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.

Fixed-dose combination of rosuvastatin and ezetimibe: treating hypercholesteremia according to cardiovascular risk.

Introduction: Reducing low-density lipoprotein cholesterol (LDL-C) with lipid-lowering therapies has been associated with a decrease in the frequency of cardiovascular events.Areas covered: A systematic search was conducted on PubMed (MEDLINE), using the MeSH terms [Rosuvastatin] + [Ezetimibe] + [Dyslipidemia] + [treatment]. Original data from clinical trials, prospective and retrospective studies and more useful reviews were selected.Expert opinion: While statins continue to be the cornerstone of dyslipidemia management, many patients do not attain LDL-C targets with high-intensity statins alone. Rosuvastatin is a high-intensity statin with a low risk of adverse effects and drug-drug interactions and proven benefits in the prevention of cardiovascular disease. Rosuvastatin and ezetimibe have complementary mechanisms of action that enhance their ability to reduce LDL-C levels. Various studies have shown that the combination of rosuvastatin 10-40 mg and ezetimibe 10 mg enables considerable reductions in LDL-C (up to 60-75%) with a good safety profile in a broad spectrum of patients with hypercholesterolemia, including those at high risk and those with atherosclerotic cardiovascular disease. In addition, a fixed-dose combination of rosuvastatin and ezetimibe may improve adherence to medication. In this review, the available evidence on the combination of rosuvastatin and ezetimibe is updated.

High dose simvastatin and rosuvastatin impair cognitive abilities of healthy rats via decreasing hippocampal neurotrophins and irisin.

BACKGROUND: Statins are cholesterol lowering drugs that decrease the risk of cardiovascular events, but they are related with a few unfavorable symptoms in skeletal muscle including myopathy, and mild to moderate fatigue. Additionally, there has been discrepancies about the impacts of statins on brain and cognition. This study aimed to examine the impacts of two different statins, lipophilic simvastatin and hydrophilic rosuvastatin on cognitive functions in normal healthy rats. Simultaneously, we investigated the alterations of neurotropins and irisin levels in hippocampus and myokine levels in skeletal muscle. METHODS: The rats were dosed with 88 mg kg body weight-1 day-1 simvastatin (n = 8), 150 mg kg body weight-1 day-1 rosuvastatin (n = 8) or vehicle (n = 8) for 18 days via oral gavage. After that behavioral assessment was performed and hippocampus and skeletal muscle samples were taken for the analysis of neurotrophins and irisin levels. RESULTS: Locomotion and learning and memory functions were lower, but anxiety levels were higher in the simvastatin and rosuvastatin groups than in the control group (P < 0.05). Hippocampal neurotrophins and irisin levels were lower, but skeletal muscle brain-derived neurotrophic factor (BDNF) and irisin levels were higher in the simvastatin and rosuvastatin groups than in the control group (P < 0.05). CONCLUSION: These findings suggest that high dose simvastatin and rosuvastatin impair cognitive functions via decreasing BDNF, NGF and irisin levels in the hippocampus.

Effects of High-Dose Rosuvastatin on Ventricular Remodelling and Cardiac Function in ST-Segment Elevation Myocardial Infarction.

