Coste-efectividad de la polipíldora CNIC frente a los monocomponentes separados en prevención secundaria cardiovascular en España / Cost-effectiveness of the CNIC-Polypill versus separate monocomponents in cardiovascular secondary prevention in Spain

Introducción y objetivos A pesar de los avances en el tratamiento, la enfermedad cardiovascular es la segunda causa de muerte en España. El objetivo de este estudio fue determinar el coste-efectividad de la estrategia polipíldora CNIC (ácido acetilsalicílico 100mg, atorvastatina 20/40mg, ramipril 2,5/5/10mg) comparada con los mismos monocomponentes por separado para la prevención secundaria de eventos cardiovasculares recurrentes en adultos en España. Materiales y métodos Se adaptó un modelo Markov considerando 4 estados de salud (estable, evento cardiovascular adverso mayor posterior, ictus isquémico posterior y muerte) y la ecuación de riesgo SMART con un horizonte temporal de toda la vida desde la perspectiva del Sistema Nacional de Salud español. La estrategia polipíldora CNIC se comparó con monocomponentes en una cohorte hipotética de 1.000 pacientes en prevención secundaria.Los datos de efectividad, epidemiológicos, de costes y de utilidades se obtuvieron del estudio NEPTUNO, de bases de datos oficiales y de la literatura. Los resultados fueron los costes (en euros de 2021) por año de vida (AV) ganados y por años de vida ajustados por calidad (AVAC) ganados. Se aplicó una tasa de descuento del 3%. Se realizaron análisis de sensibilidad determinísticos univariantes y probabilísticos para evaluar la solidez del modelo. Resultados La estrategia polipíldora CNIC, en prevención secundaria, produce más ganancias de AV (13,22) y AVAC (11,64) a un coste inferior que los monocomponentes. La polipíldora CNIC es dominante y ahorra 280,68euros por paciente en comparación con los monocomponentes por separado. El análisis de sensibilidad probabilístico muestra que el 82,4% de las simulaciones están por debajo del umbral de 25.000euros por AVAC ganado (AU)

Introduction and objectives Despite advances in treatment, cardiovascular disease is the second leading cause of death in Spain. The objective of this study was to determine the cost-effectiveness of the CNIC-Polypill strategy (acetylsalicylic acid 100mg, atorvastatin 20/40mg, ramipril 2.5/5/10mg) compared with the same separate monocomponents for the secondary prevention of recurrent cardiovascular events in adults in Spain. Materials and methods A Markov cost-utility model was adapted considering four health states (stable, subsequent major adverse cardiovascular event, subsequent ischemic stroke and death) and the SMART risk equation over a lifetime horizon from the perspective of the Spanish National Healthcare System. The CNIC-Polypill strategy was compared with monocomponents in a hypothetical cohort of 1000 secondary prevention patients. Effectiveness, epidemiological, cost and utilities data were obtained from the NEPTUNO study, official databases and literature. Outcomes were costs (in 2021euros) per life-year (LY) and quality-adjusted LY (QALY) gained. A 3% discount rate was applied. Deterministic one-way and probabilistic sensitivity analyses evaluated the robustness of the model. Results The CNIC-Polypill strategy in secondary prevention results in more LY (13.22) and QALY (11.64) gains at a lower cost than monocomponents. The CNIC-Polypill is dominant and saves €280.68 per patient compared with monocomponents. The probabilistic sensitivity analysis shows that 82.4% of the simulations are below the threshold of €25,000 per QALY gained. Conclusions The CNIC-Polypill strategy in secondary cardiovascular prevention is cost-effective compared with the same separate monocomponents, resulting in a cost-saving strategy to the Spanish National Healthcare System (AU)

[Influence of Loading Dose Of Atorvastatin on the Risk of Contrast-Induced Nephropathy in Patients With ST-Segment Elevation Myocardial Infarction].

