The Cardiovascular Pharmacology of
COX-2 Inhibition
Susanne Fries and Tilo Grosser
Selective inhibitors of cyclooxygenase (COX)-2, the
coxibs, were developed to inhibit inflammatory
prostaglandins derived from COX-2, while sparing
gastroprotective prostaglandins primarily formed by
COX-1. However, COX-2-derived prostaglandins
mediate not only pain and inflammation but also affect
vascular function, the regulation of hemostasis/
thrombosis, and blood pressure control. All coxibs
depress COX-2-dependent prostacyclin (PGI2) biosyn-
thesis without effective suppression of platelet COX-1-
derived thromboxane (Tx) A2, unlike aspirin or tradi-
tional nonsteroidal anti-inflammatory drugs, which
inhibit both COX-1 and COX-2. The actions of PGI2
Traditional nonsteroidal anti-inflammatory drugs (tNSAIDs)
and selective inhibitors of COX-2, the coxibs, are a chemi-
cally heterogeneous group of compounds, characterized
by varying degrees of anti-inflammatory, analgesic and
antipyretic activity. Their unifying therapeutic effect is the
inhibition of prostaglandin (PG) biosynthesis. PGs are lipid
mediators formed from arachidonic acid by the PG G/H
synthases 1 and 2, commonly termed cyclooxygenases
(COX). Recruitment of leukocytes and induction of COX-2
expression by inflammatory stimuli account for the high
levels of PGs found in inflammatory lesions. PGE2, which
sensitizes nociceptors, prostacyclin (PGI2) and perhaps
thromboxane (Tx) A2 mediate pain and inflammation.1 Both
PGI2 and PGE2 contribute to the vasodilation at sites of
injury. In addition to such peripheral mechanisms, COX-1
and COX-2 products modulate nociception centrally.
tNSAIDs such as ibuprofen, naproxen or indomethacin in-
hibit both COX isoforms reversibly. Aspirin is distinct, as it
blocks the COXs irreversibly, which explains the cardio-
protective effect of low-dose aspirin; it inactivates platelet
COX-1 irreversibly and new platelets have to be formed to
restore function.
Correspondence: Tilo Grosser, MD, Institute for Translational
Medicine and Therapeutics, University of Pennsylvania School
of Medicine, 809 Biomedical Research Building, 421 Curie
Blvd., Philadelphia, PA 19104-6084; Phone (215) 573 7600, Fax
(215) 573 9004, tilo@spirit.gcrc.upenn.edu
Acknowledgements: Supported by grants from the American
Heart Association (S.F.: Pennsylvania-Delaware Affiliate
Postdoctoral Fellowship; T.G.: Scientist Development Grant
0430148N).
Hematology 2005
oppose mediators, which stimulate platelets, elevate
blood pressure, and accelerate atherogenesis,
including TxA2. Indeed, structurally distinct inhibitors
of COX-2 have increased the likelihood of hyperten-
sion, myocardial infarction and stroke in controlled
clinical trials. The detection of these events in patients
is related to the duration of exposure and to their
baseline risk of cardiovascular disease. Thus, coxibs
should be withheld from patients with preexisting
cardiovascular risk factors, and exposed patients at
low cardiovascular baseline risk should be monitored
for changes in their risk factor profile, such as in-
creases in arterial blood pressure.
The discovery of the second, rapidly inducible COX
isoform in the early 1990s afforded an opportunity to sup-
press PG formation in a more targeted fashion by designing
inhibitors with higher affinity for COX-2 than for COX-1,
the coxibs. The underlying hypothesis—sometimes referred
to as the ‘COX-2 hypothesis’—was that inflammatory pros-
taglandins are primarily derived from COX-2, while pros-
taglandins formed by COX-1 have generally homeostatic
roles, including the protection of the gastrointestinal mu-
cosa. Thus, selective inhibitors of COX-2 were expected to
be as efficacious as non-selective tNSAIDs and cause less
serious gastrointestinal side effects, which are attributed to
inhibition of COX-1. Although biological reality turned
out to be more complex—COX-2 has also important physi-
ological functions in the absence of inflammation2 and
COX-1 plays also a role in nociception3—all coxibs were
indeed shown to cause less gastroduodenal ulcerations than
comparator tNSAIDs, as visualized by endoscopy. 2
Celecoxib (Celebrex, Pfizer) and rofecoxib (Vioxx, Merck)
were approved by the FDA in 1999, valdecoxib (Bextra,
Pfizer) in 2001. Other compounds (etoricoxib/Arcoxia,
Merck; lumiracoxib/Prexige, Novartis; parecoxib/Dynastat,
Pfizer) are pending approval. Boosted by the attraction of
the ‘COX-2 hypothesis’—and by aggressive marketing cam-
paigns—the coxibs achieved sales of about $9 billion by
the time of the withdrawal of rofecoxib in September 2004.
