Prevention of NSAID-induced ulcers

Opinion statement Cyclooxygenase-2 (COX-2) selective inhibitors were developed as gastrointestinal (GI) safer alternatives to nonselective NSAIDs—providing equivalent analgesic and anti-inflammatory efficacy. Their GI sparing is impaired by concomitant aspirin use, and concerns regarding adverse cardiovascular effects have emerged. Risk factors for NSAID-related complications include a history of ulcer disease or bleeding, concomitant corticosteroid or anticoagulant therapy, use of high-dose or multiple NSAIDs (including low-dose aspirin), advanced age, and certain chronic diseases. If an NSAID must be used in a patient at risk, the lowest-risk NSAID should be used with, in many cases, cotherapy to reduce the risk for ulcers. COX-2 drugs have been associated with a significantly higher risk of vascular events than placebo or naproxen. This increase may be shared by nonselective NSAIDs and appears to be medication-and dose-dependent. Prostaglandin depletion is a central mechanism for NSAID ulcer development, and replacement therapy with misoprostol reduces NSAID toxicity; however, it is rarely used due to side effects. The acid suppression provided by traditional doses of histamine 2-receptor antagonists (H₂RAs) does not prevent most NSAID-related gastric ulcers. Despite a single study demonstrating that H₂RAs at double the dose may be effective, studies comparing such high doses with misoprostol or proton pump inhibitors (PPIs) for preventing NSAID ulcers are not available. PPIs are effective at single daily doses, do not demonstrate tachyphylaxis, and are superior to H₂RAs and misoprostol in reducing ulcers and NSAID-associated dyspepsia. NSAID choice should be predicated by an assessment of an individual’s cardiovascular and GI risk. For those with competing cardiovascular and GI risks, the tradeoffs between reducing adverse GI events (COX-2 inhibitor instead of a nonselective NSAID) must be explicitly weighed against concerns about cardiovascular side effects (naproxen instead of other agents). Considering cost is appropriate because it may not be feasible to recommend the “safest” regimen in every circumstance. The cost effectiveness of risk-reducing therapies is intimately tied to the patient’s underlying risk. For those at highest GI risk, using a PPI and a low-dose COX-2 inhibitor seems appropriate for those without high cardiovascular risk. For patients whose cardiovascular risk parallels or exceeds GI concerns, naproxen with a PPI is recommended when non-NSAID approaches fail.     

Coxibs interfere with the action of aspirin by binding tightly to one monomer of cyclooxygenase-1

Pain associated with inflammation involves prostaglandins synthesized from arachidonic acid (AA) through cyclooxygenase-2 (COX-2) pathways while thromboxane A₂ formed by platelets from AA via cyclooxygenase-1 (COX-1) mediates thrombosis. COX-1 and COX-2 are both targets of nonselective nonsteroidal antiinflammatory drugs (nsNSAIDs) including aspirin whereas COX-2 activity is preferentially blocked by COX-2 inhibitors called coxibs. COXs are homodimers composed of identical subunits, but we have shown that only one subunit is active at a time during catalysis; moreover, many nsNSAIDS bind to a single subunit of a COX dimer to inhibit the COX activity of the entire dimer. Here, we report the surprising observation that celecoxib and other coxibs bind tightly to a subunit of COX-1. Although celecoxib binding to one monomer of COX-1 does not affect the normal catalytic processing of AA by the second, partner subunit, celecoxib does interfere with the inhibition of COX-1 by aspirin in vitro. X-ray crystallographic results obtained with a celecoxib/COX-1 complex show how celecoxib can bind to one of the two available COX sites of the COX-1 dimer. Finally, we find that administration of celecoxib to dogs interferes with the ability of a low dose of aspirin to inhibit AA-induced ex vivo platelet aggregation. COX-2 inhibitors such as celecoxib are widely used for pain relief. Because coxibs exhibit cardiovascular side effects, they are often prescribed in combination with low-dose aspirin to prevent thrombosis. Our studies predict that the cardioprotective effect of low-dose aspirin on COX-1 may be blunted when taken with coxibs.     

