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Background:Inclisiran is a cholesterol-lowering small interfering RNA treatment licensed in the UK for lowering low-density lipoprotein cholesterol (LDL-C). VICTORION-Spirit (NCT04807400) is an implementation science study designed to provide evidence for inclisiran implementation within the National Health Service. The aim was to describe the process of patient identification employed in VICTORION-Spirit.Methods:A Phase IIIb, multicentre, randomisedcontrolled study, VICTORION-Spirit is evaluating inclisiran implementation in participants with atherosclerotic cardiovascular disease (ASCVD) or ASCVD-risk equivalents and elevated LDL-C. Feasibility Assessment and Recruitment System for Improving Trial Efficiency (FARSITE) software utilising natural language search functions identified patients who may benefit from inclisiran. FARSITE searches were performed within Salford, Manchester, Trafford and Bury Clinical Commissioning Groups to identify individuals with elevated LDL-C or total cholesterol and pre-existing cardiovascular disease (CVD) or at risk of ASCVD.Results:FARSITE used ‘total cholesterol >4 mmol/l’ terminology rather than ‘LDL-C’; the former yielded >3 times the number of eligible patients. The search for individuals with pre-existing CVD identified 24,196 people in a population of 560,969 (4.3%); including ‘total cholesterol >4 mmol/l’ identified 10,431 individuals with pre-existing CVD and elevated total cholesterol. Searches for individuals at risk of ASCVD identified 65,457 people, narrowing to 26,580 at risk of ASCVD plus elevated total cholesterol. The most discriminatory SNOMED concept codes and their prevalence within the dataset can inform national approaches to develop similar searches. Conclusions: FARSITE searches employed in VICTORION-Spirit identified a population at risk of ASCVD in Greater Manchester, England, who may benefit from a cholesterol-lowering medication such as inclisiran.
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Background: Translational gaps exist in implementing health innovations rapidly in clinical practice. Pragmatic effectiveness and implementation studies, therefore, play a pivotal role in understanding how high-value health innovations could be deployed and delivered in healthcare systems to reduce barriers to adoption and provide more rapid patient benefit. VICTORION-Spirit is an ongoing pragmatic, 9-month, phase IIIb, open-label, multicentre, randomised controlled study evaluating the implementation, patient experience, and delivery of the subcutaneous lipid-lowering therapy, inclisiran sodium 300 mg, in participants with elevated low-density lipoprotein cholesterol (LDL-C) who are on established lipid-lowering medication, or have been recommended lipid-lowering therapy but are unable to tolerate treatment. Methods: VICTORION-Spirit utilises a type 1 hybrid effectiveness-implementation design, where the primary objective is to demonstrate superiority of inclisiran with or without (±) behavioural support versus standard of care (SOC; e.g., statin and/or other lipid-lowering therapies) + behavioural support in terms of percentage reduction in LDL-C from baseline to Day 270 in a primary care setting. Secondary objectives will evaluate implementation of inclisiran ± behavioural support versus SOC + behavioural support through assessment of: patient satisfaction and patient activation/empowerment after treatment at Day 90; adherence to cardiovascular disease self-management; and serious adverse event profile. Additionally, a process evaluation ascertaining the views of: patients, providers, and National Health Service (NHS) commissioners will explore barriers and enablers to integrating inclisiran within primary care. Conclusions: The results of VICTORION-Spirit have potential to change our approach to lipid management and inform further implementation efforts in healthcare systems, such as the NHS. Trial registration: ClinicalTrials.gov NCT04807400.
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Resumen: La hiperlipidemia es altamente prevalente y contribuye de forma sustancial a la enfermedad cardiovascular aterosclerótica, que es una de las principales causas de morbilidad y mortalidad en Colombia. La reducción del colesterol LDL (c-LDL) produce una disminución del riesgo de enfermedad cardiovascular aterosclerótica y de eventos cardiovasculares adversos. La terapia dirigida a la proproteína convertasa subtilisina/kexina tipo 9 (PCSK9; su sigla en inglés) ha surgido como una herramienta novedosa para el tratamiento de la hiperlipidemia. Inclisiran es un ARN pequeño de doble hebra, que actúa inhibiendo la transcripción de PCSK-9 en los hepatocitos, lo que conduce a una reducción marcada y sostenida del c-LDL. En contraste con otras terapias hipolipemiantes, como estatinas, ezetimibe y anticuerpos monoclonales (MAbs; su sigla en inglés) e inhibidores de PCSK9, inclisiran propone un régimen de dosificación infrecuente de dos o tres veces al año. Su efecto prolongado representa una ventaja frente al incumplimiento del tratamiento, que es una de las principales causas por las que no se alcanzan los objetivos de c-LDL con la terapia estándar. Esta revisión tiene como objetivo presentar y discutir los datos científicos actuales con relación a la eficacia, tolerabilidad y seguridad del inclisiran en el tratamiento de la hipercolesterolemia.