Aim      This retrospective cohort study focused on evaluating the incidence of contrast-induced nephropathy (CIN) associated with administration of an atorvastatin loading dose (80 mg) prior to invasive coronary angiography (CAG) in patients with ST-segment elevation myocardial infarction (STEMI).Material and methods  This retrospective cohort study included 386 patients with STEMI. The patients were divided into two groups: intervention group (n=118) and control group (n=268). Patients in the intervention group, at the stage of admission to the catheterization laboratory, were administered a loading dose of atorvastatin (80 mg, p.o.) immediately before access (introducer placement). The endpoints were development of CIN, which was determined by increased serum creatinine 48 h following the intervention by at least 25% (or 44 µmol/l) of baseline value. In addition, in-hospital mortality and incidence of CIN resolution were assessed. To adjust the groups for dissimilar characteristics, a "pseudorandomization" method was used by comparing propensity scores.Results The incidence of CIN was significantly lower in the intervention group than in the control group (10.5 % vs. 24.4 %; p=0.016) with the odds for the CIN development lower than in the control group (odds ratio (OR) 0.36; 95 % confidence interval (CI), 0.16-0.85). Creatinine concentrations returned to the baseline value in 7 days more frequently than in the control group (66.3 % vs. 50.6 %, respectively; OR, 1.92; 95 % CI, 1.04-3.56; p=0.037). In-hospital mortality was higher in the control group but did not differ significantly between the groups.Conclusion      ~Administration of atorvastatin 80 mg to STEMI patients immediately before CAG was associated with a reduced risk of CIN and a higher likelihood of serum creatinine returning to the values at admission by day 7.

Treat-to-Target or High-Intensity Statin in Patients With Coronary Artery Disease: A Randomized Clinical Trial.

Importance: In patients with coronary artery disease, some guidelines recommend initial statin treatment with high-intensity statins to achieve at least a 50% reduction in low-density lipoprotein cholesterol (LDL-C). An alternative approach is to begin with moderate-intensity statins and titrate to a specific LDL-C goal. These alternatives have not been compared head-to-head in a clinical trial involving patients with known coronary artery disease. Objective: To assess whether a treat-to-target strategy is noninferior to a strategy of high-intensity statins for long-term clinical outcomes in patients with coronary artery disease. Design, Setting, and Participants: A randomized, multicenter, noninferiority trial in patients with a coronary disease diagnosis treated at 12 centers in South Korea (enrollment: September 9, 2016, through November 27, 2019; final follow-up: October 26, 2022). Interventions: Patients were randomly assigned to receive either the LDL-C target strategy, with an LDL-C level between 50 and 70 mg/dL as the target, or high-intensity statin treatment, which consisted of rosuvastatin, 20 mg, or atorvastatin, 40 mg. Main Outcomes and Measures: Primary end point was a 3-year composite of death, myocardial infarction, stroke, or coronary revascularization with a noninferiority margin of 3.0 percentage points. Results: Among 4400 patients, 4341 patients (98.7%) completed the trial (mean [SD] age, 65.1 [9.9] years; 1228 females [27.9%]). In the treat-to-target group (n = 2200), which had 6449 person-years of follow-up, moderate-intensity and high-intensity dosing were used in 43% and 54%, respectively. The mean (SD) LDL-C level for 3 years was 69.1 (17.8) mg/dL in the treat-to-target group and 68.4 (20.1) mg/dL in the high-intensity statin group (n = 2200) (P = .21, compared with the treat-to-target group). The primary end point occurred in 177 patients (8.1%) in the treat-to-target group and 190 patients (8.7%) in the high-intensity statin group (absolute difference, -0.6 percentage points [upper boundary of the 1-sided 97.5% CI, 1.1 percentage points]; P < .001 for noninferiority). Conclusions and Relevance: Among patients with coronary artery disease, a treat-to-target LDL-C strategy of 50 to 70 mg/dL as the goal was noninferior to a high-intensity statin therapy for the 3-year composite of death, myocardial infarction, stroke, or coronary revascularization. These findings provide additional evidence supporting the suitability of a treat-to-target strategy that may allow a tailored approach with consideration for individual variability in drug response to statin therapy. Trial Registration: ClinicalTrials.gov Identifier: NCT02579499.

Detecção de microalbuminúria em pacientes diabéticos tipo 2 como preditor de lesão endotelial / Detection of microalbuminuria in type 2 diabetic patients as a predictor of endothelial injury