NSAIDs and the gastrointestinal tract

NSAIDs incur significant gastrointestinal (GI) side effects. The complication risk increases with history of peptic ulcer or older age. Helicobacter pylori infection and cardioprotective aspirin have independent and additive risks in the presence of NSAID use. NSAID enteropathy is increasingly recognized. Cardiovascular and GI risk stratification and H. pylori infection testing should be done before initiating NSAIDs. An NSAID combined with a proton pump inhibitor (PPI) is comparable to cyclooxygenase (COX)-2 inhibitors for gastroprotection, but for high-risk patients, COX-2 plus PPI should be considered. Aspirin and COX-2 inhibitors are associated with reduced colon adenoma risk, but higher dose and longer duration of treatment with aspirin appears effective. Hence, patients at high risk of colorectal cancer (with significant family or personal history of premalignant adenoma) must be identified, and cardiovascular and GI risk must be assessed before using these agents as chemopreventive drugs.     

Primer: managing NSAID-induced ulcer complications--balancing gastrointestinal and cardiovascular risks

Ulcer complications associated with the use of NSAIDs, in high-risk patients, are often caused by a failure to identify patients' risk factors, concomitant use of aspirin or multiple NSAIDs, and underutilization of gastroprotective agents. Current data suggest that cyclo-oxygenase 2 (COX2) inhibitors and some nonselective NSAIDs increase the risk of myocardial infarction. Physicians must, therefore, take into account both the gastrointestinal and the cardiovascular risks of individual patients when prescribing NSAIDs. In patients with a low cardiovascular risk, NSAIDs can be prescribed according to the level of gastrointestinal risk. Patients with a moderate gastrointestinal risk (one or two risk factors) should receive a COX2 inhibitor or an NSAID plus a PPI or misoprostol. Patients with more than two gastrointestinal risk factors or prior ulcer complications require the combination of a COX2 inhibitor and a PPI. Patients with a high cardiovascular risk (e.g. coronary heart disease or an estimated 10-year cardiovascular risk greater than 10%) should receive prophylactic aspirin and combination therapy with a PPI or misoprostol irrespective of the presence of gastrointestinal risk factors. Naproxen is the preferred NSAID because it is not associated with excess cardiovascular risk. Patients with a high cardiovascular risk and a very high gastrointestinal risk should avoid using NSAIDs or COX2 inhibitors.     

Role of cyclooxygenase-2 in pathogenesis and prevention of colorectal cancer

Chemoprevention of colorectal cancer is a promising science that has particular importance due to the limited success of current treatments for most advanced common malignancies. Many chemopreventive agents have been studied including cyclooxygenase (COX) inhibitors. Two isoforms of the COX enzymes are COX-1 and COX-2. COX-1 is constitutively expressed in normal tissue, serving an important role in tissue homeostasis, whereas COX-2 is an inducible enzyme, which is markedly overexpressed at sites of inflammation and colorectal neoplasms. The preventive efficacy of traditional nonsteroidal anti-inflammatory drugs (NSAIDs), which inhibit COX-1 and/or COX-2, has considerable support from animal and epidemiological studies; however, there are well-documented toxicities associated with NSAID use. These adverse effects are attributed to NSAIDs' inhibition of COX-1. The development of COX-2 specific inhibitors gave hopes of bypassing the associated traditional NSAID toxicities while better targeting tissues sustaining inflammation and neoplasia. The PrsSAP, APC and APPROVe trials demonstrated the efficacy of COX-2 specific inhibitors in preventing the recurrence of sporadic colorectal polyps. However, the trials were terminated early due to discovery of significant cardiovascular toxicity, although the exact extent of this toxicity remains unclear. The exact mechanisms through which NSAIDs exert their cancer preventing effects are currently unknown; inhibition of COX-2 is of great importance, but COX-2 independent pathways exist as well. In addition, the efficacy of NSAID use for cancer prevention can differ significantly between individuals. Personalized medicine in this field is also greatly anticipated. Combination therapy is under extensive research in order to improve efficacy while reducing toxicity profiles. Chemoprevention of colorectal cancer is largely possible, but the ultimate drug and proper patient selection, among other elements of the cancer prevention equation, are still needed.     

