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Intensified lipid lowering using ezetimibe after publication of the IMPROVE-IT trial: A contemporary analysis from the SPUM-ACS cohort.
Gencer, B, Carballo, D, Nanchen, D, Koskinas, KC, Klingenberg, R, Räber, L, Auer, R, Carballo, S, Heg, D, Windecker, S, et al
International journal of cardiology. 2020;:8-13
Abstract
BACKGROUND The relevance of the IMPROVE-IT trial on real-life practice has not been explored in patients with ACS. METHODS A prospective Swiss cohort of 6266 patients hospitalized for ACS between 2009 and 2017 with a one-year follow-up. The primary endpoints were the ezetimibe use overall or in combination with high-intensity statin at discharge and at one year after ACS. Secondary endpoint was LDL-C target achievement at one year in a subsample of 2984 patients. Relative Ratios (RR) were used to assess changes in primary endpoints before and after the publication of IMPROVE-IT, adjusting for age, sex, diabetes, prior myocardial infarction, LDL-C and attendance to cardiac rehabilitation. RESULTS The period following the publication of the IMPROVE-IT trial was associated with a steady increase in the use of ezetimibe at discharge (from 1.8% to 3.8%, P < 0.001, adjusted RR 2.85, 95% CI 1.90-4.25) and at one year (from 5.0% to 13.8%, P < 0.001, adjusted RR 3.00, 95% CI 2.40-3.75). The combination of high-intensity statin and ezetimibe rose from 0.9% to 2.1% at discharge (P < 0.001, adjusted RR 3.35, 95% CI 1.90-5.89) and from 2.1% to 7.8% at one year (P < 0.001, adjusted RR 3.98, 95% CI 2.90-5.47). The period following the publication of the IMPROVE-IT trial was associated with an improvement of LDL-C target <1.8 mmol/L (adjusted RR 1.37, 95% CI 1.12-1.68). CONCLUSIONS After the publication of the IMPROVE-IT trial, the use of ezetimibe was increased by three-fold in a large contemporary cohort of ACS patients, concomitant with an improved LDL-C target achievement.
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Safety of two different doses of simvastatin plus rifaximin in decompensated cirrhosis (LIVERHOPE-SAFETY): a randomised, double-blind, placebo-controlled, phase 2 trial.
Pose, E, Napoleone, L, Amin, A, Campion, D, Jimenez, C, Piano, S, Roux, O, Uschner, FE, de Wit, K, Zaccherini, G, et al
The lancet. Gastroenterology & hepatology. 2020;(1):31-41
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Abstract
BACKGROUND Statins have beneficial effects on intrahepatic circulation and decrease portal hypertension and rifaximin modulates the gut microbiome and might prevent bacterial translocation in patients with cirrhosis. Therefore, this drug combination might be of therapeutic benefit in patients with decompensated cirrhosis. However, there is concern regarding the safety of statins in patients with decompensated cirrhosis. We assessed the safety of two different doses of simvastatin, in combination with rifaximin, in patients with decompensated cirrhosis. METHODS We did a double-blind, randomised, placebo-controlled, phase 2 trial in patients with decompensated cirrhosis and moderate-to-severe liver failure from nine university hospitals in six European countries (Italy, France, Holland, Germany, the UK, and Spain). Patients older than 18 years with Child-Pugh class B or C disease were eligible. We randomly assigned patients (1:1:1) to receive either simvastatin 40 mg/day plus rifaximin 1200 mg/day, simvastatin 20 mg/day plus rifaximin 1200 mg/day, or placebo of both medications for 12 weeks. Randomisation was stratified according to Child-Pugh class (B vs C) and restricted using blocks of multiples of three. The primary endpoint was development of liver or muscle toxicity, as defined by changes in liver aminotransferases (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]), alkaline phosphastase, and creatine kinase. The study is registered with the European Union Clinical Trials Register, 2016-004499-23, and with ClinicalTrials.gov, NCT03150459. FINDINGS The study recruitment period was between July 28, 2017, and Jan 2, 2018. Follow-up finished on March 12, 2018. 