
An increased cardiovascular risk associated with
NSAIDs derives from the degree of COX-1 and COX-
2 inhibition which differently reduce both the antith-
rombotic PGI2 and the pro-aggregatory and vasocon-
strictive TXA2. NSAID-induced PGI2 lowering leads to
increased platelet aggregation which might be counter-
balanced by a simultaneous inhibition of platelet COX-
1 activity resulting in reduced TXA2 levels. However,
except for low-dose acetylsalicylate (75–150 mg) and
high-dose naproxen (1000 mg), both nonselective and
COX-2 selective NSAIDs do not modify platelet
COX-1 activity to the degree necessary (>95%) to inhi-
bit TXA2 pro-aggregatory effects. Thus the net effect
will be an impairment of the balance between TXA2
and PGI2 levels, thereby fostering atherosclerosis,
thrombosis and other cardiovascular complications.10,26
Apart from the latter effects mediated via the inhibition
of the COX pathway, both non selective and COX-2
selective NSAIDs may induce cell apoptosis and
increase the generation of reactive oxygen species by
altering specific cell signalling pathways thus contribut-
ing, through different mechanisms, to the genesis of car-
diovascular complications such as thrombosis,
myocardial infarction (MI), HF and arrhythmia.27
PGE2, the most abundant prostaglandin in humans,
shows a diversified effect on vascular tone based on
the district studied.21 This effect is dependent on binding
to the four membrane receptors for EP1, EP2, EP3 and
EP4, coupled to different signalling pathways.
Vasodilation and hypotension obtained after PGE2
infusion is mediated through EP2/EP4 receptors, both
coupled to adenylyl cyclase activation, whereas vaso-
constriction (in cerebral circulation) is related to stimu-
lation of EP1 receptors that are coupled to Gaq proteins,
resulting in increased phosphatidylinositol hydrolysis
and elevation of intra-cellular calcium levels. The EP2
receptor plays a greater role in modulating vascular tone
and blood pressure regulation as observed in knock-out
mice, inducing a rise in blood pressure levels associated
with impaired sodium handling.10,28 EP2 and EP4 are
generally considered the relaxant receptors mainly
because of their effect on vascular smooth muscle
cells. A complex role for the EP4 receptor in the control
of vascular tone and pathogenesis of arterial hyperten-
sion has recently been suggested.29 Using conditional
gene targeting techniques, the authors generated mice
853
with a specific loss of EP4 receptor only in vascular
smooth muscle, finding an attenuation of the acute
PGE2-mediated vasodilation. They also reported the
ability to attenuate a rise in blood pressure after high-
salt feeding or long-term angiotensin II infusion in mice
where the loss of EP4 receptors occurred in all tissues
but not in those where the loss of EP4 was limited only
to vascular smooth muscle cells. The concept of a cen-
tral and dominant role played by EP4 receptors in vas-
cular tone control and arterial hypertension prevention
is emerging.29
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Heart
Several reports indicate a direct and specific effect of
PGs on cardiac tissue; most of this information derives
from studies in transgenic animal models that evaluated
the effects of prostanoids on cardiac fibrosis, ischaemia
and arrhythmias. PGE2 stimulates cardiac myocyte
hypertrophy, acting through EP4 receptors and seems
to have a protective effect after ischaemia/reperfusion
injury.30,31 A similar effect on cardiomyocyte preserva-
tion after ischaemia/reperfusion injury had been
reported for PGI2 in a IP –/– model of mice. PGI2
showed favourable action on ventricular remodelling,
with increased cardiac fibrosis (perivascular and inter-
stitial) in IP –/– mice following different kinds of vas-
cular injuries, namely MI and aortic banding.32 Tissue
specific gene-deletion of COX-2 in cardiomyocytes sug-
gested a role for PGs in preserving normal ventricular
function that otherwise appeared to be depressed and
with an increased susceptibility to ventricular
arrhythmias.33
Kidney
COX-1 is expressed in the kidney and regulates physio-
logical renal vascular and tubular functions as well as
hormonal secretion; COX-2 is constitutively expressed
in the kidney.16 Both are located at the endothelial and
tubular levels as well as expressed in the interstitial
medullary cells. PG synthesis is not uniformly distribu-
ted along the nephron.34 The medullary synthesis of PG
exceeds that of the cortex.34 In the renal medulla most
PG synthesis comes from interstitial medullary cells and
collecting tubules, whereas in the cortex the interlobular
arteries, the afferent arterioles and the glomeruli are the
major biosynthetic sites. Reduced COX activity is
observed in proximal tubules and the loops of Henle.
PGE2 is the major prostanoid secreted by tubules,
while at the glomerular levels both PGE2 and PGI2 are
present in a similar amount. Renal PGE2 and PGI2 are
responsible for renin secretion from the macula densa,
even if other arachidonic acid metabolites have been
suggested to participate directly in renin release
854
regulation.35 A specific role for COX-2-generated PGs in
the macula densa has been demonstrated in acute and
chronic regulation of renin release.36,37 COX-2 specific
antagonism or COX-2-deficient mice showed reduced
levels of renin expression and activity.35,38 Conversely,
increased COX-2 expression has been associated with
high-renin conditions such as in volume-depleted long-
term furosemide-treated rats and in patients with Bartter
syndrome, linking COX-2-related PG synthesis to NaCl
uptake through NKCC2 in the loop of Henle.39 PGs are
also able to antagonise the antidiuretic effect of vaso-