Interestingly, the majority of patients prescribed with a coxib
were not at particularly high risk for serious tNSAID re-
lated gastrointestinal complications and the incidence of
uncomplicated gastric upset on a coxib turned out to be no
different from that of tNSAIDs. Only three randomized, con-
trolled outcome trials have studied whether the coxibs ac-
tually reduce the incidence of serious gastrointestinal com-
plications in larger populations. The Vioxx Gastrointesti-
445
nal Outcomes Research (VIGOR) Study and the Therapeu-
tic Arthritis Research and Gastrointestinal Event Trial
(TARGET) have shown that rofecoxib and lumiracoxib,
cause less serious gastrointestinal adverse events than non-
isoform selective tNSAIDs.4,5 The trial studying the oldest
marketed COX-2 inhibitor, the Celecoxib Long-term Ar-
thritis Safety Study (CLASS) study,6 failed to support the
hypothesis, as its gastrointestinal endpoint did not differ-
entiate this coxib from the comparator tNSAIDs.6 Never-
theless, celecoxib became the best selling coxib and, in-
deed, remains the only such drug on the market.
While no randomized controlled outcome trial of a
coxib has sought to demonstrate superiority of pain relief
over comparator tNSAIDs, some patients report a unique
quality of pain relief by COX-2 inhibitors, which they had
not experienced on tNSAIDs. It has been long recognized,
but never systematically studied, that the clinical response
to a particular tNSAID—or its toxicity—may vary substan-
tially from patient to patient. Interestingly, the pharmaco-
logical response within the group of selective COX-2 in-
hibitors is similarly variable,7 and detailed analyses of fac-
tors that condition such diverse responses may lead to a
more individualized therapy with both, tNSAIDs and
coxibs.7
Concurrent with the clinical development of the
coxibs, it was recognized that—in contrast to the initial
hypothesis—COX-2-derived prostaglandins mediate not
only pain and inflammation, but also affect vascular func-
tion, thrombosis and blood pressure.8,9 Thus, COX-2 in-
hibitors depress the vascular biosynthesis of PGI2, leaving
platelet COX-1-derived TxA2 unaffected—in contrast to
tNSAIDs or aspirin, which inhibit both COX-1 and COX-
2.8,9 The actions of PGI2 oppose all mediators that stimulate
Figure 1. The cyclooxygenase (COX)-1 and -2 pathway. Prostaglandins
(PG) are formed by specific isomerases from the COX product PGH2. They act
through G protein transmembrane receptors.
Abbreviations: IP, prostacyclin receptor; TP, thromboxane receptor; DP, PGD2
receptor, EP, PGE2 receptor, FP, PGF2α receptor.
446
platelets, elevate blood pressure, and accelerate atherogen-
esis, including TxA2.10-12 Thus, drug selectivity for inhibi-
tion of COX-2 may increase the likelihood of hyperten-
sion, myocardial infarction and stroke.1 Three structurally
distinct compounds, rofecoxib, valdecoxib, and celecoxib,
have increased the incidence of these cardiovascular com-
plications significantly in controlled trials,4,13-15 suggest-
ing that the entire class of COX-2 inhibitors confers a car-
diovascular hazard. Rofecoxib and valdecoxib have been
withdrawn from the market. This paper reviews the phar-
macology of COX inhibition, discusses mechanisms by
which coxibs may promote thrombosis, atherosclerosis and
hypertension, summarizes results of clinical trials that de-
tected a cardiovascular risk and provides perspective on
how this may inform clinical decisions regarding coxib
and tNSAID use.
Pharmacology of COX Inhibition
Arachidonic acid, released from cell membranes by the ac-
tivity of phospholipases, is the main COX substrate. Both,
COX-1 and COX-2 synthesize PGH2, a labile intermediate
that is further metabolized by downstream isomerases to
form the prostaglandins, PGE2, PGF2α, PGD2, PGI2 and TxA2
(Figure 1), which activate specific transmembrane recep-
tors coupled to G proteins. COX-1 is expressed constitu-
tively in most tissues. It is the only form of the enzyme in
mature platelets and is expressed in vascular endothelium,
gastrointestinal epithelium, spinal cord, brain and kidney,
amongst other tissues. COX-2 is highly inducible by
cytokines, tumor promoters and mitogens. In addition to
its role in prostaglandin formation in inflammation it has
been implicated in carcinogenesis. The strict distinction
between ‘inducible’ and ‘constitutive’ forms of the enzyme,
however, is an oversimplification;2 COX-2 is
constitutively expressed in several tissues,
such as spinal cord, brain, kidney and COX-1
can be upregulated to a certain degree in in-
flammation. COX-2 is also induced in vascu-
lar endothelium under physiological condi-
tions of flow16 and both isoforms both are de-
velopmentally regulated.17
While COX-1 and COX-2 are structurally
similar, the substrate-binding channel of COX-
2 contains a side pocket, which is absent in
COX-1. This allowed for the design of inhibi-
tors with side chains that fit within the COX-2
channel, but are too large to block COX-1 with
equally high affinity. Thus, the ratio of the
affinities to COX-1 and COX-2 determines
how ‘selective’ a compound is and represents
a continuous, rather than a discrete, variable.
