RESUMEN
OBJECTIVE: To evaluate the efficacy, safety, and tolerability of inclisiran in participants with atherosclerotic cardiovascular disease (ASCVD) from ORION-10 and ORION-11 stratified by key patient characteristics. PATIENTS AND METHODS: Participants were randomized 1:1 to receive 300 mg inclisiran sodium (284 mg inclisiran) or placebo on days 1, 90, 270, and 450, alongside background lipid-lowering therapy. This pooled, post hoc analysis stratified participants with ASCVD by sex, age, race, kidney function, body mass index, and glycemic status. Co-primary endpoints were percentage changes in low-density lipoprotein cholesterol (LDL-C) from baseline to day 510, and after day 90 and up to day 540 (time-adjusted). LDL-C goal attainment and safety were also assessed. RESULTS: This analysis of 2975 participants included: female, n=827; Black, n=213; 75 years of age or older, n=458; obese, n=1474; diabetes, n=1182; and moderate-to-severe chronic kidney disease, n=538. Mean baseline LDL-C levels in the total ASCVD population were balanced between treatment arms (inclisiran, 103.4 mg/dL; placebo, 102.0 mg/dL). With inclisiran, mean placebo-corrected percentage changes in LDL-C from baseline were -51.5% (95% CI, -54.0% to -49.0%) and -52.1% (95% CI, -53.9% to -50.4%) to day 510 and day 540 (time-adjusted), respectively; this was consistent across subgroups. LDL-C less than 55 mg/dL at 1 or more visits was reached by 87.6% of participants receiving inclisiran. The inclisiran safety profile was consistent across subgroups. CONCLUSION: Twice-yearly inclisiran (after initial and 3-month doses) was well-tolerated and provided significant, consistent LDL-C reductions for up to 18 months in participants with ASCVD independent of key patient characteristics (ORION-10 [Inclisiran for Participants With Atherosclerotic Cardiovascular Disease and Elevated Low-density Lipoprotein Cholesterol]; NCT03399370 and ORION-11 [Inclisiran for Subjects With ASCVD or ASCVD-Risk Equivalents and Elevated Low-density Lipoprotein Cholesterol]; NCT03400800).
RESUMEN
BACKGROUND: In the CLEAR (Cholesterol Lowering via Bempedoic Acid, an ACL-Inhibiting Regimen) Outcomes trial, treatment of statin-intolerant patients with bempedoic acid produced a 21% decrease in low-density lipoprotein cholesterol (LDL-C) relative to placebo and a 13% relative reduction in the risk of major adverse cardiovascular events. OBJECTIVES: This study sought to determine whether the relationship between LDL-C lowering and cardiovascular benefit achieved with bempedoic acid resembles that observed with statins when standardized per unit change in LDL-C. METHODS: To compare the treatment effect of bempedoic acid with statins, the methodology of the Cholesterol Treatment Trialists' Collaboration (CTTC) was applied to outcomes among the 13,970 patients enrolled in the CLEAR Outcomes trial. The CTTC endpoint of "major vascular event" was a composite of coronary heart disease death, nonfatal myocardial infarction, fatal or nonfatal stroke, or coronary revascularization. HRs for CTTC-defined endpoints were normalized to 1 mmol/L differences in LDL-C levels between bempedoic acid and placebo groups. RESULTS: A first major vascular event occurred in 703 (10.1%) patients in the bempedoic acid group and 816 (11.7%) patients in the placebo group (HR: 0.85; 95% CI: 0.77-0.94). When normalized per 1 mmol/L reduction in LDL-C, the HR was 0.75 (95% CI: 0.63-0.90), comparable to the rate ratio of 0.78 reported for statins in the CTTC meta-analysis. Normalized risk reductions were similar for bempedoic acid and statins for the endpoints of major coronary events, nonfatal myocardial infarction, and coronary revascularization. CONCLUSIONS: Cardiovascular risk reduction with bempedoic acid is similar to that achieved with statins for a given absolute magnitude of LDL-C lowering. (Evaluation of Major Adverse Cardiovascular Events in Participants With, or at High Risk for, Cardiovascular Disease Who Are Statin Intolerant Treated with Bempedoic Acid [ETC-1002] or Placebo [CLEAR Outcomes]; NCT02993406).