OBJECTIVE: To investigate the effects of high-dose rosuvastatin on ventricular remodelling and cardiac function in ST-segment elevation myocardial infarction (STEMI). MATERIALS AND METHODS: From January 2017 to March 2019, the clinical data of 93 patients with STEMI were collected and analysed, with 46 cases in the conventional-dose group (rosuvastatin, 10 mg/d) and 47 cases in the high-dose group (rosuvastatin, 20 mg/d). Blood lipid (TC, TG, LDL-C and HDL-C), serum inflammatory markers (hs-CRP, IL-6, TNF-α and ICAM-1), ventricular remodelling markers (NT-pro BNP, MMP-9, TIMP-4 and Gal-3) and indicators of cardiac function (LVESD, LVESD, LVESV, LVEDV, IVST and LVEF) were collected from all patients at the time of admission and 8 weeks after rosuvastatin treatment. RESULTS: After treatment with rosuvastatin for 8 weeks, compared with those in conventional-dose group, the levels of TC, TG, LDL-C, hs-CRP, IL-6, TNF-α, ICAM-1, NT-pro BNP, MMP-9 and Gal-3 in the high-dose group decreased significantly (P<0.05), while the increase of HDL-C and TIMP-4 levels was more obvious (P<0.05) than that in the conventional-dose group. Moreover, LVEF was significantly higher (P<0.05) and LVESD, LVESD, LVESV, LVEDV and IVST were significantly lower (P< 0.05) after treatment than before treatment in both groups. The improvement of cardiac ultrasound results in the high-dose group was more significant than that in the conventional-dose group (P< 0.05). CONCLUSION: This study suggests that high-dose rosuvastatin was better than conventional-dose rosuvastatin for improving blood lipid metabolism, reducing the inflammatory response, and preventing and treating ventricular remodelling and myocardial fibrosis, indicating that high-dose rosuvastatin had stronger therapeutic effect on STEMI than conventional-dose rosuvastatin.

Effect of Preloading With High Dose of Rosuvastatin on Serum Levels of Inflammatory Markers After Percutaneous Coronary Intervention.

OBJECTIVES: We sought to assess the effects of a high loading dose of rosuvastatin (40 mg) on acute inflammatory response after coronary stenting. METHODS: Patients with stable coronary disease without statin use (≥7 days) and undergoing elective percutaneous coronary intervention (PCI) in a native coronary artery were randomized to receive a loading dose of rosuvastatin (n = 64) or not (n = 61). Blood samples were obtained before statin intake (time point A), 3 hours after medication (time point B), and 3 hours after PCI (time point C). The primary goal was the comparison in the variation of the serum inflammatory markers and their gene expression at the different time points between the two groups. RESULTS: Baseline clinical, angiographic, and procedural characteristics did not significantly differ between the groups, except for the more frequent use of postdilation in the control group (73.4% vs 90.2%; P=.02). Patients pretreated with statin showed a reduction in the serum levels of interleukin (IL)-1ß (Δ = -0.491 pg/mL; Pinteraction<.001), IL-6 (Δ = -0.209 pg/mL; Pinteraction<.001), and plasminogen activator inhibitor 1 (Δ = -1.573 pg/mL; Pinteraction<.001) as well as in their genetic expression, which was not observed in the control group. Regarding high-sensitivity c-reactive protein, there was no significant variation in its value from time point A to C in patients pretreated with statin (P=.58) while it significantly increased in the control group (P=.04). CONCLUSIONS: Among patients with stable coronary artery disease undergoing PCI with stents, pretreatment with high dose of rosuvastatin resulted in significant reduction in the serum levels of important inflammatory markers and their genetic expression.

Comparison of High-Dose Rosuvastatin Versus Low-Dose Rosuvastatin Plus Ezetimibe on Carotid Atherosclerotic Plaque Inflammation in Patients with Acute Coronary Syndrome.

We compared the effects of ezetimibe/rosuvastatin 10/5 mg versus rosuvastatin 20 mg on carotid atherosclerotic plaque inflammation measured by 18FDG PET/CT. Fifty patients with acute coronary syndrome (ACS) were randomly assigned to the ezetimibe/rosuvastatin 10/5 mg and rosuvastatin 20 mg groups. The primary outcome was the percent change in the target-to-background ratio (TBR) of the index vessel in the most diseased segment (MDS), as assessed by 18FDG PET/CT at baseline and at 6 months. Forty-eight patients completed follow-up PET/CT. MDS TBR was - 6.2 ± 13.9% for patients in the ezetimibe/rosuvastatin group and - 10.8 ± 17.7% for those in the rosuvastatin group (difference, 4.6 percentage points; upper limitation of one-sided confidence interval = 13.8; p = 0.60 for noninferiority). In conclusion, combination therapy with ezetimibe 10 mg and rosuvastatin 5 mg compared with rosuvastatin 20 mg did not meet the criterion for non-inferiority for primary outcome, and the present study was not conclusive on whether the former was non-inferior to the latter. Graphical Abstract.

