To the Editor: In their article on adoption of celecoxib and rofecoxib by Australian general practitioners, Kerr et al noted that “the increase in COX-2 [cyclooxygenase-2] prescribing coincided with a period of energetic marketing to the medical profession, which promoted the message that the new C2SNs [COX-2-selective non-steroidal anti-inflammatory drugs] were ‘safer’ than traditional NSAIDs [non-steroidal anti-inflammatory drugs].”1 The implication is that the decision of Australian GPs to prescribe these new drugs may have been less than independent or rationally informed.

The reason for prescribing C2SNs is that, like traditional NSAIDs, they relieve arthritic pain and so promote mobility, although, unlike traditional NSAIDs, they do not inhibit cyclooxygenase-1. While the power of advertising is undeniable, the simple message about C2SNs is that there is an approximate 50% reduction in clinically significant gastrointestinal (GI) complications compared with traditional NSAIDs.2 There are over a dozen articles to support the better GI side-effect profile of C2SNs. Most data support a non-cumulative, reversible, but constant, risk of peptic and other, more distal GI bleeds, or perforation, with the coefficient of risk being significantly greater for NSAIDs.3 Although the data from the CLASS study did suggest that the higher GI morbidity of NSAIDs seemed to diminish with time,4 that of celecoxib remained at a constantly lower rate.5 This is clinically important for all our patients, and especially for our ageing population with their comorbid conditions and polypharmacy. I suggest that it is for this single reason that many doctors have been quick to take up C2SNs for their patients. The better GI safety enfranchised patients who previously could not take NSAIDs safely, and could explain why the overall anti-inflammatory market increased by 20%.1

However, no one suggests that the C2SNs are free of non-GI side-effects. To the best of my knowledge, COX-2-specific NSAIDs have not been promoted as being free of non-GI side-effects or better than COX-1-specific NSAIDs in this regard.

While agreeing with the last sentence of Dowden’s editorial that “new is not always better”,3 the opposite — that “new is sometimes better” — is also true. Thus, we persuaded the accountants in our hospital, who rightly participate in the determination of which drugs are available on its formulary, to accept one of the COX-2 drugs because of its better GI complication profile. While this will not reduce its pharmacy budget, it is anticipated to reduce overall hospital costs in this area,5 which should allow a reapportionment of its budget to other areas of need. Of course, the hospital is watching carefully for any unforeseen “serious adverse effects which sometimes only emerge after marketing”.3

In reply: The advantage of the COX-2-selective NSAIDs (C2SNs) is the reduction in clinically significant gastrointestinal complications compared with conventional NSAIDs, but, as Florin agrees, other toxicities, including the risk of renal failure and heart failure, are similar for C2SNs and the older drugs.1 We speculated that doctors may have been more aware of the differences between the new and the conventional anti-inflammatories rather than the similarities: between 4.7% and 7.9% of patients in our study cohorts were treated with a combination of drugs which placed the patient at risk of renal complications. Florin points out that there is an approximate 50% reduction in clinically significant gastrointestinal (GI) complications with C2SNs compared with conventional NSAIDs. If, in a population, the annual incidence of serious GI complications with NSAID use is around 1.4%,2 then the absolute risk reduction is 0.7%. This means that about 140 patients would need to be treated with a C2SN for one year to prevent one serious GI complication. Messages conveyed in this way may be more pertinent to clinical decision making than a statement about relative risk reduction.

Florin also notes the problems with elderly patients who often take multiple medications, and are probably at increased risk of upper-GI events with NSAIDs. Our data demonstrated very high prescribing rates in patients who were not elderly. Over 20% of patients in our cohorts were aged less than 50 years, and over 50% were aged less than 65 years. Furthermore, between 34.5% and 61.3% had no pain medication prescribed in the 12 months before the first C2SN prescription, suggesting that C2SNs may have been used as a first-line pain medication in these patients. Quality use of medicines advocates prescribing which is safe, judicious, effective and cost-effective. Recent pharmacoeconomic studies suggest the cost-effectiveness may only be realised when prescribing of C2SNs is confined to patients who are at high risk of GI complications.3,4

In reply: The general practitioners’ decision to prescribe COX-2 inhibitors was rational, but the information underpinning their decision was less than independent. A big reduction in short-term relative risk can be persuasive, even if the absolute benefit is small.

General practitioners deal with whole patients, so they consider the overall risks of treatment, and not just one adverse effect. While COX-2 inhibitors may have gastrointestinal advantages, they may have cardiovascular disadvantages.

Treatments for chronic conditions should be based on long-term data. The observation that most of the ulcer complications in the second half of the CLASS study were in patients taking celecoxib is therefore important.1

Undoubtedly, some patients who could not take non-selective non-steroidal anti-inflammatory drugs (NSAIDs) were able to tolerate COX-2 inhibitors. However, Kerr et al found that up to 61% of patients given a COX-2 inhibitor had not previously been prescribed any analgesia.2 It seems unlikely that so many people suddenly required analgesia that only a COX-2 inhibitor could provide.

The Pfizer-funded study by MacDonald et al shows that UK general practitioners tended to prescribe COX-2 inhibitors for patients at risk of gastrointestinal haemorrhage.3 This follows the advice of the National Institute of Clinical Excellence (NICE). However, NICE also recommended against the routine use of COX-2 inhibitors.4 A review by the Canadian Co-ordinating Office for Health Technology Assessment has also concluded that COX-2 inhibitors may have no significant safety advantage over diclofenac.5

Solomon et al conclude that the cost of adverse effects of NSAIDs in low-risk elderly patients is modest.6 However, there is no comparison with COX-2 inhibitors, so we do not know if they reduce this cost. Hospital accountants may be interested to know that researchers at the Mayo Clinic concluded that, in terms of averting gastrointestinal events, the most cost-effective analgesic is paracetamol.7