Asunto(s)
Enfermedades Cardiovasculares , LDL-Colesterol , Ácidos Dicarboxílicos , Ácidos Grasos , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Humanos , Masculino , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Femenino , Persona de Mediana Edad , Ácidos Dicarboxílicos/uso terapéutico , Ácidos Grasos/uso terapéutico , LDL-Colesterol/sangre , LDL-Colesterol/efectos de los fármacos , Anciano , Enfermedades Cardiovasculares/prevención & control , Resultado del Tratamiento , Método Doble CiegoRESUMEN
The spectrum of cardiorenal and metabolic diseases comprises many disorders, including obesity, type 2 diabetes (T2D), chronic kidney disease (CKD), atherosclerotic cardiovascular disease (ASCVD), heart failure (HF), dyslipidemias, hypertension, and associated comorbidities such as pulmonary diseases and metabolism dysfunction-associated steatotic liver disease and metabolism dysfunction-associated steatohepatitis (MASLD and MASH, respectively, formerly known as nonalcoholic fatty liver disease and nonalcoholic steatohepatitis [NAFLD and NASH]). Because cardiorenal and metabolic diseases share pathophysiologic pathways, two or more are often present in the same individual. Findings from recent outcome trials have demonstrated benefits of various treatments across a range of conditions, suggesting a need for practice recommendations that will guide clinicians to better manage complex conditions involving diabetes, cardiorenal, and/or metabolic (DCRM) diseases. To meet this need, we formed an international volunteer task force comprising leading cardiologists, nephrologists, endocrinologists, and primary care physicians to develop the DCRM 2.0 Practice Recommendations, an updated and expanded revision of a previously published multispecialty consensus on the comprehensive management of persons living with DCRM. The recommendations are presented as 22 separate graphics covering the essentials of management to improve general health, control cardiorenal risk factors, and manage cardiorenal and metabolic comorbidities, leading to improved patient outcomes.
RESUMEN
AIM: To assess whether implementation of the 2019 ESC/EAS dyslipidaemia guidelines observed between 2020-2021 improved between 2021-2022 in the SANTORINI study. METHODS: High- or very-high cardiovascular (CV) risk patients were recruited across 14 European countries from March 2020-February 2021, with 1-year prospective follow-up until May 2022. Lipid-lowering therapy (LLT) and 2019 ESC/EAS risk-based low-density lipoprotein cholesterol (LDL-C) goal attainment (defined as <1.4 mmol/L for patients at very high CV risk and <1.8 mmol/L for patients at high CV risk) at 1-year follow-up were compared with baseline. . RESULTS: Of 9559 patients enrolled, 9136 (2626 high risk, 6504 very high risk) had any follow-up data, and 7210 (2033 high risk, 5173 very high risk) had baseline and follow-up LDL-C data. LLT was escalated in one-third of patients and unchanged in two-thirds. Monotherapy and combination therapy usage rose from 53.6% and 25.6% to 57.1% and 37.9%, respectively. Mean LDL-C levels decreased from 2.4 mmol/L to 2.0 mmol/L. Goal attainment improved from 21.2% to 30.9%, largely driven by LLT use among those not on LLT at baseline. Goal attainment was greater with combination therapy compared with monotherapy at follow-up (39.4 vs 25.5%). CONCLUSIONS: LLT use and achievement of risk-based lipid goals increased over 1-year follow-up particularly when combination LLT was used. Nonetheless, most patients remained above goal, hence strategies are needed to improve implementation of combination LLT.
Cardiovascular diseases, a group of disorders of the heart and blood vessels, are the most common cause of death worldwide. Lowering low-density lipoprotein (LDL) cholesterol in the bloodstream reduces the risk of developing cardiovascular diseases, such as heart attacks and strokes. Guidelines recommend that those at highest risk of cardiovascular disease should achieve the lowest levels of LDL cholesterol. Several medications are available that help lower LDL cholesterol levels and prevent cardiovascular events, however, recent studies have shown that the majority of patients continue to have LDL cholesterol levels above optimal value in part due to suboptimal use of these medications. Here we report the results after 1 year of follow-up of the SANTORINI study (started in 2020) which aimed to document the management of LDL cholesterol in clinical practice across 14 countries in Europe. We found that better control of LDL cholesterol occurred when more than one drug was used (combination therapy). Use of combination therapy was low at the start of the study 25.6% but increased over 1 year to 37.9%, resulting in better control of LDL cholesterol at 1 year than observed at the start of the study. Nonetheless, only 31% of patients achieved their LDL cholesterol target levels based on the European guidelines. Greater use of combination therapies is needed in order to improve the overall population level control of LDL cholesterol.