50 patients were randomly assigned to simvastatin 40 mg/day plus rifaximin 1200 mg/day (n=18), simvastatin 20 mg/day plus rifaximin 1200 mg/day (n=16), or placebo of both medications (n=16). Six patients (two from each group) were excluded. Therefore, the full analysis set included 44 patients (16 in the simvastatin 40 mg/day plus rifaximin 1200 mg/day group, 14 in the simvastatin 20 mg/day plus rifaximin mg/day group, and 14 in the placebo group). After a safety analyses when the first ten patients completed treatment, treatment was stopped prematurely in the simvastatin 40 mg/day plus rifaximin group due to recommendations by the data safety monitoring board. Patients in the simvastatin 40 mg/day plus rifaximin group showed a significant increase in AST and ALT compared with the placebo group (mean differences between the groups at the end of treatment for AST 130 IU/L [95% CI 54 to 205; p=0·0009] and for ALT 61 IU/L [22 to 100; p=0·0025]. We observed no significant differences at 12 weeks in AST and ALT between the simvastatin 20 mg/day plus rifaximin and placebo group (for AST -14 IU/L [-91 to 64; p=0·728] and for ALT -8 IU/L [-49 to 33; p=0·698]). We observed no significant differences in alkaline phosphatase between the the simvastatin 40 mg/day plus rifaximin or the simvastatin 20 mg/day plus rifaximin groups compared with placebo. Patients in the simvastatin 40 mg/day plus rifaximin group showed an increase in creatine kinase at the end of treatment compared with patients in the placebo group (1009 IU/L [208 to 1809]; p=0·014). We observed no significant changes in creatine kinase in the simvastatin 20 mg/day plus rifaximin group (4·2 IU/L [-804 to 813]; p=0·992). Three (19%) patients in the simvastatin 40 mg/day group developed liver and muscle toxicity consistent with rhabdomyolysis. The number of patients who stopped treatment because of adverse events was significantly higher in the simvastatin 40 mg/day plus rifaximin group (nine [56%] of 16 patients) compared with the other two groups (two [14%] of 14 for both groups; p=0·017). There were no serious unexpected adverse reactions reported during the study. INTERPRETATION Treatment with simvastatin 40 mg/day plus rifaximin in patients with decompensated cirrhosis was associated with a significant increase in adverse events requiring treatment withdrawal, particularly rhabdomyolysis, compared with simvastatin 20 mg/day plus rifaximin. We recommend simvastatin 20 mg/day as the dose to be used in studies investigating the role of statins in patients with decompensated cirrhosis. FUNDING Horizon 20/20 European programme.
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Inflammatory biomarkers in patients in Simvastatin treatment: No effect of co-enzyme Q10 supplementation.
Hansen, M, Kuhlman, ACB, Sahl, RE, Kelly, B, Morville, T, Dohlmann, TL, Chrøis, KM, Larsen, S, Helge, JW, Dela, F
Cytokine. 2019;:393-399
Abstract
PURPOSE Atherosclerosis is a major risk factor for cardiovascular disease (CVD) and is known to be an inflammatory process. Statin therapy decreases both cholesterol and inflammation and is used in primary and secondary prevention of CVD. However, a statin induced decrease of plasma concentrations of the antioxidant coenzyme Q10 (CoQ10), may prevent the patients from reaching their optimal anti-inflammatory potential. Here, we studied the anti-inflammatory effect of Simvastatin therapy and CoQ10 supplementation. METHODS 35 patients in primary prevention with Simvastatin (40 mg/day) were randomized to receive oral CoQ10 supplementation (400 mg/d) or placebo for 8 weeks. 20 patients with hypercholesterolemia who received no cholesterol-lowering treatment was a control group. Plasma concentrations of lipids and inflammatory biomarkers (interleukin-6 (IL6); -8 (IL8); -10 (IL10), tumor necrosis factor-α (TNFα); high-sensitivity C reactive protein (hsCRP)) as well as glycated hemoglobin (HbA1c) were quantified before and after the intervention. RESULTS No significant change in inflammatory markers or lipids was observed after CoQ10 supplementation Patients in Simvastatin therapy had significantly (P < 0.05) lower baseline concentration of IL6 (0.31 ± 0.03 pg/ml), IL8 (1.6 ± 0.1 pg/ml) IL10 (0.16 ± 0.02 pg/ml) and borderline (P = 0.053) lower TNFα (0.88 ± 0.05 pg/ml), but not hsCRP (1.34 ± 0.19 mg/l) compared with the control group (0.62 ± 0.08, 2.6 ± 0.2, 0.25 ± 0.01, 1.07 ± 0.09, and 1.90 ± 0.35, respectively). CONCLUSIONS Simvastatin therapy has beneficial effects on inflammatory markers in plasma, but CoQ10 supplementation seems to have no additional potentiating effect in patients in primary prevention. In contrast, glucose homeostasis may improve with CoQ10 supplementation.
