Risk Of Thrombotic Cardiovascular Events Research Articles

The Impact of Convertase Subtilisin/Kexin Type 9 Monoclonal Antibodies with and without Apheresis on Platelet Aggregation in Familial Hypercholesterolemia

Background and aimsIt is well known that elevated cholesterol is associated with enhanced platelet aggregation and patients suffering from familial hypercholesterolemia (FH) have a high risk of thrombotic cardiovascular events. Although decreasing cholesterol level is associated with attenuation of platelet hyperactivity, there are currently no data on the effect of convertase subtilisin/kexin type 9 monoclonal antibodies (PCSK9ab) on platelet reactivity in FH. The aim of the study was to analyse the impact of different therapies including PCSK9ab on platelet aggregation in FH.MethodsThis study enrolled all 15 patients treated in the University Hospital Hradec Králové for FH. PCSK9ab have been administered in 12 of 15 patients while 8 patients were also undergoing lipid apheresis. Blood samples from all patients including pre- and post-apheresis period were tested for platelet aggregation triggered by 7 inducers, and the effect of 3 clinically used drugs (acetylsalicylic acid, ticagrelor and vorapaxar) was compared as well.ResultsAlthough apheresis decreased the reactivity of platelets in general, platelet responses were not different between non-apheresis patients treated with PCSK9ab and apheresis patients (post-apheresis values) with the exception of ristocetin. However, when compared to age-matched healthy population, FH patients had significantly lower platelet aggregation responses to 4 out of 7 used inducers and higher profit from 2 out of 3 used antiplatelet drugs even after exclusion of FH patients regularly receiving conventional antiplatelet treatment.ConclusionThis study showed for the first time the suitability of PCSK9ab treatment for reduction of platelet reactivity in FH patients.

Stable Discovery of Interpretable Subgroups via Calibration in Causal Studies

SummaryBuilding on Yu and Kumbier's predictability, computability and stability (PCS) framework and for randomised experiments, we introduce a novel methodology for Stable Discovery of Interpretable Subgroups via Calibration (StaDISC), with large heterogeneous treatment effects. StaDISC was developed during our re‐analysis of the 1999–2000 VIGOR study, an 8076‐patient randomised controlled trial that compared the risk of adverse events from a then newly approved drug, rofecoxib (Vioxx), with that from an older drug naproxen. Vioxx was found to, on average and in comparison with naproxen, reduce the risk of gastrointestinal events but increase the risk of thrombotic cardiovascular events. Applying StaDISC, we fit 18 popular conditional average treatment effect (CATE) estimators for both outcomes and use calibration to demonstrate their poor global performance. However, they are locally well‐calibrated and stable, enabling the identification of patient groups with larger than (estimated) average treatment effects. In fact, StaDISC discovers three clinically interpretable subgroups each for the gastrointestinal outcome (totalling 29.4% of the study size) and the thrombotic cardiovascular outcome (totalling 11.0%). Complementary analyses of the found subgroups using the 2001–2004 APPROVe study, a separate independently conducted randomised controlled trial with 2587 patients, provide further supporting evidence for the promise of StaDISC.

The Cost to Society of Pharmaceutical Mass Tort Litigation

This lecture for the Foundation for Law, Justice and Society, at Wolfson College, University of Oxford, addresses the cost to society of pharmaceutical mass tort litigation, nearly 15 years after the withdrawal by Merck & Co., Inc. of Vioxx® (rofecoxib) from markets worldwide. When Merck withdrew Vioxx based on an increased relative risk of thrombotic cardiovascular events seen in the APPROVe study in “the interests of patients” and “as the responsible course to take,” the company’s stock dropped nearly 27%; it took a charge of more than USD 726 million to effect the withdrawal; physicians prescribed alternative pain relievers in the non-steroidal anti-inflammatory drug (NSAID) class such as celecoxib, diclofenac, ibuprofen, and naproxen that did not have rofecoxib’s gastrointestinal safety data; governments investigated the company; and lawyers launched more than 50,000 claims and class actions in the US and many jurisdictions across six continents. Although Merck won most of the cases heard in the United States and prevailed in jurisdictions around the world, the company spent more than USD 2 billion on its own legal defense and nearly USD 7 billion more for the resolution of Vioxx litigation and investigations through the end of 2016. When the interim results of APPROVe were received, “no other non-aspirin NSAIDs or selective COX-2 inhibitors had been studied in this large a patient group for this duration,” and no one knew whether a similar increased relative risk would be seen with other NSAIDs, such as diclofenac and ibuprofen. It now appears that all of the non-aspirin NSAIDs, with the possible exception of naproxen, have a similar cardiovascular safety profile to Vioxx. Merck spent approximately USD 10 billion in connection with withdrawing Vioxx and defending and resolving litigation and investigations. Those funds were not available to fund the discovery and development of up to four or more new breakthrough medications.

