Prevention of nonsteroidal anti-inflammatory drug-induced gastropathy

Transcription

1 J Gastroenterol 2009; 44[Suppl XIX]:44 52 DOI /s Prevention of nonsteroidal anti-inflammatory drug-induced gastropathy BARRY SCHLANSKY and JOO HA HWANG University of Washington School of Medicine, 1959 N.E. Pacific Street, Seattle, WA 98195, USA Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used for their analgesic, antipyretic, and antiinflammatory properties, and aspirin is increasingly employed in the primary and secondary prevention of cardiovascular disease and ischemic stroke. Despite undisputed therapeutic efficacy for these indications, all NSAIDs impart a considerable risk of peptic ulcer disease and upper gastrointestinal hemorrhage. A growing body of evidence supports an association between non-aspirin NSAIDs and acute coronary syndromes, and an expanding understanding of the gastroduodenal effects of aspirin, COX-2 selective agents, clopidogrel, and Helicobacter pylori synergism fuel controversies in NSAID use. In this review, we discuss risk stratification of patients taking NSAIDs and the appropriate application of proven gastro-protective strategies to decrease the incidence of gastrointestinal hemorrhage based upon an individualized assessment of risk for potential toxicities. Prevention of NSAID-related gastropathy is an important clinical issue, and therapeutic strategies for both the primary and secondary prevention of adverse events are continually evolving. Key words: nonsteroidal anti-inflammatory drugs, peptic ulcer disease, gastropathy, gastric ulcer, duodenal ulcer in this class, possesses additional antiplatelet activity, and is increasingly used in the primary and secondary prevention of cardiovascular disease and ischemic stroke. More than 100 million NSAID prescriptions are written annually in the United States, not including over-the-counter nonprescription NSAIDs and aspirin. 2 Each year in the United States, gastrointestinal (GI) toxicity related to NSAID use is estimated to cause more than hospitalizations and more than deaths, mostly as a consequence of upper GI tract bleeding. 3 Aspirin has become a standard modality in the armamentarium of cardiovascular disease prevention, and, in the setting of NSAID usage, poses a significantly increased risk for GI complications. The addition of antisecretory agents or prostaglandins is a proven gastro-protective strategy in these patients. Further, recent findings regarding both cardiovascular and GI effects of nonselective NSAIDs, cyclooxygenase (COX)- 2 selective inhibitors, aspirin dosage, and clopidogrel now mandate an individualized assessment of baseline risk in each patient. Prevention of NSAID-induced GI damage is an important clinical issue, and strategies for both the primary and secondary prevention of adverse events are continually evolving. Historical perspective Introduction Popular because of their analgesic, antipyretic, and antiinflammatory efficacy, nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin, are the most widely used medications worldwide. 1 Aspirin, the oldest drug Received: June 12, 2008 / Accepted: August 3, 2008 Reprint requests to: J.H. Hwang Aspirin and NSAIDs have a storied history in the treatment of pain and rheumatic diseases. In the 4th century B.C., Hippocrates detailed the use of powder made from the bark and leaves of the willow tree (Salix spp.) for headache, pain, and fever. Ancient Egyptians and Assyrians also used a willow extract to relieve the pain and erythema of inflamed joints. 4 In 1828, Johann Buchner at the University of Munich extracted and purified salicin from willow, and three decades later, Charles Gerhardt succeeded in synthesizing a

