Median Low-density Lipoprotein Cholesterol Research Articles

Cardiovascular outcomes in patients with homozygous familial hypercholesterolaemia on lipoprotein apheresis initiated during childhood: long-term follow-up of an international cohort from two registries

Homozygous familial hypercholesterolaemia (HoFH) is a rare genetic disease characterised by extremely high plasma LDL cholesterol from birth, causing atherosclerotic cardiovascular disease at a young age. Lipoprotein apheresis in combination with lipid-lowering drugs effectively reduce LDL cholesterol, but long-term health outcomes of such treatment are unknown. We aimed to investigate the long-term cardiovascular outcomes associated with lipoprotein apheresis initiated in childhood or adolescence. In this cohort study, data were drawn from the HoFH International Clinical Collaboration (HICC) and the international registry for Children with Homozygous Hypercholesterolemia on Lipoprotein Apheresis (CHAIN). An overall cohort included patients diagnosed with HoFH aged 0-18 years who were alive and in follow-up between Jan 1, 2010, and Nov 8, 2021, and whose high plasma LDL cholesterol concentrations made them eligible for lipoprotein apheresis. To compare cardiovascular outcomes, patients who initiated lipoprotein apheresis in childhood (lipoprotein apheresis group) and patients who only received lipid-lowering drugs (pharmacotherapy-only group) were matched by sex and untreated plasma LDL cholesterol concentrations. The primary outcome was a composite of cardiovascular death, myocardial infarction, ischaemic stroke, percutaneous coronary intervention, coronary artery bypass grafting, aortic valve replacement, peripheral artery disease, carotid endarterectomy, angina pectoris, and supra-aortic or aortic stenosis (collectively referred to as atherosclerotic cardiovascular disease), for which survival analyses were performed in the matched cohort. Cox regression analyses were used to compare disease-free survival between cohorts and to calculate hazard ratio (HR) and 95% CI adjusted for sex, age at diagnosis, untreated plasma LDL cholesterol concentration, and number of lipid-lowering therapies other than lipoprotein apheresis. The overall cohort included 404 patients with a median age at diagnosis of 6·0 years (IQR 3·0-9·5) and median untreated plasma LDL cholesterol of 17·8 mmol/L (14·7-20·8). The matched cohorts included 250 patients (125 patients per group), with a median untreated LDL cholesterol of 17·2 mmol/L (14·8-19·7). Mean reduction in plasma LDL cholesterol concentrations between baseline and final follow-up was greater in the lipoprotein apheresis group (-55% [95% CI -60 to -51] vs -31% [-36 to -25]; p<0·0001). Patients in the lipoprotein apheresis group had longer atherosclerotic cardiovascular disease-free survival (adjusted HR 0·52 [95% CI 0·32-0·85]) and longer cardiovascular death-free survival (0·0301 [0·0021-0·4295]). Cardiovascular death was more common in the pharmacotherapy-only group than in the lipoprotein apheresis group (ten [8%] vs one [1%]; p=0·010), whereas median age at coronary artery bypass grafting was lower in the lipoprotein apheresis group than in the pharmacotherapy-only group (15·0 years [IQR 12·0-24·0] vs 30·5 years [19·0-33·8]; p=0·037). Among patients with HoFH, lipoprotein apheresis initiated during childhood and adolescence is associated with reduced long-term risk of atherosclerotic cardiovascular disease and death, and clear benefits of early initiation of high-frequency treatment on reducing plasma cholesterol were found. Consensus recommendations are now needed to guide more widespread and timely use of lipoprotein apheresis for children with HoFH, and research is required to further optimise treatment and ensure benefits of early and aggressive treatment delivery are balanced against effects on quality of life. Amsterdam University Medical Centers, Location Academic Medical Center; Perelman School of Medicine at the University of Pennsylvania; European Atherosclerosis Society; and the US National Heart, Lung, and Blood Institute, National Institutes of Health.

Prescription of lipid-lowering therapy, LDLc control, and risk of MACE in patients after ST-elevation myocardial infarction in Mexico

Abstract Funding Acknowledgements None. Background/Introduction Optimal control of low-density lipoprotein cholesterol (LDLc) has been demonstrated to reduce cardiovascular event rates after ST-elevation myocardial infarction (STEMI). However, real-world data shows that a low proportion of patients achieve LDLc targets. Furthermore, the association of LDLc levels and major cardiovascular adverse events (MACE) in post-STEMI patients is limited in developing countries. Purpose In this study, we aimed to assess the prescription patterns of lipid-lowering therapies, LDLc control, and their impact on the risk of MACE after STEMI in Mexico. Methods We conducted a prospective observational study of patients with STEMI. LDLc levels and prescriptions of lipid-lowering therapy were assessed during the first scheduled visit following STEMI hospital discharge. LDLc control was determined in accordance with the 2023 European Society of Cardiology Acute Coronary Syndrome Guidelines, which recommend achieving LDLc levels below 55 mg/dL for secondary prevention. Patients were categorized as controlled (if LDLc &amp;lt;55 mg/dL) and not controlled (if LDLc &amp;gt;55 mg/dL) and were followed for a median of 4.5 years to evaluate the rate of MACE, including cardiovascular death, cardiogenic shock, recurrent MI, and heart failure. Results We included 447 patients with a mean age of 57.87 (± 10.5 years), predominantly male (84.5%). Hypertension (43.8%), smoking (41.1%), type 2 diabetes mellitus (33.5%), obesity (26.6%), and dyslipidemia (21.4%) were highly prevalent. The median LDLc level in the total population was 65.4 mg/dL (IQR 49.2- 87.7). Among these, 34% (152) were considered controlled, while 66% (295) were not. Baseline clinical characteristics did not significantly differ among the groups. Prescription of high-intensity statins reached 94.7%, and ezetimibe and PCSK-9i were used in 1.8% and 0.4% of cases, respectively. We observed no statistically significant difference (Hazard ratio: 1.03, 95% confidence interval 0.74-1.73) in the rate of MACE based on LDLc control (Fig.1). The risk of MACE was also not different based on the use of high-intensity statins. Conclusions In this real-world study of patients post-STEMI, LDLc control was achieved in just one-third of the population. While the prescription of high-intensity statins was high, combination therapy was low. We did not observe a statistically significant association with an increased long-term risk of MACE; however, we noted a higher rate of events compared with other series.

