After Vioxx: The Issue of Safety in Prescribing COX-2 Inhibitors
Author: Robert A. Hawkins, MD, FACR, Associate Professor of Medicine, Wright State University, Dayton, OH; Associate Residency Program Director, Internal Medicine Residency Program, Kettering Medical Center, Kettering, OH.
Peer Reviewer: Allan J. Wilke, MD, Associate Professor, Family Medicine, Medical College of Ohio, Toledo.
After the voluntary withdrawal of Vioxx (rofecoxib) from the market in September 2004 following reports of increased cardiovascular events associated with the drug, there was a call from some quarters for a similar action for all selective COX-2 inhibitors (coxibs). Traditional nonselective nonsteroidal antiinflammatory drugs (NSAIDs) always have been troubled by a significant risk of serious gastrointestinal complications resulting in substantial morbidity and mortality. The discovery of two isomers of cyclooxygenase (COX-1 and COX-2) in the 1990s led to the development of the coxibs, with their ability to selectively inhibit the inflammatory effects of COX-2 while preserving the beneficial effects of COX-1 on the gastrointestinal tract.
Selective COX-2 inhibition, however, may block the ability of the vascular endothelial cell to protect itself against platelet adhesion while allowing COX-1 mediated platelet adhesion to proceed, tilting the balance of hemostasis toward thrombosis.
As they are faced with concerned patients and the need to make decisions regarding appropriate use of anti-inflammatory drugs, clinicians will benefit if they are aware of the events that led to the withdrawal of rofecoxib from the market. They also need to understand the unique properties of the coxibs and how they may impact on the cardiovascular system and on the concept of a coxib class effect. This article reviews the current clinical knowledge regarding the coxibs and their cardiovascular effects. Recommendations for prescribing anti-inflammatory drugs in common clinical situations are provided.—The Editor
Introduction
On September 30, 2004 Vioxx (rofecoxib) was voluntarily withdrawn from the worldwide market by Merck and Co. due to a reported increase in cardiovascular events associated with the drug.1
A selective COX-2 inhibitor of prostaglandin production, rofecoxib was approved by the U.S. Food and Drug Administration (FDA) for the treatment of osteoarthritis, rheumatoid arthritis, severe menstrual cramps, acute pain, and juvenile rheumatoid arthritis. It accounted for $2.5 billion in worldwide sales in 2003, and was used by 20 million people at the time of its recall.2
This article will review the events leading to the withdrawal of rofecoxib from the market, describe the unique properties of selective COX-2 inhibitors (also known as coxibs) that may impact the cardiovascular system, and explore the concept of a class effect that could influence clinical decisions regarding available coxibs. This review will conclude with recommendations for prescribing anti-inflammatory drugs in common clinic situations.
The Rofecoxib Story
NSAIDS commonly have been used for many years to treat arthritis, menstrual pain, and other acute and chronic painful conditions. Their use has been limited by dyspepsia and gastric or duodenal ulcers leading to perforation, obstruction, and serious gastrointestinal bleeding. NSAID gastropathy was estimated to cause 16,500 deaths annually in patients with osteoarthritis or rheumatoid arthritis in the United States.3 The discovery in the early 1990s of two isomers of the cyclooxygenase enzyme that catalyzes transformation of arachadonic acid to prostaglandins and thromboxanes led to the development of the coxibs.4
In 1999 the FDA approved rofecoxib for treatment of acute pain, dysmenorrhea, and osteoarthritis. This approval was based on phase III clinical trials involving approximately 5000 patients that did not anticipate or assess for an increased cardiovascular risk. In 2000 the Vioxx Gastrointestinal Outcomes Research study (VIGOR)5 was published. This randomized, double-blind study of 8076 patients with rheumatoid arthritis compared the occurrence of gastrointestinal toxicity of rofecoxib 50 mg/day to naproxen (Aleve, Anaprox, Naprosyn) 1000 mg/d. Median study duration was 9 months, and aspirin use was not allowed. The primary conclusion of the study was that treatment with rofecoxib was associated with 60% fewer clinically important upper gastrointestinal events (gastroduodenal perforation or obstruction, upper gastrointestinal bleeding, and symptomatic gastroduodenal ulcers) than treatment with naproxen. It also confirmed that both drugs had similar efficacy in the treatment of rheumatoid arthritis. It is important to note that investigators chose a high (50 mg/day) dose of rofecoxib for this study. The good news was that even this high dose of the drug was associated with a reduced incidence of upper gastrointestinal events compared with naproxen.
