Motion – Cyclooxygenase-2 selective nonsteroidal anti-inflammatory drugs are as safe as placebo for the stomach : Arguments for the motion

This article was originally presented at a symposium entitled, “Controversies in Gastroenterology”, sponsored by Axcan Pharma, Toronto, Ontario, April 8 to 10, 2002 Division of Gastroenterology, McMaster University Medical Centre, Hamilton, Ontario Correspondence: Dr Richard H Hunt, Division of Gastroenterology, McMaster University Medical Centre, 1200 Main Street West, Room 4W8A, Hamilton, Ontario L8N 3Z5. Telephone 905-521-2100 ext 73219, fax 905-521-5072, e-mail huntr@mcmaster.ca RH Hunt. Motion – Cyclo-oxygenase-2 selective nonsteroidal anti-inflammatory drugs are as safe as placebo for the stomach: Arguments for the motion. Can J Gastroenterol 2003;17(5):339-341.

T he gastroscopic demonstration of the toxicity of acetylsali- cylic acid was first demonstrated a century ago and the gastrointestinal (GI) adverse effects of nonsteroidal anti-inflammatory drugs (NSAIDs) have been reported increasingly in the literature ever since (1)(2)(3)(4).These agents are undoubtedly effective in the treatment of joint inflammation and musculoskeletal injury, but a significant proportion of patients experience upper GI symptoms, usually dyspepsia, and endoscopic lesions ranging from petechial hemorrhages to bleeding peptic ulcers.
The risk of developing a severe GI adverse event varies from patient to patient, and from NSAID to NSAID.Numerous epidemiological studies have shown that the use of these drugs increases the overall risk of peptic ulcer bleeding (OR 3.09-4.5),adverse events-related hospitalization (OR 3.9-5.5),GI surgery (OR 7.75) and GI adverse events-related death (OR 4.79-7.62)(1-3).Certain risk factors predispose NSAID users to a greater risk of developing a severe GI complication.These risks include age over 60 years (OR 2.86), previous history of ulcer disease or ulcer bleeding (OR 4.76-9.5),use of high-dose or multiple NSAIDs (OR 4.0-23.3),concomitant corticosteroid therapy (OR 1.83-4.4)and concomitant anticoagulant therapy (OR 2.1-16.0).
Many drugs have been developed in attempts to minimize these adverse effects, with varying degrees of success and acceptance.Several classes of NSAIDs are available, including propionic acids, anthranilic acids, salicylic acids, acetic acids, oxicams, naphthylalkanones and cyclo-oxygenase-2 (COX-2)

CONTROVERSIES IN GASTROENTEROLOGY
selective inhibitors.Results from the Arthritis, Rheumatism, and Aging Medical Information System (ARAMIS) database of adverse events and meta-analysis have shown that, among the conventional NSAIDs, ibuprofen and salsalate are the least toxic, whereas tolmetin, fenoprofen, indomethacin, piroxicam, ketoprofen and azapropazone are among the most toxic to the GI tract (3,5).
More recent studies have shown that some of the newer NSAIDs, specifically nabumetone, meloxicam and etodolac produce significantly fewer peptic ulcer bleeds than do other agents (6)(7)(8).Consequently, it has been suggested that there is a correlation between the risk of GI complications and relative degree of inhibition of COX-1 and COX-2 isoenzymes (9,10).In other words, a more selective inhibition of COX-2 compared with COX-1 is associated with a decreased risk of adverse GI events.The published ratios of the effects of various conventional NSAIDs on COX-2 and COX-1 may not be accurate, however, because of significant variability in the assay methods that have been used.Nevertheless, the GI toxicity of the highly selective COX-2 inhibitors, celecoxib (Celebrex, Searle, Mississauga, Ontario) and rofecoxib (Vioxx, Merck Frosst, Kirkland, Quebec), and of newer coxibs that are being developed, valdecoxib and etoricoxib, appears to be minimal.
Studies of safety for the digestive tract have been an essential component of the development of new anti-inflammatory drugs (11).Extensive safety studies for selective COX-2 inhibitors have been conducted and have involved the detection of microscopic quantities of blood in the stool using the 51 Chromium-labeled fecal red blood cell loss method (12); macromolecular permeability of the small intestine (13); endoscopic examination of the upper GI tract (14-16); and assessment of relevant clinical outcome measures, such as the presence of ulcers, perforation or bleeding (15)(16)(17)(18)(19).These studies have shown conclusively that patients who are taking a coxib experience significantly lower rates of gastric and duodenal ulcers, and of bleeding ulcers, than do patients taking conventional NSAIDs.The reduction in risk is approximately 50% for perforations, ulcers and upper GI bleeds.
Other types of studies have also demonstrated the safety of coxibs.In contrast to ibuprofen, the amount of bleeding, as measured by 51 Chromium-labeled fecal red cell loss, is similar between rofecoxib and placebo (12).Similarly, rofecoxib does not cause the abnormalities in small intestinal permeability, as assessed by 51 Chromium-EDTA and L-rhamnose absorption, that are seen with ibuprofen (13).
Short term endoscopic studies have shown that selective COX-2 inhibitors induce significantly less gastric mucosal damage than do naproxen or ibuprofen, and are similar to placebo.Even at doses that are two to four times higher than those known to be effective for the treatment of osteoarthritis, rofecoxib is as safe as placebo with respect to GI blood loss (12).Endoscopic studies involving patients with rheumatoid arthritis or osteoarthritis (including patients who are at high risk because of advanced age or history of ulcer disease) have shown that rofecoxib causes significantly fewer ulcers than either naproxen or ibuprofen, and the same number as placebo (14)(15)(16)18,20).
Low rates of endoscopically confirmed ulcers and complications with coxibs have been confirmed by the Celecoxib Long-Term Arthritis Safety Study (CLASS ) (21) and the Vioxx Gastrointestinal Outcomes Research Study (VIGOR) (22).The latter study, which enrolled more than 8000 patients with rheumatoid arthritis, found that rofecoxib produced 54% fewer clinical upper GI events, 57% fewer complicated upper GI events, and 62% fewer episodes of GI bleeding from any site in the GI tract than did naproxen.The risk reduction was especially dramatic in patients with more than one risk factor (RR 0.49, 95% CI 0.32 to 0.65), compared with those with no risk factors (RR 0.12, 95% CI 0.04 to 0.98).The risk of ulcer disease in these low risk patients is close to baseline, but is not zero.This is because the background prevalence of ulcer disease is approximately 7%, although this might be expected to fall in the future because of the decreasing prevalence of Helicobacter pylori in the general population.
The VIGOR study revealed a slight but significantly lower rate of myocardial infarction in patients taking naproxen (0.1%) compared with those taking rofecoxib (0.4%) (22).This effect has been attributed by some to the protective effect of naproxen, which results in a roughly 95% inhibition of thromboxane synthesis, an effect similar to that of aspirin.
The introduction of COX-2-selective agents offers the opportunity for the safe and effective treatment of patients who are at high risk of developing GI complications.Large, long term, randomized, controlled studies are underway to confirm the safety of these agents, particularly in organs outside of the GI tract.