RESUMEN
BACKGROUND: Familial hypercholesterolemia (FH), while highly prevalent, is a significantly underdiagnosed monogenic disorder. Improved detection could reduce the large number of cardiovascular events attributable to poor case finding. We aimed to assess whether machine learning algorithms outperform clinical diagnostic criteria (signs, history, and biomarkers) and the recommended screening criteria in the United Kingdom in identifying individuals with FH-causing variants, presenting a scalable screening criteria for general populations. METHODS AND RESULTS: Analysis included UK Biobank participants with whole exome sequencing, classifying them as having FH when (likely) pathogenic variants were detected in their LDLR, APOB, or PCSK9 genes. Data were stratified into 3 data sets for (1) feature importance analysis; (2) deriving state-of-the-art statistical and machine learning models; (3) evaluating models' predictive performance against clinical diagnostic and screening criteria: Dutch Lipid Clinic Network, Simon Broome, Make Early Diagnosis to Prevent Early Death, and Familial Case Ascertainment Tool. One thousand and three of 454 710 participants were classified as having FH. A Stacking Ensemble model yielded the best predictive performance (sensitivity, 74.93%; precision, 0.61%; accuracy, 72.80%, area under the receiver operating characteristic curve, 79.12%) and outperformed clinical diagnostic criteria and the recommended screening criteria in identifying FH variant carriers within the validation data set (figures for Familial Case Ascertainment Tool, the best baseline model, were 69.55%, 0.44%, 65.43%, and 71.12%, respectively). Our model decreased the number needed to screen compared with the Familial Case Ascertainment Tool (164 versus 227). CONCLUSIONS: Our machine learning-derived model provides a higher pretest probability of identifying individuals with a molecular diagnosis of FH compared with current approaches. This provides a promising, cost-effective scalable tool for implementation into electronic health records to prioritize potential FH cases for genetic confirmation.
Asunto(s)
Apolipoproteína B-100 , Hiperlipoproteinemia Tipo II , Aprendizaje Automático , Proproteína Convertasa 9 , Humanos , Hiperlipoproteinemia Tipo II/genética , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/epidemiología , Femenino , Masculino , Proproteína Convertasa 9/genética , Apolipoproteína B-100/genética , Persona de Mediana Edad , Receptores de LDL/genética , Reino Unido/epidemiología , Secuenciación del Exoma , Pruebas Genéticas/métodos , Adulto , Valor Predictivo de las Pruebas , Predisposición Genética a la Enfermedad , MutaciónRESUMEN
AIMS: To conduct a pooled analysis of Phase 3 trials investigating the efficacy and safety of inclisiran across glycaemic and body mass index (BMI) strata. MATERIALS AND METHODS: Participants were randomized 1:1 to receive 300 mg inclisiran sodium or placebo twice yearly, after initial and 3-month doses up to 18 months, with background oral lipid-lowering therapy. Analyses were stratified by glycaemic status (normoglycaemia, prediabetes, and diabetes) or BMI (<25, ≥25 to <30, ≥30 to <35, and ≥35 kg/m2). Co-primary endpoints were percentage and time-adjusted percentage change in low-density lipoprotein (LDL) cholesterol from baseline. Safety was also assessed. RESULTS: Baseline characteristics were balanced between treatment arms and across strata. Percent LDL cholesterol change (placebo-corrected) with inclisiran from baseline to Day 510 ranged from -47.6% to -51.9% and from -48.8% to -54.4% across glycaemic/BMI strata, respectively. Similarly, time-adjusted percentage changes after Day 90 and up to Day 540 ranged from -46.8% to -52.0% and from -48.6% to -53.3% across glycaemic/BMI strata, respectively. Inclisiran led to significant reductions in proprotein convertase subtilisin/kexin type 9 and other atherogenic lipids and lipoproteins versus placebo across the glycaemic/BMI strata. The proportions of individuals achieving LDL cholesterol thresholds of <1.8 mmol/L and <1.4 mmol/L with inclisiran increased with increasing glycaemic and BMI strata. Across the glycaemic/BMI strata, a higher proportion of individuals had mild/moderate treatment-emergent adverse events (TEAEs) at the injection site with inclisiran (2.8%-7.7%) versus placebo (0.2%-2.1%). CONCLUSION: Inclisiran provided substantial and sustained LDL cholesterol lowering across glycaemic/BMI strata, with a modest excess of transient mild-to-moderate TEAEs at the injection site.
Asunto(s)
LDL-Colesterol , Obesidad , Humanos , Femenino , Masculino , Persona de Mediana Edad , Obesidad/complicaciones , Obesidad/sangre , LDL-Colesterol/sangre , Glucemia/análisis , Glucemia/metabolismo , Adulto , Anciano , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/sangre , Hemoglobina Glucada/análisis , Índice de Masa Corporal , Ensayos Clínicos Fase III como Asunto , Método Doble Ciego , Hipoglucemiantes/uso terapéutico , Hipoglucemiantes/administración & dosificación , Resultado del Tratamiento , ARN Interferente PequeñoRESUMEN
BACKGROUND: 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. METHODS: 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. FINDINGS: 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). INTERPRETATION: 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. FUNDING: 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.