An unexpected finding of the VIGOR trial5 was an increased rate of acute myocardial infarction (AMI) in the rofecoxib group compared to the naproxen group (0.4% vs. 0.1%). Although aspirin use was not allowed, 4% of the patients met FDA criteria for the use of aspirin for secondary cardiovascular prophylaxis. These patients accounted for a disproportionately large 38% of the patients who had AMI. The investigators theorized that this effect could be due to a coronary protective effect of naproxen, based on its ability to inhibit platelet aggregation.5 Other possibilities included a random event or a deleterious effect of rofecoxib.
An FDA advisory committee met in February 2001 to review results of the VIGOR study. The committee determined that, based on current data, the risk/benefit ratio still was sufficiently favorable but recommended changes in labeling and additional studies of cardiovascular risk. The new labeling advised caution in prescribing rofecoxib to patients with ischemic heart disease and stated that the 50 mg dose should not be used for more than five days.
Three large prospective, randomized, placebo-controlled trials of rofecoxib already had been initiated in 2000. These included the Adenomatous Polyp Prevention on Vioxx (APPROVe) trial and the Vioxx in Colorectal Therapy, Definition of Optimal Regimen (VICTOR) study. A third study for prostate cancer had begun. These studies were structured to include the incidence of cardiovascular outcomes as a prespecified secondary end point.
Three studies6-8 concluded that naproxen exerted a cardiovascular protective effect. This supported the hypothesis put forth in the VIGOR study that the reason more patients taking rofecoxib had AMI than those taking naproxen was that naproxen decreased the incidence of myocardial infarction. Other studies, however, failed to show a cardioprotective benefit of naproxen or other NSAIDs.9,10
Two other retrospective cohort studies found an increased cardiovascular risk associated with doses of rofecoxib higher than 25 mg daily.11,12
Recently a nested case control study was performed by the FDA in collaboration with Kaiser Permanente, California to evaluate the relative frequency of cardiovascular events in approximately 1.4 million patients receiving a variety of NSAIDs.13 After adjusting outcomes for other cardiovascular risk factors, the risk for serious coronary heart disease associated with rofecoxib 25 mg/day was increased 1.29 relative to remote NSAID use, and the relative risk of doses higher than 25 mg/day was 3.15 compared to controls. Naproxen use also was associated with an increased cardiovascular risk of 1.18, a finding not supportive of a cardioprotective property of the drug.
On the heels of the FDA-Kaiser Permanente study came the premature cessation of the APPROVe1 study by the data safety and monitoring board due to a significant increase in cardiovascular risk associated with rofecoxib. APPROVe was a randomized, placebo-controlled, double-blind study initiated in 2000 to evaluate the efficacy of rofecoxib 25 mg/day in reducing recurrence of neoplastic colon polyps in patients with colon cancer. This long-term trial did not identify any early issues; however, by 18 months there was a two-fold increased risk of confirmed cardiovascular events, including myocardial infarction and stroke, associated with rofecoxib. As a result of this outcome, Merck & Co. withdrew rofecoxib from the world-wide market on Sept. 30, 2004.