Pragmatic Trial of Messaging to Providers About Treatment of Hyperlipidemia (PROMPT-LIPID): A Randomized Clinical Trial.

Lipid-lowering therapy (LLT) is underutilized for very high-risk atherosclerotic cardiovascular disease. PROMPT-LIPID (PRagmatic Trial of Messaging to Providers about Treatment of HyperLIPIDemia) sought to determine whether electronic health record (EHR) alerts improve 90-day LLT intensification in patients with very high-risk atherosclerotic cardiovascular disease. PROMPT-LIPID was a pragmatic trial in which cardiovascular and internal medicine clinicians within Yale New Haven Health (New Haven, CT) were cluster-randomized to receive an EHR alert with individualized LLT recommendations or no alert for outpatients with very high-risk atherosclerotic cardiovascular disease and LDL-C (low-density lipoprotein cholesterol), ≥70 mg/dL. The primary outcome was 90-day LLT intensification (change to high-intensity statin and addition of ezetimibe or PCSK9i [proprotein subtilisin/kexin type 9 inhibitors]). Secondary outcomes included LDL-C level, proportion of patients with LDL-C of <70 or < 55 mg/dL, rate of major adverse cardiovascular events, ED visit incidence, and 6-month mortality. Results were analyzed using logistic and linear regression clustered at the provider level. The no-alert group included 47 clinicians and 1370 patients (median age, 71 years; 50.1% female, median LDL-C, 93 mg/dL); the alert group included 49 clinicians and 1130 patients (median age, 72 years; 47% female, median LDL-C 91, mg/dL). The primary outcome was observed in 14.1% of patients in the alert group as compared with 10.4% in the no-alert group. There were no differences in any secondary outcomes at 6 months. Among 542 patients whose clinicians (n=46) did not dismiss the EHR alert recommendations, LLT intensification was significantly greater (21.2% versus 10.4%, odds ratio, 2.33 [95% CI, 1.48-3.66]). With a real-time, targeted, individualized EHR alert as compared with usual care, the proportion of patients with atherosclerotic cardiovascular disease with LLT intensification was numerically higher but not statistically significant. Among clinicians who did not dismiss the alert, there was a > 2-fold increase in LLT intensification. EHR alerts, coupled with strategies to reduce clinician dismissal, may help address persistent gaps in LDL-C management. URL: https://www.clinicaltrials.gov; Unique identifier: NCT04394715, https://www.clinicaltrials.gov/ct2/show/study/NCT04394715.

Lipoprotein-associated phospholipase A2 predicts cardiovascular death in patients on maintenance hemodialysis: a 7-year prospective cohort study

BackgroundCardiovascular diseases (CVD) is the leading cause of death among maintenance hemodialysis patients, with dyslipidemia being a prevalent complication. The paradoxical relationship between cardiovascular outcomes and established lipid risk markers, such as low-density lipoprotein cholesterol (LDL-C), complicates lipid management in this population. This study investigated Lipoprotein-associated phospholipase A2 (Lp-PLA2), an emerging biomarker known for its proinflammatory and proatherogenic properties, as a potential cardiovascular prognostic marker in this cohort. In this context, the association between Lp-PLA2 levels and cardiovascular outcomes was evaluated, with the aim to facilitate more accurate stratification and identification of high-risk individuals.MethodsFrom August 2013 to January 2014, 361 hemodialysis patients were prospectively enrolled. Lp-PLA2 activity and laboratory measures at baseline were quantified. Comorbidities and medications were recorded. All patients were followed until the end of April, 2022. The individual and combined effects of Lp-PLA2 activity and LDL-C on patient outcomes were examined. The association between Lp-PLA2 activity and all-cause mortality, cardiovascular mortality, and major adverse cardiovascular events (MACEs) was analyzed.ResultsThe median Lp-PLA2 activity was 481.2 U/L. In subjects with Lp-PLA2 activity over 481.2 U/L, significantly higher total cholesterol (4.89 vs. 3.98 mmol/L; P < 0.001), LDL-C (3.06 vs. 2.22 mmol/L; P < 0.001), and apolipoprotein B (0.95 vs. 0.75 mmol/L; P < 0.001) were observed. Over a median follow-up of 78.1 months, 182 patients died, with 77 cases identified as cardiovascular death, 88 MACEs happened. Cardiovascular mortality and MACEs, but not all-cause mortality, were significantly increased in the high Lp-PLA2 group. Cox regression analyses showed that high Lp-PLA2 activity was associated with cardiovascular mortality and MACE occurrence. After comprehensive adjustment, high Lp-PLA2 activity was independently associated with cardiovascular mortality(as a dichotomous variable: HR:2.57, 95%CI:1.58,4.18, P < 0.001; as a continuous variable: HR:1.25, 95%CI:1.10,1.41, P = 0.001) and MACEs(as a dichotomous variable: HR:2.17, 95%CI:1.39,3.40, P = 0.001; as a continuous variable: HR:1.20, 95%CI:1.07,1.36, P = 0.002). When participants were grouped by median Lp-PLA2 activity and LDL-C values, those with high Lp-PLA2 and low LDL-C had the highest CV mortality. The addition of Lp-PLA2 significantly improved reclassification (as a dichotomous variable NRI = 42.51%, 95%CI: 5.0%,61.33%; as a continuous variable, NRI = 33.32%, 95% CI: 7.47%,56.21%).ConclusionsHigh Lp-PLA2 activity is an independent risk factor for cardiovascular mortality and MACEs occurrence in patients on hemodialysis. The combined measures of Lp-PLA2 and LDL-C help to identify individuals with a higher risk of cardiovascular death.

