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Nsaid upper gi nomber (2)
The document discusses the risks of upper gastrointestinal adverse effects from NSAID use. It summarizes that: 1) NSAIDs can cause gastric mucosal damage through inhibition of both COX-1 and COX-2 enzymes and their topical irritant effects. 2) NSAID-associated gastroduodenal damage is dependent on gastric luminal pH, with more damage occurring at lower pH levels. 3) NSAID use is associated with increased risks of upper GI symptoms like dyspepsia, peptic ulcers, and complications from ulcers like bleeding. COX-2 selective NSAIDs still carry risks, especially in high-risk patients. 4) Upper GI side effects from
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Nsaid upper gi nomber (2)
- 1. NSAID Upper G/IAdverse Effects Minimizing Risks The 1st Palestinian G/I Conference May 20-22-2010
- 2. NSAIDs– a longhistory of analgesia & toxicity First recorded use of willow leaf extracts for musculoskeletal conditions found on Sumerian stone tablets. Aspirin first synthesised in 1899. First pathological evidence of gastric damage from aspirin in 1938. New non-aspirin, non-selective NSAIDs identified in the 1950s and developed in the 1970s. COX-2 selective NSAIDs discovered in 1992. First COX-2 selective NSAIDs approved in 1998.
- 3. NSAIDs inhibit theCOX enzyme, which exists in two forms Arachidonic acid COX-1 COX-2 (constitutive) (induced by inflammatory stimuli) COX-2 selective NSAIDs × × Non-selective NSAIDs × Prostaglandins Prostaglandins • Gastrointestinal cytoprotection • Inflammation • Platelet activity • Pain • Fever Vane & Botting 1995
- 4. Gastric mucosal damagerequires inhibition of both COX-1 and COX-2 Gastric damage score (%) 15 * * 10 * p<0.05 5 0 Vehicle Celecoxib SC-560 Celecoxib Indo- + methacin SC-560 Wallace et al 2000
- 5. Topical irritant effectsfrom NSAIDs NSAID damage to the gastric mucosa. Scanning electron micrographs of normal gastric mucosa (left) and mucosal surface (right) 16 minutes after administration of aspirin. Baskin et al 1976
- 6. NSAID-associated gastroduodenal damage is pH-dependent Total haemorrhagic mucosal area (%) intraduodenal saline 5 intraduodenal 4 indomethacin, 40 mg/kg 3 2 1 0 2.0 4.0 5.5 7.0 Gastric luminal pH Elliott et al 1996
- 7. NSAID-associated gastroduodenal damage is pH-dependent Total haemorrhagic mucosal area (%) intraduodenal saline 5 intraduodenal 4 indomethacin, 40 mg/kg 3 2 1 0 2.0 4.0 5.5 7.0 Gastric luminal pH Elliott et al 1996
- 8.
- 9. NSAID use isassociated with upper GI side-effects NSAIDs, including COX-2 selective NSAIDs, are associated with an increased risk of upper GI symptoms. NSAIDs, including COX-2 selective NSAIDs, are associated with peptic ulceration. Complications of NSAID use – bleeding, perforated or obstructed peptic ulcers – are a major cause of morbidity and mortality. Langman et al 1999; Silverstein et al 2000; Wolfe et al 1999
- 10. Incidence of upperGI symptoms in patients free from ulcer is similar with non-selective andGI symptoms selective NSAIDs Patients with upper COX-2 † (%) 35 30 25 All doses taken twice daily 20 15 10 5 0 Celecoxib, Celecoxib, Celecoxib, Naproxen, 100 mg 200mg 400 mg 500mg n=240 n=235 n=217 n=225 Simon et al 1999 † Dyspepsia, diarrhoea, abdominal pain, nausea and flatulence.