The Unique Properties of the Coxibs
NSAIDs exert their major effects through inhibition of cyclooxygenase, the enzyme that converts cell membrane arachadonic acid into prostaglandins and thromboxanes.4,14 Cyclooxygenase exists in two forms, COX-1 and COX-2. These two isomers are present in different cells in the body and are activated under different circumstances leading to different physiologic and pathologic effects. (See Figure 1.) COX-1 is constitutively expressed (regularly produced) in all cells, thus it is sometimes referred to as a "housekeeping" enzyme. Gastric mucosal-protective prostaglandin E2 is COX-1-derived, as is platelet aggregation-enhancing thromboxane A2 (TXA2). COX-2 is found only in certain cells such as inflammatory and endothelial cells, and its production is induced by inflammatory or mitogenic stimuli. These distinctions are not absolute; COX-1 is inducible in some situations, and COX-2 can be constitutively expressed in some tissues such as the kidney or brain.14 Traditional (nonselective) NSAIDs such as indomethacin (Indocin) and naproxen inhibit the activity of both isomers of cyclooxygenase. The newly developed coxibs (also known as COX-2 selective or COX-1 sparing inhibitors) include celecoxib (Celebrex), rofecoxib, and valdecoxib (Bextra). Etoricoxib is available in Europe, and lumiracoxib is being evaluated for approval by the FDA. The development of the COX-2 inhibitors was based on the premise that they might suppress undesirable COX-2 mediated inflammation while sparing desirable COX-1 protective functions related to gastric mucosa. The VIGOR trial was a resounding success in this regard. Rofecoxib was as effective as naproxen in treating patients with rheumatoid arthritis, yet was associated with substantially fewer major gastrointestinal complications.5
Undesirable vascular thrombosis is a potential downside of unopposed COX-2 inhibition. Platelet-derived TXA2 promotes platelet adhesion, vasoconstriction, and vascular proliferation.1,4,10 Low-dose aspirin exerts its protective effect largely by blocking platelet COX-1-induced TXA2 production. (See Figure 2.)
Figure 2.
Low Dose Aspirin Platelet-Endothelial Cell Effects
The irreversible acetylation of the platelet COX-1 receptor allows aspirin to exert its effect for the life of the platelet, long after the drug has disappeared from the blood. Aspirin reduces vascular events by approximately 30%.15 Prostaglandin I2 (PGI2), which is produced by vascular endothelial cell COX-2, counters thrombosis by inhibiting platelet adhesion, vascular proliferation, and by promoting vasodilatation.1 Non-selective NSAIDs inhibit both platelet TXA2 production and endothelial cell PGI2 production. (See Figure 3.)
Figure 3.
Non-selective NSAID Platelet-Endothelial Cell Effects
Coxibs have pharmacological actions almost diametrically opposite to those of aspirin. (See Figure 4.)
Figure 4.
Coxib Platelet-Endothelial Cell Effects
By selectively inhibiting COX-2-mediated PGI2 production, coxibs may block endothelial cell protection against platelet adhesion and vasoconstriction, leading to an undesirable tendency toward vascular thrombosis. This effect appears to be more pronounced in patients who are already at risk for cardiovascular events. Only 4% of the VIGOR study patients met FDA indications for secondary cardiovascular prophylaxis, yet these patients accounted for 38% of myocardial infarctions observed in the study.5 Increasing vascular laminar shear stress, as would be expected to occur in atherosclerotic lesions, stimulates endothelial cell expression of COX-2 (thus PGI2 formation) presumably as a protective action.1,14,16 By blocking this response to injury, coxibs could increase risk particularly in patients predisposed to cardiovascular disease. It is important to emphasize, however, that PGI2 is only one of several endothelial-derived substances that oppose platelet adhesion. Nitric oxide, CD39/ecto-ADP-ase, and platelet endothelial cell adhesion molecule all serve to counter platelet adhesion and aggregation and counteract thrombosis.14
NSAID Effects on Blood Pressure