2 B. Schlansky and J.H. Hwang: NSAID induced gastropathy 45 buffered form of salicylate to reduce dyspepsia, acetylsalicylic acid. This synthetic compound, containing no willow derivatives, was marketed by Felix Hoffmann of the Bayer company in 1899 as aspirin. The U.S. Food and Drug Administration (FDA) approved aspirin for the primary and secondary prevention of cardiovascular disease, and the secondary prevention of stroke and transient ischemic attacks, in Additional NSAIDs were developed, such as phenylbutazone in 1949, indomethacin in 1963, and ibuprofen in 1969; however, the mechanism of action of these NSAIDs was unknown. In 1972, John R. Vane demonstrated that aspirin blocks the synthesis of a proinflammatory cytokine, prostaglandin E, for which he was granted the Nobel Prize in Prostaglandin synthase (COX), the enzyme inhibited by aspirin, which converts arachidonic acid to prostaglandins, was discovered in 1989, and was found to have two isoforms, COX-1 and COX-2; this discovery paved the way for the development of COX-2 selective inhibitors, which were hypothesized and later proven to have reduced GI toxicity. 6,7 The first COX-2 selective inhibitor, celecoxib (Celebrex), approved by the FDA in 1998 based upon the results of five clinical trials involving more than 5000 patients with degenerative or rheumatoid arthritis, showed comparable analgesia and efficacy to nonselective NSAIDs and placebo with fewer clinical and endoscopic gastroduodenal ulcers. 8,9,10,11 Two other COX-2 selective inhibitors, valdecoxib and rofecoxib, were subsequently approved; however, in the wake of concerns of an increased risk of thromboembolic events, and with valdecoxib an additional risk of Stevens Johnson syndrome, both were withdrawn from the U.S. market in ,13,14,15 Celecoxib remains available for the treatment of pain associated with degenerative joint disease and rheumatoid arthritis, but as of April 2005 carries a black box warning alerting consumers to the increased cardiovascular risk associated with this medication. 16 Epidemiology of NSAID-induced gastrointestinal toxicity The discovery by Barry J. Marshall and J. Robin Warren of Helicobacter pylori as the principal causative agent of peptic ulcer disease ultimately led to a shift in thinking about ulcer pathogenesis from a multifactorial view to one dominated by two overwhelming environmental factors: H. pylori infection and NSAID usage. 17 Experts state that perhaps only 5% 10% of ulcer patients have no H. pylori infection or history of NSAID use. 18 The prevalence of H. pylori infection in ulcer disease exhibits significant geographic variation but remains greater than 90% in both gastric and duodenal ulcers occurring in southern Europe and Japan. 19,20 False-negative H. pylori test results (particularly with serological assays) and surreptitious NSAID use are common events, and underestimation of these two major risk factors occurs frequently. However, increased antibiotic usage and improved hygiene is expected to reduce the prevalence of H. pylori infection in the future; one recent prospective study of 361 Dutch patients with peptic ulcer disease (PUD) revealed NSAID use in 52% and H. pylori positivity in only 47% of patients. 21 A recent meta-analysis of 21 studies performed in Western countries indicated that H. pylori infection and NSAID usage are highly synergistic risk factors for ulcer development, with the risk of uncomplicated PUD estimated to be 17.5 times higher among H. pylori-positive NSAID users compared to H. pylori-negative non-users, compared with only a 3- to 4-fold increase in ulcer incidence with either risk factor alone. 22 The same year, a small Japanese case-control study suggested that the copresence of both risk factors had only an additive effect on the risk of ulcer disease. 23 The impact of geographic and cultural considerations on the magnitude and interplay of risk factors in peptic ulcer disease is not well elucidated. The spectrum of NSAID-induced GI pathology includes shallow mucosal changes, erosive gastritis, peptic ulcer disease, and ulcer complications, such as upper GI bleeding, perforation, penetration, and obstruction. Dyspepsia occurs in 10% 20% of patients taking NSAIDs but also occurs frequently with non- NSAID analgesics, such as acetaminophen, and it is not predictive of ulcer development. Similarly, although two-thirds of patients taking NSAIDs have superficial mucosal lesions visible by endoscopy, these are not predictive of adverse outcomes. Recognition of frank ulcers, which represent 15% 25% of patients with dyspepsia, is clinically important. 24 The incidence of hospitalization for NSAID-related upper GI bleeding is 1% 2%/year and confers 5% 10% mortality; although the overall annual mortality rate for GI bleeding in this context is relatively low (0.22%/year), the large number of patients with chronic NSAID exposure results in substantial morbidity and mortality. 3 Unfortunately, many patients are poorly informed of the risks associated with this class of medications. A 1999 survey revealed that almost 75% of long-term NSAID-using patients were unaware or unconcerned about potential GI complications, and most expected warning signs, such as dyspepsia, to precede a serious complication, which rarely occurs in practice. 25 Pathogenesis of gastroduodenal toxicity Aspirin and other NSAIDs damage the GI mucosa by topical and systemic mechanisms. Many drugs in this

