Canadian consensus guidelines on long-term nonsteroidal anti-inflammatory drug therapy and the need for gastroprotection: benefits versus risks

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1 Alimentary Pharmacology & Therapeutics Canadian consensus guidelines on long-term nonsteroidal anti-inflammatory drug therapy and the need for gastroprotection: benefits versus risks A. ROSTOM*, P. MOAYYEDI &R.HUNT, FOR THE CANADIAN ASSOCIATION OF GASTROENTEROLOGY CONSENSUS GROUP 1 *Division of Gastroenterology, University of Calgary Medical Clinic, AB, Canada; Division of Gastroenterology, McMaster University, Hamilton, ON, Canada Correspondence to: Dr A. Rostom, Division of Gastroenterology, University of Calgary Medical Clinic, 3330 Hospital Drive NW G176, Calgary, AB T2N 4N1, Canada. arostom@ucalgary.ca 1 See list of voting participants in Appendix S1. This consensus conference was endorsed and organized by the Canadian Association of Gastroenterology and was held in Banff, Alberta, Canada, on February Publication data Submitted 15 August 2008 First decision 5 September 2008 Resubmitted 5 November 2008 Resubmitted 20 November 2008 Accepted 21 November 2008 Epub Accepted Article 27 November 2008 SUMMARY Background Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used, but are not without risks. Aim To provide evidence-based management recommendations to help clinicians determine optimal long-term NSAID therapy and the need for gastroprotective strategies based on an assessment of both gastrointestinal (GI) and cardiovascular (CV) risks. Methods A multidisciplinary group of 21 voting participants revised and voted on the statements and the strength of evidence (assessed according to GRADE) at a consensus meeting. Results An algorithmic approach was developed to help manage patients who require long-term NSAID therapy. The use of low-dose acetylsalicylic acid in patients with high CV risk was assumed. For patients at low GI and CV risk, a traditional NSAID alone may be acceptable. For patients with low GI risk and high CV risk, full-dose naproxen may have a lower potential for CV risk than other NSAIDs. In patients with high GI and low CV risk, a COX-2 inhibitor plus a proton pump inhibitor (PPI) may offer the best GI safety profile. When both GI and CV risks are high and NSAID therapy is absolutely necessary, risk should be prioritized. If the primary concern is GI risk, a COX-2 inhibitor plus a PPI is recommended; if CV risk, naproxen 500 mg b.d. plus a PPI would be preferred. NSAIDs should be used at the lowest effective dose for the shortest possible duration. Conclusion More large, long-term trials that examine clinical outcomes of complicated and symptomatic upper and lower GI ulcers are needed. 481 doi: /j x

2 482 A. ROSTOM et al. INTRODUCTION Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used to treat arthritis, menstrual, musculoskeletal and post-operative pain, as well as headache and fever. NSAIDs include acetylsalicylic acid (ASA), traditional NSAIDs (tnsaids) (e.g. diclofenac, ibuprofen, indomethacin and naproxen) and inhibitors of the COX-2 isoform of cyclo-oxygenase (e.g. celecoxib, lumiracoxib, etoricoxib, rofecoxib). Nonsteroidal anti-inflammatory drugs are prescribed short term to about 25% of Canadians and long term (defined in this study as 6 months) to about 4%. 1 However, this underestimates the magnitude of NSAID use as it does not include over-the-counter NSAIDs and low-dose ASA is extensively used for cardiovascular risk reduction. Nonsteroidal anti-inflammatory drugs are associated with increased risks of upper gastrointestinal adverse events, 2 6 which are compounded by co-prescription with ASA. 6 COX-2 inhibitors and tnsaids are also associated with an increased risk of cardiovascular events 7, 8 leading regulatory authorities to require warning statements. 9, 10 In addition, rofecoxib, valdecoxib and lumiracoxib have been withdrawn from the market because of cardiovascular, cutaneous and hepatic adverse events, respectively Previous guidelines addressing the issues surrounding the use of NSAIDs have either not integrated all the issues or were published before the full implications of the cardiovascular harms became evident. 15 Recently two consensus groups, one US and the other international, have published clinical practice guidelines aimed at reducing the gastrointestinal risks of 16, 17 NSAID and antiplatelet therapy. However, these groups have also focused only on the risks and have not discussed the benefits of these therapies. This multidisciplinary group developed Canadian guidelines, with international input, to help clinicians make informed decisions regarding the benefits and risks for an individual patient when choosing an NSAID for long-term (defined as >4 weeks) pain management. METHODS Clinically relevant consensus statements relating to the chronic use of tnsaids, ASA and COX-2 inhibitors were developed according to generally accepted standards. 18 The need for clinical practice guidelines on the chronic use of tnsaids, ASA and COX-2 inhibitors was identified by an initial review of the existing literature and provoked by controversy and concern over recent clinical trial data surrounding the use of these drugs. Membership of the consensus group An organizing committee selected a nonvoting facilitator and a multidisciplinary group of 21 voting Canadian and international physicians (Appendix S1). Nonvoting observers included physicians (members of CAG) and representatives from the pharmaceutical industry (Appendix S1). Industry representatives did not participate in any consensus discussions. Representatives of Canadian regulatory stakeholders were also invited to attend. Nature and extent of background preparation Literature review methods for relevant articles included MEDLINE searches and manual searches of bibliographies of key articles published in English between 1966 and February Search terms are shown in the online Appendix S1. We identified past systematic reviews and meta-analyses and if these were out of date or absent, appropriate additional systematic reviews were conducted. These data were presented at the consensus conference before formal voting on the statements. Data available only in abstract form were also considered. Modified Delphi consensus process The preliminary statements generated by the co-chairs were circulated electronically for review before the meeting. These statements were circulated once for comment, they were revised, and circulated again for an initial vote to determine the premeeting strength of agreement with the statements. A summary of the evidence was provided before the meeting. The strength of evidence was assessed using the process suggested by the GRADE working group (Table S1) and each statement was assigned a grade to indicate the quality of evidence. 19 During the meeting each statement was voted on twice. The first vote was to determine the level of agreement with the statement itself and the second to determine the level of agreement with the strength of evidence assigned to the statement. All voting at the