- 11. NSAID ingestion isone of the few drug- related risk factors for dyspepsia NSAIDs Calcium blockers Corticosteroids ACE inhibitors Methylxanthines 0.0 0.4 0.8 1.2 1.6 2.0 2.4 Adjusted rate ratio (CI) of prescription preceeding the use of an anti-ulcer drug Hallas & Bytzer 1998
- 12. Poor health-related qualityof life among patients free from ulcer taking NSAIDs, including COX-2 selective NSAIDs US population Mean SF-36 score n=2474 100 asthma n=110 80 diabetes mellitus n=541 60 NSAIDs (NASA 1) n=500 40 NSAIDs (SPACE 1) n=579 20 0 y n n i ia l ol ing l em lth th l l n a na Bo ica li t ai tio sic en eal tio oc ea ta ng e n ly p io ys Vi nc y nc S ot lh h fu Ph ph di al Data on file, NASA 1 & SPACE 1; ta er e Gralnek et al 2000; van der Molen et e fu M ol R G R al 1997; Ware & Sherbourne 1992
- 13. Upper GI side-effectsimpact negatively on patients‘ lives and can lead to withdrawal from treatment Productivity at work and daily activities are reduced amongst NSAID users: 13% reduced productivity at work (n=27) 26% reduced daily activities (n=61). More than half of all patients who switch NSAIDs do so because of side-effects. 44% of prescribers select the NSAID dose to minimise side-effects – at the expense of pain relief. Knott 2000; Steinfeld et al 2002; Wahlqvist et al 2003
- 14. NSAID users areat risk of reflux esophagitis Reflux esophagitis: the presence of definite mucosal breaks or metaplasia of the esophagus, visible under .endoscopy A B Among patients taking non-selective NSAIDs for osteoarthritis, the prevalence rate of erosive .esophagitis was 21% C D Photos reproduced with permission from Professor G Tytgat Reflux esophagitis LA Grades A–D. Avidan et al 2001
- 15. NSAID-associated peptic ulceration The majority of patients develop some gastric erosions after each dose .of a non-selective NSAID Approximately 15–30% of NSAID users develop endoscopically evident ulcers at any one time– these will be .generally silent COX-2 selective NSAIDs reduce the incidence of peptic ulcers compared with non- selective NSAIDs, but patients with risk factors or those who also use low-dose aspirin remain Photo reproduced from the Interactive .at risk Atlas of Gastroenterology Hawkey & Skelly 2002; Laine 1996; Silverstein et al 2000
- 16. Annual Rates ofHospitalisation for Ulcer Complications Saskatchewan, Canada 1982-86 Hospitalisations per 1000 person/years 25 Male users 20 Female users Male 15 non-users Female non-users 10 5 0 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85+ years Age Pérez Gutthann et al. Epidemiology 1997;8:18-24
- 17. NSAID-associated dyspepsia may predict peptic ulcer disease Relative risk of developing an ulcer/multiple erosions in those with moderate/severe dyspepsia 10 OMNIUM ASTRONAUT 8 7.8 6 5.3 4 3.9 2 1.8 0 Healing Maintenance Hawkey et al 1997
- 18. Risk of pepticulceration is similar between non-selective and COX-2 selective NSAIDs with concomitant low-dose aspirin Cumulative incidence of ulcers placebo (%) n=410 18 *** *** aspirin 16 n=406 14 rofecoxib + aspirin 12 n=399 10 ibuprofen 8 n=400 6 *** p<0.001 versus 4 placebo + aspirin 2 0 Laine et al 2004
- 19.
- 20. Aspirin, alone orwith another NSAID, increases the risk of upper GI Relative risk complications 8 7 6 5 4 3 2 1 0 Aspirin, Aspirin, Aspirin, NSAIDs Aspirin 75 mg 150 mg 300 mg + other once daily once daily once daily NSAIDs Weil et al 1995
- 21. Rofecoxib carries alower overall risk of upper GI events than naproxen Cumulative incidence of a naproxen, 500 mg confirmed upper GI event† (%) twice daily 5 rofecoxib, 50 mg once daily 4 3 n=8076 2 1 0 0 2 4 6 8 10 12 Duration of follow-up (months) † Perforation, obstruction, bleeding Bombardier et al 2000 or symptomatic peptic ulcer.
- 22. Risk of ulcercomplications with celecoxib remains high among patients with other risk factors Patients with ulcer complications (%) celecoxib, 400 mg twice daily 2 ibuprofen, 800 mg three times daily, or diclofenac, 75 mg twice daily n=8059 1 0 No risk factor More than one risk factor Hawkey & Skelly 2002
- 23. High-risk patients withprevious GI disease remain at risk of upper GI bleeding with COX-2 selective NSAIDs Adjusted odds ratio for upper GI bleeding 3.5 3.0 2.5 n=3686 2.0 1.5 1.0 0.5 0.0 Celecoxib Rofecoxib Non-aspirin, non-selective NSAIDs Nørgard et al 2004 Prescription within 30 days of hospital admission
- 24.
