MeReC Monthly No.

Update on the prescribing of NSAIDs
Summary • Diclofenac (especially 150mg/day) is associated with a similar thrombotic risk to COX-2 selective inhibitors (coxibs). Naproxen (1000mg/day) and low-dose ibuprofen (e.g. <1200mg/day) are associated with a lower thrombotic risk; they are a more appropriate choice for patients who require a non-steroidal anti-inflammatory drug (NSAID) and where cardiovascular (CV) risk is of concern. • Although prescribing of diclofenac appears to have declined slightly over the last year, in January 2008 diclofenac still accounted for 44% of the total number of NSAID items prescribed. • NICE guidance for osteoarthritis recommends first-line use of paracetamol or topical NSAIDs, ahead of oral NSAIDs, for pain relief. Where NSAIDs are necessary, the lowest effective dose should be used for the shortest possible time. Either a traditional NSAID or a coxib (other than etoricoxib 60mg) can be used, taking into account individual patient risk factors, including age. NICE recommends co-prescription of a proton-pump inhibitor (PPI) with an NSAID regardless of which is chosen. • There is no robust evidence that prescribing a coxib plus a PPI offers any significant advantage over prescribing a traditional NSAID plus a PPI in preventing GI complications. Background In October 2006, in a review of the cardiovascular (CV) safety of selective and non-selective non-steroidal anti-inflammatory drugs (NSAIDs), the Commission on Human Medicines identified that diclofenac (especially 150mg/day) was associated with a small increased thrombotic risk similar to that of etoricoxib and possibly other COX-2 selective inhibitors (coxibs).1 High-dose ibuprofen (e.g. 2400mg/day) also appeared to be associated with a small increased thrombotic risk, whereas low-dose ibuprofen (e.g. <1200mg/day) and naproxen (1000mg/day) were not.1,2 Taking into account the high prescribing volume of diclofenac and the increased thrombotic risk, the prescribing of diclofenac could be associated with up to 2000 extra or premature CV events in England each year, compared with no treatment.2 In November 2007, in MeReC Extra 30,2 we recommended reviewing the prescribing of NSAIDs and, where they were still necessary, reconsidering which to prescribe based on an assessment of the patient’s CV and gastrointestinal (GI) risk. For patients where CV risk is of concern, low-dose ibuprofen or naproxen with a proton pump inhibitor (PPI) is a more appropriate choice than diclofenac.2 Prescribing trends for traditional NSAIDs Examination of trends in prescribing data from January 2007 to January 2008, indicates that total NSAID prescribing decreased from 1.47 to 1.44 million items (a decrease of 2%).3 Diclofenac prescribing decreased from 45% to 44% of total NSAID items over the same period (a 2% relative reduction); however, some individual PCTs demonstrated relative reductions of more than 20%. Naproxen prescribing increased from about 7% to 9% of the total number of NSAID items prescribed (a relative increase of 25%). Ibuprofen prescribing levels remained essentially unchanged at 26% of total NSAID items prescribed. 3 Although there are some encouraging trends towards more appropriate prescribing of NSAIDs, there is continued need for medication reviews to reconsider their use, and the prescribing of diclofenac in particular. NICE guidance on NSAIDs for osteoarthritis? In February 2008, the National Institute for Health and Clinical Excellence (NICE) issued its clinical guideline on the management of osteoarthritis.4 This was reviewed in a recent NPCi blog.5 In addition to core treatments (e.g. exercise, advice and access to information, weight loss if overweight/obese), NICE recommends considering paracetamol and/or topical NSAIDs ahead of oral NSAIDs (traditional or coxibs) or opioids. Where oral NSAIDs are necessary, the lowest effective dose for the shortest possible time should be used. In view of potential GI, cardio-renal or liver toxicity, health professionals should take account of individual patient risk factors, including age.4 When prescribing these drugs, consideration should be given to appropriate assessment and/or ongoing monitoring of these risk factors.4 NICE also recognises that all NSAIDs may antagonise the cardioprotective effects of

Naproxen (1000mg/day) and low-dose ibuprofen (e.g. 1200mg/day or less) are a more appropriate choice for patients who require an NSAID and where (CV) risk is of concern.