The second generation coxibs, etoricoxib and
lumiracoxib, were developed to be more se-
lective for COX-2 than rofecoxib and
valdecoxib, which are roughly similar in their
degree of selectivity but more selective than
American Society of Hematology
celecoxib (Figure 2).2 In human studies, the degree of COX-
2 selectivity is commonly determined by whole blood as-
says that measure the ratio of COX-1 and COX-2 inhibition
ex vivo.18 As ‘selectivity’ is conditioned by differences in
the affinity to the COX isoforms, the concentration of the
compound has an effect on ‘selectivity.’ Thus, high drug
concentrations will also inhibit COX-1 to a certain degree
and very high, supratherapeutic concentrations may not be
COX-2 selective at all. Thus ‘selectivity’ achieved in hu-
mans is not a purely structural property of a compounds
but may also be influenced by pharmacokinetic (e.g.,
plasma concentration) and pharmacodynamic factors (e.g.,
genetic variations of the target enzymes).7 tNSAIDs can
also be ranked on the selectivity scale using the same crite-
ria. Naproxen or ibuprofen are slightly more potent inhibi-
tors of COX-1 than of COX-2, while the degrees of selectiv-
ity of diclofenac, nimesulide and meloxicam are—perhaps
surprisingly—comparable to that of celecoxib.2 One would
expect that these characteristics relate to the safety profile
of both tNSAIDs and coxibs. For example, the similarity of
diclofenac and celecoxib may be one reason why the CLASS
trial failed to detected difference in the gastrointestinal
endpoint between the groups.6 Very little information ex-
ists about the cardiovascular safety of tNSAIDs 19 and pro-
spective, placebo-controlled outcome studies have not
been performed.
Impact of COX Inhibition on Thrombogenesis,
Atherogenesis and Blood Pressure Regulation
Products of the COX pathway have established relevance
in clinical syndromes of vascular occlusion. Thus, aspirin
reduces the secondary incidence of myocardial infarction,
stroke and important vascular events by roughly 25%.20
Suppression of the major product of platelet COX-1, TxA2,
which is a potent platelet activator, vasoconstrictor, and
mitogen,21 is the basis of cardioprotection by aspirin. TXA2
biosynthesis is increased in conditions of acute or chronic
platelet activation, such as coronary thrombosis and dia-
betes, and augmented TxA2 biosynthesis has been linked
to the risk of future events.22 Low-dose aspirin suppresses
platelet TxA2 formation by acetylation of a serine residue
within the substrate binding channel of COX-1 obstructing
access of arachidonic acid to the active site. This modifica-
tion results in the irreversible inhibition of platelet func-
tion, due to the limited capacity of the anucleate platelets
to form new proteins. tNSAIDs other than aspirin attain
maximal inhibition of platelet COX-1 only transiently dur-
ing the dosing interval, due to their reversible interaction
with the enzyme. Thus, tNSAIDs are not cardioprotective.
COX-2 is not expressed in mature platelets, although small
quantities of COX-2 protein are detectable in immature
platelet forms.23,24 Thus, the coxibs depress platelet TxA2
formation only marginally at high concentrations and have
no effect on platelet function.8,9
The possibility that selective inhibitors of COX-2 may
increase cardiovascular risk was raised in 1999 based on
Hematology 2005
observations that both rofecoxib and celecoxib reduced
PGI2 formation in healthy individuals by about 70% with-
out concurrent inhibition of platelet function.8,9 Biosyn-
thesis of prostacyclin, a potent inhibitor of platelet aggre-
gation, is increased in syndromes of platelet activation,
such as severe atherosclerosis and unstable angina prob-
ably as a homeostatic response to accelerated platelet-vas-
cular interactions.10 Thus, deletion of the PGI2 receptor (IP)
in mice augmented the cardiovascular effects of TxA2 in
vivo.10 The mice responded with an exaggerated formation
of TxA2 to vascular injury followed by more pronounced
neointimal proliferation (Figure 3). Both responses were
reverted by simultaneous deletion of the TxA2 receptor
(TP).10 Thus, depression of COX-2 dependent PGI2 biosyn-
thesis, without concomitant inhibition of platelet function
provides a mechanism for a prothrombotic effect of COX-2
inhibitors. However, the impact of PGI2 depression on throm-
botic events would be expected to pertain only when the
baseline risk of thrombosis is augmented, as mice deficient
in the prostacyclin receptor do not develop thrombosis
spontaneously.
