Cardiovascular System and COVID-19

Objective Different hypotheses suggest a contradictory association of statins, angiotensin receptor blockers(ARBs) or angiotensin-converting enzyme(ACE) inhibitors with potential adverse or favorable effects in patients with Coronavirus disease 2019(COVID-19). This study aimed to compare the association of statins, ARB, and ACE inhibitors in COVID-19 and in pneumonia. Design and Method All patients with laboratory-confirmed COVID-19 through April 16, 2020, in Korea were retrieved. We evaluated the association of statins, ARBs, and ACE inhibitors on COVID-19-related mortality within 60 days. Furthermore, a comparison of hazard ratio (HR) was performed between COVID-19 patients and a retrospective cohort of patients hospitalized with pneumonia between January and June 2019 in Korea. Lastly, meta-analysis was performed to compare the results of this study and other reports. Results The median age of the 10,448 COVID-19 patients was 45 years, and statins, ARBs and ACE inhibitors were prescribed in 533 (5.1%), 1,231(11.8%) and 47(0.4%) patients, respectively. As of April 24, 228 patients (2.2%) succumbed to death. After adjusting age, sex, residential area, the history of comorbidities, Cox regression showed significant decrease in HR by 36% associated with statin use (HR 0.635, 95% CI 0.424 - 0.951, p = 0.0274). However, ARBs group showed neutral association (HR 1.034, 95% CI 0.765 - 1.399, p = 0.8270) and ACE inhibitor groups showed insignificant results mainly due to small sample size (HR 0.736, 95% CI 0.314 - 1.726, p = 0.4810). When comparing the HR between COVID-19 patients and a retrospective cohort of patients hospitalized with pneumonia between January and June 2019, the trend of statins and ACE inhibitors showed similar benefit, whereas the protective effect of ARBs observed in the retrospective cohort was lost in the COVID-19 patients. Meta-analysis including the results of this study showed significant benefit of statins and ACE inhibitors, whereas neutral association with ARBs and the mortality. Conclusions Statins were associated with significantly lower mortality of COVID-19, consistent with usual pneumonia patients. While ARBs or ACE inhibitors were not associated with fatal outcome, the possible beneficial effect of ARBs observed in usual pneumonia was attenuated in COVID-19.

Association of statin use with outcomes of patients admitted with COVID-19: an analysis of electronic health records using superlearner.

IMPORTANCE: Statin use prior to hospitalization for Coronavirus Disease 2019 (COVID-19) is hypothesized to improve inpatient outcomes including mortality, but prior findings from large observational studies have been inconsistent, due in part to confounding. Recent advances in statistics, including incorporation of machine learning techniques into augmented inverse probability weighting with targeted maximum likelihood estimation, address baseline covariate imbalance while maximizing statistical efficiency. OBJECTIVE: To estimate the association of antecedent statin use with progression to severe inpatient outcomes among patients admitted for COVD-19. DESIGN, SETTING AND PARTICIPANTS: We retrospectively analyzed electronic health records (EHR) from individuals ≥ 40-years-old who were admitted between March 2020 and September 2022 for ≥ 24 h and tested positive for SARS-CoV-2 infection in the 30 days before to 7 days after admission. EXPOSURE: Antecedent statin use-statin prescription ≥ 30 days prior to COVID-19 admission. MAIN OUTCOME: Composite end point of in-hospital death, intubation, and intensive care unit (ICU) admission. RESULTS: Of 15,524 eligible COVID-19 patients, 4412 (20%) were antecedent statin users. Compared with non-users, statin users were older (72.9 (SD: 12.6) versus 65.6 (SD: 14.5) years) and more likely to be male (54% vs. 51%), White (76% vs. 71%), and have ≥ 1 medical comorbidity (99% vs. 86%). Unadjusted analysis demonstrated that a lower proportion of antecedent users experienced the composite outcome (14.8% vs 19.3%), ICU admission (13.9% vs 18.3%), intubation (5.1% vs 8.3%) and inpatient deaths (4.4% vs 5.2%) compared with non-users. Risk differences adjusted for labs and demographics were estimated using augmented inverse probability weighting with targeted maximum likelihood estimation using Super Learner. Statin users still had lower rates of the composite outcome (adjusted risk difference: - 3.4%; 95% CI: - 4.6% to - 2.1%), ICU admissions (- 3.3%; - 4.5% to - 2.1%), and intubation (- 1.9%; - 2.8% to - 1.0%) but comparable inpatient deaths (0.6%; - 1.3% to 0.1%). CONCLUSIONS AND RELEVANCE: After controlling for confounding using doubly robust methods, antecedent statin use was associated with minimally lower risk of severe COVID-19-related outcomes, ICU admission and intubation, however, we were not able to corroborate a statin-associated mortality benefit.

