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Dose-Dependent Inhibitory Effect of Rosuvastatin in Japanese Patients with Acute Myocardial Infarction on Serum Concentration of Matrix Metalloproteinases-INVITATION Trial.
Shirakawa, T, Fujisue, K, Nakamura, S, Yamamoto, N, Oshima, S, Matsumura, T, Tsunoda, R, Hirai, N, Koide, S, Tayama, S, et al
Journal of atherosclerosis and thrombosis. 2022;(2):229-241
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Abstract
AIM: Matrix metalloproteinases (MMPs) play critical roles in acute myocardial infarction (AMI). This trial was conducted to determine the potential effects of higher-dose rosuvastatin on circulating MMP levels in patients with AMI. METHODS This was a multicenter, open-label, 1:1 randomized, parallel-group study. Patients with AMI were randomly assigned to the appropriate-dose group (10 mg rosuvastatin once daily) or the low-dose group (2.5 mg rosuvastatin once daily) within 24 hours after percutaneous coronary intervention. MMP-2 and MMP-9 levels were measured on day 1 and at week 4, 12, and 24 after enrollment. The primary endpoint was the change in MMP levels at 24 weeks after enrollment. The secondary endpoints were change in MMP levels at day 1 and weeks 4 and 12 after enrollment. RESULTS Between August 2017 and October 2018, 120 patients with AMI from 19 institutions were randomly assigned to either the appropriate-dose or the low-dose group. There were 109 patients who completed the 24-week follow-up. The primary endpoint for both MMP-2 and MMP-9 was not significantly different between the two groups. The change in the active/total ratio of MMP-9 at week 12 after baseline was significantly lower in the appropriate-dose group compared with the low-dose group (0.81 [-52.8-60.1]% vs. 70.1 [-14.5-214.2]%, P=0.004), while the changes in MMP-2 were not significantly different between the two groups during the study period. CONCLUSIONS This study could not demonstrate the superiority of appropriate-dose of rosuvastatin in inhibiting serum MMPs levels in patients with AMI.
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Effect of Preloading With High Dose of Rosuvastatin on Serum Levels of Inflammatory Markers After Percutaneous Coronary Intervention.
Slhessarenko, JR, Hirata, M, Sousa, A, Bastos, GM, Higa, EMS, Mouro, MG, Sobrera, GC, Slhessarenko, RD, Viana, R, Abizaid, A, et al
The Journal of invasive cardiology. 2020;(9):335-341
Abstract
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)-1β (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.
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Rosuvastatin use increases plasma fibrinolytic potential: a randomised clinical trial.
Schol-Gelok, S, de Maat, MPM, Biedermann, JS, van Gelder, T, Leebeek, FWG, Lijfering, WM, van der Meer, FJM, Rijken, DC, Versmissen, J, Kruip, MJHA
British journal of haematology. 2020;(6):916-922
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Abstract
We conducted a study to assess the effect of rosuvastatin use on fibrinolysis in patients with previous venous thromboembolism (VTE). This was a post hoc analysis within the STAtins Reduce Thrombophilia (START) study (NCT01613794). Plasma fibrinolytic potential, fibrinogen, plasmin inhibitor, plasminogen activator inhibitor-1 (PAI-1) and thrombin-activatable fibrinolysis inhibitor (TAFI) were measured before and after four weeks of rosuvastatin or no treatment in participants with prior confirmed VTE, after ending anticoagulant therapy. In the non-rosuvastatin group (n = 121), plasma fibrinolytic potential and individual fibrinolysis parameters did not change at the end of the study versus the baseline, whereas in the rosuvastatin group (n = 126), plasma fibrinolytic potential increased: the mean clot lysis time decreased by 8·75 min (95% CI -13·8 to -3·72), and plasmin inhibitor levels and TAFI activity were lower at the end of the study (-0·05 U/ml; 95% CI -0·07 to -0·02 and -4·77%; 95% CI -6·81 to -2·73, respectively). PAI-1 levels did not change and fibrinogen levels were 0·17 g/l (95% CI 0·04-0·29) higher. In participants with prior VTE, rosuvastatin use led to an increased fibrinolytic potential compared with non-statin use. Our findings support the need for further studies on the possible role for statins in the secondary prevention of VTE.
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Effects of Fatty Acid Therapy in Addition to Strong Statin on Coronary Plaques in Acute Coronary Syndrome: An Optical Coherence Tomography Study.