3 CANADIAN CONSENSUS ON NSAIDS, ASA AND COX-2 INHIBITORS 483 meeting was conducted using keypads to ensure that the process was anonymous. Statement and evidence grades were accepted when more than 80% of participants voted a or b (agree strongly or agree with minor reservations). of whom approved the final draft. It was then submitted to the Board of the CAG for approval and posted on the CAG website for review by the CAG membership prior to submission for peer review. General meeting organization A 2-day consensus conference was held in February 2007 under the auspices of the Canadian Association of Gastroenterology (CAG) in accordance with generally accepted standards for the development of clinical practice guidelines. 18, 20 At the consensus conference, data were presented and the statements and the grades attributed to evidence were discussed, modified if necessary and voted on by each participant according to the criteria shown in Table S1. The CAG, which administered all aspects of the meeting, secured multi-partner funding from the Canadian Institute for Health Research (CIHR) and industry sponsors. Statements of conflicts of interest were obtained from all voting participants. 21 Preparation process and format of the report A working group drafted the manuscript, which was then reviewed by all voting conference participants and co-chairs, as well as the nonvoting facilitator, all RECOMMENDATION STATEMENTS Each statement is followed by the grade of supporting evidence and the results of the two votes: (i) agreement with the statement and (ii) agreement with the grade of evidence followed by a brief summary. Statements were classified as benefit or harm statements. A consensus was considered reached when more than 80% of participants voted a or b (agree strongly or agree with minor reservations). An algorithmic approach to risk assessment is provided in Figure 1. Benefits of tnsaids, ASA and COX-2 inhibitors Statement 1: NSAIDs are effective in improving pain and function in patients with arthritis. Grade A (vote statement: a 76%, b 19%, c 5%; vote grade: a 52%, b 38%, c 10%). Statement 2: In general, tnsaids have similar effectiveness in improving pain and function in patients with arthritis. Grade A (vote statement: a 57%, b 38%, c 5%; vote grade: a 38%, b 48%, c 5%, d 10%). Patient requires NSAID HIGH GI Risk LOW GI Risk HIGH CV Risk (on ASA) LOW CV Risk HIGH CV Risk (on ASA) LOW CV Risk Avoid NSAID if Possible Can t Avoid NSAID COX-2 Alone Or tnsaid + PPI * Naproxen + PPI tnsaid Very High CV Risk Primary Concern Naproxen + PPI Very High GI Risk Primary Concern COX-2 + PPI Figure 1. Algorithm for the use of long-term NSAID therapy and gastroprotective agents according to a patient s gastrointestinal and cardiovascular risk. *In high-risk patients, a COX-2 inhibitor and a tnsaid + proton pump inhibitor (PPI) show similar reductions of rebleeding rates, but these reductions may be incomplete. In general, most patients on acetylsalicylic acid + naproxen would need the addition of a PPI. However, for some patients at very low GI risk, naproxen alone may be appropriate.

4 484 A. ROSTOM et al. Statement 3: COX-2 inhibitors are as effective as tnsaids in improving pain and function in patients with arthritis. Grade A (vote statement: a 62%, b 33%, c 0%, d 5%; vote grade: a 52%, b 43%, c 0%, d 5%). Statement 4: In general, tnsaids and COX-2 inhibitors are more effective than acetaminophen in the management of moderate-to-severe arthritis pain. Grade B (vote statement: a 57%, b 38%, c 5%; vote grade: a 29%, b 57%, c 10%, d 5%). Statement 5: Topical NSAIDs have similar effectiveness as oral tnsaids in improving pain and function in patients with osteoarthritis of the knee. Grade B (vote statement: a 29%, b 62%, c 10%; vote grade: a 14%, b 67%, c 14%, d 5%). Statement 6: Low-dose ASA reduces the risk of secondary ischaemic heart disease events and mortality. Grade A (vote statement: a 90%, b 10%; vote grade: a 90%, b 10%). Acetylsalicylic acid affects platelet and endothelial function through thromboxane A2 and prostacyclin pathways 22 and demonstrates beneficial antithrombotic effects. Systematic review data support the use of low-dose ASA for the secondary prevention of cardiovascular events in patients who had a previous event (secondary prevention). 23 The Canadian Cardiovascular Society and the American Heart Association (AHA) recommend ASA be considered for all patients with 24, 25 coronary disease. Statement 7: Low-dose ASA reduces the risk of primary cardiovascular events, but not mortality. The benefit increases with increasing baseline cardiovascular risk. Grade A (vote statement: a 57%, b 33%, c 0% d 10%; vote grade: a 81%, b 14%, c 5%). Meta-analyses indicate that low-dose ASA decreases the risk of a first ischaemic heart disease event, but does not decrease overall mortality. 26, 27 ASA statistically significantly decreased the risk of total coronary heart disease (CHD), nonfatal myocardial infarction (MI) and total cardiovascular events and numerically but not significantly reduced the risk of stroke and mortality. 26 The benefits associated with ASA therapy increase with increasing baseline cardiovascular risk; 28 therefore, it is important to assess an individual s risk. Cardiovascular guidelines recommend low-dose ASA for primary prevention in select patient groups based on 29, 30 risk. Statement 8: tnsaids, ASA and COX-2 inhibitors reduce the risk of recurrent colorectal adenomas. Grade A (vote statement: a 52%, b 38%, c 10%; vote grade: a 29%, b 62%, c 5%, d 5%). Statement 9: Observational data show an association between tnsaids or ASA and reduced incidence of luminal gastrointestinal cancers. Grade B (vote statement: a 29%, b 71%; vote grade: a 33%, b 57%, c 5%, d 5%). The COX-2 isoenzyme shows enhanced expression in precancerous and cancerous lesions including colonic adenomas and oesophageal, gastric and colorectal carcinomas. 31, 32 COX-2 derived prostaglandin (PG) E2 is involved in cell proliferation, apoptosis and 33, 34 angiogenesis. Systematic reviews indicate that tnsaids, ASA and COX-2 inhibitors can reduce the risk of colonic adenomas and colorectal cancer (CRC). 35, 36 However, observational studies suggest that these drugs may need to be used in relatively high doses for long durations to have a protective effect on CRC; thus, the analyses recommended against use of these agents for CRC chemoprevention when the balance of benefits to harms 35, 36 was considered. Meta-analyses of observational studies also provide early evidence of a protective effect of ASA tnsaids for oesophageal cancer 37 and for gastric cancer. 34 Harms of tnsaids, ASA and COX-2 inhibitors Statement 10: ASA increases the risk of intracranial bleeding. Grade A (vote statement: a 48%, b 48%, c 5%; vote grade: a 52%, b 38%, c 10%). When using ASA for its beneficial antiplatelet effects, it is important to assess not only the gastrointestinal risks but also the risk of haemorrhagic stroke. Eight systematic reviews reported the risk for acute stroke (haemorrhagic and ischaemic) with ASA use. 23, 26, 28, Although the overall relative risk of intracranial haemorrhage with ASA was statistically significant, the absolute risk of these events over placebo is small. The risk does not appear to be increased 26, 28, 38, 39 when ASA is used for primary prevention. In the setting of secondary prevention, the overall benefits of ASA in terms of significant reductions in MI and ischaemic stroke outweigh the risk of haemorrhagic stroke. 23, 40, 42 However, the risk does increase 40, 41 with increasing ASA dose. Statement 11: ASA and tnsaids increase the risk of upper gastrointestinal complications. Grade A (vote statement: a 62%, b 29%, c 10%; vote grade: a 57%, b 38%, c 5%).