Prevention and treatment of NSAID-induced gastroduodenal injury

Opinion statement NSAIDs increase the risk of gastrointestinal (GI) complications. Those at risk should be considered for alternatives to NSAID therapy, modifications of risk factors, and prevention strategies with co-therapy with gastroprotective agents (proton-pump inhibitors [PPIs] or misoprostol) or COX-2 selective inhibitors (coxibs). Since coxibs, and probably other nonselective NSAIDs, may increase the risk of cardiovascular events, prevention strategies must take into account both GI and cardiovascular risk factors. All NSAIDs and coxibs should be prescribed at the lowest possible dose and for the shortest period of time. In patients with GI risk factors but no cardiovascular risk, coxibs or NSAIDs plus PPI or misoprostol are valid options. Patients with a history of ulcer bleeding should receive coxib plus PPI therapy and should be tested and treated for Helicobacter pylori infection. Most patients with increased cardiovascular risk will be treated with antiplatelet agents. It is not known whether co-therapy with low-dose aspirin will reduce the incidence of cardiovascular events, but it will further increase GI risk. It is currently unclear whether the risk of developing upper GI events with coxib plus aspirin is lower than it is with NSAIDs plus aspirin. However, all these patients should benefit from PPI co-therapy. Helicobacter pylori eradication should be considered as an additional therapeutic option when we want to further reduce the GI risk in specific patients. When the lower GI tract is of concern, coxib rather than NSAID therapy should be considered as the first option. Coxib therapy has better GI tolerance than NSAIDs, but patients with peptic ulcers or dyspepsia during NSAID/coxib treatment need PPI co-therapy.     

Drug insight: cyclo-oxygenase 2 inhibitors and cardiovascular risk--where are we now?

Cyclo-oxygenase (COX) 1 mediates the production of thromboxane A2 in platelets, leading to platelet aggregation and vasoconstriction. Conversely, COX2 catalyzes endothelial prostacyclin synthesis, which effectively counteracts thromboxane A2, triggering vasodilation and platelet inhibition. Selective COX2 inhibitors decrease prostacyclin production, potentially disrupting homeostasis and creating a prothrombotic state. The VIGOR study findings of increased cardiovascular risk with rofecoxib were subsequently confirmed by large meta-analyses, observational studies and recent APPROVe trial publication. The APC trial findings of increased cardiovascular risk with Celebrex (celecoxib) conflict with those in the ADAPT trial, the upcoming PreSAP publication, a case-control study by Graham et al. and prior large clinical trials, meta-analyses and observational studies of this drug. Therefore, while an adverse class effect is a possibility for COX2 inhibitors, the published data are inconsistent. Baseline cardiovascular risk in patients might contribute significantly to these findings. In light of the negative Vioxx (rofecoxib) publicity, however, COX2 inhibitors might forever remain underinvestigated. The relative selectivity of these compounds for COX2 is extremely variable, casting significant doubt on the class-effect hypothesis. Improved endothelial function has also been reported with celecoxib, leading to endothelium-dependent vasodilation, and associated decreases in C-reactive protein and LDL cholesterol. The addition of meloxicam to low-dose aspirin and heparin has improved clinical outcomes after acute coronary syndromes. These are the first studies suggesting improvement in endothelial function and reduction of inflammation with COX2 inhibition. Thus, more randomized controlled trials are needed to study the relative cardiovascular effects of different COX2 inhibitors, alone and in combination with aspirin.     

