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NICE:
More impact on gastroenterologists?
Dr Robert Walt Dr Nick Michell
Consultant Gastroenterologists, Birmingham Heartlands Hospital
The National Institute for Clinical Excellence NICE) has reported once again. This time it sanctions the use of COX-2 selective inhibitors in at-risk patients needing NSAIDS1 but with what impact on gastroenterologists? The mode of surgery for patients with colorectal cancer and the use of proton pump inhibitors are just two of the numerous reports already collated by the National Institute for Clinical Excellence and the ones likely to have had at least some impact on most gastroenterologists. A new report on the use of COX-2 inhibitors may also have an impact on this speciality [1]. The efficacy of the NSAIDs is suggested by their frequent prescription 26 million scripts are written every year in the UK alone [2]. Despite their popularity the NSAIDs are not without side effects; gastrointestinal symptoms are common and serious intestinal haemorrhage occurs in 3-4% [4]. Recognition that the antiinflammatory and ulceragenic effects are mediated by different pathways (COX-2 and COX-1 inhibition respectively) has led to the development of several selective COX-2 inhibitors. The use of four of these have been reported on by NICE and its recommendation may reduce the number of patients suffering such gastrointestinal side effects.

COX-2 inhibitors
The COX-2 inhibitors affect the COX-2 isoenzyme dominant in prostaglandin mediated pain and inflammation, while allowing the COX-1 enzyme to maintain its physiological effects including protection for the gastrointestinal mucosa. One potential difficulty with these agents is that the effect of NSAIDs on platelet function is through COX-1 inhibition which these agents either do not exhibit or do so to a limited extent [6]. The gains of fewer life-threatening GI events could be counterbalanced by less protection from cardiovascular events or negated by co-prescribing of aspirin. This area remains contentious and more evidence is required before a very proscriptive role of COX-2 specific agents can be made.

The NICE Recommendations

COX-2 inhibitors, instead of conventional non-steroidal anti-inflammatory drugs, may be prescribed in at risk patients who should benefit from a reduced risk of side effects. The gastroenterologist's workload may also decrease to some extent.

The legacy of NSAIDs

Gastroenterologists are accustomed to dealing with the toxic legacy of NSAID use, particularly in the elderly. Between 50 and 75% of arthritis patients on conventional NSAIDS show mucosal damage and between 10 and 30% suffer peptic ulcers or at least erosions which may be indistinguishable from ulcers [3]. Every year, between 3 and 4% of chronic NSAID users suffer a serious gastrointestinal bleed, accounting for up to 2000 deaths and 10 000 non fatal hospital admissions each year [4]. Other side effects include fluid retention (which may result in, or exacerbate, hypertension and heart failure), renal failure (which may occur in those with apparently normal pre-existing renal function) [5] and seizures in addition to the commonly reported dyspepsia, nausea and diarrhoea.

Who is at risk? According to NICE, patients at high risk of developing serious gastrointestinal adverse events include: [1] Those over 65 Those using concomitant medication known to increase the risk of upper GI adverse events Those with serious co-morbidity Those needing prolonged use of maximum recommended doses of standard NSAIDs.
The guidelines remind us that the risk of NSAID-induced complications is particularly increased in patients with a history of gastroduodenal ulcer, gastrointestinal bleeding or perforation. Evidence of a reduced risk by COX2 inhibitors in this group is less and therefore the cautionary warning has been added that "the use of even a COX-2 selective agent should therefore be considered especially carefully in this situation".

Clinical Evidence for Selective COX-2 Inhibitors The four agents claiming COX-2 selective inhibition celecoxib (Celebrex), etodolac (Lodine), meloxicam (Mobic), and rofecoxib (Vioxx) are the subject of the NICE report. There is debate about selectivity and specificity as some of the agents above do have anti-COX-1
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that they should not be prescribed routinely in preference to standard NSAIDs [1]. They add that concomitant low dose aspirin would reduces the benefit of using COX-2 selective agents by increasing the risk of GI events [1].

activity and thus variable COX-2 selectivity (at least according to certain in vitro tests) [6]. Thus the drugs are similar but not all exactly the same. However, the NICE report does not demonstrate a difference in either efficacy or adverse events between them [1]. Some details of efficacy and adverse reaction data are highlighted in this article.