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The International Polycap Study-3 (TIPS-3): Design, baseline characteristics and challenges in conduct.
Joseph, P, Pais, P, Dans, AL, Bosch, J, Xavier, D, Lopez-Jaramillo, P, Yusoff, K, Santoso, A, Talukder, S, Gamra, H, et al
American heart journal. 2018;:72-79
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BACKGROUND It is hypothesized that in individuals without clinical cardiovascular disease (CVD), but at increased CVD risk, a 50% to 60% reduction in CVD risk could be achieved using fixed dose combination (FDC) therapy (usually comprised of multiple blood-pressure agents and a statin [with or without aspirin]) in a single "polypill". However, the impact of a polypill in preventing clinical CV events has not been evaluated in a large randomized controlled trial. METHODS TIPS-3 is a 2x2x2 factorial randomized controlled trial that will examine the effect of a FDC polypill on major CV outcomes in a primary prevention population. This study aims to determine whether the Polycap (comprised of atenolol, ramipril, hydrochlorothiazide, and a statin) reduces CV events in persons without a history of CVD, but who are at least at intermediate CVD risk. Additional interventions in the factorial design of the study will compare the effect of (1) aspirin versus placebo on CV events (and cancer), (2) vitamin D versus placebo on the risk of fractures, and (3) the combined effect of aspirin and the Polycap on CV events. RESULTS The study has randomized 5713 participants across 9 countries. Mean age of the study population is 63.9 years, and 53% are female. Mean INTERHEART risk score is 16.8, which is consistent with a study population at intermediate CVD risk. CONCLUSION Results of the TIP-3 study will be key to determining the appropriateness of FDC therapy as a strategy in the global prevention of CVD.
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Effect Modifications of Lipid-Lowering Therapy on Progression of Aortic Stenosis (from the Simvastatin and Ezetimibe in Aortic Stenosis [SEAS] Study).
Greve, AM, Bang, CN, Boman, K, Egstrup, K, Forman, JL, Kesäniemi, YA, Ray, S, Pedersen, TR, Best, P, Rajamannan, NM, et al
The American journal of cardiology. 2018;(6):739-745
Abstract
Observational studies indicate that low-density lipoprotein (LDL) cholesterol acts as a primary contributor to an active process leading to aortic stenosis (AS) development. However, randomized clinical trials have failed to demonstrate an effect of lipid lowering on impeding AS progression. This study explored if pretreatment LDL levels and AS severity altered the efficacy of lipid-lowering therapy. The study goal was evaluated in the analysis of surviving patients with baseline data in the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial of 1,873 asymptomatic patients with mild-to-moderate AS. Serially measured peak aortic jet velocity was the primary effect estimate. Linear mixed model analysis adjusted by baseline peak jet velocity and pretreatment LDL levels was used to assess effect modifications of treatment. Data were available in 1,579 (84%) patients. In adjusted analyses, lower baseline peak aortic jet velocity and higher pretreatment LDL levels increased the effect of randomized treatment (p = 0.04 for interaction). As such, treatment impeded progression of AS in the highest quartile of LDL among patients with mild AS at baseline (0.06 m/s per year slower progression vs placebo in peak aortic jet velocity, 95% confidence interval 0.01 to 0.11, p = 0.03), but not in the 3 other quartiles of LDL. Conversely, among patients with moderate AS, there was no detectable effect of treatment in any of the pretreatment LDL quartiles (all p ≥0.14). In conclusion, in a non-prespecified post hoc analysis, the efficacy of lipid-lowering therapy on impeding AS progression increased with higher pretreatment LDL and lower peak aortic jet velocity (SEAS study: NCT00092677).