Introdução: A detecção da microalbuminúria tem sido amplamente estudada como um indicador precoce de lesão endotelial em pacientes com diabetes tipo 2. A microalbuminúria é caracterizada pela presença de níveis aumentados de albumina na urina, refletindo disfunção endotelial e comprometimento da barreira glomerular. A lesão endotelial é um importante fator de risco para o desenvolvimento de complicações vasculares, como doença arterial coronariana, acidente vascular cerebral e insuficiência renal. Objetivos: Investigar a detecção da microalbuminúria através do teste rápido de urina de fita, como um preditor de lesão endotelial em pacientes diabéticos tipo 2. Métodos: Estudo observacional, analítico e transversal, realizado no Ambulatório de Geriatria do Hospital do Servidor Público Municipal de São Paulo. A amostra foi composta por 36 pacientes diabéticos tipo 2, avaliados entre dezembro de 2022 e abril de 2023. Todos os pacientes consentiram e assinaram o Termo de Consentimento Livre e Esclarecido. Resultados: Perfil composto principalmente por mulheres, com idade média de 76,9 anos e tempo médio de diagnóstico de 12,5 anos. A maioria dos pacientes não apresentava complicações macro ou microvasculares. Entre aqueles com complicações macrovasculares(19,4%), a doença arterial coronariana foi a mais comum. Apenas 8,3% dos pacientes possuíam clearence de creatinina abaixo de 30ml/min e os níveis de albuminuria avaliados pelo teste rápido estavam alterados em 52,8% dos participantes. Conclusão: Embora a microalbuminúria possa ser um indicador importante de lesão endotelial em pacientes diabéticos tipo 2 em trabalhos prévios, nossa pesquisa não conseguiu demonstrar associação com relevância estatística entre presença de complicação macro e microvascular e microalbuminúria, provavelmente devido ao número reduzido de pacientes analisados. Ainda assim, a detecção da microalbuminúria deve ser considerada na avaliação e monitoramento desses pacientes, visando uma intervenção precoce e o controle adequado das complicações vasculares. Palavras-chave: Diabetes Mellitus. Microalbuminúria. Angiopatias Diabéticas. Controle glicêmico. Testes de Função Renal.

Prescription of statins according to the ASCVD estimator at Pablo Arturo Suarez Hospital, March 2021 to February 2022 / Prescripción de estatinas según el estimador ASCVD en el Hospital Pablo Arturo Suárez, marzo 2021 a febrero 2022

Worldwide, the leading cause of death is cardiovascular disease. The study details the prescription of statins at the Pablo Arturo Suarez Hospital in Ecuador between March 2021 and February 2022 following the ASCVD risk scale of the American College of Cardiology and the American Heart Association. There are 563 people in this cross-sectional and retrospective study: 70% women, 30% men, 93.30% mestizos, 48.10% diabetics, 62.30% hypertensives, and 18.70% smokers. 26.10% of all patients received statins, with simvastatin being the most common (96.60%). The mean cardiovascular risk in the general population was 15.52 ± 14.51%, 44.99% of subjects had a risk lower than 7.50%, and 29% had a risk higher than 20%, with a statistically significant difference (p<0.001) according to sex. The study determined that 58.60% of the population received a statin or an inadequate dosage.

A nivel mundial, la principal causa de muerte es la enfermedad cardiovascular. El estudio detalla la prescripción de estatinas en el Hospital Pablo Arturo Suárez de Ecuador entre marzo de 2021 y febrero de 2022, siguiendo la escala de riesgo ASCVD del Colegio Americano de Cardiología y la Asociación Americana del Corazón. Son 563 personas en este estudio transversal y retrospectivo: 70% mujeres, 30% hombres, 93.30% mestizos, 48.10% diabéticos, 62.30% hipertensos y 18.70% fumadores. El 26.10% de los pacientes recibía estatinas, siendo la simvastatina la más frecuente (96.60%). El riesgo cardiovascular medio en la población general fue de 15.52 ± 14.51%, el 44.99% de los sujetos tenía un riesgo inferior al 7.50%, y el 29% tenía un riesgo superior al 20%, con una diferencia estadísticamente significativa (p<0.001) según el sexo. El estudio determinó que el 58.60% de la población recibía una estatina o una dosis inadecuada.

Comparison of statins for primary prevention of cardiovascular disease and persistent physical disability in older adults.

PURPOSE: Recent epidemiological evidence has suggested that use of lipid-lowering medications, particularly statins, was associated with reduced cardiovascular disease (CVD) events and persistent physical disability in healthy older adults. However, the comparative efficacy of different statins in this group remains unclear. This study aimed to compare different forms of statins in their associations with CVD and physical disability in healthy older adults. METHODS: This post hoc analysis included data from 5981 participants aged ≥ 70 years (≥ 65 if US minorities; median age:74.0) followed for a median of 4.7 years, who had no prior CVD events or physical disability and reported using a statin at baseline. The incidence of the composite and components of major adverse cardiovascular events and persistent physical disability were compared across different statins according to their type, potency, and lipophilicity using multivariable Cox proportional-hazards models. RESULTS: Atorvastatin was the most used statin type at baseline (37.9%), followed by simvastatin (29.6%), rosuvastatin (25.5%), and other statins (7.0%, predominantly pravastatin). In comparisons of specific statins according to type and lipophilicity (lipophilic vs. hydrophilic statin), observed differences in all outcomes were small and not statistically significant (all p values > 0.05). High-potency statin use (atorvastatin and rosuvastatin) was marginally associated with lower risk of fatal CVD events compared with low-/moderate-potency statin use (hazard ratio: 0.59; 95% confidence interval: 0.35, 1.00). CONCLUSION: There were minimal differences in CVD outcomes and no significant difference in persistent physical disability between various forms of statins in healthy older adults. Future investigations are needed to confirm our results.