Rofecoxib Rofecoxib has been shown to be highly COX-2 selective and it does appear to be safer than the "intermediate risk" NSAID naproxen and presently it is licensed in osteoarthritis in the dose range 12.5 - 25mg daily [8,9].
The Vioxx Gastrointestinal Outcomes Research (VIGOR) trial studied rofecoxib and standard NSAIDs in 8000 patients with rheumatoid arthritis. The risk of clinically important upper GI events with rofecoxib (50mg once daily) was 2.1 per 100 patient years, compared with 4.5 with naproxen (500mg twice daily). Dyspepsia and abdominal pain were also reduced compared with naproxen [10]. However, this study which did not allow aspirin use also found that the rofecoxib group had a higher incidence of serious thrombotic events such as myocardial infarction (1.67 events per 100 patient years compared with 0.7 events for naproxen). This is presumably due to the positive antiplatelet effect (COX-1) of naproxen rather than a negative effect with rofecoxib. 9 A recent analysis which includes this trial and others highlights possible increased risks of cardiovascular events with rofecoxib and advises caution [11]. Publishing in Current Problems in Pharmacovigilance, [11] the Committee on Safety of Medicines and Medicine Control Agency reported that, up to July 2000 a year after launch 1,120 reports of possible adverse reactions with rofecoxib, almost half of which were gastrointestinal, were received. There had been 68 reports (12%) of upper GI perforations, ulceration and bleeds (PUBs) of which five had a fatal outcome. Over two-thirds of PUBs were in the over 65s. In addition, the article documents 177 CSM reports of suspected cardiovascular reactions with rofecoxib mostly oedema and 15 reports of cardiac failure, three of which were fatal. In addition, psychiatric reactions with rofecoxib were also reported (28 for depression, 14 for confusion and 11 for hallucinations). Voluntary notification of side effects is notoriously difficult to interpret but reflect "real life more closely than the profiles discovered in trials. In its review, the CSM reminded prescribers that rofecoxib is contra-indicated in severe congestive heart failure and caution should be exercised in those with a history of cardiac failure, left ventricular dysfunction, or hypertension [12]. The NICE guidelines state that there remains uncertainty over the use of all COX-2 selective inhibitors in patients with cardiovascular disease and
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Celecoxib Celecoxib is highly COX2 selective and is licensed for use in osteoarthritis and rheumatoid arthritis at 200 to 400mg daily and is less likely to cause GI ulceration than other NSAIDs [6,13].
The CLASS (celecoxib long-term arthritis safety study) study is one of the current key trials involving the COX-2 inhibitor celecoxib in rheumatoid- and osteo-arthritis. About 8,000 patients were given either celecoxib (400mg twice daily), ibuprofen 800mg three times daily or diclofenac 75mg daily. An annualised incidence of upper GI complications and symptomatic ulcers was found to be significantly lower at 2.08% for celecoxib and 3.54% for the other NSAIDs. However, ulcer complications were not significantly lower. Use of low dose aspirin in the celecoxib group may have increased upper GI complications compared with the other NSAIDs group [13]. The celecoxib data sheet mentions gastrointestinal side effects as common (>1 %); including abdominal pain, diarrhoea, dyspepsia flatulence. Other undesirable effects listed as common include dizziness, insomnia, rash, upper respiratory tract infection 8 and fluid retention (although hypertension and heart failure were uncommon and rare respectively).

Meloxicam Meloxicam is a selective COX-2 inhibitor with some anti- COX-1 activity [6]. It is licensed for use in rheumatic disease, osteoarthritis and ankylosing spondylitis at a dose of 7.5 to 15mg daily. Several studies show that meloxicam is better tolerated in terms of GI effects than many conventional NSAIDs. There have been two large prospective studies of NSAID tolerability MELISSA and SELECT [14,15].
MELISSA involved over 9,000 patients with osteoarthritis treated either with 7.5 mg meloxicam or slowrelease diclofenac 100 mg daily for 28 days [14]. GI events were significantly less frequent in the meloxicam group and fewer of these patients were hospitalised because of adverse events. The total duration of hospitalisation in the small numbers of patients who required it was considerably shorter in the meloxicam group: 12 days versus 157 days. SELECT compared meloxicam with piroxicam in about 8600 patients. 15 GI adverse events including dyspepsia, abdominal pain, nausea and diarrhoea were significantly less frequent with meloxicam. It was thought that these "minor" side effects might make a considerable difference to the patient's quality of life.

