Systematic review of pharmacoeconomic evaluation on PCSK9 inhibitors for the prevention of cardiovascular disease in patients with hypercholesterolemia / 中国药房

OBJECTIVE To systematically review the pharmacoeconomic evaluation literature about proprotein convertase subtilisin/kexin type 9 （PCSK9） inhibitors for the prevention of cardiovascular disease in patients with hypercholesterolemia， and to provide a reference for clinical treatment， health decision-making and future follow-up research. METHODS Retrieved from English and Chinese databases such as PubMed and CNKI， the pharmacoeconomic literature about PCSK9 inhibitors （evolocumab and alirocumab） for the prevention of cardiovascular disease in patients with hypercholesterolemia was collected from the establishment of the database to October 8， 2023. The quality of the included literature was assessed with Consolidated Health Economic Evaluation Reporting Standards 2022 （CHEERS 2022） scale. The descriptive analysis was performed for basic information， model structure， related parameters， sensitivity analysis and the results of included studies. RESULTS & CONCLUSIONS A total of 29 literature were included， with overall good quality. The evaluation mainly adopted the Markov model from the healthcare system， payer and societal perspective. The effectiveness and utility data mainly came from the previous studies； the direct cost was mainly considered with a discount rate of 1.5%-5.0% per year， while the willingness-to-pay threshold was often set at 1-3 times the gross domestic product per capita. Most health output indicators were measured in life years and quality-adjusted life years. The sensitivity analysis of most studies demonstrated the robustness and the main influential factor was the drug cost. Most Chinese studies showed that PCSK9 inhibitor was not cost-effective for the prevention of cardiovascular disease in patients with acute coronary syndrome， myocardial infarction and atherosclerotic cardiovascular disease. It was cost-effective to use PCSK9 inhibitors for the prevention of cardiovascular disease only in specific groups， such as patients with triple vessel disease， patients with newly diagnosed acute coronary syndrome and low-density lipoprotein cholesterol≥100 mg/dL. Future research should refer to the CHEERS 2022 scale to improve the design， and strive to select large-scale， high-quality data to enhance the quality of reports and the transparency of health decisions， so as to more accurately assess the cost-effectiveness of PCSK9 inhibitors.

Impacto de la optimización del tratamiento hipolipemiante en el riesgo cardiovascular residual / Impact of Optimizing Lipid-Lowering Therapy on Residual Cardiovascular Risk

RESUMEN Introducción: el modelo SMART-REACH predice el riesgo de eventos cardiovasculares recurrentes. Objetivos: los objetivos de este estudio fueron: a) evaluar el riesgo residual en una población en prevención secundaria y niveles de colesterol asociado a lipoproteínas de baja densidad (C-LDL) fuera de meta; b) mediante un modelo de simulación, determinar el impacto de optimizar las terapias hipolipemiantes en términos de reducción del riesgo residual. Material y métodos: estudio transversal, descriptivo y multicéntrico. Se incluyeron consecutivamente pacientes con antecedentes cardiovasculares y un C-LDL mayor o igual que 55 mg/dL. El riesgo de eventos recurrentes (infarto agudo de miocardio, accidente cerebrovascular o muerte vascular) a 10 años y a lo largo de la vida se estimó utilizando el modelo SMART-REACH. Mediante una simulación, se optimizó el tratamiento hipolipemiante de cada paciente (utilizando estatinas, ezetimibe o inhibidores de proproteína convertasa subtilisina kexina tipo 9 [iPCSK9]), se estimó el descenso del C-LDL, se verificó el alcance del objetivo lipídico y se calculó la reducción del riesgo cardiovascular y el número necesario a tratar (NNT) correspondiente. Resultados: se incluyeron 187 pacientes (edad media 67,9 ± 9,3 años, 72,7% hombres). Los riesgos residuales calculados a 10 años y a lo largo de la vida fueron 37,1 ± 14,7% y 60,3 ± 10,7%, respectivamente. Globalmente, se pudo optimizar una sola estrategia farmacológica con estatinas, ezetimibe o un iPCSK9 en el 38,5%, el 11,5% y el 5,5% de la población, respectivamente. La optimización basada en dos tratamientos se realizó en el 27,5% (estatinas + ezetimibe), el 7,7% (estatinas + iPCSK9) y el 1,1% (ezetimibe + iPCSK9) de los casos. En 15 pacientes se optimizó el tratamiento considerando los tres fármacos. El 53,9% y el 62,9% de las acciones para optimizar el tratamiento mostraron un NNT menor que 30 para evitar un evento a 10 años o a lo largo de la vida, respectivamente. Conclusión: en este estudio, los pacientes con antecedentes cardiovasculares que no alcanzan la meta de C-LDL mostraron un riesgo residual considerable. La simulación mostró un importante margen para optimizar el tratamiento, con un impacto notable en el riesgo residual.