5 CANADIAN CONSENSUS ON NSAIDS, ASA AND COX-2 INHIBITORS 485 Acetylsalicylic acid and tnsaids increase the risk of gastrointestinal complications, predominantly through an increased risk of peptic ulceration and associated bleeding. For the purposes of this article, clinically important upper gastrointestinal complications included: (i) the POB endpoint (perforations, obstructions or bleeding) and (ii) the PUB endpoint (symptomatic ulcer and or POB) used in the clinical outcome trials. Studies using the surrogate endpoint of asymptomatic ulcers detected at endoscopy were considered, but greater emphasis was placed on the clinical endpoints. Meta-analysis, RCT and case control data demonstrate that long-term therapy with ASA or tnsaids is associated with a significant increase in the incidence of gastrointestinal haemorrhage. 2, 3, 28, 36, 43, 44 The risk was about 1.5 2% per year in average-risk individuals, but as high as 10% or more in high-risk individuals (i.e. previous peptic ulcers, older age, comorbid conditions such as cardiovascular disease). 36 Statement 12: ASA and tnsaids increase the risk of small and large bowel bleeding and other complications. Grade B (vote statement: a 62%, b 33%, c 5%; vote grade: a 29%, b 67%, c 5%). The gastrointestinal risks with NSAIDs are not limited to the upper gastrointestinal tract. These drugs can cause small bowel ulceration, haemorrhage and strictures and can precipitate bleeding from colonic diverticula. A systematic review reported a consistent increase in lower gastrointestinal injury and clinical events in patients using tnsaid compared to those not using tnsaid. 45 In addition, data from RCTs have demonstrated that the risk of lower gastrointestinal events is higher with tnsaids than with COX-2 inhibitors. 46, 47 Statement 13: COX-2 inhibitors increase the risk of upper gastrointestinal ulcers and complications but to a lesser extent than tnsaids. Grade A (vote statement: a 57%, b 43%; vote grade: a 38%, b 62%). COX-2 inhibitors have demonstrated some increased risk of upper gastrointestinal ulcers and complications compared to placebo. 4, 5 The increased risk was demonstrated in a polyp prevention study with rofecoxib, 4, 5 but not in two such studies with celecoxib; 48, 49 however, the latter two studies did not 48, 49 predefine or adjudicate these endpoints. The risk of upper gastrointestinal ulcers and complications with COX-2 inhibitors is lower than that seen with tnsaids. 6 Compared with tnsaids, COX-2 inhibitors were associated with a 61% lower risk of clinically important ulcer complications (POB) and a 59% lower risk of the combined endpoint of upper gastrointestinal symptomatic ulcers and POB. 6 Statement 14: The risk of gastrointestinal bleeding is increased when ASA is co-prescribed with tnsaids compared to tnsaids alone. Grade B (vote statement: a 43%, b 52%, c 5%; vote grade: a 48%, b 48%, c 5%). Statement 15: The risk of gastrointestinal bleeding is increased when ASA is co-prescribed with COX-2 inhibitors compared with COX-2 inhibitors alone. Grade B (vote statement: a 62%, b 38%; vote grade: a 71%, b 29%). Observational, cohort data suggested that the concomitant use of tnsaid or COX-2 inhibitor with ASA increases the risk of upper gastrointestinal bleeding by more than just an additive effect of the drugs. 44 The effect of co-administration of ASA with a COX- 2 inhibitor or a tnsaid was examined in post hoc subgroup meta-analyses. 6 These represented nonrandomized comparisons; therefore, differences could have been influenced by factors other than ASA use. Based on data from four trials, COX-2 users also taking ASA had a four-fold greater relative risk of POBs than those not taking ASA. Among tnsaid users, those taking ASA had a numerically but not statistically greater risk of POBs than those not taking ASA. In a pooled subgroup analysis, the benefit of COX-2 inhibitors over tnsaids that was seen in the overall analysis was attenuated in patients taking ASA. 6 With publication of the MEDAL programme, 54 a 50 52, 54 meta-analysis of four large trials was performed for this consensus (Figure 2). In this analysis of patients taking ASA, use of a COX-2 inhibitor plus ASA was associated with a statistically significant 23% reduction in the risk of the combined outcome of POB plus symptomatic ulcers (95% CI: 5 38) compared to a tnsaids plus ASA; however, this is a nonrandomized post hoc analysis that should be interpreted with caution. Taken together, the data suggest a gastrointestinal advantage of adding a COX-2 inhibitor rather than a tnsaid to therapy for patients who are on low-dose ASA. Therefore, for patients who are at both high cardiovascular risk (requiring ASA) and high gastrointestinal risk and in whom the gastrointestinal risk is the primary concern, a COX-2 inhibitor may be preferred.