3 46 B. Schlansky and J.H. Hwang: NSAID induced gastropathy class are absorbed across the gastric mucosa, where direct injury to the gastric epithelium occurs. As mentioned earlier, this topical injury may result in endoscopically visible shallow mucosal changes that are not believed to evolve to clinically important ulcers. In support of this hypothesis, enteric-coated aspirin, which resists degradation in the stomach, decreases macroscopic signs of gastroduodenal injury but offers no additional protection against GI bleeding compared to regular aspirin. 26 Further, parenteral administration of NSAIDs has been demonstrated to cause both gastric and duodenal ulcers. 27,28 The systemic effects of NSAIDs, which dominate clinically relevant endpoints, are mediated through COX-1 and COX-2 inhibition. 29 The COX-1 enzyme is constitutively expressed in most cells of the body, and in the gastroduodenal mucosa the prostaglandins it produces serve to protect the mucosal lining from injury by luminal acid pepsin. 18 COX-1 is also implicated in platelet aggregation (mediated by thromboxane A 2 ) and maintenance of renal function. In contrast to COX- 1, COX-2 expression is inducible by proinflammatory cytokines, and the products of its reaction are implicated in activation of the inflammatory cascade as well as maintenance of renal function. Nonselective NSAIDs, such as aspirin, therefore reduce inflammation via COX-2 inhibition at the expense of platelet inhibition and GI toxicity from COX-1 inhibition. COX-2 selective inhibitors then reduce inflammation without platelet inhibition or adverse GI effects. As renal perfusion is affected by both enzymes, COX-2 selective inhibitors may still impart renal toxicity. Gastrointestinal risks of NSAIDs An individualized risk assessment of patients taking NSAIDs facilitates optimal management. A multitude of risk factors for NSAID-induced GI toxicity are identified, but with differing likelihoods of association with peptic ulcers and their complications. The Committee on Practice Parameters of the American College of Gastroenterology (ACG) critically reviewed the relevant literature in 1998, and identified the five most important risk factors for NSAID-induced GI complications 30 (Table 1). The presence of these risk factors permits identification of high-risk patients who benefit most from ulcer prophylaxis; indeed, patients with multiple risk factors incur a 9% risk of a GI event at 6 months. 31 These dominant risk factors prior history of a GI event, age >60 years, high NSAID dosage, and concurrent corticosteroid or anticoagulant usage are most useful in clinical practice; however, other important risk factors are acknowledged. Notably, usage of multiple NSAIDs or NSAIDs plus aspirin, duration of Table 1. Key risk factors for nonsteroidal anti-inflammatory drug (NSAID)-related gastrointestinal (GI) complications Risk factor Relative risk 95% CI Overall Age >60 years Prior GI event High dosage (>2 normal) Concurrent corticosteroids Concurrent anticoagulants CI, confidence interval Source: reproduced from Lanza, 30 with permission NSAID treatment, the specific NSAID used, H. pylori infection, smoking, cocaine use, stress, cytomegalovirus (CMV) or herpesvirus (HSV) infection, and concurrent non-aspirin antiplatelet agents, chemotherapeutic agents, bisphosphonates, or selective serotonin reuptake inhibitors (SSRIs) also impart increased risk for GI complications in NSAID users. 3,32 NSAID-specific risk factors for GI complications include dosage, duration, NSAID polypharmacy, and the specific NSAID compound used. With respect to dose and duration, short-term usage and overthe-counter dosages are unlikely to cause significant toxicity compared to chronic NSAID usage (more than 1 week) at higher prescription doses (more than twice the over-the-counter dose). Even low doses of aspirin result in gastric damage and platelet inhibition, although the risk of serious GI events increases in dose-dependent fashion. 