Effect of Green Tea and (-)-Epigallocatechin Gallate on the Pharmacokinetics of Rosuvastatin.

BACKGROUND: Green tea can inhibit OATPs, so it may interact with the substrate of OATPs, such as rosuvastatin. OBJECTIVE: This study aimed to investigate the effects of green tea on the pharmacokinetics of rosuvastatin and its mechanism. METHODS: Male Sprague-Dawley rats received different doses of green tea extract (GTE) and (-)- epigallocatechin-3- gallate (EGCG). Caco-2 cells and OATP1B1-HEK293T cells were used in drug uptake and transport assay. The matrix concentrations of rosuvastatin and catechins were determined by ultra-performance liquid chromatographytandem mass spectrometry (UPLC-MS/MS). RESULTS: GTE and EGCG were both found to increase the area under the plasma concentration-time curve (AUC0-∞) of rosuvastatin ((p<0.050). In the Caco-2 cell model, the uptake and transport of rosuvastatin in the GTE groups were 1.94-fold (p<0.001) and 2.11-fold (p<0.050) higher, respectively, than those of the control group. However, in the EGCG group, the uptake and transport of rosuvastatin were decreased by 22.62% and 44.19%, respectively (p<0.050). In the OATP1B1- HEK293T cell model, the OATP1B1-mediated rosuvastatin uptake was decreased by GTE to 35.02% of that in the control (p<0.050) and was decreased by EGCG to 45.61% of that in the control (p<0.050). CONCLUSION: GTE increased the systemic rosuvastatin exposure in rats. The mechanism may include an increase in rosuvastatin absorption and a decrease in liver distribution by inhibiting OATP1B1. EGCG may be the main ingredient of green tea that affects the pharmacokinetic parameters of rosuvastatin. Our results showed the importance of conducting green tea-rosuvastatin study.

Capsaicinoid nonivamide improves nonalcoholic fatty liver disease in rats fed a high-fat diet.

Nonalcoholic fatty liver disease (NAFLD) is a chronic disease that causes morbidity associated with metabolic syndrome. NAFLD is a worldwide problem and represents a major cause of liver injury, which can lead to liver cell death. We investigated the effects of nonivamide (pelargonic acid vanillylamide, PAVA; 1 mg/kg) and rosuvastatin (RSV; 10 mg/kg) on hepatic steatosis induced by a high-fat diet (HFD). Male Sprague-Dawley rats were fed a HFD for 16 weeks then received PAVA or RSV for 4 additional weeks. We examined the metabolic parameters, function, fat content, histological alterations, reactive oxygen species production, and apoptotic cell death of the liver, in addition to the expression of the following important molecules: transient receptor potential cation channel subfamily V member 1 (TRPV1) phosphorylation of sterol regulatory element binding protein (pSREBP-1c/SREBP-1c), total and membrane glucose transporter 2 (GLUT2), 4-hydroxynonenal (4-HNE), and cleaved caspase-3. HFD-induced hepatic steatosis was associated with significantly increased morphological disorganization, injury markers, oxidative stress, lipid peroxidation, and apoptosis. However, metabolic dysfunction and hepatic injury were reduced by RSV and PAVA treatment. PAVA regulated lipid deposition, improved insulin resistance, and decreased oxidative stress and apoptotic cell death. Therefore, PAVA represents a promising therapeutic approach for treating metabolic disorders in patients with NAFLD.

Engineering of Long-Term Stable Transparent Nanoemulsion Using High-Gravity Rotating Packed Bed for Oral Drug Delivery.

