An integrated tool for assessing the modifiable pharmacotherapeutic load of nonsteroidal anti-inflammatory drugs

Background . Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most frequently prescribed drug classes, with a dose-dependent, multidomain profile of adverse reactions. Existing prescribing-appropriateness tools (STOPP/START, Beers criteria) flag the fact of inappropriate prescribing but do not separate the modifiable component of risk from the patient's irreducible vulnerability, and are insensitive to exposure intensity. Objective . To develop a reproducible instrument for measuring the modifiable pharmacotherapeutic burden of NSAIDs across four organ domains, and to establish its structural soundness and transportability as a normative audit measure that guides intervention rather than predicting outcome. Methods . A hierarchical instrument was constructed with a two-level output: an overall burden score and a profile of orthogonal domain residuals. The domain index is assembled multiplicatively from renally individualized exposure, a pharmacodynamic multiplier, and a vulnerability scale; logarithmic transformation separates the modifiable (exposure, interactions) and irreducible (vulnerability) components. Development was performed on a clinical pharmacology audit cohort (n = 200); transportability of measurement properties was tested on an independent intensive-care cohort, MIMIC-IV (n = 38,663), within the COSMIN framework. Results . The overall burden was unidimensional: the first principal component explained 76 % of subindex variance in the development cohort and 83.4 % on external validation. The residual profile was organ-specific across all four domains (own rank correlations 0.19–0.71 versus smaller cross-correlations; bootstrap stability 99–100 %). Patient ranking was invariant to the exposure parameter (rank correlation ≥ 0.98). The "triple whammy" was associated with acute kidney injury (adjusted odds ratio 1.71; 95 % CI 1.56–1.88). Conclusion . A reproducible, externally validated instrument for measuring the modifiable NSAID burden is proposed, separating modifiable risk from patient vulnerability and suitable for targeted audit. The instrument is a normative measure and does not claim to predict individual outcomes; testing effectiveness on outcomes is the task of a prospective study.