Sustained increases in blood pressure are associated with AMI and stroke. Both nonselective as well as COX-2 selective NSAIDs raise blood pressure through renal prostaglandin blockade.4 This effect most often is seen in hypertensive patients receiving angiotensin-converting enzyme inhibitors, beta-blockers, or loop diuretics.17,18 In the VIGOR study, rofecoxib 50 mg/day was associated with a 3.6 mm increase in systolic blood pressure compared to naproxen 1000 mg/day.5 In a study of older hypertensive patients with osteoarthritis, valdecoxib 25 mg/day was associated with a mean rise in systolic pressure of 2.6 mmHg compared with -.05 mmHg for celecoxib 200 mg/day.17 Edema was experienced by 9.5% of rofecoxib but only 4.9% of celecoxib-treated patients. Two other studies of rofecoxib and celecoxib in older hypertensive patients produced similar findings, suggesting that all coxibs are not alike.19,20
NSAIDs, Inflammation, and Atherosclerosis
Alternatively, NSAIDs theoretically could reduce atherogenesis by their anti-inflammatory actions. There are several lines of evidence suggesting that systemic inflammation may play a role in promoting atherosclerotic disease.21-26 This is true of both chronic inflammation and acute inflammatory processes that are associated with a transient increased risk of AMI.24 High levels of C-reactive protein, a marker of systemic inflammation, are associated with an increased risk of coronary artery disease.23 Two systemic diseases, rheumatoid arthritis and systemic lupus erythematosus, are independent risk factors for AMI.26 NSAIDs, by virtue of their anti-inflammatory effects, could reduce systemic inflammation and reduce risk of acute or chronic atherosclerotic disease. This idea is supported by a recent intriguing study reporting, in chronic nonselective NSAID users, an almost three-fold increase in myocardial infarction within one month of discontinuation of the drug.25 The authors also offered other theories, such as a vascular tissue inflammatory rebound effect or activated platelet aggregation after termination of cyclooxygenase mediated inhibition of thromboxane. Regardless of cause, this study suggested that there may be a vulnerable period for AMI after discontinuation of nonselective NSAID use.25
Is There a Coxib Class Effect?
The removal of rofecoxib from the market has heightened concern regarding use of all coxibs and has led some critics to claim that the burden of proof of safety now lies with the FDA and the manufacturers of coxibs.1 The underlying theoretical premise is that all coxibs are equally pro-thrombotic by virtue of their selective inhibition of COX-2 and that this is the sole cause of cardiovascular events. All coxibs, however, are not alike. There are substantial variations in the relative ability of the currently available coxibs to inhibit COX-2 (and COX-1) activity in laboratory assays.14 (See Figure 1.) Rofecoxib is approximately nine times more potent in its ability to inhibit COX-2 relative to COX-1 than is celecoxib,14 and high-dose celecoxib also may have a COX-1 blocking effect on platelet thromboxane production.27 Regardless, the in vitro characteristics of the coxibs may not translate uniformly into equal effects in vivo.
The Clinical Studies
The CLASS trial (Celecoxib Long-term Arthritis Safety Study)28,29 studied approximately 8000 patients receiving either high dose celecoxib (800 mg/day), ibuprofen (Advil, Motrin, Nuprin) 2400 mg/day, or diclofenac (Voltaren) 150 mg/day in patients with rheumatoid arthritis or osteoarthritis. Average time of exposure to drug was nine months. Twenty-one percent of patients were receiving aspirin for cardiovascular prophylaxis. No differences in rate of myocardial infarction or stroke were observed between the celecoxib and control groups. It is important to note that the investigators chose a very high study dose of celecoxib (800 mg/day). The subsequent FDA-approved dose of celecoxib was 200 mg/day for osteoarthritis, and up to 400 mg/day for rheumatoid arthritis. The FDA-approved dose for familial adenomatous polyposis is 800 mg/day.
