Gastrointestinal and Cardiovascular Risks of Nonsteroidal Anti-inflammatory Drugs

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1 REVIEW Gastrointestinal and Cardiovascular Risks of Nonsteroidal Anti-inflammatory Drugs Roger Jones, DM, a Greg Rubin, FRCGP, b Francis Berenbaum, MD, c James Scheiman, MD d a Department of General Practice and Primary Care, King s College London School of Medicine, London, UK; b Department of Primary Health Care, University of Sunderland, Sunderland, UK; c Department of Medicine, Paris 6 University, APHP Saint-Antoine, Paris, France; d Department of Medicine, University of Michigan, Ann Arbor. ABSTRACT Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely prescribed but can have serious gastrointestinal (GI) and cardiovascular side effects, which have led to the withdrawal of some of these drugs and continuing uncertainty about the best approach to patients requiring NSAID therapy, particularly in those with GI or cardiovascular risk factors. To define the risks to the GI and cardiovascular systems associated with NSAID therapy, we have undertaken a series of systematic reviews of original articles published between January 1995 and December In this article we describe the mechanisms and patterns of GI and cardiovascular side effects in NSAID-taking patients and identify a range of drug and patient factors that contribute to an increased risk of adverse events. We conclude that NSAID therapy should not be started unless it is essential, and that Helicobacter pylori eradication should be considered in patients at increased GI risk. We discuss the use of gastroprotective agents and provide practical advice to help physicians assess and balance both cardiovascular and GI risks and benefits in their prescribing decisions Elsevier Inc. All rights reserved. The American Journal of Medicine (2008) 121, KEYWORDS: Cardiovascular symptoms; Gastrointestinal symptoms; Gastroprotection; Morbidity; Mortality; Nonsteriodal anti-inflammatory drugs; Risks 4 Nonsteroidal anti-inflammatory drugs (NSAIDs) are among against further gastrointestinal damage. These drugs include H 2 -receptor antagonists, proton pump inhibitors, and the most widely prescribed of all therapeutic agents, but their therapeutic efficacy comes at a price. Damage to the upper prostaglandin analogues. 5,6 gastrointestinal (GI) tract was the first unwanted effect to be The introduction of the cyclooxygenase-2 (COX-2)-specific NSAIDs 7 in the late 1990s promised a revolution in recognized clinically, 1 but other organ systems can be affected by NSAIDs. 2,3 The gastrointestinal damage caused NSAID therapy because of their much higher specificity for by the nonselective NSAIDs can be ameliorated either by the COX-2 system, but evidence of cardiovascular side discontinuing the drug or by adding a second drug to protecteffects including an increased risk of myocardial infarction began to emerge, 8 and some of the COX-2 NSAIDs were eventually withdrawn from general use in Europe and North America. 9,10 Confusion about the best approach to the management of patients requiring NSAID treatment, particularly for more complex patients, has been made worse by recent concerns about ibuprofen and diclofenac, which were previously regarded as having excellent safety records but also have been associated with a significantly increased risk of myocardial infarction. 11 Long-term NSAID therapy may, of course, Roger Jones has received consultancy and speaking payments from AstraZeneca, Altana Pharma, Glaxo SmithKline, and Novartis. Greg Rubin has received conference support and lecture and consultancy fees from Altana Pharma. Francis Berenbaum has received advisory and consultancy fees from AstraZeneca, Takeda, Pfizer, and Nicox and research grant funding from Expanscience and Pfizer. James Scheiman has acted as a paid consultant and speaker for AstraZeneca, Merck, McNeil, Novartis, TAP, Pfizer, PLx Pharma, NiCox, Horizon Therapeutics, The GI Company, Pozen, Bayer, Glaxo SmithKline and Santarus. Requests for reprints should be addressed to Roger Jones, DM, Department of General Practice & Primary Care, King s College London School of Medicine at Guy s, King s College and St Thomas Hospitals, 5 Lambeth Walk, London SE11 6SP. address: roger.jones@kcl.ac.uk have benefits, including reducing the risk of some cancers. This review provides clinicians with evidence-based guidance on NSAID treatment. We briefly review the differences /$ -see front matter 2008 Elsevier Inc. All rights reserved. doi: /j.amjmed