BACKGROUND: Oil-in-water drug nanoemulsion forms drug delivery systems with high oral bioavailability. The conventional fabrication methods of nanoemulsion are low energy emulsification methods and high energy emulsification methods. However, both two methods are not ideal for industrial production. The problem of low energy emulsification methods is the high dosage of surfactant and co-surfactant which has potential biosecurity issues. What is more, high energy emulsification methods have some disadvantages, like the destruction of drug components, the price of equipment and the difficulties of industrial production. Hence, there have been a few commercial drug nanoemulsions so far. METHODS: In this work, we reported a novel method for the fabrication of stable and transparent drug nanoemulsion which contains hydrophilic drug rosuvastatin (ROS) calcium or hydrophobic drug silybinin (SYN) by using high-gravity rotating packed bed (RPB). The drug nanoemulsion was systematically characterized by droplet size, size distribution, stability and in vitro drug release as well as Caco-2 cells permeability. RESULTS: Compared with the self-emulsification method (SE), high-gravity technology could reduce 75% amount of mixed surfactants. The as-prepared nanoemulsion exhibited a very narrow droplet size distribution with a size of 13.53 ± 0.53 nm and a polydispersity index of 0.073 ± 0.018. Meanwhile, the drug nanoemulsion was physicochemically stable at 25°C and 4°C for one-year storage. Furthermore, both ROS and SYN nanoemulsion displayed higher cell permeability and in vitro dissolution than that of commercial formulations. CONCLUSION: These results demonstrate that RPB can be a potential device to facilitate the industrial production of drug nanoemulsion.

Cost-Effectiveness Analysis of Ezetimibe as the Add-on Treatment to Moderate-Dose Rosuvastatin versus High-Dose Rosuvastatin in the Secondary Prevention of Cardiovascular Diseases in China: A Markov Model Analysis.

BACKGROUND: For patients with inadequate control of cholesterol using moderate-dose statins in the secondary prevention of cardiovascular diseases (CVD), either doubling the dose of statins or adding ezetimibe should be considered. The cost-effectiveness of them is unknown in the Chinese context. The aim of this study is to compare the cost and effectiveness of the two regimens, and estimate the incremental cost-effectiveness ratio (ICER). METHODS: A Markov model of five health statuses were used to estimate long-term costs and quality-adjusted life-years (QALYs) of the two treatment regimens from the healthcare perspective. The effectiveness data used to calculate the transition probability was based on a previously published randomized trial. The utility data was gathered from literature and the costs were gathered from the electronic medical record system of West China Hospital in Chinese Yuan (CNY) in 2017 price. One-way sensitivity analysis and probabilistic sensitivity analysis were conducted. RESULTS: The ICER for ezetimibe plus moderate-dose rosuvastatin was 47,102.99 CNY per QALY for 20 years simulation, which did not reach the threshold of per capita gross domestic product (GDP) of 59,660 CNY per QALY in 2017 in China. Non-CVD-related mortality and CVD-related mortality contributed most to the ICER. CONCLUSION: Adding ezetimibe to the moderate-dose statin in secondary prevention for CVD is cost-effective, compared with the high-dose statin in the Chinese context whose low-density lipoprotein cholesterol (LDL-c) was not inadequately controlled by moderate-dose statin alone.

An overview of rosuvastatin/ezetimibe association for the treatment of hypercholesterolemia and mixed dyslipidemia.

Introduction: Although statin therapy is a powerful lipid-lowering strategy, only one-fifth of statin users currently reach their lipid goals. In addition, statin treatment alone has relatively low efficacy in reducing other lipid fractions than low-density lipoprotein-cholesterol (LDL-C). In such cases, most guidelines recommend adding the cholesterol absorption inhibitor ezetimibe.Areas covered: This paper summarizes the main pharmacological characteristics of rosuvastatin and ezetimibe (mechanism of action, metabolism), their lipid-lowering and pleiotropic effects, with particular attention to the clinical effects of the combined drugs in hypercholesterolemia and mixed dyslipidemia patients (such as the ones affected by diabetes mellitus and Acquired Immune Deficiency Syndrome (AIDS)).Expert opinion: The additive effect of rosuvastatin and ezetimibe helps to reach lipid goals in a large number of high-risk patients, while avoiding some safety issues related to high dosages of intensive statin therapy. Patients with diabetes receive additional benefits from ezetimibe as they seem to absorb cholesterol more effectively than non-diabetic ones, because of increased NPC1L1 gene expression. Ezetimibe augments rosuvastatin triglyceride-lowering and anti-inflammatory effects, as well. Taking into account its excellent safety profile and lack of clinically relevant drug-drug interactions, the rosuvastatin/ezetimibe association is a valuable alternative to statin dose uptitration.