- 25. Risk factors forupper GI complications occurring with NSAIDs Patient-related factors: age >60 years history of peptic ulcer disease/upper GI complications. Drug-related factors use of a relatively toxic NSAID use of a high dose of NSAID (or two NSAIDs used concurrently) concurrent use of an anticoagulant concurrent use of a corticosteroid. H pylori infection. Seager & Hawkey 2001
- 26. Risk factors forpeptic ulcer bleeding NSAID use Oral corticosteroid use Warfarin use Previous peptic ulcer Dyspepsia in past year Heart failure Diabetes Current smoking 0 1 2 3 4 5 6 7 8 Odds ratio Weil et al 2000
- 27. Risk of upperGI events may be silent 50–60% of NSAID-associated peptic ulcers, presenting for the first time as a complication, have been silent previously. Most patients with endoscopic lesions do not develop dyspepsia: 9% of patients with abnormal endoscopy had dyspeptic symptoms (n=45). Larkai et al 1987; Singh 1998
- 28. NSAIDs are associatedwith the risk of serious upper GI complications, hospitalisation and mortality Non-selective NSAIDs account for approximately 20–25% of all reported drug adverse events. 80% of peptic ulcer-related deaths occur in non-selective NSAID users. In the USA, NSAID use accounts for approximately 107,000 hospitalisations and 16,500 deaths per year. Armstrong & Blower 1987; Singh 1998; Wolfe et al 1999
- 29. Strategies to Prevent andTreat NSAID complications
- 30. Mortality from bleedingulcers: 5-10%
- 31. Management of NSAID-induced peptic ulcer disease Discontinue use of NSAIDs or substitute with less toxic agents q Low-toxicity NSAIDs or COX-2 inhibitors Suppress acid secretion q Normal-dose PPI therapy q High-dose H2RA therapy Use mucosal protectants q Misoprostol (substantial side-effects, ) Seager & Hawkey, BMJ 2001; 323: 1236–9. Silverstein et al., Ann Intern Med 1995; 123: 241– 9. Graham et al., Ann Intern Med 1993; 119: 257–62. Yeomans et al., N Engl J Med 1998; 338: 719–26.
- 32. Acid suppression in NSAID-induced peptic ulcer Antacids q Limited efficacy, especially in preventing gastric ulcer s H2RAs q Effective in preventing DU >GU; some drug interactions, well tolerated PPIs q More effective than H2RAs for healing NSAID-induced ulcers, well tolerated Seager & Hawkey, BMJ 2001; 323: 1236–9. Goldstein et al., Gut 1999; 25(Suppl V): A101. Yeomans et al., N Engl J Med 1998; 338: 719–26. 32
- 33. The simplest waysto avoid or ..… reduce NSAID risks Don’t use an NSAID or COX-2 inhibitor – use something else (e.g. paracetamol) Use the lowest effective dose of the NSAID or COX-2 inhibitor But this often doesn‘t work
- 34. NSAID- G/I complication 2 1.5 1 0.5 1982 1992 2000 Fries etal .2004
- 35. Endoscopic Photograph of Gastropathy
- 36. Endoscopic Photograph of Gastric Ulcer
- 37. Cardiovascular benefits and GIrisks of low-dose Aspirin
- 38. Low-dose Aspirin )75-325MG(for prevention of CV events 2 prevention )established CV disease( - Decreases CV events and mortality (RCTs) * RRR= 19%, ARR=1.49% per yr. - CV benefit generally outweighs harm (bleeding). • 1 prevention )no overt CV disease(. - Decreases CV events, but not mortality (RCTs) * RRR= 12%, ARR= 1.49% per yr. - Increased bleeding may outweigh CV benefit. - Use if increased risk for future cardiac events. * >10% risk of CHD in 10 yrs (AHA).
- 39. Potential implication ofa Low incidence of Aspirin-induced ulcers Anti-platelet effect may be more important than mucosal injury as cause of GI complications. - Aspirin may complicate pre-existing GI injury. - Aspirin an infrequent cause of endoscopic ulcers but higher proportion are complicated.
- 40. ACCF/ACG/AHA Consensus Document management of low-dose Aspirin GI injury PPIs preferred agents for the therapy and prophylaxis of aspirin-associated GI injury. Risk factors necessitating PPI therapy. - Ulcer history (complicated or uncomplicated. - GI bleeding. - Concomitant anticoagulant or antiplatelets. - Two or more of the following 3 “risk” factors: • Age >_ 60, steroids, dyspepsia or GERD symptoms
- 41. Cardiovascular Benefits And GI Risks Of Clopidogrel
- 42. Aspirin + Clopidogrelvs. Aspirin Conclusions Form Double– Blind RCTS for CV Disease In patients with acute coronary syndrome or atria fibrillation Clopidogrel plus aspirin produces small but significant relative risk reductions of – 10-20% in CV events compared to aspirin alone.
