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PRavastatin Versus FlUVastatin After Statin Intolerance: The PRUV-Intolerance Study With Propensity Score Matching.
Roh, JW, Chun, KH, Kang, M, Lee, CJ, Oh, J, Shim, CY, Ahn, CM, Kim, JS, Kim, BK, Park, S, et al
The American journal of medicine. 2019;(11):1320-1326.e1
Abstract
BACKGROUND Limited data are available on the relapse of statin intolerance after resumption of statins. We aimed to evaluate the relapse rates of statin intolerance in patients who subsequently received pravastatin or fluvastatin and to identify associated factors. METHODS This retrospective, propensity score-matched cohort study screened data obtained from a tertiary university hospital between 2006 and 2015. Of 8073 patients screened, 488 with statin intolerance who received pravastatin or fluvastatin with regular follow-up were enrolled. After propensity score matching of patients, 384 were finally analyzed. The primary outcome variables were relapse of statin intolerance and stopping (ie, discontinuation or switching to other statins) rate for the 2 statins. RESULTS During the median follow-up period of 37 months, the rate of relapse of intolerance was 10.4% and 18.2% among users of pravastatin and fluvastatin, respectively (P = 0.04). However, the log-rank test showed no difference in the relapse-free rates between the 2 groups (P = 0.34). The stopping rates of the 2 statins were 36.5% and 42.2% (P = 0.30), respectively, for various reasons, including low efficacy of the drugs. After adjustment, chronic kidney disease (hazard ratio [HR] 1.83, P = 0.03) and previous creatine kinase elevation (HR 3.13, P = 0.001) were identified as independent determinants of relapse. Older age (HR 1.03, P = 0.057) and female sex (HR 1.70, P = 0.059) were associated, but not significantly, with relapse. CONCLUSION Although a small proportion of patients taking pravastatin or fluvastatin experienced a relapse of intolerance, many patients eventually discontinued or changed these agents. Chronic kidney disease and history of creatine kinase elevation were independent determinants of relapse.
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Pravastatin and Simvastatin Pretreatment in Combination with Pyrimethamine and Sulfadiazine Reduces Infection Process of Toxoplasma gondii Tachyzoites (RH Strain) in HeLa Cells.
Sanfelice, RADS, da Silva, SS, Bosqui, LR, Machado, LF, Miranda-Sapla, MM, Panagio, LA, Navarro, IT, Conchon-Costa, I, Pavanelli, WR, Almeida, RS, et al
Acta parasitologica. 2019;(3):612-616
Abstract
PURPOSE Toxoplasma gondii is a protozoan from phylum Apicomplexa, which causes the toxoplasmosis infection; this one exhibits an apicoplast organelle which assists in the metabolism of isoprenoids and other pivotal mediators for the parasite survival. Statins are drugs that inhibit cholesterol synthesis, blocking the conversion of the substrate HMG-CoA to mevalonate, thus preventing the initial processes of the biosynthesis of these precursors, both in humans and parasite. Our goal was to verify whether the Toxoplasma gondii (RH strain) tachyzoites form pretreated with pravastatin and simvastatin in association with pyrimethamine and sulfadiazine at low concentrations could affect the infection processes, suggesting direct action on protozoa intracellular proliferation through the inhibition of isoprenoids in the parasite's apicoplast. METHODS To have the adhesion, infection, and parasite proliferation during experimental infection investigated, HeLa cells (105) were subjected to a 24-hour infection by T. gondii tachyzoites forms of RH strain (5 × 105) pretreated for 30 min with pravastatin and/or simvastatin combined or not with pyrimethamine and sulfadiazine. RESULTS Combined with conventional drugs at low concentrations pravastatin and simvastatin inhibit the adhesion, invasion, and intracellular proliferation of T. gondii in HeLa cells which are similar to the positive control. CONCLUSION Pravastatin and simvastatin in association with pyrimethamine and sulfadiazine at low concentrations can be regarded as a promising, effective alternative to toxoplasmosis treatment with reduced side effects.
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Pilot randomized trial of short-term changes in inflammation and lipid levels during and after aspirin and pravastatin therapy.