Effect of high-dose strong statin for preventing periprocedural ischemic complications of carotid artery stenting.

Statin therapy has been shown to induce carotid atherosclerotic plaque regression and reduce the periprocedural ischemic complications of carotid artery stenting (CAS). This study assessed the safety and usefulness of pretreatment using a high-dose strong statin (HDSS) to reduce the periprocedural ischemic complications of CAS. We analyzed 117 carotid lesions treated by CAS that were evaluated with magnetic resonance imaging (MRI) within 48 h after the procedure. For 67 lesions, an HDSS (rosuvastatin 20 mg or atorvastatin 40 mg daily) were prescribed from at least 14 days before CAS to at least 14 days after procedure (HDSS group). Clinical and angiographic data, as well as in-hospital outcomes, of the HDSS group were retrospectively compared with 50 lesions with conventional treatment without an HDSS (non-HDSS group). There were no significant differences in the baseline clinical and procedural characteristics between the two groups. There was no side effect related to the HDSS. Stroke rates were similar between the two groups (3.0% in HDSS group vs 8.0% in non-HDSS group, p = 0.22). All were minor strokes. Compared to the non-HDSS group, the HDSS group had a lower frequency of new lesions on diffusion-weighted imaging (DWI) with MRI (25.4% vs 44.0%, p = 0.0345). New ipsilateral DWI-positive rate in the HDSS group was significantly lower than in the non-HDSS group (16.4% vs 34.0%, p = 0.0275). Nonipsilateral (contralateral or posterior circulation) DWI-positive rates were similar between the two groups (13.4% vs 20.0%, p = 0.34). Pretreatment with an HDSS might reduce the periprocedural ischemic complications of CAS.

High dose rosuvastatin increases ABCA1 transporter in human atherosclerotic plaques in a cholesterol-independent fashion.

BACKGROUND: ATP-binding cassette A1 (ABCA1) and G1 (ABCG1) mediate cholesterol efflux from lipid-laden macrophages, thus promoting anti-atherosclerotic outcomes. The mechanism(s) linking treatment with statins and ABCA1/ABCG1 in human atherosclerosis are not fully understood and require further investigation. Therefore, we studied whether short-term treatment with low- or high-dose rosuvastatin may affect ABCA1 and ABCG1 expression in human atherosclerotic plaques. METHODS: Seventy patients with severe stenosis of the internal carotid artery were randomized to receive low (10 mg/day) or high (40 mg/day) dose rosuvastatin for 12 weeks before elective endarterectomy. As controls, we analyzed a reference group of 10 plaques from subjects with hypercholesterolemia but not receiving statin treatment and an additional set of 11 plaques collected from normocholesterolemic patients. On atherosclerotic plaques, ABCA1 and ABCG1 expression was evaluated at RNA level by qPCR and at protein level by immunoblotting and immunohistochemistry. RESULTS: Both rosuvastatin doses were associated with lower plaque ABCA1 mRNA levels and with a trend toward reduction for ABCG1. However, ABCA1 protein was paradoxically higher in patients treated with high-dose rosuvastatin and was associated with lower levels of miR-33b-5p, a microRNA known as a regulator of ABCA1. Multivariate analyses showed that the effect is cholesterol-independent. Finally, no effects were found for ABCG1 protein. CONCLUSIONS: High-dose rosuvastatin increases macrophage ABCA1 protein levels in human atherosclerotic plaque despite mRNA reduction in a mechanism unrelated to plasma cholesterol reduction and potentially involving miR-33b-5p. This pathway may reflect an additional feature contributing to the anti-atherosclerotic effect for high-dose rosuvastatin. TRIAL REGISTRATION: ISRCTN16590640.