ABSTRACT Background: The SMART-REACH model predicts the risk or recurrent cardiovascular events. Objectives: The objectives of this study were: a) to evaluate the residual cardiovascular risk in a secondary prevention population with LDL-C levels above the recommended goal, using a simulation model; and b) to determine the impact of optimizing lipid-lowering therapies in terms of residual cardiovascular risk reduction. Methods: We conducted a cross-sectional, descriptive and multicenter study. Patient with a history of cardiovascular disease and a LDL-C ≥55 mg/dL were consecutively included. The 10-year and lifetime risk of recurrent events (myocardial infarction, stroke, or vascular death) were estimated using the SMART-REACH model. By means of a simulation, lipid-lowering treatment was optimized for each patient [using statins, ezetimibe and/or PCSK9 (PCSK9) inhibitors], with estimation of LDL-C reduction, checking if lipid-lowering goal was achieved and calculating the reduction in cardiovascular risk and the corresponding number needed to treat (NNT). Results: The cohort was made up of 187 patients; mean age was 67.9 ± 9.3 years and 72.7% were men. The calculated 10-year and lifetime residual risks were 37.1 ± 14.7% and 60.3 ± 10.7%, respectively. Overall, treatment was optimized with a single pharmacological strategy with statins, ezetimibe or PCSK9 inhibitor in 38.5%, 11.5% and 5.5% of the population, respectively. Optimization based on two treatments was performed in 27.5% (statins + ezetimibe), 7.7% (statins + PCSK9 inhibitor) and 1.1% (ezetimibe + PCSK9 inhibitor) of the cases. In 15 patients, treatment was optimized when the three drugs (statins + ezetimibe + PCSK9 inhibitor) were considered. Overall, 53.9% and 62.9% of the actions implemented to optimize treatment showed a 10-year or lifetime NNT < 30 to prevent an event, respectively. Conclusion: In this study, patients with a history of cardiovascular disease who do not reach LDL-C goal showed significant residual cardiovascular risk. The simulation model showed a significant margin for optimizing treatment, with a marked reduction in residual cardiovascular risk.

Research progress of PCSK9 in the mechanism of atherosclerotic cardiovascular disease / 中国医师杂志

Proprotein Convertase Subtilisin/Kexin 9 (PCSK9) inhibitor has become a new drug for the treatment of hypercholesterolemia and atherosclerotic cardiovascular disease. Recent studies have shown that the mechanism of PCSK9 in atherosclerotic cardiovascular disease is very complex, which is closely related to the increase of plasma low-density lipoprotein cholesterol level, apoptosis, autophagy, inflammation, foam cell formation and vascular smooth muscle cell calcification, which will help us better understand the " multiple effects" of PCSK9 inhibitors. This review aims to analyze the research status of PCSK9 in molecular structure, cell function and cardiovascular disease treatment, which will further consolidate the success of new treatment strategies for atherosclerosis.