The impact of statin therapy on in-hospital prognosis and endothelial function of patients at high-to-very high cardiovascular risk admitted for COVID-19.

Statins may protect against adverse outcomes from Coronavirus disease 2019 (COVID-19) through their pleiotropic effects. Endothelial dysfunction seems to be implicated in the pathophysiology of COVID-19, and can be attenuated by statins. This study assessed the role of preadmission statin therapy and its interaction with endothelial function, measured using flow-mediated dilation (FMD) at hospital admission, in predicting in-hospital outcomes among patients with COVID-19 having high-to-very high cardiovascular (CV) risk. We conducted a retrospective cohort study of hospitalized patients with COVID-19 having high-to-very high CV risk, including a subgroup of patients who underwent FMD assessment. Among 342 patients, 119 (35%) were treated with statins at study baseline. Preadmission statin therapy was independently associated with a 75% risk reduction of intensive care unit admission/in-hospital death (adjusted hazard ratio 0.252, 95% confidence interval 0.122-0.521, p < 0.001). In the subgroup of patients with an FMD assessment (245 patients, 40% statin-treated), preadmission statin therapy was independently associated with higher FMD values (ß = 0.159, p = 0.013). However, preadmission statin therapy × FMD interaction was not associated with in-hospital outcomes (F = 0.002, pinteraction = 0.960). Preadmission statin therapy is associated with better in-hospital outcomes among patients with COVID-19 having high-to-very high CV risk, independent of the endothelium-protective effects of these drugs.

Efficacy of Statin Therapy in Patients with Hospital Admission for COVID-19.

PURPOSE: COVID-19 is characterized by dysfunctional immune responses and metabolic derangements, which in some, lead to multi-organ failure and death. Statins are foundational lipid-lowering therapeutics for cardiovascular disease and also possess beneficial immune-modulating properties. Because of these immune-modulating properties, some have suggested their use in COVID-19. We sought to investigate the association between statin use and mortality in patients hospitalized with COVID-19. METHODS: Five thousand three hundred seventy-five COVID-19 patients admitted to Mount Sinai Health System hospitals in New York between February 27, 2020, and December 3, 2020, were included in this analysis. Statin use was classified as either non-user, low-to-moderate-intensity user, or high-intensity user. Multivariate Cox proportional hazards models were used to evaluate in-hospital mortality rate. Considered covariates were age, sex, race, and comorbidities. RESULTS: Compared to non-statin users, both low-to-moderate-intensity (adjusted hazard ratio; aHR 0.62, 95% confidential intervals; CI 0.51-0.76) and high-intensity statin users (aHR 0.53, 95% CI 0.43-0.65) had a reduced risk of death. Subgroup analysis of 723 coronary artery disease patients showed decreased mortality among high-intensity statin users compared to non-users (aHR 0.51, 95% CI 0.36-0.71). CONCLUSIONS: Statin use in patients hospitalized with COVID-19 was associated with a reduced in-hospital mortality. The protective effect of statin was greater in those with coronary artery disease. These data support continued use of statin therapy in hospitalized patients with COVID-19. Clinical trials are needed to prospectively determine if statin use is effective in lowering the mortality in COVID-19 and other viral infections.

Clinical Outcomes of COVID-19 Patients Following Treatment with Atorvastatin: A Non-Randomized Clinical Trial

Objective: There are controversial data regarding the utility of statins in hospitalized COVID-19 patients. This study aimed to assess the efficacy of statins on clinical outcomes of patients hospitalized with COVID-19. Methods: A non-randomized clinical trial was performed among confirmed COVID-19 patients who were admitted to the BooAli hospital in Tehran, Iran. The intervention group received atorvastatin 20 mg orally once daily plus standard of care, while the control group received standard of care alone. The primary endpoints were clinical improvement rate at day 7 as well as in-hospital mortality rate. The secondary endpoints were the duration of hospitalization, the number of intensive care unit (ICU) admissions, the number of patients who needed invasive mechanical ventilation, the incidence of acute respiratory distress syndrome (ARDS), and the reduction of inflammatory markers. Result: In total 94 patients were enrolled (treatment group: 41 patients, control group: 53 patients). The results showed that nearly 59% of patients who received atorvastatin manifested clinical improvement within 7 days compared to 62% of patients in the control group (P > 0.05). There was no significant difference between treatment and control groups in terms of in-hospital mortality, duration of hospitalization, ICU admissions, need for invasive mechanical ventilation, and incidence of ARDS. Conclusion: Atorvastatin 20 mg daily in hospitalized OOVID-19 patients was not associated with significant changes in clinical improvement of patients within 7 days, in-hospital mortality rate, and other clinical outcomes.

