Carefully controlled study show that all class of non-aspirin NSAIDs cause increased risk of
myocardial infraction.
Another
study showed that aspirin reduces MI 32%.
ARCHIVES OF INTERNAL MEDICINE, Vol.
165 No. 9. May 9, 2005
Risk of Hospitalization for Myocardial Infarction Among Users of Rofecoxib,
Celecoxib, and Other NSAIDs
A Population-Based
Case-Control Study
Søren P. Johnsen, MD, PhD; Heidi Larsson, MSc; Robert E. Tarone, PhD; Joseph K.
McLaughlin, PhD; Bente Nørgård, MD, PhD; Søren Friis, MD; Henrik T. Sørensen, DMSc
Arch Intern Med. 2005;165:978-984.
Background It remains uncertain if the excess cardiovascular risk of rofecoxib and celecoxib reported
in clinical trials is present in routine practice and whether the use of other nonaspirin nonsteroidal
anti-inflammatory drugs (NSAIDs) also carries an increased cardiovascular risk. We performed a population-based
case-control study to examine the risk of myocardial infarction (MI) among users of various categories of
nonaspirin NSAIDs.
Methods Using data from hospital discharge registries in the counties of North Jutland, Viborg,
and Aarhus, Denmark, and the Danish Civil Registration System, we identified 10 280 cases of first-time
hospitalization for MI and 102 797 sex- and age-matched non-MI population controls. All prescriptions
for nonaspirin NSAIDs filled before the date of admission for MI were identified using population-based prescription
databases. Relative risk estimates for MI were adjusted for a history of cardiovascular disease, hypertension,
diabetes mellitus, chronic bronchitis or emphysema, alcoholism, liver cirrhosis, upper gastrointestinal
bleeding, rheumatoid arthritis, systemic lupus erythematosus and the use of high-dose aspirin, platelet inhibitors,
insulin or oral hypoglycemic drugs, antihypertensive drugs, lipid-lowering drugs, oral anticoagulants, nitrates,
penicillamine, gold, oral glucocorticocoids, and hormone therapy before the date of admission for MI.
Results Current users of rofecoxib had an elevated risk estimate for hospitalization for MI compared
with nonusers of any category of nonaspirin NSAIDs (adjusted relative risk [ARR], 1.80; 95% confidence
interval [CI], 1.47-2.21). Increased risk estimates were also found among current users of celecoxib (ARR,
1.25; 95% CI, 0.97-1.62), other cyclooxygenase-2 selective inhibitors (ARR, 1.45; 95% CI, 1.09-1.93), naproxen
(ARR, 1.50; 95% CI, 0.99-2.29), and other conventional non-aspirin NSAIDs (ARR, 1.68; 95% CI, 1.52-1.85). The highest
ARRs were found among new users of all examined drug categories.
Conclusions Current and new users of all classes of non-aspirin NSAIDs had elevated relative risk
estimates for MI. Although the increased risk estimates may partly reflect unmeasured bias, they indicate
the need for further examination of the cardiovascular safety of all non-aspirin NSAIDs.
Author Affiliations: Department of Clinical Epidemiology, Aarhus Hospital, Aarhus University Hospital,
Aarhus, Denmark (Drs Johnsen, Nørgård, and Sørensen and Ms Larsson); Center of Cardiovascular Research, Aalborg Hospital,
Aarhus University Hospital, Aalborg, Denmark (Dr Johnsen); International Epidemiology Institute, Rockville, Md (Drs Tarone
and McLaughlin); Department of Medicine, Vanderbilt University Medical Center, Vanderbilt-Ingram Cancer Center, Nashville,
Tenn (Drs Tarone and McLaughlin); and Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark (Dr Friis).
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Painkillers — new and old —
increase the risk for heart attack, from the Harvard Heart
Letter
BOSTON — Cardiovascular side effects
aren’t limited to the use of the newer painkillers called COX-2 inhibitors — a category that includes Celebrex
and the recently discontinued Vioxx and Bextra. Old standbys, like ibuprofen and aspirin, aren’t entirely blameless,
reports the October 2006 issue of the Harvard Heart
Letter. The cardiovascular risks associated with traditional NSAIDs are small, but worth being aware of.
Ibuprofen, aspirin, and COX-2s all belong to the class of medicines called nonsteroidal
anti-inflammatory drugs (NSAIDs). Most of them boost blood pressure and can counteract the effect of some blood-pressure drugs.
They can also impair blood vessels’ ability to relax and may stimulate the growth of smooth muscle cells inside arteries.
