Non‐steroidal anti‐inflammatory drugs and proton‐pump inhibitors vs. cyclo‐oxygenase‐2 selective inhibitors in reducing the risk of recurrent ulcer bleeding in patients with arthritis

Abstract

A history of ulcer bleeding is the single most important risk factor for non-steroidal anti-inflammatory drug (NSAID)-related ulcer complications.1 While the use of cyclo-oxygenase-2 (COX-2) selective NSAIDs decreases the risk of gastrointestinal complications in those not receiving concurrent aspirin therapy, their safety in patients with a prior history of ulcer bleeding is unknown. In a post hoc analysis of patients enrolled in the VIGOR trial, Laine et al.2 did not find a significant safety benefit with the use of the COX-2 selective NSAID rofecoxib compared with the traditional NSAID naproxen in the subgroup of patients with a history of ulcer complications (Figure 1) or in those infected with Helicobacter pylori (Figure 2). It is unclear whether the lack of an advantage of rofecoxib over naproxen in these subgroups indicates a failure of rofecoxib in high-risk patients, was a reflection of the small sample size that was inadequate to detect the difference, or other more complex issues. Prior ulcer complications negate the gastrointestinal sparing effect of rofecoxib. No significant benefit in the risk for complications was seen with the use of a cyclo-oxygenase-2 (COX-2) selective non-steroidal anti-inflammatory drug (NSAID) in those with prior ulcer disease. Adapted from Laine et al.2 Infection with Helicobacter pylori and prior gastrointestinal event negate the gastrointestinal sparing effect of cyclo-oxygenase-2 (COX-2) selective non-steroidal anti-inflammatory drugs (NSAIDs). In those with a clinical upper gastrointestinal event who are H. pylori-positive there was no significant benefit to the use of a COX-2 selective NSAID. Adapted from Laine et al.2 A randomized, double-blind study confirmed the findings of the post hoc analysis – patients treated with COX-2 selective NSAIDs who have a history of ulcer complications are still at-risk for recurrent ulcer bleeding.3 Further, the study observed that in those with a history of recurrent gastrointestinal bleed the risk for recurrence was similar in those treated with either a COX-2 selective NSAID (4.9% within 6 months) or a traditional NSAID plus a proton-pump inhibitors (PPI; 6.4% within 6 months) (Figure 3).4-6 Using the combined end-point of endoscopic and bleeding ulcers, 24% of the patients receiving celecoxib and 31% of those receiving diclofenac plus omeprazole had recurrent ulcers within 6 months.6 These results indicate that neither a COX-2 selective NSAID nor a traditional NSAID plus a PPI completely eliminates the risk of ulcer in very high risk patients. Efficacy of cyclo-oxygenase-2 (COX-2) selective non-steroidal anti-inflammatory drugs (NSAIDs) vs. traditional NSAIDs plus a proton-pump inhibitors (PPI) in reducing the risk of ulcer bleeding in high-risk patients. Those with a recent gastrointestinal bleed have a reduced risk for recurrence when treated with either a traditional NSAID plus a PPI or a COX-2 selective NSAID. What strategies should be considered to reduce the risk for recurrence in a patient with a history of upper gastrointestinal bleeding on NSAIDs who requires ongoing analgesic therapy? Strategies for preventing recurrent as well as new NSAID-related gastrointestinal complications should be based on the patient's individual risk factors. Traditionally, patients with no risk factors (e.g. use of high dose or multiple NSAIDs, age over 60 years, co-morbid illness, etc.) have been considered to be at average risk, those with one or two factors at moderate risk, and those with multiple factors or taking concomitant aspirin, corticosteroids or anticoagulants to be at high risk. The data regarding a history of ulcer bleeding suggests a need for a fourth category – very high risk. Clinically, these individuals should be treated accordingly. Intuitively, the combination of a COX-2 selective NSAID plus co-therapy with either a PPI or misoprostol would be anticipated to provide a high level of gastroprotection, although this approach has not been studied in prospective clinical trials.7 Should a high-risk patient (one with more than two risk factors) be treated with a COX-2 selective NSAID plus a PPI? Among workshop participants, nearly all (94%) strongly agreed (38%) or agreed with reservation (56%) that high risk patients should be treated with a COX-2 selective NSAID plus a PPI. About 6% disagreed with reservation. Does successful eradication of H. pylori obviate the need for PPI treatment in high-risk patients requiring low-dose aspirin? One quarter (25%) of workshop participants strongly disagreed that H. pylori cure obviates the need for PPI treatment in high-risk patients taking low-dose aspirin, an additional 57% disagreed with reservation. Only 12% strongly agreed and 6% agreed with reservation.