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Effect of Rosuvastatin on Cholesterol Efflux Capacity and Endothelial Function in Type 2 Diabetes Mellitus and Dyslipidemia.
Jung, KY, Kim, KM, Han, SK, Yun, HM, Oh, TJ, Choi, SH, Park, KS, Jang, HC, Lim, S
Circulation journal : official journal of the Japanese Circulation Society. 2018;(5):1387-1395
Abstract
BACKGROUND Quality and quantity of high-density lipoprotein cholesterol (HDL-C) may be associated with cardiovascular risk. We investigated the effect of rosuvastatin on cholesterol efflux (CE) for HDL function and vascular health.Methods and Results:We enrolled 30 dyslipidemic patients with type 2 diabetes mellitus and 20 healthy subjects as controls. Vascular health was assessed on flow-medicated dilation (FMD), nitroglycerin-induced dilatation of the brachial artery and carotid artery intima-media thickness (cIMT). These parameters were compared between patients and controls, and between baseline and at 12 weeks of treatment with rosuvastatin 20 mg. Age and body mass index were 49.8±11.3 years and 25.8±3.7 kg/m2in the patients, and 28.8±3.2 years and 22.4±2.4 kg/m2in the controls, respectively. The biomarkers related to lipid and glucose metabolism and lipoprotein (a), high-sensitivity C-reactive protein, and cIMT were significantly higher, and CE and FMD were significantly lower in the patients than in the controls. In the patients, rosuvastatin 20 mg decreased low-density lipoprotein cholesterol by 54.1% and increased HDL-C by 4.8%. The CE increased significantly after rosuvastatin treatment (12.26±2.72% vs. 14.05±4.14%). FMD also increased, and lipoprotein (a) and cIMT decreased significantly and were associated with changes of CE. CONCLUSIONS Rosuvastatin-induced changes in HDL function are significantly associated with cardiovascular benefit.
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Association of Mild to Moderate Aortic Valve Stenosis Progression With Higher Lipoprotein(a) and Oxidized Phospholipid Levels: Secondary Analysis of a Randomized Clinical Trial.
Capoulade, R, Yeang, C, Chan, KL, Pibarot, P, Tsimikas, S
JAMA cardiology. 2018;(12):1212-1217
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Abstract
IMPORTANCE Several studies have reported an association of levels of lipoprotein(a) (Lp[a]) and the content of oxidized phospholipids on apolipoprotein B (OxPL-apoB) and apolipoprotein(a) (OxPL-apo[a]) with faster calcific aortic valve stenosis (CAVS) progression. However, whether this association is threshold or linear remains unclear. OBJECTIVE To determine whether the plasma levels of Lp(a), OxPL-apoB, and OxPL-apo(a) have a linear association with a faster rate of CAVS progression. DESIGN, SETTING, AND PARTICIPANTS This secondary analysis of a randomized clinical trial tested the association of baseline plasma levels of Lp(a), OxPL-apoB, and OxPL-apo(a) with the rate of CAVS progression. Participants were included from the ASTRONOMER (Effects of Rosuvastatin on Aortic Stenosis Progression) trial, a multicenter study conducted in 23 Canadian sites designed to test the effect of statin therapy (median follow-up, 3.5 years [interquartile range, 2.9-4.5 years]). Patients with mild to moderate CAVS defined by peak aortic jet velocity ranging from 2.5 to 4.0 m/s were recruited; those with peak aortic jet velocity of less than 2.5 m/s or with an indication for statin therapy were excluded. Data were collected from January 1, 2002, through December 31, 2005, and underwent ad hoc analysis from April 1 through September 1, 2018. INTERVENTIONS After the randomization process, patients were followed up by means of echocardiography for 3 to 5 years. MAIN OUTCOMES AND MEASURES Progression rate of CAVS as assessed by annualized progression of peak aortic jet velocity. RESULTS In this cohort of 220 patients (60.0% male; mean [SD] age, 58 [13] years), a linear association was found between plasma levels of Lp(a) (odds ratio [OR] per 10-mg/dL increase, 1.10; 95% CI, 1.03-1.19; P = .006), OxPL-apoB (OR per 1-nM increase, 1.06; 95% CI, 1.01-1.12; P = .02), and OxPL-apo(a) (OR per 10-nM increase, 1.16; 95% CI, 1.05-1.27; P = .002) and faster CAVS progression, which is marked in younger patients (OR for Lp[a] level per 10-mg/dL increase, 1.19 [95% CI, 1.07-1.33; P = .002]; OR for OxPL-apoB level per 1-nM increase, 1.06 [95% CI, 1.02-1.17; P = .01]; and OR for OxPL-apo[a] level per 10-nM increase, 1.26 [95% CI, 1.10-1.45; P = .001]) and remained statistically significant after comprehensive multivariable adjustment (β coefficient, ≥ 0.25; SE, ≤ 0.004 [P ≤ .005]; OR, ≥1.10 [P ≤ .007]). CONCLUSIONS AND RELEVANCE This study demonstrates that the association of Lp(a) levels and its content in OxPL with faster CAVS progression is linear, reinforcing the concept that Lp(a) levels should be measured in patients with mild to moderate CAVS to enhance management and risk stratification. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT00800800.