Depression of COX-2-derived PGI2 formation may also
impact atherosclerotic plaque development, as deletion of
the IP accelerates the initiation and early development of
atherosclerosis in mice (Figure 3).12,25 In this context, PGI2
acts to limit the interactions of platelets and leukocytes
with the vasculature and the attendant oxidant stress.12,25
Deletion of the IP increases the biosynthesis of TxA2 in
Figure 2. The degrees of cyclooxygenase (COX)-selectivity
of various traditional non-steroidal anti-infammatory
drugs (tNSAIDs) and coxibs (open circles). The
concentrations required to inhibit COX-1 and COX-2 by 50%
(IC50) have been measured using whole blood assays of COX-1
and COX-2 activity in vitro.18 The line indicates equivalent COX-1
and COX-2 inhibition. Drugs plotted below the line are more
potent inhibitors of COX-2 than drugs plotted above the line. The
distance to the line is a measure of selectivity. Lumiracoxib is
the compound with the highest degree of selectivity for COX-2
as its distance to the line is the largest. Celecoxib and diclofenac
have similar degrees of COX-2 selectivity, as their distances to
the line are similar; however, diclofenac is active at lower
concentrations and, thus, located more to the left. (Updated
from FitzGerald GA, Patrono C. The coxibs, selective inhibitors
of cyclooxygenase-2. N Engl J Med. 2001;345:433-442.)
447
 that an increasing degree of selectivity for
COX-2 may proportionately accelerate pro-
gression of atherogenesis.
The elevation of blood pressure by the
COX-inhibitors is a more indirect mechanism
by which they may accelerate atherogenesis
and increase cardiovascular risk. It is well rec-
ognized that tNSAIDs and coxibs can induce
sodium retention, edema and hypertension.29,30
Figure 3. The impact of deletion of the prostacyclin receptor on the However, it remains unclear whether the coxibs
thrombotic (left panel) and proliferative (right panel) response to differ from tNSAIDs in their effects on blood
catheter-induced carotid vascular injury in mice. The endothelium of the pressure regulation. Very little data exist on
common carotid artery was denuded in this model using a fine wire. This
activates platelets, as reflected by an enhanced biosynthesis of thromboxane the relative roles of COX isoforms in the hu-
(Tx) A2 (left panel), and causes neointimal formation, which can be quantified man kidney. Some information, however, can
on histological crossections two weeks after the procedure (right panel). The be derived from experiments in mice. Interest-
procedure-related platelet activation and thromboxane biosynthesis, as ingly, these show—just like in the case of
reflected by urinary excretion of its metabolite 2,3 dinor TxB2, was augmented
in mice deficient for the prostacyclin receptor (IP). Deletion of the atherogenesis—that COX-1 and COX-2 may
thromboxane receptor (TP) reduced the procedure-related increment in have opposing functions in the kidney.11 In
thromboxane biosynthesis. Simultaneous deletion of both receptors (IPTP) mice, COX-1 products, likely TxA2 and per-
compensated for the effects of the individual receptors. haps PGF2α, contribute to blood pressure ho-
Redrawn with permission from Cheng Y, Austin SC, Rocca B, et al. Role of
prostacyclin in the cardiovascular response to thromboxane A2. Science. meostasis by the renin angiontensin system
2002; 296(5567):539-541. and increase blood pressure.31 Conversely, the
vasodilator COX-2 products, PGI2 and PGE2,
increase renal medullary blood flow, which
hypercholesterolemic mice, as an index of increased plate- drives pressure natriuresis and diuresis.29 COX-2 inhibition,
let activation in vivo.25 Platelet activation contributes to just like nonselective COX-inhibition, reduces acutely
atherogenesis and suppression of TxA2 activity retards medullary blood flow, sodium excretion and urine vol-
atherogenesis (Figure 4).12,26,27 These observations suggest ume.11 However, this results only in a hypertensive response
that COX-1-derived TxA2 and COX-2-derived PGI2 may have when the autoregulatory mechanisms are already otherwise
opposing activities in atherogenesis,12,28 although this has stressed.11,32 In humans, hypertensive responses to COX in-
not yet been addressed directly in humans. This implies hibition tend to occur when predisposing conditions exist,
such as excessive salt intake, preexisting hypertension,
heart disease and diabetes, or depletion of the effective
circulating volume. This is consistent with clinical obser-
vations in young and healthy individuals, in which both
nonselective COX inhibition and selective COX-2 inhibi-
tion have no effects on arterial pressure despite transient
changes in sodium handling and glomerular filtration rate
on initiation of dosing.33 The latter may be caused by the
inhibition of dilator prostanoids that contribute to the pa-
tency of afferent arterioles and by a reduction of COX-2
dependent, cortical PGE2 formation, a component of the
tubuloglomerular feedback mechanism.31,34 Thus, given the
role of COX-1 in elevating blood pressure, one would ex-
pect that the degree of selectivity of COX-2 inhibition could
affect blood pressure control in susceptible individuals.