Black tea extract and theaflavin derivatives affect the pharmacokinetics of rosuvastatin by modulating organic anion transporting polypeptide (OATP) 2B1 activity.

Theaflavins (TFs) are derived from black tea, an important source of dietary polyphenols. Although the potential interactions between dietary polyphenols and drugs have been demonstrated through in vitro and in vivo studies, little information is available concerning the influence of TFs on drug disposition. Organic anion transporting polypeptide 2B1 (OATP2B1) is expressed in human enterocytes and plays a role in the intestinal absorption of numerous drugs. The current study evaluated the effects of black tea extracts on the pharmacokinetics of rosuvastatin in rats, and investigated the effect of four major TFs (theaflavin, theaflavin-3-gallate, theaflavin-3'-gallate and theaflavin-3,3'-digallate) on the transport activity of OATP2B1. Black tea extracts significantly decreased the maximum plasma concentration (Cmax ) and area under the plasma concentration-time curve (AUC0 -8 ) of rosuvastatin by 48% and 37%, respectively (p < 0.001 and p < 0.01, respectively). Moreover, OATP2B1-mediated rosuvastatin and estrone-3-sulfate uptake was significantly reduced in the presence of TFs. A kinetic study revealed that the uptake efficiency (in terms of Vmax /Km ) of rosuvastatin was decreased following treatment with TFs. Black tea extracts also reduced OATP2B1-mediated rosuvastatin uptake. These results suggest that black tea reduces the plasma concentrations of rosuvastatin by inhibiting the intestinal OATP2B1-mediated transport of rosuvastatin.

A Comparison of the Anti-Inflammatory Effects of Four Combined Statin and Antiplatelet Therapies on Tumor Necrosis Factor-Mediated Acute Inflammation in vivo.

BACKGROUND: Combination therapy has been administered to patients with chronic or complex diseases due to its improved therapeutic effects compared with the results of monotherapy. Due to the pleiotropic effects of statins and antiplatelets, these drugs have been studied in combination with other drugs, but not all combinations exerted obvious beneficial effects compared with individual drugs. In this study, we aimed to compare the anti-inflammatory effects of 4 different combination therapies of statins and antiplatelets on the tumor necrosis factor (TNF)-mediated inflammation in vivo. METHODS: Mice were orally administered cilostazol plus pravastatin (CILOP) or cilostazol plus rosuvastatin (CILOR), clopidogrel plus pravastatin (CLOP), or clopidogrel plus rosuvastatin (CLOR); then, acute inflammation was induced by the injection of lipopolysaccharide (LPS) or TNF. Serum TNF levels, macrophage accumulation in the lesioned aortas, and mouse mortality were observed to be comparable to the anti-inflammatory effects of the combination therapies. RESULTS: In mice with LPS-induced inflammation, CILOP and CILOR substantially reduced macrophage infiltration of aortic lesions and the serum TNF levels compared with CLOP and CLOR. Moreover, among the 4 combinations, CILOP significantly improved the survival rate of mice with TNF-mediated acute lethal inflammation. CONCLUSIONS: The combination therapy comprising cilostazol and statins, particularly pravastatin, exerted the best anti-TNF effect compared with clopidogrel and statin therapy; thus, a suitable combination therapy, such as CILOP, can be a potential remedy to cure TNF-related diseases.

Index of microvascular resistance to assess the effect of rosuvastatin on microvascular function in women with chest pain and no obstructive coronary artery disease: A double-blind randomized study.

