FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2014184499> ?p ?o ?g. }

• W2014184499 endingPage "770" @default.
• W2014184499 startingPage "759" @default.
• W2014184499 abstract "HomeCirculationVol. 112, No. 5Cyclooxygenase Inhibition and Cardiovascular Risk Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessReview ArticlePDF/EPUBCyclooxygenase Inhibition and Cardiovascular Risk Elliott M. Antman, MD, David DeMets, PhD and Joseph Loscalzo, MD, PhD Elliott M. AntmanElliott M. Antman From the Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Boston, Mass (E.M.A., J.L.); and Department of Biostatistics and Medical Informatics, University of Wisconsin, Madison (D.D.). Search for more papers by this author , David DeMetsDavid DeMets From the Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Boston, Mass (E.M.A., J.L.); and Department of Biostatistics and Medical Informatics, University of Wisconsin, Madison (D.D.). Search for more papers by this author and Joseph LoscalzoJoseph Loscalzo From the Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Boston, Mass (E.M.A., J.L.); and Department of Biostatistics and Medical Informatics, University of Wisconsin, Madison (D.D.). Search for more papers by this author Originally published2 Aug 2005https://doi.org/10.1161/CIRCULATIONAHA.105.568451Circulation. 2005;112:759–770Over the past several months clinicians have been confronted at an escalating rate with reports describing the risks of COX-2 inhibitors (coxibs). Information on this class of drugs appears not only in traditional medical journals and textbooks, but also on the Web sites of regulatory agencies, professional societies, and pharmaceutical manufacturers.1–9 An unusual, but noteworthy, aspect of the state of affairs is the high rate of reporting new findings and opinions (at times voiced in a strident tone) in the lay press.10–13 Understandably, patients are concerned about the potential risks associated with their antiinflammatory medications, and now, either spontaneously or in response to a public health warning, call their healthcare professional with questions or arrive for an office visit armed with publicly accessed information they wish to discuss.Owing to the widespread use of antiinflammatory drugs and the fact that the reported risks are cardiovascular in nature, we offer the readers of Circulation this special article. Our goals are to provide an overview of the relevant biology and pharmacology, to synthesize the data on the cardiovascular risks associated with antiinflammatory medications, to offer suggestions on strategies for prescribing these medications, and to make observations on the regulatory and research implications of the data and their interpretation.Biology of EicosanoidsEicosanoids are oxidized derivatives of the polyunsaturated long-chain fatty acids, arachidonic acid and eicosapentaenoic acid, that serve many roles in cardiovascular biology and disease. 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. Download figureDownload PowerPointFigure 1. Molecular pathways for formation of eicosanoids and prostanoids. Arachidonic acid released from the cell membrane is metabolized along the 4 eicosanoid pathways shown. The COX pathway is responsible prostanoid formation.The fate of PGH2 and the distribution of prostanoids formed from it depend on the cell type in which it is synthesized and the tissue-specific isomerases found within that cell. For example, leukocytes, vascular smooth muscle cells, endothelial cells, and platelets express PGE synthase and, as a result, are all capable of generating the inflammatory prostanoid PGE2; platelets express thromboxane synthase and elaborate the prothrombotic, vasoconstrictor prostanoid thromboxane A2; and endothelial cells express PGI synthase and synthesize the antithrombotic, vasodilator prostanoid PGI2 or prostacyclin. In addition to cell-specific synthesis, the biological effects of prostanoids are governed by cell-specific receptor-dependent signaling pathways (the receptors DP, EP, FP, IP, and TP for PGD2, PGE2, PGF2alpha, PGI2, and TxA2, respectively) that define biological responses. Importantly, prostanoid intermediates can also undergo transcellular metabolism (ie, PGH2 can be produced in a platelet and then taken up by a leukocyte in which it is converted to PGE2).17Pharmacology and Molecular Biology of