Abstract 39: Platelet Reactivity to Prostaglandin E2 is a Novel Modifiable Risk Factor for St-Elevation Myocardial Infarction

Background: Patients with lower thresholds for platelet activation are at increased risk for primary and recurrent myocardial infarction (MI) and overall cardiovascular (CV) mortality. We have demonstrated that there are two phenotypes of platelet response to Prostaglandin E 2 (PGE 2 ), such that it increases threshold for aggregation in 45% of individuals (inhibitory) and lowers threshold for aggregation in 55% (potentiating). As PGE 2 is present in atherosclerotic plaques, and its receptors are present on platelets, biologic variability in PGE 2 responses may have clinical implications. We hypothesized that patients with higher thresholds for platelet activation would have a lower risk of thrombotic CV events, specifically ST-Elevation MI (STEMI). Methods: 85 patients undergoing percutaneous coronary intervention for stable or unstable coronary disease were phenotyped for PGE 2 response. Platelet rich plasma was treated with various concentrations of U46,619 (thromboxane agonist) with or without PGE 2 100 nM, and phenotype determined by light aggregometry. Analysis of the maximum PGE 2 effect (maximum aggregation with PGE 2 minus maximum aggregation without it) was performed using linear and non-linear statistical methods. Results: Traditional cardiovascular risk factors were similar between groups. A higher percentage of patients with the potentiating phenotype had a history of STEMI than those with the inhibitory phenotype. Logistic regression using restricted cubic spline showed that the predicted probabilities of STEMI increased from 0.04 (at the strongest inhibitory phenotype) to 0.43 (at the median phenotype). The OR of phenotype at the median relative to that at the 10th quantile was 7.4 (95 % CI=1.6, 34.8). Conclusions: PGE 2 inhibitory phenotype confers a decreased lifetime risk of STEMI in individuals at high risk for CV events. We have previously shown that an EP3 receptor antagonist converts the potentiating to the inhibitory phenotype. Thus, the PGE2 phenotype may be a novel marker of cardiovascular risk that may also identify patients who would benefit from an EP3 antagonist.

Hyperglycemia repression of miR-24 coordinately upregulates endothelial cell expression and secretion of von Willebrand factor

AbstractAn elevated level of von Willebrand factor (VWF) in diabetic patients is associated with increased risk of thrombotic cardiovascular events. The underlying mechanism of how VWF expression is upregulated in diabetes mellitus is poorly understood. We now report that hyperglycemia-induced repression of microRNA-24 (miR-24) increases VWF expression and secretion in diabetes mellitus. In diabetic patients and diabetic mouse models (streptozotocin/high-fat diet-induced and db/db mice), miR-24 is reduced in both tissues and plasma. Knockdown of miR-24 in mice leads to increased VWF mRNA and protein levels and enhanced platelet tethering (spontaneous thrombosis). miR-24 tightly controls VWF levels through pleiotropic effects, including direct binding to the 3′ untranslated region of VWF and targeting FURIN and the histamine H1 receptor, known regulators of VWF processing and secretion in endothelial cells. We present a novel mechanism for miR-24 downregulation through hyperglycemia-induced activation of aldose reductase, reactive oxygen species, and c-Myc. These findings support a critical role for hyperglycemic repression of miR-24 in VWF-induced pathology. miR-24 represents a novel therapeutic target to prevent adverse thrombotic events in patients with diabetes mellitus.

Cardiovascular risk with non-steroidal anti-inflammatory drugs: clinical implications.

In February 2014, the US Food and Drug Administration (FDA) convened an advisory committee meeting to discuss the accumulated data relating to the cardiovascular risk of non-steroidal anti-inflammatory drugs (NSAIDs) and the potential implications on the class prescription labeling. The committee recommended, though not unanimously, that (1) the current data does not support the conclusion that naproxen has a lower risk of thrombotic events than other NSAIDs; (2) there is no latency period for the risk of cardiovascular thrombotic events; (3) there are some patient populations at increased risk for events; and (4) equipoise remains in the major ongoing trial designed to address these issues further. The clinical implications of the FDA deliberations as well as the recently published meta-analyses and observational studies are discussed. With the information available today, there is insufficient evidence to conclude that there are significant differences between the approved NSAIDs with regard to the potential for cardiovascular events. An approach for balancing the major risks associated with NSAIDs is suggested. Clinicians should continue to use the current FDA NSAID labeling language to guide their decision making for individual patients until such time as the FDA makes changes.