Efficacy of high-dose atorvastatin or rosuvastatin loading in patients with acute coronary syndrome undergoing percutaneous coronary intervention: a meta-analysis of randomized controlled trials with GRADE qualification of available evidence.

PURPOSE: We aimed to summarize current evidence regarding the impact of a high-dose statin loading before percutaneous coronary intervention (PCI) on short-term outcomes in patients presenting with the acute coronary syndrome (ACS). METHODS: This meta-analysis was based on a search of the MEDLINE, Cochrane Central Register of Controlled Trials, Ovid Journals, and SCOPUS for randomized controlled trials that compared high-dose atorvastatin or rosuvastatin with no or low-dose statin administered before planned PCI in statin-naive patients with ACS. The primary endpoints were major adverse cardiovascular and cerebrovascular events (MACCE), myocardial infarction (MI), and all-cause mortality at 30 days. Prespecified subanalyses were performed with respect to statin and ACS type. RESULTS: A total of eleven trials enrolling 6291 patients were included, of which 75.4% received PCI. High-dose statin loading was associated with an overall 43% relative risk (RR) reduction in MACCE at 30 days (RR 0.57, 95% CI 0.41-0.77) in whole ACS population. This effect was primarily driven by the 39% reduction in the occurrence of MI (RR 0.61, 95% CI 0.46-0.80). No significant effect on all-cause mortality reduction was observed (RR 0.92, 95% CI 0.67-1.26). In the setting of ST-elevation myocardial infarction (STEMI), atorvastatin loading was associated with a 33% reduction in MACCE (RR 0.67, 95% CI 0.48-0.94), while in non-ST-elevation myocardial infarction ACS (NSTE-ACS), rosuvastatin loading was associated with 52% reduction in MACCE at 30 days (RR 0.48, 95% CI 0.34-0.66). The level of evidence as qualified with GRADE was low to high, depending on the outcome. CONCLUSION: A high-dose loading of statins before PCI in patients with ACS reduces MACCE and reduces the risk of MI with no impact on mortality at 30 days. Atorvastatin reduces MACCE in STEMI while rosuvastatin reduces MACCE in NSTE-ACS at 30 days.

The effects of atorvastatin on emotional processing, reward learning, verbal memory and inflammation in healthy volunteers: An experimental medicine study.

BACKGROUND: Growing evidence from clinical trials and epidemiological studies suggests that statins can have clinically significant antidepressant effects, potentially related to anti-inflammatory action on several neurobiological structures. However, the underlying neuropsychological mechanisms of these effects remain unexplored. AIMS: In this experimental medicine trial, we investigated the 7-day effects of the lipophilic statin, atorvastatin on a battery of neuropsychological tests and inflammation in healthy volunteers. METHODS: Fifty healthy volunteers were randomised to either 7 days of atorvastatin 20 mg or placebo in a double-blind design. Participants were assessed with psychological questionnaires and a battery of well-validated behavioural tasks assessing emotional processing, which is sensitive to putative antidepressant effects, reward learning and verbal memory, as well as the inflammatory marker, C-reactive protein. RESULTS: Compared to placebo, 7-day atorvastatin increased the recognition (p = 0.006), discriminability (p = 0.03) and misclassifications (p = 0.04) of fearful facial expression, independently from subjective states of mood and anxiety, and C-reactive protein levels. Otherwise, atorvastatin did not significantly affect any other psychological and behavioural measure, nor peripheral C-reactive protein. CONCLUSIONS: Our results reveal for the first time the early influence of atorvastatin on emotional cognition by increasing the processing of anxiety-related stimuli (i.e. increased recognition, discriminability and misclassifications of fearful facial expression) in healthy volunteers, in the absence of more general effects on negative affective bias. Further studies exploring the effects of statins in depressed patients, especially with raised inflammatory markers, may clarify this finding and inform future clinical trials.

Effects of Low-Dose Atorvastatin on the Peripheral Blood Mononuclear Cell Secretion of Angiogenic Factors in Type 2 Diabetes.

