Lipoprotein apheresis reduces major adverse cardiovascular event incidence in high-lipoprotein (a) subjects on proprotein convertase subtilisin/kexin type 9 inhibitor therapy

Abstract

Dear Editor, Lipoprotein (a) [Lp(a)] is a prevalent genetic risk factor for coronary artery disease,1 awaiting specific antisense oligonucleotide directed to apo(a), the 2022 European Atherosclerosis Society (EAS) consensus recommends an intensive management of the other risk factors. The proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i), although effective in the LDL cholesterol reduction, have demonstrated variable Lp(a)-lowering effects2 that could lead to a reduction in Lp(a) up to 25–30%, while lipoprotein apheresis (LA) is the only therapy that reduces Lp(a) values by 70–80%.1 The aim of this study is to evaluate the impact of LA in reducing major adverse cardiovascular events (MACE) in patients with familial hypercholesterolaemia, Lp(a) hyperlipidaemia (plasma level > 50 mg/dL), and coronary heart disease on PCSK9i therapy. To evaluate the LA effect, we retrospectively reviewed the incidence of four-point MACE [definite as acute myocardial infarction, coronary artery bypass graft (CABG)/percutaneous coronary intervention (PCI), stroke, cardiovascular death3] in 35 patients (mean age 61 ± 9 years, male 91%) affected by familial hypercholesterolaemia, Lp(a) hyperlipidaemia, and coronary heart disease, who achieved on PCSK9i therapy an LDL cholesterol below 55 mg/dL, with or without chronic LA (8 and 27 subjects, respectively). These subjects were selected in the cohort enrolled in the CERTI study (Area Vasta Nord Ovest ethics committee, Italy—Unique Protocol ID: 11188). No uncontrolled diabetes mellitus, arterial hypertension, current smoking exposure, and renal failure were present in any patients. Moreover, previous multiple MACEs, concomitant peripheral vascular disease, or previous cerebrovascular accident are reported respectively in 20, 9, and 2 patients. Table 1 summarizes the patients’ clinical characteristics. Clinical characteristics of patients treated with proprotein convertase subtilisin/kexin type 9 inhibitors only or in combination with lipoprotein apheresis Statistical analysis used paired t-test or χ2 with Yates’ correction as appropriate; statistical significance is P < 0.05. aConfirmed genetically diagnosis in 13/20 (65%) patients. bRespectively, 20/27 (74%) in PCSK9i group and 6/8 (75%) in PCSK9i + LA group. cModerate intensity statins in 15/19 (79%) subjects; high-intensity statins in 4/19 (21%) subjects. CFH, combined familial hyperlipidaemia; HeFH, heterozygous familial hypercholesterolaemia; MACE, major adverse cardiovascular events; LA, lipoprotein apheresis; PCSK9i, proprotein convertase subtilisin/kexin type 9 inhibitors. According to the patient characteristics [biocompatibility for LA systems, concomitant angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor blocker (ARB) therapy, etc.],4 LA treatments were performed by dextran sulphate absorption from plasma (Liposorber®-LA MA-03 systems; Kaneka, Osaka, Japan; 5/8 patients) or heparin-induced LDL precipitation apheresis (HELP®, Plasmat Futura®; B. Braun, Melsungen, Germany; 3/8 patients). Lipoprotein apheresis procedures agree with guidelines’5 and manufacturer’s instructions with bi-weekly inter-apheretic interval treating 1.5 patient plasma volumes per session. The PCSK9i treatment was administered every 2 weeks (evolocumab 140 mg s.c. or alirocumab 150 mg s.c. on 23 and 12 subjects, respectively) on top of lipid-lowering therapy (Table 1). According to previous experience,6 the PCSK9i therapy was administered 1 week after the LA treatment. The two study groups had not significant difference in lipid profile, but during the follow-up (45 ± 31 months), a significant higher MACE incidence was reported on subjects without LA treatment (P < 0.010; Table 2). Lipid plasma level and major adverse cardiovascular event incidence in patients treated with proprotein convertase subtilisin/kexin type 9 inhibitors only or proprotein convertase subtilisin/kexin type 9 inhibitors and lipoprotein apheresis Statistical analysis used paired t-test, Wilcoxon test, or χ2 with Yates’ correction as appropriate; statistical significance is P < 0.05. aRespectively, pre-LA value, post-LA value, and mean inter-apheretic concentration.7 bThree percutaneous trans-luminal coronary angioplasty (PTCA), one coronary artery bypass graft (CABG), one acute coronary syndrome, and one cardiovascular death. cOne percutaneous trans-luminal coronary angioplasty (PTCA). MACE, major adverse cardiovascular events; LA, lipoprotein apheresis; PCSK9i, proprotein convertase subtilisin/kexin type 9 inhibitors. There is a general agreement on the reduction of MACE by LA. Previous multicentre study, performed without PCSK9i therapy, has shown a significant reduction of mean annual cardiovascular event rate in patients with regular LA treatment, Lp(a) hyperlipidaemia, and chronic ischaemic heart disease on maximally tolerated lipid-lowering therapy.8 Lipoprotein apheresis is able to act on many atherogenic factors as vascular inflammation, rheology, mobilization of adult stem cells, and gene expressions in blood and endothelial cells.9 Furthermore, previous single-centre experience showed a lower impact on high-sensitivity C-reactive protein shifting between LA to PCSK9i therapy.10 In our clinical practice, patients referred to LA had previous multiple MACE and/or associated peripheral vascular disease (Table 1). According to previous experience,6 to optimize lipid profile in subjects on LA slowing down the rebound curve of Lp(a) concentrations, the PCSK9i was administered 1 week after the LA treatment. These aspects may explain the observed additive effect on the MACE reduction. Probably, the 2022 EAS consensus recommends1 it should be supplemented with the LA treatment option to reduce cardiovascular events in subjects with multiple MACEs and/or polydistrict atherosclerotic vascular disease. Our study is affected by some limitations: (i) the small number of patients, (ii) the high prevalence of statin-intolerant patients (46% of subjects referred muscular symptoms), and (iii) the retrospective single-centre study design. With the aim of improving the personalized therapy, individual risk assessment and specific treatment to reduce Lp(a) can represent a very interesting and useful approach, although prospective and randomized multicentre clinical trials are needed. B.D.P. and F.S. contributed to the conception or design of the work. C.C. and F.B. contributed to the acquisition, analysis, or interpretation of data for the work. F.S., C.C., and B.D.P. drafted the manuscript; F.B. critically revised it. All authors read and approved the final version of the manuscript. None declared. Ethical approval was obtained. Patient and public involvement: Patients and/or the public were not involved in the design, conduct, reporting, or dissemination plans of this research. Research data are not shared.

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