6 486 A. ROSTOM et al. Study or sub-category Treatment n/n Control n/n Silverstein 2000, CLASS Schnitzer 2004, TARGET Singh 2006, SUCCESS1 Laine 2007, MEDAL 14/298 33/2167 3/ / /283 45/2159 4/ /5680 RR (fixed) 95% Cl Favours treatment Favours control Weight % Total (95% Cl) Total events: 150 (Treatment),190 (Control) Test for heterogeneity: Chi 2 = 0.98,df = 3 (P = 0.81), I 2 = 0% Test for overall effect: Z = 2.44 (P = 0.01) RR (fixed) 95% Cl [0.39, 1.56] [0.47, 1.14] [0.09, 1.69] [0.61, 1.03] 0.77 [0.62, 0.95] Figure 2. Comparison of clinical ulcer complications [symptomatic ulcers plus POBs (perforations, obstructions or bleeding)] with COX-2 inhibitor plus acetylsalicylic acid (ASA) (treatment) vs. tnsaid plus ASA (control). Source: Silverstein et al. (CLASS); 50 Schnitzer et al. (TARGET); 51 Singh et al. (SUCCESS 1); 52 Laine et al. (MEDAL). 54 Statement 16: The risk of gastrointestinal bleeding is increased when clopidogrel is prescribed with ASA compared with ASA alone. Grade B (vote statement: a 29%, b 67%, c 5%; vote grade: a 29%, b 71%). The increased risk of gastrointestinal bleeding with the use of ASA is further increased by co-prescription of clopidogrel. Clopidogrel is often perceived as relatively safe in terms of gastrointestinal adverse events, but data show that even as monotherapy clopidogrel is associated with a high risk of rebleeding in patients with prior ulcer bleeding. 55, 56 When used in combination with ASA, clopidogrel increases the risk of bleeding compared to ASA alone. Three large RCTs have assessed the combination of clopidogrel and ASA compared to ASA alone: CURE, 57 COMMIT 58 and CHARISMA. 59 CURE found a significantly higher risk of any major bleeding over 12 months, 57 while CHARISMA found an significantly increased risk of moderate bleeding and a numerically but not significantly increased risk of severe bleeding over 28 months 60 with the combination compared to ASA alone. COMMIT showed no increased risk in major bleeding with the combination compared to ASA alone; however, mean duration of treatment was only 15 days. 58 For patients at high gastrointestinal risk, it may be better to avoid the combination of clopidogrel and ASA. Statement 17: The risk of gastrointestinal bleeding with tnsaids and or ASA is increased in patients infected with H. pylori. Grade B (vote statement: a 24%, b 71%, c 5%; vote grade: a 38%, b 52%, c 5%, d 0%, e 0%, f 5%). A majority of peptic ulcer-related upper gastrointestinal events may be attributed to NSAID use or H. pylori infection. 61 Systematic reviews of observational data indicate that both H. pylori infection and NSAID use represent independent risk factors for 62, 63 uncomplicated and bleeding peptic ulcers. Helicobacter pylori infection increased the risk of bleeding both in patients taking tnsaids and those not taking tnsaids. 63 Among patients with both H. pylori infection and NSAID use, the relative risk of bleeding was 6 20 times greater than that seen in 62, 63 patients having neither risk factor. Statement 18: Certain patient characteristics increase the risk of NSAID-induced upper gastrointestinal clinical events (see Table 1). Grade A (vote statement: a 76%, b 19%, c 0%, d 0%, e 0%, f 5%; vote grade: a 57%, b 43%). Analyses of risk factors for upper gastrointestinal clinical events in patients taking NSAIDs are available from observational studies, meta-analyses of observational studies and from prespecified assessments of RCTs. While there is some variability, older age (>60 75 years), comorbidity, history of previous gastrointestinal bleeding, high NSAID dose, multiple NSAIDs and concomitant use of selective serotonin reuptake inhibitors are consistently associated with increased risk of gastrointestinal events in patients taking NSAIDs (see Table 1 for more complete list). 2, 43, 44, As these studies included differing patient populations and not all studies considered all risk factors, direct comparisons of the magnitudes of the risks should be avoided. Statement 19: tnsaids, ASA and COX-2 inhibitors increase the risk of upper gastrointestinal symptoms. Grade A (vote statement: a 70%, b 30%; vote grade: a 76%, b 24%). Dyspeptic symptoms are commonly associated with the use of ASA and tnsaids. COX-2 inhibitors were

7 CANADIAN CONSENSUS ON NSAIDS, ASA AND COX-2 INHIBITORS 487 Table 1. Risk factors associated with upper gastrointestinal clinical events Characteristic RR* range Age years 2, 43, History of upper gastrointestinal symptoms 2, 64, 66, 67 History of peptic ulcer 64, History of gastrointestinal bleeding 2, 43, High-dose NSAID Multiple NSAIDs Concomitant low-dose ASA 44, 66, Concomitant anticoagulants 2, Concomitant corticosteroids 2, 43, 64, Concomitant selective serotonin reuptake inhibitors 68 Severe rheumatoid arthritis disability History of cardiovascular disease 65, Helicobacter pylori positive 62, NSAID, nonsteroidal anti-inflammatory drug; ASA, acetylsalicylic acid. * RR, relative risks associated with various risk factors. As these studies included differing patient populations and not all studies considered all risk factors, direct comparisons of the magnitudes of the risks (i.e. rows of the table) should be avoided. associated with significantly more overall gastrointestinal symptoms, dyspepsia, nausea and abdominal pain than placebo, but less than tnsaids in a large metaanalysis. 6 Withdrawals for adverse symptoms associated with COX-2 inhibitors were significantly greater than placebo at high dose and less than tnsaids at both low and high doses. Acetylsalicylic acid can also be associated with some adverse gastrointestinal symptoms; 69 but a meta-analysis showed no significant increase in discontinuation rates for this reason with low-dose ASA used for cardiovascular protection compared to placebo. 