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Why COX-2 inhibitors (VIOXX) kill, mechanism explained

Cyclooxygenase Inhibition and Cardiovascular Risk


Elliott M. Antman, MD; David DeMets, PhD; Joseph Loscalzo, MD, PhD

Circulation. 2005;112:759-770.)
2005 American Heart Association, Inc.


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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THERE IS A FUNDAMENTAL CONFUSION ABOUT BLEEDING.  ONE IS CAUSED BY PLATELET REDUCTION, THE OTHER BY IRRITATION TO THE GASTRO INTESTIONAL TRACK.  Aspirin and other NSAID cause stomach bleeding by the fact that they are corrosive.  Dissolve one on your tongue and you’ll taste the proof.  This confusion has been promoted by drug companies which have been marketing COX-2 inhibitors.  They claim that it is the platelet reduction caused by COX-1 reduction that produces GI incidents.  Wrong, it is the caustic nature of those drugs that produce GI incidences—the platelet reduction would then increase the amount of bleeding.  COX-1 inhibitors produce excessive bleeding that is why there ought not be taken prior to an operation or following one. 

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