2 Jones et al Gastrointestinal and Cardiovascular Risks of NSAIDs 465 and similarities between the nonselective and COX-2 selective NSAIDs, the range of GI and cardiovascular side effects with different NSAIDs, and the impact of dosing and other drug factors affecting toxicity. We discuss the agents available to provide protection against NSAID-induced gastrointestinal damage, and consider approaches to the estimation and stratification of NSAID risks. Finally, we look at key questions for prescribing these agents when not to prescribe them, prescription in low- and highrisk patients, when NSAIDs should be discontinued, and the role of Helicobacter pylori infection eradication. Our recommendations are based largely on medium- to longterm studies which show that increased rates of thrombotic side effects of NSAIDs become significant after about 18 months, although an increased incidence of congestive heart failure is apparent in as early as 5 months. 13 Although duration of therapy is a risk factor, serious gastrointestinal and cardiovascular side effects may develop even during short-term treatment, particularly in patients with preexisting risk factors CLINICAL SIGNIFICANCE METHODS We systematically searched the Cochrane Library, Medline, and EMBASE for publications between 1995 and December We used the search terms non steroidal anti inflammatory agent or NSAID or COX, and also searched under the pharmaceutical names of available NSAIDs, combining this search with the terms GI, gastro$, gastric AND protection, prevent$, prophylaxis, co-medication OR proton pump inhibitor, proton pump inhibitor AS WELL AS safety, side effect, complication, event, symptoms, intolerance, toxicity, tolerability, risk for both ( GI, gastro$, gastric ) and ( cardiovascular, coronary, myocardial ), limiting our search to human studies. We also searched the reference lists of articles identified by this search strategy and selected those we judged relevant. In discussing treatment and prevention, we have concentrated on randomized controlled trials and metaanalyses, and have not included information derived from less powerful studies. These searches identified over 2000 articles, which, after checking for relevance and duplication, were reduced to 97 for GI complications of NSAIDs, 131 for NSAIDs and the cardiovascular system, and 47 for NSAIDs and gastroprotective agents. Selected references are included in the text and a full list of references is available from the authors. Nonsteroidal anti-inflammatory drugs (NSAIDs) have significant cardiovascular and gastrointestinal toxicity. Helicobactor pylori eradication reduces the risk of gastrointestinal complications of NSAIDs. Patients at normal cardiovascular risk may receive nonselective and COX-2 selective NSAIDs, with or without proton pump inhibitor cover. Patients at increased cardiovascular risk should receive naproxen with or without proton pump inhibitor co-prescription. A COX-2 NSAID plus proton pump inhibitor is recommended in patients with previous gastrointestinal bleeding. NSAIDS Terminology A variety of terms has been applied to the NSAID class of drugs. For consistency we use only 2 terms nonselective NSAIDs and COX-2 selective NSAIDs although we recognize a spectrum of COX-2 selectivity across the range of NSAIDs. Mechanisms of Action Cells synthesize prostaglandins in response to tissue injury, and inhibition of prostaglandins inhibits inflammation. NSAIDs exert their anti-inflammatory action by inhibition of cyclooxygenase activity, which transforms phospholipidderived arachidonic acid into prostaglandins. COX-1, which is not stimulated by proinflammatory cytokines such as IL-1, is a constitutive enzyme, present in most cells, and is associated with the regulation of hemostasis, the integrity of the gastrointestinal and renal tracts, platelet function, and macrophage differentiation (Figure 1). Although inhibition of COX-1 by NSAIDs may have some anti-inflammatory effect, the adverse effects of NSAIDs are predominantly related to the inhibition of the other important functions of COX-1. COX-2, by contrast, is an inducible enzyme and is more specifically associated with inflammation. Specific inhibition of COX-2 leads to reduction of inflammation without these adverse effects. However, all NSAIDs have some inhibitory effects on COX-1 and COX-2 activities, so that none is absolutely selective for COX-2. The adverse effects reported for COX-2 NSAIDs can occur with the older, COX-1 NSAIDs, and there also is a dose effect for the COX-2 agents, with greater COX-1 effects at higher doses. The recently described COX-3 system has opened up further avenues of therapeutic opportunity in the treatment of inflammatory conditions, not least because of the ability of paracetamol to inhibit COX-3 activity. 