Prevention of thrombosis and vascular inflammation: importance of combined cyclooxygenase and 5-lipoxygenase inhibitors

Aspirin, a standard non-steroidal anti-inflammatory drug (NSAID) is currently used in antithrombotic treatment. However, its use is limited by largely recognized gastrotoxicity and recommended doses are low. The major side effect of aspirin is related to its ability to suppress prostaglandin (PG) synthesis by constitutive cyclooxygenase-1 (COX-1). Specific inhibitors of COX-2, the inducible isoform of COX which was more recently described, have potent antiinflammatory effects. They are associated with minor risk of gastric tractus toxicity and reduced inflammatory leukocyte components known for their proatherothrombotic properties. Nevertheless, recent findings attributed a significant cardiovascular risk to some of them. 5-lipoxygenase (5-LOX), an enzyme mainly expressed by leukocytes, is responsible for the generation of leukotrienes, the major lipidic proinflammatory mediators. Development of combined inhibitors of 5-LOX and COX isoforms 1 and 2 inaugurate an interesting new therapeutic pathway. Indeed, such inhibitors suppress not only the activation of platelets, leukocytes and endothelial cells but also prevent their metabolic and functional interactions. In addition to their broad spectrum inhibition, they may be associated with the minor gastrotoxic effect. Thus, platelet-leukocyte interactions which dominate the underlying inflammatory process particularly in atherosclerosis, might reinforce the benefits of such inhibitors.     

Prevalence and mechanism of nonsteroidal anti-inflammatory drug-induced clinical relapse in patients with inflammatory bowel disease.

BACKGROUND & AIMS: It has been variably suggested that nonselective NSAIDs and cyclooxygenase (COX)-2 selective inhibitors aggravate or ameliorate clinical disease activity in patients with inflammatory bowel disease. We assessed the effect of these drugs in patients with inflammatory bowel disease (n = 209) and the possible mechanisms. METHODS: First, patients with quiescent Crohn's disease and ulcerative colitis received the non-NSAID analgesic acetaminophen (n = 26) and the conventional NSAIDs naproxen (n = 32), diclofenac (n = 29), and indomethacin (n = 22) for 4 weeks. The Harvey-Bradshaw index was used to define relapse. Second, to assess the mechanism of relapse, intestinal inflammation was quantitated (fecal calprotectin) before and during treatment (20 patients/group) with acetaminophen, naproxen (topical effect, COX-1 and -2 inhibitor), nabumetone (COX-1 and -2 inhibitor), nimesulide (selective COX-2 inhibitor), and low-dose aspirin (selective COX-1 inhibition). RESULTS: Nonselective NSAIDs were associated with a 17%-28% relapse rate within 9 days of ingestion. No patient had an early relapse on acetaminophen, nimesulide, or aspirin, whereas those on naproxen and nabumetone (20%) experienced relapse. These clinical relapses were associated with escalating intestinal inflammatory activity. CONCLUSIONS: NSAID ingestion is associated with frequent and early clinical relapse of quiescent inflammatory bowel disease, and the mechanism appears to be due to dual inhibition of the COX enzymes. Selective COX-2 inhibition with nimesulide and COX-1 inhibition with low-dose aspirin appear to be well-tolerated in the short-term.     

Gastroprotective therapy and risk of gastrointestinal ulcers: risk reduction by COX-2 therapy

OBJECTIVE: Proton pump inhibitors (PPI) and misoprostol decrease the risk of development of nonsteroidal antiinflammatory drug induced gastric ulcers and aid healing of upper gastrointestinal (GI) ulcers. H2 receptor antagonists (H2RA) are less effective for this task, but are widely used by patients and physicians for the treatment of GI symptoms and duodenal ulcers. Sucralfate is a weaker agent that is sometimes used for prophylaxis or treatment of upper GI ulcers. We investigated the effect of GI drugs and selective and nonselective NSAID on the incidence of GI ulcer development in a cohort of patients immediately after the release of celecoxib and rofecoxib to investigate the effect of confounding by indication when effective GI agents and cyclooxygenase 2 (COX-2)-specific inhibitors are prescribed to a high risk population. METHODS: During a 6 month period of observation 8547 NSAID users were evaluated by mailed questionnaire concerning NSAID drug use and ulcer development. In the first half of 1999, patients took 12,177 separate NSAID courses. GI therapy that followed the development of upper GI ulcers was excluded from analysis. Ulcer reports were confirmed by followup validation. RESULTS: GI drugs were used concomitantly in this population by 42% of patients using an NSAID. GI drugs were associated with an increased risk of ulcer. But this risk was confined to PPI (OR 4.1, 95% CI 2.95, 5.69), and not to other GI drugs. Overall, patients using nonselective NSAID compared to those taking COX-2-specific inhibitors had an increased risk of upper GI ulcers (OR 2.12, 95% CI 1.43, 3.34). Patients taking nonselective NSAID plus PPI were also at increased risk for upper GI ulcers compared to those taking nonselective NSAID alone (OR 5.09. 95% CI 3.88, 6.67). Similarly, the risk of upper GI ulcers was increased in the nonselective NSAID plus PPI group (OR 3.83, 95% CI 2.32, 6.31) compared to the COX-2 plus PPI group. CONCLUSION: PPI use, but not other GI drug use, is a marker for increased susceptibility to ulcers among NSAID users. This risk of upper GI ulcers is increased in PPI users regardless of which NSAID is used (nonselective or COX-2-specific inhibitor). Although COX-2 use is associated with greater risk factors for upper GI ulcers due to channeling bias, COX-2 users have significantly fewer ulcers than equivalent nonselective NSAID users regardless of concomitant PPI utilization.     

