Median Low-density Lipoprotein Cholesterol Research Articles

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 <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<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 <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 <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) >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 < 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 < 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<0.0001). LDL-C and hsCRP were associated with all-cause death (p<0.0001), but not Lp(a) (p>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.

Treatment gaps in the implementation of LDL cholesterol control among high- and very high-risk patients in Europe between 2020 and 2021: the multinational observational SANTORINI study

European data pre-2019 suggest statin monotherapy is the most common approach to lipid management for preventing cardiovascular (CV) events, resulting in only one-fifth of high- and very high-risk patients achieving the 2019 ESC/EAS recommended low-density lipoprotein cholesterol (LDL-C) goals. Whether the treatment landscape has evolved, or gaps persist remains of interest. Baseline data are presented from SANTORINI, an observational, prospective study that documents the use of lipid-lowering therapies (LLTs) in patients ≥18 years at high or very high CV risk between 2020 and 2021 across primary and secondary care settings in 14 European countries. Of 9602 enrolled patients, 9044 with complete data were included (mean age: 65.3±10.9 years; 72.6% male). Physicians reported using 2019 ESC/EAS guidelines as a basis for CV risk classification in 52.0% (4706/9044) of patients (overall: high risk 29.2%; very high risk 70.8%). However, centrally re-assessed CV risk based on 2019 ESC/EAS guidelines suggested 6.5% (308/4706) and 91.0% (4284/4706) were high- and very high-risk patients, respectively. Overall, 21.8% of patients had no documented LLTs, 54.2% were receiving monotherapy and 24.0% combination LLT. Median (interquartile range [IQR]) LDL-C was 2.1 (1.6, 3.0) mmol/L (82 [60, 117] mg/dL), with 20.1% of patients achieving risk-based LDL-C goals as per the 2019 ESC/EAS guidelines. At the time of study enrolment, 80% of high- and very high-risk patients failed to achieve 2019 ESC/EAS guidelines LDL-C goals. Contributory factors may include CV risk underestimation and underutilization of combination therapies. Further efforts are needed to achieve current guideline-recommended LDL-C goals. ClinicalTrials.gov Identifier: NCT04271280. This study is funded by Daiichi Sankyo Europe GmbH, Munich, Germany.

Elevated low-density lipoprotein cholesterol: An inverse marker of morbidity and mortality in patients with myocardial infarction.

The incidence of atherosclerotic cardiovascular disease increases with levels of low-density lipoprotein cholesterol (LDL-C). Yet, a paradox may exist where lower LDL-C levels at myocardial infarction (MI) are associated with poorer prognoses. To assess the association between LDL-C levels at MI with risk factor burden and cause-specific outcomes. Statin-naive patients hospitalized for a first MI and registered in SWEDEHEART were included. Data were linked to Swedish registers. Primary outcomes were all-cause mortality and nonfatal MI. Associations between LDL-C and outcomes were assessed using adjusted proportional hazards models. Among 63,168 patients (median age, 66 years), the median LDL-C level was 3.0mmol/L (interquartile range 2.4-3.6). Patient age and comorbidities increased as LDL-C decreased. During a median follow-up of 4.5 years, 10,236 patients died, and 4973 had nonfatal MI. Patients with the highest LDL-C had a lower risk of mortality (hazard ratio [HR] 0.75; 95% confidence interval [CI] 0.71-0.80). The risk of hospitalization for pneumonia, hip fracture, chronic obstructive pulmonary disease, and new cancer diagnosis was lower with higher LDL-C (HR range, 0.40-0.81). Patients with the highest LDL-C had a greater risk of recurrent MI (HR 1.16; 95% CI 1.07-1.26). Patients with the highest LDL-C levels at MI had the lowest incidence of mortality and morbidity. This seems to reflect lower age at MI, less underlying morbidities, paired with the modifiability of LDL-C. However, supporting the causal association between LDL-C and ischemic heart disease, elevated LDL-C was simultaneously associated with an increased risk of nonfatal MI.

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).

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.

Effect of high-dose statin therapy on coagulation factors: Lowering of factor XI as a modifier of fibrin clot properties in coronary artery disease