33,34 Many studies have sought to quantify the relative GI toxicity of various NSAIDs. In 2004, the World Health Organization (WHO) conducted a meta-analysis of major trials and published a consensus statement in which the risk of GI complications ascribed to specific NSAIDs was, in descending order, indomethacin [relative risk (RR) 2.25], naproxen (RR 1.83), diclofenac (RR 1.73), piroxicam (RR 1.66), tenoxicam (RR 1.43), ibuprofen (RR 1.43), and meloxicam (RR 1.24). 35 Etodolac and salsalate, which are believed to cause less GI toxicity than any of the aforementioned NSAIDs, were unfortunately not included in this review. Pharmacokinetics may also influence the risk of bleeding, with short-acting NSAIDs thought to have less toxicity than long-acting agents. Although COX-2 selective inhibitors were initially conceived as a strategy to minimize the adverse GI and antiplatelet effects of nonselective NSAIDs while providing comparable analgesic and anti-inflammatory action, these medications have demonstrated GI toxicity when compared to placebo in some, but not all, large clinical trials. Celecoxib, when not used in conjunction with aspirin, has generally been associated with a gastroduodenal ulcer incidence similar to placebo and considerably less than nonselective NSAIDs. 8,9,10,11,36

4 B. Schlansky and J.H. Hwang: NSAID induced gastropathy 47 However, a post hoc analysis of one large prospective study revealed no significant difference in the rate of ulcer complications between celecoxib, ibuprofen, and naproxen when the cohort was followed for 1 year rather than the initial 6 months included in the original study design. 37 This singular finding is criticized for bias introduced by reanalyzing data post hoc, the use of aspirin by many patients, and the high celecoxib dose in the experimental group. 38 Several studies have demonstrated negation of the GI-sparing benefits of COX-2 selective inhibitors when used concurrently with lowdose aspirin. 10,39 As COX-2 selective medications are known to increase the risk of cardiovascular disease, and prophylactic aspirin is indicated only in patients at increased cardiovascular risk, concomitant use of these medications should be avoided if possible. Gastro-protective strategies Strategies for the primary prevention of adverse GI outcomes in NSAID users include cotherapy with proton pump inhibitors (PPIs) or prostaglandin analogues, minimal dosing of less toxic NSAIDs for short durations, COX-2 selective inhibitors, and treatment of comorbidities and modifiable risk factors (Fig. 1). Several other approaches, including use of clopidogrel instead of aspirin for primary prevention of cardiac disease, the use of H 2 -receptor antagonist antihistamines (H 2 RA) or sucralfate, and preferential use of NSAID use plus comorbid risks? No Average Risk for Gastroduodenal Complication Use lower-risk NSAIDs with minimal duration and dosage Ask about surreptitious OTC NSAID and aspirin use Treat known H. pylori infection, but routine testing not indicated Assess cardiovascular risks Yes High Risk for Gastroduodenal Complication All average-risk measures plus strongly consider Assess for and treat H. pylori infection if present Institute gastroprotection with misoprostol or a proton pump inhibitor COX-2 selective agent if low cardiovascular risk COX-2 selective agent + PPI in those with a history of GI bleeding (very high risk) Fig. 1. Algorithm for prevention of nonsteroidal antiinflammatory (NSAID)-related gastroduodenal toxicity. OTC, over the counter; H. pylori, Helicobacter pylori; COX, cyclooxygenase; PPI, proton pump inhibitor. (Adapted from ref. 47,50) enteric-coated or buffered aspirin over regular aspirin, were demonstrated to be ineffective for prevention of peptic ulcer disease or its complications. Clearly, patients with risk factors for the development of ulcer disease, history of peptic ulcers, or at-risk chronic NSAID users need rational strategies to reduce the risk of adverse GI events. Unfortunately, gastro-protection is underutilized, with greater than 80% of NSAID users with additional risk factors for ulcer complications failing to receive any gastro-protective agent. 