17,18 NSAIDs can be divided into a number of groups. The nonselective NSAIDs are mostly derived from carboxylic and enolic acids. The first COX-2 selective NSAIDs were celecoxib and rofecoxib, with the subsequent development of second generation COX-2-specific NSAIDS, including lumiracoxib and etoricoxib (Table 1). Mechanisms of Damage The mechanisms underlying the damage caused by NSAIDs to the gastrointestinal tract include disruption of the protective mucus layer, inhibition of protective bicar-

3 466 The American Journal of Medicine, Vol 121, No 6, June 2008 Phospholipids Arachidonic Acid COX-1 COX-3? cpges PGG2 PGH2 COX-2 mpges thromboxane PGE2 PGI2 platelet functions Homeostatic functions Inflammation vasodilation Gastrointestinal tract Renal tract Macrophage differentiation Figure 1 Cyclooxygenase mechanisms. bonate secretion, vasoconstriction (causing local tissue hypoxia), and a likely topical effect, in which the NSAIDs are trapped within cell membranes, leading to superficial epithelial necrosis NSAID injury occurs acutely in most patients taking aspirin and NSAIDs, 22 and serious adverse effects, including gastric and duodenal and their complications perforation and hemorrhage can occur during acute or after chronic use, 23,24 and might be asymptomatic, especially in the elderly Gastrointestinal Side Effects of NSAIDs These side effects are common and potentially serious, with as many as 60% of all NSAID users experiencing adverse effects. 26,28 Endoscopic studies indicate that 20%-30% of regular NSAID users develop, and symptoms dyspepsia and heartburn occur in up to 60% of patients taking NSAIDs. 23,33 The annual incidence of NSAID-related complicated and symptomatic is between 2.5% and 4.5%, 25,34 and the annual incidence of serious NSAID complications (perforation, hemorrhage, and obstruction) amounts to 1%-1.5%. 35,36 These risks are summarized in Table 2. For example, the relative risk of developing clinically significant adverse events is 4.4 with concomitant use of corticosteroids at doses 10 mg/day, 51 rising to 10.6 in patients over the age of 75 years and to 12.7 with concomitant anticoagulant prescription. 52 The relative risk of ulcer complications for patients aged over 75 years is 10.6, 53,54 and in those with a history of complicated peptic ulceration, lies between 12.5 and ,55 Cardiovascular Side Effects of NSAIDs NSAIDs increase both systolic and diastolic blood pressure, 56,57 and this can precipitate congestive cardiac failure and myocardial infarction. Most NSAIDs tend to increase cardiovascular risk, 12 and a recent database analysis of 9218 cases of first-ever diagnosis of myocardial infarction (MI) suggested an increased risk of MI with current use of rofecoxib, diclofenac, and ibuprofen, but not with naproxen. 11 A recent meta-analysis has confirmed a class effect of COX-2 drugs 12 compared with placebo (odds ratio [OR] 1.41, number needed to harm 357) and naproxen (OR 1.56, number needed to harm 256). Rofecoxib and celecoxib appear to increase the risk of vascular events to a similar extent. There was no increased risk of stroke in this study, but nonselective NSAIDs other than naproxen also may be associated with a higher risk of stroke than COX-2 NSAIDs. 56 In other words, if a patient is at a higher risk of cardiovascular events, switching from a COX-2 NSAID to a nonselective NSAID may not decrease treatment-related cardiovascular risk and is likely to increase GI risk. It appears that naproxen may be the safest NSAID, but this remains a subject of debate. 58 The unexpected increase in cardiovascular events reported in the VIGOR study, 8 which compared rofecoxib with naproxen in patients with rheumatoid arthritis, could have reflected either an increased risk due to rofecoxib, a decreased risk due to naproxen, or a chance result. Subsequently, however, the APPROVE trial reported an excess of myocardial infarction and stroke in patients taking rofecoxib to prevent the development of adenomatous polyps, and led to the withdrawal of the drug in September The increased cardiovascular risk of rofecoxib (relative risk