The aim of this study was to investigate the influence of statins on the secretion of angiogenesis mediators by the peripheral blood mononuclear cells (PBMCs) derived from patients suffering from type 2 diabetes. The study group comprised 30 participants and included: 10 statin-treated patients with diabetes, 10 statin-free diabetic subjects, and 10 statin-free non-diabetic individuals. PBMCs isolated from the blood were cultured in vitro in standard conditions and in an environment mimicking hyperglycemia. Culture supernatants were evaluated for VEGF, MCP-1, Il-10, and Il-12 by flow cytometry using commercial BDTM. Cytometric Bead Array tests. The secretion of VEGF, MCP-1 and Il-12 by PBMCs, cultured both in standard and hyperglycemic conditions, was significantly lower in the statin-treated patients with type 2 diabetes in comparison with the statin-free diabetic patients. Conversely, the secretion of Il-10 was higher in the statin-treated than in the statin-free diabetic patients. VEGF, MCP-1 and Il-12 levels in PBMCs supernatants from the glucose-containing medium were higher than those from the standard medium in each of the diabetic groups. The results of the study suggest that statins in low doses exhibit an antiangiogenic activity, reducing the secretion of potent proangiogenic factors, such as VEGF and MCP-1, and increasing the secretion of antiangiogenic Il-10 by PBMCs, also under hyperglycemic conditions characteristic for type 2 diabetes.

Protective effects of atorvastatin and rosuvastatin on 3,4-methylenedioxymethamphetamine (MDMA)-induced spatial learning and memory impairment.

3,4-Methylenedioxymethamphetamine (MDMA) or "Ecstasy", which has been used for recreational purposes, is shown to impair memory and brain functions. Statins, beyond their efficient cholesterol-lowering impact through inhibition of HMG-COA reductase enzyme, possess multiple actions referred to as pleiotropic effects. In this regard, we aimed to investigate the neuroprotective effects of atorvastatin and rosuvastatin on MDMA-induced neurotoxicity. Adult male Wistar rats received atorvastatin (5, 10, and 20 mg/kg; orally) and rosuvastatin (5, 10, 20 mg/kg; orally) for 21 consecutive days. Then, spatial memory and learning were evaluated by Morris water maze (MWM) test. Rats were intraperitoneally injected with MDMA (2.5, 5, and 10 mg/kg) 30 min before the first training session in 4 training days of MWM task. Afterward, rats were euthanized and their hippocampuses were dissected to evaluate reactive oxygen species (ROS) production, lipid peroxidation (LPO), and caspase-3 and -9 activities. Our findings showed that MDMA (5 and 10 mg/kg) significantly impaired spatial memory functions and dramatically increased ROS production, LPO, and caspase-3 and -9 activities compared to control. Also, atorvastatin (5, 10, and 20 mg/kg) and rosuvastatin (20 mg/kg) significantly improved memory performances and inhibited the elevation of ROS, LPO, and caspase-3 and -9 activities induced by MDMA. In conclusion, the results indicated that MDMA-induced cognitive impairment is followed by oxidative stress and activation of apoptotic pathways in the hippocampus. However, atorvastatin and rosuvastatin suppressed these deleterious consequences of MDMA and revealed protective effects against activation of pathways leading to cell damage.

Study of the Possible Alleviated Role of Atorvastatin on Irinotecan-Induced Lingual Mucosal Damage: Histological and Molecular Study.

BACKGROUND: Oral mucositis is the most debilitating and troublesome adverse effect of irinotecan (CPT-11) treatment. It adversely affects the patient quality of life. The aim of this work was to study the histological, immunohistochemical, and molecular changes in the oral mucosa by CPT-11 and the possible alleviated role of atorvastatin. METHODS: Rats were randomly divided into control, CPT-11-treated group, and CPT-11+ atorvastatin-treated group. At the end of the experiment, the anterior two-thirds of the tongue was dissected out and divided into two parts: one part for light microscopic examination and the second for molecular study. RESULTS: CPT-11-treated group revealed loss of normal mucosal organization, areas of ulceration and inflammation, and loss of architecture of lingual papillae. A significant decrease in immunohistochemical and molecular gene expression of Ki-67 and antiapoptotic Bcl-2 levels was observed. A significant increase in NF-κB immunohistochemical and mRNA gene expression level and a nonsignificant increase in Nrf2 gene expression were detected. Coadministration of atorvastatin showed remarkable improvement in the histopathological picture with a significant increase in Ki-67 and Bcl-2, a significant decrease in NF-κB protein and gene expression, and a significant increase in Nrf2 gene expression. CONCLUSION: Atorvastatin substantially attenuates CPT-11-induced oral mucositis through the initiation of the antiapoptotic gene, modulation of the inflammatory, and antioxidant gene expression.