- 43. ACC/AHA GUIDELINES Clopidogrel + Aspirin >- 1month after a bare metal stent. >- 1 year after a drug-eluting stent. >- 1month and ideally one year following unstable angina or NSTEMI managed without intervention. Long-term (e.g., 1year) following STEMI
- 44. ACCF/ACG/AHA Consensus Document Patients taking dual antiplatelet therapy should receive a PPI. Recommendation of PPI based on: - RCTs in low-dose aspirin users. - 1 case-control study of peptic ulcer bleeding among Clopidogrel or ticlopidine users. * RR of current PPI use=0.21(0.1-0.5).
- 45. PPI-Clopidogrel Interaction fact or fiction 3 observational studies show association - OR/RR: 1.25-1.5. • Due to confounding, when RRs < 1.5-2 can’t conclude whether observed statistical association is valid. - All 5 PPIs showed positive association. • 5 observational studies do not show significant association . • Laine 2010
- 46. Potential PPL-Clopidogrel interction U.S.FDA: -’’Concomitant use of drugs that inhibit CYP2C19(e.g.omeprazole) should be discouraged’’ -EMEA: -Discourages ‘’concomitant use of PPi and Clopidogrel – containing medicines unless absolutely necessary’’ . Laine 2010
- 47. PPL-C Clopidogrel interaction Totality of evidence currently insufficient to conclude whether valid statistical association or make judgment of causality Nonetheless, healthcare providers must make decisions for their patients based on the available evidence. Laine 2010
Editor's Notes
- #3 2. NSAIDs – a long history of analgesia and toxicity The use of willow extracts to soothe musculoskeletal complaints has a long history that stretches back to the Sumerian period. In 1828, the active ingredient, salicin, was first extracted and salicylic acid was later synthesised. 1 Aspirin was developed because the use of salicylic acid in its unmodified state causes severe dyspepsia, but upper gastrointestinal (GI) side-effects continue to mar the benefits from this class of drug, despite progress in reducing toxicity through the development of non-aspirin, non-selective non-steroidal anti-inflammatory drugs (NSAIDs). The discovery of the primary mechanism behind NSAID-associated upper GI side-effects, namely the systemic inhibition of cyclooxygenase (COX)-1-mediated prostaglandin synthesis in the gastric mucosa, provided the rationale for the development of COX-2 selective NSAIDs. Although these drugs are associated with fewer side-effects than non-selective NSAIDs, the early hopes that COX-2 selective NSAIDs would be free from toxicity have not been realised. The use of NSAIDs, including COX-2 selective NSAIDs, continues to carry significant risk of injury to the gastroduodenal mucosa. 2–4
- #4 3. NSAIDs inhibit the COX enzyme, which exists in two forms NSAID-mediated inhibition of prostaglandin synthesis is the central mechanism behind both the therapeutic and toxic activity of these drugs. Prostaglandins are synthesised through the action of the COX enzyme on the cell membrane constituent, arachidonic acid. 2 COX exists in two forms; the COX-1 isoform is constitutively expressed in most tissues and is believed to have a ‘housekeeping’ role, producing prostaglandins that regulate normal cell activity. The COX-2 isoform is virtually undetectable in most tissues under normal physiological conditions, but can be induced in the presence of inflammation, tissue damage or malignant transformation. 2–4 Prostaglandins produced by COX-2 are thought to be mediators of pain, inflammation and fever, 2–4 and the anti-inflammatory effects of NSAIDs appear to be largely attributable to inhibition of COX-2. 2–4 The cardioprotective effects of NSAIDs stem from inhibiting the COX-1-mediated synthesis of thromboxanes by platelets. Aspirin has the most pronounced anti-thrombotic effect of all NSAIDs as it irreversibly inhibits COX-1 in platelets. 5
- #5 4. Gastric mucosal damage requires inhibition of both COX-1 and COX-2 Although the inhibition of COX-1-mediated synthesis of prostaglandins in the gastric mucosa is the primary mechanism through which NSAIDs exert their toxicity, upper GI side-effects are unlikely to be caused solely by COX-1 inhibition. Many studies have suggested that COX-2 can contribute to gastric mucosal defence and that the inhibition of both COX isoforms is necessary for damage to the gastric mucosa. This was recently shown in a study in which the COX-1 and COX-2 isoforms in rats were selectively inhibited; 6 the COX-2 selective NSAID celecoxib had no effect on gastric prostaglandin synthesis, whereas the COX-1 selective inhibitor SC-560 reduced gastric prostaglandin synthesis. However, neither of these agents caused gastric damage when given alone; significant increases in gastric damage only became apparent when both COX-1 and COX-2 were inhibited with either celecoxib plus SC-560 or with indomethacin (which inhibits COX-1 and COX-2). This evidence strongly implicates COX-2 inhibition in mucosal damage.