Familial hypercholesterolaemia in children and adolescents from 48 countries: a cross-sectional study

Approximately 450 000 children are born with familial hypercholesterolaemia worldwide every year, yet only 2·1% of adults with familial hypercholesterolaemia were diagnosed before age 18 years via current diagnostic approaches, which are derived from observations in adults. We aimed to characterise children and adolescents with heterozygous familial hypercholesterolaemia (HeFH) and understand current approaches to the identification and management of familial hypercholesterolaemia to inform future public health strategies. For this cross-sectional study, we assessed children and adolescents younger than 18 years with a clinical or genetic diagnosis of HeFH at the time of entry into the Familial Hypercholesterolaemia Studies Collaboration (FHSC) registry between Oct 1, 2015, and Jan 31, 2021. Data in the registry were collected from 55 regional or national registries in 48 countries. Diagnoses relying on self-reported history of familial hypercholesterolaemia and suspected secondary hypercholesterolaemia were excluded from the registry; people with untreated LDL cholesterol (LDL-C) of at least 13·0 mmol/L were excluded from this study. Data were assessed overall and by WHO region, World Bank country income status, age, diagnostic criteria, and index-case status. The main outcome of this study was to assess current identification and management of children and adolescents with familial hypercholesterolaemia. Of 63 093 individuals in the FHSC registry, 11 848 (18·8%) were children or adolescents younger than 18 years with HeFH and were included in this study; 5756 (50·2%) of 11 476 included individuals were female and 5720 (49·8%) were male. Sex data were missing for 372 (3·1%) of 11 848 individuals. Median age at registry entry was 9·6 years (IQR 5·8-13·2). 10 099 (89·9%) of 11 235 included individuals had a final genetically confirmed diagnosis of familial hypercholesterolaemia and 1136 (10·1%) had a clinical diagnosis. Genetically confirmed diagnosis data or clinical diagnosis data were missing for 613 (5·2%) of 11 848 individuals. Genetic diagnosis was more common in children and adolescents from high-income countries (9427 [92·4%] of 10 202) than in children and adolescents from non-high-income countries (199 [48·0%] of 415). 3414 (31·6%) of 10 804 children or adolescents were index cases. Familial-hypercholesterolaemia-related physical signs, cardiovascular risk factors, and cardiovascular disease were uncommon, but were more common in non-high-income countries. 7557 (72·4%) of 10 428 included children or adolescents were not taking lipid-lowering medication (LLM) and had a median LDL-C of 5·00 mmol/L (IQR 4·05-6·08). Compared with genetic diagnosis, the use of unadapted clinical criteria intended for use in adults and reliant on more extreme phenotypes could result in 50-75% of children and adolescents with familial hypercholesterolaemia not being identified. Clinical characteristics observed in adults with familial hypercholesterolaemia are uncommon in children and adolescents with familial hypercholesterolaemia, hence detection in this age group relies on measurement of LDL-C and genetic confirmation. Where genetic testing is unavailable, increased availability and use of LDL-C measurements in the first few years of life could help reduce the current gap between prevalence and detection, enabling increased use of combination LLM to reach recommended LDL-C targets early in life. Pfizer, Amgen, Merck Sharp & Dohme, Sanofi-Aventis, Daiichi Sankyo, and Regeneron.

Use of inclisiran in a real-world setting: results from the italian Cholinet registry

Abstract Background Real world data indicate that PCSK9 inhibitors (PCSK9i) are started in very high-risk patients at higher LDL cholesterol (LDL-C) values than those recommended by guidelines. Different reimbursement rules may have an impact on access to injectable therapy among different countries. In Italy, reimbursement of injectable lipid lowering therapies (LLT) (i.e., PCSK9i and inclisiran) has been recently allowed for very high risk patients with LDL-C levels &amp;gt;70 mg/dl while on statin/ezetimibe LLT or statin intolerant, and, thereafter, inclisiran has been introduced in clinical practice. No data are available on inclisiran real world use in Italy and on the impact of new reimbursement rules on patient access to inclisiran. Purpose Cholinet (Cholesterol inclisiran Italian network) is an Italian multicenter prospective phase 4 registry involving 21 Italian centers, designed to assess efficacy, safety, adherence and persistence, as well characteristics of very high risk patients with atherosclerotic CV disease (ASCVD) and/or familial hypercholesterolemia (FH) receiving inclisiran. Methods From November 2022 through February 2023, the Cholinet registry enrolled patients receiving inclisiran due to elevated LDL-C levels in Italian centers as part of their medical therapy. Baseline characteristics, concomitant therapies, blood chemistry, were recorded at the time of first prescription and at follow-up. Results We enrolled 105 patients (14% FH, 30% female, mean age 64 years) receiving inclisiran according to standard clinical practice. 37 of them reached 3 months follow up (i.e., time of first reinjection dose) and none of them missed the reinjection dose. At the time of inclisiran first prescription median LDL-C was 96.6 mg/dl and reached 48.8 mg/dl at the time of 3 months observation (49% reduction). In patients with ASCVD median LDL-C at baseline was 90.4 mg/dL and 44.4 mg/dl at follow-up (51% reduction). In patients with FH median LDL-C at baseline was 177.4 mg/dL and 109.5 mg/dL at follow-up (38% reduction). Of 105 patients enrolled, 92 patients (88%) were on LLT. Heterogeneity was found on the LDL-C reduction across our cohort (Figure 1) (Shapiro-Wilk test p&amp;lt;0.05) that appeared to be influenced by background LLT (Kruskal-Wallis rank for previous PCSK9i exposure p=0.0028, for background LLT p=0.0435) (Figure 2), but not by baseline LDL-C levels (ANOVA p=0.06). LDL-C target was achieved in 21 (66%) of 32 patients receiving background LLT and in 2 (40%) of 5 patients who did not. No patient reported side effects. Conclusion These preliminary results from the Cholinet registry show that, in a context of facilitated reimbursement access, inclisiran is introduced at substantially lower baseline LDL-C values than previously reported for PCSK9i, reflecting a favorable change in clinical practice. Inclisiran effectively and safely reduces LDL-C in patients with ASCVD or FH, with some etherogeneity that was associated with background LLT.Kernel density plot, LDL-C % reductionStratified Kernel density plot

