Cost-effectiveness of non-steroidal anti-inflammatory drugs (NSAIDs)—what makes a NSAID good value for money?

N. Freemantle

Medicines Evaluation Group, Centre for Health Economics, University of York, UK.

Family practitioners in England prescribe about 1.5 million person years of non-steroidal anti-inflammatory drugs (NSAIDs) [1]. Most treatment is for the relief of pain in patients with osteoarthritis managed in primary care, although often these patients do not formally gain a diagnosis, their symptoms being managed pragmatically. NSAIDs are also widely used in the long-term management of patients with rheumatoid arthritis, but the volume of use for these patients is considerably less. There is good evidence that, in the management of pain, NSAIDs have some advantages over simple analgesics such as paracetamol (acetaminophen). However, these advantages are associated with an increase in the risk of serious gastrointestinal episodes [1].

The problems associated with traditional NSAIDs have fostered pharmacological research aiming to discover the mode of action leading to gastrointestinal events [2, 3] and to identify new agents which achieve the benefits of traditional NSAIDs but at reduced risk. Specifically, both the therapeutic and toxic actions of NSAIDs result from their inhibition of prostaglandin, mediated by the cyclooxygenase (COX) enzyme. COX-2-specific drugs have been developed on the basis that they have a differential action on the inhibition of COX-1 and COX-2, an action proposed to enhance efficacy while reducing or removing toxic effects. Although the evolution of pharmaceuticals that avoid iatrogenic morbidity and mortality is clearly a positive development, the availability of new drugs also raises the question of the degree to which they are likely to be good value in practice, in the light of alternative demands upon scarce health service resources.

When can a pharmaceutical be considered cost-effective? First, pharmaceuticals can appear worth their purchase cost when they are more effective than available alternatives (securing worthwhile additional improvement in health status). A drug that achieved twice the benefits, but at less than twice the costs associated with the standard treatment may appear relatively good value for money (although in practice differences in effectiveness of this magnitude are unusual). Second, pharmaceuticals may be cost-effective where they achieve a greater reduction in other health service costs than the cheaper alternatives. Drugs for the treatment of ulcers, although expensive, have largely made surgical interventions extinct. Third, pharmaceuticals may be cost-effective where they reduce broader social costs (for example, they achieve improved work attendance). It could be argued that a costly but effective treatment for migraine headache that prevented white collar workers from taking time off work could be good value for money if it led to worthwhile productivity otherwise lost. Finally, drugs may be considered cost-effective where they are effective when cheaper alternatives have failed to perform adequately. I will argue below that unless they are priced at a level similar to that of existing NSAIDS, it is on this last criterion alone that COX-2-specific drugs will need to register to be considered cost-effective.

Although two COX-2-specific agents, rofecoxib and celecoxib, are available in the USA (and are either licensed or approaching licensing in other markets), there are remarkably few data available in the public domain describing the trial programmes upon which they were licensed. Indeed, the best data available to this commentator came from the US data sheets for the products (more detail in the package inserts on the safety and efficacy of pharmaceuticals is required for the US market than the UK market). The manufacturers of rofecoxib claim efficacy equivalent to ibuprofen 800 mg TID and diclofenac 50 mg TID in trials in osteoarthritis. Similarly, the manufacturers of celecoxib claim efficacy equivalent to naproxen 500 mg BID on the basis of direct comparison in randomized trials in osteoarthritis and rheumatoid arthritis. The manufacturers also compared celecoxib with diclofenac sodium (75 mg twice daily) or ibuprofen (800 mg three times daily), but the efficacy outcomes for these trials are not reported in the data sheet (which describes only endoscopically detected lesions). Thus, claims for the cost-effectiveness of COX-2-specific drugs are not supported by evidence on increased analgesic efficacy but on suggested equivalence.

