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Background: Variability in low-density lipoprotein cholesterol (LDL-C) response to statins is underappreciated. We characterised patients by their statin response (SR), baseline risk of cardiovascular disease (CVD) and 10-year CVD outcomes., Methods and Results: A multivariable model was developed using 183,213 United Kingdom (UK) patients without CVD to predict probability of sub-optimal SR, defined by guidelines as <40% reduction in LDL-C. We externally validated the model in a Hong Kong (HK) cohort (n = 170,904). Patients were stratified into four groups by predicted SR and 10-year CVD risk score: [SR1] optimal SR & low risk; [SR2] sub-optimal SR & low risk; [SR3] optimal SR & high risk; [SR4] sub-optimal SR & high risk; and 10-year hazard ratios (HR) determined for first major adverse cardiovascular event (MACE). Our SR model included 12 characteristics, with an area under the curve of 0.70 (95% confidence interval [CI] 0.70-0.71; UK) and 0.68 (95% CI 0.67-0.68; HK). HRs for MACE in predicted sub-optimal SR with low CVD risk groups (SR2 to SR1) were 1.39 (95% CI 1.35-1.43, p<0.001; UK) and 1.14 (95% CI 1.11-1.17, p<0.001; HK). In both cohorts, patients with predicted sub-optimal SR with high CVD risk (SR4 to SR3) had elevated risk of MACE (UK HR 1.36, 95% CI 1.32-1.40, p<0.001: HK HR 1.25, 95% CI 1.21-1.28, p<0.001)., Conclusions: Patients with sub-optimal response to statins experienced significantly more MACE, regardless of baseline CVD risk. To enhance cholesterol management for primary prevention, statin response should be considered alongside risk assessment., Competing Interests: NQ is a member of the most recent NICE Familial Hypercholesterolaemia & Lipid Modification Guideline Development Groups (CG71 & CG181). SW, IW are members of the Clinical Practice Research Datalink (CPRD) Independent Scientific Advisory Committee (ISAC). RKA currently holds an NIHR-SPCR funded studentship (2018-2021). SW reports honorarium from AMGEN and is also an employee of Janssen. KM holds the CW Malpethorpe Fellowship Award and reports personal fees from IQVIA Ltd have been received outside the submitted work. JB is supported by the Hong Kong Research Grants Council as a recipient of the Hong Kong PhD Fellowship Scheme. EC and IW report grants from Amgen. The remaining authors have no competing interests. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Objectives: Guidance recommends statin treatment in familial hypercholesterolaemia (FH) to achieve at least a 50% reduction in low-density lipoprotein cholesterol (LDL-C). We assessed statin prescribing rates and LDL-C treatment goal attainment among individuals with FH in primary care., Methods: Using primary care electronic health records from the UK Clinical Practice Research Datalink, we identified adults with recorded diagnosis of FH, statin treatment and measures of LDL-C prior to (baseline) and 12 months after initiating statin treatment. The percentage change in LDL-C was determined, and then baseline and treatment characteristics were assessed by LDL-C treatment goal attainment., Results: Of 3064 adults (mean age 50.8 years) with recorded diagnosis of FH and repeat LDL-C measures, 50% reduction in LDL-C from baseline was attained in 895 individuals (29.2%) in 12 months. Compared with those who did not attain this goal, these people were predominantly women; they were older at time of FH diagnosis (53.4 years vs 49.7 years) and first statin treatment (53.2 years vs 49.2 years) and had higher pretreatment total cholesterol (8.20 (SD 1.38) mmol/L vs 7.57 (SD 1.39) mmol/L) and pretreatment LDL-C (5.83 (SD 1.36) mmol/L vs 5.25 (SD 1.40) mmol/L). A higher proportion of individuals who attained the treatment goal was prescribed high-potency and medium-potency statins (24.3% and 71.7% vs 20.2% and 69.3%, respectively)., Conclusions: Less than a third of individuals on statin treatment for FH in the community achieve recommended reductions in LDL-C. Greater awareness and optimisation of treatment for FH using higher-potency statins are needed., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Background: Statins inhibit proliferative signalling in oesophageal adenocarcinoma (OAC) and their use is associated with better survival in observational studies. The present study was undertaken to examine the feasibility of assessing adjuvant statin therapy in patients with operable OAC in a phase III RCT., Methods: For this multicentre, double-blind, parallel-group, randomized, placebo-controlled feasibility trial, adults with OAC (including Siewert I-II lesions) who had undergone oesophagectomy were centrally allocated (1 : 1) to simvastatin 40 mg or matching placebo by block randomization, stratified by centre. Participants, clinicians and investigators were blinded to