Risk of GI bleeding varies by NSAID type, dosage

The use of certain nonsteroidal anti-inflammatory drugs (NSAIDs) by healthy people is associated with an increased risk of cardiovascular death, but naproxen (Aleve, Bayer Consumer) appears to have a safer cardiovascular risk profile, according to a study published online June 8 in Circulation: Cardiovascular Quality and Outcomes, as reported by HealthDay News.

The risk of gastrointestinal (GI) complications because of the use of nonsteroidal anti-inflammatory drugs (NSAIDs) varies by the specific drug and dosage, and those with a slow-release formulation or long half-life are associated with a greater risk, according to research published in the June issue of Arthritis & Rheumatism, as reported by HealthDay News.

Researchers conducted a systematic review of observational studies from 2000 to 2008 on NSAIDs and upper GI bleeding or perforation. The article criteria was to report case-control or cohort studies evaluating traditional NSAID or coxib use and upper GI bleeding/perforation in the general population, and provide either an estimate, or enough data to estimate, a relative risk comparing NSAID users with nonusers. The pooled relative risk estimates of upper GI bleeding/perforation for individual NSAIDs was calculated, as well as whether the degree of inhibition of whole blood cyclooxygenase-1 (COX-1) and COX-2 in vitro by average circulating concentrations predicted the relative risk of upper GI bleeding/perforation.

The relative risk of upper GI bleeding/perforation was 4.50 for traditional NSAIDs and 1.88 for coxibs. Relative risks varied widely by specific drug: 1.42 for celecoxib (Celebrex, Pfizer); 1.44 for aceclofenac (Hifenac, Intas Pharma), which is not available in the United States; 2.12 for rofecoxib, which was pulled off the market in the United States and worldwide in 2004 because of heart-related side effects, but the study period included calendar years prior to the withdrawal; 2.69 for ibuprofen (Advil, Wyeth Consumer Healthcare and Motrin, McNeil Consumer Healthcare); 3.98 for diclofenac (Voltaren, Novartis Pharmaceuticals); 4.15 for meloxicam (Mobic, Boehringer Ingelheim); 5.40 for indomethacin (Indocin, Merck & Co.); 5.57 for ketoprofen (Oruvail, Wyeth); 5.63 for naproxen (Aleve, Bayer Consumer); 9.94 for piroxicam (Feldene, Pfizer); and 14.54 for ketorolac (Toradol, Roche Pharmaceuticals).

NSAIDs with a longer plasma half-life or extended-release formulations and those that inhibited both COX-1 and COX-2 were associated with a higher risk of upper GI bleeding/perforation.

“All NSAIDs share an increased risk of serious complications in the upper GI tract such as bleeding,” Luis Alberto García Rodríguez, MD, research leader and director of CEIFE – the Spanish Centre for Pharmacoepidemiologic Research in Madrid, told Formulary. “Yet, some present a greater risk than others as used in daily practice. We were able to show that one of the predictors of increased risk is a marked inhibition of two isozymes (COX-1 and COX-2) in the GI tract. Also, NSAIDs with long half-lives, or delivered as slow-release formulations, as well as NSAIDs taken at high dose will result in greater risk of developing these complications.”

NSAIDs with short half-life and used at low daily dose, such as ibuprofen, have a smaller risk of upper GI bleeding, Dr. Rodríguez said. NSAIDs with long half-life and potent inhibition of both cyclooxigenase, such as piroxicam, carry the greatest risk. NSAIDs interfering little with the inhibition of COX-1 carry a smaller risk such as celecoxib.

“Beyond the risk intrinsic to NSAIDs, old age and a history of peptic ulcer are two other major factors increasing the risk of upper GI bleeding,” he said.

One of the study’s authors disclosed financial relationships with the pharmaceutical industry.