Investigation of the Relationship between the Use of Statins with the Mortality Rate and Duration of Hospitalization Due to Covid-19

Introduction: Statins are a group of lipid-lowering medications that have anti-inflammatory and immune system-modulating effects. Considering the existence of severe inflammatory reactions in patients with covid-19, this study aimed to investigate the effects of statins on the mortality rate of covid-19 patients. Material(s) and Method(s): The present research is a descriptive-analytical case-control study that was carried out in the first half of 2021 at Kowsar Hospital in Semnan, Iran. The study was conducted on 191 patients taking statins as the case group and 191 patients with no history of taking statins. Demographic and clinical information of the patients who met the inclusion criteria of the research were extracted from the files and collected in the researcher's questionnaire. Finally, the results were statistically analyzed using SPSS software version 26. Result(s): In this study, a case group of 191 people, who had a history of taking statins, and a control group of 191 people, who did not use statins, were investigated. The average age of people was 64.7 years. Among the studied patients, 51.7% were men and 48.3% were women. Most of the patients were hospitalized for 4 days. Also, 351 patients were discharged and 32 people died. After analyzing the data, no significant relationship was observed between the use of statin and mortality due to Covid-19. Discussion and Conclusion(s): According to the results of this study, no relationship was observed between the use of statins and the reduction of mortality caused by covid-19. Copyright © 2022 Wolters Kluwer Medknow Publications. All rights reserved.

Statin Use and COVID-19 Infectivity and Severity in South Korea: Two Population-Based Nationwide Cohort Studies.

BACKGROUND: Basic studies suggest that statins as add-on therapy may benefit patients with COVID-19; however, real-world evidence of such a beneficial association is lacking. OBJECTIVE: We investigated differences in SARS-CoV-2 test positivity and clinical outcomes of COVID-19 (composite endpoint: admission to intensive care unit, invasive ventilation, or death) between statin users and nonusers. METHODS: Two independent population-based cohorts were analyzed, and we investigated the differences in SARS-CoV-2 test positivity and severe clinical outcomes of COVID-19, such as admission to the intensive care unit, invasive ventilation, or death, between statin users and nonusers. One group comprised an unmatched cohort of 214,207 patients who underwent SARS-CoV-2 testing from the Global Research Collaboration Project (GRCP)-COVID cohort, and the other group comprised an unmatched cohort of 74,866 patients who underwent SARS-CoV-2 testing from the National Health Insurance Service (NHIS)-COVID cohort. RESULTS: The GRCP-COVID cohort with propensity score matching had 29,701 statin users and 29,701 matched nonusers. The SARS-CoV-2 test positivity rate was not associated with statin use (statin users, 2.82% [837/29,701]; nonusers, 2.65% [787/29,701]; adjusted relative risk [aRR] 0.97; 95% CI 0.88-1.07). Among patients with confirmed COVID-19 in the GRCP-COVID cohort, 804 were statin users and 1573 were matched nonusers. Statin users were associated with a decreased likelihood of severe clinical outcomes (statin users, 3.98% [32/804]; nonusers, 5.40% [85/1573]; aRR 0.62; 95% CI 0.41-0.91) and length of hospital stay (statin users, 23.8 days; nonusers, 26.3 days; adjusted mean difference -2.87; 95% CI -5.68 to -0.93) than nonusers. The results of the NHIS-COVID cohort were similar to the primary results of the GRCP-COVID cohort. CONCLUSIONS: Our findings indicate that prior statin use is related to a decreased risk of worsening clinical outcomes of COVID-19 and length of hospital stay but not to that of SARS-CoV-2 infection.

