TY - JOUR
T1 - LDL-cholesterol lowering and clinical outcomes in hypercholesterolemic subjects with and without a familial hypercholesterolemia phenotype: Analysis from the secondary prevention 4S trial
AU - Vallejo-Vaz, Antonio J.
AU - Packard, Chris J.
AU - Ference, Brian A.
AU - Santos, Raul D.
AU - Kastelein, John J. P.
AU - Stein, Evan A.
AU - Catapano, Alberico L.
AU - Pedersen, Terje R.
AU - Watts, Gerald F.
AU - Ray, Kausik K.
N1 - Funding Information: The authors thank MSD for granting them access to 4S trial data to conduct the present study. Dr Ray acknowledges support from the National Institute for Health Research Imperial Biomedical Research Centre, United Kingdom. Dr Santos is recipient of a scholarship from the Conselho Nacional de Pesquisa e Desenvolvimento Tecnológico (CNPq) # 303734/2018-3 , Brazil. The work of Dr Catapano has been supported by Ministry of Health of Italy - Ricerca Corrente - IRCCS MultiMedica , PRIN 2017H5F943 and ERANET ER-2017-2364981. Funding Information: The authors thank MSD for granting them access to 4S trial data to conduct the present study. Dr Ray acknowledges support from the National Institute for Health Research Imperial Biomedical Research Centre, United Kingdom. Dr Santos is recipient of a scholarship from the Conselho Nacional de Pesquisa e Desenvolvimento Tecnol?gico (CNPq) #303734/2018-3, Brazil. The work of Dr Catapano has been supported by Ministry of Health of Italy - Ricerca Corrente - IRCCS MultiMedica, PRIN 2017H5F943 and ERANET ER-2017-2364981. Funding Information: Dr Vallejo-Vaz reports honoraria for lectures from Amgen, Mylan, and Akcea; personal fees for consultancy from Bayer; and participation in research grants to Imperial College London from Pfizer, Amgen, MSD, Sanofi, Regeneron, and Daiichi-Sankyo; all outside the submitted work. Dr Packard reports honoraria from Amgen, Daiichi-Sankyo, DalCor, and MSD; all ouside the submitted work. Dr Ference reports research grants and/or honoraria for lectures, consulting and/or advisory board membership, from Merck, Novartis, Amgen, Regeneron, Sanofi, Pfizer, Eli Lilly, Novo Nordisk, The Medicines Co, Mylan, Daiichi-Sankyo, Alnylam, Esperion Therapeutics, Ionis Pharmaceuticals, Silence Therapeutics, dalCOR, CiVi Pharma, KrKa Phamaceuticals, Medtronic, American College of Cardiology, European Atherosclerosis Society, and European Society of Cardiology; outside the submitted work. Dr Santos reports honoraria related to consulting, research and/or speaker activities from Ache, Amgen, Astra Zeneca, Esperion, EMS, Kowa, Novo-Nordisk, Merck, MSD, Pfizer, PTC, and Sanofi/Regeneron. Dr Kastelein reports consulting fees and honoraria for lectures from Astra Zeneca, CSL-Behring, Daichii-Sankyo, Esperion, Genentech, Menarini, Novartis, Novo Nordisk, Pfizer, and Regeneron. Dr Stein has received fees for consulting from Gemphire, CymaBay, and AstraZeneca; has received expert witness fees from Amgen; and is a founder and CEO of LIB Therapeutics. Dr Catapano reports grants, consulting fees and/or honoraria and delivering lectures from Aegerion, Abbot, Akcea, Amgen, BMS, Eli Lilly, Genzyme, Kowa, Merck, Novartis, Pfizer, Recordati, Roche, Sanofi, and Sigma-Tau; all outside the submitted work. Dr Pedersen has received honoraria from Amgen and Merck for consulting and speaking. Dr Watts reports grants, advisory board and lecture fees from Amgen, Sanofi, Regneron, Arrowhead, and Kowa. Dr Ray reports personal fees for consultancy from AbbVie, Amgen, AstraZeneca, Sanofi, Regeneron, Merck Sharp & Dohme, Pfizer, Resverlogix, Akcea, Boehringer Ingelheim, Novo Nordisk, Takeda, Kowa, Algorithm, Cipla, Cerenis, Dr Reddys, Lilly, Zuellig Pharma, Bayer, Daiichi-Sankyo, The Medicines Company, and Esperion, and research grant support from Pfizer, Amgen, Sanofi, Regeneron, and Merck Sharp & Dohme. Publisher Copyright: © 2021 Elsevier B.V. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/3/1
Y1 - 2021/3/1