Prognostic impact of inflammation in myocardial infarction with non-obstructive coronary arteries

Abstract Background The prognosis of patients with myocardial infarction with non-obstructive coronary arteries (MINOCA) is worse than that of the general population. Nevertheless, the predictors for a worse outcome in patients with MINOCA are not fully determined. Purpose The aim of this study was to evaluate the prognostic value of C-Reactive Protein (CRP) in MINOCA patients. Methods Retrospective analysis of 706 consecutively admitted patients due to acute myocardial infarction (AMI), in whom coronary angiography revealed absence of obstructive coronary artery disease (≥50% stenosis). CRP levels were measured at admission. Demographic characteristics, symptoms at presentation, past medical history, laboratory characteristics and medication at discharge were examined. The primary endpoint analysed was all-cause mortality at 5 years. Possible predictors of the endpoint were assessed by Cox regression models. When statistically significant values were found in univariable analysis, multivariate analysis was used to determine whether CRP was an independent predictor of the outcome. Results In the studied sample, 55% of the patients were male. Median age was 64 [interquartile range (IQR) 55–72] and median body mass index was 27.3 kg/m2 (IQR 24.6-30.1). Regarding past medical history, 76.5% were hypertensive, 77.8% were dyslipidemic, 12.6% were smokers, 37.4% were diabetic and 59.3% had a previous history of angina. At presentation, 94.8% were in Killip 1, 3.8% were in Killip 2, 1% were in Killip 3 and 0.4% were in Killip 4. At admission, median CRP was 0.38 mg/dL (IQR 0.14-0.81), median Troponin I was 0.09 ng/ml (IQR 0.04-1.65), median creatinine was 0.85 mg/dL (IQR 0.73-1), median low density lipoprotein cholesterol (LDL-C) was 121.5 mg/dL (IQR 97.5-146), median haemoglobin was 13.6 g/dL (IQR 12.5-14.6) and median left ventricular ejection fraction (LVEF) was 58% (IQR 50-60). At discharge, 74.2% had a beta-blocker prescribed, 88.4% had a renin-angiotensin system inhibitor (RASi) prescribed, 98.2% had a statin prescribed and 76.5% had aspirin prescribed. All-cause mortality at 5 years was 8.5%. In univariable analysis, CRP was significantly associated with the endpoint [hazard ratio (HR) 1.138 per 1 mg/dL increase, 95% CI 1.090–1.188, p&amp;lt;0.001], as was age, diabetes, Killip class, troponin I, creatinine, LDL-C, haemoglobin, LVEF and absence of prescription of RASi. In multivariate analysis, CRP remained significantly associated with the endpoint (HR 1.141, 95% CI 1.087–1.199, p&amp;lt;0.001), as did age, creatinine and absence of prescription of RASi. Conclusions CRP at admission seems to be an independent predictor of all-cause mortality at the 5-year mark. This could indicate that inflammation has an important role in the pathophysiology and prognosis of MINOCA patients. It would be interesting to investigate if targeting inflammation would improve the long-term prognosis of these patients.

Dyslipidaemia and its management in patients with type 2 diabetes across the Middle East and Africa: the PACT-MEA study

Abstract Background There is a scarcity of high-quality epidemiological data on the clinical burden of type 2 diabetes (T2D) and cardiovascular risk (CV) in the Middle East and Africa due to under-representation of these regions in contemporary diabetes and cardiovascular trials. Multiple risk factors, including dyslipidaemia, increase CV risk in patients with T2D and established atherosclerotic cardiovascular disease (eASCVD) and those at risk for ASCVD. According to the European Society of Cardiology (ESC) 2021 Guidelines, target low-density lipoprotein cholesterol (LDL-C) for patients with T2D is &amp;lt;1.8 mmol/L (&amp;lt;1.4 mmol/L in patients with eASCVD or at very high risk). Purpose To establish the status of dyslipidaemia and its management in patients with T2D and eASCVD or high/very high ASCVD risk across the Middle East and Africa. Methods Adult patients with T2D participating in a cross-sectional, observational study in seven Middle East and African countries were included in the analysis. Laboratory and medication data were collected from medical charts of patients attending a routine health visit in 2022. Descriptive statistics were used to characterize the lipid profile and management of patients with T2D by age, diabetes duration, body mass index, HbA1c, microvascular complications, estimated glomerular filtration rate (eGFR), and urinary albumin to creatinine ratio (UACR). Results There were 3726 patients in the overall study sample (mean age, 58 ± 12; male, 53%), almost all of whom were at high (69%)/very high (30%, includes eASCVD) risk according to ESC 2021 guidelines. In patients for whom data was available in the medical record, median LDL-C (n=2525) was 2.2 mmol/L (IQR, 1.7 to 3.0), HDL-C (n=2453) was 1.1 mmol/L (IQR, 0.9 to 1.3), and triglycerides (n=2488) were 1.6 mmol/L (IQR, 1.2 to 2.3). Of the patients with high/very high ASCVD risk (n=2313), 30% met the ESC guideline-recommended target for LDL-C of &amp;lt;1.8 mmol/L and 16% met the target of &amp;lt;1.4mmol/L. Most patients were on statin therapy (77%, range across countries: 60%-87%, Table 1), with use increasing with age and duration of diabetes. More patients with T2D for ≥10 years were on high intensity statin therapy than those with T2D &amp;lt;10 years (37% vs 33%). A similar pattern was observed for patients with HbA1c levels ≥7% (37% vs 31%, Table 2). Most patients with nephropathy were on statins (87%); use increased with lower eGFR and higher UACR levels. Very few patients were on Ezetimibe (6.4%), fibrates (4.8%), fish oil (including icosapent ethyl) (1.4%), or proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors (0.5%). Conclusions Utilization of moderate intensity statin therapy (less than 50% LDL reduction) despite high and very high CV risk leads to failure to achieve cardioprotective LDL targets in most patients. Given the high burden of ASCVD in patients with T2D, prioritization of high intensity lipid lowering therapy is recommended.Table 1Table 2