Inhibition of Prostanoid SynthesisThe pharmacological inhibition of prostanoid synthesis has been the focus of drug development for >100 years. From aspirin and other nonsteroidal antiinflammatory drugs (NSAIDs) that inhibit COX, the field evolved rapidly in the 1980s to yield a wide range of agents with varying antiinflammatory and analgesic potencies and varying pharmacodynamics. These NSAIDs comprise a class of agents with heterogeneous structures (Figure 2). As a therapeutic class, they provide antipyretic, analgesic, and inflammatory activities, but the relative degree of these effects varies markedly among the compounds (eg, acetaminophen has antipyretic and analgesic effects but little antiinflammatory activity). In addition, as a therapeutic class, the NSAIDs share the common side effects of gastrointestinal ulceration, inhibition of uterine motility, inhibition of PG-mediated renal function, and hypersensitivity reactions. The relative frequencies of these side effects, however, vary markedly among the members of the class. Download figureDownload PowerPointFigure 2. NSAIDs. The 9 chemical groupings of NSAIDs are shown, along with key compounds in each class. Relative degree of COX-1 vs COX-2 selectivity is shown at the bottom of the figure (adapted with permission from Warner and Mitchell19). Common therapeutic effects (in varying degrees of activity) for NSAIDs are antipyretic, analgesic, and antiinflammatory. Common side effects (in varying relative frequencies) are gastrointestinal ulceration, inhibition of platelet aggregation, inhibition of uterine motility, inhibition of PG-mediated renal function, and hypersensitivity reactions.With the recognition that aspirin inhibits platelet function, the antithrombotic effect of these agents gained unique therapeutic emphasis and, of course, has proved to be a most important treatment strategy in atherothrombotic disease. Because the endothelial prostanoid prostacyclin has antithrombotic action while the platelet prostanoid thromboxane A2 has prothrombotic action, investigators realized in the 1970s that nonselective inhibition of COX pools in these 2 cell types could theoretically result in an attenuation of the antithrombotic effect of inhibition of platelet COX. At that time, investigators defined doses and conditions under which the suppression of thromboxane A2 synthesis by aspirin predominates over the suppression of prostacyclin synthesis; as a result of the irreversible inhibition (via acetylation) of COX by aspirin and the difference in half-lives of inhibited platelet and endothelial COX, low-dose aspirin was found to provide sufficient antithrombotic selectivity for primary and secondary prevention of atherothrombotic events.In the early 1990s, a new wrinkle in the complex molecular events governing vascular prostanoid synthesis arose with the identification of 2 members of the COX family. COX-1 is constitutively expressed in many cells and is the only isozyme expressed in platelets; COX-2 is induced by inflammatory cytokines in many cell types (Table 1 and Figure 3).18,19 This distinction developed in the face of concern about the hemorrhagic risk of nonselective COX inhibition, especially gastrointestinal bleeding. The recognition that there are 2 different COXs led to the straightforward view that COX-2 is responsible for the adverse proinflammatory effects of prostanoids and that nonspecific COX inhibitors cause bleeding by inhibiting COX-1 in platelets. This working paradigm led the pharmaceutical industry to develop COX-2–selective inhibitors, the coxibs, arguing that these agents would provide adequate analgesia and antiinflammatory effects without hemorrhagic risk. The incidence of gastropathy accompanying the use of nonselective NSAIDs was felt to be of sufficient magnitude to warrant the development of coxibs; according to one meta-analysis,20 approximately one-third of patients taking NSAIDs had gastric or duodenal ulcers by endoscopy, but the risk of serious gastrointestinal bleeding is much lower,21 with 107 000 patients hospitalized each year for gastrointestinal complications of NSAID use.22 Despite their development to provide a therapeutic option for patients at risk of gastrointestinal bleeding, survey reports suggest that coxibs are prescribed with approximately equal frequency to patients who are at low or high risk of