An Update on Pharmacotherapy of Dyslipidemia for Adults

Dyslipidemia is an important cause of atherosclerotic cardiovascular disease (ASCVD) worldwide that leads to increased risk of morbidity and mortality; treating dyslipidemia to goal reduces the risks. This article reviews the pharmacological therapy of dyslipidemiawhich is often required in addition to life style intervention to achieve target lipid levels.Currently, there are seven types of approvedlipid modifying drugs which are effective in treating dyslipidemiawhen used singly or in combination. Statins are considered as first line drug and havebeen used extensively in the primary and secondary prevention of ASCVD. Ezetimibe is used as a first line add-on drug for patients already on a statin who have not reached their low density lipoprotein (LDL-C) goals;however,ezetimibe can be used as initial drug in statin intolerant patients. Bile acid sequestrants are a useful alternative to statins or ezetimibe in pregnant women or patients with liver disease. They also lower blood glucose and are useful in diabetes mellitus (DM). The PCSK9 inhibitors are powerful lipid modifying drugs, are expensive, needinjection for delivery, and are used when statin in maximum doses with other drugs cannot lower the LDL-C level to targets in patients with very high CV risk. Fibrates have recently shown to slow the progression of microvascular diseases and are found beneficial for DM with hypertriglyceridemia and microvascular complications. Currently, niacin use is markedly decreased due to development of more effective alternative drugs for managing dyslipidemia andbecause of the adverse effects related to niacin use.Recent trials reveal that, ω-3 fatty acids, when added in pharmacological doses to statin therapy (after controlling LDL-C), are effective in reducing CV events in patientshaving moderate hypertriglyceridemia with high or very high CV risks

Eficacia, seguridad y aplicabilidad clínica de los inhibidores de la PCSK9 / Efficacy, Safety and Clinical Applicability of PCSK9 Inhibitors

RESUMEN Los inhibidores de la proproteína convertasa subtilisina kexina tipo 9 (iPCSK9) representan un nuevo grupo de fármacos hipolipemiantes, que han generado un cambio sustancial en el manejo clínico de los lípidos. En pocos años, una gran cantidad de estudios han evaluado la eficacia antilipídica y la seguridad de estos fármacos. Más recientemente, grandes ensayos clínicos aleatorizados demostraron que el descenso del C-LDL alcanzado con estos fármacos se asoció con una menor incidencia de eventos cardiovasculares. Dicha evidencia dio lugar a la aprobación y comercialización de los iPCSK9 en muchos países. En consecuencia, diversas sociedades científicas y organismos de referencia en salud incorporaron estos fármacos en el arsenal terapéutico de la dislipidemia, con el objetivo de reducir el riesgo cardiovascular residual. En esta revisión describiremos la eficacia y la seguridad de estos fármacos, analizaremos la evidencia disponible acerca del beneficio cardiovascular y discutiremos en qué población podría ser más efectiva su utilización.

SUMMARY Proprotein convertase subtilisin kexin type 9 (iPCSK9) inhibitors represent a new group of lipid-lowering drugs that have generated a substantial change in lipid management. In a few years, a large number of studies have evaluated the lipid efficacy and safety of these drugs. More recently, large randomized clinical trials showed that the decrease in LDL-C achieved with these drugs was associated with a lower incidence of cardiovascular events. Such evidence resulted in the approval and commercialization of iPCSK9 in many countries. Consequently, various scientific societies and health reference agencies incorporated these drugs into the therapeutic arsenal of dyslipidemia, with the aim of reducing residual cardiovascular risk. In this review, we will describe the efficacy and safety of these drugs, analyze the available evidence about cardiovascular benefit, and discuss in which population their use might be most effective.

Inhibidores de la PCSK9: una nueva era en el control del riesgo cardiovascular / PCSK9 inhibitors: a new era in the control of cardiovascular risk / Inibidores da PCSK9: uma nova era no controle do risco cardiovascular

Resumen: Las estatinas constituyen aún la pieza fundamental para el manejo del riesgo cardiovascular. Utilizadas en dosis de alta intensidad logran reducciones de colesterol asociado a lipoproteínas de baja densidad (C-LDL) de 50%-60%. Sin embargo, en pacientes con hipercolesterolemia severa, las estatinas solas o asociadas a ezetimibe pueden no ser suficientes para alcanzar los objetivos de descenso de C-LDL. Tal es el caso de las dislipemias genéticas como la hipercolesterolemia familiar. Lo mismo ocurre en pacientes con intolerancia total o parcial a estatinas, en los que se requiere de alternativas farmacológicas modernas que permitan reducir el riesgo cardiovascular elevado. En este escenario, los inhibidores de la proproteína convertasa subtilisina kexina tipo 9, se han convertido en una piedra angular para lograr no solo una reducción jamás antes vista del C-LDL, sino también del riesgo cardiovascular. La nueva evidencia posiciona a estos fármacos en un lugar de privilegio, siendo eficaces y bien tolerados, con el costo como principal limitante, a pesar de su marcado descenso en los últimos años.

