Considerations for the safe prescribing and use of COX-2-specific inhibitors

The availability of the COX-2-specific inhibitor (CSI) class of anti-inflammatory drugs, namely celecoxib and rofecoxib, has raised a number of questions. These include:

• to what extent do the CSIs reduce serious gastrointestinal (GI) toxicity?

• what is their place in patients with peptic ulcers or cardiovascular disease, or with risk factors for these conditions?

• do they still have a place in patients who need low-dose aspirin for its antiplatelet effect?

• are they safer than non-steroidal anti-inflammatory drugs (NSAIDs) in patients with hypertension and renal impairment?

• are there significant issues in patients with other diseases or taking other drugs?

• is the benefit/toxicity profile the same for both celecoxib and rofecoxib?

As every clinician considering the use of a CSI or an NSAID must somehow take such questions into account, it seemed appropriate that physicians and general practitioners with experience in the use of these drugs offer their own assessment of the issues and the approach they consider reasonable in different clinical situations.

Therefore, a working group was formed with the following aims:

• to survey published data from therapeutic studies to determine the strength of evidence bearing on GI safety, cardiovascular safety, renal and blood pressure effects, co-prescribing and comorbidity effects, and allergy and intraclass differences; and

• to generate from that survey considerations for safe CSI use.

The working group was constituted primarily by the rheumatologists on the medical advisory boards of Pharmacia/Pfizer and Merck, Sharp & Dohme, the two pharmaceutical companies responsible for the development and marketing of celecoxib and rofecoxib, respectively. Meloxicam was not considered, as it was not marketed at the time the working group met. A number of experts from general practice, clinical epidemiology, gastroenterology, cardiology, nephrology, and individuals associated with relevant bodies including the National Prescribing Service, the Arthritis Foundation of Australia (AFA), the Australian Rheumatology Association (ARA) and the medical departments of the pharmaceutical companies, were invited to join. Financial support for meetings of the working group was provided by Pharmacia/Pfizer, Merck Sharp & Dohme, the AFA and the ARA; these funds were used for travel and meeting expenses. No remuneration was paid to members of the working group.

We acknowledged that the exercise could only have value if undertaken independently of any but scientific influence (ie, that working group members should not continue to act in the capacity of an advisory group to industry, but rather broadly in the best interest of all stakeholders — patients, doctors, the pharmaceutical industry and the public. The working party agreed that it must be autonomous with respect to its terms of reference, and that its conclusions and recommendations should be based on a fair assessment of the literature published up to the end of May 2001 and pertinent sections of the United States Food and Drug Administration (FDA) website, accessible in the public domain. The cost of CSIs was not considered, as there is little pertinent "cost-effectiveness" literature in the public domain. The working group acknowledged that cost should be a consideration in the prescribing decision.

The working group met four times between 11 April 2001 and 7 November 2001, and corresponded by email between meetings and up until submission of the CSI Prescribing Considerations on 30 November 2001. A comprehensive statement was prepared, which represents the consensus view of group members and was the source document (to be published separately) for this summary paper.

The key points identified by that process and a set of "considerations" relevant to the use of these new anti-inflammatory agents are presented here. The considerations are not claimed to be the result of a systematic review, but represent an extensively debated consensus view. These are not guidelines on the appropriate management of musculoskeletal disorders, but a guide to the safe use of CSIs. Some contributors removed themselves from the working group because of concerns about the prescribing considerations summary (see end of article).

The group's broad conclusion was that NSAIDs and CSIs are equivalent in efficacy as anti-inflammatory agents. The major difference is a reduced risk of clinically significant upper GI complications with CSIs.1-6 Renal adverse event rates are similar to those with conventional NSAIDs,7-11 and it should be noted that cardiovascular safety of CSIs remains subject to debate. We recommend that all patients prescribed CSIs or NSAIDs who need continuing treatment should be reviewed within the first few weeks of therapy to assess effectiveness and identify adverse effects. Further, the need for continuing treatment should be reviewed at regular intervals.

CSIs are associated with considerably fewer peptic ulcers, and slightly fewer upper GI symptoms (such as dyspepsia), compared with non-selective, conventional NSAIDs. Published studies report an approximate halving of serious upper GI complications, notably bleeding, although in one major study this difference was not statistically significant,1 and an FDA analysis of the entire study results showed less advantage for the CSI.12 The other major study excluded patients with CV risk factors,2 which may be significant.

However, if patients taking aspirin (eg, for prophylaxis or treatment of thromboembolic disorders) are given CSIs for arthritis symptoms, then the GI advantages of CSIs may be lost. Studies have shown that the GI advantages of CSIs may persist for up to nine months,2 but few data are available for longer periods.5,6 Risk factors for serious upper GI bleeding complications, such as age over 65 years, previous history of peptic ulceration, concomitant medications such as aspirin or anticoagulants and cardiovascular disease, apply equally to CSIs and NSAIDs.

It is important to note that use of CSIs does not eliminate the occurrence of ulcers or their serious complications. Monitoring for the development of an ulcer or ulcer complication is particularly indicated in patients with risk factors and should include:

• educating patients about the symptoms of GI bleeding;

• monitoring for new or severe upper-GI symptoms; and

• possibly performing baseline and periodic haemoglobin concentration measurement.

There is limited evidence about the exact effects of CSIs on renal function. However, overall, there appear to be no significant differences from conventional NSAIDs. Therefore, similar precautions and contraindications apply to both drug groups. An absolute contraindication for their use is the presence of hyperkalaemia. Caution is required for those patients with renal risk factors, which include age over 60 years, glomerular filtration rate (GFR) ≤ 60 mL per minute, patients on salt-restricted diets, those receiving diuretics, angiotensin-converting enzyme inhibitors, angiotensin-2 receptor blockers, cyclosporin, aspirin and patients with cirrhosis or congestive heart failure. These patients are at a higher risk of deterioration of renal function if CSI or NSAID therapy is prescribed.

Plasma sodium, potassium and creatinine levels, blood pressure, the presence of oedema, and urinalysis should be monitored as in the Box.

A 20% fall in GFR, provided the total GFR remains greater than 20 mL per minute, is an acceptable "trade-off", provided there is a good clinical response to these drugs.

As with NSAIDs, blood pressure may rise, sometimes substantially, with prescribing of CSIs. Blood pressure should be monitored and the dose of antihypertensive medication adjusted to maintain blood pressure at treatment target levels. CSIs, like NSAIDs, can exacerbate cardiac failure. Occasional patients may present with pulmonary oedema.

There is evidence that rheumatoid arthritis (RA) may be a risk factor for cardiovascular disease.13 A large, long-term clinical trial in RA, using supratherapeutic doses of rofecoxib, showed an increase in the rate of myocardial infarction compared with naproxen. The reason for this difference is under debate. An increased rate of myocardial infarction has not been shown in other clinical trials of CSIs. Therefore, until there is more definitive information, we advocate caution when considering the use of CSIs in patients with risk factors for coronary disease, especially in those with RA.

The use of CSIs also needs careful consideration in other situations in which NSAIDs have caused concern.

Prescribers should remember that CSIs are symptom-modifying drugs and do not alter the course of musculoskeletal disease, so benefits to patients must outweigh potential risks. This is a rapidly changing field and these considerations may require modification as new data emerge.