Background: “Triple whammy” (TW) refers to the simultaneous use of diuretics, renin-angiotensin-aldosterone system inhibitors and nonsteroidal anti-inflammatory drugs (NSAIDs). To date, the risk of developing acute kidney injury (AKI) associated to this combination has not been deeply investigated. The objectives are to analyze the incidence of AKI associated to the exposure to “triple whammy” including all NSAIDs versus non-exposure to this combination. Secondarily, the risk of hospitalization, severe adverse events, requirement of renal replacement therapy and mortality will be assessed. Also, the incidence of AKI associated to the exposure to “triple whammy” versus non-exposure will be analyzed, including only metamizole as NSAID. Methods: A systematic literature search of intervention studies and analytical observational studies will be conducted in the Cochrane Library, Medline and EMBASE, among others. AKI 12 months after the last prescription of the triple combination will be the main outcome. Relative frequencies, risk of bias and certainty of evidence will be analyzed. Additionally, sensitivity and subgroup analyses will be performed. Results: Once this systematic review has been completed, the results are expected to provide an estimate of the risk associated with this triple combination and the renal variables, in addition to new guidance on the renal treatment of patients potentially receiving triple therapy. Conclusions: This is intended to be the first systematic review of observational studies to analyse TW combination and AKI's risk based on well-validated epidemiological databases exploring drug safety issues.

Background: “Triple whammy” (TW) refers to the simultaneous use of diuretics, renin-angiotensin-aldosterone system inhibitors and nonsteroidal anti-inflammatory drugs (NSAIDs). To date, the risk of developing acute kidney injury (AKI) associated to this combination has not been deeply investigated. The objectives are to analyze the incidence of AKI associated to the exposure to “triple whammy” including all NSAIDs versus non-exposure to this combination. Secondarily, the risk of hospitalization, severe adverse events, requirement of renal replacement therapy and mortality will be assessed. Also, the incidence of AKI associated to the exposure to “triple whammy” versus non-exposure will be analyzed, including only metamizole as NSAID. Methods: A systematic literature search of intervention studies and analytical observational studies will be conducted in the Cochrane Library, Medline and EMBASE, among others. AKI 12 months after the last prescription of the triple combination will be the main outcome. Relative frequencies, risk of bias and certainty of evidence will be analyzed. Additionally, sensitivity and subgroup analyses will be performed. Results: Once this systematic review has been completed, the results are expected to provide an estimate of the risk associated with this triple combination and the renal variables, in addition to new guidance on the renal treatment of patients potentially receiving triple therapy. Conclusions: This is intended to be the first systematic review of observational studies to analyse TW combination and AKI's risk based on well-validated epidemiological databases exploring drug safety issues.

Aims: “Triple whammy” (TW) refers to the concomitant use of diuretics, renin‐angiotensin‐aldosterone system inhibitors (RAASI) and non‐steroidal anti‐inflammatory drugs (NSAIDs). The aim of this article is to analyse the association between TW exposure and acute kidney injury (AKI), among other morbi‐mortality outcomes. Methods: We included studies published up to August 2023 in the Cochrane Library, Medline or EMBASE, among others. The risk of AKI within 12 months after TW vs . not exposed to TW was the main outcome. Results: We included five case–control studies, involving 410 130 participants. The risk of AKI was significantly higher among those exposed to TW vs . not exposed (odds ratio [OR] 2.01, 95% confidence interval [CI] 1.30–3.10; four studies; I ² : 90%; low certainty of evidence). Three studies provided data on all‐cause mortality, not showing a significantly higher risk with TW exposure (very low certainty of evidence). Conclusion: The available evidence reveals that TW may lead to a significantly higher risk of AKI and related hospitalizations, with no detrimental effect on mortality.