Therapeutic gaps in low-density lipoprotein cholesterol management have narrowed over time but remain wide: a wide study of 40,141 acute coronary syndrome patients from 2016 to 2021

Abstract Background There are significant therapeutic gaps in ‘real-word’ low-density lipoprotein cholesterol (LDL-C) management in very-high risk patients. Understanding these gaps is important for developing strategies to bridge these gaps. Purpose We aimed to evaluate trends and identify therapeutic gaps in LDL-C management in very-high risk patients. Methods We retrospectively analyzed consecutive patients admitted with a diagnosis of acute coronary syndrome (ACS) to 16 public hospitals in between 2016 and 2021. Baseline and 12-month lipid-lowering therapy (LLT) including statins, ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor and LDL-C levels were recorded. We evaluated trends-over-time in percentage achievement of guideline Class I recommendations including (i) in-hospital initiation of high-intensity LLT; (ii) lipid-profile at follow-up post discharge; (iii) achieve at least 50% reduction in LDL-C from baseline with a goal of (iv) LDL-C &amp;lt;1.4 mmol/L. Results Of 40,141 ACS patients (mean age 71, male 66.5%), 61.2% were statin-naïve on admission. Baseline average LDL-C was 2.35 mmol/L (IQR 1.74 to 3.13 mmol/L). LLT prescription on discharge increased over time from 63.8% in 2016 to 96.2% in 2021. The use of high-intensity statins on discharge also increased over time from 24.7% to 53.7% but still suboptimal. The use of high-intensity statins increased significantly at 12-months (29.4% in 2016 and 59% in 2021) compared to on discharge (44.1% vs. 40.9% overall, p&amp;lt;0.001). The use of combination LLT was very low (1.3%-3.8%). Up to 22% of patients did not have repeated lipid profile after discharge. Of patients who had follow-up lipid profile, the median LDL-C was 1.74 mmol/L with a median LDL-C reduction of 29%. Only 27.5% reached the LDL-C goal of &amp;lt;1.4 mmol/L and 22.5% achieved at least 50% of LDL-C reduction. LDL-C reduction improved over time from 25.8% in 2016 to 31% in 2021, proportion of patients who reached LDL-C goal of &amp;lt;1.4 mmol/L improved over time from 20.8% in 2016 to 28.7% in 2021, and proportion of patients who achieved at least 50% of LDL-C reduction improved over time from 18.5% in 2016 to 24.6% in 2021, respectively. Conclusion Despite an increasing trend in the use of high-intensity statins and combination LLT over time, most patients did not reach guideline-recommended LDL-C target. Early up-titration of statin and addition of non-statin LLT may be required in the majority of patients.

LDL cholesterol target attainment in a representative German cohort of high- and very-high-CV risk patients with statin intolerance: a simulation study

Abstract Background The LDL cholesterol (LDL-C) treatment goals recommended by the 2019 ESC/EAS guidelines are only achieved in a minority of patients. Reasons include the inability to tolerate sufficient doses of statins. To reduce cardiovascular risk in these patients, alternative lipid-lowering therapies (LLT) are required. Purpose Simulation of LDL-C target attainment and achievable LDL-C reductions with oral LLT including ezetimibe and bempedoic acid in patients with statin intolerance (SI) using electronic health records. Methods Data were obtained from the IQVIATM Disease Analyzer database containing a representative sample of German outpatients. We selected patients with high or very-high cardiovascular risk based on ESC/EAS guidelines and diagnosed hypercholesterolaemia. Within this cohort, statin-intolerant patients were classified by applying the following literature-informed definitions pointing towards SI with high confidence (among others): patients with LLT only consisting of non-statins, long-term discontinuation of statin therapy, down-titration of statins, and documented side effects in the electronic health records. We used a Monte Carlo approach to simulate sequentially escalating oral LLT, by adding ezetimibe and bempedoic acid in patients with uncontrolled LDL-C in this population. Results Of the total study population (n=130,778 patients), 33.9% had high and 66.1% had very-high cardiovascular risk. Within this cohort, 11,286 patients (8.6%) met the criteria of SI. Compared to the total study population, in the SI group, there were higher proportions of patients who exhibited atherosclerotic manifestations and who were classified as "very-high cardiovascular risk" (73.7% vs. 66.1%). Their LDL-C levels were slightly higher (105.6 vs. 103.6 mg/dL). 46.5% received a low-intensity statin monotherapy. Ezetimibe, both as monotherapy or in combination, was more frequently prescribed. 12.3% did not receive any LLT (Table). Patients classified as statin-intolerant entered into the simulation model. At baseline, 7.7% were at LDL-C target. In patients without ezetimibe, consecutive treatment with ezetimibe and bempedoic acid increased the calculated proportion of patients at goal to 22.6% and 52.0%. A higher proportion of patients classified as high risk achieved the target compared to those at very-high risk (58.1% vs. 49.9%). The median LDL-C (IQR) after simulation of ezetimibe and bempedoic acid treatment was 62 (48–84) mg/dL (Figure). Conclusions Patients meeting the definition of SI based on their electronic health records represented 8.6% of the total cohort of the patients with high or very-high cardiovascular risk. In this population, oral combination LLT with ezetimibe and bempedoic acid has the potential to substantially increase the proportion of patients achieving clinically relevant LDL-C reductions.