gastrointestinal bleeding.23TABLE 1. Comparison of COX-1 and COX-2 EnzymesCOX-1COX-2Chromosome location for gene coding for protein91Location in cellMembrane boundBiochemical actionCatalyzes conversion of arachidonic acid liberated from cell membrane to PGG2 and PGH2Basis for selectivity of inhibitors (see Figure 3)Isoleucine (bulky) in position 523 blocks access to side pocketLess bulky valine in position 523 allows binding of “selective” drugs to side pocketCellular expressionConstitutively in many cellsInduced by inflammatory cytokines but can be expressed in normal endothelial cells exposed to shear stress; role in atherosclerotic plaque development is uncertainDownload figureDownload PowerPointFigure 3. Structural determinants of inhibition of arachidonic acid binding to COXs. A, Arachidonic acid binding sites for COX-1 (left) and COX-2 (right), illustrating the location of arg 120, which forms an ionic bond with the carboxyl group of the fatty acid, and the hydrophobic pocket. In addition, note difference in amino acid at position 523, which is isoleucine in COX-1 and valine in COX-2, neither of which affects arachidonic acid binding. B, COX inhibitor binding to the arachidonic acid binding site for naproxen bound to COX-1 (left) and celecoxib bound to COX-2 (right). The difference in the amino acid at position 523 accounts, in part, for the selectivity of coxib, with the smaller valine accommodating the binding of the sulfonamide moiety in the side pocket.Unfortunately, this clean mechanistic distinction between the COXs is an oversimplification. As a class, the NSAIDs have a broad range of relative COX-1 and COX-2 selectivity (Figure 2). Furthermore, COX-2 is expressed in normal endothelial cells in response to shear stress,24 and inhibition of COX-2 is associated with significant suppression of prostacyclin synthesis in human subjects25,26 (Figure 4). Both COX-1 and COX-2 are detectable in human atherosclerotic lesions27,28; however, the specific effect of COX inhibition on lesion progression is currently controversial. Low-dose aspirin and selective COX-2 inhibitors have been shown to improve29,30 or worsen31 endothelial dysfunction in hypercholesterolemia and hypertension. COX-2 may also play a role in destabilizing plaques as suggested by its increased expression and colocalization with microsomal PGE synthase-1 and metalloproteinases-2 and -9 in carotid plaques from individuals with symptomatic disease before endarterectomy.32 Studies in hypercholesterolemic mice have also been inconsistent, with reports showing that COX-2 inhibitors worsen, retard, or fail to affect the course of atherosclerosis,33–35 and evidence exists to support the view that COX-2–derived prostacyclin is atheroprotective, but only in female mice.36 Possible explanations for these divergent outcomes include differences among the methods of suppressing COX-2 activity, the timing of administration of the inhibitor, and the genetic backgrounds of the animals studied. In addition, COX-2–derived prostanoid products have divergent effects on the molecular and cellular mechanisms underlying disease pathogenesis. For example, through its interaction with the E-prostanoid receptor EP4 on macrophages, COX-2–derived PGE2 suppresses chemokine production,37 whereas TP antagonism retards atherogenesis.38 Moreover, COX-2 is differentially expressed among cell types in the plaque, as are the predominant prostanoids derived from those cells. Download figureDownload PowerPointFigure 4. Consequences of COX inhibition for prostacyclin and thromboxane A2 production in normal and atherosclerotic arteries. Endothelial cells are shown as a source of prostacyclin (PGI2) and platelets as a source of thromboxane A2 (TxA2) under untreated conditions (top row) or treated with low-dose aspirin (middle row) or a coxib (bottom row) in the normal (left column) and atherosclerotic artery (right column) for comparison. COX-1 is the only isoenzyme expressed in platelets; endothelial cells express both COX-1 and COX-2. In the normal artery, the balance between PGI2 and TxA2 production favors PGI2 and inhibition of platelet-dependent thrombus formation. In the atherosclerotic artery, both PGI2 and TxA2 production is increased, owing in part to increased platelet activation with compensatory PGI2 formation via both COX-1 and COX-2 in endothelial cell; the net