Introduction: The pandemic caused by SARS-CoV-2 has put the global scientific community in an accelerated pace of research for an effective treatment for COVID-19. Objective: To identify and evaluate drugs in Latin American protocols of pharmacological treatment for COVID-19. Method: The evidence and mega trial results available to date on the most frequent medications are analyzed. Results: The most common drugs in national protocols are hydroxychloroquine, lopinavir/ritonavir, and remdesivir. None of the drugs that collect the most data from clinical studies, with the except for dexamethasone in a small subgroup of patients, so far showed significant differences in mortality. Conclusions: The emerging situation of COVID-19 has determined hasty and controversial decision-making based on questionable and/or low-quality studies. This highlights the provisional nature of the information and the possibility of generating changes as more results become available. Advance medication authorization exposes a known problem. Although regulatory agility is required at this time, speed should not overlap with basic ethical standards and trust in evidence. TÍTULO PT: Tratamento farmacológico para COVID-19 em protocolos latinoamerica: uma revisão narrativa da eficácia e da segurança Introducción: La pandemia causada por el SARS-Cov-2 ha puesto a la comunidad científica mundial en ritmo acelerado de investigación y busca por un tratamiento efectivo para COVID-19. Objetivo: Identificar y evaluar medicamentos en protocolos latinoamericanos de tratamiento farmacológico para el COVID-19. Método: Se analiza la evidencia y resultados de mega ensayo disponibles hasta la fecha sobre los medicamentos más frecuentes. Resultados: Los medicamentos más frecuentes en protocolos nacionales son hidroxicloroquina, lopinavir/ritonavir y remdesivir. Ninguno de los medicamentos que recopilan mayor cantidad de datos provenientes de estudios clínicos, a excepción de la dexametasona en un subgrupo reducido de pacientes, mostró, hasta el momento, diferencias significativas en la mortalidad. Conclusión: La situación emergente de la COVID-19 ha determinado la toma de decisiones apresuradas y controversiales con base a estudios cuestionables y/o de baja calidad. Esto pone de relieve el carácter provisorio de la información y la posibilidad de generar cambios a medida que se dispongan de más resultados. La autorización anticipada de medicamentos expone un problema conocido. A pesar de que la agilidad regulatoria es necesaria en este momento, la velocidad no debe sobreponerse a los patrones básicos éticos y de confianza en la evidencia. Título PT: Tratamento farmacológico para COVID-19 em protocolos Latinoamérica: Uma revisão narrativa da eficácia e da segurança Introducción: La pandemia causada por el SARS-Cov-2 ha puesto a la comunidad científica mundial en ritmo acelerado de investigación y busca por un tratamiento efectivo para COVID-19. Objetivo: Identificar y evaluar medicamentos en protocolos latinoamericanos de tratamiento farmacológico para el COVID-19. Método: Se analiza la evidencia y resultados de mega ensayo disponibles hasta la fecha sobre los medicamentos más frecuentes. Resultados: Los medicamentos más frecuentes en protocolos nacionales son hidroxicloroquina, lopinavir/ritonavir y remdesivir. Ninguno de los medicamentos que recopilan mayor cantidad de datos provenientes de estudios clínicos, a excepción de la dexametasona en un subgrupo reducido de pacientes, mostró, hasta el momento, diferencias significativas en la mortalidad. Conclusiones: La situación emergente de la COVID-19 ha determinado la toma de decisiones apresuradas y controversiales con base en estudios cuestionables y/o de baja calidad. Esto pone de relieve el carácter provisorio de la información y la posibilidad de generar cambios a medida que se dispongan de más resultados. La autorización anticipada de medicamentos expone un problema conocido. A pesar de que la agilidad regulatoria es necesaria en este momento, la velocidad no debe sobreponerse a los patrones básicos éticos y de confianza en la evidencia.

The concurrent use of (a) diuretics, (b) renin–angiotensin–aldosterone system inhibitors (RAASIs), and (c) non-steroidal anti-inflammatory drugs (NSAIDs) or metamizole, known as the triple whammy (TW) combination, increases the risk of acute kidney injury (AKI). This study compared TWs including metamizole versus NSAIDs regarding hospitalisation for AKI, need for renal replacement therapy (RRT), and all-cause mortality during hospitalisation. Serum creatinine (sCr) and estimated glomerular filtration rate (eGFR) changes in the first year after TW initiation were also assessed. A nested case–control study was conducted within a cohort of adults receiving TW therapy (2009–2018). Logistic regression models analysed the associations between TW type and outcomes. Among 65,077 individuals (mean age 79.7 years; 26.3% male), TW including an NSAID was associated with a lower risk of AKI-related hospitalisation [adjusted odds ratio (aOR) 0.81, 95%CI 0.74–0.87] and all-cause mortality (aOR 0.64, 95%CI 0.49–0.82) compared to TW including metamizole. No significant differences were found in other variables. These findings suggest that TW including an NSAID may reduce the risk of AKI-related hospitalisation and mortality compared to TW including metamizole, although kidney function parameters remained unaffected. Further research is needed to confirm these results.