INTRODUCTION: Many women undergoing coronary angiography for chest pain have no or only minimal coronary artery disease (CAD). However, despite the lack of obstructive CAD, they still have an increased risk of major adverse cardiovascular events. Pleiotropic effects of statins may influence microvascular function, but if statins improve microvascular function in unselected chest pain patients is not well studied. This study assessed microvascular function by using the thermodilution-derived test "the index of microvascular resistance" (IMR) with the aim of determining the (i) IMR level in women with chest pain and non-obstructive CAD and if (ii) IMR is modified by high-dose statin treatment in these patients. Additional objectives were to identify the influence of statins on the health status as assessed with generic health questionnaires and on biomarkers of endothelial activation. MATERIALS AND METHODS: The study was a randomized, double-blind, single-center trial comparing 6 months of rosuvastatin treatment with placebo. In total, 66 women without obstructive CAD were included. Mean age was 52.7 years and 55.5 years in the placebo and rosuvastatin group, respectively. Microvascular function was assessed using the IMR, health status was assessed using the SF-36 and EQ-5D questionnaires, and biochemical values were assessed at baseline and 6 months later. RESULTS AND CONCLUSIONS: In the placebo group IMR was 14.6 (SD 5.7) at baseline and 14.4 (SD 6.5) at follow-up. In the rosuvastatin group IMR was 16.5 (SD 7.5) at baseline and 14.2 (SD 5.8) at follow-up. IMR did not differ significantly between the two study groups at follow-up controlled for preintervention values. C-reactive protein (CRP) was comparable between the groups at baseline, while at follow-up CRP was significantly lower in the rosuvastatin group compared to placebo [0.6 (±0.5) mg/L vs. 2.6 (±3.0) mg/L; p = 0.002]. Whereas rosuvastatin treatment for 6 months attenuated CRP levels, it did not improve microvascular function as assessed by IMR (Clinical Trials.gov NCT01582165, EUDRACT 2011-002630-39.3tcAZ).

Comparative effects of high-dose atorvastatin versus rosuvastatin on lipid parameters, oxidized low-density lipoprotein, and proprotein convertase subtilisin kexin 9 in acute coronary syndrome.

AIM: Current guidelines recommend administration of high-dose statins in acute coronary syndrome (ACS). It has been reported that statins upregulate proprotein convertase subtilisin kexin 9 (PCSK9) mRNA expression and increase circulating PCSK9 levels. We aimed to compare the effects of high-dose atorvastatin and rosuvastatin on serum oxidized low-density lipoprotein (oxidized-LDL) and PCSK9 levels in statin-naive patients with ACS. PATIENTS AND METHODS: One hundred and six patients with ACS were enrolled in this study. The patients were assigned randomly to receive atorvastatin (80 mg/day) or rosuvastatin (40 mg/day) by using a ratio of 1 : 1 in randomization. The levels of total cholesterol (TC), triglyceride, high-density lipoprotein cholesterol, LDL-cholesterol, oxidized-LDL, and PCSK9 were compared between groups after a 4-week treatment. RESULTS: Our study population included 53 patients in the atorvastatin group (age: 58.13±11.30 years, 11.32% female) and 53 patients in the rosuvastatin group (age: 59.08±12.44 years, 15.09% female). In both groups, lipid parameters, oxidized-LDL, and PCSK9 values changed significantly according to the baseline following treatment. High-dose atorvastatin and rosuvastatin induced similar decreases in LDL-cholesterol, oxidized-LDL, and triglyceride levels and similarly increased in high-density lipoprotein cholesterol and PCSK9 levels (P>0.05). CONCLUSION: We showed that atorvastatin and rosuvastatin treatment regimens have comparable effects on lipid parameters and PCSK9 levels in ACS patients.

Comparative Efficacy of Statins for Prevention of Contrast-Induced Acute Kidney Injury in Patients With Chronic Kidney Disease: A Network Meta-Analysis.

Contrast-induced acute kidney injury (CI-AKI) is a common complication of iodinated contrast medium administration during cardiac catheterization. Statin treatment has been shown to be associated with reduced risk of CI-AKI; however, the results are inconsistent, especially for patients with chronic kidney disease (CKD). Thus, we conducted a network meta-analysis to evaluate the effects of statins in the prevention of CI-AKI. We systematically searched several databases (including, Embase, PubMed, the Cochrane Library, and ClinicalTrials.gov ) from inception to January 31, 2018. The primary outcome was occurrence of CI-AKI in patients with CKD undergoing cardiac catheterization. Both pairwise and network meta-analysis were performed. Finally, 21 randomized controlled trials with a total of 6385 patients were included. Results showed that statin loading before contrast administration was associated with a significantly reduced risk of CI-AKI in patients with CKD undergoing cardiac catheterization (odds ratio: 0.46; P < .05). Atorvastatin and rosuvastatin administered at high dose may be the most effective treatments to reduce incidence of CI-AKI, with no difference between these 2 agents.