Investigation of the Relationship between the Use of Statins with the Mortality Rate and Duration of Hospitalization Due to Covid-19

Introduction: Statins are a group of lipid-lowering medications that have anti-inflammatory and immune system-modulating effects. Considering the existence of severe inflammatory reactions in patients with covid-19, this study aimed to investigate the effects of statins on the mortality rate of covid-19 patients.Materials and Methods: The present research is a descriptive-analytical case-control study that was carried out in the first half of 2021 at Kowsar Hospital in Semnan, Iran. The study was conducted on 191 patients taking statins as the case group and 191 patients with no history of taking statins. Demographic and clinical information of the patients who met the inclusion criteria of the research were extracted from the files and collected in the researcher's questionnaire. Finally, the results were statistically analyzed using SP SS software version 26.Results: In this study, a case group of 191 people, who had a history of taking statins, and a control group of 191 people, who did not use statins, were investigated. The average age of people was 64.7 years. Among the studied patients, 51.7% were men and 48.3% were women. Most of the patients were hospitalized for 4 days. Also, 351 patients were discharged and 32 people died. After analyzing the data, no significant relationship was observed between the use of statin and mortality due to Covid-19.Discussion and Conclusion: According to the results of this study, no relationship was observed between the use of statins and the reduction of mortality caused by covid-19.

Simvastatin Therapy Increased miR-150-5pExpression in the Patients with Type 2 Diabetes and COVID-19.

BACKGROUND/AIMS: Corona virus disease 2019 (COVID-19) has become a deadly infectious disease, especially for those with co-morbidities such as diabetes. People with diabetes developing a viral infection, seem to have harder treatments due to fluctuations in blood glucose levels therefore, effective therapeutic approaches need to be considered for them. Statins are well-known lipid-lowering drugs; they also have anti-inflammatory and immunomodulatory effects and can impact on expression of microRNAs (miRNAs). METHODS: In this study we investigate the effects of simvastatin on the expression of miR-150-5p as a famous regulator of inflammation and its association with multiple cancers in 30 patients with Type 2 diabetes mellitus (T2DM) and COVID-19 compared to the COVID-19 hospitalized patients before and after treatment with simvastatin with real-time-PCR after 2month, and evaluate its targets gens and functions with the help of bioinformatics and GO enrichment analysis respectively. RESULTS: Our results showed that simvastatin can increase miR-150-5p and therefore down regulate expression of its target genes involving in immune stimulation and decrease lipid profile including LDL-C, total cholesterol, and ApoB, especially in the group with type 2 diabetes mellitus (T2DM) and COVID-19 compared to the patients with only COVID-19. CONCLUSION: Simvastatin as an anti-inflammatory agent can modulate miRNAs expression; it can be suggested as an adjunct therapy especially for T2DM patients with COVID-19. Further studies may help us for developing better treatments about therapeutic manipulation of miRNAs in vivo.

Patterns of statin adherence in primary cardiovascular disease prevention during the pandemic.

Background: Study of medication adherence patterns can help identify patients who would benefit from effective interventions to improve adherence. Objectives: To identify and compare groups of statin users based on their adherence patterns before and during the COVID-19 pandemic, to characterize the profile of users in each group, and to analyze predictors of distinct adherence patterns. Methods: Participants of the CARhES (CArdiovascular Risk factors for HEalth Services research) cohort, comprising individuals aged >16 years, residing in Aragón (Spain), with hypertension, diabetes mellitus and/or dyslipidemia, took part in this observational longitudinal study. Individuals who began statin therapy during January-June 2019 were selected and followed up until June 2021. Those with a cardiovascular event before or during follow-up were excluded. Data were obtained from healthcare system data sources. Statin treatment adherence during the implementation phase was estimated bimonthly using the Continuous Medication Availability (CMA9) function in the AdhereR package. Group-based trajectory models were developed to group statin users according to their adherence pattern during July 2019-June 2021. Group characteristics were compared and predictors of each adherence pattern were analyzed using multinomial logistic regression. Results: Of 15,332 new statin users, 30.8% had a mean CMA9 ≥80% for the entire study period. Four distinct adherence patterns were identified: high adherence (37.2% of the study population); poor adherence (35.6%); occasional use (14.9%); and gradual decline (12.3%). The latter two groups included users who showed a change in adherence (increase or decrease) during the pandemic emergence. Users with suboptimal adherence were likely to be younger, not pensioners, not institutionalized, with low morbidity burden and a low number of comorbidities. Female sex and switching between statins of different intensity increased the likelihood of belonging to the occasional use group, in which improved adherence coincided with the pandemic. Conclusion: We identified four distinct adherence patterns in a population of new statin users; two of them modified their adherence during the pandemic. Characterization of these groups could enable more effective distribution of resources in future similar crisis and the routine implementation of patient-centered interventions to improve medication adherence.