effect is an imbalance favoring TxA2 production and platelet-dependent thrombus formation. Low-dose aspirin selectively impairs COX-1–mediated TxA2 production in platelets restoring the net antithrombotic balance. Coxib use suppresses COX-2–dependent PGI2 production in endothelial cells, which has only a marginal effect on the net antithrombotic balance owing to the importance of COX-1 as a source of PGI2 in the normal state. In the setting of atherosclerosis, however, COX-2 plays a greater role as a source of PGI2 and more TxA2 is produced; thus, inhibiting COX-2 has a more profound effect on prostanoid balance, favoring TxA2 production and promoting platelet-dependent thrombosis.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. 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.41Mehrabian 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.54Consideration 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. Download figureDownload PowerPointFigure 5. Relationships between vascular eicosanoids and NO under normal conditions (A) and in inflammatory states. PGI2S indicates prostacyclin synthase; TxA2S, thromboxane synthase; TxA2R, thromboxane A2/PGH2 receptor; and blue lines, factors that modulate specific pathways positively (solid blue line) or negatively (dashed blue line).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.71Synthesis of Data on Risk of Cardiovascular EventsThe emerging data on the potential for an increased risk of cardiovascular events with coxib use present a disturbing and confusing message for clinicians and patients. The concept of assessing the risk-to-benefit ratio of any medication is familiar to clinicians but is difficult to operationalize for the coxibs. Although the benefits of coxibs (eg, a convenient form of analgesia for arthritic and musculoskeletal discomfort) are more apparent, the risks associated with their use are less clear. Critical questions remain unanswered: What is the magnitude of the increased risk of cardiovascular events with coxib use? Does the risk vary among the coxibs, or is it a true class effect? Is a similar increased risk of cardiovascular events seen with the nonselective NSAIDs?The evidence base with regard to the risk of cardiovascular events consists of randomized controlled trials (RCTs), new drug application databases submitted to regulatory authorities, and analyses from community- and hospital-based prescription practices. Many of the individual RCT and prescription practice reports can be found in the medical literature, although some are unpublished reports that have been made available on Web sites.72 Meta-analyses of the available RCT data have also been published.73 Rather than reiterate the details of previous reports, we offer potential explanations for the nature of the data and present a model that synthesizes the information in a clinically meaningful fashion.We begin the discussion of the RCT data by a worked example summarizing the cardiovascular risk associated with celecoxib in a clinical trial (APC) for prevention of colorectal adenoma (Figure 6).74 A total of 2035 patients with a history of colorectal neoplasia were randomized to receive either placebo or 1 of 2 doses of celecoxib (200 or 400 mg twice daily). After 2.8 to 3.1 years of follow-up, an independent Data Safety Monitoring Board concluded that continued exposure to celecoxib placed patients at increased risk for serious cardiovascular events. The APC study was designed for a noncardiovascular purpose–prevention of colorectal adenoma–yet an increased risk of cardiovascular events was identified. The situation surrounding the APC study and cardiovascular risk is representative of many of the coxib trial data to date. Download figureDownload PowerPointFigure 6. Biostatistical considerations in a trial of a coxib vs placebo. Left, Main findings of the APC trial. Right, A 2×2 table is used to arrange the data for the calculation of statistical tests of treatment effect. Clinically useful methods of describing the treatment effect are shown (bottom right). Data from Solomon et al.74.What kind of observations might have concerned the Data Safety Monitoring Board? Of the 679 patients randomized to placebo, 4 patients (0.6%) either died or sustained a nonfatal MI. In contrast, of the 1356 patients assigned to either of the celecoxib arms, 27 (2.0%) died or