Indeed, a recent meta-analysis of approximately 45,000
Figure 4. Quantification of atherosclerotic lesions area patients in 19 clinical trials suggests that selective inhibi-
in aortas of wildtype (+/+), TP deficient (TP-/-) and IP tion of COX-2 elevates blood pressure more than non-se-
deficient (IP -/-) mice on an apoE deficient background at
20 weeks of age. TP deficiency retarded and IP deficiency
lective inhibition.30
accelerated atherogenesis, suggesting that these mediators
have opposing roles in atherosclerotic lesion development. Data Detection of a Cardiovascular Risk of the Coxibs
are means ± SEM (n = 5 each). Epidemiological approaches and clinical trials have rela-
(Redrawn with permission from Kobayashi T, Tahara Y,
Matsumoto M, et al. Roles of thromboxane A2 and prostacyclin
tively poor precision for the detection of uncommon but
in the development of atherosclerosis in apoE-deficient mice. J serious adverse effects, such as clinical events that are preva-
Clin Invest. 2004;114(6):784-94.) lent in the relevant populations. The first clinical evidence

448 American Society of Hematology

of a cardiovascular hazard of the coxibs arose when a 5-
fold higher incidence of myocardial infarction was observed
in the rofecoxib group as compared to the naproxen com-
parator group of the VIGOR study, the prospective trial
designed to assess rofecoxib’s gastrointestinal safety.4 Ap-
proximately 8000 rheumatoid arthritis patients were treated
either with rofecoxib or naproxen with a median follow-up
of 9 months. The gastrointestinal event rate was reduced
from 4.5 to 2.1 per 100 patient-years by rofecoxib. The
study population would probably be considered medium
cardiovascular risk at baseline—with chronic rheumatoid
inflammation as an independent risk factor. Two explana-
tions for the adverse cardiovascular outcome were discussed
at the time—aside from the possibility that this was due to
chance:2 (i) a reduction of the cardiovascular event rate in
the control group by a cardioprotective effect of naproxen;
and/or (ii) a cardiovascular hazard of rofecoxib. Naproxen,
unlike other tNSAIDs, has a long elimination half-life and
causes an extended inhibition of platelet function and
might provide some degree of cardioprotection.2 However,
the substantial interindividual variability of its activity
suggests that much fewer patients would benefit from
naproxen than from aspirin.35 This is consistent with obser-
vational studies that detected a small cardioprotective ben-
efit from naproxen—approximately half that of aspirin.36
While the absolute number of cardiovascular events in
VIGOR was too small to estimate accurately the size of the
effect, the potential cardioprotective effect of naproxen
alone is unlikely to account for the 5-fold difference be-
tween the groups. It seems more plausible that this coin-
cided with a cardiovascular hazard of rofecoxib. In contrast
to rofecoxib, no excess cardiovascular risk was initially
associated with celecoxib therapy in its gastrointestinal
safety study, the CLASS trial.6 However, in this study the
use of low-dose aspirin was allowed and one of the tNSAID
comparators was diclofenac, which is similar to celecoxib
in its degree of COX-2 selectivity. Additionally, the patient
population in the CLASS trial was probably at lower
baseline risk for cardiovascular events as compared to the
VIGOR trial. The third large gastrointestinal safety study,
the TARGET trial, assessed also the cardiovascular safety
profile of lumiracoxib in comparison to ibuprofen and
naproxen in approximately 18,000 osteoarthritis patients,
of which a quarter took also low-dose aspirin. An impor-
tant finding of this study was that the favorable gastrointes-
tinal safety profile of the COX-2 inhibitor was offset by
concurrent low-dose aspirin therapy and the advantage over
a tNSAID was lost.5 Lumiracoxib was not associated with a
statistically significant increase in cardiovascular risk in
this population of apparently low baseline risk exposed for
only 12 months.37
The trial that led to the withdrawal of rofecoxib—the
Adenomatous Polyp Prevention on Vioxx (APPROVe) study,
a placebo controlled cancer prevention trial of approxi-
mately 2600 patients—detected the cardiovascular risk
only after a much longer time of drug exposure.13 It was
Hematology 2005
stopped at 36 months of treatment when a twofold increase
in the cardiovascular event rate (rofecoxib: 1.5% vs pla-
cebo: 0.78%) was noticed. This suggests that a small mi-
nority of the patients, apparently of initial low risk of car-
diovascular disease, might have proceeded to increase that
risk to a point that culminated in clinical events. A similar
pattern, again, implying a time-dependent change of car-
diovascular risk, was observed in a long-term cancer pre-
vention trials of celecoxib in patients of initially low ap-
parent cardiovascular risk. The Adenoma Prevention with
Celecoxib (APC) study detected a dose-dependent increase
in the cardiovascular event rate (placebo, 1%; celecoxib
200 mg/bid, 2.3%; celecoxib 400 mg/bid, 3.4%) in a study
population of 2035 patients after 36 months of exposure.14
An unpublished, smaller trial (“preSAP Trial”) that included
approximately 1500 adenoma patients receiving a single
daily dose of 400 mg celecoxib has shown a non-signifi-
cant increase in cardiovascular events (placebo: 0.91% vs
celecoxib: 1.23%; FDA Advisory Committee Meeting,
Gaithersburg, Maryland, February 16–18, 2005). This may
relate to the difference in dosing (once daily vs twice daily
in the APC study) and to the lower power of the preSAP
trial.