treatment allocation. Patients received treatment for up to 1 year. Feasibility outcomes were recruitment, retention, drug absorption, adherence, safety, quality of life, generalizability and survival., Results: A total of 120 patients were assessed for eligibility at four centres, of whom 32 (26·7 per cent) were randomized, 16 in each group. Seven patients withdrew. Participants allocated to simvastatin had lower low-density lipoprotein cholesterol levels by 3 months (adjusted mean difference -0·83 (95 per cent c.i. -1·4 to -0·22) mmol/l; P = 0·009). Median adherence to medication was greater than 90 per cent between 3 and 12 months' follow-up. Adverse events were similar between the groups. Quality-of-life data were complete for 98·3 per cent of questionnaire items. Cardiovascular disease, diabetes and aspirin use were more prevalent in the non-randomized group, whereas tumour site, stage and grade were similar between groups. Survival estimates were imprecise., Conclusion: This RCT supports the conduct and informs the design considerations for a future phase III trial of adjuvant statin therapy in patients with OAC. Registration number: ISRCTN98060456 (www.isrctn/com)., (© 2019 The Authors. BJS Open published by John Wiley & Sons Ltd on behalf of BJS Society Ltd.)

Background: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are a major development in the prevention of cardiovascular disease (CVD) and is one of the most significant discoveries since the development of statin therapy. Administration of two human monoclonal antibodies to PCSK9 (alirocumab and evolocumab) can significantly reduce low-density lipoprotein cholesterol (LDL-c) concentrations, thus improving lipid management. Accordingly, guidelines on the specific indications for alirocumab and evolocumab usage have been released. This multicentre study aimed to estimate the proportion of patients treated for an acute myocardial infarction (MI) who could be considered for PCSK9 inhibitors under the current National Institute for Health and Care Excellence (NICE) lipid targets criteria., Methods: The records of 596 patients in two large hospitals in Liverpool, UK were analysed. Information was collected on lipid profiles during and after admission, lipid-lowering therapy and previous CVD., Results: At least 2.2% of patients were eligible for PCSK9 inhibitors post-MI under the current NICE guidance. Additionally, 29% of patients failed to achieve LDL-c concentrations <2.0 mmol/L despite maximum statin therapy and failed to meet eligibility for PCSK9 inhibitors as per the NICE criteria. This cohort represents a group of patients 'in limbo', in which statin therapy alone is not sufficient to reduce LDL-c., Conclusions: PCSK9 inhibitors are expensive and so their use must be highly selective. At present, in a real-world setting with ezetimibe underprescribing, ~2% of patients are eligible and a further 30% are deprived of benefit and improved outcomes by lack of optimisation and/or potential use of PCSK9 inhibitors., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Background In statin trials, men and women derived similar relative risk reductions in cardiovascular events per 39 mg/ dL low-density lipoprotein cholesterol ( LDL -C) reduction. We explored whether lower LDL -C levels and greater LDL -C percentage reductions than those achieved with statins are associated with reduced major adverse cardiovascular event ( MACE ) rates in women as well as men. Methods and Results Data pooled from 10 phase 3 ODYSSEY randomized trials (n=4983) comparing alirocumab with control (placebo/ezetimibe) were assessed for association between 39 mg/dL lower on-treatment LDL -C and percentage LDL -C change from baseline, and MACE risk by sex, using multivariable Cox regression. Mean baseline LDL -C was 135 mg/dL (women) and 121 mg/dL (men). Average on-treatment LDL -C levels with alirocumab, ezetimibe, and placebo were 71, 114, and 134 mg/dL, respectively, in women (n=1882) and 52, 93, and 122 mg/dL, respectively, in men (n=3090). Overall, 36.5% and 58.7% of women and men, respectively, achieved on-treatment LDL -C <50 mg/dL. Each 39 mg/dL lower LDL -C was associated with a 33% and 22% lower risk of MACE in women ( P=0.0209) and men ( P=0.0307), respectively, with no significant between-sex difference ( P for heterogeneity=0.4597). Results were similar when analyzed per 50% LDL -C reduction, 24% ( P=0.1094) and 29% ( P=0.0125) lower MACE risk in women and men, respectively ( P for heterogeneity=0.7499). Alirocumab was generally well tolerated in both sexes. Conclusions The present analysis reinforces the notion that both sexes derive a similar cardiovascular benefit from LDL -C lowering. Although women had slightly higher on-treatment LDL -C than men, both sexes showed a similar lower MACE risk with lower LDL -C.

