Abstract Background Xanthine oxidase inhibitors (XOIs) suppress uric acid production and preserve adenosine triphosphate (ATP) levels, potentially improving cardiovascular outcomes. However, the effects of XOI withdrawal on ATP dynamics and clinical outcomes remain unclear. Purpose To investigate the impact of XOI treatment and withdrawal on mortality in cardiovascular patients and to explore ATP dynamics in a preclinical model. Methods We analysed hospitalised patients (aged 20-90) with acute coronary syndrome or heart failure using the Japanese Registry of All Cardiac and Vascular Diseases (J-ROAD). Patients were categorised into XOI treatment, XOI withdrawal, and non-XOI groups. Multiple logistic regression analysis was performed to adjust for confounding factors. Additionally, we conducted a preclinical study in mice to investigate ATP changes before, during, and after administration of XOIs and uricosuric agents, following the "Principles of laboratory animal care". Mice were randomised into three groups: XOI, uricosuric agent, and control. ATP levels were measured at baseline, during treatment, and post-withdrawal. Results The J-ROAD study included 1,648,891 hospitalised patients. After multiple adjustments, patients with XOI treatment showed significantly lower mortality compared to those without XOI treatment (odds ratio 0.576, 95% CI 0.567-0.587, P.001). In the sensitivity analyses, there was no significant difference in mortality among each XOI medicine (allopurinol, febuxostat, and topiroxostat). In contrast, XOI withdrawal led to significantly higher death rates compared to continuous XOI use (19.8% vs. 0.03%; P.001). In our preclinical mouse study using XOI and uricosuric agents, we observed ATP levels across the three phases of the experiment: at baseline, during treatment, and post-withdrawal. Detailed results from this experimental study will be presented at the conference. Conclusion XOI treatment in cardiovascular patients is associated with significantly reduced mortality, while XOI withdrawal is linked to elevated mortality risk. Our preclinical data demonstrate ATP level changes during treatment with XOI and uricosuric agents across the three phases of the experiment: at baseline, during treatment, and post-withdrawal. These results suggest that maintaining XOI therapy may be crucial for patients with cardiovascular diseases and highlight the potential of ATP-focused treatments. Future studies should explore the optimal duration of XOI treatment and potential strategies to mitigate the effects of XOI withdrawal in high-risk cardiovascular patients.
Kuwabara et al. (Sat,) studied this question.