Phenotypical and Functional Alteration of γδ T Lymphocytes in COVID-19 Patients: Reversal by Statins.

(1) Background: statins have been considered an attractive class of drugs in the pharmacological setting of COVID-19 due to their pleiotropic properties and their use correlates with decreased mortality in hospitalized COVID-19 patients. Furthermore, it is well known that statins, which block the mevalonate pathway, affect γδ T lymphocyte activation. As γδ T cells participate in the inflammatory process of COVID-19, we have investigated the therapeutical potential of statins as a tool to inhibit γδ T cell pro-inflammatory activities; (2) Methods: we harvested peripheral blood mononuclear cells (PBMCs) from COVID-19 patients with mild clinical manifestations, COVID-19 recovered patients, and healthy controls. We performed ex vivo flow cytometry analysis to study γδ T cell frequency, phenotype, and exhaustion status. PBMCs were treated with Atorvastatin followed by non-specific and specific stimulation, to evaluate the expression of pro-inflammatory cytokines; (3) Results: COVID-19 patients had a lower frequency of circulating Vδ2+ T lymphocytes but showed a pronounced pro-inflammatory profile, which was inhibited by in vitro treatment with statins; (4) Conclusions: the in vitro capacity of statins to inhibit Vδ2+ T lymphocytes in COVID-19 patients highlights a new potential biological function of these drugs and supports their therapeutical use in these patients.

Statin Therapy and the Risk of Viral Infection: A Retrospective Population-Based Cohort Study.

Statins exert cholesterol-independent beneficial effects, including immunomodulatory effects. In this study, we attempted to investigate the association between statin therapy and the risk of viral infection. We conducted a retrospective cohort study using data from Taiwan's National Health Insurance Research Database. We identified patients with hyperlipidemia and divided them into two cohorts: statin users and statin nonusers. A 1:1 propensity score matching was conducted between the two cohorts, and a Cox proportional hazards model was used to evaluate the risk of viral infection. Overall, a total of 20,202 patients were included in each cohort. The median follow-up durations were 4.41 and 6.90 years for statin nonusers and users, respectively. The risk of viral infection was 0.40-fold (95% confidence interval = 0.38-0.41) in statin users than in statin nonusers after adjustment for potential confounders. Statin treatment was associated with a significantly lower risk of viral infection in all age groups older than 18 years in both men and women. Moreover, the risk of viral infection substantially reduced as the duration of statin treatment increased. Our findings suggest that statin therapy is associated with a significantly lower risk of viral infection in patients with hyperlipidemia.

Systematic Review and Meta-Analysis of Statin Use and Mortality, Intensive Care Unit Admission and Requirement for Mechanical Ventilation in COVID-19 Patients.

There is mounting evidence that statin use is beneficial for COVID-19 outcomes. We performed a systematic review and meta-analysis to evaluate the association between statin use and mortality, intensive care unit (ICU) admission and mechanical ventilation in COVID-19 patients, on studies which provided covariate adjusted effect estimates, or performed propensity score matching. We searched PubMed, Embase, Web of Science and Scopus for studies and extracted odds or hazard ratios for specified outcome measures. Data synthesis was performed using a random-effects inverse variance method. Risk of bias, heterogeneity and publication bias were analyzed using standard methods. Our results show that statin use was associated with significant reductions in mortality (OR = 0.72, 95% CI: 0.67-0.77; HR = 0.74, 95% CI: 0.69, 0.79), ICU admission (OR = 0.94, 95% CI: 0.89-0.99; HR = 0.76, 95% CI: 0.60-0.96) and mechanical ventilation (OR = 0.84, 95% CI: 0.78-0.92; HR = 0.67, 95% CI: 0.47-0.97). Nevertheless, current retrospective studies are based on the antecedent use of statins prior to infection and/or continued use of statin after hospital admission. The results may not apply to the de novo commencement of statin treatment after developing COVID-19 infection. Prospective studies are lacking and necessary.

The impact of HMG-CoA reductase inhibitors use on the clinical outcomes in critically ill patients with COVID-19: A multicenter, cohort study.