BackgroundMultiple pleiotropic effects of statins include antithrombotic properties with formation of looser fibrin networks more susceptible to lysis. Recently, rosuvastatin 20 mg/d has been reported to decrease coagulation factors (F) VII, FVIII and FXI in venous thrombosis patients. ObjectivesWe investigated how high-dose statin therapy recommended in coronary artery disease (CAD) alters plasma levels of coagulation factors and if such changes might affect fibrin clot properties. MethodsWe studied 130 advanced CAD patients, who initially did not achieve the target low-density lipoprotein cholesterol (LDL-C). Before high-dose statin therapy (rosuvastatin 40 mg/d or atorvastatin 80 mg/d) and 6–12 months after its initiation, FII, FV, FVII, FVIII, FIX, FX, FXI and fibrinogen were assessed. We evaluated the impact of statin-induced alterations to the factors on plasma fibrin clot permeability (Ks) reflecting a fibrin pore size, and clot lysis time (CLT) reflecting fibrinolytic potential. ResultsAt baseline LDL-C (median 3.2, interquartile range 2.7–3.7 mmol/L) was independently associated solely with FXI (β = 0.58, P < 0.001). Median LDL-C reduction by 25% (P < 0.001) on high-dose statin treatment was accompanied by lowering of FVII, FVIII, and FXI (for all P < 0.001). On high-dose statin treatment, Ks (R = 0.65, P < 0.001) inversely associated with CRP (β = −0.41, P < 0.001), LDL-C (β = −0.26, P = 0.001), and FXI (β = −0.18, P = 0.016). In turn, CLT (R = 0.45, P < 0.001) was positively associated with LDL-C (β = 0.19, P = 0.043) and FXI (β = 0.17, P = 0.049). ConclusionsHigh-dose statin therapy in CAD patients decreases FVII, FVIII, and FXI. The statin-induced reduction in FXI may contribute to less prothrombotic fibrin clot phenotype, indicating additional antithrombotic effect of high-dose statins.

Prognostic Implication of Small Dense LDL-Cholesterol Levels following Acute Coronary Syndrome.

Background and Objectives: Small dense LDL cholesterol is a strong risk factor for atherosclerosis. However, few studies have investigated the impacts of this specific lipid profile on the incident risk of adverse cardiovascular events in patients with acute coronary syndrome. Materials and Methods: Patients with acute coronary syndrome, who underwent revascularization, were included and followed for 2 years. The levels of small dense LDL cholesterol were measured at index discharge (day 0) in the setting of newly administered therapies for secondary prevention, including aspirin and statins, during the index hospitalization. The prognostic impact of small dense LDL-cholesterol levels on the risk of a primary composite endpoint, including cardiac death, non-fatal myocardial infarction, unstable angina pectoris, stroke, and heart failure, was investigated. Results: In total, 46 patients (median 75 (59, 83) years old, 63% men) were included. Median small dense LDL cholesterol was 19.4 (13.5, 23.8) mg/dL at index discharge. All patients initiated statin treatment before the index discharge, with a median LDL-cholesterol level of 77 (64, 109) mg/dL. Small dense LDL-cholesterol level was independently associated with an incremental risk for the primary endpoint (p &lt; 0.05 by adjusting for several potential risk factors, including LDL cholesterol) with a cutoff of 32.6 mg/dL. Conclusions: Small dense LDL-cholesterol level was a significant risk factor for cardiovascular events following presentations of acute coronary syndrome.

Evolocumab is Initiated in Central and Eastern Europe at Much Higher LDL-C Levels Than Recommended in Guidelines: Results from the Observational HEYMANS Study.

Purpose: We examined clinical characteristics and low-density lipoprotein cholesterol (LDL-C) lowering in patients initiating evolocumab in real-world practice in a Central and Eastern European (CEE) cohort from the pan-European HEYMANS study. Methods: Patients from Bulgaria, Czech Republic, and Slovakia were enrolled at initiation of evolocumab (baseline) as per local reimbursement criteria. Demographic/clinical characteristics, lipid-lowering therapy (LLT) and lipid values were collected from medical records for ≤6 months before baseline and ≤30 months after evolocumab initiation. Results: Overall, 333 patients were followed over a mean (SD) duration of 25.1 (7.5) months. At initiation of evolocumab, LDL-C levels were markedly elevated in all three countries, with a median (Q1, Q3) LDL-C of 5.2 (4.0, 6.6) mmol/L in Bulgaria, 4.5 (3.8, 5.8) mmol/L in the Czech Republic, and 4.7 (4.0, 5.6) mmol/L in Slovakia. Within the first three months of evolocumab treatment, LDL-C levels were reduced by a median of 61% in Bulgaria, 64% in the Czech Republic, and 53% in Slovakia. LDL-C levels remained low throughout the remaining period of observation. The 2019 ESC/EAS guideline-recommended risk-based LDL-C goals were attained by 46% of patients in Bulgaria, 59% in the Czech Republic, and 43% of patients in Slovakia. LDL-C goal attainment was higher in patients receiving a statin ± ezetimibe-based background therapy (Bulgaria: 55%, Czech Republic: 71%, Slovakia: 51%) compared to those receiving evolocumab alone (Bulgaria: 19%, Czech Republic: 49%, Slovakia: 34%). Conclusion: In the HEYMANS CEE cohort, patients initiated on evolocumab had baseline LDL-C levels approximately three-fold higher than guideline-recommended thresholds for PCSK9i initiation. Risk-based LDL-C goal attainment was highest in patients receiving high-intensity combination therapy. Lowering the LDL-C reimbursement threshold for PCSK9i initiation would allow more patients to receive combination therapy, thus improving LDL-C goal attainment. Trial registration: ClinicalTrials.gov (NCT02770131; registration date: 27 April 2016).