This publication was correct at the time of preparation: May 2008

This MeReC Publication is produced by the NHS for the NHS

MeReC Extra No. 29 2 Monthly No.

aspirin,6 and recommends that where a patient with osteoarthritis needs to take lowdose aspirin, other analgesics should be considered before substituting or adding an NSAID if pain relief was ineffective or insufficient.4 In developing the guideline, NICE evaluated the cost-effectiveness of paracetamol, traditional NSAIDs and coxibs at doses relevant to clinical practice, and also assessed the impact of the addition of PPIs. NICE recognised that the choice of NSAID is influenced by their separate side-effect profiles, which tended to favour coxibs, whereas cost tended to favour traditional NSAIDs.6 However, because of the uncertainties over the relative incidences of adverse effects, especially when co-prescribed with a PPI, clear conclusions about relative cost-effectiveness could not be made. Only etoricoxib 60mg was specifically ruled out as a first-line choice on this basis.6 Health economic modelling found that it was always more cost-effective to prescribe a PPI with an NSAID than not to do so, because of their effect in reducing serious GI problems.6 Regardless of which NSAID is prescribed, NICE recommends co-prescription of a PPI, choosing the one with the lowest acquisition cost.4 Do coxibs offer advantages over other NSAIDs when co-prescribed with a PPI? There is evidence from a systematic review that, as a class, coxibs are associated with a lower GI risk than traditional NSAIDs when prescribed without a PPI.7 Analysis of data from the MEDAL study suggested that use of etoricoxib reduced the risk of upper GI clinical events and dyspepsia compared with diclofenac.8 However, the reductions in risk of these clinical events were seen only in the more common, but less serious, uncomplicated events. 8 Two large, observational studies in elderly people provide additional information on the

There is no robust evidence that prescribing a coxib plus a PPI offers any significant advantage over prescribing a traditional NSAID plus a PPI in preventing GI complications.

incidences of serious GI complications following the prescribing of coxibs or traditional NSAIDs, with or without a PPI.9,10 In both studies, the 95% confidence intervals (CIs) of the hazard ratios (HRs) for the comparisons between traditional NSAIDs plus PPI and coxib plus PPI overlapped. Therefore, these studies do not provide evidence for a significant difference in the risk of GI complications between these two approaches. The first study examined the effect of coprescribing a PPI with celecoxib or traditional NSAIDS in more than 2 million elderly people in Canada. The adjusted HRs for hospitalisation for GI complications versus celecoxib alone were 0.69 (95%CI 0.52 to 0.93) for celecoxib plus PPI, 0.98 (95%CI 0.67 to 1.45) for traditional NSAIDs plus PPI, and 2.18 (95%CI 1.82 to 2.61) for traditional NSAIDs alone.9 The second study examined the medical records of nearly half a million elderly (98% male) patients (mean age 74) in the USA. After adjusting for confounding influences, compared with periods of non-exposure, the HRs of serious of upper GI events were 1.8 (95%CI 1.5 to 2.0) during exposure to coxibs and 1.8 (95%CI 1.6 to 2.0) during exposure to other NSAIDs. During periods in which a PPI was co-prescribed, the HRs were not statistically significantly different for coxibs (HR 1.1, 95%CI 0.6 to 5.2) or other NSAIDs (HR 1.1, 95%CI 0.7 to 4.6) compared with periods of non-exposure.10 It remains uncertain whether or not GI benefits for coxibs are maintained over traditional NSAIDs when both are prescribed with a PPI. Randomised controlled clinical trials are required to specifically answer this point. You can find more information on the risks and benefits of NSAIDs on the musculoskeletal pain floor of NPCi.

References 1. Duff G. Chairman, Commission of Human Medicines. Safety of selective and non-selective. NSAIDs. Letter. October 2006. Accessed from =GET_FILE&dDocName=CON2025036&RevisionSelectionMethod=Latest on 23/04/08 2. National Prescribing Centre. Cardiovascular and gastrointestinal safety of NSAIDs. MeReC Extra 30. November 2007. Accessed from on 23/04/08 3. Personal communication. NHS Business Service Authority Prescription Pricing Division. April 2008 4. National Institute for Health and Clinical Excellence. Osteoarthritis: the care and management of osteoarthritis in adults. NICE clinical guideline 59. February 2008. Accessed from on 23/04/08 5. National Prescribing Centre. NICE publishes clinical guidance on management of osteoarthritis. NPCi blog 85. March 2008. Accessed from on 23/04/08 6. The National Collaborating Centre for Chronic Conditions. Osteoarthritis: national clinical guideline for care and management in adults. NICE Full Clinical Guideline 59. Accessed from on 23/04/08 7. Rostom A, Muir K, Dube C, et al. Gastrointestinal safety of cyclooxygenase-2 inhibitors: a Cochrane collaboration systematic review. Clin Gastroenterol Hepatol 2007;5:818–28 8. Laine L, Curtis SP, Cryer B, et al. Assessment of upper gastrointestinal safety of etoricoxib and diclofenac in patients with osteoarthritis and rheumatoid arthritis in the Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) programme: a randomised comparison. Lancet 2007;369:465-73 9. Rahme E, Barkun AN, Toubouti Y, et al. Do proton-pump inhibitors confer additional gastrointestinal protection in patients given celecoxib? Arthritis Rheum 2007; 57:748–55 10. Abraham NS, Hartman C, Castillo D, et al. Effectiveness of national provider prescription of PPI gastroprotection among elderly NSAID users. Am J Gastroenterol 2008;103:323–32

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