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Simvastatin as a Potential Disease-Modifying Therapy for Patients with Parkinson's Disease: Rationale for Clinical Trial, and Current Progress.
Carroll, CB, Wyse, RKH
Journal of Parkinson's disease. 2017;(4):545-568
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Many now believe the holy grail for the next stage of therapeutic advance surrounds the development of disease-modifying approaches aimed at intercepting the year-on-year neurodegenerative decline experienced by most patients with Parkinson's disease (PD). Based on recommendations of an international committee of experts who are currently bringing multiple, potentially disease-modifying, PD therapeutics into long-term neuroprotective PD trials, a clinical trial involving 198 patients is underway to determine whether Simvastatin provides protection against chronic neurodegeneration. Statins are widely used to reduce cardiovascular risk, and act as competitive inhibitors of HMG-CoA reductase. It is also known that statins serve as ligands for PPARα, a known arbiter for mitochondrial size and number. Statins possess multiple cholesterol-independent biochemical mechanisms of action, many of which offer neuroprotective potential (suppression of proinflammatory molecules & microglial activation, stimulation of endothelial nitric oxide synthase, inhibition of oxidative stress, attenuation of α-synuclein aggregation, modulation of adaptive immunity, and increased expression of neurotrophic factors). We describe the biochemical, physiological and pharmaceutical credentials that continue to underpin the rationale for taking Simvastatin into a disease-modifying trial in PD patients. While unrelated to the Simvastatin trial (because this conducted in patients who already have PD), we discuss conflicting epidemiological studies which variously suggest that statin use for cardiovascular prophylaxis may increase or decrease risk of developing PD. Finally, since so few disease-modifying PD trials have ever been launched (compared to those of symptomatic therapies), we discuss the rationale of the trial structure we have adopted, decisions made, and lessons learnt so far.
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Estimated cardiovascular relative risk reduction from fixed-dose combination pill (polypill) treatment in a wide range of patients with a moderate risk of cardiovascular disease.
Lafeber, M, Webster, R, Visseren, FLj, Bots, ML, Grobbee, DE, Spiering, W, Rodgers, A, ,
European journal of preventive cardiology. 2016;(12):1289-97
Abstract
AIMS: Recent data indicate that fixed-dose combination (FDC) pills, polypills, can produce sizeable risk factor reductions. There are very few published data on the consistency of the effects of a polypill in different patient populations. It is unclear for example whether the effects of the polypill are mainly driven by the individuals with high individual risk factor levels. The aim of the present study is to examine whether baseline risk factor levels modify the effect of polypill treatment on low-density lipoprotein (LDL)-cholesterol, blood pressure (BP), calculated cardiovascular relative risk reduction and adverse events. METHODS This paper describes a post-hoc analysis of a randomised, placebo-controlled trial of a polypill (containing aspirin 75 mg, simvastatin 20 mg, lisinopril 10 mg and hydrochlorothiazide 12.5 mg) in 378 individuals without an indication for any component of the polypill, but who had an estimated five-year risk for cardiovascular disease ≥7.5%. The outcomes considered were effect modification by baseline risk factor levels on change in LDL-cholesterol, systolic BP, calculated cardiovascular relative risk reduction and adverse events. RESULTS The mean LDL-cholesterol in the polypill group was 0.9 mmol/l (95% confidence interval (CI): 0.8-1.0) lower compared with the placebo group during follow-up. Those with a baseline LDL-cholesterol >3.6 mmol/l achieved a greater absolute LDL-cholesterol reduction with the polypill compared with