Background: The cardiovascular complications of Coronavirus Disease 2019 (COVID-19) may be attributed to the hyperinflammatory state leading to increased mortality in patients with COVID-19. HMG-CoA Reductase Inhibitors (statins) are known to have pleiotropic and anti-inflammatory effects and may have antiviral activity along with their cholesterol-lowering activity. Thus, statin therapy is potentially a potent adjuvant therapy in COVID-19 infection. This study investigated the impact of statin use on the clinical outcome of critically ill patients with COVID-19. Methods: A multicenter, retrospective cohort study of all adult critically ill patients with confirmed COVID-19 who were admitted to Intensive Care Units (ICUs) between March 1, 2020, and March 31, 2021. Eligible patients were classified into two groups based on the statin use during ICU stay and were matched with a propensity score based on patient's age and admission APACHE II and SOFA scores. The primary endpoint was in-hospital mortality, while 30 day mortality, ventilator-free days (VFDs) at 30 days, and ICU complications were secondary endpoints. Results: A total of 1,049 patients were eligible; 502 patients were included after propensity score matching (1:1 ratio). The in-hospital mortality [hazard ratio 0.69 (95% CI 0.54, 0.89), P = 0.004] and 30-day mortality [hazard ratio 0.75 (95% CI 0.58, 0.98), P = 0.03] were significantly lower in patients who received statin therapy on multivariable cox proportional hazards regression analysis. Moreover, patients who received statin therapy had lower odds of hospital-acquired pneumonia [OR 0.48 (95% CI 0.32, 0.69), P < 0.001], lower levels of inflammatory markers on follow-up, and no increased risk of liver injury. Conclusion: The use of statin therapy during ICU stay in critically ill patients with COVID-19 may have a beneficial role and survival benefit with a good safety profile.

Rhabdomyolysis-Induced AKI (RIAKI) Including the Role of COVID-19.

Rhabdomyolysis is a compound disease that may be induced by many factors, both congenital and acquired. Statin therapy is considered one of the most common acquired factors. However, recent scientific reports suggest that serious complications such as rhabdomyolysis are rarely observed. Researchers suggest that, in many cases, side effects that occur with statin therapy, including muscle pain, can be avoided with lower-dose statin therapy or in combination therapy with other drugs. One of the most recent agents discovered to contribute to rhabdomyolysis is COVID-19 disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Rhabdomyolysis is defined as a damage to striated muscle cells with escape of intracellular substances into the bloodstream. These substances, including myoglobin, creatine kinase (CK), potassium, and uridine acid, are markers of muscle damage and early complications of rhabdomyolysis. Symptoms may be helpful in establishing the diagnosis. However, in almost 50% of patients, they do not occur. Therefore, the diagnosis is confirmed by serum CK levels five times higher than the upper limit of normal. One of the late complications of this condition is acute kidney injury (AKI), which is immediately life-threatening and has a high mortality rate among patients. Therefore, the prompt detection and treatment of rhabdomyolysis is important. Markers of muscle damage, such as CK, lactate dehydrogenase (LDH), myoglobin, troponins, and aspartate aminotransferase (AST), are important in diagnosis. Treatment of rhabdomyolysis is mainly based on early, aggressive fluid resuscitation. However, therapeutic interventions, such as urinary alkalinization with sodium bicarbonate or the administration of mannitol or furosemide, have not proven to be beneficial. In some patients who develop AKI in the course of rhabdomyolysis, renal replacement therapy (RRT) is required.

Co-Application of Statin and Flavonoids as an Effective Strategy to Reduce the Activity of Voltage-Gated Potassium Channels Kv1.3 and Induce Apoptosis in Human Leukemic T Cell Line Jurkat.

Voltage-gated potassium channels of the Kv1.3 type are considered a potential new molecular target in several pathologies, including some cancer disorders and COVID-19. Lipophilic non-toxic organic inhibitors of Kv1.3 channels, such as statins and flavonoids, may have clinical applications in supporting the therapy of some cancer diseases, such as breast, pancreas, and lung cancer; melanoma; or chronic lymphocytic leukemia. This study focuses on the influence of the co-application of statins-simvastatin (SIM) or mevastatin (MEV)-with flavonoids 8-prenylnaringenin (8-PN), 6-prenylnarigenin (6-PN), xanthohumol (XANT), acacetin (ACAC), or chrysin on the activity of Kv1.3 channels, viability, and the apoptosis of cancer cells in the human T cell line Jurkat. We showed that the inhibitory effect of co-application of the statins with flavonoids was significantly more potent than the effects exerted by each compound applied alone. Combinations of simvastatin with chrysin, as well as mevastatin with 8-prenylnaringenin, seem to be the most promising. We also found that these results correlate with an increased ability of the statin-flavonoid combination to reduce viability and induce apoptosis in cancer cells compared to single compounds. Our findings suggest that the co-application of statins and flavonoids at low concentrations may increase the effectiveness and safety of cancer therapy. Thus, the simultaneous application of statins and flavonoids may be a new and promising anticancer strategy.