4 Jones et al Gastrointestinal and Cardiovascular Risks of NSAIDs 467 Table 1 Drugs Classification of Nonsteroidal Anti-inflammatory Carboxylic acids Salicylic acids and esters Aspirin Aloxpirin Benorylate Salsalate Diflunisal Acetic acids Phenylacetic acids Diclofenac Etodolac Sulindac Carbo- and heterocyclic acetic acids Indomethacin Ketorolac Tolmetin Propionic acids Flurbiprofen Ketoprofen Tiaprofenic acid Ibuprofen Naproxen Fenoprofen Oxaprozin Fenbufen Enolic acids Pyrazolones Phenylbutazone Azapropazone Oxicams Piroxicam Meloxicam Tenoxicam Lornoxicam Naphthylalkanone Nabumetone Fenamates Meclofenamic acid Flufenamic acid COX-2 specific NSAIDs Celecoxib Rofecoxib Valdecoxib/parecoxib Lumiracoxib Etoricoxib Abbreviations: COX cyclooxygenase; NSAID nonsteroidal antiinflammatory drug. 2.25, 95% confidence interval, , P.007) 60 has been confirmed in the meta-analysis of a total of 18 randomized controlled trials, and 2 recent systematic reviews 61,62 have confirmed the drug s association with an elevated risk of cardiovascular events (relative risk depending on dose). Valdecoxib was withdrawn on request in April Two short-term studies of patients 14,15 undergoing coronary artery bypass grafting found an increase in cardiovascular and thromboembolic events, which was statistically significant (2% vs 0.55%, P.03) in the larger trial. 15 Celecoxib is still available, although a large colorectal cancer prevention study reported a dose-dependent increased risk of serious cardiovascular events, 63 and the CLASS trial 34 also detected an increased overall cardiovascular risk for celecoxib. A pooled analysis of randomized controlled trials comparing different dosages of celecoxib with different NSAIDs did not identify an increased cardiovascular risk, 64 and the most recent meta-analysis has shown that whereas the event rate for myocardial infarction was elevated with celecoxib (OR 2.26), overall cardiovascular and cerebrovascular risks were not elevated. 65 Lumiracoxib, one of the most selective COX-2 NSAIDs, was not associated with cardiovascular toxicity in the TAR- GET trial, 66 or in subsequent studies, but recent reports of liver toxicity have resulted in its withdrawal in Australia, New Zealand, and Canada A recent systematic review and meta-analysis 70 has shown that, in postsurgical patients, parecoxib and valdecoxib are both associated with increased cardiovascular risk, and a systematic review and meta-analysis of cardiovascular risk with etoricoxib, with limited data, found weak evidence of increased cardiovascular risk (OR 1.49). 71 The accumulating evidence from these studies argues strongly for a class effect of COX-2 inhibitors. Probable mechanisms include blood pressure elevation and an effect on endothelial function, 75,76 both of which are likely to be related to the choice of drug and the dose and duration of treatment. Mechanisms of Gastroprotection NSAIDs inhibit the production of prostaglandin in the gastroduodenal mucosa. Although most mucosal prostaglandin is derived from COX-1, animal studies suggest that both COX-1 and COX-2 must be inhibited for gastric ulceration to occur, and that selective inhibition of one or the other alone does not result in gastric damage. 77 The reduced GI toxicity of COX-2 specific inhibitors may be due to their lack of dual COX inhibition rather than their COX-1 sparing effects. In this framework, taking both antithrombotic doses of aspirin (primarily a COX-1 inhibitor at low dose) and a Table 2 Factors that Increase the Risk of Developing GI Side Effects of NSAID Therapy Drug factors Patient factors Type and dose of NSAID 31,32,37 Age 25,40 Co-prescription of aspirin 38 History of peptic ulcer 25,36,41 Multiple NSAID use 39 History of dyspepsia 42,43 Duration of NSAID use 36 Helicobacter pylori status Concomitant drug prescription, Concurrent disease 49,50 eg, corticosteroids, anticoagulants 37,38 Abbreviation: NSAID nonsteroidal anti-inflammatory drug.