42 ASA was associated with significantly more diarrhoea and constipation, but not dyspepsia, compared with placebo. Based on these summaries and data from population studies, it is likely that ASA has an increased risk of upper gastrointestinal symptoms compared to placebo. Statement 20: COX-2 inhibitors increase the risk of coronary heart disease events. Grade A (vote statement: a 67%, b 24%, c 10%; vote grade: a 43%, b 48%, c 10%). Statement 21: Non-naproxen tnsaids increase the risk of coronary heart disease events. Grade B (vote statement: a 52%, b 43%, c 5%; vote grade: a 43%, b 52%, c 5%). Statement 22: Naproxen is associated with a lower risk of coronary heart disease events than other tnsa- IDs and COX-2 inhibitors. Grade B (vote statement: a 29%, b 71%; vote grade: a 57%, b 33%, c 10%). COX-2 inhibitors are thought to increase the risk of cardiovascular events because of inhibition of COX-2 mediated prostacyclin production without inhibition of COX-1 mediated thromboxane production. As tnsaids also inhibit the COX-2 enzyme, they might also be associated with this risk. 70 However, individual tnsa- IDs may have different cardiovascular risks or benefits. Naproxen has a relatively long half life of 14 h and when used regularly at 500 mg b.d. can result in sustained inhibition of thromboxane B2 production, an index of platelet COX-1 activity that persists 7, 71 throughout the dosing interval. Both ibuprofen and diclofenac have much shorter half lives (1 2 h) and standard two or three times daily regimens have only transient antiplatelet effects. 7 Thus, naproxen at a dose of 500 mg b.d. may inhibit platelet aggregation sufficiently to have a safer cardiovascular risk profile than other NSAIDs. There are insufficient data to allow comparisons of the cardiovascular safety of lower doses of naproxen compared with the other NSAIDs. Meta-analyses of RCTs have demonstrated an excess risk for serious cardiovascular events associated with COX-2 inhibitors compared with placebo or naproxen, which was predominantly related to an increased risk of MI. 7, 36 The risk with COX-2 inhibitors was similar to that seen with non-naproxen tnsaids (mostly high-dose diclofenac and ibuprofen). 36 The evidence of increased cardiovascular risk with non-naproxen tnsaids is not quite as strong as it is for COX-2 inhibitors as it is based on both direct and indirect comparisons. In the meta-analysis by Kearney et al., 7 naproxen was not associated with an increased risk; there was a trend towards an increased risk with ibuprofen and the risk was significantly increased with diclofenac. However, in this analysis, naproxen was compared with placebo or no NSAID therapy, but not with other tnsaids and the 95% confidence intervals for the risks with naproxen overlap those for the other tnsaids. The lower risk of MI with naproxen compared with non-naproxen tnsaids is supported by a meta-analysis of observational studies. 72 However, a recent large

8 488 A. ROSTOM et al. epidemiological study found that all NSAIDs, including naproxen, were associated with at least a modest risk of first time MI compared with no NSAID therapy. 73 An AHA review of the evidence concluded that COX-2 inhibitors have important adverse cardiovascular effects. 13 They recommended that in patients with a history of, or at high risk for, cardiovascular disease, COX-2 inhibitors only be used if there are no appropriate alternatives and then only in the lowest dose and for the shortest duration necessary. In summary, the risk of cardiovascular events (primarily MI) with COX-2 inhibitors appears to be greater than placebo but comparable with non-naproxen 7, 36 tnsaids. Therefore, the cardiovascular risk with non-naproxen tnsaids is likely also greater than placebo. Naproxen at a dose of 500 mg b.d. may not increase the risk of cardiovascular events compared to placebo, while diclofenac and ibuprofen may increase these risks. 7 In addition, naproxen demonstrated a lower risk of cardiovascular events compared with COX-2 inhibitors. 7 Statement 23: tnsaids and COX-2 inhibitors increase the risk of hypertension, renal impairment and fluid retention. Grade B (vote statement: a 62%, b 38%; vote grade: a 33%, b 67%). Nonsteroidal anti-inflammatory drugs may affect renal function by inhibiting synthesis of renal PGs, which are important for solute homeostasis and for maintaining renal blood flow. 74 In addition, COX-2 is constitutively expressed in kidney tissues and plays a role in renal ischaemia, salt depletion status, prostacyclin synthesis and renin-release from the kidney. 75, 76 Evidence for the renal effects of NSAIDs is largely based on observational studies. The most clinically important NSAID-associated renal events occur in less than 1% of the population. 77 These include sodium and fluid retention, secondary hypertension, hyperkalaemia and acute renal failure. 74, 75, 77, 78 A meta-analysis of COX-2 inhibitor RCTs found that the increased risk of adverse renal effects varied by drug and was not a class effect. 75 Rofecoxib was associated with an increased risk compared to placebo, while the other COX-2 inhibitors were not. A large case-control study including over NSAID users found an increased risk of acute renal failure for all NSAIDs combined with no significant difference with rofecoxib, celecoxib naproxen or non-naproxen tnsaids. 79 Data from the FDA s Adverse Event Reporting System and published case reports suggest that use of COX-2 inhibitors is associated with renal effects similar to that of tnsaids. Serious or life-threatening renal failure has been reported in patients with normal or impaired renal function after short-term therapy with celecoxib and rofecoxib. 80 Some of the risk factors for NSAID-induced renal toxicity include chronic NSAID use, multiple NSAID use, congestive heart failure, hepatic disease, pre-existing renal impairment, concomitant drug therapy (e.g. diuretics, ACE inhibitors) and age ( 60 years) with 77, 80 comorbidity. Reducing harms of tnsaids, ASA and COX-2 inhibitors Statement 24: Compared to tnsaids, COX-2 inhibitors are associated with a lower risk of upper gastrointestinal bleeding. Grade A (vote statement: a 90%, b 10%; vote grade: a 90%, b 10%). A meta-analysis of RCTs demonstrated a 61% lower risk of clinically important ulcer complications (POB) and a 59% lower risk of the combined endpoint PUB (POB plus symptomatic ulcer) with COX-2 inhibitors compared to tnsaids. 