had a nonfatal MI. After the data are entered into a 2×2 table, several statistical tests of the treatment effect (harm in this case) of celecoxib can be performed. Regardless of whether one uses a χ2 test (or the equivalent binomial comparison of proportions) or Fisher’s exact test, the difference in event rates in the combined celecoxib group is statistically significantly higher than that in the placebo group (Figure 6).Another important message is also illustrated by the APC trial findings. The event rates are relatively low compared with those seen in trials enrolling acute coronary syndrome patients in which the death/MI rate may be 10% at 1 year, depending on the level of risk at the time of enrollment. Statements about the relative risk (RR) and odds ratio (OR) convey information about the proportionate increase in risk with celecoxib use versus placebo (3.4-fold increased risk in this example) (Figure 6). (For low event rates, as in this example, the OR approximates the RR.) Such ratios are often the only statistic quoted in the lay press but do not present the full range of clinically relevant information. For example, the absolute risk difference (ARD) in event rates is 1.4%. To interpret the information from the APC trial in the context of data from other trials, it is useful to calculate the number of patients who need to be treated with celecoxib to observe 1 death or MI event, ie, the number needed to harm (NNH). In this case, NNH=1/ARD=71 patients (Figure 6).In contrast to the APC trial in which there was a straightforward comparison of a coxib (celecoxib) with placebo, the Vioxx Gastrointestinal Outcome Study (VIGOR) compared the occurrence of gastrointestinal toxicity with a different coxib (rofecoxib 50 mg/d) and another NSAID (naproxen 1000 mg/d) in patients with rheumatoid arthritis.75 Aspirin use was not permitted in VIGOR. A signal of increased risk (RR, 2.38; 95% CI, 1.39 to 4.00; P<0.001) of serious thrombotic cardiovascular events (MI, unstable angina, cardiac thrombus, resuscitated cardiac arrest, sudden or unexplained death, ischemic stroke, and transient ischemic attacks) was found in a report submitted to the US Food and Drug Administration (FDA) subsequent to the publication of the original VIGOR manuscript. This increased risk of cardiovascular events with rofecoxib was observed whether or not the patient would (RR, 4.89; 95% CI, 1.41 to 16.88; P=0.01) or would not (RR, 1.89; 95% CI, 1.03 to 3.45; P=0.04) have been eligible to receive aspirin.76The active comparator naproxen in VIGOR was a confounding factor that made interpretation of the RR associated with rofecoxib more difficult to assess. It was initially argued that naproxen had a protective antithrombotic effect that reduced the event rate (compared with a putative placebo) and led to an apparent increased RR with rofecoxib. However, more compelling data consistent with a true increase in the RR with rofecoxib emerged from reports such as a cumulative meta-analysis of RCTs comparing rofecoxib with placebo,73 a case-control study of 54 475 Medicare beneficiaries,77 a case-control study of 8518 patients from a database of 36 hospitals in 5 counties,78 a retrospective case-control study of 113 927 patients in Quebec’s administrative health databases,79 and a nested case-control study from the Kaiser Permanente database in California.80Eventually, when the Adenomatous Polyp Prevention on Vioxx trial (APPROVe), comparing rofecoxib 25" @default.
• W2014184499 created "2016-06-24" @default.
• W2014184499 creator A5019612250 @default.
• W2014184499 creator A5028396638 @default.
• W2014184499 creator A5049652855 @default.
• W2014184499 date "2005-08-02" @default.
• W2014184499 modified "2023-10-01" @default.
• W2014184499 title "Cyclooxygenase Inhibition and Cardiovascular Risk" @default.
• W2014184499 cites W1497420961 @default.
• W2014184499 cites W1780627874 @default.
• W2014184499 cites W1967773292 @default.
• W2014184499 cites W1968569156 @default.
• W2014184499 cites W1983707947 @default.
• W2014184499 cites W1992025930 @default.
• W2014184499 cites W1994883059 @default.
• W2014184499 cites W1995528018 @default.
• W2014184499 cites W1998343049 @default.
• W2014184499 cites W2002383541 @default.
• W2014184499 cites W2005239390 @default.
• W2014184499 cites W2011327495 @default.
• W2014184499 cites W2018122321 @default.