30 EVOLOCUMAB USE IN CLINICAL PRACTICE IN ITALY: FINAL DATA OF THE HEYMANS STUDY.

Abstract Background Controlling lipid levels, in particular low-density lipoprotein cholesterol (LDL-C), is a proven therapeutic approach to reducing cardiovascular (CV) risk. Greater use of combination lipid-lowering therapies (LLTs) may be required to achieve the LDL-C goals recommended by the guidelines. A better understanding of the characteristics of patients receiving PCSK9is in Europe could offer the medical community an opportunity to redefine existing care pathways to better implement European guidelines, thus potentially reducing modifiable residual CV risk further. Purpose Using data from the HEYMANS registry (NCT02770131), the objective of this analysis is to describe the Italian cohort of evolocumab patients and the long-term effectiveness and safety of the treatment. Methods HEYMANS was a prospective registry including adults initiating evolocumab treatment in 12 European countries as part of their routine clinical management, based on local reimbursement criteria, between August 2015 and June 2020. Patient data were collected for ≤6 months before evolocumab initiation (baseline) and ≤30 months post initiation. LDL-C measurements were collected per clinical practice. At each 3-month time point in the study, we analysed median (and 95% CI) reductions in LDL-C, and the proportion of patients achieving ≥50% reductions in LDL-C from baseline. Results Data from 311 patients from Italy were included in this final analysis (67% male, median baseline LDL-C 146 [Q1-Q3 120-177] mg/dL). Most patients (84%) were receiving evolocumab for secondary prevention, with 24% not on oral LLT, of whom the majority reported a history of statin intolerance. Within 3 months of initiating evolocumab treatment, LDL-C levels had reduced by a median of 61% and this reduction was maintained over 30 months (Figure 1). Among patients with an LDL-C value, between 66 and 76% achieved a ≥50% reduction at each visit (Figure 2). Moreover, 65% of patients receiving LLT at baseline reached an LDL-C level &amp;lt;55 mg/dL at any time post baseline, whilst among patients not receiving a background therapy this percentage was 48%. At the 12-month follow up, more than 97% of patients were still receiving evolocumab, with just 8 patients discontinuing the treatment (and 2 more patients leaving the study but keeping on with the treatment). That was confirmed at the 30-month follow up: almost 98% of patients still in the study beyond month 12 were receiving the drug at month 30. Moreover, at each timeframe, more than 99% had no missed dose. There were very few adverse drug reactions reported and no evolocumab-related adverse events were serious. Conclusions In Italian clinical practice, evolocumab treatment was associated with early and sustained reductions in LDL-C, maintained over 30 months. Within 3 months of treatment, patients demonstrated a reduction in LDL-C levels greater than 60% and maintained throughout the study. These data demonstrate that meaningful, consistent additional reductions in LDL-C can be achieved with use of evolocumab. Moreover, the therapy was well tolerated by patients, with a very low discontinuation and very few missed doses.

Persistence with long-term PCSK9 inhibitor treatment and its effectiveness in familial hypercholesterolaemia: data from the SAFEHEART study.

Most heterozygous familial hypercholesterolaemia (FH) patients require intensive lipid-lowering therapy (LLT) including PCSK9 inhibitors (PCSK9is) to reach current low-density lipoprotein cholesterol (LDL-C) goals. Persistence with chronic treatment is important to reduce the burden of atherosclerotic cardiovascular disease. We analysed persistence, efficacy, and impact on quality of life (QoL) of PCSK9i in FH patients in clinical practice setting. Spanish Familial Hypercholesterolaemia Cohort Study (SAFEHEART) is an open, prospective study in genetically defined FH patients in Spain. Patients ≥18 years of age (n = 696, 46% females) on stable LLT treated with PCSK9i were analysed. Median LDL-C at starting PCSK9i was 145 mg/dL [interquartile range (IQR), 123-177], 3.8 mmol/L (IQR 3.2-4.6). After a median follow up of 3.7 years (IQR 2.3-4.8), 27 patients (4%) discontinued PCSK9i treatment: 5 temporarily (0.7%) and 22 permanently (3.2%). Persistence with PCSK9i was 96.1% in the whole period. Median LDL-C levels and % LDL-C reduction attained after 1 year of treatment and in the last follow-up visit were 63 mg/dL (IQR 43-88), 1.6 mmol/L (IQR 1.1-2.23); 61 mg/dL (IQR 44-82), 1.6 mmol/L (IQR 1.1-2.1); 57.6% (IQR 39.5-69); and 58% (IQR 44-68), respectively. 2016 and 2019 ESC/EAS LDL-C goals were attained by 77 and 48% of patients, respectively, at the last follow-up visit (P < 0.001). Mean QoL score increased slightly in the first year and remained stable. Long-term persistence with PCSK9i in FH patients is very high, with a good QoL. Effectiveness in LDL-C reduction and LDL-C goal achievement dramatically improved with PCSK9i in this high-risk population in clinical practice setting. ClinicalTrials.gov number NCT02693548.