6 Several RCTs have suggested that COX-2 inhibitors are also associated with a 46, 47 reduced risk of lower gastrointestinal events. Therefore, COX-2 inhibitors may provide a suitable alternative to tnsaids for patients who are at high risk for upper or lower gastrointestinal bleeding. Statement 25: Proton pump inhibitor therapy reduces the risk of tnsaid associated endoscopic ulcer disease, but there is less evidence for a reduction in bleeding events. Grade B (vote statement: a 33%, b 48%, c 10%, d 10%; vote grade: a 57%, b 43%). A meta-analysis of RCTs found that proton pump inhibitors (PPIs), at standard once daily dosing, significantly reduced the risk of endoscopic duodenal ulcers by 81% and gastric ulcers by 60% compared to NSAIDs alone. 81 In the MEDAL programme, use of a PPI at baseline was associated with a significantly lower risk of clinical gastrointestinal events (POB plus symptomatic ulcers) and complicated events (POB). 66 After healing of an ulcer, maintenance PPI therapy for 6 months was more effective at preventing recurrent ulcer bleeding than H. pylori eradication therapy given for 1 week among patients taking naproxen who had prior NSAID-associated ulcer bleeding (absolute risk reduction 14.4%, 95% CI: ). 82 Thus, a PPI will be required in patients who have had a prior

9 CANADIAN CONSENSUS ON NSAIDS, ASA AND COX-2 INHIBITORS 489 gastrointestinal complication even after successful eradication of H. pylori infection, if they require continued NSAID therapy. Statement 26: Among patients with a prior ulcer bleed, treatment with a COX-2 inhibitor or a tnsaid plus PPI is still associated with a clinically important risk of recurrent ulcer bleed. Grade B (vote statement: a 57%, b 38%, c 0%, d 0%, e 0%, f 5%; vote grade: a 52%, b 43%, c 0%, d 0%, e 0%, f 5%). Two small RCTs found no significant difference in the rate of recurrent bleeding or ulcer complications (about 4 6%) at 6 months with a COX-2 inhibitor 67, 83, 84 alone vs. a tnsaid plus PPI. The relatively small numbers in both of these studies do not exclude a small benefit of one strategy over the other. Although the rates of recurrent bleeding may have been lower than those seen with tnsaids alone, this was not assessed in these studies and the risk was not 67, 83, 84 eliminated with either of these strategies. Therefore, patients with prior ulcer bleeding require close monitoring and alternative strategies including discontinuation of the NSAID when possible or use of a COX-2 inhibitor plus PPI (discussed below) could be considered. A tnsaid plus twice daily PPI may be useful; however, data from the VENUS and PLUTO studies did not show any advantage with double- vs. single-dose PPIs for the prevention of endoscopic ulcers. 85 Statement 27: In patients with prior gastrointestinal bleeding, the combination of a PPI and a COX-2 inhibitor reduces the risk of upper gastrointestinal bleeding from that of COX-2 inhibitors alone. Grade B (vote statement: a 43%, b 52%, c 5%; vote grade: a 43%, b 43%, c 14%). One RCT found a significantly lower rate of recurrent upper gastrointestinal ulcer bleeding with a COX- 2 inhibitor plus a PPI (0%) compared to the COX-2 inhibitor alone (8.9%) over 1 year (95% CI for difference: ). 86 Use of a COX-2 inhibitor plus a PPI is also supported by two RCTs using endoscopic ulcers as the primary outcome. Pooled analysis of the data from the VENUS and PLUTO studies in high-risk patients showed that among patients taking COX-2 inhibitors (n = 400), the use of concomitant PPI therapy was associated with significantly lower rates of endoscopic ulcers compared with placebo. 85 A subgroup analysis of the MEDAL programme suggested a lower incidence of clinical gastrointestinal events among patients taking a COX-2 inhibitor plus a PPI compared with a COX-2 inhibitor alone; however, statistical analysis was not performed. Based on the limited data available, the combination of a COX-2 inhibitor with a PPI may offer the best gastrointestinal safety profile in patients at very high gastrointestinal risk. Statement 28: High-dose misoprostol reduces the risk of upper gastrointestinal ulcer complications from tnsaids. Grade B (vote statement: a 57%, b 38%, c 5%; vote grade: a 52%, b 48%). Another approach to ulcer prophylaxis is to use misoprostol to replace the cytoprotective PGs that are depleted by NSAIDs from the gastroduodenal 65, 87, 88 mucosa. A meta-analysis of placebo-controlled trials demonstrated that misoprostol significantly reduced the risk of gastric and duodenal endoscopic ulcers by 74% and 53%, respectively. 81 Misoprostol was associated with nausea, diarrhoea and abdominal pain and while the risk of diarrhoea was higher with the 800 lg day doses, it was significant at the 400 lg day as well. 81 For the prevention of clinical ulcer complications, the MUCOSA trial demonstrated a 40% reduction with misoprostol 800 lg day compared to placebo. 65 There are insufficient data to support the efficacy of lower doses of misoprostol either alone or in combination fixed dose misoprostol diclofenac tablets for the prevention of upper gastrointestinal bleeding. Statement 29: There is insufficient evidence to support the use of H 2 RAs for the prevention of upper gastrointestinal bleeding. Grade C (vote statement: a 48%, b 48%, c 0%, d 5%; vote grade: a 38%, b 57%, c 5%). In a meta-analysis of RCTs, standard doses of H 2 RAs reduced the risk of endoscopic duodenal but not gastric ulcers; however, double-dose H 2 RAs were effective in reducing the risk of both. 81 A PPI was more effective than an H 2 RA for prophylaxis of endoscopic NSAID-induced ulcers in a RCT with a 68% reduction in the risk of gastric ulcer and 89% reduction in the risk of duodenal ulcers. 89 Standard doses of H 2 RAs are not recommended because they have not been shown to be consistently effective in reducing the risk of endoscopic ulcers and were less effective than a PPI in a RCT. 81, 89 Like PPIs, long-term clinical outcome studies are not available. Statement 30: Proton pump inhibitor therapy is better tolerated than misoprostol. Grade A (vote statement: a 76%, b 24%; vote grade (n = 20): a 70%, b 25%, c 0%, d 5%).