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In a proportion of patients on NSAIDs, concurrent prescribing of PPIs and H2-receptor antagonists place substantial additional costs. It has been argued that the need for such co-prescribing would be removed by the use of COX-2 inhibitors with consequent savings. However, NICE report that there is no evidence to support this premise and thus the report does not advocate switching patients who are receiving concurrent antisecretory treatment and NSAIDs to COX-2 selective agents. DRUG PRICE: BNF (Sept 2000) price per day per dose for COX-2 selective agents: Meloxicam Etodalac Celecoxib Rofecoxib 7.5mg 33p 600mg 52p 200mg 61p 12.5mg 77p 15mg 46p

One retrospective global safety analysis of meloxicam against the comparator NSAIDs piroxicam 20mg, diclofenac 100mg retard, and naproxen 750-1000mg, found that there were significantly fewer GI adverse events with meloxicam, including less dyspepsia, fewer PUBs and less frequent withdrawal because of adverse events [16]. A more recent meta-analysis involving patients on meloxicam versus those on non-COX-2 selective agents including naproxen, diclofenac and piroxicam reported similarly [17]. A summary of ADR reports for meloxicam was published in Current Problems in Pharmacovigilance in 1998 [18]. By the beginning of June, 1998 when about 1 million prescriptions for meloxicam had been dispensed, 1,339 suspected adverse drug reactions had been reported. Of the reports, 41% involved gastrointestinal reactions of which 18% involved PUBs, five of which were fatal. The mean age of these patients was 64 years. Other side effects included fatigue, skin rash, urticaria, head ache and oedema.

400mg 122p 25mg 77p

Changing Practice
It may not be easy for clinicians to make a decision about the use of COX-2 selective agents in arthritis. Most prescribing is in general practice and pressure on budgets is justifiably firm. These agents are comparatively expensive, but there is much data to justify their use and now NICE backs their prescription in at risk patients . Perhaps we, as gastroenterologists, should be promoting their use to rheumatologists and GP colleagues as we will doubtless continue to deal with many of the consequences of traditional prescribing. How hard we "sell" the virtues of COX-2 selectivity will become clearer as the impact of the need for concurrent aspirin in many cases becomes known. The savings could be in reducing hospitalisation and endoscopy and lives should be saved. However, the NHS is unwieldy because we need to argue that spending more from one budget line may produce gains in another separate budget. The pressure on the managers of drug budgets, particularly GPs, is to save within that budget rather than in the hospitalisation spend and thus it might be difficult to generate enthusiasm in this way. If it turns out that PPI prescribing can be reduced by using a more expensive anti-inflammatory agent, the cost savings may prove to be massive and then would fall within the same budget and thus change of practice could be more likely. There is a sufficient body of evidence for gastroenterologists to follow the NICE lead and recommend COX-2 selective agents for patients in the high risk groups who would otherwise be given standard NSAIDs. References
1. National Institute for Clinical Excellence. Guidance on the use of cyclo-oxygenase (Cox) II selective inhibitors, celecoxib, rofecoxib, meloxicam and etodolac for osteoarthritis and rheumatoid arthritis. London: NICE. July 2001. 2. Haslock I. Clinical Economics Review: Gastrointestinal complications of NSAIDs. Aliment Pharmacol Therap. 1998;12:127-33. 117
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Etodolac Etodolac is a selective inhibitor of COX-2 with some anti-COX-1 activity and is licensed for use in rheumatoid and osteo-arthritis at a dose of 600mg daily [6,19].
There are few large-scale safety studies with this agent. Smaller trials show similar incidences of adverse effects of etodolac and the more conventional NSAIDs naproxen, piroxicam and nabumetone [20,21]. In a study of long-term effects, etodalac 150mg bd, etodalac 500mg bd or ibuprofen 600mg qid were given to over 1400 rheumatoid arthritis patients. Gastrointestinal ulcers and bleeding were significantly less frequent in the etodolac group [22]. There were only four episodes of GI ulcers or bleeding in 1029 patients on etodalac compared with nine episodes in 417 patients on ibuprofen. Dyspepsia was less frequent in the etodalac group but this only reached significance in the lower dose etodalac group. Other GI effects were as frequent in all groups.