Vorapaxar: Antiplatelet agent reduces risk of thrombotic cardiovascular events

Vorapaxar (Zontivity—Merck Sharp & Dohme), the first in a new class of drug called a protease-activated receptor-1 (PAR-1) antagonist, has received FDA approval. The drug reduces the risk of heart attack, stroke, cardiovascular death, and need for procedures to restore the blood flow to the heart in patients with a history of heart attack or peripheral arterial disease.

Cilostazol-Based Triple Antiplatelet Therapy Compared to Dual Antiplatelet Therapy in Patients with Coronary Stent Implantation: A Meta-Analysis of 5,821 Patients

Background: Uncertainties still remain in terms of what kinds of patients benefit most from cilostazol-based triple antiplatelet therapy (TAT) after coronary stenting. Methods: We performed a meta-analysis of all relevant randomized controlled trials (RCTs) to investigate the effect of TAT versus dual antiplatelet therapy (DAT) in terms of major adverse cardiovascular events (MACEs) in patients undergoing coronary stenting. Results: Fourteen RCTs with 5,821 patients were included in this study. TAT was associated with a significant reduction in the risk of MACEs compared to DAT [9.2 vs. 13.4%; odds ratio 0.59 (0.46, 0.76)] with consistent benefits among patients with diabetes, long lesions and small vessels. There were no significant between-group differences in the risk of cardiac death, myocardial infarction, stent thrombosis and bleeding events; however, the risk of target lesion revascularization was significantly lower in the TAT group. TAT resulted in borderline significant reduction in the risk of cardiovascular thrombotic events in unselected patients and significant decrease in patients with acute coronary syndrome [odds ratio 0.51 (0.27, 0.94)]. Conclusion: Under the treatment of standard DAT, the addition of cilostazol is an effective and relatively safe strategy in preventing MACEs after coronary stenting, especially for patients at high risk of restenosis or clinical events.

Reduced larger von Willebrand factor multimers at dawn in OSA plasmas reflect severity of apnoeic episodes

Plasma von Willebrand factor (VWF), produced in and released from vascular endothelial cells by various stimuli including hypoxia, induces platelet aggregation under high shear stress and plays dual pivotal roles in haemostasis and thrombosis within arterioles, which are regulated by the size of vWF multimers (VWFMs). Patients with obstructive sleep apnoea (OSA) have increased risk of thrombotic cardiovascular events, but the pathogenesis is unclear. We examined the relationship between VWF and OSA by measuring VWF antigen (VWF:Ag), VWFMs, VWF collagen binding activity (VWF:CB) and a disintegrin-like, metalloproteinase, and thrombospiondin type 1 motifs 13. A total of 58 OSA patients were enrolled. Blood samples were collected before sleep, after sleep, and after one night of nasal continuous positive airway pressure therapy. Based on VWFM analysis, OSA patients were classified into three groups; consistently normal VWFMs (group 1, n=29), increased high molecular weight (HMW)-VWFMs at 06:00 h (group 2, n=18), and decreased or absent HMW-VWFMs at 06:00 h (group 3, n=11). Patients in group 3 had significantly worse apnoea/hypopnoea index; VWF:CB followed a similar pattern. We observed a significant decrease in platelet count between 21:00 h and 06:00 h in OSA patients, potentially associated with reduced larger VWFMs together with decreased VWF:Ag levels. Severe OSA may contribute to an arterial pro-thrombotic state.

Cardiovascular Risk Markers and Mechanisms in Targeting the COX Pathway for Colorectal Cancer Prevention

COX-2 inhibition reduces the incidence of colorectal neoplasia. The increased risk of thrombotic cardiovascular events produced by selective or nonselective COX-2 inhibitors, however, has confounded the consideration of employing them in cancer prevention. Developing a strategy for preventing colorectal cancer by inhibiting COX-2 depends on research advances in several key areas, including predictive biomarkers to identify people at the lowest risk for cardiovascular events, the molecular mechanisms whereby interdicting the COX-2 pathway produces thrombotic events, and the pharmacology of the widely divergent agents that act on COX-2 and its downstream pathway.

