COVID-19 Pandemic Waves and 2024–2025 Winter Season in Relation to Angiotensin-Converting Enzyme Inhibitors, Angiotensin Receptor Blockers and Amantadine

<b>Background:</b> Early pandemic reports suggested improved outcomes in hypertensive COVID-19 patients treated with angiotensin-converting enzyme inhibitors (ACEI) or amantadine. This study evaluates their impact on disease progression. <b>Methods:</b> We analyzed 55,936 infected patients (March 2020-January 2025) and 2024 hospital admissions within a free-access Barcelona metropolitan health consortium (<i>n</i> = 192,651 as of March 2025). Hospitalizations, stratified by polypharmacy level (nT), were compared via Chi-square tests. ICU admissions and length of stay in hospitalized patients were assessed during the first month of key waves: initial A2a + B3a + B9 (<i>n</i> = 184, March 2020), Delta (<i>n</i> = 158, July 2021), Omicron21K (<i>n</i> = 142, January 2022), and Omicron 24F (<i>n</i> = 8, January 2025). <b>Results:</b> Non-survivors were predominantly aged >60 years (96.3%) in the first wave and >70 years (100%) in Delta/Omicron waves. Post-vaccination, mortality decreased in high-comorbidity groups, though hospitalizations/ICU admissions in younger patients surpassed first-wave levels during Delta. Vaccinated ACEI/ARB-treated patients showed reduced hospitalizations across all polypharmacy groups: OR (noACEI/ACEI) = 1.21 (≥2 nT) to 4.26 (1 nT, <i>p</i> = 0.014); OR (noARB/ARB) = 1.24 (≥8 nT) to 1.74 (2-7 nT, <i>p</i> = 0.01). No hospitalizations occurred in amantadine-treated patients aged <70. Conclusions: These findings suggest a potential protective effect of ACEI, ARBs, and amantadine against severe COVID-19 and support the safety and continuity of these treatments. Multicentric studies incorporating post-COVID syndrome data are needed to validate these observations if hospitalizations persist.