The primary concern for bleeding risk for non-steroidal anti-inflammatory (NSAID) agents is mainly via the inhibition of cyclooxygenase-1 (COX-1) within the gastrointestinal (GI) tract, although COX-2 may also be involved in gastric healing. All NSAIDs have been demonstrated to increase the risk of upper GI complications to varying extents. For example, celecoxib and ibuprofen are considered lower risk for upper GI complications, while ketorolac and piroxicam are considered the highest. The higher-risk agents typically have greater selectivity for COX-1. Higher doses are also associated with increased inhibition of COX-1 and COX-2, which have been linked to an increased risk of GI-related complications compared to lower doses. [1], [2], [3]
Concomitant use of NSAIDs with other medications and how their effects on GI bleeding rates have also been investigated. The combination of antithrombotics and NSAIDs and subsequently increased risk of upper GI bleeding is well established. Randomized trials observing the addition of antithrombotic therapy to low-dose aspirin observed an increased risk of GI bleeding by approximately 2-folds. Suggested management involves proper education, prescription and over-the-counter (OTC) NSAIDs assessment, and minimizing exposure to NSAIDs or recommending a COX-2-specific agent. Gastroprotective agents may also be added to the regimen. [3], [4]
In a 2007 meta-analysis, researchers pooled data to provide an educational update on the current evidence of NSAIDs' efficacy and adverse effects. They determined which NSAIDs are more effective and associated with fewer adverse effects. Of the adverse effects, GI incidences were among the most serious complications of NSAID use. Moreover, recent studies indicated that some NSAIDs are associated with a higher GI risk than others. In terms of risk variation, data showed that ibuprofen has the lowest risk among NSAIDs, while diclofenac and naproxen have intermediate risks, and piroxicam and ketorolac carry the greatest risk (Table 3). However, the advantages of “low-risk” options may be lost at higher doses. Additionally, it was noted that COX-2 inhibitors could be used as an alternative analgesic to decrease the risk of gastrointestinal events. [5]
A 2011 network meta-analysis compared available evidence on the CV safety of NSAIDs. A total of 31 trials (N= 11,6429 patients with more than 115,000 patient-years of follow-up) were included for analysis. Patients were allocated to naproxen, ibuprofen, diclofenac, celecoxib, etoricoxib, rofecoxib, lumiracoxib, or placebo. Compared to placebo, rofecoxib had the highest risk of myocardial infarction (rate ratio [RR] 2.12; 95% credibility interval [CrI] 3.56), whereas etoricoxib had the lowest (RR 0.75; 95 CrI 0.23 to 2.39). Ibuprofen had the highest risk of stroke (RR 3.36; 95% CrI 1.00 to 11.60), whereas rofecoxib had the lowest (RR 1.07; 95% CrI 0.60 to 1.82). Etoricoxib had the highest risk of CV death (RR 4.07; 95% CrI 1.23 to 15.70), and naproxen had the lowest (RR 0.98; 95% CrI 0.41 to 2.37). For the composite of non-fatal myocardial infarction, non-fatal stroke, or CV death, ibuprofen had the highest risk (RR 2.26; 95% CrI 1.11 to 4.89), whereas celecoxib had the lowest risk (RR 1.43; 95% CrI 0.94 to 2.16). Overall, the authors determined that, in general, naproxen seems to be the safest analgesic for patients with osteoarthritis concerning CV safety, but this advantage has to be weighed against GI toxicity and the need for a concomitant prescription of a proton pump inhibitor in many patients. [6]
A 2006 meta-analysis of controlled observational studies compared the risk of serious CV events with individual NSAIDs and COX-2 inhibitors. A total of 17 case-control and 6 cohort studies were included for analysis. Of COX-2 inhibitors, celecoxib was determined to have the lowest risk of serious CV events (risk ratio [RR] 1.06; 95% confidence interval [CI] 0.91 to 1.23). Rofecoxib with a dose > 25 mg/day had the highest risk of serious CV events (RR 2.19; 95% CI 1.64 to 2.91). Of the nonselective NSAIDs, naproxen had the lowest risk of serious CV events (RR 0.97; 95% CI 0.87 to 1.07), and diclofenac had the highest risk (RR 1.40; 95% CI 1.16 to 1.70). [7]