Search strategy and selection criteria
We conducted the study in accordance with the 2020 Preferred Reporting
Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines
[18]. As this is a meta-analysis, there was no need for
Institutional Review Board (IRB) approval or patient informed consent.
To define the clinical question and formulate a comprehensive search
strategy, we applied the PECOS model, focusing on population,
intervention, comparison, outcomes, and study design
(Table S1 ).
Databases were systematically searched up to November 30, 2024. These
included PubMed-Medline, EMBASE, Scopus, Google Scholar, the Cochrane
Central Register of Controlled Trials, and ClinicalTrials.gov, using
specific keywords to identify relevant studies: ”Proprotein convertase
subtilisin/kexin type 9” OR ”PCSK9 inhibitors” OR ”PCSK9i” OR
Angiopoietin-like protein 3 inhibitors” OR ”ANGPTL3 inhibitors” OR
”ANGPTL3 i” OR ”Alirocumab” OR ”Evolocumab” OR ”Evinacumab” AND
”Homozygous Familial Hypercholesterolemia” OR ”Homozygous FH” OR ”HoFH”
(Table S2 ).To identify additional relevant studies,
references from review articles and abstracts from key congresses, such
as the European Society of Cardiology (ESC), European Atherosclerosis
Society (EAS), American Heart Association (AHA), and American College of
Cardiology (ACC) were reviewed. The wildcard term ”*” was employed to
enhance search sensitivity, with the search restricted to human studies
published in English and no filters applied. Each article was
independently evaluated by two reviewers (M.S. and D.G.). In cases of
uncertainty regarding the suitability of a paper, the senior
investigators (I.B. and M.B.) were consulted. The selected articles were
assessed in full text, and data extraction was performed by the same
researchers, while data analysis was conducted by two other researchers
(S.B. and I.B.). Typically, the extracted data were compared with the
original articles, and errors were corrected as needed. For each trial,
the risk of bias was independently assessed by the same investigators
using the revised Cochrane risk-of-bias tool for randomized trials
(Cochrane RoB2 tool), which evaluates five domains: the randomization
process, deviations from intended interventions, missing outcome data,
outcome measurement, and the selection of reported results. The risk of
bias in each study was categorized as “low,” “high,” or “unclear.”
[19].
Articles were considered eligible if they reported the treatment of HoFH
patients with PCSK9 inhibitors (PCSK9i) or ANGPTL3 inhibitors (ANGPTL3i)
under the following criteria: i) trials investigating the efficacy
and/or safety of PCSK9i/ANGPTL3i pre-post-treatment in HoFH patients
after treatment with standard lipid-lowering therapy (LLT); ii) studies
using genetic and/or clinical criteria for the diagnosis of HoFH
according to the available guidelines; and iii) trials with a follow-up
period of at least 3 months. Exclusion criteria were: i) insufficient
statistical data to test the efficacy and safety of treatment, ii)
patients with heterozygous FH, iii) studies not in humans, and iv)
ongoing studies (unless they had reported relevant interim results).