The cardiovascular signal was detected very early in
two postoperative pain management trials of high risk pa-
tients, referred to as ‘CABG-1’ and ‘CABG-2.’15, 38 Patients
undergoing coronary bypass surgery were initially treated
intravenously with the prodrug of valdecoxib, parecoxib,
or placebo and then switched to oral valdecoxib or pla-
cebo. The majority of cardiovascular events occurred
within days of treatment initiation in these populations,
who were subject to intense hemostatic activation after
bypass surgery. The outcomes of the CABG studies are com-
patible with a prothrombotic effect of the coxibs in situa-
tions of elevated thrombotic risk. In summary, the com-
bined clinical experience of trials that detected cardiovas-
cular complications attributable to the coxibs suggests that
the emergence of events relates to baseline cardiovascular
risk and to the duration of drug exposure, which accords
remarkably with the biological observations discussed
above.
Conclusions and Future Directions
The distinct roles of the COX isoforms in platelet function,
atherogenesis and blood pressure control provide a uni-
tary, plausible mechanism—depression of vascular PGI2
biosynthesis—by which selective inhibition of COX-2 may
increase the likelihood of myocardial infarction and stroke
in at-risk patients and in patients who are exposed for ex-
tended periods of time. Mouse biology, human pharmacol-
ogy, and clinical evidence suggest that the cardiovascular
hazard pertains to all coxibs. However, it seems likely that
differences in the degree of selectivity attained by various
drugs may translate into quantitative differences in clini-
cal outcomes. Both the US Food and Drug Administration
(FDA) and the European Agency for the Evaluation of
449
Medicinal Products (EMEA) concluded that rofecoxib,
valdecoxib and celecoxib conveyed a small (1%–2%), but
absolute risk of cardiovascular adverse events. Rofecoxib
and valdecoxib have been withdrawn from the market in
the US and Europe. The FDA applied a “black box” warn-
ing to celecoxib, which remains on the market, and the
EMEA imposed restrictions on celecoxib (and on etori-
coxib, which is on the market in some European countries),
and it is possible that new coxibs will be introduced to the
market probably with similar restrictions.
What role, then, can the coxibs play in the treatment of
chronic inflammatory conditions in the future?
i. They should be reserved for patients who are most
likely to benefit from them, for example those who
develop gastrointestinal complications on tNSAIDs in
combination with a gastroprotective medication, such
as a proton pump inhibitor. The dilemma is that the
only drug presently on the US market, celecoxib, has
not convincingly demonstrated a gastrointestinal ben-
efit in its outcome trial even if this may relate in part to
a suboptimal study design.6
ii. Coxibs should be avoided when patients have preex-
isting risk factors for cardiovascular events.
iii. The cardiovascular roles of the COX products affected
by the coxibs are not meant to be viewed as an imbal-
ance of PGI2 and TxA2, which might imply that sup-
pression of TxA2 by low-dose aspirin would be com-
pletely protective against a cardiovascular hazard. PGI2
acts as a constraint on the biological activity of all
agonists, which stimulate platelets, elevate blood pres-
sure, and accelerate atherogenesis, of which TxA2 is
only one mediator. Thus, low dose aspirin would be
expected to attenuate, rather than abolish the cardio-
vascular hazard deriving from selective inhibition of
COX-2.
iv. We know very little about the cardiovascular safety
profile of individual tNSAIDs. The FDA applied a
“black box” warning of potential cardiovascular risks
also to all tNSAIDs, while the EMEA concluded that
there was no evidence to prompt a change in their ad-
vice about tNSAIDs. Clearly, prospective studies are
warranted to determine if patients are at elevated car-
diovascular risk with long-term use of specific
tNSAIDs. Pharmacologic studies have already found
that ibuprofen and naproxen can undermine the anti-
platelet effectiveness of low-dose aspirin, but not
diclofenac.39,40 This indicates that tNSAIDs are not a
homogenous group of compounds and it is likely that
differences in their cardiovascular safety profiles will
be revealed, just like the differences in their gastrointes-
tinal safety profiles.
v. Finally, as we move towards an individualization of
therapy, we should identify paradigms within which
these useful drugs can be administered safely for ex-
tended periods in individuals at low cardiovascular
risk. The detectable variability between individuals
450
in their response to the coxibs7 and the existence of
clinical conditions that can modulate the response may
be exploited to identify the small number of patients
at emerging cardiovascular risk. Regular monitoring
of risk factors during the treatment, including frequent
blood pressure measurement, is a first step.