- #6 9. Topical irritant effects from NSAIDs Topical irritant properties are predominantly seen with acidic NSAIDs, of which aspirin is the best known example. Indeed, there is evidence of significant localised foci and damaged cells only 16 minutes after administration of aspirin, compared with the normal mucosa. 9 The ability of NSAIDs to cause topical damage to the gastric mucosa is related, in part, to their accumulation within epithelial cells and their ability to decrease the hydrophobicity of the mucus layer in the stomach. Topical irritant effects on the epithelium are not, however, as strongly implicated in the development of gastroduodenal pathology as the systemic effects of NSAIDs. Thus, peptic ulceration and other upper GI side-effects are also observed after non-oral administration of NSAIDs.
- #7 11. NSAID-associated gastroduodenal damage is pH-dependent The central role that gastric acid plays in NSAID-associated gastroduodenal injury has been highlighted in animal studies, which demonstrate that NSAID-associated damage is highly pH-dependent. 10 Intraduodenal indomethacin, 40 mg/kg, caused marked macroscopic gastric mucosal damage in pylorus-ligated rats when the luminal pH was 2.0 or 4.0, but damage fell to control levels when the luminal pH was raised to 5.5 or 7.0. Elevation of the intragastric pH above 4 is, therefore, key in the management and prevention of NSAID-associated upper GI side-effects.
- #8 11. NSAID-associated gastroduodenal damage is pH-dependent The central role that gastric acid plays in NSAID-associated gastroduodenal injury has been highlighted in animal studies, which demonstrate that NSAID-associated damage is highly pH-dependent. 10 Intraduodenal indomethacin, 40 mg/kg, caused marked macroscopic gastric mucosal damage in pylorus-ligated rats when the luminal pH was 2.0 or 4.0, but damage fell to control levels when the luminal pH was raised to 5.5 or 7.0. Elevation of the intragastric pH above 4 is, therefore, key in the management and prevention of NSAID-associated upper GI side-effects.
- #10 14. NSAID use is associated with upper GI side-effects The pain relief and control of inflammation provided by NSAIDs are an essential part of therapy for a range of conditions. However, NSAID-associated upper GI side-effects represent a major clinical problem. These side-effects range in severity from commonly occurring nuisance symptoms, such as dyspepsia and heartburn, that are not life threatening, but have a significant effect on quality of life, to peptic ulcers and, most seriously of all, to complicated peptic ulcer disease. 12,13 Many patients who are at risk continue to be treated with non-selective NSAIDs and, while the COX-2 selective NSAIDs reduce the overall risk of upper GI side-effects compared with non-selective NSAIDs, they are not completely free from these effects. 14,15
- #11 16. Incidence of upper GI symptoms in patients free from ulcer is similar with non-selective and COX-2 selective NSAIDs The incidence of the most commonly occurring upper GI symptoms associated with NSAID use was investigated in a randomised, controlled trial by Simon et al. 16 Patients with rheumatoid arthritis who were free from esophageal or gastroduodenal ulceration were randomised to a non-selective or COX-2 selective NSAID for 12 weeks. The incidence of upper GI symptoms (dyspepsia, diarrhoea, abdominal pain, nausea and flatulence) was similar between the treatment groups, with 28%, 25% and 26% of patients experiencing such symptoms with celecoxib, 100, 200 and 400 mg twice daily, respectively, compared with 31% of patients taking naproxen, 500 mg twice daily. These data show that, as with non-selective NSAIDs, a significant proportion of patients are likely to experience upper GI symptoms during treatment with a COX-2 selective NSAID and may be at risk from upper GI complications.