Blood Pressure and Cardiovascular Outcomes in Patients Taking Nonsteroidal Antiinflammatory Drugs

The increased thrombotic cardiovascular (CV) risk in trials of cyclo-oxygenase-2 (COX-2) inhibitors versus placebo, and the apparent similar risk with nonsteroidal antiinflammatory drugs (NSAIDs), may be related to their potential to elevate blood pressure (BP). We evaluated the relationship between baseline BP and change in BP on CV events (CVEs) in patients receiving NSAIDs or COX-2 inhibitors in the prospective randomized, double-blind, Multinational Etoricoxib and Diclofenac Arthritis Long-term Program (N = 34,701) comparing etoricoxib 60 or 90 mg or diclofenac 150 mg daily for a mean duration of 18 months. The main outcome measure was confirmed thrombotic CVEs. The Antiplatelet Trialists' Collaboration endpoint, all-cause mortality, CV/congestive heart failure (CHF) mortality, and CHF incidence were similarly evaluated. We found that baseline systolic BP (SBP) was associated with significantly higher risk of all events (P < 0.001). Baseline diastolic BP (DBP) was inversely and significantly associated with risk of all events (P < 0.001 to P = 0.016) except CV/CHF mortality (P = 0.054). There was no significant differential effect between etoricoxib and diclofenac in relation to CVEs, except for confirmed CHF, for which the risk was significantly higher with etoricoxib (P = 0.019). Only CHF risk (P = 0.020 for both SBP and DBP change), but not thrombotic endpoints, was significantly associated with change in BP from months 0 to 4. These findings were not meaningfully altered after covariate adjustment for baseline CV risk. Baseline BP, but not change in BP, was significantly associated with risk of thrombotic CVEs through 18 months. The CV risk of COX-2s and NSAIDs did not appear to be related to the BP-elevating effects of these agents, although such analyses, i.e., from randomized controlled trials, are unable to definitively exclude such a relationship.

The Effect of Aspirin on C-Reactive Protein in Hypertensive Patients

High level of C-reactive protein (CRP), most popular inflammatory marker, increases the risk of thrombotic cardiovascular events. Aspirin, which has both anti-inflammatory and anti-thrombotic effects, has the potential to influence CRP release. Several studies have been reported investigating clinical effects of aspirin on CRP levels. Some studies have reported aspirin reduced CRP levels, but other studies did not. This study was designed to assess the effect of low-dose aspirin on CRP levels in controlled hypertensive patients who had low inflammatory burden. Two hundred twenty-five patients with controlled hypertension were randomly divided into two groups; aspirin group (n = 122, 100 mg of aspirin) and the control group (n = 134). Patients with a CRP level >1 mg/dL (10 mg/L) were excluded because these high levels suggest infection. C-reactive protein level and lipid profiles were measured before therapy and 3 months after therapy. There were no differences in baseline clinical characteristics between the two groups. Low-dose aspirin showed no significant influence on CRP levels over 3 months (from 0.10 ± 0.0099 to 0.12 ± 0.0097 mg/dL, p = 0.12). Statin therapy did not influence CRP levels. Aspirin-resistance also had no influence on CRP levels. We conclude that low-dose aspirin has no significant effect on decreasing CRP levels in the patients with controlled hypertension which had low inflammatory burden. The anti-inflammatory mechanism may not play an important role in the cardioprotective effect of aspirin in the population with low inflammatory burden such as controlled hypertensive patients.

C-Reactive Protein and Markers for Thrombophilia in Patients with Chronic Plaque Psoriasis

Chronic plaque psoriasis is associated to an increased risk of cardiovascular events. The aim of our study is to test patients with psoriasis for common markers of acquired and inherited thrombophilia. A cross-sectional study on 172 patients with psoriasis and 198 controls was carried out. The plasma levels of coagulation protein C, coagulation protein S, homocysteine, folic acid, C-reactive protein (CRP) and fibrinogen as well as activated protein C resistance and antithrombin III activity, were measured. CRP and homocysteine levels were higher in patients with psoriasis than in controls (5.9 ± 7.1 vs 3.1 ± 2.4 mg/L, p=0.0003 and 16.3 ± 12.8 vs 10.4 ± 4.6 umol/L, p=0.0001; mean ± SD) whereas folic acid was lower in psoriatic patients compared to controls (4.3 ± 7.2 vs 12.6 ± 7.9 p=0.006). Levels of coagulation protein C, coagulation protein S, fibrinogen as well as activated protein C resistance, antithrombin III activity were within normal ranges both in cases and controls. In a multivariate regression analysis, psoriasis severity was an independent predictor of higher CRP. In conclusion, high levels of serum CRP and homocysteine were found in patients with psoriasis, related to the severity of the disease. These data suggest that the increased risk of thrombotic cardiovascular events observed in psoriasis patients should be ascribed to an acquired rather than inherited thrombophilic status.