5 468 The American Journal of Medicine, Vol 121, No 6, June 2008 COX-2 inhibitor creates the ulcer risk of a nonselective NSAID. A prostaglandin-depleted mucosa is vulnerable to continuous exposure to acid. Strategies for gastroprotection therefore include supplementation with a synthetic prostaglandin analogue, gastric acid suppression, or the selective use of those NSAIDs least likely to inhibit prostaglandin synthesis. The effectiveness of these agents has been the subject of 3 systematic reviews and a small number of randomized controlled trials, and is summarized in Tables 3 and 4. Proton Pump Inhibitors Proton pump inhibitors are effective in reducing endoscopic and symptomatic ulceration Dyspepsia symptoms also were significantly reduced in 4 trials using them as an endpoint 78 and in one trial published after the systematic reviews appeared. 81 Limited evidence from a small number of comparative studies shows that misoprostol and proton pump inhibitors are both superior to ranitidine, and that in 2 secondary prevention trials, proton pump inhibitors are superior to misoprostol for the prevention of duodenal but not gastric ulcer. 78 Lansoprazole at doses of 15 mg and 30 mg daily appears equally effective in preventing duodenal ulcer recurrence. 82 Helicobacter pylori Eradication Two studies using endoscopic ulceration as an end point provide limited evidence that H. pylori eradication alone prevents ulceration in NSAID users. 44,83 In a comparative study of H. pylori eradication and proton pump inhibitor therapy in patients with a recent history of upper GI bleeding healed by proton pump inhibitor, both treatments were equally effective in preventing rebleeding a month later in patients taking low dose aspirin, but proton pump inhibitor was superior to H. pylori eradication for those taking other NSAIDs. 84 COX-2 NSAIDs versus Conventional NSAIDs COX-2 NSAIDs carry less risk of symptomatic peptic than non-selective NSAIDs and probably less risk of serious gastrointestinal complications. Subanalyses of the CLASS 34 and TARGET 85 trials suggest that this benefit is lost when patients also are taking aspirin, although both studies were underpowered for this end point. COX-2 NSAIDs versus Conventional NSAIDs Plus Proton Pump Inhibitor Two trials inform this choice, both conducted in patients with complications of peptic ulceration. 86,87 Nonsignificant differences in recurrent bleeding rates, higher in the celecoxib group, were found in the first, and no difference was found in the second. A large database study in the UK suggested that adverse upper GI events were increased in both COX-2 and conventional NSAID groups, 11 and that concomitant use of ulcer healing drugs reduced the risk in both groups. 11 A recent systematic review suggested that treatment with a COX-2 inhibitor alone may be appropriate in patients with chronic pain who are at higher risk of GI complications, lower cardiovascular risk, and in whom cost is not a constraint. 88 Misoprostol Misoprostol is effective in reducing endoscopic gastric and duodenal ulceration, and also reduces clinically serious adverse outcomes. There is no significant difference in relative risk reduction for duodenal ulceration between doses of 400 g and 800 g daily, but for gastric ulceration the higher dose is more effective. Only the MUCOSA study 29 has evaluated misoprostol against more serious outcomes, and in this high risk group, the number needed to treat to prevent one clinically important GI event was 264. The frequency of side effects of misoprostol has meant that its utility as a gastroprotective agent is limited. H 2 Receptor Antagonists H 2 receptor antagonists in double doses significantly reduced the risk of endoscopic ulceration. In normal doses they reduce the risk of duodenal but not gastric ulceration. A recent systematic review 89 found that, in cost-utility analyses, a nonselective NSAID plus an H 2 blocker is safer and less costly than nonselective NSAIDs alone, and equally effective and less costly than COX-2 NSAIDs. RECOMMENDATIONS In formulating our recommendations for practice, we recognize the limitations of the available evidence, the significance of financial constraints, and the different implications for primary and secondary care (Table 5). Many patients receive prescriptions for NSAIDs without being given appropriate trials of non-nsaid analgesia or nonpharmacological therapies. Regular paracetamol has been shown to be equivalent to NSAID therapy in patients with painful musculoskeletal conditions, 90,91 and there is evidence that exercise therapy, supplemented by cognitive behavioral support, is effective in patients with musculoskeletal and joint pain The European Helicobacter pylori Study Group 95 has recommended that H. pylori eradication is considered in patients planning long-term NSAID treatment. H. pylori infection remains a risk factor for NSAID complications, and eradication should be offered to high-risk patients with a history of ulcer disease in whom NSAID therapy is contemplated. Physicians need to assess both cardiovascular and gastrointestinal risk and benefit in the decision to prescribe NSAIDs, with or without gastroprotective agents, for both short-term and long-term use. The increased cardiovascular risk of the whole class of NSAIDs should influence these prescribing decisions, recognizing that preexisting cardiovascular disease is likely to increase NSAID risk, although this remains unproven.