Kita, Y, Watanabe, M, Kamon, D, Ueda, T, Soeda, T, Okayama, S, Ishigami, K, Kawata, H, Horii, M, Inoue, F, et al
Journal of the American Heart Association. 2020;(16):e015593
Abstract
BACKGROUND Vascular healing response associated with adjunctive n-3 polyunsaturated fatty acid therapy therapy in patients receiving strong statin therapy remains unclear. The aim of this study was to evaluate the effect of polyunsaturated fatty acid therapy with eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA) in addition to strong statin therapy on coronary atherosclerotic plaques using optical coherence tomography. METHODS AND RESULTS This prospective multicenter randomized controlled trial included 130 patients with acute coronary syndrome treated with strong statins. They were assigned to either statin only (control group, n=42), statin+high-dose EPA (1800 mg/day) (EPA group, n=40), statin+EPA (930 mg/day)+DHA (750 mg/day) (EPA+DHA group, n=48). Optical coherence tomography was performed at baseline and at the 8-month follow-up. The target for optical coherence tomography analysis was a nonculprit lesion with a lipid plaque. Between baseline and the 8-month follow-up, fibrous cap thickness (FCT) significantly increased in all 3 groups. There were no significant differences in the percent change for minimum FCT between the EPA or EPA+DHA group and the control group. In patients with FCT <120 µm (median value), the percent change for minimum FCT was significantly higher in the EPA or EPA+DHA group compared with the control group. CONCLUSIONS EPA or EPA+DHA therapy in addition to strong statin therapy did not significantly increase FCT in nonculprit plaques compared with strong statin therapy alone, but significantly increased FCT in patients with thinner FCT. Registration URL: https://www.umin.ac.jp/ctr/; Unique identifier: UMIN 000012825.
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[Evaluation of drug-drug interactions between yimitasvir phosphate capsules with sofosbuvir tablets, omeprazole magnesium enteric-coated tablets, and rosuvastatin calcium tablets].
Mai, JJ, Zhang, H, Peng, YY, Yang, X, Mao, L, Luo, L, Xie, HM, Zhang, YJ, Li, XJ, Ding, YH
Zhonghua gan zang bing za zhi = Zhonghua ganzangbing zazhi = Chinese journal of hepatology. 2020;(10):838-843
Abstract
Objective: To evaluate the drug-drug interactions and the tolerability of combined medication between yimitasvir phosphate capsules with sofosbuvir tablets, omeprazole magnesium enteric-coated tablets, and rosuvastatin calcium tablets in healthy volunteers. Methods: A randomized, open, and continuous administration design was used in trial 1 (yimitasvir phosphate capsules with sofosbuvir tablets). 28 subjects were randomly divided into two groups. A non-randomized, open design was used in trial 2 (yimitasvir phosphate capsules with omeprazole magnesium enteric-coated tablets), and included 42 subjects divided into three groups. The open design method was used in trial 3 (yimitasvir phosphate capsules with rosuvastatin calcium tablets), and included 14 subjects. The plasma concentrations of yimitasvir phosphate, sofosbuvir and their main metabolites GS-331007, omeprazole and rosuvastatin were validated by a liquid chromatography/tandem mass spectrometry (LC-MS/MS). The pharmacokinetic parameters were calculated by Phoenix winNonlin software. Results: (1) in trial 1, after single and co-administration, the 90% CI of sofosbuvir C(max) and AUC(0-tau) geometric mean ratio (GMR) were 152.0% (118.0% ~ 197.0%) and 230.0% (184.0% ~ 287.0%), with an increase of 52.0% and 130.0% compared to single dose of sofosbuvir, respectively. The 90% CI of GS-331007 C(max) GMR was 74.0% (67.5% ~ 81.2%) and reduced by 26% compared to single dose of sofosbuvir. (2) in trial 2, the 90% CI of C(max) GMR after yimitasvir single or co-administration at the same time, with a 4-hours interval, or with a 12- hours interval were 68.9% (44.5% ~ 106.7%) , 64.0% (43.8% ~ 93.6%) and 56.4%(38.9% ~ 81.9%), and the 90% CI of AUC(0-t) GMR were 68.6% (46.5% ~ 101.2%), 68.3% (47.6% ~ 98.0%) and 60.5% (41.8% ~ 87.5%), respectively. Compared with single dose of yimitasvir, the C(max) and AUC(0-t) were decreased by 31.1% and 31.4%, 36.0% and 31.7%, 43.6% and 39.5%, respectively. (3) In trial 3, after single and co-administration, the 90% CI of rosuvastatin C(max) and AUC(0-72) GMR were 172.4% (153.6% ~ 193.5%) and 158.0% (144.3% ~ 172.9%), respectively, with an increase of 74.9% and 60.5% compared to single dose of rosuvastatin. There were no serious adverse events and adverse events leading to withdrawal from the trial. Conclusion: Yimitasvir phosphate capsules have drug-drug interactions with sofosbuvir tablets, omeprazole magnesium enteric-coated tablets, and rosuvastatin calcium tablets.