Cardiovascular Risks of Anemia Correction with Erythrocyte Stimulating Agents: Should Blood Viscosity Be Monitored for Risk Assessment?

To date, all major clinical trials for anemia correction using erythrocyte stimulating agents (ESAs) failed to show improved outcomes for cardiovascular disease (CVD), stroke, and vascular thrombosis. Even moderate elevations in hemoglobin (e.g., to 13 g/dL) using erythropoietin have been associated with significantly increased risk of thrombotic cardiovascular events and heart failure. This review presents a biophysical rationale for increased risk of CVD among certain patients treated with ESAs and suggests a risk management approach based on blood viscosity. Whole blood viscosity is a key determinant of the work of the heart, and elevated blood viscosity appears to be both a strong predictor of cardiovascular disease and an important pathophysiological factor in the development of atherothrombosis. Blood donation has been shown to reduce viscosity. Reflecting these findings, studies in male blood donors and in women of premenopausal age with regular menstruation have shown reduced incidence of cardiovascular events such as myocardial infarction, angina, stroke, and the requirement for procedures such as percutaneous transluminal coronary angioplasty and coronary artery bypass graft compared with non-donors and postmenopausal women, respectively. We propose that blood viscosity monitoring should be considered as part of a cardiovascular risk assessment, whenever an increased cardiovascular risk is detected and particularly in the context of anemia correction.

Cyclooxygenase-2 Inhibitors in Colorectal Cancer Prevention: Counterpoint

Aspirin is the best chemoprevention agent for colorectal cancer risk reduction despite the fact that the evidence for a decrease in mortality is weak. The cyclooxygenase-2 selective agents (COXIBS) have an efficacy similar to that of aspirin for most gastrointestinal (GI) lesions but not esophagus. Specifically, there are beneficial short term effects of COXIBs on the risk of colorectal adenoma as shown in the Approve, PreSAP, and APC studies. However, there is still an increased risk of upper GI complications with COXIBs when compared with placebo, and this risk may increase further in some people when aspirin is also consumed. Whereas aspirin reduces the risk of cardiovascular events, COXIBs and most traditional nonsteroidal anti-inflammatory drugs (but not all) are both associated with an increased risk of thrombotic cardiovascular events compared with placebo. In conclusion, COXIBs have a niche role for patients with familial adenomatous polyposis. The value of aspirin remains with respect for efficacy, mainly in the esophagus, and the side effect profile, especially in the elderly if given with acid suppression therapy. COXIBs should be used in younger populations, but if they are considered in the elderly because of increased GI risks, and the cardiovascular risk is also increased, then combination treatment with aspirin and a proton-pump inhibitor should also be considered instead, such as in the ASPECT trial.

Microparticle-associated vascular adhesion molecule-1 and tissue factor follow a circadian rhythm in healthy human subjects

An increased risk of death or severe injury due to late-morning thrombotic events is well established. Tissue factor (TF) is the initiator of the coagulation cascade, and endothelial stresses, coupled with production of pro-coagulant microparticles (MP) are also important factors in loss of haemostasis. TF and vascular cell adhesion molecule-1 (VCAM-1) -positive cell microparticles were assessed periodically over a 24-hour (h) period in healthy human subjects to ascertain if they followed a circadian rhythm. Eleven healthy male subjects were assessed in a temperature-controlled environment with dietary intake consistent between subjects. Blood samples were taken every 4 h by venipuncture, and TF and VCAM-1 positive microparticles were quantified by flow cytometry. A significant circadian rhythm was observed in VCAM-1 MP (p=or<0.0001), and a trend was shown, although not statistically significant (p=0.065) in TF microparticles. A peak was observed at 9 a.m. for VCAM-1 positive MP, followed by a decrease and subsequent peak at 9 p.m. and a minimum at 5 a.m. TF-positive MP followed a strikingly similar trend in both variation and absolute numbers with a delay. A circadian rhythm was observed in VCAM-1 and less so TF-positive MP. This has significant implications in terms of the well known increased risk of cardiovascular thrombotic events matching this data. To our knowledge this is the first such report of quantified measurements of these MP over a 24-h period and the only measurement of a 24-h variation of in-vivo blood-borne TF.