Statin and aspirin as adjuvant therapy in hospitalised patients with SARS-CoV-2 infection: a randomised clinical trial (RESIST trial).

BACKGROUND: Statins and aspirin have been proposed for treatment of COVID-19 because of their anti-inflammatory and anti-thrombotic properties. Several observational studies have shown favourable results. There is a need for a randomised controlled trial. METHODS: In this single-center, open-label, randomised controlled trial, 900 RT-PCR positive COVID-19 patients requiring hospitalisation, were randomly assigned to receive either atorvastatin 40 mg (Group A, n = 224), aspirin 75 mg (Group B, n = 225), or both (Group C, n = 225) in addition to standard of care for 10 days or until discharge whichever was earlier or only standard of care (Group D, n = 226). The primary outcome variable was clinical deterioration to WHO Ordinal Scale for Clinical Improvement ≥ 6. The secondary outcome was change in serum C-reactive protein, interleukin-6, and troponin I. RESULTS: The primary outcome occurred in 25 (2.8%) patients: 7 (3.2%) in Group A, 3 (1.4%) in Group B, 8 (3.6%) in Group C, and 7 (3.2%) in Group D. There was no difference in primary outcome across the study groups (P = 0.463). Comparison of all patients who received atorvastatin or aspirin with the control group (Group D) also did not show any benefit [Atorvastatin: HR 1.0 (95% CI 0.41-2.46) P = 0.99; Aspirin: HR 0.7 (95% CI 0.27-1.81) P = 0.46]. The secondary outcomes revealed lower serum interleukin-6 levels among patients in Groups B and C. There was no excess of adverse events. CONCLUSIONS: Among patients admitted with mild to moderate COVID-19 infection, additional treatment with aspirin, atorvastatin, or a combination of the two does not prevent clinical deterioration. Trial Registry Number CTRI/2020/07/026791 ( http://ctri.nic.in ; registered on 25/07/2020).

Statins and Risk of Thrombosis in Critically ill Patients with COVID-19: A Multicenter Cohort Study.

PURPOSE: Coagulation abnormalities are one of the most important complications of severe COVID-19, which might lead to venous thromboembolism (VTE). Hypercoagulability with hyperfibrinogenemia causes large vessel thrombosis and major thromboembolic sequelae. Statins are potentially a potent adjuvant therapy in COVID-19 infection due to their pleiotropic effect. This study aims to evaluate the effectiveness of statins in reducing the risk of thrombosis among hospitalized critically ill patients with COVID-19. METHODS: A multicenter, retrospective cohort study of all critically ill adult patients with confirmed COVID-19 admitted to Intensive Care Units (ICUs) between March 1, 2020, and March 31, 2021. Eligible patients were categorized based on their usage of statins throughout their ICU stay and were matched with a propensity score. The primary endpoint was the odds of all cases of thrombosis; other outcomes were considered secondary. RESULTS: A total of 1039 patients were eligible; following propensity score matching, 396 patients were included (1:1 ratio). The odds of all thrombosis cases and VTE events did not differ significantly between the two groups (OR 0.84 (95% CI 0.43, 1.66), P = 0.62 and OR 1.13 (95% CI 0.43, 2.98), P = 0.81, respectively. On multivariable Cox proportional hazards regression analysis, patients who received statin therapy had lower 30-day (HR 0.72 (95 % CI 0.54, 0.97), P = 0.03) and in-hospital mortality (HR 0.67 (95 % CI 0.51, 0.89), P = 0.007). Other secondary outcomes were not statistically significant between the two groups except for D-dimer levels (peak) during ICU stay. CONCLUSION: The use of statin therapy during ICU stay was not associated with thrombosis reduction in critically ill patients with COVID-19; however, it has been associated with survival benefits.