pressin and are involved in the natriuretic effect of dopa-
mine and natriuretic peptides.16,40 Renal function,
including vascular perfusion and resistance, glomerular
filtration and sodium excretion in normal subjects is
marginally dependent on PG secretion. In fact,
NSAID administration does not affect renal function
when other regulatory mechanisms, such as adrenergic
tone, the renin-angiotensin aldosterone system, the
endothelin system or the adenosine and dopamine sys-
tems, are not activated.34 When hypoperfusion or a
hypovolaemic setting occurs, and a concurrent higher
circulating release of vasoconstrictors (angiotensin II,
norepinephrine, vasopressin and endothelin) is elicited,
PG generation becomes fundamental to maintain renal
perfusion and limit ischaemia. Norepinephrine, angio-
tensin and vasopressin stimulate PGE2 and PGI2
(a)
PG ANG II
INTERLOBULAR ARTERY
AFFERENT ARTERIOLE
EFFERENT ARTERIOLE
RBF normal
GFR normal
Figure 2. (a) Prostaglandin (PG)-mediated vasodilation of afferent arterioles prevents renal vasoconstriction and reduction of
glomerular filtration rate (GFR) in clinical conditions characterised by low effective volume such as heart failure. (b) Non-steroidal
anti-inflammatory drugs impair afferent arteriole vasodilation leading to renal hypoperfusion (renal blood flow (RBF)) and reduced
GFR. ANG II: angiotensin II; COX: cycloxygenase.
European Journal of Preventive Cardiology 27(8)
release from glomerular mesangial and epithelial cells
and renal medullary interstitial cells, which is blunted
by COX-1 and COX-2 inhibition leading to an increase
in arteriolar constriction (Figure 2(a) and (b)).
Therefore, when true hypovolaemia due to gastro-
intestinal or renal losses (as occurs with diuretic ther-
apy) or an effective volume depletion due to HF or
cirrhosis or nephrotic syndrome occurs, PG generation
becomes clinically relevant in order to antagonise the
renal effects of vasoconstrictors and the reduction in
renal blood flow and glomerular filtration rate. Thus
an increased risk of ischaemia-related acute tubular
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necrosis exists when there is a reduction of peritubular
flow following NSAID inhibition of PG-related affer-
ent arteriole vasodilation.41 The risk of tubular
damage related to nephrotoxic drugs or contrast
media can be facilitated by concomitant NSAID
intake.41 In addition, in human and experimental
glomerulonephritis the increased generation of PGs
and TXA2 by the glomeruli are involved in the severe
reduction of glomerular filtration rate with relative
renal blood flow sparing. NSAIDs can differently
affect not only afferent arteriolar and glomerular
haemodynamics, but also glomerular capillary ultrafil-
tration coefficients.41,42 Hence, NSAIDs can be
responsible for kidney dysfunction and for altered
electrolyte and water balance.16,41
(b)
PG COX-1 and COX-2
ANG II
inhibition
INTERLOBULAR ARTERY
AFFERENT ARTERIOLE
EFFERENT ARTERIOLE
RBF reduced
GFR reduced
Cabassi et al.
Pharmacology of NSAIDs
NSAIDs derive from different chemical structures and
are classified, based on their half-lives, into short and
long acting drugs (Table 1). This is an important issue
to deal with, because the evaluation of efficacy and
toxicity must include the time it takes for an NSAID
to reach a plasma steady-state level, which is about
3–5 times its half-life. Most NSAIDs, after oral admin-
istration, are well absorbed, show minimal first-pass
hepatic metabolism and bind tightly to serum pro-
teins.43 When plasma albumin concentration falls,
because of reduced hepatic synthesis, as occurs in cir-
rhosis, during the active phase of inflammatory diseases
or because of urinary albumin loss in nephrotic syn-
drome, higher levels of free protein-unbound active
NSAIDs are circulating. The risk of different events
varies depending upon the clinical context, medication
Table 1. Non-steroidal anti-inflammatory drug (NSAID) classification based on duration of action, chemical structure and
cyclooxygenase (COX) isoform selectivity.
Short acting (< 6 hours)
Diclofenac
Ketoprofen
Acetaminophen
Acetylsalycilate (Aspirin)
Indomethacin
Ibuprofen
Ketorolac
Chemical Structure
Salycilic Acid: Acetylsalycilate
Acetic Acid: Ketorolac, Indomethacin,
Nabumetone, Sulindac
Phenylacetic Acid: Diclofenac
Propionic Acid: Naproxen, Ketoprofen,
Ibuprofen, Fenoprofen
COX 1 selectivity
Ketorolac
Ketoprofen
Indomethacin
Acetylsalycilate (Aspirin)
Nabumetone
Sulindac
Naprossen
Piroxicam
855
and dose. Because NSAIDs (except for acetylsalicylate)
tightly bind to protein, they can increase the risk of
bleeding in patients treated with vitamin K antagonists
through warfarin displacement from plasma proteins.44
The level of COX isoform inhibition is responsible for
NSAIDs efficacy and toxicity.14,43 As specified above,
COX possesses both cyclooxygenase and hydroperoxi-
dase catalysis properties: NSAIDs and acetylsalicylate
are able to inhibit both reactions whereas acetamino-
phen acts by blocking only hydroperoxidase catalysis.45
Such a specific effect explains why acetaminophen
does not display anti-inflammatory or antithrombotic
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effects as NSAIDs do, but rather antipyretic and
analgesic properties. NSAIDs efficacy and toxicity
are also dependent on non-PG-mediated NSAID
effects, involving a modulatory effect on specific tran-
scription factors such as nuclear factor kappa B and
Long acting (> 6 hours)
Naproxen
Piroxicam
Nabumetone
Valdecoxib
Celecoxib
Etoricoxib
Sulindac
Diarylheterocyclic: Celecoxib, Valdecoxib,
Etoricoxib
Enolic acid: Piroxicam
Aniline derivative: Acetaminophen
COX 1 COX 2 COX 2 selectivity
Ibuprofen