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Influence of rosuvastatin dose on total fatty acids and free fatty acids in plasma: Correlations with lipids involved in cholesterol homeostasis.
Ciucanu, CI, Olariu, S, Vlad, DC, Dumitraşcu, V
Medicine. 2020;(48):e23356
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Abstract
This study investigates for the first time the influence of four doses of rosuvastatin on total fatty acids (TFA) and free fatty acids (FFA) in human plasma and correlates their changes in concentration with changes in the concentration of other lipids involved in cholesterol homeostasis.This study was a placebo-controlled, randomized, double-blind, crossover experiment. The study used a single group of 16 men and consisted of 5 treatment periods lasting 4 weeks each with placebo and 4 doses of rosuvastatin (5, 10, 20, and 40 mg). Each subject changed 5 medical treatments and received in each new treatment different tablets of rosuvastatin or placebo compared to those taken in previous treatments, in a random order. Between treatment periods there was a wash-out period of 2 weeks, without treatment.Changes in TFA and FFA were significant compared to placebo and between different doses of rosuvastatin. We found a continuous logarithmic decrease in levels of TFA, FFA, low-density lipoprotein (LDL)-cholesterol, total cholesterol, triglycerides, phospholipids, and apolipoprotein B-100, and a continuous increase in levels of high-density lipoprotein (HDL)-cholesterol and apolipoprotein A-1 by increases the dose of rosuvastatin. Analysis of the correlation of TFA and FFA with the main lipids and lipoproteins in cholesterol homeostasis indicated a linear regression with high correlation coefficients and all P-values were less than .05 level.The concentrations of TFA and FFA are significantly influenced by the dose of rosuvastatin. They are strongly correlated with those of other lipids and lipoproteins involved in cholesterol homeostasis. The mechanisms of cholesterol homeostasis regulation are involved in changing the concentrations of TFA and FFA.
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Effects of different doses of atorvastatin, rosuvastatin, and simvastatin on elderly patients with ST-elevation acute myocardial infarction (AMI) after percutaneous coronary intervention (PCI).
He, W, Cao, M, Li, Z
Drug development research. 2020;(5):551-556
Abstract
OBJECTIVE To conduct a randomized double-blind prospective study to investigate effect of different doses of atorvastatin, rosuvastatin, and simvastatin on elderly patients with ST-elevation AMI after PCI. METHODS One hundred and ninety-two AMI patients over 60 years old who underwent PCI were randomly divided into six groups: the low atorvastatin group, high atorvastatin group; low rosuvastatin group; high rosuvastatin group; low simvastatin group; high simvastatin group. Demographic data and clinical information as well as coronary angiography parameters were recorded. Plasma levels of CK-MB, BNP, ALT, and TnI were measured at 12 hr, 24 hr, and 1 week after PCI. Major cardiovascular events (MACE) were recorded and analyzed using Kaplan-Meier (K-M) curve. RESULTS No significant differences were observed in angiographic and procedural characteristics. In all high dose groups, all levels of CK-MB, BNP, ALT, and TnI were significantly lower. However, after 1 week of PCI, only CK-MB, BNP, and TnI showed significant difference between high and low dose groups. Patients in high dose groups had significantly lower rates for surgical or percutaneous intervention, recurrence of angina, and rehospitalization. K-M curve analysis also showed cumulative incidence freedom time of overall MACE in high dose groups was significantly longer. No significant differences were found among different drugs with the same doses. CONCLUSION Patients with higher doses had lower level of CK-MB, BNP, ALT, and TnI and lower occurrence of MACE after PCI.
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Concomitant Use of Rosuvastatin and Eicosapentaenoic Acid Significantly Prevents Native Coronary Atherosclerotic Progression in Patients With In-Stent Neoatherosclerosis.
