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Among patients with recent MI, therapy with a polypill containing aspirin, ramipril, and atorvastatin led to a lower incidence of major adverse cardiovascular events at a median of 3 years than usual care.

Cerebral cavernous malformations (CCMs) carry a high risk of rebleeding after symptomatic haemorrhage, with serious clinical sequelae. Atorvastatin was shown to prevent CCM growth and bleeding in animal models. We aimed to assess the safety and efficacy of atorvastatin on rebleeding in patients with CCMs after a symptomatic haemorrhage. We did a phase 1/2a randomised trial at the University of Chicago's CCM Center of Excellence. Patients aged 18–80 years with untreated CCMs who had had symptomatic bleeding from a CCM lesion within the previous year were eligible. Patients were randomly allocated (1:1) to oral atorvastatin (80 mg daily for 2 years) or matching placebo. Investigators, clinical staff, and participants were masked to the assigned treatment. The primary efficacy outcome was the percentage change in mean lesional iron deposition per year, measured by quantitative susceptibility mapping (QSM) on MRI and averaged over 2 years; a decrease would signal potential benefit and an increase a safety concern. The primary efficacy outcome was analysed in the modified intention-to-treat cohort, including patients with at least one annual paired QSM assessment. Safety outcomes included rates of bleeds and serious adverse events necessitating drug discontinuation. This trial is registered at ClinicalTrials.gov (NCT02603328) and is completed. Between July 25, 2018, and July 22, 2022, 326 patients were assessed for eligibility, and 80 patients were allocated either atorvastatin (n=41) or placebo (n=39). 29 (36%) patients were male and 51 (64%) were female. 64 (80%) patients (33 in the atorvastatin group and 31 in the placebo group) had at least one annual paired QSM assessment and were included in the modified intention-to-treat analyses. The mean annual percentage change in lesional QSM was 10·88 (SE 7·29) with atorvastatin versus 12·09 (SE 7·54) with placebo (treatment effect –1·22, 95% CI –22·25 to 19·81; p=0·91). Symptomatic haemorrhage was reported in six patients assigned atorvastatin and seven patients assigned placebo (relative risk 0·81, 95% CI 0·31 to 2·13). No patients had a serious adverse event requiring drug discontinuation and no deaths were recorded. For people with symptomatic haemorrhage caused by CCMs, atorvastatin did not affect the mean change in lesional iron deposition on brain MRI over 2 years when compared with placebo. Atorvastatin was well tolerated and no safety concerns were noted. The study provides a useful framework for biomarker driven drug assessment in a rare disease. US National Institutes of Health.

Purpose Systemic exposure to rosuvastatin is approximately double that of Caucasians in Asian subjects. We investigated whether this pattern of increased exposure exists for other statins. Methods Plasma exposure following single-dose rosuvastatin 20 mg, atorvastatin 40 mg or simvastatin 40 mg was studied in Chinese, Japanese and Caucasian subjects. Plasma concentrations were determined using LC-MS methods. Impact of polymorphisms in SLCO1B1 (T521>C and A388>G) and in ABCG2 (C421>A) on exposure to rosuvastatin, atorvastatin, simvastatin and simvastatin acid was assessed. Results Relative to Caucasians, geometric mean area under the curve from time zero to time of last quantifiable concentration was 86 % (90 % confidence interval (CI), 51–130 %) and 55 % (26–91 %) higher for rosuvastatin in Chinese and Japanese subjects, respectively, 53 % (25–88 %) and 69 % (37–108 %) higher for atorvastatin, 23 % (0–52 %) and 12 % (−0.9–39 %) higher for simvastatin and 28 % (5–56 %) and 34 % (10–64 %) higher for simvastatin acid. Geometric mean maximum drug concentration was also proportionally higher for each statin. Polymorphisms in SLCO1B1 T521>C or ABCG2 C421>A were associated with higher exposure to rosuvastatin, atorvastatin and simvastatin acid (but not simvastatin) within a population, but only the ABCG2 C421>A polymorphism contributed towards between-population exposure differences. In individuals carrying wild-type alleles for both SLCO1B1 and ABCG2 , area under the plasma concentration-time curve (AUC) still appeared to be higher for rosuvastatin, atorvastatin and simvastatin acid in Chinese and Japanese subjects compared with Caucasians, respectively. Conclusion Increased exposure to statins in Asian subjects versus Caucasians may represent a more general class phenomenon than previously recognized.