Acetaminophen
Diclofenac
Celecoxib
Valdecoxib
Etoricoxib
856
activator proteins on neutrophil-endothelial adhesion
molecules and on nitric oxide synthase enzymes.46
The interactions between NSAIDs and other drugs
can clearly increase the risk of toxicity, with both
renal (haemodynamic) and cardiovascular (haemor-
rhagic risk) adverse effects. Several NSAIDs can
increase the plasma levels of drugs by partially inhibit-
ing CYP-2C9 (indomethacin, ibuprofen and diclofenac)
or CYP-2C8/2D6 (celecoxib).47 A careful clinical and
pharmacological anamnesis is a fundamental step of
NSAID therapy. Multiple NSAID combinations as
well as concurrent NSAID use with acetaminophen at
high doses should be avoided because of the possibility
of a higher risk of gastrointestinal complications and
no greater efficacy of their combination.48
Acute and chronic renal damage by non-
selective and COX-2 selective NSAIDs
Around 3% of all patients using NSAIDs can experi-
ence adverse renal effects translating into more than
2.5 m patients experiencing one or more nephrotoxic
events annually.49 Both non-selective and COX-2
selective NSAIDs can induce an acute kidney injury
(AKI).16,41 NSAIDs can induce several forms of
kidney damage including haemodynamically mediated
AKI, oedema, electrolyte and acid-base disorders,
acute tubular necrosis and acute interstitial nephritis
(AIN), which may be accompanied by the nephrotic
syndrome and papillary necrosis.41 Both non-selective
and COX-2 selective NSAIDs were able to reduce
glomerular filtration rate to a similar degree in an
elderly population.50 The presence of only one of the
following risk factors is necessary to generate NSAID-
induced AKI: absolute volume depletion and dehydra-
tion, reduced effective arterial volume or severe hyper-
calcaemia.16 Chronic kidney disease and old age are
also major risk factors leading to NSAID-induced
AKI. Diuretics, angiotensin-converting enzyme inhibi-
tors (ACEis), angiotensin II receptor 1 blockers, also
increase the risk of AKI. Patients with HF and reduced
effective arterial volume doubled the risk of developing
AKI when treated with COX-2 selective and non-
selective NSAIDs by blunting PG-mediated vasodila-
tion of afferent arterioles, thus favouring renal hypo-
perfusion and reducing glomerular filtration rate
(GFR) (Figure 2(a) and (b)).16,34 Special attention
should be paid even in chronic kidney disease patients
with mild reductions of GFR when chronic treatment
with NSAIDs is started.51 In haemodynamically-
mediated AKI following recent NSAID use, the labora-
tory pattern includes increased plasma creatinine levels,
the absence of significant proteinuria (proteinuria less
than 1 g/24 h), haematuria and a bland urine sediment.
The presence of higher levels of proteinuria (more than
European Journal of Preventive Cardiology 27(8)
1 g/24 h) can suggest a NSAID-induced glomerular
lesion (minimal change disease or membranous nephro-
pathy) often associated with hyaline casts.16 NSAID-
related AKI could be also due to acute tubular necrosis:
in this case urinary sediment contains renal tubular epi-
thelial cell casts, renal tubular epithelial cells or granu-
lar casts. Furthermore, NSAIDs can lead to AIN
showing in this case an increase in white blood cells
and white blood cell casts in the urinary sediment.
NSAIDs as a class (in particular propionic acid deriva-
tives such as fenoprofen) (Table 1), including COX-2
selective drugs, can induce both AIN and a nephrotic
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syndrome associated with minimal change or mem-
branous nephropathy.52,53 A 30% rise of NSAID-
mediated AIN cases is reported especially in elderly
people, mainly because of polypharmacy. Nephrotic
syndrome can occur in NSAID-mediated AIN but
is rare (less than 1%).53 AIN occurrence is not
dose-dependent and can recur if the same drug is re-
administered.54 There may be a period of variable
latency (from a few days to several months) between
the onset of NSAIDs treatment and the appearance of
AIN. Patients with AIN show an acute rise in creatin-
ine levels associated with both oliguria or non-oliguria.
Fever, rash or blood eosinophilia and urine eosinophils
can sometimes (less than 10% in combination) accom-
pany the AIN clinical pattern. Discontinuation of
NSAIDs allows recovery from AIN within several
weeks to several months. The exact mechanism of
NSAID-mediated AIN is not clear, even if T-helper
lymphocyte activation by leukotrienes (whose gener-
ation seems facilitated by NSAID-mediated COX
inhibition), has been suggested.55 In addition to AKI,
an excessive use of NSAIDs, in particular analgesic
mixtures containing phenacetin, was found to be a rele-
vant cause of progressive kidney disease, through direct
renal papillary ischaemia up to necrosis or chronic
interstitial nephritis. Up to the late 1980s, at least
10% of end-stage renal disease in Switzerland, and in
other countries such as Belgium and Australia, was due
to analgesic-mediated nephropathy: only reduced use of
analgesic mixtures containing phenacetin allowed a
marked lowering of its incidence.56 The renal medulla
is the major site of ischaemic damage associated with
vasa recta capillary sclerosis and consequent papillary
tip necrosis. Both low PG generation and glutathione
depletion contribute to the toxic medullary effect of
NSAIDs. The laboratory pattern of analgesic nephro-
pathy is not specific and includes a long-period, slow-
rising increase in plasma creatinine levels associated
with normal urine sediment, or only mild proteinuria.
If the analgesic mixture is discontinued, the progression
of chronic renal disease can be stopped, and glomerular