N2 - Background and aims: Trial evidence for the benefits of cholesterol-lowering is limited for familial hypercholesterolemia (FH) patients, since they have not been the focus of large outcome trials. We assess statin use in coronary artery disease (CAD) subjects with low-density lipoprotein cholesterol (LDL-C) ≥4.9 mmol/L with or without an FH phenotype. Methods: The 4S trial randomized hypercholesterolemic CAD patients to simvastatin or placebo. We first stratified participants into baseline LDL-C <4.9 and ≥ 4.9 mmol/L; next, based on the DLCN criteria for FH, the latter group was stratified into four subgroups by presence of none, one or both of “premature CAD” and “family history of CAD”. Participants having both are defined as having an FH phenotype. Results: 2267 and 2164 participants had LDL-C <4.9 and ≥ 4.9 mmol/L, respectively. Mortality endpoints and major coronary events (MCE) were significantly reduced with simvastatin versus placebo in both groups over 5.4 years, but the latter derived greater absolute risk reductions (ARR) (4.1–4.3% for mortality endpoints, versus 2.5–2.8%). LDL-C reductions were similar among the 4 subgroups with levels ≥4.9 mmol/L. Participants with FH phenotype (n = 152) appeared to derive greater relative benefits with simvastatin than the other three subgroups (all-cause death: 84% relative risk reduction, p = 0.046; MCE: 55% reduction, p = 0.0297); statistical interaction was non-significant. Participants with FH phenotype derived greater ARR than any other group with simvastatin versus placebo (all-cause mortality: 6.6% ARR; MCE 13.2%; versus 3.8% and 8.3%, respectively, among participants with LDL-C ≥4.9 mmol/L but without features suggestive of FH). Conclusions: The FH phenotype appeared to be associated with greater clinical benefits from a given magnitude of LDL-C reduction as compared to individuals without FH phenotype.
AB - Background and aims: Trial evidence for the benefits of cholesterol-lowering is limited for familial hypercholesterolemia (FH) patients, since they have not been the focus of large outcome trials. We assess statin use in coronary artery disease (CAD) subjects with low-density lipoprotein cholesterol (LDL-C) ≥4.9 mmol/L with or without an FH phenotype. Methods: The 4S trial randomized hypercholesterolemic CAD patients to simvastatin or placebo. We first stratified participants into baseline LDL-C <4.9 and ≥ 4.9 mmol/L; next, based on the DLCN criteria for FH, the latter group was stratified into four subgroups by presence of none, one or both of “premature CAD” and “family history of CAD”. Participants having both are defined as having an FH phenotype. Results: 2267 and 2164 participants had LDL-C <4.9 and ≥ 4.9 mmol/L, respectively. Mortality endpoints and major coronary events (MCE) were significantly reduced with simvastatin versus placebo in both groups over 5.4 years, but the latter derived greater absolute risk reductions (ARR) (4.1–4.3% for mortality endpoints, versus 2.5–2.8%). LDL-C reductions were similar among the 4 subgroups with levels ≥4.9 mmol/L. Participants with FH phenotype (n = 152) appeared to derive greater relative benefits with simvastatin than the other three subgroups (all-cause death: 84% relative risk reduction, p = 0.046; MCE: 55% reduction, p = 0.0297); statistical interaction was non-significant. Participants with FH phenotype derived greater ARR than any other group with simvastatin versus placebo (all-cause mortality: 6.6% ARR; MCE 13.2%; versus 3.8% and 8.3%, respectively, among participants with LDL-C ≥4.9 mmol/L but without features suggestive of FH). Conclusions: The FH phenotype appeared to be associated with greater clinical benefits from a given magnitude of LDL-C reduction as compared to individuals without FH phenotype.
KW - Cardiovascular disease prevention
KW - Coronary artery disease
KW - Familial hypercholesterolemia
KW - LDL cholesterol
KW - Statins
UR - http://www.scopus.com/inward/record.url?scp=85099989570&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.atherosclerosis.2021.01.003
DO - https://doi.org/10.1016/j.atherosclerosis.2021.01.003
M3 - Article
C2 - 33497862
VL - 320
SP - 1
EP - 9
JO - Atherosclerosis
JF - Atherosclerosis
SN - 0021-9150
ER -