Asunto(s)
Eliminación de Componentes Sanguíneos , Enfermedades Cardiovasculares , Hiperlipoproteinemia Tipo II , Sistema de Registros , Humanos , Femenino , Masculino , Hiperlipoproteinemia Tipo II/terapia , Hiperlipoproteinemia Tipo II/sangre , Hiperlipoproteinemia Tipo II/complicaciones , Niño , Eliminación de Componentes Sanguíneos/métodos , Adolescente , Preescolar , Estudios de Seguimiento , Enfermedades Cardiovasculares/prevención & control , Lactante , LDL-Colesterol/sangre , Lipoproteínas/sangre , Estudios de Cohortes , Resultado del Tratamiento , HomocigotoRESUMEN
BACKGROUND AND AIMS: Data describing the long-term efficacy, safety, and tolerability of inclisiran are limited. This was explored in ORION-8, an open-label extension study of preceding Phase 2 and Phase 3 placebo-controlled and open-label extension trials. METHODS: Adults with ASCVD, ASCVD risk equivalent, or HeFH received open-label inclisiran every 180 days (after completion of the parent trial) until Day 990, followed by an end-of-study (EOS) visit at Day 1080 or ≥90 days after last dose. Study endpoints included proportion of patients achieving pre-specified LDL-C goals (ASCVD: <1.8 mmol/L [<70 mg/dL]; ASCVD risk equivalent: <2.6 mmol/L [<100 mg/dL]), percentage and absolute changes in LDL-C at EOS, and safety of inclisiran. RESULTS: Of 3274 patients included in the analysis, 2446 (74.7%) were followed until EOS. Mean age was 64.9±9.9 years, 82.7% (n=2709) had ASCVD, and mean baseline LDL-C was 2.9±1.2 mmol/L. Mean cumulative exposure to inclisiran (including parent trials) was 3.7 years; maximum exposure was 6.8 years. With inclisiran, 78.4% (95% CI: 76.8, 80.0) of patients achieved pre-specified LDL-C goals and mean percentage LDL-C reduction was -49.4% (95% CI: -50.4, -48.3). No attenuation of LDL-C lowering over time was observed. Treatment-emergent adverse events at the injection site (all mild or moderate) occurred in 5.9% of inclisiran-treated patients. Inclisiran-associated anti-drug antibodies were infrequent (5.5%) and had no impact on the efficacy or safety of inclisiran. No new safety signals were identified. CONCLUSIONS: In the largest and longest follow-up to date, inclisiran demonstrated sustained and substantial LDL-C lowering with a favourable long-term safety and tolerability profile. ClinicalTrials.gov identifier: NCT03814187.
RESUMEN
BACKGROUND: Obicetrapib, a novel, selective cholesteryl ester transfer protein (CETP) inhibitor, reduces low-density lipoprotein cholesterol (LDL-C), LDL particles, apolipoprotein (Apo) B, and lipoprotein(a) [Lp(a)] and increases high-density lipoprotein cholesterol (HDL-C) when added to statins with or without ezetimibe. By substantially reducing LDL-C, obicetrapib has the potential to lower atherogenic lipoproteins in patients with atherosclerotic cardiovascular disease (ASCVD) or heterozygous familial hypercholesterolemia (HeFH) whose LDL-C levels remain high despite treatment with available maximally tolerated lipid-modifying therapies, addressing an unmet medical need in a patient population at high risk for cardiovascular events. METHODS AND RESULTS: BROADWAY (NCT05142722) and BROOKLYN (NCT05425745) are ongoing placebo-controlled, double-blind, randomized Phase III trials designed to examine the efficacy, safety, and tolerability of obicetrapib as an adjunct to dietary intervention and maximally tolerated lipid-modifying therapies in participants with a history of ASCVD and/or underlying HeFH whose LDL-C is not adequately controlled. The primary efficacy endpoint was the percent change in LDL-C from baseline to day 84. Other endpoints included changes in Apo B, non-HDL-C, HDL-C, Apo A1, Lp(a), and triglycerides in addition to parameters evaluating safety, tolerability, and pharmacokinetics. BROADWAY also included an adjudicated assessment of major adverse cardiovascular events, measurements of glucose homeostasis, and an ambulatory blood pressure monitoring substudy. A total of 2,532 participants were randomized in BROADWAY and 354 in BROOKLYN to receive obicetrapib 10 mg or placebo (2:1) for 365 days with follow-up through 35 days after the last dose. Results from both trials are anticipated in 2024. CONCLUSION: These trials will provide safety and efficacy data to support the potential use of obicetrapib among patients with ASCVD or HeFH with elevated LDL-C for whom existing therapies are not sufficiently effective or well-tolerated.