filtration can even improve, except in those with previ-
ous severe decline of renal function when high doses
Cabassi et al.
were used.56,57 Even acetaminophen (paracetamol), the
main metabolite of phenacetin and a widely prescribed
antipyretic and analgesic drug, may be associated with
a progressive loss of renal function in patients with
advanced renal failure, especially when the lifetime
accumulated dose is elevated. In patients whose renal
function is only mildly reduced, no risk of progression
was observed with less frequent drug consumption.58
Yet, as recently reported, if acetaminophen therapeutic
doses are used in association with low-moderate alco-
hol consumption, a higher percentage of patients with
progressive loss of renal function occurs.59 Chronic
therapeutic use of low doses of acetylsalycilate does
not seem to be related to progressive risk of renal fail-
ure in the majority of studies, but an increased risk can
occur when they are given in combination with acet-
aminophen and other NSAIDs.58,60 There is consider-
able evidence that high doses of both COX-2-selective
and non-selective NSAIDs should be avoided in
patients with chronic renal insufficiency.16,41 The
recent Prospective Randomized Evaluation of
Celecoxib Integrated Safety Versus Ibuprofen or
Naproxen (PRECISION) trial, which included osteo-
arthritis and rheumatoid arthritis patients with at
least one cardiovascular risk factor, clearly showed
that the COX-2 selective drug celecoxib, when admin-
istered at moderate doses, may be associated with fewer
renal events than ibuprofen (–39%). A similar trend
was also observed when celecoxib was compared with
naproxen.61
NSAID effects on blood pressure,
electrolytes and water balance
COX-2 selective and non-selective NSAIDs can induce
a rise of blood pressure in both normotensive and
hypertensive patients. An estimate of NSAID-related
blood pressure increase is around 1–2 mm Hg in normo-
tensive subjects and can reach 14 mm Hg in patients
with hypertension.62,63 These drugs can impair the effi-
cacy of antihypertensive drugs in already treated hyper-
tensive patients; the negative impact of NSAIDs (COX-
2 selective included) on blood pressure control is not
observed when calcium channel blockers are used, and
is minimal for beta adrenergic blockers.64 Renal COX-2
inhibition appears to be one of the mechanisms leading
to a lower natriuresis and increased intravascular
volume, with a subsequent significant rise in blood pres-
sure. Recently the results of the PRECISION-ABPM
trial, where moderate doses of a COX-2 selective inhibi-
tor were compared to two non-selective NSAIDs on
24-hour ambulatory blood pressure in patients affected
by osteoarthritis and rheumatoid arthritis, indicate a
neutral effect on mean systolic blood pressure of cele-
coxib, but a significant increase in the ibuprofen-treated
857
arm.65 High doses of acetylsalicylate can affect blood
pressure levels, whereas a low dose (75 mg/day) does
not.66 Long-term oral administration of acetaminophen
can increase both systolic and diastolic blood pressure
levels,67 even if several studies showed a neutral effect in
hypertensive patients.68 On the contrary, acute intra-
venous acetaminophen administration lowers blood
pressure.69 Therefore, because NSAIDs exert their
effects in a dose-dependent way, they should be used
at the lowest effective dose and for the shortest duration
of time in hypertensive patients. It is also known that
NSAIDs use can cause alterations in electrolyte and
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water balance. These alterations include hyperkalaemia,
hyponatraemia and oedema. Hyperkalaemia can be the
result of both reduced renin and aldosterone secretion
by lowering PG generation in the macula densa and
angiotensin II sensitivity in the adrenal cortex respect-
ively. Hyperkalaemia can also be the result of NSAID-
related kidney damage, and the concurrent use of drugs
which can raise potassium plasma levels (ACEis, angio-
tensin II receptor 1 blockers, direct renin inhibitors and
potassium sparing diuretics). The magnitude of the rise
in plasma potassium ranges from less than half of a
millimole to more than a millimole per litre in elderly
people.70 No rise or a smaller increase can be observed
in healthy subjects. Less common is NSAID-induced
hypokalaemia. A few case reports have shown that ibu-
profen, at high doses, can induce renal tubular acidosis
with severe hypokalaemia and that its discontinuation
allows rapid recovery from hypokalaemia and hyper-
chloraemic acidosis.71 Both non-selective and COX-2
selective NSAIDs can also affect free water excretion
by facilitating antidiuretic hormone (ADH) activity
leading to hyponatraemia.16 When effective arterial
volume is reduced, such as in severe HF patients,
ADH levels are increased. Administering NSAIDs can
further increase ADH secretion and activity, and deter-
mine or worsen hyponatraemia in these patients.
Hyponatraemia can also be induced in patients with
cirrhosis and nephrotic syndrome or in those affected
by a syndrome of inappropriate ADH secretion.16,41
Hyponatraemia is a well-recognised complication of
thiazide diuretic treatment through mechanisms inter-
fering with maximal urinary dilution and stimulation of
ADH release. Concurrent therapy with NSAIDs can
facilitate its appearance.72 Both nonselective and
COX-2 selective NSAIDs can induce sodium retention
leading to oedema formation and diuretic resistance in
HF patients.16,34 They can also decompensate chronic
HF patients by diminishing diuretic efficacy, inducing
sodium and water retention: This leads to weight gain
and increased vascular resistance. All NSAIDs
bring about these effects; sulindac and low-dose acetyl-