6 Table 3 Proton pump inhibitor Helicobacter pylori eradication Summary of Evidence of the Effectiveness of Proton Pump Inhibitors and Helicobacter pylori Eradication in Preventing the GI Side Effects of NSAIDs Study Type Rostom et al 78 SR Pantoprazole 40 mg, lansoprazole mg, omeprazole 20 mg Gastroprotector (Daily Dose) Control n Studies Follow-up Outcome Measures Placebo months All endoscopic Hooper et al 79 SR Omeprazole 20 mg Placebo days Symptomatic Hooper et al 79 SR Omeprazole 20 mg Placebo days Serious GI complications Leandro et al 80 SR Omeprazole 20 mg Placebo month All endoscopic lansoprazole 30 mg gastroduodenal Chan et al 44 Single-blind RCT 1 week triple therapy (Bismuth subcitrate, tetracycline, methronidazole) Chan et al 84 RCT 1 week triple therapy (Omeprazole, clarithromycin, amoxicillin) 1 week of Omeprazole plus placebo antibiotics damage months All endoscopic months All endoscopic ARR (%) ( 95% CI) NNT (95% CI) 21.2 (5.0) 5 (4-7) 9.1 (4.5) 11 (8-22) 0.3 (0.7) 323 (98- ) 10.7 (7.5) 10 (6-32) 18.9 (14.4) 6 (3-23) 20.8 (15.3) 5 (3-19) Abbreviations: GI gastrointestinal; NSAIDs nonsteroidal anti-inflammatory drugs; ARR absolute risk reduction; NNT number needed to treat; SR systematic review; RCT randomized controlled trial. Jones et al Gastrointestinal and Cardiovascular Risks of NSAIDs 469

7 Table 4 Summary of Evidence of the Effectiveness of Misoprostol, H 2 Receptor Antagonists, and COX-2 NSAIDs in Preventing the GI Side Effects of NSAIDs Study Type Gastroprotector (Daily Dose) Control n Studies Follow-up Outcome Measures ARR (%) ( 95% CI) NNT (95% CI) Misoprostol Rostom et al 78 SR Misoprostol g Placebo months All endoscopic 11.6 (2.9) 9 (7-12) Rostom et al 78 SR Misoprostol g Placebo months All clinical 0.4 (0.8) 264 (87- ) Hooper et al 79 SR Misoprostol g Placebo days Symptomatic 0.6 (0.3) 176 ( ) Hooper et al 79 SR Misoprostol g Placebo 11, days Serious GI 0.3 (0.3) 323 ( ) complications Leandro et al 80 SR Misoprostol g Placebo month All endoscopic 10.2 (4.3) 10 (7-17) gastroduodenal damage H 2 Receptor Antagonists Rostom et al 78 SR Famotidine 80 mg Placebo months All endoscopic 21.5 (9.6) 5 (4-9) ( high dose ) Rostom et al 78 SR Ranitidine 300 mg, cimetidine 400 mg, famotidine 40 mg ( low dose ) Hooper et al 79 SR Famotidine mg, ranitidine 300 mg Leandro et al 80 SR Cimetidine mg, ranitidine 300 mg, famotidine mg Placebo months All endoscopic Placebo days Symptomatic Placebo month All endoscopic gastroduodenal damage COX-2 NSAIDs Hooper et al 79 SR COX-2 specific NSAIDs COX-1 NSAIDs 21, days Symptomatic Hooper et al 79 SR COX-2 specific NSAIDs COX-1 NSAIDs 21, days Serious GI complications Schnitzer et al 85 RCT Lumiracoxib Naproxen, 18, months Upper GI ibuprofen complications 5.7 (4.4) 17 (10-77) 0.4 (0.9) 222 (74- ) 10.8 (5.8) 10 (6-20) 1.0 (0.3) 99 (77-141) 0.4 (0.2) 270 ( ) 0.6 (0.2) 169 ( ) Abbreviations: COX cycloxygenase; NSAIDs nonsteroidal anti-inflammatory drugs; GI gastrointestinal; ARR absolute risk reduction; NNT number needed to treat; SR systematic review; RCT randomized controlled trial. 470 The American Journal of Medicine, Vol 121, No 6, June 2008