Changes in Coronary Plaque Composition in Patients With Acute Myocardial Infarction Treated With High-Intensity Statin Therapy (IBIS-4): A Serial Optical Coherence Tomography Study.

OBJECTIVES: This study assessed changes in optical coherence tomography (OCT)-defined plaque composition in patients with ST-elevation myocardial infarction (STEMI) receiving high-intensity statin treatment. BACKGROUND: OCT is a high-resolution modality capable of measuring plaque characteristics including fibrous cap thickness (FCT) and macrophage infiltration. There is limited in vivo evidence regarding the effects of statins on OCT-defined coronary atheroma composition and no evidence in the context of STEMI. METHODS: In the IBIS-4 (Integrated Biomarker Imaging Study-4), 103 patients underwent intravascular ultrasonography and OCT of 2 noninfarct-related coronary arteries in the acute phase of STEMI. Patients were treated with high-dose rosuvastatin for 13 months. Serial OCT imaging was available in 153 arteries from 83 patients. We measured FCT by using a semi-automated method. Co-primary endpoints consisted of the change in minimum FCT (measured in fibroatheromas) and change in macrophage line arc. RESULTS: At 13 months, median low-density lipoprotein cholesterol had decreased from 128 mg/dl to 73.6 mg/dl. Minimum FCT, measured in 31 lesions from 27 patients, increased from 64.9 ± 19.9 µm to 87.9 ± 38.1 µm (p = 0.008). Macrophage line arc decreased from 9.6° ± 12.8° to 6.4° ± 9.6° (p < 0.0001). The secondary endpoint, mean lipid arc, decreased from 55.9° ± 37° to 43.5° ± 33.5°. In lesion-level analyses (n = 191), 9 of 13 thin-cap fibroatheromata (TCFAs) at baseline (69.2%) regressed to non-TCFA morphology, whereas 2 of 178 non-TCFA lesions (1.1%) progressed to TCFAs. CONCLUSIONS: In this observational study, we found significant increase in minimum FCT, reduction in macrophage accumulation, and frequent regression of TCFAs to other plaque phenotypes in nonculprit lesions of patients with STEMI treated with high-intensity statin therapy.

Reproductive outcomes in rat female offspring from male rats co-exposed to rosuvastatin and ascorbic acid during pre-puberty.

Dyslipidemias are occurring earlier in different countries due to the increase of obesity, bad eating habits, and sedentary lifestyle. Rosuvastatin reduces serum cholesterol; however, several studies associated statin exposure with male reproduction impairment. Ascorbic acid (AA) is an antioxidant substance that plays a protective role in the male reproductive system. Male rats were randomly divided into 6 experimental groups (n = 10), which received saline solution 0.9%, 3 or 10 mg/kg/day of rosuvastatin, 150 mg/day of AA or 3 or 10 mg/kg/day of rosuvastatin associated with 150 mg/day of AA from post-natal day (PND) 23 until PND 53. On PND 100, males were mated with non-treated female rats to obtain the female pups. The day of vaginal opening and the first estrus were assessed in the offspring. Two sets of females were euthanized on the first estrus after PND 42 and PND 75 to evaluate the histology of reproductive organs and hormone levels. A third set was used for sexual behavior and fertility test around PND 75. Female offspring from males exposed or co-exposed to the higher dose of statin exhibited a lower number of corpora lutea during puberty. On sexual maturity, the experimental group from males that were exposed to 3 mg displayed lower uterine luminal epithelium area. Paternal exposure to rosuvastatin at pre-puberty diminished uterine luminal epithelium in female offspring suggesting epigenetic changes were initiated by statin. Ascorbic acid co-administered to pre-pubertal males was able to ameliorate the reproductive damage in rat female offspring in adulthood.