The VIOXX in prostate cancer prevention study: cardiovascular events observed in the rofecoxib 25 mg and placebo treatment groups

ABSTRACTBackground: A double-blind, randomized, placebo-controlled study was designed to determine the cumulative incidence of developing prostate cancer over 6 years of treatment with rofecoxib 25 mg/day versus placebo. Before completion, this trial was terminated following the voluntary withdrawal of rofecoxib. (On September 30, 2004, Merck & Co., Inc. announced the voluntary worldwide withdrawal of rofecoxib from the market.) Here we report the cardiovascular (CV) safety data collected from this study.Methods: A total of 4741 men (44–81 years old) exhibiting prostate-specific antigen levels (PSA) between 2.5 and 10 ng/mL were enrolled. Patients were stratified by PSA level and use of low-dose aspirin (LDA), then randomized to rofecoxib 25 mg (n = 2369) or placebo (n = 2372). Safety data were analyzed in all patients receiving ≥1 dose of study medication. All reported thrombotic CV events occurring on-treatment or within 14 days after study drug discontinuation were adjudicated by an independent panel of clinical experts blinded to treatment assignment. Rates per 100 patient-years and relative risk (RR) of thrombotic CV events, rofecoxib vs. placebo, were determined.Results: Approximately 36% of patients had ≥2 CV risk factors or LDA indicated. Median treatment duration was 4.14 (range: 0.03–15.90) months. Twenty-nine patients (14 rofecoxib, rate 1.27; 15 placebo, rate 1.36) experi­enced confirmed thrombotic CV events; RR 0.94 (95% CI: 0.45, 1.94) vs. placebo. Four patients (one rofecoxib; three placebo) died due to a confirmed thrombotic event. Significantly ( p = 0.002) more patients receiving rofecoxib (n = 20; 0.8%) experienced hypertension-related adverse events versus placebo (n = 2; 0.1%). There were no cases of congestive heart failure.Conclusions: Rofecoxib 25 mg and placebo demon­strated similar risk of thrombotic CV events in this limited dataset.

Smoking, Haemostatic Factors, and Cardiovascular Risk

There is a strong relationship between cigarette smoking and haemostatic parameters to increase the risk of cardiovascular events. Smoking influences negatively coagulation-fibrinolysis cascade at any level, although it acts primarily on those pathways that are most important for an effective clot formation: endothelium, platelets, and fibrinogen. Endothelial dysfunction is a main consequence of smoke compounds with significant changes in initiating physiologic coagulation process; platelet adhesiveness and aggregation increases as a result of smoking; finally, fibrinogen/fibrin framework strengthens clot thickness. Therefore, the whole coagulation cascade activates the thrombi formation pathway under smoking action. The risk of thrombotic cardiovascular events increases its frequency with more severe atherosclerotic alterations if compared to similar events in nonsmokers. Changes in haemostatic factors produced by smoking appear to be related to female sex, especially for those women who use oral contraceptives. Thrombosis of coronary and cerebral arteries are found with a major incidence in young women who are users. In conclusion, cigarette smoking modifies haemostatic parameters via thrombosis with consequently more rate of cardiovascular events.

COX-2: Friend or Foe?

It wasn't until 1990, when the existence of two different cyclooxygenases was hypothesized, based on the evidence that steroids inhibited the increase in COX activity induced by bacterial lipopolysaccharides in macrophages, without any effects on the basal production of prostaglandins or leukotrienes. The first isoform, COX-1 is responsible for the production of "housekeeping" prostaglandins critical to the maintenance of normal renal function, gastric mucosal integrity, platelet aggregation, and the autocrine response to circulating hormones. COX-2 on the other hand is an inducible enzyme, upregulated 20-fold in macrophages, monocytes, synoviocytes, chondrocytes, fibroblasts, osteoblasts and endothelial cells by various inflammatory stimuli and cytochines. Classical findings shown that the therapeutics effects of NSAIDs are largely dependent on COX-2 inhibition, whereas some undesirable side effects are bound to COX-1 blockade, such as gastrointestinal bleeding and renal failure. Therefore, agents that selectively inhibit COX-2 over COX-1 are desirable for the treatment of inflammation. However, since September 2004 reports of increased risk of thrombotic cardiovascular events had accumulated for coxibs, the COX-2 inhibitors. Our goal is to provide an overview of the relevant biology and pharmacology of this enzyme in atherosclerosis.

This Month in Gastroenterology

This Month in Gastroenterology