References
1. FitzGerald GA. COX-2 and beyond: approaches to prostag-
landin inhibition in human disease. Nat Rev Drug Discov.
2003;2:879-890.
2. FitzGerald GA, Patrono C. The coxibs, selective inhibitors of
cyclooxygenase-2. N Engl J Med. 2001;345:433-442.
3. Ballou LR, Botting RM, Goorha S, Zhang J, Vane JR.
Nociception in cyclooxygenase isozyme-deficient mice.
Proc Natl Acad Sci U S A. 2000;97:10272-10276.
4. Bombardier C, Laine L, Reicin A, et al. Comparison of upper
gastrointestinal toxicity of rofecoxib and naproxen in patients
with rheumatoid arthritis. VIGOR Study Group. N Engl J Med.
2000;343:1520-1528.
5. Schnitzer TJ, Burmester GR, Mysler E, et al. Comparison of
lumiracoxib with naproxen and ibuprofen in the Therapeutic
Arthritis Research and Gastrointestinal Event Trial (TAR-
GET), reduction in ulcer complications: randomised
controlled trial. Lancet. 2004;364:665-674.
6. Silverstein FE, Faich G, Goldstein JL, et al. Gastrointestinal
toxicity with celecoxib vs nonsteroidal anti-inflammatory
drugs for osteoarthritis and rheumatoid arthritis: the CLASS
study: a randomized controlled trial. Celecoxib Long-term
Arthritis Safety Study. JAMA. 2000;284:1247-1255.
7. Fries S, Grosser T, Price TS, et al. Marked interindividual
variability in the response to selective inhibitors of
cyclooxygenase-2. Gastroenterology. 2005;in press.
8. McAdam BF, Catella-Lawson F, Mardini IA, Kapoor S,
Lawson JA, FitzGerald GA. Systemic biosynthesis of
prostacyclin by cyclooxygenase (COX)-2: the human
pharmacology of a selective inhibitor of COX-2. Proc Natl
Acad Sci U S A. 1999;96:272-277.
9. Catella-Lawson F, McAdam B, Morrison BW, et al. Effects of
specific inhibition of cyclooxygenase-2 on sodium balance,
hemodynamics, and vasoactive eicosanoids. J Pharmacol
Exp Ther. 1999;289:735-741.
10. Cheng Y, Austin SC, Rocca B, et al. Role of prostacyclin in
the cardiovascular response to thromboxane A2. Science.
2002;296:539-541.
11. Qi Z, Hao CM, Langenbach RI, et al. Opposite effects of
cyclooxygenase-1 and -2 activity on the pressor response
to angiotensin II. J Clin Invest. 2002;110:61-69.
12. Kobayashi T, Tahara Y, Matsumoto M, et al. Roles of
thromboxane A2 and prostacyclin in the development of
atherosclerosis in apoE-deficient mice. J Clin Invest.
2004;114:784-794.
13. Bresalier RS, Sandler RS, Quan H, et al. Cardiovascular
events associated with rofecoxib in a colorectal adenoma
chemoprevention trial. N Engl J Med. 2005;352:1092-1102.
14. Solomon SD, McMurray JJ, Pfeffer MA, et al. Cardiovascular
risk associated with celecoxib in a clinical trial for colorectal
adenoma prevention. N Engl J Med. 2005;352:1071-1080.
15. Nussmeier NA, Whelton AA, Brown MT, et al. Complications
of the COX-2 inhibitors parecoxib and valdecoxib after
cardiac surgery. N Engl J Med. 2005;352:1081-1091.
16. Topper JN, Cai J, Falb D, Gimbrone MA, Jr. Identification of
vascular endothelial genes differentially responsive to fluid
mechanical stimuli: cyclooxygenase-2, manganese
superoxide dismutase, and endothelial cell nitric oxide
synthase are selectively up-regulated by steady laminar
shear stress. Proc Natl Acad Sci U S A. 1996;93:10417-
10422.
American Society of Hematology
17. Grosser T, Yusuff S, Cheskis E, Pack MA, FitzGerald GA.
Developmental expression of functional cyclooxygenases in
zebrafish. Proc Natl Acad Sci U S A. 2002;99:8418-8423.
18. Patrignani P, Panara MR, Greco A, et al. Biochemical and
pharmacological characterization of the cyclooxygenase
activity of human blood prostaglandin endoperoxide
synthases. J Pharmacol Exp Ther. 1994;271:1705-1712.
19. Jick SS. The risk of gastrointestinal bleed, myocardial
infarction, and newly diagnosed hypertension in users of
meloxicam, diclofenac, naproxen, and piroxicam. Pharmaco-
therapy. 2000;20:741-744.
20. Collaborative meta-analysis of randomised trials of
antiplatelet therapy for prevention of death, myocardial
infarction, and stroke in high risk patients. Br Med J.
2002;324:71-86.
