Elsevier

The Lancet

Volume 390, Issue 10106, 28 October–3 November 2017, Pages 1962-1971
The Lancet

Articles
Clinical efficacy and safety of achieving very low LDL-cholesterol concentrations with the PCSK9 inhibitor evolocumab: a prespecified secondary analysis of the FOURIER trial

https://doi.org/10.1016/S0140-6736(17)32290-0Get rights and content

Summary

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.

Introduction

LDL cholesterol has been well established as a modifiable risk factor for atherosclerotic cardiovascular disease in epidemiological studies. In a series of landmark randomised controlled trials with statins, significant reductions in cardiovascular events were shown in patients with very high LDL-cholesterol concentrations (eg, decreasing LDL cholesterol from 5 to 3 mmol/L), average LDL-cholesterol concentrations (eg, decreasing LDL cholesterol from 3·5 to 2·5 mmol/L), and below average LDL-cholesterol concentrations (eg, decreasing LDL cholesterol from 2·5 to 1·5–2 mmol/L).1 Although the trials did not allocate patients to different LDL-cholesterol targets, the data suggested that lowering LDL cholesterol across a broad range of concentrations conferred similar cardiovascular risk reduction per unit reduction of LDL cholesterol. Based on these trials, the LDL-cholesterol target or threshold for treatment in published guidelines decreased to 2·5 mmol/L and then 1·8 mmol/L in high-risk patients.2, 3, 4, 5

Research in context

Evidence before this study

We searched MEDLINE on July 24, 2017, with the terms “cholesterol, LDL” and either “myocardial infarction” or “stroke.” The search was limited to publications from 2014 onwards since that was the date of a comprehensive meta-analysis on this topic. Abstracts were reviewed by two of the authors (RPG and MSS) to find publications describing the association of on-treatment LDL cholesterol and cardiovascular outcomes in patients with atherosclerotic cardiovascular disease. Relevant publications were supplemented with additional relevant publications known by the authors. None of the trials studying patients treated with statins provided data on a cutpoint of less than 1·3 mmol/L. We have published data on ezetimibe from IMPROVE-IT, in which the lowest cutpoint was 0·8 mmol/L, but there were fewer than 1000 patients in that subgroup. There is a published pooled analysis of smaller lipid-lowering trials of another proprotein convertase subtilisin-kexin type 9 inhibitor, alirocumab, but with approximately a tenth of the number of patients with an LDL-cholesterol concentration of less than 0·5 mmol/L.

Added value of this study

We found a strong relationship between achieved LDL cholesterol down to concentrations 0·2 mmol/L and a progressive reduction in major cardiovascular outcomes, with no increase in safety events. These observations extend previous findings with statins and ezetimibe to lower concentrations of LDL cholesterol than previously reported, in a larger sample size, and with the newest and most potent lipid-lowering therapy approved to date.

Implications of all the available evidence

All evidence to date from trials of intensive lipid lowering supports reduction of LDL cholesterol in high-risk patients to concentrations below those currently recommended in cholesterol guidelines. Studies with a longer follow-up period than in this study are needed to exclude the development of late complications of persistent very-low concentrations of LDL cholesterol.

Findings from the Further cardiovascular OUtcomes Research with PCSK9 Inhibition in subjects with Elevated Risk (FOURIER) trial6 showed that the proprotein convertase subtilisin-kexin type 9 (PCSK9) monoclonal antibody evolocumab, when added to background statin therapy, lowered LDL-cholesterol concentrations to a median of 0·8 mmol/L (IQR 0·5–1·2) and significantly reduced the risk of cardiovascular events in patients with stable atherosclerotic cardiovascular disease who were followed up for a median of 2·2 years. No significant differences were found in major safety events or in prospective cognitive function testing between treatment groups.7

Notably, the LDL-cholesterol concentrations achieved were substantially lower than those in previous clinical outcome trials with lipid-lowering therapies, and it is not known whether there is a threshold below which there is no added clinical benefit, or whether there is an increase in adverse safety events. Our aim was to explore the relationship between progressively lower LDL cholesterol achieved at 4 weeks and clinical efficacy and safety in this prespecified, secondary analysis of the FOURIER trial.

Section snippets

Study design and participants

FOURIER6, 8 was a randomised, double-blind, placebo-controlled trial that enrolled 27 564 patients aged 40–85 years with stable atherosclerotic cardiovascular disease (previous myocardial infarction, previous non-haemorrhagic stroke, or symptomatic peripheral arterial disease) and additional risk factors placing them at increased cardiovascular risk. Eligible patients had LDL-cholesterol concentrations of 1·8 mmol/L or higher or non-HDL concentrations of 2·6 mmol/L or higher while taking an

Results

Of 27 564 patients who were randomly assigned either evolocumab or placebo in the FOURIER trial between Feb 8, 2013, and June 5, 2015, 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. There were no differences between treatment groups in the number of patients who did not have a week-4 LDL cholesterol measurement or in patients who had a clinical

Discussion

In an analysis of over 25 000 patients with atherosclerotic cardiovascular disease, we found a strong relationship between on-treatment LDL-cholesterol concentration and major cardiovascular outcomes. Conversely, we found no significant association between LDL-cholesterol concentrations and prespecified adverse events in patients followed up for a median of 2·2 years.

These data are supported by previous observations from several types of analyses. First, subgroup analyses from clinical trials

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