BACKGROUND/PURPOSE: Safety studies have shown that risks associated with non-steroidal anti-inflammatory drugs (NSAIDs) are related to dose; however, there is little evidence regarding this dose-toxicity relationship for meloxicam, including in the United States (US). Prior studies assessing the meloxicam dose-toxicity relationship have been limited in sample size, the ability to control adequately for potential confounders and changes in dose over time, and the inclusion of a comprehensive set of adverse event outcomes. This study assessed the relationships between meloxicam dose and risks of gastrointestinal (GI), cardiovascular (CV), and renal events in a commercially insured US population.
METHODS: MarketScan©claims databases (2010-14) were used to analyze the risks of GI (upper GI bleed/perforation [UGIB], uncomplicated ulcer [UU], lower GI bleed [LGIB]), CV (myocardial infarction [MI], stroke, congestive heart failure [CHF], hypertension), and renal events by meloxicam daily dose (DD) category (>7.5mg to ≤15mg [higher dose]; ≤7.5mg [lower dose]) in a cohort of adult new users of meloxicam with osteoarthritis (OA). A separate cohort was created to assess each event. Patients with prior history of GI, CV or renal disease were excluded from the cohort constructed for that event. Hazard ratios (HRs) were estimated using multivariable Cox analyses with DD as a time-dependent covariate. The models controlled for baseline patient demographics and clinical characteristics, selected a priori based on published NSAID analyses and clinical guidance.
RESULTS: In total, 337,260 meloxicam new users (62.5% female; median age at index 59 years) met the initial study inclusion criteria. HRs and 95% confidence intervals are presented in Table 1. Increased risks of GI and CV events were associated with higher versus lower doses of meloxicam. HRs for higher dose (> 7.5 mg to ≤15mg) versus lower dose (≤ 7.5 mg) for MI (1.05), stroke (1.03), hypertension (1.07), UGIB (1.50), UU (1.18), and LGIB (1.10) were above 1.0.
CONCLUSION: In this cohort study, numerically increased risks of CV and GI events were observed with higher doses versus lower doses of meloxicam among adult new users of meloxicam with OA and no prior history of the event. Of note are increased risks of hypertension, an event of substantial clinical importance previously inadequately studied, and upper GI events. These findings support the US Food and Drug Administration (FDA) recommendation to use the lowest effective dose of NSAIDs. This study suggests the importance of studying the effect of meloxicam dose on risks of serious adverse events in a large sample, adequately adjusting for potential confounders, and treating dose as a time-dependent covariate.