All these changes can contribute to the artery-clogging process known as atherosclerosis.
Researchers have determined that use of a COX-2 inhibitor increases the chances of having
a heart attack. Vioxx, which was taken off the market because of possible heart complications, may lead to or worsen heart
failure — but so can traditional NSAIDs. In general, cardiovascular side effects are most likely to happen in people
with existing heart disease or those at high risk for it.
It is very easy to take the safety of medications for granted, and sometimes we get a harsh
reminder that even FDA-approved medications carry risks as well as benefits. Take, for example, the story of the pain relievers
Vioxx and Bextra. These COX-2 specific nonsteroidal anti-inflammatory drugs (NSAIDs) were withdrawn from the market after
being linked with cardiovascular problems. Now it turns out that even some of our old standby NSAIDs aspirin and ibuprofen
carry some cardiovascular risks you should be aware of. This issue of HEALTHbeat explains these new concerns and who may be
at particular risk.—Nancy Ferrair, Managing Editor of Harvard Health Publications.
Unfortunate most doctors still are unaware that all NSAIDs promote the development of
atherosclerosis—the one exception being ASPIRIN. The problem lies with the 800 pound guerrilla (big PHARMA) dominating
the dissemination of medical information--jk. |
All NSAIDS INHIBIT AN ENZYME COX-2. AMONG THE EFFECTS OF COX-2 IS THE SHUTTING OF THE MECHANISM WHICH STOPS THE
BUILD OF PLAQUE IN THE ARTERIES. The article below describes the research which found this phenomena. However,
only aspirin,though it inhibits COX-2 doesn't interferes with mechanism. That is why only aspirin in long-term studies
lowers the risk of heart attacks, all the other increase the risk (over placebo) of heart attacks.
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BIOLOGY OF THE EICOSANOIDS
Eicosanoids are
oxidized derivatives of the polyunsaturated long-chain fatty acids, arachidonic acid and eicosapentaenoic
acid, that serve many roles in cardiovascular biology and disease. They are a class of oxygenated, endogenous,
unsaturated fatty acids derived from arachidonic acid. They are hormone like substances that act near the site of synthesis without altering
functions throughout the body. Eicosanoid
biosynthesis can be initiated by release of arachidonic acid from membrane phospholipids by lipases (predominantly
of the phospholipase A2 type) (Figure 1). Once mobilized, arachidonic acid is oxygenated into eicosanoids along the
following 4 pathways: (1) prostaglandin (PG) endoperoxide synthase (cyclooxygenase [COX]), (2) lipoxygenase
(LO), (3) P450 epoxygenase, and (4) (nonenzymatic) isoprostane synthesis. Details of the pharmacology of
products of the LO, epoxygenase, and isoprostane pathways, as well as the lipoxins, are reviewed elsewhere.14–16 Here, we focus on products of the COX pathway. These derivatives
of arachidonic acid are collectively referred to as prostanoids and comprise the PGs and thromboxanes. COX,
a key enzyme in eicosanoid metabolism, converts arachidonic acid liberated from membrane phospholipids
into PGG2 and PGH2.
WHY COX-2 INHIBITION CAUSES CARDIAC EVENTS: Inhibition of COX-2 also has as a theoretical side effect an increase in the flux of arachidonate through
the LO pathways, which may be especially important in the setting of inflammation in the atheromatous plaque. The 12-,15-, and 5-LOs all have key roles in inflammation, and the role of each in atherosclerosis
has been examined. [Inflammation’s role in development of atheromatous plaque was reported in Scientific American in 1978—jk] Although 12-LO and 15-LO appear to contribute to LDL oxidation, the data
supporting the proatherogenic role of these enzymes are inconsistent.39 Data suggest that 15-LO products may be antiinflammatory.40 Furthermore, work from Serhan’s group shows that acetylation of COX-2
by low-dose aspirin leads to its biosynthesis of 15R-hydroxyeicosatetraenoic acid.40 This intermediate is then converted by transcellular metabolism to the
antiinflammatory lipoxin 15-epi-lipoxin A4 in leukocytes.41
Mehrabian and colleagues42 have demonstrated convincingly that 5-LO is a critical determinant of atherogenesis
in mouse models of the disease, even in the setting of profound hypercholesterolemia. The inflammatory
eicosanoids derived from increased 5-LO expression in plaque–leukotriene B4 and the cysteinyl-leukotrienes–are
active in the atherothrombotic vasculature, having been shown to promote inflammatory cell activation, cell
proliferation, and vasoconstriction. In human subjects, Dwyer and colleagues43 showed that variant 5-LO genotypes–tandem promoter repeats
of Sp-1 binding motifs–identify a subpopulation of individuals with increased atherosclerosis (determined
as carotid intima-media thickness). Helgadottir and colleagues44 showed that a promoter haplotype comprising 4 linked polymorphisms in
the 5-LO activating peptide (an accessory protein that facilitates presentation of substrate arachidonate
to 5-LO) confers an approximately 2-fold increased risk of myocardial infarction (MI) and stroke in
an Icelandic population. Thus, the potential importance of shifting the flux of arachidonate through the LO pathway
by inhibiting COX activity bears consideration as we attempt to dissect the vascular consequences of
coxib use.