Summary: Statins are still the fundamental piece for cardiovascular risk management. Used in doses of high intensity achieve reductions in cholesterol associated with low density lipoproteins of 50%-60%. However, in patients with severe hypercholesterolemia, statins alone or associated with ezetimibe may not be sufficient to achieve cholesterol associated with low density lipoproteins decrease targets. Such is the case of genetic dyslipidemias as familial hypercholesterolemia. Also in patients with total or partial statin intolerance, a modern pharmacological alternative is required to reduce high cardiovascular risk. In this scenario, proprotein convertase subtilisin kexin type 9 inhibitors have become a cornerstone to achieve not only a reduction never seen before of cholesterol associated with low density lipoproteins levels, but also of cardiovascular risk. These drugs are in a privilege position due to the new evidence, being effective and well tolerated, with cost as its main limitation despite its marked decline in recent years.

Resumo: As estatinas ainda são a peça fundamental da gestão de risco cardiovascular. Utilizada em dose de alta intensidade atinge reduções associadas com colesterol da lipoproteína de baixa densidade de 50%-60%. No entanto em pacientes com hipercolesterolemia grave, estatinas, sozinhas ou associadas a ezetimiba podem não ser suficientes para alcançar os objetivos de redução de colesterol da lipoproteína de baixa densidade. Tal é o caso das dislipidemias genéticas como a hipercolesterolemia familiar. O mesmo ocorre em pacientes com intolerância total ou parcial de estatinas, que exige modernas alternativas farmacológicas que permitem reduzir o risco cardiovascular alto. Neste panorama, os inibidores da pró-proteína convertasa subtilisina kexina tipo 9, se tornaram uma pedra angular para alcançar não apenas uma redução em nunca antes visto colesterol da lipoproteína de baixa densidade, mas de risco cardiovascular. Novas provas colocam essas drogas em um lugar de privilégio, por ser eficaz e bem tolerado, com o custo como sua principal limitante a pesar do seu grande declínio nos últimos anos.

Tratamento atual da hipercolesterolemia e novas perspectivas / Current dyslipidemia treatments and new perspectives

Novos fármacos para o tratamento da hipercolesterolemia foram desenvolvidos, que poderão ser incorporadas nas diretrizes, resultantes de estudos clínicos robustos que demonstraram redução de desfechos cardiovasculares adicionais aos resultados obtidos com a otimização terapêutica disponível com as estatinas. O objetivo deste artigo é atualizar o conhecimento para o tratamento das dislipidemias baseado nas melhores evidências e as novas opções terapêuticas para reduzir o risco de eventos cardiovasculares em pacientes com dislipidemia refratária à otimização do tratamento atual.

New drugs for dyslipidemia treatment have been developed in solid clinical studies, which demonstrated an additional reduction of cardiovascular outcomes compared to therapeutic treatment with statins, and might be incorporated in new treatment guidelines. The aim of this article is to update the knowledge for the treatment of dyslipidemias based on the best evidences and the new therapeutic options incorporated to reduce the risk of cardiovascular events in patients with dyslipidemia refractory to treatment optimization.

Inhibidores de proproteína convertasa subtilisina kexina tipo 9 (PCSK9): Revisión y puesta al día farmacológica / Pro protein convertase subtilisin kexin type 9 (PCSK9) inhibitors: Pharmacological review and update / Inibidores de pró-proteína convertase subtilisina kexina tipo 9 (PCSK9): Revisão e atualização farmacológica

La enfermedad cardiovascular aterosclerótica es la causa número uno de morbi-mortalidad a nivel mundial. La relación directa entre los niveles del colesterol unido a lipoproteínas de baja densidad y la aterosclerosis ha llevado a optimizar los esfuerzos en regular y controlar esta sub-fracción lipoproteica. El descubrimiento de la pro proteína convertasa subtilisina kexina tipo 9 (PCSK9) como regulador del receptor de la lipoproteína de baja densidad a nivel hepático, y por consiguiente de los niveles circulantes del colesterol unido a la lipoproteína de baja densidad, desencadenó un esfuerzo inusual a fin de disminuir su concentración plasmática. La inhibición de PCSK9, a través de anticuerpos monoclonales, ha demostrado ser una estrategia farmacológica con un amplio perfil de seguridad y una alta eficacia en los estudios de fase 3. Esto ha llevado a su aprobación por distintos entes reguladores en determinados grupos específicos, como los pacientes portadores de hipercolesterolemia familiar y los pacientes en prevención secundaria que no alcanzan las metas con las herramientas farmacológicas disponibles. A la espera de resultados sobre eventos clínicos, se propone revisar en el siguiente artículo los aspectos farmacológicos de los inhibidores de PCSK9.