- #12 18. NSAID ingestion is one of the few drug-related risk factors for dyspepsia NSAIDs are one of the few classes of drug that increase the risk of dyspepsia. The association between NSAIDs, other drugs, and dyspepsia was investigated in an analysis of prescription data from more than 30,000 incident users of ulcer-healing drugs in a Danish community. 20 As most patients with severe dyspepsia are treated empirically with anti-ulcer drugs, prescriptions for an NSAID that were followed within 100 days by a prescription for an anti-ulcer drug were considered indicative of NSAID-associated dyspepsia. Conversely, if the anti-ulcer medication preceded the NSAID prescription, no association was assumed. This reasoning was applied to other commonly prescribed categories of drugs. Thus, among patients who had started their first recorded therapies with an ulcer drug and another non-ulcer drug within a 100-day span, NSAID ingestion emerged as one of the few definite drug-associated risk factors for dyspepsia (adjusted rate ratio 1.8, 95% CI 1.6–2.0). A recent meta-analysis of NSAIDs and dyspepsia studies has also shown an increased risk of dyspepsia with indomethacin, meclofenamate or piroxicam (odds ratio 2.8) and for high doses of other NSAIDs (odds ratio 3.1). 21
- #13 19. Poor health-related quality of life among patients free from ulcer taking NSAIDs, including COX-2 selective NSAIDs The upper GI side-effects associated with regular NSAID use can lower patients’ quality of life to a greater extent than many chronic diseases. Compared with a healthy US population, patients free from ulcer taking NSAIDs, including COX-2 selective NSAIDs, had an impaired quality of life, as measured by the Short-Form (SF)-36 Health Survey. The reduction in health-related quality of life was also apparent in comparison with reference populations of patients with chronic conditions. 22–25
- #14 20. Upper GI side-effects impact negatively on patients’ lives and can lead to withdrawal from treatment Upper GI symptoms associated with NSAID use can impact significantly upon patients’ lives and reduce both their productivity at work and routine daily activities. This was confirmed by recent results from a Swedish study, in which a questionnaire was given to patients taking NSAIDs, of whom 36% were taking COX-2 selective NSAIDs: productivity at work was reduced by 13% and daily activities were reduced by 26% because of upper GI symptoms. 26 These symptoms cause many patients to switch between different types of NSAIDs in an attempt to lessen their severity and frequency. Thus, a postal survey of Norwegian NSAID users found that of the 1823 responders, 66% had switched brands or used different NSAID brands in the previous 2 years, and 52% of those switching cited side-effects as their main reason for switching brands. 27 A high rate of discontinuation of NSAID treatment was also found in a US study of 1405 patients with osteoarthritis; only 15 –20% of patients were still using their original NSAID after 12 months of follow-up . 28 The compromise between using doses high enough to control the pain of arthritis and low enough to minimise gastric toxicity in patients receiving long-term NSAIDs has been highlighted by a survey of primary care physicians in the UK. 29 Of the physicians surveyed, 44% reported their main aim when prescribing NSAIDs for osteoarthritis was not to eradicate pain completely but to minimise GI-associated side-effects by using low doses.
- #15 21. NSAID users are at risk of reflux esophagitis Patients taking NSAIDs with symptoms of GERD may have esophagitis; however, these symptoms are a poor indicator of the presence of esophagitis. Patients with esophagitis often have a similar profile of symptoms to patients with GERD without esophagitis 30 and, when esophagitis is present, the severity of heartburn is a poor indicator of the severity of esophagitis. 31 Thus, patients taking NSAIDs are at risk of erosive esophagitis and the risk may be silent. Indeed, the prevalence rate of erosive esophagitis among patients taking regular therapy with a non-selective NSAID for osteoarthritis was found to be 21%. 32 There are also reports implicating non-selective NSAIDs in the pathogenesis of more extensive mucosal injury such as esophageal ulceration and stricture formation . 33
- #16 22. NSAID-associated peptic ulceration Peptic ulceration is a common consequence of NSAID, including COX-2 selective NSAID, use and ranges in severity from endoscopically visible ulcers that are usually silent, to the life-threatening complication of a perforated ulcer. After a single dose of a non-selective NSAID, almost all patients develop some degree of gastric erosion and approximately 15–30% of chronic users will develop a peptic ulcer. 12,34 The healing of pre-existing ulcers is delayed by the use of non-selective NSAIDs; 35 COX-2 selective NSAIDs are also known to inhibit peptic ulcer healing. 36 The increased risk of NSAID users developing a peptic ulcer compared with those not taking NSAIDs has been investingated in a UK population-based cohort of 458,840 individuals. The relative risk of developing a clinically symptomatic but uncomplicated peptic ulcer was estimated as 4.0 (95% CI 3.2 – 5.1) for users of non-aspirin NSAIDs and 2.9 (95% CI 2.3 – 3.6) for users of aspirin compared with those not taking aspirin. The overall population incidence of peptic ulcer was 1.03 (95% CI 0.97 – 1.08) cases per 1000 person-years. 37 Although the incidence of gastric and duodenal ulcers is lower with COX-2 selective compared with non-selective NSAIDs, patients with risk factors, or who also use low-dose aspirin, remain at risk. 15,38
- #18 23. NSAID-associated dyspepsia may predict peptic ulcer disease The presence of peptic ulcer disease can, in some cases, be signalled by the presence of NSAID-associated dyspepsia. In the OMNIUM 39 and ASTRONAUT 40 studies, which compared omeprazole with misoprostol and ranitidine in the healing and maintenance of NSAID-associated lesions, patients were questioned about their overall dyspeptic symptoms at each visit prior to endoscopy, and these were related to the endoscopic findings. 41 Overall, 45% of patients reported moderate-to-severe dyspeptic symptoms on entry to these studies, which diminished in most patients during treatment. Patients who experienced moderate or severe NSAID-associated dyspepsia during healing or maintenance therapy were, however, found to have a two- to eightfold increased risk of having a gastroduodenal lesion than those without dyspepsia. Although many patients with lesions did not have moderate or severe dyspepsia, the authors recommended that patients who do suffer such symptoms should be considered for endoscopy.