placebo, than patients with an LDL-cholesterol ≤3.6 mmol/l (-1.1 versus -0.6 mmol/l, respectively). The mean systolic BP was 10 mm Hg (95% CI: 8-12) lower in the polypill group. In participants with a baseline systolic BP >135 mm Hg the polypill resulted in a greater absolute systolic BP reduction with the polypill compared with placebo, than participants with a systolic BP ≤ 135 mm Hg (-12 versus -7 mm Hg, respectively). Calculated from individual risk factor reductions, the mean cardiovascular relative risk reduction was 48% (95% CI: 43-52) in the polypill group. Both baseline LDL-cholesterol and estimated cardiovascular risk were significant modifiers of the estimated cardiovascular relative risk reduction caused by the polypill. Adverse events did not appear to be related to baseline risk factor levels or the estimated cardiovascular risk. CONCLUSION This study demonstrated that the effect of a cardiovascular polypill on risk factor levels is modified by the level of these risk factors. Groups defined by baseline LDL-cholesterol or systolic BP had large differences in risk factor reductions but only moderate differences in estimated cardiovascular relative risk reduction, suggesting also that patients with mildly increased risk factor levels but an overall raised cardiovascular risk benefit from being treated with a polypill.
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Multifactorial intervention to prevent cardiovascular disease in patients with early rheumatoid arthritis: protocol for a multicentre randomised controlled trial.
Svensson, AL, Christensen, R, Persson, F, Løgstrup, BB, Giraldi, A, Graugaard, C, Fredberg, U, Blegvad, J, Thygesen, T, Hansen, IM, et al
BMJ open. 2016;(4):e009134
Abstract
INTRODUCTION Cardiovascular morbidity is a major burden in patients with rheumatoid arthritis (RA). In this study, we compare the effect of a targeted, intensified, multifactorial intervention with that of conventional treatment of modifiable risk factors for cardiovascular disease (CVD) in patients with early RA fulfilling the 2010 American College of Rheumatology European League Against Rheumatism (ACR/EULAR) criteria. METHODS AND ANALYSIS The study is a prospective, randomised, open label trial with blinded end point assessment and balanced randomisation (1:1) conducted in 10 outpatient clinics in Denmark. The primary end point after 5 years of follow-up is a composite of death from cardiovascular causes, non-fatal myocardial infarction, non-fatal stroke and cardiac revascularisation. Secondary outcomes are: the proportion of patients achieving low-density lipoprotein cholesterol <2.5 mmol/L, glycated haemoglobin <48 mmol/mol, blood pressure <140/90 mm Hg for patients without diabetes and <130/80 mm Hg for patients with diabetes and normoalbuminuria (urinary albumin creatinine ratio <30 mg/g) after 1 year of follow-up and the proportion of patients in each treatment group achieving low RA disease activity after 1 year, defined as a disease activity score C-reactive protein (DAS28-CRP) <3.2 and a DAS28-CRP score <2.6 after 12, 24 and 60 months. Furthermore, all hospitalisations for acute and elective reasons will be adjudicated by the event committee after 12, 24 and 60 months. Three hundred treatment-naive patients with early RA will be randomly assigned (1:1) to receive either conventional treatment administered and monitored by their general practitioner according to national guidelines (control group) or a stepwise implementation administered and monitored in a quarterly rheumatological nurse-administered set-up of behaviour modification and pharmacological therapy targeting (1) hyperlipidaemia, (2) hypertension, (3) hyperglycaemia and (4) microalbuminuria (intervention group). ETHICS AND DISSEMINATION This protocol is approved by the local ethics committee (DK-S-2014007) and The Danish Health and Medicines Authority. Dissemination will occur through presentations at National and International conferences and publications in international peer-reviewed journals. TRIAL REGISTRATION NUMBER NCT02246257.