Development of the Binary and Ternary Atorvastatin Solid Dispersions: In Vitro and In Vivo Investigations.

The object of this study was to prepare binary and ternary solid dispersions of atorvastatin (ATR) by the melting method using PEGs and poloxamer 188 (P188) as the carriers, singly and in combination with each other. Dissolution behavior, solubility studies, X-ray diffractometry, differential scanning calorimetry, and Fourier transform infrared spectroscopy were studied. Furthermore, antihyperlipidemic activities of formulations were compared to each other by serum lipid analyses in hyperlipidemic rats. Based on the results, the highest dissolution efficiency (DE30 = 83%) was obtained by binary systems consisted of ATR and P188. Also, no additional improvement was observed in dissolution properties of ternary solid dispersion formulations. Solubility studies showed enhancement of ATR phase solubility in water and a buffer solution containing P188 or PEG 10000. Furthermore, saturated solubility of ATR in the buffer solution improved more than twofold in the optimized ternary dispersion system. No crystalline changes occurred in PEG-based formulations; meanwhile, partial amorphization happened in the ATR-P188 combination. Finally, the in vivo study in hyperlipidemic rats exhibited a rapid decrease in the lipid profile of all formulations compared to ATR (after 7 days). Moreover, reduction of serum triglycerides and total cholesterol on the 14th day in the ATR group (p value < 0.01) was less than solid dispersion or physical mixing preparations (p value < 0.001). These findings proved the appropriate influence of using PEG and P188 in solid dispersion systems for the improvement of the therapeutic efficiency of ATR.

Atorvastatin facilitates chemotherapy effects in metastatic triple-negative breast cancer.

BACKGROUND: Metastatic triple-negative breast cancer (mTNBC) is treated mainly with chemotherapy. However, resistance frequently occurs as tumours enter dormancy. Statins have been suggested as effective against cancer but as they prolong and promote dormancy, it is an open question of whether the concomitant use would interfere with chemotherapy in primary and mTNBC. We examined this question in animal models and clinical correlations. METHODS: We used a xenograft model of spontaneous metastasis to the liver from an ectopic tumour employing a mTNBC cell line. Atorvastatin was provided to sensitise metastatic cells, followed by chemotherapy. The effects of statin usage on outcomes in women with metastatic breast cancer was assessed respectively by querying a database of those diagnosed from 1999 to 2019. RESULTS: Atorvastatin had limited influence on tumour growth or chemotherapy effects in ectopic primary tumours. Interestingly, atorvastatin was additive with doxorubicin (but not paclitaxel) when targeting liver metastases. E-cadherin-expressing, dormant, breast cancer cells were resistant to the use of either statins or chemotherapy as compared to wild-type cells; however, the combination of both did lead to increased cell death. Although prospective randomised studies are needed for validation, our retrospective clinical analysis suggested that patients on statin treatment could experience prolonged dormancy and overall survival; still once the tumour recurred progression was not affected by statin use. CONCLUSION: Atorvastatin could be used during adjuvant chemotherapy and also in conjunction with metastatic chemotherapy to reduce mTNBC cancer progression. These preclinical data establish a rationale for the development of randomised studies.

[18F]Atorvastatin Pharmacokinetics and Biodistribution in Healthy Female and Male Rats.