10 490 A. ROSTOM et al. A meta-analysis of two head-to-head RCTs comparing a PPI to either low-dose (400 lg day) or high-dose (800 lg day) misoprostol 87, 90 found no significant difference between PPIs and misoprostol for the prevention of endoscopic ulcers overall. 81 However, PPIs were statistically superior for the prevention of duodenal ulcers. The individual studies suggested a greater benefit with misoprostol over PPIs for the prevention of gastric ulcers, but the meta-analysis failed to demonstrate a statistically significant benefit. 81 PPIs were better tolerated and associated with fewer drop-outs and although the incidence of side effects with misoprostol is dose-dependent, reducing the dose will reduce both side effects and efficacy. Statement 31: Proton pump inhibitor therapy reduces upper gastrointestinal symptoms associated with COX-2 inhibitors and tnsaids. Grade B (vote statement: a 38%, b 48%, c 10%, d 0%, e 0%, f 5%; vote grade: a 19%, b 67%, c 10%, d 0%, e 0%, f 5%). Meta-analyses of RCTs have demonstrated that PPI therapy significantly reduce dyspeptic and overall gastrointestinal symptoms, as well as drop-outs due to gastrointestinal symptoms in patients receiving NSA- 81, 91 IDs. Three more recent 6-month RCTs confirm a lower rate of gastrointestinal side effects with concurrent PPI treatment in patients at taking tnsaids or COX-2 inhibitors A meta-analysis of RCTs demonstrated that highdose H 2 RA therapy can also significantly reduce gastrointestinal symptoms. 91 Statement 32: Helicobacter pylori eradication reduces the risk of upper gastrointestinal endoscopic ulcers in patients starting tnsaids. Grade B (vote statement (n = 18): a 50%, b 33%, c 11%, d 6%; vote grade (n = 18): a 50%, b 39%, c 6%, d 0%, e 0%, f 6%). As discussed in Statement 18, H. pylori infection is a risk factor for peptic ulcer disease. A meta-analysis of RCTs found that H. pylori eradication significantly reduced the risk of endoscopic ulcers by 57% among patients currently using tnsaids and by 74% in patients not currently taking NSAIDs compared to a control group. 92 However, RCTs demonstrated that maintenance PPI therapy was superior to H. pylori eradication alone in primary or secondary prevention of endoscopic ulcers among NSAID users. 82, While an inadequate rate of successful H. pylori eradication may have reduced the apparent efficacy of this strategy, it does not appear to be sufficient to prevent NSAID-induced ulcers among patients at high-risk and is less effective than PPI therapy. A test and treat strategy was recommended for all patients initiating long-term NSAID therapy by the Canadian Helicobacter Study Group Consensus Conference. 96 Subsequently, the Canadian Dyspepsia Working Group (CanDys) recommended eradication for those patients who have a history of previous ulcers or ulcer bleeding. 97 This consensus group felt that a strategy of test and treat for all patients taking NSAIDs would not be justified based on the prevalence of H. pylori in Canada of 29%; 98 however, it may be useful for patients at high gastrointestinal risk (as described in Statement 18) before starting a tnsaid plus a PPI or COX-2 inhibitor plus a PPI. Statement 33: H. pylori eradication reduces the risk of upper gastrointestinal complications in patients already taking ASA. Grade C (vote statement: a 33%, b 48%, c 14%, d 5%; vote grade: a 24%, b 62%, c 0%, d 10%, e 5%). Among patients already treated with ASA, a RCT found that H. pylori eradication was as effective as PPI therapy in preventing recurrent bleeding; rate of recurrence at 6 months was 1.9% with H. pylori eradication compared to 0.9% with PPI. 82 However, H. pylori eradication alone may not be sufficient; in another RCT, the risk of recurrent ulcer complications at 12 months was 14.8% in patients taking placebo compared to 1.6% in patients receiving PPI therapy after H. pylori eradication and healing of an ulcer. 99 Helicobacter pylori eradication prior to starting ASA was shown to significantly reduce the risk of endoscopic ulcers compared to placebo in a small RCT. 100 Economic considerations The cost of NSAID-induced gastrointestinal or cardiovascular events can have a substantial impact on the healthcare system. An analysis of a Canadian provincial health insurance database found that for each dollar spent on tnsaid therapy, an additional $0.73 was spent on their side effects. 101 A Canadian analysis, which considered the costs of both gastrointestinal and cardiovascular adverse events, found that COX-2 inhibitors were more cost effective than tnsaid plus PPI among patients at high risk of gastrointestinal adverse events. 102 Analysis from the perspective of patients at high risk of cardiovascular events was not performed. Similarly, another

11 CANADIAN CONSENSUS ON NSAIDS, ASA AND COX-2 INHIBITORS 491 analysis found that in patients with at least moderately high risk (6.5%) of a gastrointestinal adverse event, COX-2 inhibitors were the most effective and least costly strategy followed closely by tnsaid plus PPI, both of which were more cost effective than a tnsaid alone, tnsaid plus misoprostol and strategies which include eradication of H. pylori infection. 103 However, this analysis did not include the potential risks or costs of adverse cardiovascular events. An US analysis, which considered the costs of both gastrointestinal and cardiovascular adverse events, found that the most cost effective strategies were generic tnsaid in patients at low risk for adverse events and generic tnsaid plus generic PPI for patients at higher risk. 104 Naproxen 500 mg b.d. plus a PPI was the most cost-effective strategy for patients at higher risk of both gastrointestinal and cardiovascular adverse events. 104 This consensus group is currently performing an economic analysis that will assess the cost effectiveness of different strategies for different levels of risk for gastrointestinal and cardiovascular events. Summary Recommendations were recently developed by the US and international consensus working groups. 16, 17 The US guidelines recommend the use of gastroprotective therapy (with PPIs being the preferred agents) for at-risk patients taking any NSAID. 16 These guidelines are specifically directed at reducing the risk of gastrointestinal complications and do not address cardiovascular risk. The international consensus concluded that tnsaids are appropriate for patients at average gastrointestinal risk (no risk factors), while cotherapy with a PPI misoprostol was preferred in patients with gastrointestinal risk factors. Either a tnsaid or a COX-2 inhibitor was recommended in patients with average cardiovascular risk and naproxen in patients with high cardiovascular risk. None of the options was considered appropriate in patients with multiple gastrointestinal risk factors and high cardiovascular risk. 17 Unfortunately, this provides little guidance for the clinician faced with patients at both high gastrointestinal and high cardiovascular risk. On the basis of this consensus, we recommend that when presented with a patient who requires long-term NSAID therapy, the most important first step is to review the need for the NSAID and determine whether there are alternative approaches for that individual. NSAIDs should always be used at the lowest effective dose for the shortest possible duration of treatment. For patients who do require long-term NSAID therapy, the choice of drug and the need for gastroprotective strategies should be determined by a thorough assessment of cardiovascular and gastrointestinal risks, including history, physical examination and laboratory investigations, as needed. Cardiovascular risk for an individual should be estimated and managed according to appropriate cardiovascular guidelines. 