Efficacy and safety of inclisiran in real world practice: insights from the Cholinet registry

Abstract Background Inclisiran has been recently introduced in clinical practice. Thus, efficacy and safety data from real world settings are scarce. In Italy, reimbursement of inclisiran has been recently introduced for very high cardiovascular (CV) risk patients with LDL cholesterol (LDL-C) &amp;gt;70 mg/dl on statin/ezetimibe background lipid lowering therapy (LLT). Purpose Cholinet (Cholesterol inclisiran Italian network) is an Italian multicenter prospective phase 4 registry involving 21 Italian centers, designed to assess efficacy, safety, adherence and persistence of inclisiran, and clinician’s behavior on LLT in very high CV risk patients with atherosclerotic CV disease and/or familial hypercholesterolemia (FH). Methods From November 2022 through February 2023, the Cholinet registry enrolled patients receiving inclisiran in Italian centers as part of their optimal medical therapy. Clinical and demographic characteristics, concomitant therapies, blood chemistry, were recorded at the time of first prescription and in subsequent follow-up. Background therapy was assessed to evaluate treatment withdrawal, reduction of doses or any change from baseline during follow up. Results We enrolled 105 patients (14% with FH, 30% female, mean age 64 years) receiving inclisiran according to standard clinical practice. Data on follow-up at 3 months (i.e., time of first reinjection dose) were available for 37 of them. At the time of inclisiran first prescription median LDL-C was 96.6 mg/dl and reached 48.8 mg/dl at the time of 3 months observation (49% mean reduction, 47,8 mg/dl absolute median reduction). None of the 37 patients reaching 3 months follow up missed the reinjection dose administration. Of 105 patients enrolled, 92 patients (88%) were on LLT, of them 16 (17%) were on ezetimibe alone, 11 (12%) on statin alone and 65 (71%) on a statin and ezetimibe combination. Of the enrolled patients, 6 (6%) were previously treated with evolocumab and 4 (4%) with alirocumab. At the end of the observation period, of the 37 patients with a follow-up, 18 (49%) did not change background LLT. Of 19 patients changing background LLT, 3 withdrew therapy (16%) and 16 (84%) reduced dose or changed type of LLT. Among patients evaluated at 3 months follow up, 23 patients (62%) achieved their target LDL-C (Figure 1), of them 21 (91%) were on LLT (Figure 2). No adverse drug reactions were reported. Conclusion These preliminary findings from the Cholinet Italian registry show that inclisiran effectively reduces (49%) LDL-C in real world settings, with no patients missing the first reinjection dose. Yet, concomitant LLT was reduced or discontinued in 51% of patients. Target LDL-C was achieved in 23 out of 37 patients, 21 of them receiving LLT background therapy. Thus, combination of oral therapy and inclisiran is needed in the majority of very high CV risk patients to achieve LDL target, and use of inclisiran should not prompt discontinuation or reduction of concomitant LLT.LLT in patient achieving LDL-C targetLDL-C target % by LLT

Early diagnosis and treatments in childhood are associated with better prognosis in patients with familial hypercholesterolemia

Abstract Objective The early diagnosis and treatment initiation for children with familial hypercholesterolemia (FH) has been recommended in guidelines. However, there is limited data on the impact of early treatments on the prognosis of children with FH. To investigate if the early initiation of lipid-lowering therapies among Japanese pediatric patients with FH reduced the occurrence of cardiovascular disease (CVD) events in them. Methods We retrospectively investigated the occurrence of CVD events (myocardial infarction, unstable angina, or coronary artery revascularization) in patients with FH (N = 1050, male/female = 490/560), including 106 children below 20 years. We compared a variety of phenotypes, including genetic backgrounds, other complications, LDL cholesterol, medical therapies, and their prognoses between the patients’ diagnoses before the age of 20 years (children, mean age = 15 years) and after that age (adults, mean age = 52 years). Overall, 290 patients (27.6%) had a history of prior CVD events. Results The median follow-up duration was 12.6 [9.5–17.9] years. The baseline LDL cholesterol level, 239 mg/dL, dropped to 112 mg/dL with the treatments. The Achilles tendon thickness was significantly lower in children than that of adults (7.2 vs. 8.9 mm, P &amp;lt; 0.001). Over the follow-up duration, 119 CVD events were observed. Importantly, no CVD event was observed in children despite their median LDL cholesterol level at follow-up being significantly higher than that of adults (122 vs. 111 mg/dL, P &amp;lt; 0.001). Conclusion The likelihood of CVD events in those with FH diagnosed and treated in childhood is low.

Abstract 13043: LDL-C, Lp(a) and Hs-CRP Each Predict Future Cardiovascular Events After ACS on High-Intensity Statin Therapy. An Analysis of the ODYSSEY OUTCOMES Trial

Background: Atherosclerotic cardiovascular disease (ASCVD) risk has been jointly associated with levels of LDL cholesterol (LDL-C), lipoprotein [Lp](a)] and the inflammatory marker high-sensitivity C reactive protein (hsCRP). It is unclear whether and to what extent each of these biomarkers predict ASCVD risk after acute coronary syndrome (ACS), particularly in the era of intensive LDL-C lowering. Recent analysis of 3 trials in stable ASCVD patients with hypertriglyceridemia suggested that hsCRP may be a stronger predictor for recurrent events than LDL-C; however, only 52% received high-intensity statin. Methods: The ODYSSEY OUTCOMES trial enrolled post-ACS patients not at goal for atherogenic lipoproteins a median of 2.6 months after ACS and on treatment with maximum tolerated (89% high-intensity) atorvastatin or rosuvastatin. Absolute risk of major adverse cardiovascular events (MACE, the primary composite outcome of coronary heart disease death, nonfatal myocardial infarction, fatal/nonfatal ischemic stroke or unstable angina hospitalization) and all-cause death were analyzed as a function of baseline LDL-C, hs-CRP, and Lp(a) values in patients randomized to the placebo arm via natural cubic splines from Poisson regression models, adjusted for age, sex, diabetes, BMI, current smoking, and the other 2 predictor variables. Results: Among 9149 evaluable patients, median (Q1-Q3) LDL-C, hsCRP, and Lp(a) were 81 (71-97) mg/dL, 1.7 (0.8-3.9) mg/L, and 21.4 (6.6-60.1) mg/dL, respectively. For each parameter, a higher baseline value was associated with a substantial increase in risk of MACE ( Figure , all spline p&lt;0.0001). LDL-C and hsCRP were associated with all-cause death (p&lt;0.0001), but not Lp(a) (p&gt;0.05). Conclusion: In ACS patients receiving intensive statin therapy and not at goal for atherogenic lipoproteins, LDL-C, hs-CRP, and Lp(a) were independent predictors of MACE. LDL-C and hsCRP were independent predictors of all-cause death.