Non-steroidal anti-inflammatory agents with selective inhibitory activity on cyclooxygenase-2. Interest and future prospects

INTRODUCTION: Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit the production of primary prostanoids by blocking the access of arachidonic acid to the active site of the cyclooxygenases (COXs). Because the prostanoids produced by COX-1 appear to play a physiological role (protection of the gastric mucosa, platelet aggregation, vascular homeostasis, maintenance of renal sodium-water balance) while those produced by COX-2 seem mainly to intervene in the inflammatory response and in certain processes associated with cell proliferation, the hypothesis has been put forward that the NSAIDs that are selective COX-2 inhibitors should theoretically be capable of maintaining NSAID therapeutic properties but also have fewer adverse side effects due to the maintenance of prostaglandin production at normal physiological levels. CURRENT KNOWLEDGE AND KEY POINTS: The hypothesis of COX isoenzyme selectivity has led to a proposed classification for COX inhibitors: 1) COX-1 selective inhibitors (low-dosage aspirin); 2) COX non-selective inhibitors (the majority of classified NSAIDs, which when administered over the long term, e.g., in cases of rheumatoid arthritis, cause duodenal ulcers in 20% of cases and gastric hemorrhage in 1-4% of cases/year); 3) COX-2 preferential inhibitors (meloxicam and nimesulide, which have fewer gastric side effects than standard NSAIDs, but which are not risk-free at high doses); 4) COX-2 selective inhibitors (celecoxib and rofecoxib). Preliminary clinical studies have shown that COX-2 selective inhibitors are as efficient as standard NSAIDs and have fewer adverse digestive side effects, thereby confirming the interest of this proposed classification. In the UK, the aforementioned studies have led to the commercialization of rofecoxib for the treatment of pain and osteoarthritis, while celecoxib has been introduced in medical practice in the USA and other countries for the treatment of rheumatoid arthritis and osteoarthritis. FUTURE PROSPECTS AND PROJECTS: Various epidemiological and laboratory studies have indicated that NSAIDs may be able to reduce the risk of cancer (colorectal cancer in particular) and Alzheimer's disease due to their inhibitory activity on COXs, especially COX-2. The therapeutic contribution of COX-2 specific inhibitors has to be more fully evaluated, particularly as these agents could delay the healing of duodenal ulcers and interfere with several COX-2-induced physiological functions. It is therefore suggested that until further information becomes available, this new class of NSAIDs should be used with caution in certain patient populations.     

Appropriate use of NSAIDs: considering cardiovascular risk in the elderly

In the first of this two-part article, we reviewed essential gastrointestinal (GI) data necessary for choosing selective COX-2 inhibitors (coxibs) versus nonselective nonsteroidal anti-inflammatory drugs (NSAIDs), as well as other NSAID-related GI issues. Although GI considerations are critical to appropriate NSAID selection, the worldwide withdrawal of rofecoxib because of adverse cardiovascular (CV) events has changed the focus of appropriate NSAID selection. In part 2, we discuss relevant CV adverse effects related to NSAID use. Based upon data reviewed, we believe there are differences between coxibs and that all NSAIDs, including nonselective agents, have some degree of CV risk. Their use should be based upon patient's risks and benefits. Our clinical use pathway or algorithm will continue to frame the ongoing discussion and guide clinicians along what has become a difficult decision in daily practice.     