Concerns about cardiovascular toxicity raised by the VIGOR study stimulated further investigation of both rofecoxib and celecoxib. A large retrospective analysis of the Tennessee Medicaid database11 reported an increased coronary heart disease risk associated with high-dose rofecoxib (> 25 mg/day) use but not with low-dose rofecoxib, celecoxib, or traditional NSAID use. Another large retrospective study of a Canadian population failed to demonstrate significant differences in rates of myocardial infarction among new users of celecoxib, rofecoxib, naproxen, or other NSAIDs compared to controls.10 A meta-analysis of 19,000 patients found no evidence of increased cardiovascular risk associated with celecoxib compared to nonselective NSAIDs or placebo.30
Data from the huge (1.4 million patients) FDA Kaiser Permanente study13 that had demonstrated an increased risk of AMI associated with rofecoxib actually showed a slightly reduced risk of AMI associated with celecoxib (OR 0.86). High-dose rofecoxib use was greater than three times more likely than celecoxib to be associated with a serious cardiac event.13 Another recent case control study of patients admitted to Pennsylvania hospitals with first, nonfatal MI found a reduced risk of AMI in users of celecoxib compared to non-NSAID users (OR 0.43).31 Rofecoxib use (primarily 25 mg/day) was associated with a slightly greater risk of AMI (OR 1.16). Risk of MI in nonselective NSAID users was reduced (OR 0.61).31
In December 2004 the FDA halted the Adenoma Prevention with Celecoxib (APC) trial due to an approximately 2.5-fold increased risk of cardiovascular events in patients treated with celecoxib 400 mg/day compared to placebo.32 The cardiovascular risk associated with celecoxib 800 mg/day was 3.4 times greater than placebo. This trial has not been published, and there has been no opportunity to analyze the data. Another ongoing clinical trial (the PreSAP cancer trial) using identical analysis to assess cardiovascular risk has been reported to show no increased celecoxib-associated cardiovascular risk compared to placebo.32
Naproxen
In late December 2004 the National Institutes of Health suspended the use of both naproxen and celecoxib in the Alzheimer’s Disease Anti-Inflammatory Prevention Trial (ADAPT trial).33 This action was taken after naproxen 440 mg/day, but not celecoxib 400 mg/day, was associated with an increased risk of cardiovascular and cerebrovascular events compared to placebo. The FDA recommended that patients using naproxen take it for no more than 10 days, then contact their physicians for recommendations.
Valdecoxib
Valdecoxib is the most recent FDA-approved coxib, and cardiovascular risk data are less abundant compared to rofecoxib or celecoxib. A large meta-analysis was performed of 10 randomized trials of almost 8000 patients with osteo-arthritis or rheumatoid arthritis receiving valdecoxib, diclofenac, ibuprofen, or placebo.34 Study duration was from six weeks up to one year. There was no evidence of increased cardiovascular events in users of valdecoxib at either therapeutic or supratherapeutic doses compared to non-selective NSAIDs or placebo. This also was true when the data were analyzed for aspirin use or non-use. Another study compared the analgesic efficacy of valdecoxib and its IV prodrug form, parecoxib, to placebo in patients undergoing coronary artery bypass surgery.35 There was a non-statistically significant trend toward increased cardiovascular complications in the paracoxib/valdecoxib-treated patients, and there were more sternal wound infections observed in the paracoxib/valdecoxib arm. A similar finding was observed in another unpublished study resulting in the issue of a warning by the manufacturer against the use of valdecoxib in patients undergoing coronary artery bypass surgery.36
Lumiracoxib
Lumiracoxib, a structural analogue of diclofenac, is a highly selective coxib being evaluated for approval by the FDA. The Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET)37,38 compared it to naproxen and to ibuprofen in the treatment of osteoarthritis. In this study of more than 18,000 patients, there was a three- to four-fold reduction in ulcer complications compared to control NSAIDs, but no statistically increased risk for cardiovascular events in patients receiving lumiracoxib.37,38
No Proof of Coxib Class Effect
Taken altogether, available published studies do not show proof of a coxib class effect regarding cardiorenal and cardiovascular complications. Absence of proof, however, is not the same as proof of absence. Randomized controlled prospective trials are considered the gold standard in detecting differences between therapies. Unfortunately, neither the VIGOR nor CLASS study was sufficiently powered to detect small risks of cardiovascular events.39 It was estimated that a study of 20,000 patients would be required to answer this question.39 Equally daunting is the fact that clear evidence for cardiovascular risk required 18 months of exposure to rofecoxib in the APPROVe study.14 Shorter studies may fail to exclude small but important risks. On February 18, 2005, an advisory panel, convened by the FDA to evaluate the safety of the coxibs, concluded that coxibs carry cardiovascular risks, with valdecoxib posing the greatest risk and celecoxib posing the least risk. Cardiovascular risk of celecoxib 200 mg/day was not seen. The panel recommended that the benefits of the coxibs continue to outweigh the risks, and that they should not be removed from the U.S. market. It also recommended that warnings be added to product labels and that further research be done.40
Some observers41 have condemned the entire class of coxibs but others caution against such an approach.42,43 Solomon and Avorn point out that cerivastatin (a statin), troglitazone (a glitizone), and bromfenac (an NSAID) all were withdrawn from the market after initial FDA approval due to unacceptable toxicities.43 Other members of their class have stood the test of time and remain as valuable treatment options.