Flannagan, KS, Sjaarda, LA, Hill, MJ, Connell, MT, Zolton, JR, Perkins, NJ, Mumford, SL, Plowden, TC, Andriessen, VC, Radoc, JG, et al
Reproductive health. 2019;(1):132
Abstract
BACKGROUND Inflammation and elevated blood lipids are associated with infertility. Aspirin and statin therapy may improve infertility treatment outcomes among overweight and obese women with systemic inflammation, but little is known about the short-term effects of statins in this population. We conducted a pilot study of aspirin, pravastatin, or combined treatment among a group of overweight and obese, reproductive-aged women. Our goal was to characterize short-term changes in inflammatory and lipid biomarkers during and after treatment. METHODS In this open-label trial, women aged 18-40 years with a body mass index ≥25 kg/m2 were randomized to receive either 162 mg aspirin, 40 mg pravastatin, or both. The study medication was taken daily for 2 weeks, and participants were then followed for a two-week washout period. Participants provided blood samples at baseline, after the intervention period, and after the washout period. The outcomes were changes in biomarkers of inflammation and lipids measured in blood components at each timepoint. RESULTS Nine, 8, and 8 women were randomized to the aspirin, pravastatin, and combined arms, respectively. Analyses were conducted among 8, 7, and 7 women in the aspirin, pravastatin, and combined arms for whom biomarker data was available at baseline. High-sensitivity C-reactive protein (hsCRP) levels were lower after treatment in all arms and continued to decrease after washout in the pravastatin and combined arms. Results were consistent between the whole sample and women with baseline hsCRP between 2 and 10 mg/L. Low-density lipoprotein (LDL) cholesterol was lower after treatment in the pravastatin and combined arms and rose slightly after washout. CONCLUSIONS Our results provide preliminary evidence that short-term aspirin and pravastatin therapy reduces hsCRP and LDL cholesterol among overweight and obese women of reproductive age, including those with low-grade inflammation. Because of these short-term effects, these drugs may improve infertility treatment outcomes in this population, which we will assess in a future randomized trial.
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Cumulative Effects of LDL Cholesterol and CRP Levels on Recurrent Stroke and TIA.
Kitagawa, K, Hosomi, N, Nagai, Y, Kagimura, T, Ohtsuki, T, Maruyama, H, Origasa, H, Minematsu, K, Uchiyama, S, Nakamura, M, et al
Journal of atherosclerosis and thrombosis. 2019;(5):432-441
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Abstract
AIMS: To investigate the relative contribution of on-treatment low-density lipoprotein (LDL) cholesterol and C-reactive protein (CRP) to the risk of recurrent stroke and transient ischemic attack (TIA) in patients with history of ischemic stroke. METHODS A total of 1095 patients with non-cardioembolic ischemic stroke were randomized into two groups: control and patients receiving 10 mg of pravastatin per day. After excluding 18 patients who did not have baseline CRP data, the effects of LDL cholesterol and CRP on recurrent stroke and TIA were prospectively assessed in 1077 patients. RESULTS During the follow-up of 4.9±1.4 years, there were 131 recurrent stroke or TIA cases. Patients with ontreatment LDL cholesterol <120 mg/dL showed 29% reduction in recurrent stroke and TIA than those with LDL cholesterol ≥ 120 mg/dL (event rate 2.20 vs. 3.11 per 100 person-years, hazard ratio [HR] 0.71, 95% confidence interval (CI) 0.50-0.99, p=0.048). Patients with CRP <1 mg/L had 32% reduction compared with that of patients with CRP ≥ 1 mg/L (event rate 2.26 vs. 3.40 per 100 person-years; HR 0.68, 95% CI 0.48-0.96, p=0.031). Although LDL cholesterol and CRP levels were not correlated in individual patients, those who achieved both LDL cholesterol <120 mg/dL and CRP <1 mg/L showed 51% reduction compared with that of patients with LDL cholesterol ≥ 120 mg/dL and CRP ≥ 1 mg/L (event rate 2.02 vs. 4.19 per 100 person-years; HR 0.49, 95% CI 0.31-0.79). CONCLUSIONS The control of both LDL cholesterol and CRP levels appears to be effective for preventing recurrent stroke and TIA in patients with non-cardiogenic ischemic stroke.