- #19 25. Risk of peptic ulceration is similar between non-selective and COX-2 selective NSAIDs with concomitant low-dose aspirin Although COX-2 selective NSAIDs are associated with a lower risk of peptic ulceration than non-selective NSAIDs, their concomitant use with low-dose aspirin increases the risk to a level similar to that seen with non-selective NSAIDs. This was demonstrated recently in a double-blind trial with 1615 patients whose osteoarthritis required NSAID therapy but who were free from ulcers at baseline. 43 The cumulative incidence of ulcers in patients randomised to rofecoxib, 25 mg daily, plus low-dose enteric-coated aspirin, 81 mg daily, was significantly greater than with aspirin alone, 81 mg daily, or placebo (16.1%, 7.3% and 5.8%, respectively; p<0.001 for both comparisons with rofecoxib plus aspirin), but was similar to the incidence in patients randomised to ibuprofen, 800 mg three-times daily (17.1%; p=0.62). The incidence in patients receiving both ibuprofen and aspirin was not determined, as the risks from this combination were felt to be ethically unacceptable in a study in which GI-supportive therapy was not allowed. The use of low-dose aspirin for cardioprotection is widespread and, as shown in this study, significantly increases the risk of peptic ulceration with COX-2 selective NSAIDs to the level seen with non-selective NSAIDs.
- #21 28. Aspirin, alone or with another NSAID, increases the risk of upper GI complications A systematic review of epidemiological studies has shown that patients taking thromboprophylactic doses of aspirin, 75 mg daily, present a twofold increased risk of upper GI complications compared with those not taking aspirin, and the risk is further increased with the use of analgesic/anti-inflammatory doses of 150–300 mg daily. 63 Adding aspirin to another non-selective NSAID results in an eightfold increase in risk compared with not adding aspirin. Furthermore, the relative risk associated with aspirin is not reduced by buffered and enteric-coated formulations. In recognition of this risk, the use of GI supportive therapy is recommended for patients with other risk factors who need to take aspirin, including those taking low-dose aspirin as a prophylactic therapy for the prevention of cardiovascular disease (see Slide 51).
- #22 30. Rofecoxib carries a lower overall risk of upper GI events than naproxen The risk of serious upper GI events associated with NSAID use can be lessened by using a COX-2 selective NSAID instead of a non-selective NSAID. The VIGOR study investigated the incidence of gastroduodenal perforation or obstruction, upper GI bleeding and symptomatic peptic ulcers associated with the COX-2 selective NSAID rofecoxib and the non-selective NSAID naproxen. 65 During a median follow-up of 9 months, there were 2.1 upper GI events per 100 patient-years with rofecoxib, and 4.5 with naproxen. The respective rates of complicated events were 0.6 and 1.4 per 100 patient-years (p=0.005). Similar benefits over non-selective NSAIDs have been demonstrated in clinical trials with other COX-2 selective NSAIDs, including the CLASS study with celecoxib, diclofenac and ibuprofen, 15 and in a study with valdecoxib and diclofenac. 66 COX-2 selective NSAIDs do, however, present risks of their own, and the increased incidence of cardiovascular events documented during 18 months of rofecoxib treatment has led to this product’s withdrawal from the market. Whether cardiovascular side-effects are a class effect or are specific to rofecoxib has yet to be determined.