COX-2-specific agents do have the potential to reduce the health service costs through the avoidance of clinically important gastrointestinal side-effects. It has been estimated that each year in the UK there are about 30 000 hospitalizations associated with NSAID use [1], with considerable uncertainty on the number attributable to NSAID exposure, although perhaps half or less may be attributable to NSAIDs. While an impressive total, this must be considered against the substantial volume of use of NSAIDs. A useful illustration of the level of risk associated with NSAID exposure is available from Silverstein et al. [4] who examined the effectiveness of misoprostol prophylaxis in 8843 patients with rheumatoid arthritis in the prevention of NSAID-related gastrointestinal injury. Significantly, Silverstein et al. used a clinically important outcome (serious upper gastrointestinal complications) rather than the commonly used intermediate outcome of endoscopically determined gastric lesions. In 6 months of treatment with a NSAID, only 42 serious gastric events were identified among 4439 patients. This contrasted with a rate of 25 in 4404 patients treated with misoprostol [odds ratio for the comparison using Gart exact test, 0.60, 95% confidence interval (CI) 0.38–1.00]. Thus, although common at a population level, the rate of preventable events is surprisingly low. The cost-effectiveness of misoprostol prophylaxis has been estimated to be £27 300 per gastrointestinal event avoided (95% CI £12 200–572 000) [1]. The cost-effectiveness per death avoided is probably 10 times this figure, although this is based upon extrapolation from the event rates for serious upper gastrointestinal injury, and data are not available for direct estimation.

In the absence of good data it may be excusable to consider available data to estimate the likely bounds of effectiveness of COX-2-specific agents. Or, in other words, to estimate the maximum benefits that they might achieve compared with standard therapy, making strong (and unsupported) assumptions on equivalent efficacy and the relationship between endoscopically detected lesions and serious upper gastrointestinal events. The data sheet for rofecoxib reports the results for two trials comparing the rates of endoscopically detected lesions among patients randomized to rofecoxib (25–50 mg) or ibuprofen (2400 mg). These trials show a consistent 20% reduction in the absolute incidence of endoscopically detected lesions, although, as the data sheet acknowledges, ‘the correlation between the findings of endoscopic studies, and the relative incidence of clinically serious upper GI events with different products, has not been fully established’. In the literature, there have been various attempts to estimate the link and tentative estimates have suggested that there may be six or seven endoscopically detected lesions for every serious upper gastrointestinal event [1]. The figures are certainly rather hard to resolve across studies. The ibuprofen rate of endoscopically detected lesions in the rofecoxib studies was 25% in 3 months. The rate of clinically important upper gastrointestinal injury in the NSAID group of Silverstein et al. [4] was about 1% in 6 months. For both rofecoxib and celecoxib the relative risk of an endoscopically detected lesion in 6 months is about 0.25 in the trials reported in the data sheets. Thus, for 10 000 patients treated with a traditional NSAID, about 100 would experience a serious gastrointestinal event, and about 10 would be likely to die as a result. Among 10 000 patients taking a COX-2 NSAID for 6 months, about 25 might experience an event, and about two might be expected to die as a result. This would equate to a number needed to treat for 6 months with a COX-2 rather than a traditional NSAID of 133 to avoid a serious gastrointestinal event and 1333 to avoid a death. The manufacturers of rofecoxib report four incidences of serious gastrointestinal bleeding among 3357 patients in their clinical trial programme, most of whom were in 6-month trials. Similarly the manufacturers of celecoxib report two serious gastrointestinal side-effects in 5285 patients, of whom most were in 3-month trials. Since many of the patients were required to be free of ulcer at entry, and in general patients in NSAID trials are more likely to be younger and free from co-morbidity, the rate of serious gastrointestinal events in the general population treated with COX-2 inhibitors may be considerably higher.

The effectiveness of COX-2 inhibitors looks relatively unimpressive against other ‘evidence based’ priorities such as optimal treatment of heart failure [5]. The number needed to treat to avoid a death in 6 months of optimal treatment of heart failure is only 40. However, it may not be acceptable to compare effectiveness across disease areas, just as much as it may not be appropriate to focus only on the comparison of COX-2-specific agents with traditional NSAIDs. A recent clinical practice guideline on the use of NSAIDs in primary care suggested caution in the use of NSAIDs, reserving their use to patients who do not respond adequately to a proper trial of paracetamol (acetaminophen) at full dose [1]. The regular review of repeat prescriptions of NSAIDs is also recommended to avoid unnecessary exposure to the risk of iatrogenic illness.