Asunto(s)
Anticolesterolemiantes , Aterosclerosis , LDL-Colesterol , Humanos , Aterosclerosis/tratamiento farmacológico , Aterosclerosis/prevención & control , Anticolesterolemiantes/uso terapéutico , Anticolesterolemiantes/administración & dosificación , Método Doble Ciego , LDL-Colesterol/sangre , Masculino , Femenino , Proteínas de Transferencia de Ésteres de Colesterol/antagonistas & inhibidores , HDL-Colesterol/sangre , Hiperlipoproteinemia Tipo II/tratamiento farmacológico , Hiperlipoproteinemia Tipo II/sangre , Hiperlipoproteinemia Tipo II/complicaciones , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Lipoproteína(a)/sangre , Persona de Mediana EdadRESUMEN
Clinical risk scores based on traditional risk factors of atherosclerosis correlate imprecisely to an individual's complex pathophysiological predisposition to atherosclerosis and provide limited accuracy for predicting major adverse cardiovascular events (MACE). Over the past two decades, computed tomography scanners and techniques for coronary computed tomography angiography (CCTA) analysis have substantially improved, enabling more precise atherosclerotic plaque quantification and characterization. The accuracy of CCTA for quantifying stenosis and atherosclerosis has been validated in numerous multicentre studies and has shown consistent incremental prognostic value for MACE over the clinical risk spectrum in different populations. Serial CCTA studies have advanced our understanding of vascular biology and atherosclerotic disease progression. The direct disease visualization of CCTA has the potential to be used synergistically with indirect markers of risk to significantly improve prevention of MACE, pending large-scale randomized evaluation.
Asunto(s)
Angiografía por Tomografía Computarizada , Angiografía Coronaria , Enfermedad de la Arteria Coronaria , Humanos , Angiografía por Tomografía Computarizada/métodos , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Enfermedad de la Arteria Coronaria/diagnóstico , Medición de Riesgo/métodos , Angiografía Coronaria/métodos , Placa Aterosclerótica/diagnóstico por imagen , Factores de Riesgo de Enfermedad Cardiaca , Pronóstico , Estenosis Coronaria/diagnóstico por imagenRESUMEN
BACKGROUND AND AIMS: Inclisiran, an siRNA therapy, consistently reduces low-density lipoprotein cholesterol (LDL-C) with twice-yearly dosing. Potential cardiovascular benefits of implementing inclisiran at a population level, added to statins, were evaluated through simulation. METHODS: For each participant in the ORION-10 and ORION-11 trials comparing inclisiran with placebo, baseline 10-year cardiovascular risk was estimated using the SMART equation. The time-adjusted LDL-C difference from baseline observed 90-540 days after baseline was assumed to persist and used to estimate potential reduction in 10-year cardiovascular risk. Impact on 500,000 ORION-like individuals was simulated with Monte-Carlo. RESULTS: Mean baseline LDL-C and predicted 10-year major vascular risk among patients randomized to inclisiran (n = 1288) versus placebo (n = 1264) were 2.66 mmol/L versus 2.60 mmol/L and 24.9% versus 24.6%, respectively. Placebo-corrected time-adjusted absolute reduction in LDL-C with inclisiran was -1.32 mmol/L (95% CI -1.37 to -1.26; p < 0.001), which predicted a 10-year cardiovascular risk of 18.1% with inclisiran versus 24.7% with placebo (absolute difference [95% CI], -6.99% [-7.33 to -6.66]; p < 0.001) NNT 15. Extrapolating to 500,000 inclisiran-treated individuals, the model predicted large population shifts towards lower quintiles of risk with fewer remaining in high-risk categories; 3350 to 471 (≥80% risk), 11,793 to 3332 (60-<80% risk), 52,142 to 22,665 (40-<60% risk), 197,752 to 141,014 (20-<40% risk), and more moving into the lowest risk category (<20%) from 234,963 to 332,518. CONCLUSIONS: Meaningful gains in population health might be achieved over 10 years by implementing at-scale approaches capable of providing substantial and sustained reductions in LDL-C beyond those achievable with statins.