Statins are 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors that are widely used to prevent cardiovascular diseases. However, a series of pleiotropic mechanisms have been associated with statins, particularly with atorvastatin. Therefore, the assessment of [18F]atorvastatin kinetics with positron emission tomography (PET) may elucidate the mechanism of action of statins and the impact of sexual dimorphism, which is one of the most debated interindividual variations influencing the therapeutic efficacy. [18F]Atorvastatin was synthesized via a previously optimized 18F-deoxyfluorination strategy, used for preclinical PET studies in female and male Wistar rats (n = 7 for both groups), and for subsequent ex vivo biodistribution assessment. PET data were fitted to several pharmacokinetic models, which allowed for estimating relevant kinetic parameters. Both PET imaging and biodistribution studies showed negligible uptake of [18F]atorvastatin in all tissues compared with the primary target organ (liver), excretory pathways (kidneys and small intestine), and stomach. Uptake of [18F]atorvastatin was 38 ± 3% higher in the female liver than in the male liver. The irreversible 2-tissue compartment model showed the best fit to describe [18F]atorvastatin kinetics in the liver. A strong correlation (R2 > 0.93) between quantitative Ki (the radiotracer's unidirectional net rate of influx between compartments) and semi-quantitative liver's SUV (standard uptake value), measured between 40 to 90 min, showed potential to use the latter parameter, which circumvents the need for blood sampling as a surrogate of Ki for monitoring [18F]atorvastatin uptake. Preclinical assays showed faster uptake and clearance for female rats compared to males, seemingly related to a higher efficiency for exchanges between the arterial input and the hepatic tissue. Due to the slow [18F]atorvastatin kinetics, equilibrium between the liver and plasma concentration was not reached during the time frame studied, making it difficult to obtain sufficient and accurate kinetic information to quantitatively characterize the radiotracer pharmacokinetics over time. Nevertheless, the reported results suggest that the SUV can potentially be used as a simplified measure, provided all scans are performed at the same time point. Preclinical PET-studies with [18F]atorvastatin showed faster uptake and clearance in female compared to male rats, apparently related to higher efficiency for exchange between arterial blood and hepatic tissue.

Studying the Effect of Taking Statins before Infection in the Severity Reduction of COVID-19 with Machine Learning.

Statins can help COVID-19 patients' treatment because of their involvement in angiotensin-converting enzyme-2. The main objective of this study is to evaluate the impact of statins on COVID-19 severity for people who have been taking statins before COVID-19 infection. The examined research patients include people that had taken three types of statins consisting of Atorvastatin, Simvastatin, and Rosuvastatin. The case study includes 561 patients admitted to the Razi Hospital in Ghaemshahr, Iran, during February and March 2020. The illness severity was encoded based on the respiratory rate, oxygen saturation, systolic pressure, and diastolic pressure in five categories: mild, medium, severe, critical, and death. Since 69.23% of participants were in mild severity condition, the results showed the positive effect of Simvastatin on COVID-19 severity for people that take Simvastatin before being infected by the COVID-19 virus. Also, systolic pressure for this case study is 137.31, which is higher than that of the total patients. Another result of this study is that Simvastatin takers have an average of 95.77 mmHg O2Sat; however, the O2Sat is 92.42, which is medium severity for evaluating the entire case study. In the rest of this paper, we used machine learning approaches to diagnose COVID-19 patients' severity based on clinical features. Results indicated that the decision tree method could predict patients' illness severity with 87.9% accuracy. Other methods, including the K-nearest neighbors (KNN) algorithm, support vector machine (SVM), Naïve Bayes classifier, and discriminant analysis, showed accuracy levels of 80%, 68.8%, 61.1%, and 85.1%, respectively.

Atorvastatin induces adrenal androgen downshift in men with prostate cancer: A post Hoc analysis of a pilot adaptive Randomised clinical trial.

BACKGROUND: Prostate cancer (PCa) progression depends on androgen receptor activity. Cholesterol is required for biosynthesis of all steroid hormones, including androgens. Impact of cholesterol-lowering statins on androgens is unknown. We explored atorvastatin influence on serum and prostatic tissue steroidomic profiles (SP) to expose novel pathways for limiting androgen concentration in men with PCa. METHODS: This is a pre-planned post hoc analysis of ESTO-1 pilot randomised, double-blinded, clinical trial. Statin naïve men, scheduled for radical prostatectomy due to localised PCa, were randomised 1:1 to use daily 80 mg of atorvastatin or placebo before the surgery for a median of 28 days. Participants were recruited and treated at the Pirkanmaa Hospital District, Tampere, Finland. 108 of the 158 recruited men were included in the analysis based on sample availability for hormone profiling. Serum and prostatic tissue steroid profiles were determined using liquid chromatography mass spectrometry. Wilcoxon rank sum test and bootstrap confidence intervals (CI) were used to analyse the difference between placebo and atorvastatin arms. FINDINGS: Most serum and prostatic steroids, including testosterone and dihydrotestosterone, were not associated with atorvastatin use. However, atorvastatin use induced serum SP changes in 11-ketoandrostenedione (placebo 960pM, atorvastatin 617.5pM, p-value <0.0001, median difference -342.5; 95% CI -505.23 - -188.98). In the prostatic tissue, atorvastatin was associated with plausible downshift in 11- ketodihydrotestosterone (placebo 25.0pM in 100 mg tissue/1 mL saline, atorvastatin 18.5pM in 100 mg tissue/1 mL saline, p-value 0.027, median difference -6.53; 95% CI -12.8 - -0.29); however, this association diminished after adjusting for multiple testing. No serious harms were reported. INTERPRETATION: Atorvastatin was associated with adrenal androgen downshift in the serum and possibly in the prostate. The finding warrants further investigation whether atorvastatin could improve androgen deprivation therapy efficacy. FUNDING: Funded by grants from the Finnish Cultural Foundation, Finnish Cancer Society, Academy of Finland, and the Expert Responsibility Area of the Tampere University Hospital. CLINICALTRIALS. GOV IDENTIFIER: NCT01821404.

