Elegibilidad para la indicación de inhibidores de PCSK9 según las recomendaciones de diferentes sociedades científicas / Eligibility for the indication of PCSK9 inhibitors according to the recommendations of different scientific societies

La reducción del colesterol-LDL (C-LDL) es un objetivo primordial en prevención cardiovascular. Estudios recientes demostraron beneficio clínico al administrar inhibidores de la proprotein convertase subtilisin/kexin-9 (iPCSK9) a pacientes que no habían logrado la meta de C-LDL con estatinas de alta intensidad y ezetimibe, sin embargo el uso de estos fármacos está limitado por su costo. El American College of Cardiology, la Sociedad Argentina de Cardiología y la European Society of Cardiology recomiendan una meta de C-LDL menor a 70 mg/dl en prevención secundaria, determinando umbrales de C-LDL de 70, 100 o 140 mg/dl respectivamente, para iniciar el tratamiento con iPCSK9. Con el objetivo de evaluar el esquema hipolipemiante prescripto en internados por síndrome coronario agudo o revascularización coronaria y analizar la proporción de elegibles para ser tratados con iPCSK9 en un escenario real y simulado, realizamos un estudio que incluyó 351 pacientes con enfermedad coronaria, tomados de una base de datos electrónica de un hospital universitario. El 48.4% recibió estatinas de elevada intensidad, 11.4% ezetimibe y 54.7% no logró la meta de C-LDL menor a 70 mg/dl. Utilizando un modelo de simulación en el que todos serían medicados con estatinas de elevada intensidad y ezetimibe, la elegibilidad para prescribir iPCSK9 fue de 31.1%, 12.8% y 9.1% según los umbrales de C-LDL determinados por las tres sociedades científicas. Nuestro estudio demostró una brecha entre las recomendaciones de los consensos para reducir el colesterol y la práctica habitual que debería ser minimizada para optimizar la relación costo/efectividad en prevención secundaria.

LDL-cholesterol (LDL-C) lowering is a primary objective in cardiovascular prevention. Recent studies demonstrated clinical benefit when proprotein convertase subtilisin/kexin-9 inhibitors (PCSK9i) were added to the treatment in patients who had not achieved the LDL-C goal despite being treated with high intensity statins and ezetimibe, however the use of these drugs is limited by their cost. The American College of Cardiology, the Argentine Society of Cardiology and the European Society of Cardiology recommend an LDL-C goal less than 70 mg/dl in secondary prevention, determining thresholds of LDL-C to start treatment with PCSK9i of 70, 100 or 140 mg/dl respectively. In order to evaluate the lipid-lowering regimen prescribed in patients hospitalized for acute coronary syndrome or coronary revascularization and analyze the proportion of eligible to be treated with PCSK9i in a real and simulated scenario, we conducted a study that included 351 patients with coronary disease collected from an electronic database of a university hospital. The 48.4% received high intensity statins, 11.4% ezetimibe and 54.7% did not achieve the LDL-C goal of less than 70 mg/dL. Using a simulation model in which all would be treated with high intensity statins and ezetimibe, the eligibility to prescribe PCSK9i was 31.1%, 12.8% and 9.1% according to the C- LDL thresholds determined by the three scientific societies. Our study demonstrated a gap between the consensus recommendations for LDL-C lowering and the current practice that should be minimized to optimize the cost/effectiveness ratio in secondary prevention.

PCSK9 Inhibitors: Clinical Relevance, Molecular Mechanisms, and Safety in Clinical Practice / Inibidores de PCSK9: Importância Clínica, Mecanismos Moleculares, e Segurança na Prática Clínica

Abstract Coronary artery disease (CAD) is one of the leading causes of mortality. High circulating levels of low-density lipoprotein (LDL) in the blood are associated with cardiovascular mortality, whether through an etiological role or through its association with the progression of CAD per se. Randomized clinical trials have shown that, when LDL levels are reduced, cardiovascular risk is also reduced, which reinforces this association. The first major trial involving a hypolipidemic agent of the statin family, the Scandinavian Simvastatin Survival Study (4S), was published in 1994 and found a significant reduction in mortality in patients at high cardiovascular risk. However, even in subsequent studies with different statins, a residual risk persisted, and this seems not to have changed over time; it is speculated that this risk may be due to statin intolerance. In this scenario, the potential exists for novel hypolipidemic agents to drive a true revolution in the therapy of dyslipidemia. The recent discovery of PCSK9 inhibitors (PCSK9i), a class of hypolipidemic monoclonal antibodies, is extremely promising. PCSK9 inhibition is capable of promoting a mean LDL reduction of up to 60%, with potential for very significant clinical repercussions, as every 38 mg/dL reduction in LDL appears to be associated with a 22% reduction in cardiovascular risk. This review addresses a brief history of PCSK9i, major trials of these drugs, cardiovascular outcomes, and aspects related to their efficacy and safety. Finally, the molecular mechanisms and possible pleiotropic effects of PCSK9i are also discussed.

Resumo A doença arterial coronariana (DAC) é uma das principais causas de mortalidade. Níveis circulantes elevados de lipoproteína de baixa densidade (LDL) no sangue estão associados com mortalidade cardiovascular, seja por um papel etiológico ou por sua associação com a progressão da DAC em si. Estudos clínicos randomizados mostram que, quando os níveis de LDL são reduzidos, o risco cardiovascular também é reduzido, o que reforça tal associação. O primeiro ensaio importante envolvendo um agente hipolipemiante da família da estatina, o estudo Scandinavian Simvastatin Survival Study (4S), foi publicado em 1994 e encontrou uma redução significativa na mortalidade de pacientes com risco cardiovascular elevado. Contudo, mesmo em estudos subsequentes com diferentes estatinas, observou-se um risco residual persistente, o qual aparentemente não mudou ao longo dos anos. Especula-se que esse risco se deve à intolerância às estatinas. Nesse cenário, existe um potencial para novos agentes hipolipemiantes que levem a uma verdadeira revolução no tratamento das dislipidemias. A descoberta recente dos inibidores de PCSK9 (PCSK9i), uma classe de anticorpos monoclonais, é extremamente promissora. A inibição da PCSK9 é capaz de promover uma redução média nos níveis de LDL de até 60%, com potencial para repercussões clínicas muito significativas, já que para cada redução de 38 mg/dL, parece haver uma redução de 22% no risco cardiovascular. Esta revisão aborda uma breve história dos PCSK9i, os principais ensaios envolvendo esses medicamentos, desfechos cardiovasculares, e aspectos relacionados a sua eficácia e segurança. Finalmente, os mecanismos moleculares e possíveis efeitos pleiotrópicos dos PCSK9i são também discutidos.