Asunto(s)
Anticolesterolemiantes , Enfermedades Cardiovasculares , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Humanos , LDL-Colesterol , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , ARN Interferente Pequeño , Enfermedades Cardiovasculares/genética , Enfermedades Cardiovasculares/prevención & control , Enfermedades Cardiovasculares/tratamiento farmacológico , Proproteína Convertasa 9RESUMEN
BACKGROUND: Patients with heterozygous familial hypercholesterolemia (HeFH) often cannot reach guideline-recommended low-density lipoprotein cholesterol (LDL-C) goals despite multidrug therapy. OBJECTIVE: To evaluate the efficacy and safety of bempedoic acid as an add-on therapy for lowering LDL-C in patients with HeFH. METHODS: Pooled data from two 52-week phase 3 clinical trials of patients with atherosclerotic cardiovascular disease and/or HeFH receiving maximally tolerated statin therapy (randomized 2:1 to bempedoic acid or placebo) were analyzed by HeFH status. Endpoints included changes from baseline to week 12 (and up to week 52) in LDL-C and other lipid parameters, achievement of LDL-C goals, and safety. RESULTS: A total of 217 (bempedoic acid, 146; placebo, 71) patients with HeFH and 2,792 (bempedoic acid, 1,864; placebo, 928) without HeFH were included (mean baseline LDL-C, 172.8 mg/dL and 102.6 mg/dL, respectively). Bempedoic acid significantly lowered LDL-C at week 12 vs. placebo regardless of HeFH status (with HeFH, -21.2%; without HeFH, -18.2% [both P<0.0001]). Bempedoic acid significantly reduced other lipid parameters and high-sensitivity C-reactive protein vs. placebo regardless of HeFH status (all P≤0.01). Among patients with HeFH treated with bempedoic acid, 32% and 27% achieved LDL-C <100 mg/dL at weeks 12 and 52, respectively. Overall treatment-emergent adverse event incidence was comparable across all four groups (74.7-77.5%). CONCLUSION: Bempedoic acid significantly lowered LDL-C levels vs. placebo and was generally well tolerated in all patients, with no new safety findings in patients with HeFH, despite more intensive lipid-lowering therapy in patients with vs. without HeFH.
Asunto(s)
LDL-Colesterol , Ácidos Dicarboxílicos , Ácidos Grasos , Heterocigoto , Hiperlipoproteinemia Tipo II , Humanos , Ácidos Dicarboxílicos/uso terapéutico , Ácidos Dicarboxílicos/efectos adversos , Hiperlipoproteinemia Tipo II/tratamiento farmacológico , Masculino , LDL-Colesterol/sangre , Ácidos Grasos/uso terapéutico , Ácidos Grasos/efectos adversos , Persona de Mediana Edad , Femenino , Adulto , Resultado del Tratamiento , Ensayos Clínicos Fase III como Asunto , AncianoRESUMEN
AIMS: This study aimed to evaluate the stepwise approach for cardiovascular (CV) risk factor treatment as outlined by the European Society for Cardiology 2021 guidelines on CV disease (CVD) prevention in patients with established atherosclerotic CVD (ASCVD). METHODS AND RESULTS: In patients with ASCVD, included in UCC-SMART (n = 8730) and European parts of the REACH registry (n = 18 364), the 10-year CV risk was estimated using SMART2. Treatment effects were derived from meta-analyses and trials. Step 1 recommendations were LDL cholesterol (LDLc) < 1.8â mmol/L, systolic blood pressure (SBP) < 140â mmHg, using any antithrombotic medication, sodium-glucose co-transporter 2 (SGLT2) inhibition, and smoking cessation. Step 2 recommendations were LDLc < 1.4â mmol/L, SBP < 130â mmHg, dual-pathway inhibition (DPI, aspirin plus low-dose rivaroxaban), colchicine, glucagon-like peptide (GLP)-1 receptor agonists, and eicosapentaenoic acid. Step 2 was modelled accounting for Step 1 non-attainment. With current treatment, residual CV risk was 22%, 32%, and 60% in the low, moderate, and pooled (very) high European risk regions, respectively. Step 2 could prevent up to 198, 223 and 245 events per 1000 patients treated, respectively. Intensified LDLc reduction, colchicine, and DPI could be applied to most patients, preventing up to 57, 74, and 59 events per 1000 patients treated, respectively. Following Step 2, the number of patients with a CV risk of <10% could increase from 20%, 6.4%, and 0.5%, following Step 1, to 63%, 48%, and 12%, in the respective risk regions. CONCLUSION: With current treatment, residual CV risk in patients with ASCVD remains high across all European risk regions. The intensified Step 2 treatment options result in marked further reduction of residual CV risk in patients with established ASCVD. KEY FINDINGS: Guideline-recommended intensive treatment of patients with cardiovascular disease could prevent additional 198-245 new cardiovascular events for every 1000 patients treated.
Patients with established cardiovascular disease are at high risk for new cardiovascular events. The European Society of Cardiology guideline for the prevention of cardiovascular disease introduced a stepwise treatment approach. Step 1 in this approach are treatments that apply to all patients, and Step 2 are intensive treatments that can be prescribed to patients who are still at high risk of new events even with Step 1 treatments. The current study investigates the effect of Steps 1 and 2 on the risk of cardiovascular disease in 27 094 patients all across Europe. With the conventional treatments of Step 1 the risk of cardiovascular disease remains high, with a 10-year risk of new events higher than 10% in 8099% of patients. The intensive treatment options from Step 2 could prevent additional 198245 new cardiovascular events for every 1000 patients that are treated. With intensive treatment, up to 63% of patients could achieve a 10-year risk of new cardiovascular disease below 10%.