- #23 32. Risk of ulcer complications with celecoxib remains high among patients with other risk factors Patients taking celecoxib who also have other risk factors (such as those with a history of upper GI events, the elderly, or those taking concomitant corticosteroids or low-dose aspirin), remain at almost as high a risk of ulcer complications as those taking non-selective NSAIDs. 38 This has been shown in the CLASS study in 8059 patients with osteoarthritis or rheumatoid arthritis. 15 As with non-selective NSAIDs, potential risk factors should be assessed when prescribing COX-2 selective NSAIDs, and patients at high risk should be considered for prophylactic treatment (see slides 36 –44).
- #24 34. High-risk patients with previous GI disease remain at risk of upper GI bleeding with COX-2 selective NSAIDs A Danish population-based case control study has confirmed that patients with increased susceptibility to upper GI complications remain at risk of upper GI bleeding with celecoxib and rofecoxib. 68 Upper GI bleeding was investigated in patients who met one of four criteria: a history of non-bleeding ulcer; a history of esophagitis, gastritis, duodenitis or Mallory – Weiss lesions; use of proton pump inhibitors (PPIs) or H 2- receptor antagonists within the 2 years before case status; a history of alcoholism, chronic liver disease or esophageal varices before case status. Of the 780 incident cases of upper GI bleeding that were identified, 4.5% had received prescriptions for COX-2 selective NSAIDs within the 30 days prior to the event and 12.4% had received non-aspirin, non-selective NSAIDs. The equivalent proportions for the 2906 control patients were 2.7% and 4.1%, respectively. 68 Thus, the benefit of the COX-2 selective NSAIDs compared with non-selective NSAIDs may be reduced in such ‘at-risk’ patients. As with non-selective NSAIDs, potential risk factors should be assessed when prescribing COX-2 selective NSAIDs, and patients at high risk should be considered for prophylactic treatment (see slides 36 –44) .
- #26 37. Risk factors for upper GI complications occurring with NSAIDs There are a number of risk factors that are associated with upper GI complications in NSAID users. 69 Patients particularly at risk are those aged over 60 years, those with a history of peptic ulcer disease, taking a high-dose or relatively toxic NSAID, or concurrently using two NSAIDs, an anticoagulant or corticosteroid. Other factors such as Helicobacter pylori infection may also play a role. Dyspepsia is an additional factor in the quantification of ulcer risk. Patients taking NSAIDs who develop an ulcer complication are more likely than controls to report earlier dyspepsia and to link this to NSAID ingestion. 70,71
- #27 38. Risk factors for peptic ulcer bleeding Risk factors for peptic ulcer complications were investigated in a large case-control study of 1121 patients hospitalised for bleeding peptic ulcers. 72 In addition to the risk associated with the use of non-selective NSAIDs (odds ratio 3.8), other significant accessory risk factors were warfarin treatment, previous peptic ulcer or dyspepsia, heart failure, diabetes, oral corticosteroid use and smoking. With the exception of smoking, the effect of each of these risk factors was multiplied in patients who were currently using non-selective NSAIDs compared with those who were not. Thus, the odds of upper GI complications were approximately tripled by non-selective NSAID or corticosteroid use alone, and increased 10-fold when both were taken concomitantly. As described in later slides, while the COX-2 selective NSAIDs reduce the overall risk of upper GI complications compared with non-selective NSAIDs, they are not completely free from these side-effects.
- #28 40. Risk of upper GI events may be silent While upper GI symptoms are a risk factor for peptic ulcer disease and complications, the absence of dyspepsia does not indicate that a patient is free from the risk of ulcer complications. Risk can be silent, and patients often present with acute and serious pathology having had no significant prior symptoms. Indeed, it has been estimated that 50–60% of NSAID-associated peptic ulcers that present for the first time as a complication have previously been silent. 74 Symptoms cannot therefore be considered as reliable predictors of future outcomes. 75 This was illustrated when 65 patients who were regularly taking NSAIDs underwent endoscopy; of the patients shown to have mucosal lesions only 9% (4/45) had suffered from dyspepsia. 76
- #29 46. NSAIDs are associated with the risk of serious upper GI complications, hospitalisation and mortality The major clinical concern with NSAID use is the risk of peptic ulcer complications, such as bleeding and perforation, which is greater than with non-NSAID-associated peptic ulcers. Indeed, 80% of peptic ulcer-related deaths occur in users of non-selective NSAIDs. 75 Non-selective NSAIDs account for about 20% of all reported drug adverse events in the USA and approximately 25% in the UK. 75 In the USA alone, NSAID use has been estimated to account for approximately 107,000 hospitalisations and 16,500 deaths per year among patients with arthritis. 13,74
- #33 A number of agents can be used to suppress acid production for NSAID-induced peptic ulcer management, although some have limited efficacy and/or problematic side effects.