40 Just as the GI toxicity of NSAIDs is mediated through inhibition of COX-1 and subsequent gastroduodenal epithelial damage, agents that specifically reduce GI tract epithelial damage through repletion of prostaglandins or inhibition of acid pepsin are effective in gastroprotection for chronic NSAID users. Misoprostol, a prostaglandin E analogue, was originally demonstrated to reduce the relative risk of ulcer complications in patients taking NSAIDs by 40%, although diarrhea and abdominal pain limit its tolerability. 41 PPIs offer slightly decreased efficacy compared to misoprostol but are better tolerated; overall, efficacy for ulcer prevention is similar as many misoprostol users discontinue the medication because of adverse effects. 42,43 In practice, either PPIs or misoprostol may be used for gastro-protection, although many patients prefer PPIs as dyspeptic symptoms are improved. PPIs not only reduce ulcer recurrence, but are also shown to prevent ulcer development in previously ulcer-free at-risk patients on chronic NSAIDs. 44 H 2 RAs, when used in high doses, prevent both gastric and duodenal ulcers associated with NSAID use, but in standard doses are shown only to modestly reduce the incidence of duodenal ulcers; American Gastroenterological Association (AGA) guidelines recommend against the use of H 2 RAs for ulcer prevention in favor of PPIs or misoprostol These two classes of medications are the mainstays of gastro-protective therapy, and lansoprazole, esomeprazole, and misoprostol are the only FDA-approved medications for prophylaxis against NSAID-induced peptic ulcer disease. Tailoring therapy to include the safest analgesic or anti-inflammatory agents is an important component of risk reduction. Unfortunately, the therapeutic options for chronic inflammatory pain are exceedingly limited. Acetaminophen suffers from inadequate efficacy. Opioids are poorly effective for inflammatory conditions and are limited by concerns about tolerance and abuse potential. The risk of toxicity among nonselective NSAIDs is not uniform, with certain short-acting agents at low doses having considerably less GI toxicity than others, and in patients who require NSAIDs for analgesia, limiting these factors is one strategy to reduce GI damage. Over-the-counter doses of ibuprofen (200 mg three to four times daily) are effective for mild pain, particularly in combination with acetaminophen.

5 48 B. Schlansky and J.H. Hwang: NSAID induced gastropathy Salsalate, a nonacetylated NSAID, and etodolac may have partial selectivity for COX-2 inhibition and consequently have less toxicity than other nonselective NSAIDs. In contrast, long-acting NSAIDs, such as piroxicam (Feldene) and ketorolac (Toradol), are associated with a high risk of GI complications. 29,48 Cardiovascular concerns aside, COX-2 selective inhibitors are comparable to placebo in reducing the risk of GI complications, unless taken concomitantly with aspirin. 49 For many patients taking multiple NSAIDs or aspirin plus an NSAID, a gastro-protective agent is preferred over a COX-2 selective drug; however, for patients at very high risk for ulcer disease or other bleeding, and who require anti-inflammatory medications, the combination of a COX-2 inhibitor and a PPI has recently been shown to prevent recurrent bleeding ulcers effectively compared to the use of a COX-2 inhibitor without a PPI. 50 Head-to-head comparisons of GI risk for nonselective NSAIDs versus COX-2 inhibitors in patients on both aspirin and a PPI have not been performed, however. Appropriate selection of medications for the symptomatic management of chronic pain is a challenging but vital element of peptic ulcer disease prevention. The effect of NSAID dosage on GI bleeding risk was discussed previously; nonselective NSAIDs and aspirin predispose patients to ulcer complications in dosedependent fashion. Fifty million adults in the United States take aspirin regularly for the prevention of cardiovascular disease, with a significant subgroup using additional NSAIDs for pain. Despite the use of highdose aspirin (325 mg or more) for the long-term prevention of cardiovascular disease by 35% of patients taking aspirin, a recent systematic literature review revealed no increased antiplatelet inhibition or reduction in incidence of acute coronary or cerebrovascular events in patients taking 325 mg or greater doses versus patients taking mg aspirin per day. 51 The risk of GI bleeding was consistently increased in the high-dose aspirin groups of all studies analyzed. The authors note that the high prevalence of aspirin use in the United States triggers a high degree of morbidity even with only a modest increase in bleeding risk with higher dosages; an additional major bleeding events would occur per year were all 50 million patients to take a daily dose of 325 mg versus 81 mg. Current American Heart Association guidelines recommend aspirin prophylaxis at a dose of mg daily for primary prevention in all patients with a 10-year risk of coronary heart disease greater than 10% and for secondary prevention in those patients with known coronary disease. 