Aspirin-NSAID Interactions
Many patients require both aspirin for cardiovascular prophylaxis and an NSAID. It is possible that NSAIDs could interfere with aspirin’s antiplatelet effects, or that aspirin could negate the gastrointestinal-sparing properties of the coxibs. It has been demonstrated that, when ingested prior to aspirin, ibuprofen antagonizes aspirin’s ability to irreversibly inhibit platelet aggregation.44 By reversibly (temporarily) binding to the platelet COX-1 receptor, ibuprofen blocks aspirin’s permanent acetylation of the platelet, allowing recovery of platelet thrombotic function with subsequent loss of cardioprotective effect. In contrast, rofecoxib, diclofenac, and acetaminophen (Tylenol) did not produce a similar effect.44 Neither celecoxib nor valdecoxib demonstrates effects on platelet function as measured in vitro.45,46 This limited data suggests that a coxib or diclofenac may be preferable to other NSAIDs in patients requiring low-dose aspirin for cardioprophylaxis.
Although the coxibs have shown a reduction in risk of gastroduodenal ulceration and complications compared to NSAIDs, this advantage could be eliminated in patients concurrently receiving low-dose aspirin. Although the CLASS28,29 study compared ulcer complication rates in aspirin users receiving celecoxib or NSAIDs, it lacked the statistical power to definitively answer this question. Until larger and more definitive studies address this issue, those patients at high risk for upper gastrointestinal complications receiving both low-dose aspirin and a coxib may require prophylactic anti-ulcer therapy.
Anticoagulated Patients and NSAID Choice
The coxibs have little or no effect on platelet function, which may be useful in certain clinical situations such as patients receiving anticoagulant therapy. In one study of patients receiving warfarin, the risk of bleeding was approximately three times greater in patients taking nonselective NSAIDs compared to those taking coxibs.47 This result was not seen in a more recent study comparing the risk of hospitalization for upper gastrointestinal hemorrhage in warfarin-receiving patients.48 Patients taking rofecoxib or celecoxib had a similar risk of upper gastrointestinal bleeding compared to patients taking nonselective NSAIDs.
The Coxibs: Current Knowledge
Following are important summary points highlighting current clinical knowledge of coxib drugs.
• The coxibs are as effective but no more effective than nonselective NSAIDs in their ability to reduce pain and inflammation.
• The coxibs demonstrate less serious gastrointestinal toxicity with fewer symptomatic ulcers and their complications compared to nonselective NSAIDs. Many patients unable to tolerate previous antiinflammatory medicines have been able to take and tolerate a coxib. Some observers have postulated as much as a two-thirds potential reduction in gastrointestinal-related deaths as coxib use has supplanted non-selective NSAID use.42
• Rofecoxib, especially at doses higher than 25 mg/day, carries an increased risk of cardiovascular toxicity, primarily nonfatal AMI, particularly in patients with increased cardiovascular risk. The effect of rofecoxib on blood pressure, edema, and cardiovascular events appears dose-related. It has been voluntarily withdrawn from the market and is not currently available for use.
• The current evidence does not support a uniform coxib class effect in regard to increased cardiovascular events. It has not, however, conclusively ruled out this possibility. Further studies will be needed to definitively answer this important question.