Long-term treatment persistence and maintained reduction of LDL-cholesterol levels with evolocumab over 30 months: Results from the Spanish cohort of the European prospective HEYMANS study

AimsLimited data exist on low-density lipoprotein-cholesterol (LDL-C) level variability or long-term persistence with the monoclonal antibody evolocumab in routine clinical practice. HEYMANS (NCT02770131) is the first multi-country, multicenter, observational study of European patients initiating evolocumab as part of their routine clinical management, based on local reimbursement criteria (overall data recently published). The aim of this analysis is to describe clinical characteristics, baseline and changes in LDL-C levels, treatment patterns and persistence to evolocumab over 30 months in the Spanish cohort using data from the HEYMANS Registry. MethodsHEYMANS was a prospective study of adult patients (≥18 years) who received at least one dose of evolocumab. A total of 1951 patients were enrolled from 12 countries and were followed up for 30 months after evolocumab initiation. Data were collected for 6 months before evolocumab initiation and up to 30 months thereafter. The Spanish cohort included patients who started evolocumab in routine clinical practice from March 2016 to September 2019. Demographic and clinical characteristics, lipid-lowering therapies (LLT), and lipid levels were collected. ResultsIn total, 201 patients were included in the Spanish cohort. Median follow-up (Q1–Q3) was 30.0 (12–30) months. A total of 61.7% of patients were men and the mean (standard deviation) age was 59.5 (10.8) years. Most patients (68.7%) had experienced a prior cardiovascular event, 45.3% had coronary artery disease or stable angina, and 60.2% had a diagnosis of familial hypercholesterolemia. Overall, 57.7% of patients were receiving treatment with statins, most of them with high-intensity statins (85.3%); 45.8% of patients were intolerant to statins, and 26.4% of patients did not receive any LLT. At baseline, median (Q1–Q3) LDL-C levels were 151 (123–197) mg/dL. After 3 months of treatment, baseline LDL-C decreased by 66% to a median of 50 (30–83) mg/dL and these levels were maintained over time, with a median LDL-C of 55 (40–99) mg/dL at 30 months. At months 10–12 of treatment, LDL-C levels<55mg/dL were achieved by 56.3% of patients. LDL-C levels<70mg/dL were achieved by 70.1% of patients, and a lowering of LDL-C levels ≥50% was achieved by 76.8% of patients. The percentage of patients on evolocumab treatment was 95% at 12 months and 93% at 30 months. ConclusionsIn the Spanish cohort in routine clinical practice, evolocumab therapy provided a reduction in LDL-C levels consistent with that reported in previous clinical trials, which was sustained during 30 months of follow-up. Treatment with evolocumab was started at LDL-C levels 50% higher than those recommended by The Spanish Society of Arteriosclerosis and the Therapeutic Positioning Report. The probability of achieving the 2019 ESC/EAS LDL-C goals would improve with combination therapy and also with a lower LDL-C threshold when starting evolocumab. Persistence to evolocumab remained high during follow-up, with a very low percentage of discontinuation (5% at 12 months; 7% at 30 months).

Real-World Insights into Evolocumab Use in Patients with Hyperlipidemia Across Five Countries: Analysis from the ZERBINI Study.

This study characterizes patients receiving evolocumab in clinical practice and assesses treatment effectiveness, safety and persistence outcomes across five countries. This retrospective and prospective observational study enrolled patients initiated on evolocumab during August 2017 to July 2019 at 49 sites across Canada, Mexico, Colombia, Saudi Arabia and Kuwait. Medical records data were extracted within 6months prior to (baseline) and every 3months for 12months post evolocumab initiation and reported as available. A total of 578 patients were enrolled (40.1% female, median age 60 [interquartile range (IQR) 51-68] years); 83.7% had atherosclerotic cardiovascular disease and/or familial hypercholesterolemia. Median low-density lipoprotein cholesterol (LDL-C) at baseline was 3.4 (IQR 2.7-4.2) mmol/L (131.5 [IQR 104.4-162.4] mg/dL), with 75.6% of patients receiving a statin (59.2% high intensity). Compared to baseline, the median lowest LDL-C was reduced by 70.2% and remained stable over 12months of treatment. Guideline-recommended LDL-C thresholds < 1.8, < 1.4 and < 1.0mmol/L (< 70, < 55 and < 40mg/dL) were achieved by 75.3%, 63.6% and 47.4% of patients. LDL-C outcomes were consistent across high- and very high-risk patients. Background lipid-lowering therapy remained relatively stable. No serious treatment-emergent adverse events were reported, and persistence to evolocumab was 90.2% at 12months. These findings provide real-world evidence that evolocumab use is in accordance with its international guideline-recommended place in dyslipidemia therapy, as well as confirmation of its effectiveness and safety in a heterogeneous population. Evolocumab can address a healthcare gap in the management of dyslipidemia by increasing the proportion of patients achieving LDL-C goals recommended to lower cardiovascular risk.

LDL-C Reduction With Lipid-Lowering Therapy for Primary Prevention of Major Vascular Events Among Older Individuals

BackgroundReducing low-density lipoprotein (LDL) cholesterol with lipid-lowering therapy has consistently been shown to lower the risk of cardiovascular disease in primary prevention trials where the majority of individuals are aged <70 years. For older individuals, however, evidence is less clear. ObjectivesIn this study, the authors sought to compare the clinical effectiveness of lowering LDL cholesterol by means of lipid-lowering therapy for primary prevention of cardiovascular disease among older and younger individuals in a Danish nationwide cohort. MethodsWe included individuals aged ≥50 years who had initiated lipid-lowering therapy from January 1, 2008, to October 31, 2017, had no history of atherosclerotic cardiovascular disease, and had a baseline and a within-1-year LDL cholesterol measurement. We assessed the associated risk of major vascular events among older individuals (≥70 years) by HRs per 1 mmol/L reduction in LDL cholesterol compared with younger individuals (<70 years). ResultsFor both the 16,035 older and the 49,155 younger individuals, the median LDL cholesterol reduction was 1.7 mmol/L. Each 1 mmol/L reduction in LDL cholesterol in older individuals was significantly associated with a 23% lower risk of major vascular events (HR: 0.77; 95% CI: 0.71-0.83), which was equal to that of younger individuals (HR: 0.76; 95% CI: 0.71-0.80; P value for difference = 0.79). Similar results were observed across all secondary analyses. ConclusionsOur study supports a relative clinical benefit of lowering LDL cholesterol for primary prevention of major vascular events in individuals aged ≥70 years similarly as in individuals aged <70 years.