Osteoarthritis therapy--are there still unmet needs?

Non-steroidal anti-inflammatory drugs (NSAIDs) and selective cyclooxygenase (COX)-2 inhibitors are commonly used to control pain and inflammation in osteoarthritis. However, these agents have been associated with gastrointestinal, renal and cardiovascular adverse effects. Together, these complications indicate a clear unmet need in the safety of current treatment options for the management of osteoarthritis. NSAIDs are known to have adverse gastrointestinal effects, and more recently it has been suggested that some selective COX-2 inhibitors are also associated with serious gastrointestinal complications. Selective COX-2 inhibitors have a similar capacity to NSAIDs to delay ulcer healing, and may not significantly decrease the incidences of perforation, ulceration and bleeding (the most clinically relevant gastrointestinal endpoints) compared with NSAIDs. These effects may be due to overlapping roles of COX-1 and COX-2 in physiological and pathophysiological processes. Furthermore, as COX-2 is integrally involved in renal homeostasis, selective COX-2 inhibitors are associated with negative effects on kidney function similar to those seen with NSAIDs. Electrolyte disturbances, oedema and hypertension have been correlated with the use of both drug classes. Additionally, selective COX-2 inhibitors have the potential to increase cardiovascular events, although further research is required to clearly determine such a risk. With the current unmet needs in the treatment of osteoarthritis, the opportunity exists for the development of new therapies. Novel agents include the COX-inhibiting nitric oxide donors and the lipoxygenase (LOX)/COX inhibitor licofelone. Initial results suggest that these therapies may have tolerability advantages over the NSAIDs and selective COX-2 inhibitors.     

Are COX-2 inhibitors preferable to non-selective non-steroidal anti-inflammatory drugs in patients with risk of cardiovascular events taking low-dose aspirin?

Cyclo-oxygenase-2 selective inhibitors and non-selective non-steroidal anti-inflammatory drugs (NSAIDs) are associated with increased risk of acute cardiovascular events. Only aspirin offers primary and secondary cardiovascular prophylaxis, but trials have not answered directly whether low-dose aspirin is cardioprotective with COX-2 inhibitors. A large inception cohort study showed that concomitant use of aspirin reduced risk of cardiovascular events when given with rofecoxib, celecoxib, sulindac, meloxicam, and indometacin but not when given with ibuprofen. In large trials assessing gastrointestinal safety, there were fewer gastrointestinal events in patients using both COX-2 inhibitors and aspirin than in those using non-selective NSAIDs and aspirin; significantly fewer uncomplicated upper gastrointestinal events took place in the MEDAL trial. Analysis of VIGOR and two capsule endoscopy studies showed significantly less distal gastrointestinal blood loss with COX-2 inhibitors than with non-selective NSAIDs. Endoscopy trials showed that low-dose aspirin does not diminish the gastrointestinal benefits of COX-2 inibitors over non-selective NSAIDs. In an elderly epidemiological cohort receiving aspirin, both celecoxib and rofecoxib reduced risk of admission for gastrointestinal events. Comparison of the cardiovascular and gastrointestinal risks is difficult: likelihood and severity of cardiovascular events differ between individuals, agents, and exposure. Mortality associated with gastrointestinal events is less frequent than with cardiovascular events, but asymptomatic ulcers can result in severe complications. Data support the conclusion that COX-2 inhibitors are preferable to non-selective NSAIDs in patients with chronic pain and cardiovascular risk needing low-dose aspirin, but relative risks and benefits should be assessed individually for each patient.     

Are COX-2 inhibitors preferable to non-selective non-steroidal anti-inflammatory drugs in patients with risk of cardiovascular events taking low-dose aspirin?