Cost
The NICE report suggests that switching OA and RA patients at high risk of GI complications to COX-2 selective inhibitors from standard NSAIDs would lead to an annual incremental cost of approximately 25 million to the NHS, according to cost and market share. However, the cost of treating NSAID-induced GI disease in hospital is estimated at around 35 million [23], and some of this would be "saved". NICE reports that the cost effectiveness of COX-2 selective inhibitors is likely to be more favourable in "at risk" patients. It reviews manufacturers' economic evaluations and adds comments from an independent Canadian study. The latter estimated less favourable cost effectiveness ratios than manufacturers, for example, with every life year gained with rofecoxib costing 150,000 compared with NSAIDs in average-risk patients.

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3. Needleman P, Isakson PC. Selective inhibition of cyclooxygenase 2. Science and Medicine Jan/Feb. 1998 p26-35. 4. Bateman DN. NSAIDS: Time to re-evaluate gut toxicity. Lancet 1994;343:1051-52. 5. Simon LS. Actions and toxic effect of the NSAIDs. Curr Opin Rheumatol 1994;6:238. 6. Vane JR, Botting RM. The future of NSAID therapy: selective COX-2 inhibitors. Int J Clin Prac 2000;54. 7. Noble S, Bafour JA. Meloxicam. Drugs 1996;51:424-32. 8. Isakson P, Zweifel B, Masferrer et al. Specific COX-2 inhibitors: from bench to bedside. In Vane J, Blotting J Eds. Selective Cox-2 inhibitors: Pharmacology, clinical effects and therapeutic potential. William Harvey Press, London. 1997;127-33. 9. Depre M, Ehrich E, De Lepeleine I et al. Demonstration of specific COX-2 inhibition by MK966 (Vioxx) in human with supratherapeutic doses. Rheumatol Eur 1998; 27: Suppl 1. 10. Bombadier C, Laine L, Reicin A et al. Comparison of gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR study group. N Engl J Med 2000;343:1520-8. 11. Mukherjee D, Nissen SE, Topol EJ. Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA 2001;286:954-59. 12. Anon. Rofecoxib in focus. Current problems in pharmacovigilance. 2000;26:13. 13. Silverstein FE, Faich G, Goldstein JL et al. Gastrointestinal toxicity with celecoxib vs nonsteroidal antiinflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study.Celecoxib long-term arthritis safety study. JAMA 2000;284:1247. 14. Hawkey C, Kahan A, Steinbruck K et al for the International MELISSA Study Group. GI tolerability of meloxicam compared to diclofenac in osteoarthritis patients. Br J Rheumatol 1998;37:937-45. 15. Dequeker J, Hawkey C, Kahan A et al. Improvement in gastrointestinal tolerability of the COX-2 inhibitor meloxicam compared with piroxicam; results of the safety and efficacy large-scale evaluation of COX-inhibiting therapies (SELECT) in osteoarthritis. Br J Rheumatol 1998;37: 946-51. 16. Distel M, Mueller C, Bluhmki E et al. Safety of meloxicam: a global analysis of clinical trials . Br J Rheumatol 1996;35:68-77. 17. Schoenfeld P. Gastrointestinal safety profile of meloxicam : a meta-analysis and systematic review of randomised controlled trials. American Journal of Medicine 1999;107; 48-54S. 18. Anon. Meloxicam :gastrointestinal and skin reactions. Current problems in pharmacovigilance. August 1998. 19. Glaser K, Sung ML, O'Neill K et al . Etodalac selectively inhibits human prostaglandin GIH Synthase 2 (PGHS-2) versus GPGHS-1. Eur J Pharmacol 1995; 281:107-11. 20.Schnitzer TJ. Constantine G. Etodolac in the treatment of osteoarthritis:recent studies. J Rheumatol Suppl 1997;47:23-31. 21. Lightfoot R.Comparison of the efficacy and safety of etodolac and piroxicam in patients with rheumatoid arthritis. J Rheumatol Suppl 1997;47:10-16. 22. Neustadt DH Double Blind Evaluation of the longterm effects of etodalac versus ibuprofen in patients with rheumatoid arthritis J Rhematol 1997;(suppl 47)24:17-22. 23. Belsey J, Thompson G. Nsaid induced gastrointestinal toxicity in osteoarthritis. London Hayward Medical Communications, 2000. 118

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