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Cyclooxygenase-2 Inhibitors
Are They Really Atherothrombotic, and If Not, Why Not?
Graeme J. Hankey and John W. Eikelboom
Originally published 23 Oct 2003 https://doi.org/10.1161/01.STR.0000097301.50041.6E
Stroke. 2003;34:2736–2740

Other version(s) of this article 

Abstract
Background and Summary— Selective cyclooxygenase (COX)-2 inhibitors are
increasingly being used in place of “conventional” nonsteroidal anti-inflammatory drugs
(NSAIDs). This is because they are just as effective as NSAIDs in relieving arthritic pain
and yet less gastrotoxic. However, the cardiovascular safety of selective COX-2
inhibitors has been questioned because they selectively reduce prostacyclin
production, thus disrupting the normal homeostatic balance and promoting a
prothrombotic state. These theoretical concerns appear to be supported by the results
of clinical trials demonstrating an increased risk of myocardial infarction with COX-2
inhibitors compared with a conventional NSAID, and indirect comparisons of the rates
of myocardial infarction among patients treated with a selective COX-2 inhibitor
compared with aspirin in different trials. However, emerging data from animal,
experimental and clinical studies suggest that COX-2 is atherogenic and thrombogenic,
and that selective COX-2 inhibitors may be cardioprotective. Meta-analyses of
randomized trials of selective COX-2 inhibitors compared with placebo have
demonstrated no excess of cardiovascular events among patients allocated COX-2
inhibitors, and preliminary data from a randomized controlled trial of the selective COX-
2 inhibitor meloxicam, in patients with acute coronary syndrome who were treated with
aspirin, demonstrated a reduction in cardiovascular events among patients allocated
the COX-2 inhibitor.
:
Conclusions— Continuing uncertainty regarding the direction and magnitude of any
cardiovascular effects of selective COX-2 inhibitors, coupled with their widespread and
increasing use, mandates prospective randomized evaluation of their efficacy and
safety in patients at increased risk of future cardiovascular events.

Since 1999, the introduction of the selective cyclooxygenase (COX)-2 inhibitors

(celecoxib, etoricoxib, and rofecoxib) has been hailed as a major therapeutic advance.
COX-2 inhibitors are as effective as aspirin and other “conventional” nonsteroidal anti-
inflammatory drugs (NSAIDs), which inhibit both COX-1 and COX-2 activity, in relieving
arthritic pain, yet they cause only half the number of adverse upper gastrointestinal
events.1,2 Central to their effectiveness is selective inhibition of the conversion of
arachidonic acid to prostaglandin H2 by COX-2, which is upregulated in inflamed
tissues, without also inhibiting the cytoprotective effects of COX-1 in the gastric
mucosa (which causes upper gastrointestinal events in 2% to 4% of patients per
year).2

However, the “honeymoon” has been threatened by theoretical arguments that

selective COX-2 inhibitors increase the risk of arterial thrombosis, which are supported
by secondary analyses of phase III clinical trials.3

The theory is that selective COX-2 inhibitors may promote atherothrombosis by

inhibiting the formation, via COX-2 isoenzymes in macrovascular endothelial cells, of
prostacyclin (PGI2), which is a potent vasodilator, and inhibitor of smooth muscle cell
proliferation and platelet aggregation.4–6 In addition, selective COX-2 inhibitors fail to
inhibit the formation, via COX-1 isoenzymes in platelets, of thromboxane A2 (TXA2),
which facilitates vasoconstriction, platelet activation, and smooth muscle cell
proliferation.4–6

The theory is supported by the Vioxx Gastrointestinal Outcomes Research (VIGOR)

trial, which reported a 2.38-fold (95% CI, 1.4 to 4.0) increase in the relative risk (RR) of
atherothrombotic cardiovascular events among all 8076 patients with rheumatoid
arthritis (RA) who were randomly allocated to rofecoxib treatment compared with those
allocated to naproxen treatment.2 Aspirin use was not permitted in this study, but the
increase in vascular events was even greater (RR, 4.9; 95% CI, 1.4 to 16.9) among the
subgroup of patients with a clear indication for aspirin because of previous
symptomatic atherothrombosis.2 Although there was no significant difference in
cardiovascular event rates between 8059 patients allocated to celecoxib and NSAID
treatment in the Celecoxib Long-term Arthritis Safety Study (CLASS), a summary of
:
major comparative trials of selective COX-2 inhibitors (VIGOR, CLASS, and 2 smaller
clinical trials that compared rofecoxib with a nonselective NSAID, nabumetone)
concluded that both rofecoxib and celecoxib may be associated with an increase in
cardiovascular events.3 The conclusion was based on the significantly higher annual
rates of myocardial infarction (MI) among RA patients in the VIGOR trial who were
allocated to rofecoxib treatment (0.74%) and other patients in the CLASS trial allocated
to celecoxib treatment (0.80%) compared with the 0.52% annual rate of MI observed
among 23 407 individuals allocated to placebo in a meta-analysis of the 4 trials of
aspirin versus placebo for the primary prevention of vascular events: the US
Physicians’ Health Study, the UK Doctors Study, the Thrombosis Prevention Trial, and
the Hypertension Optimal Treatment trials (P=0.04 and P=0.02 for the rofecoxib and
celecoxib versus placebo comparisons, respectively).7 Because rofecoxib and
celecoxib are chemically different compounds (rofecoxib is a sulfone that is not well
distributed into tissues and is metabolized principally by cytosolic reduction, whereas
celecoxib is a sulfonamide that is well distributed into tissues and is metabolized by
the cytochrome P450 2C9, 3A4 system), it was also hypothesized that an increased
risk of cardiovascular risk may be a class effect associated with COX-2–selective
inhibitors.3