Cyclo-oxygenase-2 selective inhibitors and non-selective non-steroidal anti-inflammatory drugs (NSAIDs) are associated with increased risk of acute cardiovascular events. Only aspirin offers primary and secondary cardiovascular prophylaxis, but trials have not answered directly whether low-dose aspirin is cardioprotective with COX-2 inhibitors. A large inception cohort study showed that concomitant use of aspirin reduced risk of cardiovascular events when given with rofecoxib, celecoxib, sulindac, meloxicam, and indometacin but not when given with ibuprofen. In large trials assessing gastrointestinal safety, there were fewer gastrointestinal events in patients using both COX-2 inhibitors and aspirin than in those using non-selective NSAIDs and aspirin; significantly fewer uncomplicated upper gastrointestinal events took place in the MEDAL trial. Analysis of VIGOR and two capsule endoscopy studies showed significantly less distal gastrointestinal blood loss with COX-2 inhibitors than with non-selective NSAIDs. Endoscopy trials showed that low-dose aspirin does not diminish the gastrointestinal benefits of COX-2 inibitors over non-selective NSAIDs. In an elderly epidemiological cohort receiving aspirin, both celecoxib and rofecoxib reduced risk of admission for gastrointestinal events. Comparison of the cardiovascular and gastrointestinal risks is difficult: likelihood and severity of cardiovascular events differ between individuals, agents, and exposure. Mortality associated with gastrointestinal events is less frequent than with cardiovascular events, but asymptomatic ulcers can result in severe complications. Data support the conclusion that COX-2 inhibitors are preferable to non-selective NSAIDs in patients with chronic pain and cardiovascular risk needing low-dose aspirin, but relative risks and benefits should be assessed individually for each patient.     

Risks of clinically significant upper gastrointestinal events with etodolac and naproxen: a historical cohort analysis

BACKGROUND AND AIMS: Etodolac is a generic nonsteroidal anti-inflammatory drug (NSAID). Previous in vitro studies have shown that etodolac is a selective inhibitor of cyclooxygenase (COX)-2 with selectivity in between that of other COX-2 inhibitors such as celecoxib and rofecoxib. However, there are no outcomes data assessing clinically significant upper gastrointestinal (CSUGI) events with etodolac. METHODS: A historical cohort study was performed at the Dallas Veterans Affairs Medical Center in which 16,286 veteran patients (5596 patient-years) received etodolac or naproxen during a 3-year period without concurrent use of other ulcerogenic drugs other than low-dose aspirin. The primary outcome was the CSUGI event rate of the etodolac and naproxen groups without concomitant low-dose aspirin. RESULTS: The incidence of CSUGI events was .78% and .24% for naproxen and etodolac, respectively. In the NSAID-naive subset, the incidence of CSUGI events was .99% and .24% for naproxen and etodolac, respectively. Compared with naproxen, etodolac was associated with a reduction in upper gastrointestinal events, corresponding to an odds ratio of .39 (95% confidence interval, .20-.76; P = .006). Concomitantly used low-dose aspirin increased event rates with naproxen 2-fold and etodolac 9-fold. Hence, there was no significant difference in gastrointestinal event rates between etodolac and naproxen when low-dose aspirin was taken concomitantly. CONCLUSIONS: Etodolac is a generic COX-2 selective inhibitor that reduces CSUGI events compared with the nonselective NSAID naproxen. However, concomitant use of low-dose aspirin negates the gastrointestinal safety advantages of etodolac.     

Comparative antiplatelet activity of COX1 NSAIDS versus aspirin, encompassing regimen simplification and gastroprotection: a call for a controlled study

This study was conducted to assess the feasibility of COX1 NSAID substitution for aspirin for preventative therapy related to circulating anticoagulants, as manifest by inhibition of platelet aggregation. There was no difference in platelet aggregation inhibition between aspirin, naproxen, ketoprofen or diclofenac and misoprostol (in combination in the form of Arthrotec). As COX1 NSAIDs appear equivalent in platelet inhibition efficacy to aspirin, therapeutic regimens can be simplified in those individuals who require an NSAID for other problems. Further, despite its short serum halflife, Arthrotec appears as effective as an antiplatelet agent. Controlled, double blind studies of efficacy in blocking clinical events (both cardiovascular and gastrointestinal) are recommended.