29, 30 Assessment of gastrointestinal risk should consider the risk factors discussed in Statement 18. Figure 1 presents an algorithm for the use of long-term NSAID therapy according to individual gastrointestinal and cardiovascular risk. As low-dose ASA is recommended for patients at increased cardiovascular risk, the algorithm assumes the use 29, 30 of low-dose ASA in such patients. For patients with both low gastrointestinal and cardiovascular risks, a tnsaid alone may be acceptable. For patients with low gastrointestinal risk and high cardiovascular risk, naproxen may be preferred because of the potential lower cardiovascular risk than with other tnsaids or COX-2 inhibitors. However, as these patients are assumed to be on low-dose ASA therapy, the combination of naproxen plus ASA would increase the gastrointestinal risk and therefore the addition of a gastroprotective agent such as a PPI should be considered. Long-term NSAID therapy can be more complex in patients with high gastrointestinal risk. Testing for and eradicating H. pylori in patients at high risk of NSAID-related gastrointestinal bleeding should be considered but will be insufficient without ongoing gastroprotection. In these patients, if cardiovascular risk is low, a COX-2 inhibitor alone or a tnsaid with a PPI appear to offer similar protection from recurrent gastrointestinal bleeding, but this protection is incomplete. Therefore, for patients at very high risk of upper gastrointestinal events, a combination of a COX-2 inhibitor plus a PPI may offer the best gastrointestinal safety profile. When both gastrointestinal and cardiovascular risks are high, the optimal strategy is to avoid NSAID therapy if at all possible. If the NSAID therapy is deemed necessary, then the clinician must prioritize the cardiovascular and gastrointestinal risks recognizing that these patients are probably taking ASA for their cardiovascular risk. If gastrointestinal risk is the primary concern (i.e. a very high-risk gastrointestinal

12 492 A. ROSTOM et al. patient), a COX-2 inhibitor plus a PPI is recommended. If the primary concern is cardiovascular risk, naproxen plus a PPI in patients on ASA would be preferred; however, gastrointestinal risk should be closely monitored, as this strategy carries a higher gastrointestinal risk than a COX-2 inhibitor plus a PPI in patients on ASA. ACKNOWLEDGEMENTS The authors wish to thank Pauline Lavigne for the preparation of the manuscript. We also acknowledge the contribution of Louise Hope, Karen Moricz, and Paul Sinclair in assisting in the organization of the Consensus Conference. Declaration of personal interests: Alan Barkun, Marc Bradette, Naoki Chiba, Brian Craig, Jocelyn Dupuis, Nigel Flook, John Stewart and Hyman Tannenbaum have no personal interests to declare. Richard Hunt has served as both a speaker and consultant for AstraZeneca, Merck & Co., Novartis and Santarus; has served a consultant for Allergan, Altana, Axcan and Negma; has served as a speaker for TAP Pharmaceuticals; has received clinical trial funding from Allergan, AstraZeneca, Axcan, Negma and TAP Pharmaceuticals; and is an employee of Strategic Consultants International. Paul Moayyedi has served as both a speaker and consultant for AstraZeneca and Janssen Ortho; has served as a speaker for Altana and Esai; and has received research funding from Astra- Zeneca. Alaa Rostom has served as a consultant to Novartis. Claire Bombardier has served as a consultant for Abbot, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Hoffman-LaRoche, Merck & Co., Merck and Frosst, Pfizer, Roche, Schering, Solvay Pharma and Wyeth; and has received research funding from Abbott, Bristol-Myers Squibb, Schering, and Pfizer. Rob Enns has served as both a speaker and a consultant for Altana, AstraZeneca and Schering; has served as a consultant for Abbot and UCB Pharma. Gilles Jobin has served as both a speaker and a consultant for AstraZeneca and Janssen Ortho; and has served as a speaker for Abbott. David Morgan has served as both a speaker and consultant for Abbott, Altana, Astra- Zeneca, Axcan, Janssen Ortho, Merck & Co., Negma, Novartis, Pfizer, Procter & Gamble, Schering, Solvay Pharma and Wyeth; has served as a consultant for Ferring; and has received research funding from Altana, AstraZeneca, Heart & Stroke Foundation, Janssen Ortho, Novartis, Pfizer and Negma. Laura Targownik has served as both a speaker and a consultant for Janssen Ortho; has served as a speaker for Novartis; has served as a consultant for UCB Pharma; and has received research funding from AstraZeneca, Boston Scientific and Janssen Ortho. Peter Tugwell has served as a consultant for Bristol-Myers Squibb, Cadeuceus Group, Dimethaid, Eli Lilly, Glaxo Smith Kline, Goodwin-Procter, Immunomedics, Merck & Co., Scios, Solvay Pharma and UCB Pharma. Sander van Zanten has served as both a speaker and consultant for AstraZeneca and Janssen Ortho; has served as a speaker for Abbott; has served as a consultant for Glaxo Smith Kline; and has received research funding from AstraZeneca and Janssen Ortho. Frances Chan has served as a speaker for AstraZeneca and TAP Pharmaceuticals; has served as a consultant for Pfizer; and has received research funding from Pfizer. Loren Laine has served as a consultant for Altana, Astra- Zeneca, Eisai, Horizon, Johnson & Johnson, Merck & Co., Novartis and Santarus; and has received research funding from Merck & Co., Novartis, Pfizer and TAP Pharmaceuticals. Angel Lanas has served as both a speaker and a consultant for AstraZeneca, Merck & Co., NiCox and Pfizer; and has received research funding from AstraZeneca, Merck & Co., Nicox and Pfizer. Declaration of funding interests: This work was funded in part by AstraZeneca Canada Inc., Novartis Pharmaceuticals Canada Inc., Pfizer Canada Inc., Abbott Laboratories Ltd, McNeil Consumer Healthcare, Merck Frosst Canada Ltd, Nycomed Canada Inc. and Wyeth Consumer Healthcare Inc. Writing support was provided by Pauline Lavigne and funded by the Canadian Association of Gastroenterology. SUPPORTING INFORMATION Additional Supporting Information may be found in the online version of this article: Table S1. Grading of the quality of the evidence based on the GRADE system Appendix S1. MEDLINE search terms; List of Attendees. Please note: Wiley-Blackwell are not responsible for the content or functionality of any supporting materials supplied by the authors. Any queries (other than missing material) should be directed to the corresponding author for the article.

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