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Persistent lipid abnormalities in statin-treated patients: Portuguese diabetic subpopulation of the Dyslipidaemia International Study (DYSIS).
Marques da Silva, P, Massano Cardoso, S, Ferreira, AM, ,
Primary care diabetes. 2015;(4):283-9
Abstract
AIMS: To assess the treatment patterns and prevalence of persistent lipid abnormalities in Portuguese statin-treated patients with diabetes. METHODS DYSIS was an epidemiological, cross-sectional and multicentre international study. Outpatients ≥ 45 years old seen at primary and secondary care centres and treated with statins for at least three months were enrolled. This study presents the results for the Portuguese subpopulation, focusing on lipid control of the diabetic patients. RESULTS Of the 916 patients recruited, 348 (38%) had diabetes mellitus (DM). The majority of the diabetic patients (58%) failed to attain an LDL-C < 2.5 mmol/L, and 77% did not reach the optional goal of LDL-C < 2.0 mmol/L set by the 2007 recommendations of the European Society of Cardiology. The most frequently used statin was simvastatin, both in patients with and without diabetes (55.7% vs. 57.1%, p = 0.68). The mean (SD) statin dose in simvastatin-equivalent units was 26.1 (9.2) mg in diabetics and 25.3 (8.8 mg) in non-diabetics (p = 0.19). CONCLUSIONS The majority of Portuguese diabetic patients treated with statins failed to attain the recommended LDL cholesterol goals. Relatively low doses of medium potency statins were the prevailing therapy. There seems to be considerable room for improvement through the use of more potent statins, dose up-titration and/or the addition of other lipid-modifying therapies.
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Influence of metabolic syndrome factors and insulin resistance on the efficacy of ezetimibe/simvastatin and atorvastatin in patients with metabolic syndrome and atherosclerotic coronary heart disease risk.
Rosen, JB, Ballantyne, CM, Hsueh, WA, Lin, J, Shah, AK, Lowe, RS, Tershakovec, AM
Lipids in health and disease. 2015;:103
Abstract
BACKGROUND Metabolic syndrome (MetS) and insulin resistance (IR) are increasing in prevalence, are associated with higher risk for coronary heart disease (CHD), and may potentially influence the responses to lipid-altering drug therapy. This study evaluated the effects of MetS factors (abdominal obesity, depleted high-density lipoprotein cholesterol [HDL-C], and elevated triglycerides, blood pressure, and fasting glucose) and IR on ezetimibe/simvastatin and atorvastatin treatment efficacy in patients with MetS. METHODS This post-hoc analysis of a multicenter, 6-week, double-blind, randomized, parallel group study of 1128 subjects with hypercholesterolemia, MetS, and moderately high/high CHD risk evaluated the effects of baseline MetS factors/IR on percent change from baseline in lipids, apolipoproteins, and high-sensitivity C-reactive protein (hs-CRP), after treatment with the usual starting doses of ezetimibe/simvastatin (10/20 mg) versus atorvastatin (10 mg, 20 mg) and next higher doses (10/40 mg versus 40 mg). RESULTS Ezetimibe/simvastatin and atorvastatin efficacy was generally consistent across MetS factor/IR subgroups. Ezetimibe/simvastatin produced greater incremental percent reductions in LDL-C, non-HDL-C, apolipoprotein B, total cholesterol, and lipoprotein ratios for all subgroups, and larger percent increases in HDL-C and apolipoprotein AI for all but non-obese and HDL-C ≥ 40 mg/dL subgroups than atorvastatin at the doses compared. Triglycerides, very-LDL-C, and hs-CRP results were more variable but similar between treatment groups. CONCLUSION The magnitude of lipid-altering effects produced by each treatment regimen was generally similar across all MetS and IR subgroups. Ezetimibe/simvastatin produced greater percent reductions in most lipid fractions than atorvastatin at the dose comparisons studied, and all treatments were generally well tolerated. (Registered at clinicaltrials.gov: NCT00409773).