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Statins Reduce Epicardial Adipose Tissue Attenuation Independent of Lipid Lowering: A Potential Pleiotropic Effect.
Raggi, P, Gadiyaram, V, Zhang, C, Chen, Z, Lopaschuk, G, Stillman, AE
Journal of the American Heart Association. 2019;(12):e013104
Abstract
Background High epicardial adipose tissue (EAT) attenuation (Hounsfield units [ HUs] ) on computed tomography is considered a marker of inflammation and is associated with an increased risk of cardiovascular events. Statins reduce the volume of EAT , but it is unknown whether they affect EAT HUs . Methods and Results We reviewed the chest computed tomographic scans of 420 postmenopausal women randomized to either 80 mg of atorvastatin or 40 mg of pravastatin daily and rescanned after 1 year to measure change in coronary artery calcium score. EAT HUs were measured near the proximal right coronary artery and remote from any area of coronary artery calcium. Computed tomographic images were also queried for subcutaneous adipose tissue (SubQ) attenuation ( HUs ) change over time. The mean patients' age was 65±6 years. The baseline EAT HU value was higher than the SubQ HU value (-89.4±24.0 HU versus -123.3±30.4 HU ; P<0.001). The EAT HU value decreased significantly in the entire cohort (-5.4±29.7 HU [-6% change]; P<0.001), but equally in the patients given atorvastatin and pravastatin (-6.35+31 HU and -4.55+28 HU ; P=0.55). EAT HU change was not associated with change in total cholesterol, low-density lipoprotein cholesterol, coronary artery calcium, and EAT volume (all P=not significant). Change in high-density lipoprotein cholesterol was marginally associated with EAT HU change ( P=0.07). Statin treatment did not induce a change in SubQ HUs . Conclusions Statins induced a decrease in EAT HUs over time, independent of intensity of low-density lipoprotein cholesterol lowering. The positive effect on EAT and the neutral effect on SubQ suggest that statins induced a decrease in metabolic activity in EAT by reduction in cellularity, vascularity, or inflammation. The clinical significance of the observed change in EAT HUs remains to be demonstrated.
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Desirable Low-Density Lipoprotein Cholesterol Levels for Preventing Stroke Recurrence: A Post Hoc Analysis of the J-STARS Study (Japan Statin Treatment Against Recurrent Stroke).
Hosomi, N, Kitagawa, K, Nagai, Y, Nakagawa, Y, Aoki, S, Nezu, T, Kagimura, T, Maruyama, H, Origasa, H, Minematsu, K, et al
Stroke. 2018;(4):865-871
Abstract
BACKGROUND AND PURPOSE To define desirable target low-density lipoprotein (LDL) cholesterol levels for the prevention of stroke recurrence, a post hoc analysis was performed in the J-STARS study (Japan Statin Treatment Against Recurrent Stroke). METHODS Subjects (n=1578) were divided into groups based on mean value of postrandomized LDL cholesterol levels until the last observation in 20 mg/dL increments. Adjusted hazard ratios (HRs) and 95% confidence intervals were analyzed for each group, with adjustments for baseline LDL cholesterol, baseline body mass index, hypertension, diabetes mellitus, and statin usage. RESULTS The postrandomized LDL cholesterol level until the last observation were 104.1±19.3 mg/dL in the pravastatin group and 126.1±20.6 mg/dL in the control group. The adjusted HRs for stroke and transient ischemic attack and all vascular events decreased in the postrandomized LDL cholesterol level of 80 to 100 mg/dL (P=0.23 and 0.25 for the trend, respectively). The adjusted HR for atherothrombotic infarction significantly reduced with the usage of statin after adjusting baseline LDL cholesterol levels (HR, 0.39; 95% confidence intervals, 0.19-0.83). The adjusted HR for atherothrombotic infarction and intracranial hemorrhage were similar among the postrandomized LDL-cholesterol-level subgroups (P=0.50 and 0.37 for the trend, respectively). The adjusted HR for lacunar infarction decreased in the postrandomized LDL cholesterol level of 100 to 120 mg/dL (HR, 0.45; 95% confidence intervals, 0.20-0.99; P=0.41 for the trend). CONCLUSIONS The composite risk of stroke and transient ischemic attack reduced in the postrandomized LDL cholesterol level of 80 to 100 mg/dL after adjusting for statin usage. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00221104.