52,53 Another strategy to limit NSAID exposure in patients with cardiovascular risk is to choose alternative antiplatelet agents with less gastric mucosal toxicity. Clopidogrel (Plavix) was an attractive substitute for aspirin in patients at high risk for GI bleeding; although clopidogrel offers cardioprotective benefits similar to aspirin, COX-1 is not inhibited. However, a recent trial comparing clopidogrel to low-dose aspirin plus esomeprazole for secondary prevention of peptic ulcer disease complications demonstrated a 7.9% absolute risk reduction in the aspirin plus esomeprazole group over 12 months, 8.6% versus 0.7%, respectively. 54 Thus, barring outlier cases of recurrent thromboembolic events despite aspirin use, in which clopidogrel is often strongly indicated, low-dose aspirin should be the therapy of choice for primary and secondary cardiovascular disease prevention. Particularly when patients are at increased risk for GI bleeding, such as chronic NSAID users, patients taking aspirin should also receive a gastro-protective agent such as a PPI or misoprostol, and clopidogrel is not an acceptable alternative to aspirin for gastroprotective purposes. Of the five most important risk factors for GI complications in NSAID users, three are theoretically modifiable: concomitant use of high-dose or multiple NSAIDs, corticosteroids, or coumadin. The two latter groups are often unable to discontinue these medications because of strong indications in the prevention or treatment of prothrombotic or inflammatory disease states, respectively. Minimizing exposure to NSAIDs by limiting dosage and duration is more practical and decidedly beneficial in reducing GI risk. H. pylori infection and NSAID use are highly synergistic risk factors for peptic ulcer disease; although prior GI event is not a modifiable risk factor, the risk of ulcer recurrence can be further reduced by proving the absence of active H. pylori infection. According to AGA guidelines, patients with multiple risk factors for GI complications or an ulcer history should be tested for H. pylori and treated if positive, particularly if the ulcer was not previously treated with an approved H. pylori antibiotic regimen. 47 Asymptomatic patients without an ulcer history, however, likely do not warrant H. pylori testing. If positive H. pylori status is known, regardless of ulcer history, risk factor profile, or symptoms, infection should be eradicated with an approved therapeutic regimen. Standard triple-drug therapy clarithromycin, amoxicillin, and a PPI twice daily for 14 days has only an 83% 92% eradication rate at 1 year, and ulcers routinely recur in patients that fail treatment. 55 Notably, a recent randomized trial suggests that sequential therapy with 5 days of twice-daily pantoprazole and amoxicillin, followed by 5 days of twice-daily pantoprazole, clarithromycin, and tinidazole, may achieve a higher eradication rate than the former regimen, particularly in patients infected with clarithromycin-resistant H. pylori strains. 56 Additional risk factors for ulcer disease in patients using NSAIDs not included in the ACG guidelines, such as SSRI, antiplatelet agent, bisphos-