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A New HOPE? Lessons from Heart Outcomes Prevention Evaluation-3.
Howard, TM, Bavishi, AA, Stone, NJ
The American journal of medicine. 2018;(2):134-140
Abstract
Lifestyle modification is the cornerstone of preventing atherosclerotic cardiovascular disease. When this is not sufficient in reducing risk, statin therapy is first line. Heart Outcomes Prevention Evaluation (HOPE-3) was a randomized controlled trial of rosuvastatin versus placebo, which demonstrated a significant net benefit in a lower-risk population without known atherosclerotic cardiovascular disease. There were many novel characteristics about this trial that should not be overlooked. It contained a diverse population and was the first trial to base inclusion solely on easily ascertainable metabolic risk factors. It had high adherence in the statin arm, likely due to several factors, including a run-in phase, close follow-up, and low intolerance of moderate-dose rosuvastatin. Attempting to simulate these could increase adherence among clinic populations. Although HOPE-3 did not demonstrate a significant decrease in cardiovascular events among women, meta-analysis including prior randomized controlled trials still demonstrates significant benefit, supporting prior guidelines for statin therapy in this group. Finally, HOPE-3 provides data that potentially support the legacy effect of statins. Understanding these key points provides additional insight into the benefits of statin therapy.
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Circulating microRNA-132 levels improve risk prediction for heart failure hospitalization in patients with chronic heart failure.
Masson, S, Batkai, S, Beermann, J, Bär, C, Pfanne, A, Thum, S, Magnoli, M, Balconi, G, Nicolosi, GL, Tavazzi, L, et al
European journal of heart failure. 2018;(1):78-85
Abstract
AIMS: Non-coding microRNAs (miRNAs) are critically involved in cardiovascular pathophysiology. Since they are measurable in most body fluids, they have been proposed as circulating biomarkers. We examined the prognostic value of a specific candidate miRNA in a large cohort of patients with chronic heart failure (HF) enrolled in a multicentre clinical trial. METHODS AND RESULTS Plasma levels of miR-132 were measured using miRNA-specific PCR-based technologies at randomization in 953 patients with chronic, symptomatic HF from the GISSI-Heart Failure trial. The association with fatal (all-cause and cardiovascular death) and non-fatal events (time to first admission to hospital for cardiovascular reasons or worsening of HF) and the incremental risk prediction were estimated in adjusted models. Higher circulating miR-132 levels were independently associated with younger age, better renal filtration, ischaemic aetiology of HF, more severe HF symptoms, higher diastolic blood pressure, higher cholesterol, and male sex. After extensive adjustment for demographic, clinical, and echocardiographic risk factors and baseline NT-proBNP concentrations, miR-132 remained associated only with HF hospitalizations (hazard ratio 0.79, 95% confidence interval 0.66-0.95, P = 0.01) and improved its risk prediction with the continuous net reclassification index (cNRI 0.205, P = 0.001). CONCLUSION In well characterized patients with chronic HF, circulating miR-132 levels rise with the severity of HF. Lower circulating miR-132 levels improved risk prediction for HF readmission beyond traditional risk factors, but not for mortality. MiR-132 may be helpful to intensify strategies aimed at reducing re-hospitalization, which has a substantial health and economic burden in HF.
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Impact of Water- and Lipid-Soluble Statins on Nonculprit Lesions in Patients with Acute Coronary Syndrome.
