Bleeding the NHS dry

Non-steroidal anti-inflammatory drugs have serious gastrointestinal side effects. Consultant rheumatologist Dr Michael Lambert looks at the true cost of NSAID-induced bleedingNSAIDs are among the world's most widely prescribed medicines - not to mention the huge volume of their OTC sales. Despite being dominated by generics, the prescription NSAID market is currently worth #212 million a year in the UK. This figure is divided between 30 molecules and many more formulations.So you might think that there is little room for improvement. Surely, 30 NSAIDs is enough? Indeed, critics often cite the NSAID market as an example of the dangers of `me-too' drug development.However, NSAIDs differ markedly in their side effect profiles and efficacy. The success of newer, better-tolerated drugs underlines the largely unmet need for alternatives to conventional NSAIDs.Meloxicam, for example, was the most successful NSAID ever launched, capturing over 7 per cent of the market within three years. Celecoxib and rofecoxib seem set to repeat this success.However, the new NSAIDs are considerably more expensive than generics. As drug budgets come under increasing pressure, it seems an appropriate time to examine the evidence supporting the new agents' economic benefits.The economic burdenTo place these costs in context, it is worth noting that NSAIDs' indications and side effects impose a considerable economic burden on the NHS. For instance, NSAIDs are widely used as the first step in rheumatoid arthritis management before moving patients to more potent agents.Rheumatoid arthritis is only one of the NSAIDs' indications. But it offers an illustration of the costs associated with these diseases.A systematic review of the economic burden imposed by rheumatoid arthritis suggested that total average medical costs ranged from #3,575 to #3,638 per patient. Medication accounted for between 8 and 24 per cent of the economic burden, while physician visits accounted for 8 to 21 per cent.In contrast, hospitalisation accounted for 17-88 per cent of the disease's economic burden. On average, patients were absent from work for between three and 30 days a year.Clearly, drug costs are only a relatively minor driver of the total economic burden. Such considerations are becoming increasingly important with the advent of unified budgets.While NSAID-induced gastrointestinal bleeding costs the NHS millions of pounds each year, it also causes considerable morbidity and mortality. The prevalence of gastrointestinal ulcers among chronic NSAIDs users in the UK is 20 per cent, with an annual complication rate of 2-4 per cent. About 1,200 people die each year from NSAID complications.A recent study suggested that the annual cost of preventing and treating upper NSAID bleeds is between #166m and #367m. The cost to an average PCG ranges from #290,000 to #633,000 annually - equivalent to #32-#70 per patient. As GPs come under pressure to reduce costs, reducing the amount of NSAID-induced bleeding offers a way to free up resources.Conservative choicesDespite recent advances, clinicians remain relatively conservative in their choice of NSAID. One recent study examined NSAID usage among general practices in Nottingham. GPs prescribed NSAIDs for a wide range of conditions - a relatively small proportion of patients suffered from rheumatoid arthritis. Ibuprofen, diclofenac and naproxen were the most widely prescribed.But the study also showed that the link between compliance and side effects is not as simple as it might appear. Among patients taking short courses of NSAIDs, side effects were associated with poor compliance. However, chronic users were more willing to tolerate adverse events. Highly compliant long-term users reported more adverse effects than other patients.The study did show that NSAIDs are effective - half the patients reported good or complete symptom relief. It concluded that NSAIDs, "give symptom relief to, and are perceived as effective by, most patients taking them".Not all are the sameA growing body of evidence suggests that NSAIDs differ in their tolerability and efficacy. This differential effect on gastrointestinal complications is central to attempts at reducing the prevalence of NSAID-induced bleeding.Several studies used in a meta-analysis suggest that ibuprofen is the least likely of the conventional NSAIDs to cause gastrointestinal complications. (The analysis excluded etodolac, meloxicam, celecoxib and rofecoxib.)On the other hand, ibuprofen is relatively ineffective and most patients need to take high doses. As a result, the meta-analysis concluded that high-dose ibuprofen is associated with a similar gastrointestinal complication rate as naproxen and indomethacin.Newer drugs appear to be better tolerated than conventional NSAIDs. Etodolac, for example, does not promote faecal blood loss, in contrast to ibuprofen, indomethacin and naproxen. Recent studies suggest that celecoxib and rofecoxib are less likely to be associated with gastrointestinal side effects than conventional NSAIDs.Similarly, one study found that meloxicam was associated with less dyspepsia, nausea and vomiting, abdominal pain and diarrhoea than diclofenac. A systematic review of adverse gastrointestinal events among patients using meloxicam offers further reassurance. This found that meloxicam users developed 36 per cent fewer gastrointestinal adverse events than those taking non-COX-2- selective NSAIDs.Meloxicam users experienced 27 per cent less dyspepsia and 48 per cent fewer peptic ulcer bleeds than those taking conventional agents. Moreover, meloxicam users were 41 per cent less likely to discontinue NSAIDs following adverse gastrointestinal events.There are good pharmacological and biological reasons to expect the highly COX-2 specific inhibitors to further improve gastrointestinal safety. But the exact risk-benefit profile of celecoxib and rofecoxib awaits clarification.Recent animal studies indicate that selective COX-2 inhibitors aggravate ischaemia- reperfusion injury in the stomach. This may suggest that in some situations selective COX-2 inhibitors may be gastrotoxic.Generic prescribingAs mentioned above, generics dominate the NSAID market and offer an obvious way to reduce prescribing costs. However, recent problems with generic shortages show that financial planning may prove difficult.Generic ibuprofen, for example, is cheap. But at clinically recommended doses the complication risk increases to that associated with less benign NSAIDs. A hospital admission would soon offset any savings on the drug budget.Clearly, acquisition costs do not tell the whole story. Etodolac and meloxicam appear to be more cost effective than conventional NSAIDs because of their better gastrointestinal tolerability.One study found that meloxicam 7.5mg was associated with less demand on secondary care than diclofenac 100mg. There were three hospitalisations due to gastrointestinal adverse events among the 4,635 meloxicam users and 11 in the diclofenac group of 4688 osteoarthritis patients. But the group's total hospital stays were five and 124 days respectively, with a mean admission of 1.7 and 11.3 days respectively.So celecoxib and rofecoxib should prove cost effective. However, 28 rofecoxib 12.5mg tablets cost #21.58, while 30 meloxicam 7.5mg tablets costs #10. In other words, meloxicam's price falls between generics and rofecoxib. However, celecoxib's and rofecoxib's impact on hospitalisation and consultation rates in practice remains unresolved.In conclusion, NSAIDs' acquisition costs and the economic burden imposed by their indications and adverse events are considerable. Newer drugs reduce the risk of gastrointestinal side effects and appear to be cost effective. While generics initially appear cheaper they are still associated with a greater risk of side effects.Dr Lambert is a consultant rheumatologist at the Western General Hospital in Edinburgh.This course (module 1166), in association with multiple choice questions being published in C&D July 8, provides one hour's continuing education