Asunto(s)
Aterosclerosis , Cardiología , Enfermedades Cardiovasculares , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Humanos , Enfermedades Cardiovasculares/prevención & control , Factores de Riesgo , Aterosclerosis/prevención & control , LDL-Colesterol , Factores de Riesgo de Enfermedad Cardiaca , Colchicina , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéuticoRESUMEN
INTRODUCTION: Low-density lipoprotein cholesterol (LDL-C) is among the most important modifiable risk factors for cardiovascular disease. In very high-risk patients, the European Society of Cardiology/European Atherosclerosis Society guidelines recommend attaining LDL-C < 55 mg/dL. In the German cohort of the observational HEYMANS study, we aimed to describe the clinical characteristics and LDL-C control among patients initiating evolocumab. METHODS: Data was collected between 09/2016 and 05/2021 for ≤ 6 months before (retrospectively) and ≤ 30 months after evolocumab initiation (prospectively). Patient characteristics, lipid-lowering therapy (LLT), lipid values, evolocumab use, and safety were collected. RESULTS: Of 380 enrolled patients, 93% received evolocumab in secondary prevention and 69% had a history of statin intolerance. At study baseline, 49% did not receive any statins and LDL-C was very high (145 mg/dL). Use of evolocumab decreased LDL-C by a median of 53% within 3 months and remained stable thereafter, despite mainly unchanged background LLT. Overall, 59% attained an LDL-C level < 55 mg/dL (69% with, 49% without LLT). Persistence to evolocumab was 90.6% in months 1-12 and 93.5% in months 13-30. Adverse drug reactions were reported in 8% of patients. CONCLUSION: Data from the German HEYMANS cohort corroborate previous reports on evolocumab effectiveness and safety in clinical practice. Evolocumab initiation was associated with a rapid and sustained LDL-C reduction. Persistence with evolocumab was high. Our finding that patients receiving an evolocumab/LLT combination are more likely to attain the LDL-C goal than those receiving evolocumab alone corroborates previous data showing the importance of using highly intensive therapy. Graphical abstract available for this article. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT02770131 (registration date 27 April 2016).
Asunto(s)
Anticuerpos Monoclonales Humanizados , Anticolesterolemiantes , Enfermedades Cardiovasculares , Humanos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticolesterolemiantes/uso terapéutico , Enfermedades Cardiovasculares/tratamiento farmacológico , LDL-Colesterol , Factores de Riesgo de Enfermedad Cardiaca , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Estudios Retrospectivos , Factores de Riesgo , Resultado del TratamientoRESUMEN
Importance: The ATP citrate lyase (ACL) inhibitor, bempedoic acid, reduces low-density lipoprotein cholesterol (LDL-C) level and major adverse cardiovascular events (MACE) by 13% in patients at high cardiovascular risk with intolerance of statin and high-intensity statin medications. The effects of bempedoic acid on total cardiovascular events remain unknown. Objective: To determine the impact of bempedoic acid on the total incidence of MACE. Design, Setting, and Participants: Included in this prespecified analysis of the Cholesterol Lowering via Bempedoic Acid, an ACL-Inhibiting Regimen (CLEAR) Outcomes trial were patients with, or at high risk for, cardiovascular disease, with hypercholesterolemia and inability to take guideline-recommended statins. Study data were analyzed from December 2016 to November 2022. Interventions: Patients were randomly assigned to treatment with bempedoic acid or placebo daily. Main Outcomes and Measures: The primary end point was the time to first event for a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization (MACE-4). The key secondary end point was time to first event for cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke (MACE-3). This prespecified analysis compared the total number of cardiovascular events in the treatment groups. Results: A total of 13â¯970 patients (mean [SD] age, 65 [9] years; 7230 male [51.8%]) were included in the study. A total of 9764 participants (69.9%) had prior atherosclerotic cardiovascular disease and a baseline LDL-C level of 139 mg/dL; treatment with bempedoic acid resulted in a 21% reduction in LDL-C level and a 22% reduction in high-sensitivity C-reactive protein (hsCRP) level at 6 months. Median (IQR) follow-up was 3.4 (3.1-3.9) years. A total of 1746 positively adjudicated first MACE-4 events and 915 additional MACE events in 612 patients were recorded, with coronary revascularization representing 32.8% (573 of 1746) of first events and 69.4% (635 of 915) of additional events. For the total incidence of cardiovascular events, treatment with bempedoic acid was associated with a reduction in risk of MACE-4 (hazard ratio [HR], 0.80; 95% CI, 0.72-0.89; P <.001), MACE-3 (HR, 0.83; 95% CI, 0.73-0.93; P = .002), myocardial infarction (HR, 0.69; 95% CI, 0.58-0.83; P < .001), and coronary revascularization (HR, 0.78; 95% CI, 0.68-0.89; P <.001), although no statistically significant difference was observed for stroke (HR, 0.80; 95% CI, 0.63-1.03). A lower HR for protection with bempedoic acid was observed with increasing number of MACE events experienced by patients. Conclusion and Relevance: Lowering LDL-C level with bempedoic acid reduced the total number of cardiovascular events in patients with high cardiovascular risk, statin therapy intolerance, and elevated LDL-C levels.