Abstract: Hyperlipidemia is a highly prevalent condition and contributes substantially to atherosclerotic cardiovascular disease (ASCVD), which is one of the main causes of morbidity and mortality in Colombia. The reduction of LDL cholesterol (LDL-C) decreases the risk of ASCVD and adverse cardiovascular events. Targeted therapy for the proprotein convertase subtilisin/kexin type 9 (PCSK-9) has emerged as a novel tool for the treatment of hyperlipidemia. Inclisiran is a small double-stranded small interfering RNA that acts by blocking PCSK-9 transcription in hepatocytes, leading to a marked and sustained reduction in circulating LDL-C levels. In contrast to other lipid-lowering therapies such as statins, ezetimibe and monoclonal antibodies (MAbs) PCSK-9 inhibitors, Inclisiran proposes an infrequent dosing regimen of twice or three times a year. Its prolonged effect represents an advantage over non-compliance of the treatment, which is one of the main reasons why LDL-C goals are not achieved with standard therapy. This review aims to present and discuss current scientific data regarding the efficacy, tolerability and safety of Inclisiran in the treatment of hypercholesterolemia.
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Because of high rate of nonadherence to statins, the subcutaneously injection of Inclisiran therapy intervals are from 3 months to 6 months, which will increase the patients' adherence to the Inclisiran therapy. In this review, we summarize the latest advances of Inclisiran, and review the phase 2 and phase 3 clinical trials results, adverse events, and the clinical trials results in progress of Inclisiran. Finally, we discuss the current status of Inclisiran in the clinical works.
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Resumen La enfermedad cardiovascular aterosclerosa ocupa el primer lugar mundial en morbilidad y mortalidad. El principal factor de riesgo de enfermedad es el colesterol unido a lipoproteínas de baja densidad (C-LDL). El tratamiento farmacológico de elección para reducir el C-LDL son las estatinas; sin embargo, han sido insuficientes para eliminar el riesgo cardiovascular, especialmente en pacientes con formas primarias de hipercolesterolemia relacionadas con mutaciones genéticas, o intolerantes a estatinas. Es de gran importancia el desarrollo de nuevos fármacos para abatir el riesgo que persiste a pesar de la administración de estatinas. La proconvertasa subtilisina-kexina 9 (PCSK9) es un regulador primordial de la cantidad de receptores de LDL, ya que su función es dirigir dichos receptores a su destrucción lisosomal. El advenimiento de anticuerpos monoclonales para bloquear la PCSK9 ha permitido mejorar la cantidad y eficiencia de los receptores de LDL, de esto resulta la disminución notable del colesterol circulante. Hasta el momento, la eficacia e inocuidad de estos anticuerpos resultan aceptables, y los datos preliminares en cuanto a su efecto en la reducción de la morbilidad y mortalidad cardiovasculares son alentadores.
Abstract Atherosclerotic cardiovascular disease represents the leading cause of morbidity and mortality in most countries. The main risk factor for developing this disease is low density lipoprotein cholesterol (LDL-C). The pharmacological treatment of choice for reducing LDL-C is statins; however, in spite of the widespread use of statins, these drugs have been insufficient to eliminate cardiovascular risk. This residual risk is most relevant in patients with primary forms of hypercholes-terolemia associated with genetic mutations, or in those who are intolerant to statins. The development of new drugs to reduce residual cardiovascular risk is of vital importance. Proprotein convertase subtilisin-kexin 9 (PCSK9) is an important regulator of the amount of LDL receptors since its function is to direct these receptors to their lysosomal destruction. The development of monoclonal antibodies to block extracellular PCSK9 has allowed us to improve the quantity and efficiency of LDL receptors, resulting in a significant decrease in plasma cholesterol. Efficacy and safety of these antibodies is currently considered acceptable and preliminary data are encouraging but still insufficient to assess the favorable impact of these antibodies in reducing cardiovascular morbidity and mortality.