The concept that COX-2 inhibitors may increase the risk of cardiovascular disease has
gained additional support from a report of 4 cases of thrombosis in patients with
connective tissue diseases who were treated with COX-2 inhibitors8 and the results of
several laboratory studies, which showed that PGI2 modulates the cardiovascular
actions of TXA2,6,9 COX-2 mediates the cardioprotective effects of the late phase of
ischemic preconditioning (the ability of myocytes to survive repeated ischemia) in
rabbits,10 and COX-2 inhibition by celecoxib increases thrombosis in canine coronary
arteries.11

Indeed, the hypothesis that COX-2 inhibitors increase the risk of vascular events has
gained such momentum that there are statements in the current medical literature that
“celecoxib can lead to thrombotic cardiovascular events”5 and even articles entitled,
“Why do cyclo-oxygenase-2 inhibitors cause cardiovascular events?”5 Moreover, the
manufacturers of selective COX-2 inhibitors and the Food and Drug Administration now
recommend caution in prescribing COX-2 inhibitors for patients with a history of
ischemic heart disease (http://www.fda.gov/cder/foi/label/2002/21042s7lbl.pdf).12 It is
as if a causal association has been established.

However, before the apparent association between the use of celecoxib and rofecoxib
and an increased risk of cardiovascular events becomes entrenched in clinical practice,
there are alternative explanations to consider. The most compelling is that the
differences in the raw MI rates among the “cases” (patients treated with a selective
COX-2 inhibitor [rofecoxib in the VIGOR trial and celecoxib in the CLASS trial]) and the
:
literature “controls” (entirely unrelated, separate cohorts of generally healthy individuals
in the placebo arms of the 4 primary prevention trials of aspirin) are nonrandomized,
indirect comparisons. There was not even any statistical adjustment for the prevalence
and level of known, let alone unknown, important prognostic factors in the cases and
controls. The comparisons are therefore potentially flawed because any differences in
raw MI event rates could simply be accounted for by differences in case mix among
the cases and controls. For example, there is some evidence that patients with RA (ie,
the type of patients enrolled in the VIGOR trial) have higher vascular events rates than
individuals of the same age and sex who do not have RA, such as the cases enrolled in
CLASS and the controls in primary prevention trials of aspirin.13

Another limitation of the summary of trials is that the analysis was restricted to MI and
not all vascular outcome events (eg, stroke and death from other vascular causes).3
Finally, the 95% CIs of the reported annual MI rates for patients allocated to rofecoxib
(0.74%) and celecoxib (0.80%) treatment were wide and overlapped with those of the
events rates for the trials used to construct the placebo group in the meta-analysis
(annual event rates 0.36% to 1.33%) and the 95% CIs of the summary point estimate.3

An alternative interpretation of the VIGOR trial is that rofecoxib causes no excess risk
of vascular events, and any excess RR of vascular events associated with rofecoxib,
compared with naproxen, could be attributable to the effectiveness of naproxen in
decreasing cardiovascular risk.3 An antiplatelet effect of naproxen is supported by a
systematic review of all rofecoxib trials conducted by the manufacturer (fewer vascular
events in the naproxen group)14 and 3 recent case-control studies that found that
naproxen was associated with a modest (16% to 39%) reduction in odds of serious
coronary heart disease.15–17 However, not all observational studies have shown a
cardioprotective effect of naproxen.18–20

The results of CLASS, which showed an equal rate of vascular events among patients
randomized to celecoxib and to ibuprofen, may also reflect that ibuprofen is a NSAID
that does not reduce vascular events any more than celecoxib.1,3,21

In the midst of the present ongoing controversy and uncertainty over whether selective
COX-2 inhibitors increase cardiovascular events (by blocking PGI2 and leaving TXA2
unopposed) and whether there are differences in cardiovascular risk between different
COX-2 inhibitors, we hypothesize that selective COX-2 inhibitors may actually reduce,
rather than cause, atherothrombotic vascular events. The rationale for our hypothesis is
that COX-2 could be both atherogenic and thrombogenic (Figure).
:
 Download figure | Download PowerPoint
Proposed mechanism of action of drugs that inhibit COX on atherogenesis and
atherothrombosis. AA indicates arachidonic acid; PGH2, prostaglandin H2; PGE2,
prostaglandin E2; and MMP, matrix metalloproteinase.