Ishikawa, Y, Itoh, T, Satoh, M, Fusazaki, T, Sugawara, S, Nakajima, S, Nakamura, M, Morino, Y
International heart journal. 2018;(1):27-34
Abstract
Statins can be differentiated into two types, based on their solubility, which have potentially differing effects on the coronary artery wall. However, suspected differences in statins' effects on plaque composition have not been systemically investigated.Sixty-seven patients with acute coronary syndrome (ACS) were randomly assigned to either atorvastatin (10 mg/day) or rosuvastatin (2.5 mg/day). Intravascular ultrasound (IVUS) and integrated backscatter (IB)-IVUS, an established tool to quantify each plaque's components, were performed immediately after emergent percutaneous coronary intervention (PCI). Follow-up IVUS was performed between 6 and 12 months after PCI. Serial changes in serum lipid profiles and plaque composition volumes were compared between the two groups.Thirty-five patients were eligible for serial IB-IVUS analyses. The mean low-density lipoprotein-cholesterol level significantly decreased in the atorvastatin and rosuvastatin groups (P < 0.001); plaque volumes were also significantly reduced from 82.0 ± 46.2 to 74.9 ± 41.3 mm3 (P = 0.01) and from 74.7 ± 35.3 to 67.7 ± 27.0 mm3 (P = 0.02), respectively. IB-IVUS revealed a significant reduction in fibrous volume from 33.8 ± 20.0 to 27.5 ± 14.9 mm3 (P < 0.01) and from 29.6 ± 13.6 to 24.8 ± 7.6 mm3 (P < 0.05), respectively; however, significant changes were not noted in the volume of the lipid pool for the atorvastatin group and the rosuvastatin group, respectively.Water- and lipid-soluble statins may be similarly effective in reducing coronary plaques in patients with ACS as judged qualitatively and quantitatively. Further study is needed to determine whether differences between water- and lipid-soluble statins affect plaque components.
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Rosuvastatin use improves measures of coagulation in patients with venous thrombosis.
Biedermann, JS, Kruip, MJHA, van der Meer, FJ, Rosendaal, FR, Leebeek, FWG, Cannegieter, SC, Lijfering, WM
European heart journal. 2018;(19):1740-1747
Abstract
AIMS: Observational studies indicate that statins reduce the risk of recurrent venous thrombosis (VT). However, trials have not been performed and the mechanism is unknown. We aimed to determine whether statin therapy improves the coagulation profile in patients with prior VT. METHODS AND RESULTS Randomized clinical trial (NCT01613794). Patients were randomized to rosuvastatin 20 mg/day for 4 weeks or no intervention. Blood was drawn at baseline and at end of study. The primary outcome was factor (F) VIIIC. In total, five coagulation factors were measured: FVIIIC, von Willebrand factor:Ag, FVIIC, FXI:C, and D-dimer. Among 247 randomized participants, mean age was 58 years, 62% were women and 49% had unprovoked VT. For all tested coagulation factors, mean levels were clearly decreased at end of study in rosuvastatin users, whereas they hardly differed in non-statin users. Results were most consistent for FVIIIC where mean FVIIIC levels were 7.2 IU/dL [95% CI (confidence interval) 2.9-11.5] lower in rosuvastatin users, while among non-users, no change in FVIIIC was observed (mean difference -0.1; 95% CI -3.0 to 2.9). The mean age and sex adjusted difference in FVIIIC change was -6.7 IU/dL (95% CI -12.0 to -1.4) in rosuvastatin users vs. non-users. Subgroup analyses revealed that the decrease in coagulation factors by rosuvastatin was more pronounced in participants with unprovoked VT and in those with cardiovascular risk factors. CONCLUSION Rosuvastatin 20 mg/day substantially improved the coagulation profile among patients with prior VT. These results suggest that statin therapy might be beneficial in patients at risk of recurrent VT.
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Rosuvastatin and atorvastatin preserve renal function in HIV-1-infected patients with chronic kidney disease and hyperlipidaemia.