The acquisition cost of the COX-2-specific inhibitors is relatively high compared with commonly prescribed NSAIDs. For example, in primary care in UK, rofecoxib is reimbursed at £21.58 for 28 days' treatment, regardless of dosage (12.5 mg daily or 25 mg daily) (Merck Sharpe & Dohme Ltd, UK, personal communication). This contrasts with a price of £9.36 for a 28-tablet pack of generically prescribed diclofenac sodium 100 mg tablets sustained release, or less than £5 for generically prescribed diclofenac sodium 150 mg daily. Whatever the impact on health status, the effect of a large-scale switch to new COX-2-specific NSAIDs is likely to have a substantial impact on drug reimbursement budgets.

Just looking at the way the numbers fall, it appears that it will be difficult to make a case on efficiency grounds for the widespread use of COX-2-specific NSAIDs. Although in secondary care some costs will be avoided relating to the harm caused by traditional NSAIDs, these will quickly be overwhelmed by the relatively high acquisition costs of the drugs, since only a small proportion of patients will avoid NSAID-attributable serious upper gastrointestinal events. Most patients take NSAIDs for transient pain relief and their alternatives include non-drug treatments and simple analgesia in many cases. For patients with rheumatoid arthritis where the therapeutic choices may be limited, the risk of iatrogenic illness may appear unreasonable given the availability of an alternative, albeit at high cost. In other words, the prescriber may decide that COX-2 inhibitors present good value for money ‘because cheaper alternatives have failed to perform adequately’. Such a decision will also depend upon claims for similar efficacy for the new drugs that may not be achieved in practice in these patients. In the MELISSA trial [6] that compared meloxicam 7.5 mg daily (a selective COX-2 inhibitor) with diclofenac sodium 100 mg daily, diclofenac achieved a consistently small but statistically significant benefit in pain relief in patients with symptomatic osteoarthritis. Comparable data describing the relative efficacy of COX-2-specific agents are not fully published at the time of writing.

A further factor is the extent to which clinicians co-prescribe proton pump inhibitors as gastro-protective agents when prescribing NSAIDs. From national prescribing statistics, it is not possible to identify the extent to which co-prescribing occurs, but the relatively high cost of proton pump inhibitors indicates that there may be cost advantages for COX-2-specific NSAIDs over traditional NSAIDs plus gastro-protective strategies. However, although on this basis the COX-2 agents might be considered relatively cost-effective (assuming similar efficacy), it is not clear that co-prescribing a gastro-protective agent is often itself a cost-effective option [1].

As is increasingly common, new pharmaceuticals are presenting a challenge to the National Health Service and other health systems. Incorporating new technologies in an environment where there is no spare capacity and many competing challenges will always require painful choices. In the case of the COX-2 inhibitors, the situation is confounded with the reluctance of industry to publish the pivotal trials that describe their effectiveness and relative effectiveness. In the UK, both the National Health Service Health Technology Assessment Programme and the new National Institute for Clinical Effectiveness (NICE) have identified COX-2 agents a priority for research, although in both cases, research has not informed the decision to make drugs available for reimbursement in the National Health Service. As a result, the potential prescriber is left making a difficult decision for his/her patients without sufficient information to base that decision on, evidence concerning the likely effectiveness and cost-effectiveness of COX-2-specific drugs in different indications.

Declaration of conflict of interest

Nick Freemantle has received a grant for unrestricted research funds from Pfizer, the manufacturer of rofecoxib, and received fees and expenses from GD Searle, the manufacturer of celecoxib. He has also received research funding from the Department of Health in England to develop guidelines for NSAID use, and to perform a randomized evaluation of the use of these guidelines in practice.

Acknowledgments

I would like to thank Chris Hawkey, David Henry and James Mason for their helpful comments on an earlier draft of this article. I would also like to thank Anne Burton for her help in preparing the manuscript.

References

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