Purpose of the Study: Statins and ezetimibe reduce low-density lipoprotein cholesterol (LDL-c) and cardiovascular disease (CVD) risk. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors lower LDL-c by 50%-70% and might be useful in refractory patients. The National Institute for Health and Care Excellence (NICE) technology appraisal guidance (TAG) recommends use of these drugs in secondary prevention and familial hypercholesterolaemia (FH) at differing LDL-c thresholds. We have estimated the proportion of patients in whom this third-line drug might be useful., Study Design: We used data from a lipid-lowering audit programme to study 72 with FH and/or CVD of 271 patients referred over 12 months who failed to achieve target total cholesterol (TC) and LDL-c levels. All 72 patients were treated with ezetimibe, and 69 cases also received statins. We used LDL-c thresholds 1.5-5.5 mmol/L to estimate how many of these refractory patients could benefit from PCSK9 inhibitors., Results: In 72 patients, TC and LDL-c targets were not met by 64 and 53 patients, respectively. We judged using the NICE TAG that only one patient (1.4% ezetimibe requiring and 0.4% total referrals) required a PCSK9 inhibitor., Conclusions: We determined that the proportion of patients eligible for a PCSK9 inhibitor at various TC and LDL-c levels is modest. This may reflect the use of all available statins in UK lipid clinics often at non-daily frequency. We suggest that cost-effective use of PCSK9 inhibitors requires prescribing being restricted to clinicians working in specialised lipid clinics., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Aims: Fish consumption is inversely associated with cardiovascular mortality, presumably because of n-3 fatty acids in fish. Whether the protection of n-3 fatty acids extends beyond clinical coronary disease to influence the early vascular biology of atherosclerosis remains unclear. This study determined whether circulating levels of n-3 fatty acids are associated with vascular endothelial function in early adulthood., Methods and Results: Three hundred and twenty-six adults (157 males, 169 females, aged 20 to 28 years) had high-resolution ultrasound measurements of flow-mediated brachial artery dilatation (FMD) (endothelium-dependent) and arterial response to glyceryl trinitrate (endothelium-independent). Levels of the n-3 fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid in plasma and erythrocyte membranes of subjects were measured. n-3 Fatty acid levels were not related to vascular function in the whole group. In smokers, however, n-3 fatty acids were positively related to flow-mediated dilatation (plasma DHA vs. FMD: 0.045 mm. %(-1), 95% CI 0.011 to 0.079, P=0.01). Flow-mediated dilatation was also associated with n-3 fatty acid levels in subjects in the top third of the insulin, glucose and triglyceride distributions., Conclusion: In young smokers and those with higher fasting insulin, glucose or triglyceride concentrations (factors associated with endothelial dysfunction), n-3 fatty acid levels were positively associated with flow-mediated dilatation. This raises the possibility that physiological levels of circulating n-3 fatty acids may protect the endothelium from early adulthood., (Copyright 2001 The European Society of Cardiology.)