Sugizaki, Y, Otake, H, Kuroda, K, Kawamori, H, Toba, T, Nagasawa, A, Takeshige, R, Nakano, S, Matsuoka, Y, Tanimura, K, et al
Circulation journal : official journal of the Japanese Circulation Society. 2020;(10):1826-1836
Abstract
BACKGROUND In-stent neoatherosclerosis (NA) is a risk for future cardiovascular events through atherosclerotic progression in non-stented lesions. Using optical coherence tomography, this study assessed the efficacy of intensive therapy with 10 mg/day rosuvastatin plus 1,800 mg/day eicosapentaenoic acid (EPA) vs. standard 2.5 mg/day rosuvastatin therapy on native coronary plaques in patients with NA.Methods and Results:This was a subgroup analysis of the randomized LINK-IT trial, which was designed to compare changes in the lipid index in NA between intensive and standard therapy for 12 months. In all, 42 patients with native coronary plaques and NA were assessed. Compared with standard therapy, intensive therapy resulted in greater decreases in serum low-density lipoprotein cholesterol concentrations and greater increases in serum 18-hydroxyeicosapentaenoic acid concentrations, with significantly greater decreases in the lipid index and macrophage grade in both NA (-24 vs. 217 [P<0.001] and -15 vs. 24 [P<0.001], respectively) and native coronary plaques (-112 vs. 29 [P<0.001] and -17 vs. 1 [P<0.001], respectively) following intensive therapy. Although there was a greater increase in the macrophage grade in NA than in native coronary plaques in the standard therapy group, in the intensive therapy group there were comparable reductions in macrophage grade between NA and native coronary plaques. CONCLUSIONS Compared with standard therapy, intensive therapy prevented atherosclerotic progression more effectively in native coronary plaques in patients with NA.
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ApoCIII-Lp(a) complexes in conjunction with Lp(a)-OxPL predict rapid progression of aortic stenosis.
Capoulade, R, Torzewski, M, Mayr, M, Chan, KL, Mathieu, P, Bossé, Y, Dumesnil, JG, Tam, J, Teo, KK, Burnap, SA, et al
Heart (British Cardiac Society). 2020;(10):738-745
Abstract
OBJECTIVE This study assessed whether apolipoprotein CIII-lipoprotein(a) complexes (ApoCIII-Lp(a)) associate with progression of calcific aortic valve stenosis (AS). METHODS Immunostaining for ApoC-III was performed in explanted aortic valve leaflets in 68 patients with leaflet pathological grades of 1-4. Assays measuring circulating levels of ApoCIII-Lp(a) complexes were measured in 218 patients with mild-moderate AS from the AS Progression Observation: Measuring Effects of Rosuvastatin (ASTRONOMER) trial. The progression rate of AS, measured as annualised changes in peak aortic jet velocity (Vpeak), and combined rates of aortic valve replacement (AVR) and cardiac death were determined. For further confirmation of the assay data, a proteomic analysis of purified Lp(a) was performed to confirm the presence of apoC-III on Lp(a). RESULTS Immunohistochemically detected ApoC-III was prominent in all grades of leaflet lesion severity. Significant interactions were present between ApoCIII-Lp(a) and Lp(a), oxidised phospholipids on apolipoprotein B-100 (OxPL-apoB) or on apolipoprotein (a) (OxPL-apo(a)) with annualised Vpeak (all p<0.05). After multivariable adjustment, patients in the top tertile of both apoCIII-Lp(a) and Lp(a) had significantly higher annualised Vpeak (p<0.001) and risk of AVR/cardiac death (p=0.03). Similar results were noted with OxPL-apoB and OxPL-apo(a). There was no association between autotaxin (ATX) on ApoB and ATX on Lp(a) with faster progression of AS. Proteomic analysis of purified Lp(a) showed that apoC-III was prominently present on Lp(a). CONCLUSION ApoC-III is present on Lp(a) and in aortic valve leaflets. Elevated levels of ApoCIII-Lp(a) complexes in conjunction with Lp(a), OxPL-apoB or OxPL-apo(a) identify patients with pre-existing mild-moderate AS who display rapid progression of AS and higher rates of AVR/cardiac death. TRIAL REGISTRATION NCT00800800.
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High dose rosuvastatin increases ABCA1 transporter in human atherosclerotic plaques in a cholesterol-independent fashion.
Santovito, D, Marcantonio, P, Mastroiacovo, D, Natarelli, L, Mandolini, C, De Nardis, V, Paganelli, C, De Cesare, D, Affaitati, G, Giamberardino, MA, et al
International journal of cardiology. 2020;:249-253
Abstract
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.