In blinded randomised controlled trials, statin therapy has been associated with few adverse events (AEs). By contrast, in observational studies, larger increases in many different AEs have been reported than in blinded trials. In the Lipid-Lowering Arm of the Anglo-Scandinavian Cardiac Outcomes Trial, patients aged 40–79 years with hypertension, at least three other cardiovascular risk factors, and fasting total cholesterol concentrations of 6·5 mmol/L or lower, and who were not taking a statin or fibrate, had no history of myocardial infarction, and were not being treated for angina were randomly assigned to atorvastatin 10 mg daily or matching placebo in a randomised double-blind placebo-controlled phase. In a subsequent non-randomised non-blind extension phase (initiated because of early termination of the trial because efficacy of atorvastatin was shown), all patients were offered atorvastatin 10 mg daily open label. We classified AEs using the Medical Dictionary for Regulatory Activities. We blindly adjudicated all reports of four prespecified AEs of interest—muscle-related, erectile dysfunction, sleep disturbance, and cognitive impairment—and analysed all remaining AEs grouped by system organ class. Rates of AEs are given as percentages per annum. The blinded randomised phase was done between February, 1998, and December, 2002; we included 101 80 patients in this analysis (5101 [50%] in the atorvastatin group and 5079 [50%] in the placebo group), with a median follow-up of 3·3 years (IQR 2·7–3·7). The non-blinded non-randomised phase was done between December, 2002, and June, 2005; we included 9899 patients in this analysis (6409 [65%] atorvastatin users and 3490 [35%] non-users), with a median follow-up of 2·3 years (2·2–2·4). During the blinded phase, muscle-related AEs (298 [2·03% per annum] vs 283 [2·00% per annum]; hazard ratio 1·03 [95% CI 0·88–1·21]; p=0·72) and erectile dysfunction (272 [1·86% per annum] vs 302 [2·14% per annum]; 0·88 [0·75–1·04]; p=0·13) were reported at a similar rate by participants randomly assigned to atorvastatin or placebo. The rate of reports of sleep disturbance was significantly lower among participants assigned atorvastatin than assigned placebo (149 [1·00% per annum] vs 210 [1·46% per annum]; 0·69 [0·56–0·85]; p=0·0005). Too few cases of cognitive impairment were reported for a statistically reliable analysis (31 [0·20% per annum] vs 32 [0·22% per annum]; 0·94 [0·57–1·54]; p=0·81). We observed no significant differences in the rates of all other reported AEs, with the exception of an excess of renal and urinary AEs among patients assigned atorvastatin (481 [1·87%] per annum vs 392 [1·51%] per annum; 1·23 [1·08–1·41]; p=0·002). By contrast, during the non-blinded non-randomised phase, muscle-related AEs were reported at a significantly higher rate by participants taking statins than by those who were not (161 [1·26% per annum] vs 124 [1·00% per annum]; 1·41 [1·10–1·79]; p=0·006). We noted no significant differences between statin users and non-users in the rates of other AEs, with the exception of musculoskeletal and connective tissue disorders (992 [8·69% per annum] vs 831 [7·45% per annum]; 1·17 [1·06–1·29]; p=0·001) and blood and lymphatic system disorders (114 [0·88% per annum] vs 80 [0·64% per annum]; 1·40 [1·04–1·88]; p=0·03), which were reported more commonly by statin users than by non-users. These analyses illustrate the so-called nocebo effect, with an excess rate of muscle-related AE reports only when patients and their doctors were aware that statin therapy was being used and not when its use was blinded. These results will help assure both physicians and patients that most AEs associated with statins are not causally related to use of the drug and should help counter the adverse effect on public health of exaggerated claims about statin-related side-effects. Pfizer, Servier Research Group, and Leo Laboratories.

Rosuvastatin can block human ether-a-go-go related gene (hERG) currents and prolong the corrected QT (QTc) interval, but this effect has not been confirmed in the population. This study compared the changes of QTc interval between populations receiving atorvastatin and rosuvastatin, explained the effect of rosuvastatin on QTc interval, and the correlation between rosuvastatin and QT prolongation. The QTc interval decreased by 0.83 ms from baseline in atorvastatin group and increased by 6.57 ms in rosuvastatin group. More patients in the rosuvastatin group had an increased QTc interval (62.7% vs. 46.6%, p< 0.001). Rosuvastatin increased the risk of newly emerged QT prolongation by 42% (95% CI 1.10–1.85, p  = 0.008). But there was no correlation between rosuvastatin and severe QT prolongation (RR 1.23, 95% CI 0.74–2.06, p  = 0.426). In conclusion, rosuvastatin exhibits a modest adverse effect on the QTc interval. Rosuvastatin monotherapy does not appear to increase the risk of arrhythmia. But this study did not assess the usage of rosuvastatin with other QT-prolonging drugs, the potential for an additive effect should be considered when combining rosuvastatin with other QT-prolonging drugs. Trial registration: ChiCTR2400092701 (21/11/2024)