salicylate induce a partial and transient inhibition of
renal PG synthesis, differently from the irreversible
858
inhibition of platelets by COX-1, and therefore no
or much less frequent kidney damage occurs with
these drugs.73
Non-selective and COX-2 selective
NSAID effects on cardiac function
Atrial fibrillation and cardiac arrest
Case-controls, randomised and observational cohort
studies and a meta-analysis have evaluated the effect
of COX-1 and COX-2 inhibition on atrial fibrillation
(AF) development and recurrence (Table 2).74–79 In a
case-control study of general practitioners in the UK a
significant increase in the risk of chronic but not par-
oxysmal AF, was reported in patients taking NSAIDs.
This risk was greater in long-term users, when treat-
ment duration was longer than one year and gradually
disappeared after NSAIDs withdrawal.74 A Danish
study showed that both non-selective NSAIDs and
COX-2 selective inhibitors users were respectively
associated with a 33% and a 50% higher risk of a
first episode of AF or atrial flutter as compared to
non-users. A higher risk was identified in the elderly
and in patients with chronic kidney disease or rheuma-
toid arthritis, particularly when they started treatment
with COX-2 inhibitors.75 In another study, new users
of non-selective NSAIDs were at increased risk of AF;
in particular, the risk doubled in HF patients. Instead,
patients exposed to selective COX-2 inhibitor did not
show a higher risk (except for those with chronic
kidney or pulmonary diseases).76 In contrast, a large
cohort population study from Sweden showed a stron-
ger association between selective COX-2 inhibitor use
and the incidence of AF, although a significant risk
was also observed for non-selective NSAIDs.77 The
incidence of AF was also more common in a nation-
wide cohort study from Denmark where patients with
MI were prescribed NSAIDs for long period but also
for short-term treatment (0–14 days).78 In a meta-ana-
lysis of five observational studies with 400,000 cases of
AF, NSAID users had a 12% higher risk of AF, rising
to 53% for new users. COX-2 inhibitors, including
diclofenac, were associated with major risk as com-
pared to non-selective NSAIDs.79 The mechanisms
linking AF development and NSAID use are unclear.
It has been hypothesised that renal COX-2 inhibition
can trigger a cascade of events including fluid reten-
tion, increased blood pressure, increased end-diastolic
pressure, all leading to AF. A role for atrial fibrosis is
also suggested but still under investigation.80 Serum
potassium level changes as well as the pro-arrhythmic
effects of concomitant drug use in polypharmacy-trea-
ted subjects might be additional and contributing
mechanisms. A recent report linked NSAID
European Journal of Preventive Cardiology 27(8)
consumption and cardiac arrest. A direct association
between ibuprofen and diclofenac use and the risk of
cardiac arrest has been observed in a case-time-control
study based on the Danish Cardiac Arrest Registry. In
patients, who experienced an out-of-hospital cardiac
arrest, NSAID exposure up to 30 days before cardiac
arrest was identified as a major risk factor. Ibuprofen
increased the risk of cardiac arrest by 31% and
diclofenac by 50%, whereas no significant association
was found with COX-2 selective inhibitors nor with
naproxen.81 These findings suggest that both non-
selective and COX-2 selective NSAID prescription
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may represent a potential risk factor for AF
occurrence.
Myocardial infarction
Following the development of COX-2 selective inhibi-
tors, several concerns regarding cardiovascular safety,
in particular atherothrombotic vascular events, have
been raised. The first observation came from the
Vioxx gastrointestinal outcomes research (VIGOR)
study where rheumatoid arthritis patients taking rofe-
coxib, despite presenting less upper gastrointestinal
bleeding, experienced an excess of vascular events
when compared to the group of patients treated with
naproxen.82 However, very few events were reported,
and the study was clearly too underpowered to permit
statistical evaluation of cardiovascular safety.82 After
this observation, various randomised controlled trials
(RCTs) and observational studies concerned the cardio-
vascular safety of COX-2 selective and COX-1 COX-2
non-selective NSAID drugs (Table 3). In 2004, rofe-
coxib was withdrawn from the market because of con-
cerns over an increased risk in MI and strokes
associated with a long-term (beginning after 18
months of continuous therapy in the Adenomatous
Polyp PRevention On Vioxx (APPROVe) study), and
a high-dose usage.83 Other evidence indicated an earlier
rise in MI risk, occurring within a week after the first
prescription of rofecoxib in patients with a previous his-
tory of MI.84,85 Interestingly, in contrast with other
NSAIDs, where the risk for MI was present only
during treatment, rofecoxib-related MI risk may have
continued for an undefined period after drug with-
drawal.85,86 The first meta-analysis of data derived
from RCTs reported an increased incidence of vascular
events for coxibs versus placebo (42% proportional
increased risk), caused mainly by increased MI occur-
rence. No differences arose between coxibs vs NSAIDs
(high dose ibuprofen or diclofenac), but high doses of
naproxen evidenced a safer profile.87 Another meta-
analysis of RCTs indicating comparable risk of vascular
events with coxibs and diclofenac or high dose ibupro-
fen confirmed the results.88 Interestingly, although the
Table 2. Association between non-steroidal anti-inflammatory drug (NSAID) use and atrial fibrillation in clinical studies.