Atherosclerotic cardiovascular disease is the leading cause of morbidity and mortality worldwide. The direct relationship between cholesterol levels lipoprotein low density and atherosclerosis has led to optimize efforts to regulate and control this lipoprotein sub-fraction. The discovery of the pro protein convertase subtilisin kexin type 9 (PCSK9) as regulator receptor low-density lipoprotein in liver and therefore circulating levels of cholesterol bound to low density lipoprotein, triggered an unusual effort to reduce its plasma concentration. Inhibition of PCSK9 through monoclonal antibodies, it has proved to be a pharmacologic strategy with a broad safety profile and high efficacy in the phase 3 trials. This has led to approval by several regulatory entities in certain specific groups, such as patients with familial hypercholesterolemia and patients in secondary prevention who not reaching goals with the pharmacological toolsavailable. Pending results of clinical events, the aim of this article is to review the pharmacological aspects of the inhibitors of PCSK9.

A doença cardiovascular aterosclerótica é a principal causa de morbidade e mortalidade no mundo. A relação direta entre os níveis de colesterol de lipoproteína de baixa densidade e aterosclerose levou a otimizar os esforços para regular e controlar esse sub-fração de lipoproteína. A descoberta da pró-proteína convertase subtilisina kexin tipo 9 (PCSK9) como regulador do receptor de lipoproteína de baixa densidade no fígado e, portanto, os níveis de colesterol ligado à lipoproteína de baixa densidade em circulação, desencadeado um esforço incomum para reduzir a sua concentração no plasma. A inibição da PCSK9 por meio de anticorpos monoclonais, tem provado ser uma estratégia farmacológica com um amplo perfil de segurança e uma elevada eficácia nos estudos de fase 3. Isto levou à aprovação de várias entidades regulatórias em determinados grupos específicos, tais como pacientes com hipercolesterolemia familiar e pacientes em prevenção secundária, que não atingem metas com as ferramentas farmacológicas disponíveis. Enquanto se aguarda resultados de eventos clínicos, o objetivo deste artigo é revisar os aspectos farmacológicos dos inibidores de PCSK9.

Dislipidemias: ¿qué hay de nuevo? / Dyslipidemia: what's new?

En los últimos años han surgido algunas investigaciones y guías de práctica clínica relacionadas con el diagnóstico y tratamiento de las dislipidemias, que aportaron nuevos conocimientos (y controversias) sobre dicha problemática. En este resumen se describen, en primer lugar, las características de las "nuevas guías" norteamericanas para el manejo del colesterol publicadas a fines de 2013 y se comparan con las recomendaciones tradicionales. En segundo lugar, se analizan los últimos estudios que evaluaron el impacto cardiovascular de otros fármacos hipolipemiantes (ezetimibe y ácido nicotínico) en pacientes en prevención secundaria tratados con estatinas. Finalmente, se mencionan las nuevas drogas hipolipemiantes desarrolladas en los últimos años, como el lomitapide, el mipomersen y los inhibidores de la PCSK9, y se comentan el mecanismo de acción, su eficacia, sus efectos colaterales y los escenarios clínicos en donde podrían utilizarse. (AU)

In recent years, some research and clinical practice guidelines related to the diagnosis and treatment of dyslipidemia, which provided new knowledge (and controversy) about this problem have emerged. In this review, the characteristics of the American "new guidelines" for cholesterol management published by the end of 2013 are described, and they are compared with the traditional recommendations. In addition, recent studies assessing the cardiovascular impact of other lipid-lowering drugs (ezetimibe and nicotinic acid) in patients in secondary prevention treated with statins are analyzed. Finally, new hypolipidemic drugs developed in recent years are mentioned (lomitapide, mipomersen and PCSK9 inhibitors), discussing the mechanism of action, efficacy, side effects and clinical settings where they could be used. (AU)