Evaluation of efficacy and safety of combined rosuvastatin and atorvastatin in treating with coronary heart disease: A protocol for systematic review and meta-analysis.

BACKGROUND: Globally, coronary heart disease (CHD) is a primary cause of morbidity leading to disabilities and mortality. Modern clinical practice adopts several pharmacological methods to treat CHD. Angina pectoris refers to sever chest pain due to CHD, it has a profound impact on the wellbeing of patients. Moreover, angina pectoris is a crucial prognosis predictor. The aim of the current study is to evaluate the effectiveness and safeness of using combined rosuvastatin and atorvastatin to treat CHD patients. METHODS: A systematic literature search for articles will be conducted on several electronic databases from their inception to May 2021. The search will include all randomized controlled trials examining the use of rosuvastatin in combination with atorvastatin to treat CHD patients. The databases are as follows: MEDLINE, Web of Science, the Cochrane Library, WanFang database, China National Knowledge Infrastructure, and EMBASE. A couple of authors will independently assess the eligibility, extract study data, and assess the possibility of bias. Moreover, depending on the type of data and heterogeneity of the included studies, either the Mantel-Haensel fixed-effect model or the DerSimonian-Laird random-effect model will be used to estimate the relative risk, mean differences, or standardized mean differences and 95% confidence intervals. All differences in opinion shall be decided by involving an additional author in the discussion. Lastly, the RevMan software (version: 5.3) will be used to perform sensitivity analysis, data synthesis, and risk of bias assessment. RESULTS: The effectiveness and security of using rosuvastatin in combination with atorvastatin to treat CHD patients will be systematically evaluated. CONCLUSION: This study will provide evidence to evaluate the efficacy and security of using a combination of rosuvastatin and atorvastatin to treat CHD patients. ETHICS AND DISSEMINATION: Ethical approval will not be required since it is based on already published data. REGISTRATION NUMBER: DOI 10.17605/OSF.IO/VYBDR (https://osf.io/vybdr/).

Adjuvant Low-dose Statin Use after Radical Prostatectomy: The PRO-STAT Randomized Clinical Trial.

PURPOSE: Statin use is reportedly associated with the risk of prostate cancer, outcomes after treatment, and prostate cancer-specific mortality. We sought to determine the efficacy of adjuvant atorvastatin in prostate cancer after radical prostatectomy. PATIENTS AND METHODS: In this randomized, double-blind trial, we assigned patients with pathologic high-risk prostate cancer to receive either low-dose atorvastatin (20 mg/day, n = 183) or placebo (n = 181) for 1 year after radical prostatectomy. The primary endpoint was the 1-year biochemical recurrence rate. The secondary endpoints included the 5-year biochemical recurrence-free survival and changes in lipid, testosterone, and sex hormone binding globulin levels. RESULTS: From October 2012 through January 2019, a total of 364 patients underwent randomization. Among 59 total primary end points, 30 (16.4%) and 29 (16.0%) occurred in the atorvastatin and placebo groups, respectively. Atorvastatin did not significantly reduce the primary endpoint of 1-year biochemical recurrence [HR, 0.96; 95% confidence interval (CI), 0.58-1.60]. During a median follow-up of 24 months, 131 patients experienced biochemical recurrence (68 in the atorvastatin group and 63 in the placebo group), representing Kaplan-Meier estimated event rates of 24.0% and 25.4% in the atorvastatin and placebo groups, respectively, at 24 months (HR, 1.00; 95% CI, 0.71-1.41). We observed no significant between-group differences in the testosterone and sex hormone binding globulin levels. CONCLUSIONS: Among patients with high-risk pathologic features after radical prostatectomy for prostate cancer, 1-year adjuvant use of atorvastatin was not associated with a lower risk of disease recurrence compared with that for placebo. (ClinicalTrials.gov number, NCT01759836).See related commentary by Murtola and Siltari, p. 4947.