Asunto(s)
Ácidos Dicarboxílicos , Ácidos Grasos , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Infarto del Miocardio , Accidente Cerebrovascular , Humanos , Masculino , Anciano , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , LDL-Colesterol , Resultado del Tratamiento , Colesterol , Infarto del Miocardio/epidemiología , Accidente Cerebrovascular/epidemiologíaRESUMEN
AIMS: The HEYMANS study observed patients receiving evolocumab as part of routine clinical hyperlipidemia management. It was designed to capture data on clinical parameters relevant to health authorities and physicians. METHODS: This was a European multi-country observational cohort serial chart review study; data on the Swiss cohort are reported here. Patients were prescribed evolocumab as per the Swiss reimbursement criteria in force at the time and were invited chronologically. The study consisted of a 6-month period prior to initiation of evolocumab, a 12-month core observation period (entered by 75 patients, completed by 74 patients), and an 18-month extended observation period (entered by 40 patients, completed by 34 patients). The primary objective was to describe the clinical characteristics of patients receiving evolocumab. Secondary objectives included to describe lipid levels, evolocumab use, and patterns of use of other lipid-lowering therapies (LLT, that is, statins and/or ezetimibe) over time. The study was conducted in the Swiss cohort between May 2017 and June 2021. RESULTS: Patients who received evolocumab in Swiss routine practice mostly were in secondary prevention (93%) and had a history of statin intolerance (85%) with 53% receiving no background LLT. One-third had familial hypercholesterolemia. Patients initiated evolocumab at a median low-density lipoprotein cholesterol (LDL-C) of 3.6 mmol/L, which decreased by 54% within 3 months to 1.6 mmol/L and was stable thereafter. Overall, 61% achieved the LDL-C goal of <1.4 mmol/L with more patients attaining this goal when they received evolocumab with a statin and/or ezetimibe (84%) compared to 41% when receiving evolocumab alone. An LDL-C reduction of ⩾50% was achieved by 85% of patients. Persistence with evolocumab at 12 months was 85%. CONCLUSION: In Swiss clinical practice, evolocumab was mainly prescribed to patients with very high cardiovascular risk, who had very high LDL-C levels. Most patients continued to use evolocumab throughout the study period. In these patients, LDL-C was reduced by >50% within 3 months and LDL-C reductions were maintained over time. Guideline-recommended LDL-C goals for this very high-risk cohort were more frequently attained in patients receiving a combination of statin and/or ezetimibe and evolocumab. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02770131.
Asunto(s)
Inhibidores de Hidroximetilglutaril-CoA Reductasas , Humanos , LDL-Colesterol , Estudios de Cohortes , Ezetimiba/uso terapéutico , SuizaRESUMEN
Aims: Limited 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. Methods: HEYMANS 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. (AU)
Objetivos: Existen datos limitados sobre la variabilidad del nivel de colesterol de lipoproteínas de baja densidad (cLDL) o la persistencia a largo plazo con el anticuerpo monoclonal evolocumab en la práctica clínica habitual. HEYMANS (NCT02770131) es el primer estudio observacional multicéntrico y multinacional de pacientes europeos que iniciaron tratamiento con evolocumab en la práctica clínica habitual, basado en criterios de reembolso locales. El objetivo fue evaluar las características clínicas, los cambios en los niveles de cLDL, los patrones de tratamiento y la persistencia a este con evolocumab en la cohorte española con un seguimiento de 30 meses, utilizando datos del registro HEYMANS. Métodos: HEYMANS fue un estudio prospectivo de pacientes adultos (≥18 años) que recibieron al menos una dosis de evolocumab prescrita. Se incluyeron 1.951 sujetos de 12 países. Los datos fueron recopilados desde los seis meses previos al inicio del tratamiento hasta los 30 meses posteriores. La cohorte española incluyó pacientes que comenzaron evolocumab en la práctica clínica habitual desde marzo del 2016 hasta septiembre del 2019. Se recogieron las características demográficas y clínicas, los tratamientos hipolipemiantes (LLT) y el perfil lipídico. (AU)