Calza, L, Colangeli, V, Borderi, M, Manfredi, R, Marconi, L, Bon, I, Re, MC, Viale, P
HIV clinical trials. 2018;(3):120-128
Abstract
BACKGROUND Hyperlipidaemia is a risk factor for the progression of chronic kidney disease (CKD), which is a frequent comorbidity in patients with HIV-1 infection, but the renal effects of statins remain unclear. METHODS We performed an observational, prospective study of HIV-infected patients on suppressive antiretroviral therapy, with CKD and hyperlipidaemia, and starting a lipid-lowering treatment with rosuvastatin, atorvastatin or omega-3 fatty acids. CKD was defined as an estimated glomerular filtration rate (eGFR) ≤ 60 mL/min/1.73 m2 for >3 months. RESULTS As a whole, 69 patients (53 men, 58 Caucasian, median age 56.2 years) were enrolled. Overall, 25 patients started rosuvastatin (10 mg daily, group A), 23 patients atorvastatin (20 mg daily, group B), and 21 started omega-3 fatty acids (3 g daily, group C). At baseline, median eGFR was 54.4 mL/min/1.73 m2, and the eGFR ranged between 50 and 60 mL/min/1.73 m2 in 87% of patients. After 12 months, the median eGFR decline was significantly lower in group A (-0.84 mL/min/1.73 m2) and in group B (-0.91 mL/min/1.73 m2) in comparison with the group C (-1.53 mL/min/1.73 m2; p < 0.001 for both comparisons). The median decrease in prevalence of proteinuria and high-sensitivity C-reactive protein was also significantly greater in groups A and B than in group C, while the incidence of treatment discontinuations was comparable across the three groups. CONCLUSION In our study, rosuvastatin and atorvastatin showed a significant protective effect on the renal function compared to omega-3 fatty acids in HIV-1-infected patients with CKD and dyslipidaemia.
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Short Communication: The Effect of Rosuvastatin on Vascular Disease Differs by Smoking Status in Treated HIV Infection.
Hileman, CO, McComsey, GA
AIDS research and human retroviruses. 2018;(3):282-285
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Abstract
Smoking is an important contributor to cardiovascular disease risk and is highly prevalent in the HIV population. In the Stopping Atherosclerosis and Treating Unhealthy Bone with Rosuvastatin in HIV trial (SATURN-HIV), a 96-week, randomized placebo-controlled study testing the effect of rosuvastatin on subclinical vascular disease and immune activation in HIV-infected adults, rosuvastatin improved immune activation and arrested common carotid artery intima media thickness (CCA IMT) progression. In this exploratory analysis, ANOVA was used to test for effect modification by smoking. One-hundred forty-seven adults were included (72 in rosuvastatin group; 75 in placebo group). Groups were similar at baseline. Overall, mean ± SD age was 45.4 ± 9.9 years, 115 (78%) were men and 100 (68%) were African American. Ninety-three (63%) were current smokers (mean ± SD 0.6 ± 0.44 packs/day) and another 24 (16%) were smokers in the past. There were statistically significant randomization group by smoking status interactions for 0-24 (p = .01) and 0-48 (p < .01) week changes in proportion of activated CD4+ T cells and for 0-48 (p < .01) and 0-96 (trend only; p = .06) week changes in CCA IMT. No effect modification by smoking was detected for changes in markers of inflammation or monocyte activation. The beneficial effect of rosuvastatin on CCA IMT was not apparent in smokers although T cell activation improved to a greater degree in this subgroup.
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A Phase III, Multicenter, Randomized, Double-blind, Active Comparator Clinical Trial to Compare the Efficacy and Safety of Combination Therapy With Ezetimibe and Rosuvastatin Versus Rosuvastatin Monotherapy in Patients With Hypercholesterolemia: I-ROSETTE (Ildong Rosuvastatin & Ezetimibe for Hypercholesterolemia) Randomized Controlled Trial.