• W2014184499 cites W2020563114 @default.
• W2014184499 cites W2021900197 @default.
• W2014184499 cites W2024176341 @default.
• W2014184499 cites W2024233889 @default.
• W2014184499 cites W2025653938 @default.
• W2014184499 cites W2035093916 @default.
• W2014184499 cites W2038932922 @default.
• W2014184499 cites W2042274378 @default.
• W2014184499 cites W2046081278 @default.
• W2014184499 cites W2050656757 @default.
• W2014184499 cites W2055691692 @default.
• W2014184499 cites W2057318529 @default.
• W2014184499 cites W2057685090 @default.
• W2014184499 cites W2061857216 @default.
• W2014184499 cites W2067621583 @default.
• W2014184499 cites W2070469088 @default.
• W2014184499 cites W2072470670 @default.
• W2014184499 cites W2073937383 @default.
• W2014184499 cites W2076744535 @default.
• W2014184499 cites W2079501182 @default.
• W2014184499 cites W2080178855 @default.
• W2014184499 cites W2080605373 @default.
• W2014184499 cites W2083464592 @default.
• W2014184499 cites W2084120431 @default.
• W2014184499 cites W2084148374 @default.
• W2014184499 cites W2087830809 @default.
• W2014184499 cites W2092011140 @default.
• W2014184499 cites W2094941678 @default.
• W2014184499 cites W2105811856 @default.
• W2014184499 cites W2108014410 @default.
• W2014184499 cites W2117227343 @default.
• W2014184499 cites W2128292711 @default.
• W2014184499 cites W2129333373 @default.
• W2014184499 cites W2129481644 @default.
• W2014184499 cites W2134818302 @default.
• W2014184499 cites W2135393211 @default.
• W2014184499 cites W2136555831 @default.
• W2014184499 cites W2138650500 @default.
• W2014184499 cites W2138877935 @default.
• W2014184499 cites W2143930183 @default.
• W2014184499 cites W2147758955 @default.
• W2014184499 cites W2151840463 @default.
• W2014184499 cites W2152021373 @default.
• W2014184499 cites W2158131645 @default.
• W2014184499 cites W2158968701 @default.
• W2014184499 cites W2162582390 @default.
• W2014184499 cites W2162592603 @default.
• W2014184499 cites W2163808483 @default.
• W2014184499 cites W2164401340 @default.
• W2014184499 cites W2167974856 @default.
• W2014184499 cites W2316102942 @default.
• W2014184499 cites W2330496155 @default.
• W2014184499 cites W4247482761 @default.
• W2014184499 cites W4255226843 @default.
• W2014184499 doi "https://doi.org/10.1161/circulationaha.105.568451" @default.
• W2014184499 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/16061757" @default.
• W2014184499 hasPublicationYear "2005" @default.
• W2014184499 type Work @default.
• W2014184499 sameAs 2014184499 @default.
• W2014184499 citedByCount "257" @default.
• W2014184499 countsByYear W20141844992012 @default.
• W2014184499 countsByYear W20141844992013 @default.
• W2014184499 countsByYear W20141844992014 @default.
• W2014184499 countsByYear W20141844992015 @default.
• W2014184499 countsByYear W20141844992016 @default.
• W2014184499 countsByYear W20141844992017 @default.
• W2014184499 countsByYear W20141844992018 @default.
• W2014184499 countsByYear W20141844992019 @default.
• W2014184499 countsByYear W20141844992020 @default.
• W2014184499 countsByYear W20141844992021 @default.
• W2014184499 countsByYear W20141844992022 @default.
• W2014184499 countsByYear W20141844992023 @default.
• W2014184499 crossrefType "journal-article" @default.
• W2014184499 hasAuthorship W2014184499A5019612250 @default.
• W2014184499 hasAuthorship W2014184499A5028396638 @default.
• W2014184499 hasAuthorship W2014184499A5049652855 @default.
• W2014184499 hasConcept C126322002 @default.

• next