First author and publi- Anti-inflammatory

cation year Study type drugs Number of patients Endpoint analysed Risk modification Comments
Cabassi et al.

74
De Caterina et al., Nested case control NSAIDs and SAIDs 1570 case patients Atrial fibrillation RR of 1.44 (95% CI No effect of previously
2010 study 1.08–1.91) for diagnosis of HF in
chronic atrial fibril- modifying RR for
lation atrial fibrillation in
RR was highest for the NSAIDs users.
use of NSAIDs for
more than 1 year
(RR 1.80; 95% CI
1.20–2.72).
75
Schmidt et al., 2011 Population-based con- NSAIDs and COX-2 2925 case patients Atrial fibrillation in Adjusted incident rate Higher risk for elderly
trol-study inhibitors current or past ratio for current and CKD patients.
users NSAID users 1.17
(95% CI 1.10–1.24)
Adjusted incident rate
ratio for current
COX-2 users 1.27
(1.20–1.34).
76
Chao et al., 2012 Nationwide case-con- NSAIDs and COX-2 7280 case patients Atrial fibrillation OR 1.651 for new COX-2 use increased
trol study inhibitors users atrial fibrillation risk
OR 1.920 for new only in CKD and
users HF patients pulmonary disease.
Non-significant risk
increase for COX-2
exposure.
77
Back et al., 2012 Nation-wide popula- COX-2 inhibitors 6,991,465 patients Cardiovascular events Adjusted HR 1.16 Borderline significance
tion-based study analysis (95% CI 1.046– for increase stroke
1.289 for atrial fib- risk (p ¼ 0.08) in
rillation in COX-2 Coxib exposed
inhibitors exposed patients.
patients.
78
Schjerning Olsen Nationwide adminis- NSAIDs and COX-2 7831 case patients Atrial fibrillation in Adjusted HR 1.29 Risk greater in short
et al., 2015 trative registry inhibitors post-myocardial (95% CI 1.14–1.45) term users (0 to 14
infarction patients for NSAIDs; HR days).
1.21 (95% CI 1.00–
1.55) for COX-2
inhibitor exposed
patients.
(continued)
859

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860 European Journal of Preventive Cardiology 27(8)

(high dose increased

new users (RR 1.53,

users (more than 30

95% CI 1.37–1.70).
relative risk of vascular events seemed to be similar irre-

risk); no increased
effect was evident
Highest risk among
spective of baseline patient characteristics, after excess

risk for remote

Dose dependency
risk calculation, the authors reported that in patients

days back).
with a low basal cardiovascular risk, the predicted abso-
Comments

lute risk of major vascular events was small, irrespective

of the drug used. In contrast, in patients with a baseline
at higher vascular risk, the absolute risk of developing a

CI: confidence interval; COX-2: cyclooxygenase-2; CV: cardiovascular; HF: heart failure; HR: hazard ratio; OR: odds ratio; RR: risk ratio; SAID: steroidal anti-inflammatory drug.
MI was higher when coxibs or high dose ibuprofen or
RR 1.12 (95% CI 1.06–

2.88) in 15–30 days

diclofenac were used.88 The differences in MI risk
1.76 (95% CI 1.07–
1.18) for atrial fib-

geneity among the

Multiple adjusted HR
moderate hetero-
rillation risk with

among NSAIDs were generally attributed to their

Risk modification

pharmacodynamics, in particular to the specific

COX-2 inhibition potency. A strict correlation between
studies.

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COX-2 activity inhibition in whole blood and relative
use.

risk of MI was found in NSAID users. When the drugs

used were grouped in high COX-2 inhibition (at least
90% – rofecoxib, diclofenac, indomethacin and piroxi-
cam) and low COX-2 inhibition (<90% – ibuprofen,
meloxicam, celecoxib and etoricoxib) a significant dif-
Endpoint analysed

Atrial fibrillation

Atrial fibrillation

ference in MI risk was found (60% increase in the

former vs 18% in the latter).89 Similarly, the MI risk
for ibuprofen was dose-dependent and related to the
degree of COX-2 inhibition. This study, confirmed
that naproxen is associated with a safer profile showing
no differences when compared to a non at-risk general
population. Overall, among COX-2 selective and non-
5 studies, more than
50 thousand case
Number of patients

selective NSAID users, an increased relative risk of MI

ranging from 30–40% should be taken into account,
8243 patients

although some distinctions need to be made. The

patient

higher the dose, the higher the risk, especially in patients

with pre-existent vascular or cardiac disease; in low car-
diovascular risk patients, the additional risk of low dose
NSAIDs is reasonably marginal and their use relatively
safer.89 Because patients commonly receive both acetyl-
salicylate and ACEis, concerns had already been raised
Anti-inflammatory

about 20 years ago about a putative counteraction

between these two drugs, reducing their beneficial
effects.90 In fact, ACEis increase bradykinin PGI2 and
NSAIDs

NSAIDs
drugs

PGE2, while acetylsalicylate and NSAIDs affect and

blunt relaxant PGs generation. An analysis of this
issue, which combined the data from large clinical
trials on ischemic heart disease patients, did not confirm
this interaction, that is patients benefitted from ACEi
follow-up study
Population-based

effects irrespective of concomitant acetylsalicylate ther-

apy.91 Interestingly too, a retrospective analysis of the
Metanalysis
Study type

Survival of Myocardial Infarction Long-term

Evaluation (SMILE-4) study showed that in hyperten-
sive patients, but not in normotensive ones with acute
MI complicated by left ventricular dysfunction, the
First author and publi-

combination of zofenopril and acetylsalicylate was

Table 2. Continued

Krijthe et al., 2014

superior in terms of preventing major cardiovascular

Liu et al., 2015

outcomes to that of ramipril and acetylsalicylate.92

This observation can reopen the debate about the con-
cation year

cept of class effect. This could suggest that zofenopril, a

sulfhydryl-containing ACEi, might have protective car-
diovascular effects through mechanisms that involve
79

80
Table 3. Association between non-steroidal anti-inflammatory drug (NSAID) use and myocardial infarction in clinical studies.