21. Grosser T, Zucker TP, Weber AA, et al. Thromboxane A2
induces cell signaling but requires platelet-derived growth
factor to act as a mitogen. Eur J Pharmacol. 1997;319:327-
332.
22. Eikelboom JW, Hirsh J, Weitz JI, Johnston M, Yi Q, Yusuf S.
Aspirin-resistant thromboxane biosynthesis and the risk of
myocardial infarction, stroke, or cardiovascular death in
patients at high risk for cardiovascular events. Circulation.
2002;105:1650-1655.
23. Rocca B, Secchiero P, Ciabattoni G, et al. Cyclooxygenase-
2 expression is induced during human megakaryopoiesis
and characterizes newly formed platelets. Proc Natl Acad
Sci U S A. 2002;99:7634-7639.
24. Zimmermann N, Wenk A, Kim U, et al. Functional and
biochemical evaluation of platelet aspirin resistance after
coronary artery bypass surgery. Circulation. 2003;108:542-
547.
25. Egan KM, Lawson JA, Fries S, et al. COX-2 derived
prostacyclin confers atheroprotection on female mice.
Science. 2004;360:1954-1957.
26. Burleigh ME, Babaev VR, Oates JA, et al. Cyclooxygenase-
2 promotes early atherosclerotic lesion formation in LDL
receptor-deficient mice. Circulation. 2002;105:1816-1823.
27. Egan KM, Wang M, Lucitt MB, et al. Cyclooxygenases,
thromboxane, and atherosclerosis: plaque destabilization by
cyclooxygenase-2 inhibition combined with thromboxane
receptor antagonism. Circulation. 2005;111:334-342.
28. Cayatte AJ, Du Y, Oliver-Krasinski J, Lavielle G, Verbeuren
TJ, Cohen RA. The thromboxane receptor antagonist
S18886 but not aspirin inhibits atherogenesis in apo E-
deficient mice: evidence that eicosanoids other than
thromboxane contribute to atherosclerosis. Arterioscler
Thromb Vasc Biol. 2000;20:1724-1728.
Hematology 2005
29. Francois H, Coffman TM. Prostanoids and blood pressure:
which way is up? J Clin Invest. 2004;114:757-759.
30. Aw TJ, Haas SJ, Liew D, Krum H. Meta-analysis of
cyclooxygenase-2 inhibitors and their effects on blood
pressure. Arch Intern Med. 2005;165:490-496.
31. Athirakul K, Kim HS, Audoly LP, Smithies O, Coffman TM.
Deficiency of COX-1 causes natriuresis and enhanced
sensitivity to ACE inhibition. Kidney Int. 2001;60:2324-2329.
32. Zewde T, Mattson DL. Inhibition of cyclooxygenase-2 in the
rat renal medulla leads to sodium-sensitive hypertension.
Hypertension. 2004;44:424-428.
33. Dilger K, Herrlinger C, Peters J, Seyberth HW, Schweer H,
Klotz U. Effects of celecoxib and diclofenac on blood
pressure, renal function, and vasoactive prostanoids in
young and elderly subjects. J Clin Pharmacol. 2002;42:985-
994.
34. Cheng HF, Wang JL, Zhang MZ, Wang SW, McKanna JA,
Harris RC. Genetic deletion of COX-2 prevents increased
renin expression in response to ACE inhibition. Am J Physiol
Renal Physiol. 2001;280:F449-456.
35. Capone ML, Tacconelli S, Sciulli MG, et al. Clinical pharma-
cology of platelet, monocyte, and vascular cyclooxygenase
inhibition by naproxen and low-dose aspirin in healthy
subjects. Circulation. 2004;109:1468-1471.
36. Juni P, Nartey L, Reichenbach S, Sterchi R, Dieppe PA,
Egger M. Risk of cardiovascular events and rofecoxib:
cumulative meta-analysis. Lancet. 2004;364:2021-2029.
37. Farkouh ME, Kirshner H, Harrington RA, et al. Comparison
of lumiracoxib with naproxen and ibuprofen in the Therapeu-
tic Arthritis Research and Gastrointestinal Event Trial
(TARGET), cardiovascular outcomes: randomised con-
trolled trial. Lancet. 2004;364:675-684.
38. Ott E, Nussmeier NA, Duke PC, et al. Efficacy and safety of
the cyclooxygenase 2 inhibitors parecoxib and valdecoxib in
patients undergoing coronary artery bypass surgery. J
Thorac Cardiovasc Surg. 2003;125:1481-1492.
39. Catella-Lawson F, Reilly MP, Kapoor SC, et al.
Cyclooxygenase inhibitors and the antiplatelet effects of
aspirin. N Engl J Med. 2001;345:1809-1817.
40. Capone ML, Sciulli MG, Tacconelli S, et al. Pharmacody-
namic interaction of naproxen with low-dose aspirin in
healthy subjects. J Am Coll Cardiol. 2005;45:1295-1301.
451