To appreciate the complexity of interactions among the small-molecule vascular
mediators in the system, we also need to consider nitric oxide (NO) and superoxide anion. NO activates prostacyclin
synthase and suppresses thromboxane synthase, likely by nitrosylating bound heme.45 In addition, NO potentiates the vascular effects of prostacyclin, likely via
the cGMP-dependent inhibition of cAMP phosphodiesterase.46 This potentiation of prostacyclin by NO has also been demonstrated to account
for the synergistic inhibition of platelets by these vascular effectors.47,48 Niwano and colleagues49 have shown that a stable prostacyclin analogue (beraprost) increases endothelial
NO synthase (eNOS) expression by activating a cAMP-dependent transcriptional element in the eNOS promoter.
In the setting of an inflammatory stimulus that induces expression of inducible NO synthase (iNOS) and a source
of superoxide [such as NAD(P)H oxidase], peroxynitrite generation ensues and leads to 3-nitration of tyrosine
430 in prostacyclin synthase, inactivating the enzyme,50,51 and activation of the TxA2 receptor TP.50 TxA2, in turn, induces gp91phox expression and NAD(P)H
oxidase–dependent superoxide generation,52 increasing oxidant stress in the inflamed vasculature. NO derived
from iNOS also increases expression and activity of COX-2.53,28 In addition, other inflammatory mediators may modulate these interactions;
eg, evidence suggests that C-reactive protein decreases prostacyclin release from endothelial cells.54
Consideration of these interactions is essential for understanding the full
spectrum of activities of COX-2–dependent eicosanoid synthesis in the context of their interaction with NO.
For example, COX-2 not only has been recognized as a key source of prostacyclin under normal laminar
flow conditions in the vasculature but also is cardioprotective in ischemia-reperfusion injury55 and has antiproliferative effects toward vascular smooth muscle cells
in conjunction with NO.56 NO can also inhibit 5-LO, likely by peroxynitrite-dependent S-nitrosation
and/or 3-nitrotyrosination.57,58 Induction of iNOS by endotoxin leads to inhibition of 5-LO activity
without an effect on expression,59 likely via a peroxynitrite-dependent mechanism.
The interrelationships among COX-2, 5-LO, and NO in the endothelium can
best be analyzed when considered under 2 sets of conditions: in the normal state of laminar flow and in an inflammatory
state (Figure 5). Under normal conditions, laminar flow induces COX-2 in the endothelial cell
to promote the synthesis of prostacyclin, and stimulates elaboration of NO by eNOS. NO derived from eNOS,
in turn, stimulates prostacyclin synthase activity and suppresses thromboxane synthase activity; NO also
activates guanylyl cyclase to increase cGMP and acts synergistically with prostacyclin to increase cAMP
levels in target cells (eg, platelets). Taken together, the net effect of these actions is to impair platelet
activation, as summarized in Figure 4 (left) and Figure 5A.
In states of vascular inflammation, COX-2, iNOS, and NAD(P)H oxidase are induced
in endothelial cells; these enzymes, together with 5-LO, are also expressed in inflammatory leukocytes. High-flux
production of NO (from iNOS) together with superoxide anion [from NAD(P)H oxidase, COXs, LOs, and uncoupled
NO synthases, among other sources] leads to the synthesis of peroxynitrite (OONO–),
which inhibits prostacyclin synthase, activates TP-dependent signaling, and promotes additional COX-2 activity.