Atherosclerosis is an inflammatory disease.22 Proinflammatory mediators of

atherosclerosis induce upregulation of COX-2 in circulating blood monocytes and
endothelial cells, smooth muscle cells, and macrophages within atherosclerotic
plaque.22,23 Upregulation of COX-2 in atherosclerotic tissue enhances the production
of a range of inflammatory eicosanoids, including prostaglandin E2.23–26 Prostaglandin
E2 promotes the release and activation of matrix metalloproteinases, which promote
macrophage migration and rupture of atherosclerotic plaque.23,27–30 COX-2 also
promotes the release of active matrix metalloproteinases and has been implicated in
the development of early atherosclerotic lesions.23,31 Evidence from a recent
randomized trial suggests that simvastatin decreases inflammation and suppresses the
:
expression of cyclooxygenase-2 and prostaglandin E synthase in plaque macrophages,
and this effect in turn may contribute to plaque stabilization by inhibition of
metalloproteinase-induced plaque rupture.32

 back the production of

Upregulation of COX-2 in atherosclerotic plaque also enhances
prostaglandin H2 in monocytes and macrophages, which, because of their large
content of thromboxane synthase, involves increased production of TXA2, which
predisposes to thrombosis24–26 and atherogenesis33 and is associated with an
increased risk of atherothrombosis and death.34 The prostaglandin H2 produced by
monocytes/macrophages (and endothelial cells) can also be used by platelet
thromboxane synthase to form TXA2 through a process of “transcellular metabolism,”
thereby bypassing the platelet COX-1 blocked by aspirin.35–37 COX-2 has recently
been demonstrated to be present in platelets and may represent an additional
mechanism of thromboxane biosynthesis and thus thrombogenesis.38

Evidence supporting our hypothesis for COX-2 being atherogenic and thrombogenic
comes from laboratory and clinical studies. The administration of rofecoxib or
indomethacin for 6 weeks to mice that are deficient in the LDL receptor and fed a
Western diet led to a significant reduction of atherosclerosis.33 Compared with
placebo, celecoxib (200 mg BID) significantly improves endothelium-dependent
vasodilation and reduces low-grade chronic inflammation and oxidative stress in men
with severe coronary artery disease.39 Additionally, the Nonsteroidal Anti-Inflammatory
Drugs in Unstable Angina Treatment-2 (NUT-2) pilot study, which compared meloxicam
(15 mg daily until 30 days after discharge) with control in 120 patients who had a non–
ST-segment elevation acute coronary syndrome, showed that patients allocated to
meloxicam treatment had a significant reduction in the primary composite outcome of
recurrent angina, myocardial infarction, or death during the coronary care unit stay
(15.0% versus 38.3%; relative risk reduction, 61%; 95% CI, 23% to 80%; absolute risk
reduction, 23.3%; P=0.007).40 Although the sample size was small, treatment allocation
was open, and much of the primary outcome was recurrent angina (ie, pain that could
be reduced by COX-2 inhibitors), treatment allocation was randomized, and the
outcome evaluation was performed by an investigator who was unaware of treatment
allocation. While these data may simply reflect the play of chance or a nonspecific
effect of COX-2 inhibition on pain generation or perception, they support the
hypothesis that COX-2 inhibition may retard atherogenesis (by improving vascular
endothelial function and plaque stability) and minimize atherothrombosis (by inhibiting
TXA2 generated from monocytes, endothelial cells, and platelets through the action of
COX-2).

The body of laboratory and phase II/III clinical trial evidence is now compelling enough
to consider it ethically sound to conduct large, randomized, double-blind, placebo-
controlled trials of selective COX-2 inhibitors on the occurrence of “hard” clinical
:
outcome events such as nonfatal stroke, nonfatal myocardial infarction, and death due
to vascular causes in patients at high vascular risk who are also being treated with
aspirin.12,41 It is, however, essential that such trials adopt broad inclusion criteria and
be adequately powered with sufficient duration of follow-up to reliably detect any
excess noncardiovascular adverse effects of adding a COX-2 selective inhibitor to
aspirin on renal function and gastrointestinal bleeding risk, which could potentially
negate any cardiovascular benefits of this combination if ultimately used in everyday
clinical practice.

Footnotes
Correspondence to Dr Graeme J. Hankey, Stroke Unit, Department of Neurology, Royal
Perth Hospital, Box X2213 GPO, Perth WA 6001, Australia. E-mail
gjhankey@cyllene.uwa.edu.au

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