my personal edition > rheumatology other > news


  E-Mail this DGDispatch to a colleague

DGDispatch

Recent Gastrointestinal Outcomes With COX-2 Specific Inhibitors -- Clinical Implications: Presented at ACR

By Maria Bishop

PHILADELPHIA, PA -- December 7, 2000 -- Death induced by complications from non-steroidal anti-inflammatory drugs (NSAIDs) is the 15th most common death in the United States, noted Fred E. Silverstein, MD, at a satellite symposium of the American College of Rheumatology 2000 National Scientific Meeting held on Oct 29 to Nov. 2 in Philadelphia, Pennsylvania.

"Symptomatic ulcers and NSAID-induced gastrointestinal (GI) events need to be addressed," he emphasized.

Dr. Silverstein, clinical professor of medicine at the University of Washington and partner at Frazier and Company, Seattle, Washington, is a gastroenterologist who has spent much of his clinical career observing the GI side effects of rheumatology drugs on patients.

"We now know that over 90 percent of peptic ulcers are caused by either NSAIDs or by Helicobacter pylori [bacteria]," stated Dr. Silverstein. "Both alter mucosal defenses."

Unfortunately, many NSAID users will not experience antecedent symptoms from altered GI mucosa (Singh G, et al. Arch Intern Med. 1996;156:1530-1536), and so complications, when they arrive, are swift and severe. In fact, all NSAID patients are at high risk for ulcers. Gastroduodenal ulcers, for example, will occur in approximately 20 percent of NSAID users. (Cheatum et al. Clin Ther 1999; 21:992-1003.)

The concomitant use of misoprostol with diclofenac, for example, has been shown to reduce this risk by half (Agrawal, et al. Dig Dis Sci 1995; 40:1125-1131.), but the more reasonable therapeutic option would obviously be to avoid altering the mucosa of the GI tract from the outset, noted Dr. Silverstein.

Ulcer incidence is clearly reduced by the use of COX-2 inhibitors, which do not appear to alter GI mucosa. In two recent placebo-controlled studies comparing celecoxib and naproxen in patients with OA and RA, the risk of ulcer incidence with celecoxib was reported to be between five and six percent, whereas placebo engendered a four percent ulcer risk and naproxen demonstrated a 16 percent to 17 percent ulcer risk. (Simon, et al. JAMA 1999; 282:1921-1928. Celecoxib Prescribing Information.)

A similar study of rofecoxib versus ibuprofen showed that an ulcer risk of five percent was associated with both rofecoxib and placebo; the ulcer risk for ibuprofen was 29 percent. Hawkey et al. Arth Rheum 2000; 43:370-377

"Thus, ulcer incidence is clearly reduced from between 20 and 30 percent to five percent simply by switching to a COX-2 inhibitor," stated Dr. Silverstein.

"But what about the overall GI complications of these drugs?" he questioned.

In a pooled analysis of data from controlled arthritis trials of celecoxib, 1.68 percent of patients taking NSAIDs were found to have serious upper GI complications (e.g., perforation, ulcers, bleeding). By comparison, only 0.2 percent of celecoxib patients demonstrated such complications—equal to that found in the placebo-treated arm. (Goldstein J, et al. Am J Gastroenterol 2000; 95:681-690.)

In the six-month Celecoxib Long-Term Arthritis Safety (CLASS) trial, 8,059 patients with OA and RA were given either high-dose celecoxib (800 mg/day) or traditional-dose NSAIDS—diclofenac (150 mg/day) or ibuprofen (2,400 mg/day)—to treat their disease.

To reflect clinical practice, trial participants, many of them elderly, were allowed to take low-dose acetylsalicylic acid (ASA) for cardiovascular prophylaxis. The GI Events Committee of this trial then examined all participants for incidence of symptomatic ulcers; the primary end points included perforation, bleeding and other complications.

For all patients (both those who used ASA and those who did not), a dramatic decrease in upper GI complications -- alone and combined with symptomatic ulcers -- was seen in the patients taking celecoxib as opposed to those taking traditional NSAIDs (0.76 percent versus 1.45 percent and 2.08 percent versus 3.54 percent, respectively). (Silverstein F, et al. JAMA 2000; 284:1247-1255.)

In terms of adverse GI events, the CLASS trial demonstrated that celecoxib had a lower incidence of GI side effects and fewer bleeding-related complications than other drug classes in patients with RA or OA. (Silverstein F, et al. JAMA 2000; 284:1247-1255.

These data, noted Dr. Silverstein, "provide solid evidence for the reduced GI toxicity of COX-2 specific agents versus conventional NSAIDs".

Fred E. Silverstein is a consultant for Searle.

Supported by an unrestricted educational grant from Pharmacia.

E-Mail this DGDispatch to a colleague

To print, use this version