On 17th December, the U.S. National Institutes of Health (NIH) announced the suspension of the use of celecoxib (Celebrex®) in an ongoing clinical trial conducted by the National Cancer Institute, the Adenoma Prevention with Celecoxib (APC) because of an increased risk of cardiovascular (CV) events in patients taking celecoxib versus placebo.

The APC trial compared celecoxib with placebo for reducing the risk of colon polyps. Approximately 2,000 patients were enrolled, and the average duration of treatment was 33 months. The interim analysis revealed that patients taking 400 mg of celecoxib twice daily had a 3.4 times greater risk of CV events compared to placebo. For those taking 200 mg of celecoxib twice daily, the risk was 2.5 times higher. In terms of absolute numbers, there were 6 major events [CV death, myocardial infarction & stroke] in the placebo arm (n=679), 15 events in the celecoxib 400 mg arm (n=685) and 20 events in the celecoxib 800 mg treatment group (n=671).

A separate long-term study sponsored by Pfizer (Prevention of Spontaneous Adenomatous Polyps (PreSAP)) comparing celecoxib 400 mg once a day (n=933) versus placebo (n=628) and similar in size and duration to APC, does not appear to confirm this risk. There were 11 major events [CV death, myocardial infarction & stroke] (1.8%) in the placebo group and 16 events (1.7%) in the celecoxib arm. The dosing of this trial has been suspended as a result of the observations in the APC trial.

It is to be noted that the clinical trial data that have been submitted for all 3 currently registered COX-2 specific inhibitors (valdecoxib (Bextra®), etoricoxib (Arcoxia®) and celecoxib (Celebrex®) are for durations of less than 33 months as compared to the APC trial and the rofecoxib (Vioxx®) APPROVe trial (which was terminated in Oct 04 due to increased risk of CV events). This is in-line with internationally accepted guidelines for data submission for registration of drugs intended for long-term treatment of non-life threatening conditions.

Prior to this new development, previous studies on celecoxib, including shorter-term clinical trials and epidemiological studies have not suggested the same risk as in the APC trial. For example, in the Celecoxib Long Term Arthritis Safety Study (CLASS), in which 8,000 patients were randomised in a comparison of celecoxib 400 mg twice daily to ibuprofen or diclofenac for the treatment of osteoarthritis and rheumatoid arthritis and followed up for approximately one year, did not reveal a difference in CV risk.

On the other hand, another COX-2 specific inhibitor, valdecoxib (Bextra®) has recently been shown to have an increased risk of CV events [myocardial infarction, stroke, deep vein thrombosis and pulmonary embolism] in patients treated with valdecoxib when compared to placebo for treatment of acute pain after coronary artery bypass grafting (CABG). Over 1,500 patients were enrolled in 2 separate CABG trials and the duration of treatment was between 10-14 days (valdecoxib dose: Study 1 40 mg twice daily; Study 2 20 mg twice daily). The risk of intravenous form (2% patients had an CV event) and oral form (1% of patients) was higher in these patients compared to placebo arm (0.5%).

In addition, the US FDA has also noted in its statement issued on 17th December 04 that it is not known whether other non-steroidal anti-inflammatory drugs (NSAIDs) pose a similar risk as similar long-term studies of other products in the class of NSAIDs other than COX-2 inhibitors have not been done.

More recently on 20th December, the NIH announced the suspension of the use of naproxen (220 mg twice daily) and celecoxib (200 mg twice daily) in another large, three-arm, national Alzheimer's disease prevention trial (ADAPT). This trial was designed to assess the potential benefit of long-term use of these drugs in decreasing the risk of developing Alzheimer's Disease in older people (≥ 70-year old) involving ~2,400 volunteer participants. Preliminary findings showed no significant increase in risk for celecoxib but an apparent increase in CV and cerebrovascular events in the naproxen arm when compared to placebo group. NIH has pointed that the ADAPT study is among the first long-term clinical trial to test this class of drugs for indication which is currently not approved by any regulatory agency. NIH will continue to review this and other NSAIDs studies sponsored by NIH in the light of these findings.

Until further analyses and studies are available, it is difficult to make a conclusive statement as to whether the increased CV events observed are a class effect. Nonetheless, it may be prudent to consider the possibility of increased CV risk when using COX-2 specific inhibitors.

• In the light of recent information about CV risk associated with COX-2 inhibitors, starting with the rofecoxib (Vioxx®) worldwide recall, physicians are advised not to routinely prescribe COX-2 inhibitors to patients at risk of CV conditions.
  
  
• In view of the developing information, physicians are advised to review the risks and benefits of celecoxib when prescribing the drug to individual patients. Alternative therapies could be evaluated taking into account individual patient needs and risk factors. If continued use of celecoxib is assessed to be appropriate for the individual patient, HSA advises the use of celecoxib at the lowest effective dose and any long-term use should be regularly reviewed.
  
  
• The lowest effective dose, for the shortest duration necessary should be used for all COX-2 inhibitors (including NSAIDs)
  
  
• Physicians are referred to the December issue of the HSA's ADR News Bulletin for more information on COX-2 specific inhibitors in general:
  ADR News Bulletin Dec 2004 Vol 6 No. 3  
  
  For updates on drug safety issues please refer to Product Safety Alerts.