Giugliano, Robert P., Pedersen, Terje R., Park, Jeong-Gun, De Ferrari, Gaetano M., Gaciong, Zbigniew A., Ceska, Richard, Toth, Kalman, Gouni-Berthold, Ioanna, Lopez-Miranda, Jose ORCID: 0000-0002-8844-0718, Schiele, Francois, Mach, Francois, Ott, Brian R., Kanevsky, Estelle, Pineda, Armando Lira, Somaratne, Ransi, Wasserman, Scott M., Keech, Anthony C., Sever, Peter S. and Sabatine, Marc S. (2017). Clinical efficacy and safety of achieving very low LDL-cholesterol concentrations with the PCSK9 inhibitor evolocumab: a prespecified secondary analysis of the FOURIER trial. Lancet, 390 (10106). S. 1962 - 1972. NEW YORK: ELSEVIER SCIENCE INC. ISSN 1474-547X

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Abstract

Background LDL cholesterol is a well established risk factor for atherosclerotic cardiovascular disease. How much one should or safely can lower this risk factor remains debated. We aimed to explore the relationship between progressively lower LDL-cholesterol concentrations achieved at 4 weeks and clinical efficacy and safety in the FOURIER trial of evolocumab, a monoclonal antibody to proprotein convertase subtilisin-kexin type 9 (PCSK9). Methods In this prespecified secondary analysis of 25?982 patients from the randomised FOURIER trial, the relationship between achieved LDL-cholesterol concentration at 4 weeks and subsequent cardiovascular outcomes (primary endpoint was the composite of cardiovascular death, myocardial infarction, stroke, coronary revascularisation, or unstable angina; key secondary endpoint was the composite of cardiovascular death, myocardial infarction, or stroke) and ten prespecified safety events of interest was examined over a median of 2.2 years of follow-up. We used multivariable modelling to adjust for baseline factors associated with achieved LDL cholesterol. This trial is registered with ClinicalTrials.gov, number NCT01764633. Findings Between Feb 8, 2013, and June 5, 2015, 27564 patients were randomly assigned a treatment in the FOURIER study. 1025 (4%) patients did not have an LDL cholesterol measured at 4 weeks and 557 (2%) had already had a primary endpoint event or one of the ten prespecified safety events before the week-4 visit. From the remaining 25982 patients (94% of those randomly assigned) 13013 were assigned evolocumab and 12.969 were assigned placebo. 2669 (10%) of 25982 patients achieved LDL-cholesterol concentrations of less than 0.5 mmol/L, 8003 (31%) patients achieved concentrations between 0.5 and less than 1.3 mmol/L, 3444 (13%) patients achieved concentrations between 1.3 and less than 1.8 mmol/L, 7471 (29%) patients achieved concentrations between 1.8 to less than 2.6 mmol/L, and 4395 (17%) patients achieved concentrations of 2.6 mmol/L or higher. There was a highly significant monotonic relationship between low LDL-cholesterol concentrations and lower risk of the primary and secondary efficacy composite endpoints extending to the bottom first percentile (LDL-cholesterol concentrations of less than 0.2 mmol/L; p=0.0012 for the primary endpoint, p=0.0001 for the secondary endpoint). Conversely, no significant association was observed between achieved LDL cholesterol and safety outcomes, either for all serious adverse events or any of the other nine prespecified safety events. Interpretation There was a monotonic relationship between achieved LDL cholesterol and major cardiovascular outcomes down to LDL-cholesterol concentrations of less than 0.2 mmol/L. Conversely, there were no safety concerns with very low LDL-cholesterol concentrations over a median of 2.2 years. These data support further LDL-cholesterol lowering in patients with cardiovascular disease to well below current recommendations.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Giugliano, Robert P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pedersen, Terje R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Park, Jeong-GunUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
De Ferrari, Gaetano M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gaciong, Zbigniew A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ceska, RichardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Toth, KalmanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gouni-Berthold, IoannaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lopez-Miranda, JoseUNSPECIFIEDorcid.org/0000-0002-8844-0718UNSPECIFIED
Schiele, FrancoisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mach, FrancoisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ott, Brian R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kanevsky, EstelleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pineda, Armando LiraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Somaratne, RansiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wasserman, Scott M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Keech, Anthony C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sever, Peter S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sabatine, Marc S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-213892
DOI: 10.1016/S0140-6736(17)32290-0
Journal or Publication Title: Lancet
Volume: 390
Number: 10106
Page Range: S. 1962 - 1972
Date: 2017
Publisher: ELSEVIER SCIENCE INC
Place of Publication: NEW YORK
ISSN: 1474-547X
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
LOW-DENSITY-LIPOPROTEIN; CARDIOVASCULAR-DISEASE; COGNITIVE FUNCTION; STATIN; EVENTS; EZETIMIBE; OUTCOMES; METAANALYSIS; ALIROCUMAB; RATIONALEMultiple languages
Medicine, General & InternalMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/21389

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