6 B. Schlansky and J.H. Hwang: NSAID induced gastropathy 49 phonate, or chemotherapeutic agent usage, tobacco or cocaine abuse, psychological stress, or CMV or HSV infection may also be modifiable or treatable in selected cases. 57 The secondary prevention of peptic ulcer disease in NSAID or aspirin using patients is controversial. Certainly, H. pylori infection status should be tested, and if positive, eradicated with the most effective antibiotic regimen to prevent ulcer recurrence. 58,59 H. pylorinegative NSAID-related ulcers should be treated with a PPI for 4 8 weeks, rather than H 2 RAs or sucralfate. 30,60,61,62 Regardless of H. pylori status, discontinuation of NSAIDs and use of alternative analgesic medications should be encouraged. If NSAIDs or aspirin must be continued, the lowest dose and duration of treatment should be used, and cotherapy with misoprostol or a standard-dose PPI is mandatory. 60,62,63 Patients with treated peptic ulcers must continue maintenance therapy for as long as the NSAID or aspirin is used. Cardiovascular risks of NSAIDs NSAIDs influence the development of cardiovascular disease in several ways. In addition to the wellpublicized increased risk of thromboembolic events associated with the use of COX-2 selective inhibitors, nonselective NSAIDs also appear to confer risk. NSAIDs may interfere with the antiplatelet effects of aspirin, reducing its benefits in the prevention of coronary and cerebrovascular disease. Similar to risk reduction for the prevention of gastroduodenal complications, assessment of the patient s cardiovascular risk profile is important in optimizing analgesic and anti-inflammatory efficacy while maximizing cardiovascular benefits. The interactions between selective and nonselective NSAIDs and cardiovascular disease are complex and controversial. One of several early trials supporting the efficacy of COX-2 selective inhibitors compared with NSAIDs in the prevention of GI toxicity suggested an increased risk of cardiovascular toxicity as well, prompting the FDA to issue a statement in 2002 recommending that caution should be exercised when Vioxx is used in patients with a medical history of ischemic heart disease. 12,64 Subsequently, rofecoxib was found to have a twofold increase in the rate of cardiovascular events and was withdrawn from the U.S. market. 13,15 Research suggests that COX-2 inhibitors manifest cardiovascular toxicity because of an increase in the ratio of endothelial thromboxane A 2 to platelet-derived prostacyclin, resulting in a prothrombotic state. 65 Further trials and meta-analyses support the cardiotoxicity of rofecoxib, and other COX-2 selective inhibitors as well as nonselective NSAIDs have demonstrated similar toxicity, although inconsistently, with naproxen sometimes exerting a cardioprotective effect. 15,66,67 A recent metaanalysis of case-control and cohort studies performed between 2000 and 2006 suggested that apart from COX- 2 inhibitors, and particularly rofecoxib, the overall risk of coronary events from NSAIDs is relatively small, especially when compared to other accepted preventable cardiac risk factors. 68 Whether aspirin diminishes cardiovascular risk in patients on selective COX-2 inhibitors is also unclear. Further, in vivo and in vitro studies of platelet function suggest that ibuprofen may reduce the cardiovascular protective benefits of aspirin, presumably by binding COX-1 and preventing aspirininduced irreversible platelet inhibition. 69,70 However, no prospective clinical trials have yet been conducted to establish a harmful pharmacodynamic interaction in terms of meaningful cardiovascular endpoints, and further studies will be necessary to guide clinical management. Ultimately, optimal risk stratification and management guidelines for the use of NSAIDs and COX-2 inhibitors in patients with cardiovascular disease are not well elucidated, although most specialists would advocate a general avoidance of these medications in persons with significant cardiovascular risk. Risk stratification: balancing gastrointestinal and cardiovascular risks and benefits Because of publicity surrounding the cardiovascular safety of COX-2 selective inhibitors and other NSAIDs, there is a recent shift in emphasis on NSAIDs from GI to cardiovascular toxicity. NSAID and aspirin use is exceedingly common, and the enormous scrutiny of possible adverse effects is therefore warranted. Many NSAID-using patients have multiple comorbidities that predispose to both ulcer complications and coronary events or stroke, leading to difficult management decisions in the effort to minimize risk. Treatment recommendations encompassing both cardiac and GI risk stratification have been postulated 71,72,73 (Table 2). Patients at low risk for gastroduodenal complications and without cardiovascular risk (i.e., not taking aspirin) are good candidates for NSAID monotherapy, whereas patients at high risk for GI events without cardiovascular risk require addition of misoprostol or a PPI, or discontinuation of NSAIDs and initiation of either a non-nsaid analgesic or a COX-2 inhibitor as monotherapy. Patients with any cardiovascular risk, particularly those on aspirin, must avoid COX-2 inhibitors. Those patients on aspirin who are at low risk of developing peptic ulcer disease may be treated with a non-nsaid analgesic or a nonselective NSAID, probably with a gastro-protective agent as well, and care should be taken in choosing the NSAID with respect to potential cardiotoxic effects. That