Prevalence of FH-Causing Variants and Impact on LDL-C Concentration in European, South Asian, and African Ancestry Groups of the UK Biobank-Brief Report.

Familial hypercholesterolemia (FH) is a monogenic disease that causes high low-density lipoprotein cholesterol (LDL-C) and higher risk of premature coronary heart disease. The prevalence of FH-causing variants and their association with LDL-C in non-European populations remains largely unknown. Using DNA diagnosis in a population-based cohort, we aimed to estimate the prevalence of FH across 3 major ancestry groups in the United Kingdom. Principal component analysis was used to distinguish genetic ancestry in UK Biobank participants. Whole exome sequencing data were analyzed to provide a genetic diagnosis of FH. LDL-C concentrations were adjusted for statin use. Principal component analysis distinguished 140 439 European, 4067 South Asian, and 3906 African participants with lipid and whole exome sequencing data. There were significant differences between the 3 groups, including total and LDL-C concentrations, and prevalence and incidence of coronary heart disease. We identified 488, 18, and 15 participants of European, South Asian, and African ancestry carrying a likely pathogenic or pathogenic FH-variant. No statistical difference in the prevalence of an FH-causing variant was observed: 1 out of 288 (95% CI, 1/316-1/264) in European, 1 out of 260 (95% CI, 1/526-1/173) in African, and 1 out of 226 (95% CI, 1/419-1/155) in South Asian. Carriers of an FH-causing variant had significantly higher LDL-C concentration than noncarriers in every ancestry group. There was no difference in median (statin-use adjusted) LDL-C concentration in FH-variant carriers depending on their ancestry background. Self-reported statin use was nonsignificantly highest in FH-variant carriers of South Asian ancestry (55.6%), followed by African (40.0%) and European (33.8%; P=0.15). The prevalence of FH-causing variants in the UK Biobank is similar across the ancestry groups analyzed. Despite overall differences in lipid concentrations, FH-variant carriers across the 3 ancestry groups had similar LDL-C levels. In all ancestry groups, the proportion of FH-variant carriers treated with lipid-lowering therapy should be improved to reduce future risk of premature coronary heart disease.

Efficacy and Safety of Switching to Dolutegravir/Lamivudine in Virologically Suppressed People Living with HIV-1 Aged Over 65 Years.

Clinical trials of dual regimen dolutegravir/lamivudine (DOL/3TC) demonstrated potent efficacy and favorable safety in both antiretroviral therapy-naïve and -experienced patients, but data on older people are lacking. We aimed to evaluate virological efficacy and safety of DOL/3TC in suppressed older patients over a 12-month period. We performed a retrospective cohort study evaluating people living with HIV (PLWHIV) aged ≥65 years at our HIV Clinic who were switched to DOL/3TC. Eligible patients had baseline HIV-1 RNA <20 copies/mL, and no previous virological failures or known resistance mutations for lamivudine or dolutegravir. Inclusion criteria were met by 72 patients: 59 were men, median age was 69.2 years, and one or more comorbidities were present in 89% of patients. The most common reason for switch was simplification, followed by drug-drug interactions (DDIs) and toxicities. After 12 months, 64 (88.9%, by the intention-to-treat analysis) patients maintained HIV-1 RNA <20 copies/mL, and reasons for treatment failure were virological failure in three cases, adverse events in three, and missing data in two. Genotype resistance testing showed no resistance mutations for lamivudine or dolutegravir in subjects with virological failure. The number of potential DDIs decreased from 92 to 12 after switching to DOL/3TC, and a significant reduction in median total and low-density lipoprotein cholesterol was reported, while median change in body weight was not significant. In this real-life cohort, switching to DOL/3TC was associated with maintenance of virological control and good tolerability among persons aged >65 years, supporting use of this dual regimen in older PLWHIV.

Determining Percentiles of Atherosclerotic Cardiovascular Risk According to Sex and Age in a Healthy Brazilian Population.

Expressing the risk of atherosclerotic cardiovascular disease (ASCVD) as percentiles of the distribution according to sex and age may provide a better perception of the risk. To determine percentiles of the 10-year ASCVD risk distribution according to sex and age in a sample of the Brazilian population; to characterize individuals at low 10-year risk but high risk percentile. We analyzed individuals aged 40 to 75 years who underwent routine health evaluations from 2010 to 2020. Persons with known clinical ASCVD, diabetes mellitus, chronic kidney disease, or LDL-cholesterol ≥ 190 mg/dL were excluded. The 10-year ASCVD risk was calculated by the ACC/AHA pooled cohort equations. Local polynomial regression was used to determine risk percentiles. Two-sided p-values < 0.050 were considered statistically significant. Our sample comprised 54,145 visits (72% male, median age [interquartile range] 48 [43, 53] years). We constructed sex-specific graphs plotting age against ASCVD risk corresponding to the 10th, 25th, 50th, 75th, and 90th percentiles. Most males up to 47 years and females up to 59 years above the 75th percentile had a 10-year risk < 5%. Individuals at low 10-year risk and risk percentile ≥ 75th had a high prevalence of excess weight and median (interquartile range) LDL-cholesterol levels 136 (109, 158) mg/dL (males) and 126 (105, 147) mg/dL (females). We established ASCVD risk percentiles according to sex and age in a large sample of the Brazilian population. This approach may increase risk awareness and help identify younger persons at low 10-year risk who may benefit from more aggressive risk factor control.

Lipid lowering effects and safety of evolocumab in Chinese patients at very high cardiovascular risk: a single-center study.

Lipid lowering effects and safety of evolocumab in Chinese patients at very high cardiovascular risk: a single-center study.