Clinical efficacy and safety of achieving very low LDL-cholesterol concentrations with the PCSK9 inhibitor evolocumab: a prespecified secondary analysis of the FOURIER trial
File(s)
Author(s)
Type
Journal Article
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, 27 564 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 25 982 patients (94% of those randomly assigned) 13 013 were assigned evolocumab and 12 969 were assigned placebo. 2669 (10%) of 25 982 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. FUNDING: Amgen.
Date Issued
2017-10-28
Date Acceptance
2017-08-14
Citation
Lancet, 2017, 390 (10106), pp.1962-1971
ISSN
0140-6736
Publisher
Elsevier
Start Page
1962
End Page
1971
Journal / Book Title
Lancet
Volume
390
Issue
10106
Copyright Statement
© 2017, Elsevier. Licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/
Sponsor
Amgen Inc
National Institute for Health Research
National Institute for Health Research
Identifier
PII: S0140-6736(17)32290-0
Grant Number
20110118
NF-SI-0513-10059
NF-SI-0513-10059
Subjects
Science & Technology
Life Sciences & Biomedicine
Medicine, General & Internal
General & Internal Medicine
LOW-DENSITY-LIPOPROTEIN
CARDIOVASCULAR-DISEASE
COGNITIVE FUNCTION
STATIN
EVENTS
EZETIMIBE
OUTCOMES
METAANALYSIS
ALIROCUMAB
RATIONALE
Adult
Aged
Aged, 80 and over
Antibodies, Monoclonal
Antibodies, Monoclonal, Humanized
Anticholesteremic Agents
Cholesterol, LDL
Double-Blind Method
Female
Follow-Up Studies
Humans
Hypercholesterolemia
Male
Middle Aged
PCSK9 Inhibitors
Patient Safety
Risk Assessment
Treatment Outcome
FOURIER Investigators
Humans
Hypercholesterolemia
Antibodies, Monoclonal
Anticholesteremic Agents
Treatment Outcome
Risk Assessment
Follow-Up Studies
Double-Blind Method
Adult
Aged
Aged, 80 and over
Middle Aged
Female
Male
Cholesterol, LDL
Antibodies, Monoclonal, Humanized
Patient Safety
PCSK9 Inhibitors
General & Internal Medicine
11 Medical and Health Sciences
Publication Status
Published
Date Publish Online
2017-08-28