• The coxibs, similar to nonselective NSAIDs, impact renal function, sodium retention, and blood pressure, most prominently in hypertensive patients treated with beta-blockers, angiotensin-converting enzyme inhibitors, and loop diuretics. This influence is not uniform; rofecoxib appears to have a greater effect compared to celecoxib, whose impact appears minimal.
• There is no conclusive evidence that NSAIDs such as naproxen are cardioprotective in a manner similar to aspirin. They should not be used as cardioprotective agents.
• Ibuprofen, but not rofecoxib or diclofenac, blocks aspirin’s anti-platelet effects.
• Little is known about the cardiovascular effects of non-selective NSAIDs. They have not been studied nearly to the extent that the coxibs have in this regard. Switching a patient from a coxib (whose cardiovascular effect has been extensively, albeit imperfectly, studied) to a nonselective NSAID (which has received scant evaluation for cardiovascular safety) to avoid a cardiovascular event has no basis in logic and is, in effect, burying one’s head in the sand.
Recommendations
Following are recommendations for treatment of patients with acute or chronic musculoskeletal conditions. They include strategies for patients at varying risk for upper gastrointestinal and cardiovascular complications.
• Physicians should avoid making treatment decisions based solely on media reports of unpublished preliminary data that have not been subjected to peer review. New reports must be evaluated and placed in context with existing information. Without the benefit of this process, altering clinical decision-making may be harmful instead of helpful. Continue to consult treatment guidelines49,50 published by respected groups and await new recommendations.
• Use nonpharmacological therapy, including patient education, physical and occupational therapy, assistive devices, and other therapies when appropriate.
• Consider acetaminophen for patients requiring analgesic but not an anti-inflammatory therapy. Acetaminophen in doses up to 4 g daily has been demonstrated to be effective in the treatment of mild to moderate osteoarthritis pain.49 It should be used with caution in patients with liver disease or chronic alcohol abuse.
• Consider nonacetylated salicylates such salsalate or choline magnesium trisalicylate. These compounds lack significant prostaglandin inhibition yet still are effective analgesic and antiinflammatory agents through other mechanisms.
• Patients requiring chronic use of NSAIDs should be evaluated based on their risks of cardiovascular disease and gastroduodenal toxicity. (See Table 1, below, and Table 2.) The patient at low risk for vascular events or upper gastrointestinal complications can be treated with either a nonselective NSAID or a coxib. If there is a history of sulfonamide drug allergy, the coxibs currently available in the United States cannot be used. Patients with known coronary heart disease, cerebrovascular disease, or who have sufficient risk factors for these diseases should be receiving low-dose aspirin. If a patient is taking low-dose aspirin and requires anti-inflammatory therapy, use of a coxib may be preferred due to lack of interference with aspirin’s antiplatelet effect. Use of ibuprofen should be avoided in this situation. If a patient is at high risk for a cardiovascular event and cannot take aspirin or another antiplatelet agent, the use of a coxib should be avoided until further information is available as to its safety in this setting.
Table 1.
Risk Factors for NSAID-Associated Gastroduodenal Ulcers
• Patients at high risk for upper gastrointestinal complications who require chronic use of NSAIDs should use a coxib if possible. If a nonselective NSAID is chosen, then gastroprotective agents such as misoprostol or a proton pump inhibitor should be used.
• Patients at high risk for both upper gastrointestinal complications and a cardiovascular event should use low-dose aspirin and a coxib if possible. As aspirin appears to negate the gastrointestinal-sparing benefit of a coxib, gastrointestinal prophylaxis with misoprostol or a proton pump inhibitor should be used.
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After the voluntary withdrawal of Vioxx from the market in September 2004 following reports of increased cardiovascular events associated with the drug, there was a call from some quarters for a similar action for all selective COX-2 inhibitors (coxibs). This article reviews the current clinical knowledge regarding the coxibs and their cardiovascular effects. Recommendations for prescribing anti-inflammatory drugs in common clinical situations are provided.
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