•A fixed-dose triple combination of Fimasartan, atorvastatin, and ezetimibe (FAE) effectively controls both blood pressure and LDL-cholesterol simultaneously.•The safety profile of the FAE triple therapy is comparable to that of its individual components, confirming its tolerability.•The single-pill FAE combination may simplify treatment regimens for patients, potentially improving medication adherence.•This is the first phase III clinical trial to validate the efficacy and safety of the fixed-dose FAE combination therapy. Essential hypertension and primary hypercholesterolemia are common and independent cardiovascular risk factors that frequently coexist and warrant integrated management. This study aimed to evaluate the efficacy and safety of triple combination therapy (FMS + ATO/EZE) with Fimasartan (FMS), atorvastatin (ATV), and ezetimibe (EZE) compared with atorvastatin/ezetimibe (ATO/EZE) dual therapy or Fimasartan (FMS) monotherapy in patients with hypertension and hypercholesterolemia. This multicenter, randomized clinical trial was conducted across 25 clinical trial institutions in the Republic of Korea. A total of 315 participants were screened, of whom 148 eligible participants were randomized to receive FMS + ATO/EZE (n = 49), ATO/EZE (n = 49), or FMS (n = 50). The primary efficacy endpoints were the change in mean sitting systolic blood pressure (msSBP) from baseline to week 8 in the FMS + ATO/EZE group compared with that in the ATO/EZE group and the percentage change in low-density lipoprotein cholesterol (LDL-C) from baseline to week 8 in the FMS + ATO/EZE group compared with that in the FMS group. Safety was assessed based on treatment-emergent adverse events (TEAEs). In the full analysis set, the FMS + ATO/EZE group demonstrated superior reduction in msSBP compared to the ATO/EZE group (least squares [LS] mean difference: –7.26 ± 2.84 mm Hg; 95% confidence interval [CI]: –12.91, –1.61; P = 0.0124). Similarly, the percentage reduction in LDL-C was significantly greater in the FMS + ATO/EZE group than in the FMS group (LS mean difference: –58.02% ± 4.03%; 95% CI: –66.03, –50.02; P < 0.0001). The incidence of TEAEs was comparable across treatment groups: FMS + ATO/EZE (20.83%), ATO/EZE (22.45%), and FMS (16.00%) (P = 0.7030). Serious adverse events occurred in 1.36% of the total safety population, without significant difference between the groups (P = 0.5480). Triple combination therapy with FMS + ATO/EZE was superior to dual therapy or monotherapy in reducing both BP and LDL-C levels in patients with essential hypertension accompanied by primary hypercholesterolemia. The safety profile was comparable with that of the individual components, confirming the tolerability and safety of FMS + ATO/EZE therapy. However, the 8-week follow-up period and enrollment of an exclusively Korean cohort may limit the assessment of long-term effects and generalizability to other ethnic populations.

Patients who had discontinued statins because of side effects received four bottles of a statin, four bottles of placebo, and four empty bottles, each to be used for 1 month in a random sequence for 12 months. The symptom burden with placebo was 90% of the symptom burden with the statin.

Background Evidence supporting the use of statin therapy to reduce stroke recurrence and cardiovascular events in acute cardioembolic stroke (CES) patients without atherosclerosis is limited. Past observational studies have been hampered by selection bias and unmeasured confounding factors. This study aims to investigate the potential benefits of statin therapy in acute CES patients without established indications through a registry-based, randomized clinical trial. Methods This is a registry-based, multicenter, prospective, randomized, open-label, blinded endpoint (PROBE) study designed to evaluate the efficacy and safety of statin therapy in acute CES patients without established indications for statin use. Patients will be randomly assigned (1:1) to either statin users or non-users, with statin users receiving atorvastatin at a dose of 10 mg or higher throughout the study period. We plan to recruit 1036 participants to detect a relative risk reduction of 43% with 80% power and a two-sided alpha error of 0.05, accounting for a 10% loss to follow-up. The primary outcome is the occurrence of a major clinical event, defined as a composite of stroke recurrence, myocardial infarction, and all-cause mortality within 3 months after the index stroke. The secondary efficacy outcomes include (1) stroke recurrence, (2) all-cause mortality, (3) vascular death, and (4) major vascular events. Discussion This study will assist stroke physicians in determining the appropriate use of statin therapy for acute CES patients who do not have guideline-based indications. Trial registration CRIS Registration Number: KCT0006806. Registered on November 29, 2021. URL: https://cris.nih.go.kr/cris