First author and publi- Anti-inflammatory

cation year Study type drugs Number of patients Endopoint analysed Risk modification Comments
Cabassi et al.

83
Bresalier et al., 2005 Randomised placebo Rofecoxib 2586 patients CV thrombotic Total thombotic events Small number of CV
controlled trial vents HR 1.92 (95% CI events, single
1.19–3.11) in rofecoxib molecule tested.
group. Cardiac events
HR 2.8 (95% CI
1.44–5.45).
84
Levesque et al., 2006 Population-based COX-2 inhibitors 113,927 patients 66 Myocardial Within first 5.8 days of Risk of myocardial
cohort study years or older infarction exposure to rofecoxib infarction decreased
HR 1.7 (95% CI over time for
1.26–2.31). No con- rofecoxib.
sistent data for
celecoxib.
85
Schjerning Olsen Nationwide study in NSAIDs 102,138 patients Death or re- Increased risk of death or Naproxen and short
et al., 2011 myocardial infarction re-infarction in NSAIDs term ibuprofen had
infarction exposed patients (HR the lower risk.
1.45 (95% CI
1.29–1.62) in the first 7
days. Higher risk in
7–14 days of treatment
(HR 1.68 95% CI
1.5–1.88).
86
Ross et al., 2010 Long-term follow-up Rofecoxib 1451 patients Retrospective with RR 2.97 (95% CI 1.2–7.32) Very low number of
of study 078 (cogni- intention to for cardiovascular events and not pre-
tive impairment) treat analysis thromboembolic specified endpoint.
events in rofecoxib
patients.
87
Kearney et al., 2006 Metanalysis 138 Randomised trials Vascular events and HR 1.86 (95% CI Insufficient data for
available on COX-2 myocardial 1.33–2.59) for myocar- determining a dose
inhibitors and infarction dial infarction in coxib- dependency.
NSAIDs exposed patients
versus placebo.
88
Bhala et al., 2013 Metanalysis 280 trials on COX-2 Major coronary Coxib associated to RR Naproxen lower risk
inhibitors and events (fatal and 1.76 (95% CI 1.31– for vascular events
NSAIDs non-fatal myo- 2.37) for myocardial compared to other
cardial infarction . Diclofenac NSAIDs and coxib.
infarction) RR 1.70 (1.19–2.41) for
myocardial infarction.
Ibuprofen RR 2.22
861

(1.10–4.48).
(continued)
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862 European Journal of Preventive Cardiology 27(8)

2 inhibition in vitro.
whole blood COX-
less PGs generation than does ramipril. Appropriate

Relationship between

diclofenac, ibupro-
Increased risk for

fen and rofecoxib

compared to low
relative risk and
and scaled studies are needed to define potential differ-

higher doses of
ences in cardiovascular protective effects within the
same class of ACEis.
Comments

doses.
Heart failure
Non-selective and COX-2 selective NSAIDs lead to
NSAIDS (RR 1.35 95%
MI for current user of

impaired sodium and water excretion, and increased

Overall increased risk of

vascular tone that contribute to an increased risk of

HF. Haemodynamic and renal effects of NSAIDs and
CI 1.23– 1.48).
Risk modification

coxibs can induce the development of new cases,

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worsen congestion and contribute to rehospitalization
of patients with pre-existing HF. Their continuous use
can also increase the risk of mortality.88 Treatment with
NSAIDs for one week doubles the probability of hos-
pital admission, particularly in the elderly. Higher risk
Endopoint analysed

was observed in patients with a previous HF diagnosis.

Non-fatal myocar-
dial infarction

Risk was greater with increasing doses and use of

long vs short half-life NSAIDs.93 In an interesting
meta-analysis of randomised control trial data invol-
ving subjects not affected by rheumatic disease, an asso-
ciation between NSAID use and HF was found without
differences between non-selective and COX-2 selective
drugs.94 In a nested case-control study including sub-
Myocardial infarction
Number of patients

jects from health-care databases from four European

countries (Germany, Italy, Netherland and UK) it
CI: confidence interval; COX-2: cyclooxygenase-2; CV: cardiovascular; HR: hazard ratio; RR: risk ratio.
case 8852

was confirmed that NSAID users (in the preceding 14

days) had a 19% increased relative risk of a first HF-
related hospital admission compared to past users, and
that this risk was directly proportional to the NSAID
dosage.95 In the same study, patients with or without a
previous history of cardiac disease showed a similar
NSAIDs and COX-2

excessive risk of HF development as age increased.95

Anti-inflammatory

From the pathophysiological point of view, NSAID

inhibitors

use may antagonise the positive effects of renin-angio-

tensin blockade on vascular tone (ACE-I, angiotensin
drugs

II receptor 1 antagonists), minimising the effects of

diuretics on volume congestion in HF patients. In par-
ticular, renal COX-2 inhibition seems to be of major
nested case-control

importance in inducing vasoconstriction, antidiuresis

and antinatriuresis in both animal models of HF and
Data from THIN

in humans.16 Ahmetaj-Shala et al. reported that COX-2

gene deletion in mice, as well as treatment with cele-
Study type

coxib or naproxen in humans, resulted in increased cir-

study

culating levels of asymmetric dimethyl arginine

(ADMA), an endogenous competitive inhibitor of
endothelial nitric oxide synthase, which could explain
First author and publi-

