Efficacy and Safety of Bempedoic Acid in Association With Anti-PCSK9 and Ezetimibe in Statin-intolerant Patients

This is an investigator-initiated, phase 4, open-label, multicentre, 2-way crossover trial. The study will enlist statin-intolerant patients at high-risk and very high-risk of cardiovascular events, not reaching the LDL-C goal recommended by the 2019 ESC/EAS Guidelines for management of dyslipidaemias based on their individual risk estimate. The patients enrolled have to be intolerant to statin and have not changed their hypolipidemic therapy within 6 weeks prior recruitment. Eligible participants as per the inclusion criteria will be randomized with 1:1 allocation ratio, without restrictions, into two treatment sequences of 12 weeks, respectively, separated by a washout period of 4 weeks. Being the inclusion criteria of this study highly selective, the rationale behind the crossover design is the lower sample size needed, and the shorter times to complete the enrolment. Furthermore, since the patients will serve as their own controls, the influence by confounders will be reduced. Being the primary endpoint of this study result of laboratory measurements, the investigators assumed the absence of any carryover effect after the washout period of 4 weeks. Moreover, the investigators assumed the absence of any period effect on the study endpoint. The phase 1 will start at week 0 (P1-0)and stop at week 12 (P1-12); the phase 2 will start at week 16 (P2-0), after the washout period, and stop at week 28 (P2-12). The two study treatments will be: * PCSK9 inhibitors (Evolocumab 140 mg or Alirocumab 75 mg or Alirocumab 150 mg) plus Ezetimibe 10 mg plus Bempedoic acid (Treatment A) * PCSK9 inhibitors (Evolocumab 140 mg or Alirocumab 75 mg or Alirocumab 150 mg) plus Ezetimibe 10 mg (Treatment B) All patients will be randomly assigned to a Treatment A-Treatment B (AB Group) sequence or to a Treatment B-Treatment A (BA Group) sequence. The investigators will record laboratory and clinical variables at study visits scheduled for weeks 0, 4, 12, 16, 20, 28. Blood samples will be collected and stored at each visit by the participating centres, and analysed by a central core laboratory (University of Salerno). At the end of the study, the decision to continue or not treatment with bempedoic acid, as well as any other therapeutic decision, will be left to the treating physician.