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Pravastatin Reduces the Risk of Atherothrombotic Stroke when Administered within Six Months of an Initial Stroke Event.
Hosomi, N, Nagai, Y, Kitagawa, K, Nakagawa, Y, Aoki, S, Nezu, T, Kagimura, T, Maruyama, H, Origasa, H, Minematsu, K, et al
Journal of atherosclerosis and thrombosis. 2018;(3):262-268
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Abstract
AIMS: The J-STARS study examined whether pravastatin (10 mg/day) reduces recurrence of stroke in non-cardioembolic ischemic stroke patients who were enrolled within 1 month to 3 years after initial stroke events (ClinicalTrials.gov, NCT00221104). The main results showed that the frequency of atherothrombotic stroke was low in pravastatin-treated patients, although no effect of pravastatin was found for the other stroke subtypes. We evaluated differences of early (within 6 months) or late (after 6 months) pravastatin treatment benefits on the incidence of stroke or transient ischemic attack (TIA), as well as atherothrombotic stroke and the other subtypes. METHODS Subjects in the J-STARS study were classified into two cohorts, depending on whether they enrolled early (1 to 6 months) or late (6 months to 3 years) following initial stroke events. RESULTS A total of 1578 patients (491 female, 66.2±8.5 years) were randomly assigned to either the pravastatin group (n=793; n=426 in the early cohort, n=367 in the late cohort) or the control group (n=785; n=417 in the early cohort, n=368 in the late cohort). During the follow-up of 4.9± 1.4 years, the rate of atherothrombotic stroke was lower in the pravastatin group compared to controls in the early cohort (0.24 vs. 0.88%/year, p=0.01) but not in the late cohort (0.17 vs. 0.39%/year, p=0.29). However, this difference of pravastatin effect on atherothrombotic stroke was not significantly interacted by the early or late cohort (p=0.59). The incidence rates of other stroke subtype were not different in between pravastatin and control groups despite the timing of entry. CONCLUSIONS Pravastatin is likely to reduce atherothrombotic stroke in patients enrolled within 6 months after stroke onset. However, the clinical efficacy for prevention of recurrent stroke was not conclusive with earlier statin treatment.
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Report of the relapsed/refractory cohort of SWOG S0919: A phase 2 study of idarubicin and cytarabine in combination with pravastatin for acute myelogenous leukemia (AML).
Advani, AS, Li, H, Michaelis, LC, Medeiros, BC, Liedtke, M, List, AF, O'Dwyer, K, Othus, M, Erba, HP, Appelbaum, FR
Leukemia research. 2018;:17-20
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Abstract
Inhibition of cholesterol synthesis and uptake sensitizes acute myeloid leukemia (AML) blasts to chemotherapy. A Phase 2 study of high dose pravastatin given in combination with idarubicin and cytarabine demonstrated an impressive response rate [75% complete remission (CR), CR with incomplete count recovery (CRi)]. However, this population was a favorable risk group as eligible patients had to have a CR/CRi lasting ≥3 months following their most recent chemotherapy. Therefore, the study was amended to treat patients with poor risk disease including those with CR/CRi <6 months following their last induction regimen or with refractory disease. Here, we present results in this poor risk group. This trial included a significant number of patients with poor risk cytogenetics (43%) and poor risk molecular mutations. The response rate was 30% and approximately one-fourth of patients were able to proceed to allogeneic hematopoietic stem cell transplant (HSCT). The median overall survival for patients proceeding to allogeneic HSCT is 27.1 months. Although this trial did not meet criteria for a positive study based on the response rate (p = .062), these results are encouraging given the poor risk population and suggest that targeting the cholesterol pathway may have therapeutic benefit in AML.