reduced nitric oxide generation and contribution to

Table 3. Continued

Garcı́a Rodrı́guez

increased peripheral vascular resistance, salt and

water retention.96 In a large observational study of
et al., 2008

pre-existing HF patients, a dose-dependent rise in mor-

cation year

tality (ranging from 70 to 108% compared to untreated

patients) was reported for COX-2 selective drugs (such
as celecoxib, rofecoxib and diclofenac) whereas only
89
Cabassi et al.
high, but not low doses, of naproxen and ibuprofen
were associated with a significant increase risk of
death (from 22% to 31% vs untreated patients).93
However, in the PRECISION trial, celecoxib, at mod-
erate doses (200 mg per day for most patients), was not
associated with a higher cardiovascular risk (including
hospitalisation for HF) when compared to non-selec-
tive NSAIDs, naproxen and ibuprofen.61 Even in the
subgroup of patients with pre-existing cardiac disease
treated with low-dose acetylsalicylate, there were no
statistically significant differences among moderate
doses of celecoxib and the non-selective NSAIDs.97
Overall, the evidence available indicates that COX-2
selective as well as non-selective NSAIDs should be
avoided in patients with an elevated risk of cardiovas-
cular disease and in those with established cardiovascu-
lar disease. In all cases, short periods of treatment and
low doses should be used.
Pharmacological and non-pharmacological
alternative therapies to NSAIDs
The weak COX-2 inhibitor acetaminophen is recom-
mended as initial and useful therapy for osteoarthritic
pain even though long-term therapy with high doses
(up to 4 g in the general population or 3 g in elderly
patients) may lead to hepatic toxicity. Moreover,
high-dose acetaminophen should not be used in com-
bination with acetylsalicylate which, through glutathi-
one depletion in the kidney cortex and papilla, may
favour acetaminophen-induced nephrotoxicity.98
Some patients report improvement in pain with dietary
supplements such as glucosamine/chondroitin, but in
controlled trials glucosamine treatment did not confirm
significant improvement in pain or function.99 Intra-
articular corticosteroid and hyaluronic acid treatment
proved to be superior to NSAID treatment in knee
osteoarthritis.100 Acupuncture, therapeutic ultrasound
and manual manipulation seem to exert moderate pain
reduction especially in osteoarthritis; topical diclofenac
or ketoprophen gel and capsaicin (by reducing nocicep-
tive pain signals to the central nervous system) have
shown relative efficacy in several placebo-controlled
trials.101 A number of medicinal plants such as Arnica
montana, Boswella serrata, Curcuma longa and
Harpagophytum procumbens have been shown to signifi-
cantly improve pain and functionality in subjects with
knee and hip osteoarthritis.102 Upgrade of treatment to
weak opioids (tramadol and codeine) alone or in com-
bination with acetaminophen or even more powerful
opioids such as fentanyl or hydrocodone may be an
effective option although risk of addiction has become
a worldwide problem in western countries.103
Metamizole/dipyrone (available in Germany, Italy,
863
Portugal, Spain and Hungary) would appear to be
less toxic than NSAIDs, although a few countries
have banned the drug because of a risk of agranulo-
cytosis.104,105 In 2013, the European League Against
Rheumatism (EULAR) recommended that all patients
with osteoarticular degenerative conditions should be
offered an individualised management plan to maintain
physical activity which includes an exercise program
with aerobic and muscle-strengthening exercises,
advice on weight loss if necessary, and physiotherapy
programmes.106
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Conclusions
The widespread use of prescribed and self-prescribed
NSAIDs may lead to deleterious renal and cardiovas-
cular effects. Through multiple mechanisms related to
PG inhibition, NSAIDs may increase blood pressure
and blunt the effects of anti-hypertensive drugs,
namely ACEis, angiotensin II receptor 1 blockers and
thiazide diuretics.62,63,107 Due to their potential cardio-
vascular toxicity, patients with pre-existing vascular or
cardiac disease should avoid NSAID use, especially 3–6
months after an acute event. Hepatic and renal diseases
frequently encountered in elderly patients can alter
NSAID pharmacokinetics and pharmacodynamics,
thus predisposing them to an increased risk of toxic
effects. In particular, elderly patients with prior
impaired renal function are at greater risk of develop-
ing a wide spectrum of renal dysfunctions. Overall,
these previous conditions point to NSAIDs as a leading
cause of hospitalization, especially in the elderly.9 The
need to use the lowest effective dose for a short period
of time has been emphasised by both the US Food and
Drug Administration and the European Medicines
Agency with regard to NSAID-related thrombotic
risk.108,109 We are aware that successful restriction of
their use is arduous. Lifestyle modifications are of over-
whelming importance in patients affected by osteoarth-
ritis and rheumatic disease to maintain cardiovascular
health and reduce cardiovascular risk.110 These changes
not only limit NSAID use but also provide a holistic
approach, enabling patients to manage cartilage degen-
eration pain, reduce inflammation and prevent the dele-
terious effects of a sedentary lifestyle. However, when
NSAIDs use remains unavoidable, therapy with the
least toxic drugs (naproxen when there is no concern
about gastro-duodenal toxicity, as well as moderate
doses of celecoxib or, alternatively, acetaminophen up
to 3 g/day or low-dose ibuprofen) should be
chosen.6,89,111 Careful identification of frail at-risk indi-
viduals (e.g. older, HF and chronic renal failure
patients) together with close monitoring of side effects
(namely cardiovascular and renal) are mandatory.
864
Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with
respect to the research, authorship and/or publication of this
article.
Funding
The author(s) received no financial support for the research,
authorship and/or publication of this article.
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