Background Extracellular vesicles (EVs) derived from bone marrow mesenchymal stem cells (MSCs) pretreated with atorvastatin (ATV) (MSC ATV -EV) have a superior cardiac repair effect on acute myocardial infarction (AMI). The mechanisms, however, have not been fully elucidated. This study aims to explore whether inflammation alleviation of infarct region via macrophage polarization plays a key role in the efficacy of MSC ATV -EV. Methods MSC ATV -EV or MSC-EV were intramyocardially injected 30 min after coronary ligation in AMI rats. Macrophage infiltration and polarization (day 3), cardiac function (days 0, 3, 7, 28), and infarct size (day 28) were measured. EV small RNA sequencing and bioinformatics analysis were conducted for differentially expressed miRNAs between MSC ATV -EV and MSC-EV. Macrophages were isolated from rat bone marrow for molecular mechanism analysis. miRNA mimics or inhibitors were transfected into EVs or macrophages to analyze its effects on macrophage polarization and cardiac repair in vitro and in vivo. Results MSC ATV -EV significantly reduced the amount of CD68 + total macrophages and increased CD206 + M2 macrophages of infarct zone on day 3 after AMI compared with MSC-EV group ( P  < 0.01–0.0001). On day 28, MSC ATV -EV much more significantly improved the cardiac function than MSC-EV with the infarct size markedly reduced ( P  < 0.05–0.0001). In vitro, MSC ATV -EV also significantly reduced the protein and mRNA expressions of M1 markers but increased those of M2 markers in lipopolysaccharide-treated macrophages ( P  < 0.05–0.0001). EV miR-139-3p was identified as a potential cardiac repair factor mediating macrophage polarization. Knockdown of miR-139-3p in MSC ATV -EV significantly attenuated while overexpression of it in MSC-EV enhanced the effect on promoting M2 polarization by suppressing downstream signal transducer and activator of transcription 1 (Stat1). Furthermore, MSC ATV -EV loaded with miR-139-3p inhibitors decreased while MSC-EV loaded with miR-139-3p mimics increased the expressions of M2 markers and cardioprotective efficacy. Conclusions We uncovered a novel mechanism that MSC ATV -EV remarkably facilitate cardiac repair in AMI by promoting macrophage polarization via miR-139-3p/Stat1 pathway, which has the great potential for clinical translation.

Background Major cardiovascular events (MACE) after percutaneous coronary intervention (PCI) are among the most common causes of death in patients. Lipid-lowering strategies seem to affect these events. Reaching the best regimen for controlling lipid abnormalities is important. This study aimed to compare the effect of ezetimibe and atorvastatin versus atorvastatin alone in short-term major cardiovascular events in patients after PCI in Bandar Abbas in 2018. Methods This double-blinded randomized controlled trial was done in Bandar Abbas in 2018 on 224 patients. Patients were randomly divided into two groups either to receive ezetimibe and atorvastatin (group A) or atorvastatin alone (group B). Patients were followed for 1 month for major cardiovascular events and drug side effects. Data was analyzed using SPSS software. Results Patients in the two groups had similar baseline characteristics. The mean low-density lipoproteins (LDL) level was 69.83 ± 28.8 in group A and 82.45 ± 29.9 in group B ( P  = 0.014). At the end of the study, high-sensitivity C-reactive protein (hs-CRP) values were notably lower in group A ( P value = 0.005). Three (2.7%) patients in group A and 1 patient (0.9%) in group B had a myocardial infarction ( P value = 0.313). Also, 11 patients (9.8%) in group A and 13 patients (11.6%) in group B had unstable angina ( P value = 0.666). No patients had death, cerebrovascular event, or stent thrombosis in the two groups. Conclusion Although adding ezetimibe to atorvastatin can decrease LDL and hs-CRP levels in short-term follow-up; it is not effective in lowering short-term major cardiovascular events in patients after PCI. Studies with longer-term follow-up are recommended. Trial registration IRCT, IRCT20171028037047N1. Registered on 22 June 2018, https://irct.behdasht.gov.ir/trial/28808 .