8 Jones et al Gastrointestinal and Cardiovascular Risks of NSAIDs 471 Table 5 Clinicians Guide to Anti-inflammatory Therapy No cardiovascular risk (without aspirin) Cardiovascular risk (with aspirin) No or Low Gastrointestinal Risk Non-selective NSAID (cost consideration) Naproxen* Addition of proton pump inhibitor if gastrointestinal risk of aspirin/nsaid combination warrants gastroprotection Abbreviations: NSAID nonsteroidal anti-inflammatory drug; COX cyclooxygenase. *Nonselective or selective (low-dose) NSAID without established aspirin interaction if naproxen is ineffective. NSAID Gastrointestinal Risk COX-2 selective inhibitor or nonselective NSAID proton pump inhibitor or COX-2 selective inhibitor proton pump inhibitor for patients with previous gastrointestinal bleeding Add proton pump inhibitor irrespective of NSAID COX-2 selective inhibitor proton pump inhibitor for those with previous gastrointestinal bleeding Our recommendations are summarized in Figure 2. Recognizing that definitive data are still lacking, avoidance of most NSAIDs is recommended for patients with ischemic heart, cerebrovascular and peripheral vascular disease, or a 10-year cardiovascular event risk of 10%. Treatment with naproxen appears most appropriate for these patients. 96,97 COX-2 NSAIDs with or without gastroprotective therapy are recommended for patients at increased risk of GI injury. Because proton pump inhibitors are better tolerated and are taken once daily, they are preferable to misoprostol. A careful risk-benefit assessment is required in patients who also require prophylactic low-dose aspirin, in whom nonspecific NSAIDs (preferably naproxen) should be given priority, with the possible addition of a gastroprotective agent in those at high GI risk. For patients without cardiovascular risk, who require aspirin prophylaxis for other reasons, and who are at low risk for GI events, monotherapy with naproxen remains the initial and cost-effective approach. Patients at risk of NSAID-related GI events, but who do not require aspirin prophylaxis, may be prescribed either a COX-2 NSAID or a nonselective NSAID plus proton pump inhibitor. 98 For patients taking aspirin, naproxen is favored over COX-2 inhibitors, and gastroprotection may be added to reduce the risk of multiple NSAID therapy. Physicians should pay attention to multiple and potentially competing factors in making a decision about NSAID prescription. If these drugs had been developed during the 21 st century, it is unlikely that they would have received regulatory approval because of their side effects, despite Assess patient s CV risk * Risk factors present Average risk Consider aspirin therapy: assess NSAID GI risk ** Assess NSAID GI risk High Low High Low/none Naproxen + PPI Naproxen COX-2 specific NSAID Non-selective or or or NSAID Non-NSAID therapy Non-NSAID therapy Non-selective NSAID + PPI or Non-NSAID therapy Figure 2 Decision tree for NSAID-related gastroprotection. *Presence of ischemic heart disease, peripheral vascular disease, cerebrovascular disease, 10-year cardiovascular disease 10% (Framingham equation). **Age, GI history, co-prescriptions, co-morbidity.

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