7 50 B. Schlansky and J.H. Hwang: NSAID induced gastropathy Table 2. Initiation of gastro-protection by cardiovascular risk Low NSAID GI risk High NSAID GI risk No cardiovascular risk (without aspirin) Cardiovascular risk (with aspirin) Nonselective NSAID Naproxen a Addition of PPI if GI risk of aspirin/ NSAID combination warrants gastro-protection PPI, proton pump inhibitor; CV, cardiovascular a Nonselective or selective (low-dose) inhibitor without established aspirin interaction if naproxen is ineffective b Misoprostol at full dose (200 μg four times daily) may be substituted for PPI Source: Reproduced from Scheiman and Fendrick, 71 with permission Nonselective NSAID + PPI or COX-2 selective inhibitor COX-2 selective inhibitor + PPI for those with prior GI bleeding PPI b irrespective of NSAID Naproxen if CV risk outweighs GI risk COX-2 selective inhibitor + PPI for those with previous GI bleeding subgroup of patients with both high risks of GI and cardiovascular disease, and who take long-term aspirin, require non-nsaid analgesics or a nonselective NSAID plus a gastro-protective agent. Certain nonselective NSAIDs, such as salsalate and etodolac, may have lower rates of ulcer complications, and others, such as naproxen, may have less cardiovascular toxicity. A careful and individualized assessment of risk in the individual patient will facilitate optimal treatment of inflammatory pain or the beneficial effects of chronic low-dose aspirin use while avoiding the development of ulcers or predisposition to coronary or cerebrovascular events. References 1. Kaufman DW, Kelly JP, Rosenberg L, Anderson TE, Mitchell AA. Recent patterns of medication use in the ambulatory adult population of the United States: the Slone survey. JAMA 2002; 287: Laine L. Approaches to nonsteroidal anti-inflammatory drug use in the high-risk patient. Gastroenterology 2001;120: Wolfe MM, Lichtenstein D, Singh G. Gastrointestinal toxicity of nonsteroidal anti-inflammatory drugs. N Engl J Med 1999; 340(24): Appelboom T. Arthropathy in art and the history of pain management: through the centuries to the cyclooxygenase-2 inhibitors. Rheumatology 2002;41(suppl 1): Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nat New Biol 1971;231: Bombardier C, Laine L, Reicin A. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. N Engl J Med 1999;301: Goldstein JL, Silverstein FE, Agrawal NM, Hubbard RC, Kaiser J, Maurath CJ, et al. Reduced risk of upper gastrointestinal ulcer complications with celecoxib, a novel COX-2 inhibitor. Am J Gastroenterol 2000;95: Simon LS, Weaver AL, Graham DY. Anti-inflammatory and upper gastrointestinal effects of celecoxib in rheumatoid arthritis: a randomized controlled trial. JAMA 1999;282: Emery P, Zeidler H, Kvien TK, Guslandi M, Naudin R, Stead H, et al. Celecoxib versus diclofenac in long-term management of rheumatoid arthritis: randomized double-blind comparison. Lancet 1999;354: Silverstein FE, Faich G, Goldstein JL, Simon LS, Pincus T, Whelton A, et al. Gastrointestinal toxicity with celecoxib versus nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis. The CLASS study: a randomized controlled trial. JAMA 2000;284: Bensen WG, Fiechter JJ, McMillen JI, Zhao WW, Yu SS, Woods EM, et al. Treatment of osteoarthritis with celecoxib, a cyclooxygenase-2 inhibitor: a randomized controlled trial. Mayo Clin Proc 1999;74: Bombardier C, Laine L, Reicin A, Shapiro D, Burgos-Vargas R, Davis B, et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group. N Engl J Med 2000;343: Bresalier RS, Sandler RS, Quan H, Bolognese JA, Oxenius B, Horgan K, et al. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med 2005;352: Nussmeier NA, Whelton AA, Brown MT, Langford RM, Hoeft A, Parlow JL, et al. 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