Beyond Statistical Significance: Clinical Relevance of NPAR in Stroke Prediction

Dear Editor: We read with interest the article by Wang et al. 1 examining the association between the neutrophil percentage-to-albumin ratio (NPAR) and first stroke risk in patients with hypertension, based on data from the China Stroke Primary Prevention Trial (CSPPT). The authors should be commended for leveraging a large, well-characterized cohort and for highlighting potential sex-specific inflammatory mechanisms. However, several methodological and interpretative issues warrant further discussion before NPAR can be considered a clinically meaningful biomarker for primary stroke prevention. A central concern relates to the biological interpretation of NPAR as a stable inflammatory marker. NPAR combines neutrophil percentage, a labile parameter influenced by acute infections, stress, and medications, with serum albumin, which is strongly affected by nutritional status, hepatic function, and chronic disease burden. Hypoalbuminemia is increasingly regarded as a marker of frailty and comorbidity rather than inflammation per se, which raises the possibility that NPAR partly reflects global vulnerability instead of a specific inflammatory pathway 2. Adjustment for classical confounders may therefore be insufficient to isolate an independent inflammatory signal. In addition, the observed threshold-type association, with similar hazard ratios across the upper three quartiles, challenges a dose–response interpretation. While the authors propose biological saturation of inflammatory pathways, an alternative explanation is misclassification arising from quartile-based categorization of a continuous variable. Modeling NPAR using restricted cubic splines or time-varying analyses could have clarified whether the relationship is genuinely nonlinear or driven by residual confounding and regression dilution bias, a well-recognized issue in biomarker epidemiology 3. The reported sex-specific association also requires cautious interpretation. Women in the cohort differed substantially from men with respect to smoking status, homocysteine levels, and baseline cardiovascular risk profile. These differences may modify the apparent contribution of inflammatory markers without implying a true biological interaction. Prior studies have shown that sex differences in stroke risk are often attenuated after comprehensive adjustment for competing risk factors and socioeconomic variables, which were not fully explored in the present analysis 4. Finally, the clinical utility of NPAR remains uncertain. The study does not address whether adding NPAR to established stroke risk models improves discrimination, calibration, or reclassification. Without evidence of incremental prognostic value, the routine use of NPAR risks expanding biomarker panels without tangible benefit for decision-making. Future studies should focus on longitudinal changes in NPAR and formal comparisons with established inflammatory markers such as C-reactive protein 5. Sincerely, All of the authors contributed planning, writing, and revision. The authors have nothing to report. The authors declare no conflicts of interest. No new data was generated or analyzed in support of this letter to the editor.