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The effect of fasting status on lipids, lipoproteins, and inflammatory biomarkers assessed after hospitalization for an acute coronary syndrome: Insights from PROVE IT-TIMI 22.
Steen, DL, Umez-Eronini, AA, Guo, J, Khan, N, Cannon, CP
Clinical cardiology. 2018;(1):68-73
Abstract
BACKGROUND For decades, fasting for 8 to 12 hours has been recommended for measurement of lipid profiles. The effect of fasting on low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG) has been described in healthy cohorts and those with stable disease states. Recently, guidelines suggested that fasting may not be necessary due to its small effect on lipid measures. Little is known, however, regarding whether the impact of fasting is altered in the setting of an acute coronary syndrome (ACS). HYPOTHESIS We hypothesized that the post-ACS period would minimally effect the impact of fasting status on lipid measurements. METHODS We evaluated the association of fasting on lipid and other biomarkers at the randomization visit, which occurred at a median of 7 days after the onset of an ACS, as well as during follow-up, in a cohort of 4177 subjects from the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis In Myocardial Infarction 22 (PROVE IT-TIMI 22) trial. RESULTS Fasting samples were independently associated with a higher LDL-C of 4.1 mg/dL and apolipoprotein-B 100 of 2.6 mg/dL as well as a lower TG of 21.0 mg/dL and high-sensitivity C-reactive protein of 0.48 mg/dL. The relative difference was 3.8% for LDL-C and -11.3% for TG. Fasting did not change total cholesterol, high-density lipoprotein cholesterol, apolipoprotein A-I, lipoprotein(a), or apolipoprotein C-III. CONCLUSIONS Although fasting does impact lipid measurements, the effect on LDL-C is small (about 4 mg/dL), both early after ACS and during follow-up. These data provide support for recent guidelines that no longer advocate for fasting lipid samples, including in the setting of ACS.
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Statin Effects on Metabolic Profiles: Data From the PREVEND IT (Prevention of Renal and Vascular End-stage Disease Intervention Trial).
Kofink, D, Eppinga, RN, van Gilst, WH, Bakker, SJL, Dullaart, RPF, van der Harst, P, Asselbergs, FW
Circulation. Cardiovascular genetics. 2017;(6)
Abstract
BACKGROUND Statins lower cholesterol by inhibiting HMG-CoA reductase, the rate-limiting enzyme of the metabolic pathway that produces cholesterol and other isoprenoids. Little is known about their effects on metabolite and lipoprotein subclass profiles. We, therefore, investigated the molecular changes associated with pravastatin treatment compared with placebo administration using a nuclear magnetic resonance-based metabolomics platform. METHODS AND RESULTS We performed metabolic profiling of 231 lipoprotein and metabolite measures in the PREVEND IT (Prevention of Renal and Vascular End-stage Disease Intervention Trial) study, a placebo-controlled randomized clinical trial designed to test the effects of pravastatin (40 mg once daily) on cardiovascular risk. Metabolic profiles were assessed at baseline and after 3 months of treatment. Pravastatin lowered low-density lipoprotein cholesterol (change in SD units [95% confidence interval]: -1.01 [-1.14, -0.88]), remnant cholesterol (change in SD units [95% confidence interval]: -1.03 [-1.17, -0.89]), and apolipoprotein B (change in SD units [95% confidence interval]: -0.98 [-1.11, -0.86]) with similar effect magnitudes. In addition, pravastatin globally lowered levels of lipoprotein subclasses, with the exception of high-density lipoprotein subclasses, which displayed a more heterogeneous response pattern. The lipid-lowering effect of pravastatin was accompanied by selective changes in lipid composition, particularly in the cholesterol content of very-low-density lipoproteinparticles. In addition, pravastatin reduced levels of several fatty acids but had limited effects on fatty acid ratios. CONCLUSIONS These randomized clinical trial data demonstrate the widespread effects of pravastatin treatment on lipoprotein subclass profiles and fatty acids. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT03073018.