The COX pathways also promote NAD(P)H oxidase activation via TxA2,33 whereas 5-LO promotes NAD(P)H oxidase activation via leukotriene B460 and the cysteinyl-leukotrienes. Moreover, PGE2, the synthesis of
which is enhanced by COX2-derived PGH2 owing to kinetic selectivity and compartmentalization,61 promotes platelet activation by increasing intraplatelet calcium flux
and decreasing cAMP via its interaction with the platelet surface EP3 receptor.62 (For a review of the effects of NO-derived reactive nitrogen species in inflammatory
states on COXs, LOs, and peroxidases, see Coffey and colleagues.63) Taken together, the net effect of these actions is to promote platelet activation,
as summarized in Figure 4 (right) and Figure 5B.
We can use the models shown in Figures 4 and 5 to construct working hypotheses about the use of coxibs in the normal state
and in states of vascular inflammation. Central to this model is the balance between prostacyclin (PGI2)
and thromboxane A2 in normal and diseased vessels.27,64,65 The use of a coxib under normal (ie, noninflammatory) conditions would be
expected to have limited effects on platelet activation in that NO production by eNOS is relatively
unimpaired, and COX-1–dependent generation of prostacyclin would still be maintained. In contrast, the
use of a coxib in vascular inflammatory states would lead to a decrease in antithrombotic prostacyclin made by
arachidonate flux through COX-2 and would, therefore, make available more arachidonate for leukotriene
synthesis. Leukotrienes, especially leukotriene B4 and the cysteinyl-leukotrienes, would increase
reactive oxygen species generation by leukocytes, especially superoxide, thereby consuming antithrombotic
NO through the synthesis of peroxynitrite. Peroxynitrite, in turn, would further limit prostacyclin
synthesis via synthase nitration.47 Coxibs may also increase reactive oxygen species generation via uncoupling
of mitochondrial oxidative phosphorylation.66 Thus, the net result of coxib action in diseased vessels is an increase in
the amount of TxA2 relative to PGI2 (see Figure 4).
In addition to the considerations at the molecular level discussed above,
it should be noted that manipulation of the relative balance of COX-1 and COX-2 activity may alter important cardiorenal
responses in patients.19 COX-1 and COX-2 are colocalized in the macula densa. In elderly patients or
under conditions of sodium or fluid depletion, selective COX-2 inhibitors cause sodium retention and
may result in edema formation.67 Administration of COX-2 inhibitors has also been associated with a reduction
in glomerular filtration rate and exacerbation of hypertension.68–70 Increases in blood pressure have been proposed as a mechanism by
which COX-2 inhibitors may promote an increased risk of cardiovascular events.71
{Given that the effects of the COX-2 would increase with time, since antheorsclorsis
is accumulative, and COX-2 were often proscribed for chronic conditions such as arthritis, the risk increase for such long-term
treatments would be much greater than the 1.5 increase of 340%. For the APC trail—jk].
Additional information bearing on the issue of cardiovascular risk comes
from the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), which compared the most selective
coxib, lumiracoxib (see Figure 2), 400 mg once daily with either naproxen 500 mg twice daily or ibuprofen 800
mg 3 times daily for 1 year in 18 000 patients with osteoarthritis.86 Low-dose aspirin (75 to 100 mg daily) was permitted in TARGET. There
were only 109 cardiovascular or cerebrovascular events reported, of which 59 (0.65%) occurred in the
lumiracoxib group and 50 (0.55%) occurred in the NSAID groups (hazard ratio, 1.14; 95% CI, 0.78 to 1.66;
P=0.51). Although these findings might be interpreted as showing that lumiracoxib is as safe as either naproxen
or ibuprofen, in the absence of a placebo group, the results are also consistent with the possibility
that all 3 drugs
are associated with increased risk of events with little difference among them.
The next major event in this rapidly evolving story occurred on April 7,
2005.87 The FDA concluded that the overall risk-to-benefit profile for valdecoxib
was unfavorable and that valdecoxib lacked any demonstrable advantage compared with other NSAIDs. The agency
requested that Pfizer voluntarily withdraw valdecoxib from the market, which Pfizer agreed to do. While permitting
celecoxib to remain on the market, the FDA requested revision to the labeling of celecoxib and 18 other
nonselective NSAIDs to highlight the increased risk for cardiovascular events and stated that all NSAID
prescriptions must be accompanied by a medication guide to inform patients. In support of this decision by the
FDA is a report from a registry experience in Denmark of 10 280 cases of first-time hospitalization
for MI and 102 797 controls.88 Current and new users of all classes of non-aspirin NSAIDs
had elevated RR estimates for MI. [Only aspirin has
been shown to lower cardiac risk, which is why it has been widely proscribed for years in low doses for exactly that prupose—jk]
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