Hong, SJ, Jeong, HS, Ahn, JC, Cha, DH, Won, KH, Kim, W, Cho, SK, Kim, SY, Yoo, BS, Sung, KC, et al
Clinical therapeutics. 2018;(2):226-241.e4
Abstract
PURPOSE Combination therapy with ezetimibe and statins is recommended in cases of statin intolerance or insufficiency. The objective of this study was to compare the efficacy and safety of combination therapy with ezetimibe and rosuvastatin versus those of rosuvastatin monotherapy in patients with hypercholesterolemia. METHODS I-ROSETTE (Ildong ROSuvastatin & ezETimibe for hypercholesTElolemia) was an 8-week, double-blind, multicenter, Phase III randomized controlled trial conducted at 20 hospitals in the Republic of Korea. Patients with hypercholesterolemia who required medical treatment according to National Cholesterol Education Program Adult Treatment Panel III guidelines were eligible for participation in the study. Patients were randomly assigned to receive ezetimibe 10 mg/rosuvastatin 20 mg, ezetimibe 10 mg/rosuvastatin 10 mg, ezetimibe 10 mg/rosuvastatin 5 mg, rosuvastatin 20 mg, rosuvastatin 10 mg, or rosuvastatin 5 mg in a 1:1:1:1:1:1 ratio. The primary end point was the difference in the mean percent change from baseline in LDL-C level after 8 weeks of treatment between the ezetimibe/rosuvastatin and rosuvastatin treatment groups. All patients were assessed for adverse events (AEs), clinical laboratory data, and vital signs. FINDINGS Of 396 patients, 389 with efficacy data were analyzed. Baseline characteristics among 6 groups were similar. After 8 weeks of double-blind treatment, the percent changes in adjusted mean LDL-C levels at week 8 compared with baseline values were -57.0% (2.1%) and -44.4% (2.1%) in the total ezetimibe/rosuvastatin and total rosuvastatin groups, respectively (P < 0.001). The LDL-C-lowering efficacy of each of the ezetimibe/rosuvastatin combinations was superior to that of each of the respective doses of rosuvastatin. The mean percent change in LDL-C level in all ezetimibe/rosuvastatin combination groups was >50%. The number of patients who achieved target LDL-C levels at week 8 was significantly greater in the ezetimibe/rosuvastatin group (180 [92.3%] of 195 patients) than in the rosuvastatin monotherapy group (155 [79.9%] of 194 patients) (P < 0.001). There were no significant differences in the incidence of overall AEs, adverse drug reactions, and serious AEs; laboratory findings, including liver function test results and creatinine kinase levels, were comparable between groups. IMPLICATIONS Fixed-dose combinations of ezetimibe/rosuvastatin significantly improved lipid profiles in patients with hypercholesterolemia compared with rosuvastatin monotherapy. All groups treated with rosuvastatin and ezetimibe reported a decrease in mean LDL-C level >50%. The safety and tolerability of ezetimibe/rosuvastatin therapy were comparable with those of rosuvastatin monotherapy. ClinicalTrials.gov identifier: NCT02749994.
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LDL extracellular vesicle coagulation protein levels change after initiation of statin therapy. Findings from the METEOR trial.
Verbree-Willemsen, L, Zhang, YN, Gijsberts, CM, Schoneveld, AH, Wang, JW, Lam, CSP, Vernooij, F, Bots, ML, Peelen, LM, Grobbee, DE, et al
International journal of cardiology. 2018;:247-253
Abstract
BACKGROUND Statins are thought to have pleiotropic properties, including anticoagulant effects, in addition to reducing lipoprotein (LDL) levels. Plasma extracellular vesicles (EVs) are small bilayer membrane vesicles involved in various biological processes including coagulation. Since subsets of EVs in the LDL plasma fraction (LDL-EVs) correlate with thrombin activity, we hypothesized that changes in LDL-EVs after statin therapy may differ from that of serum levels of coagulation proteins, providing insight into the effects of statins on coagulation. METHODS The study was conducted in 666 subjects with available serum from the METEOR trial, a trial of the effect of rosuvastatin versus placebo in patients with subclinical atherosclerosis. Changes in protein levels of von Willebrand Factor (VWF), SerpinC1 and plasminogen were measured in serum and in LDL-EVs, and were compared between the rosuvastatin and placebo groups. RESULTS LDL-EV levels of plasminogen and VWF increased with rosuvastatin treatment compared to placebo (mean change of 126 ± 8 versus 17 ± 12 μg/mL for plasminogen (p < 0.001) and 310 ± 60 versus 64 ± 55 μg/mL for VWF (p = 0.015)). There was no difference between groups for change in LDL-EV-SerpinC1. In contrast, serum plasminogen levels increased to a lesser extent with rosuvastatin compared to placebo (23 ± 29 versus 67 ± 17 μg/mL, p = 0.024) and serum VWF levels showed no significant difference between both groups. CONCLUSIONS Rosuvastatin increases LDL-EV coagulation proteins plasminogen and VWF in patients with subclinical atherosclerosis, an effect that is different from the effect of rosuvastatin on the same proteins in serum. This identifies LDL-EVs as a newly detected possible intermediate between statin therapy and coagulation.