ESC Congress 2017 In Review -- Main Edition - 20

Late-Breaking Science

FOURIER Trial Shows the
Reduction of LDL-C to Extremely
Low Levels is Safe and Associated
With a Reduction in CV Events
Written by Maria Vinall

20

October 2017

For the primary composite endpoint of CV death, MI,
stroke, coronary revascularisation or unstable angina,
the adjusted event rates were reduced by 24%, 15%,
6%, and 3% for patients achieving LDL-C levels < 0.5,
0.5-1.3, 1.3-1.8, and 1.8-2.6 mM, respectively, compared
with the group achieving a LDL-C > 2.6 mM at 4 weeks.
Importantly, there was a significant (P = .0012) and progressive relationship between lower LDL-C and reductions in adverse CV events down to 0.2 mM LDL-C
(Figure 1). For the secondary composite endpoint of CV
death, MI, or stroke, there was a significant (P = .0001)
and almost linear reduction in risk.
Figure 1. Adjusted Primary Endpoint Rate by LDL-C
0.22

Adjusted Event Rate (probability)

The FOURIER trial [Sabatine MS et al. N Engl J Med. 2017]
comprised 27,564 patients (aged 40 to 85 years) with
stable cardiovascular disease (CVD), on statin therapy,
and with LDL-C levels ≥ 1.8 mM or a non-HDL-cholesterol
level ≥ 2.6 mM. Patients were randomised to subcutaneous evolocumab (140 mg Q2W or 420 mg QM) or placebo. The main results of the FOURIER trial were a 59%
reduction in LDL-C and significant reductions in CV outcomes. Evolocumab was safe and well-tolerated. Robert P.
Giugliano, MD, SM, Brigham and Women's Hospital, Boston,
Massachusetts, USA, presented the results of a prespecified secondary analysis from FOURIER that assessed the
efficacy and safety associated with achieving progressively lower LDL-C levels [Giugliano RP et al. Lancet. 2017].
Patients were stratified by achieved LDL-C at 4
weeks. The primary efficacy endpoint was the composite of CV death, myocardial infarction (MI), stroke, coronary revascularisation, or unstable angina. The key secondary endpoint was the composite of CV death, MI, or
stroke. Prespecified safety events included overall rates
of serious adverse events (SAEs), AEs leading to study
drug discontinuation, and AEs of interest (aspartate
transaminase/alanine transaminase > 3x upper limit of
normal [ULN], creatinine kinase > 5x ULN, neurocognitive events, new diabetes mellitus, cancer, haemorrhagic
stroke, cataracts, and non-CV death). Patients with an
event prior to 4 weeks were excluded. The data were
pooled for both treatment groups and analysed using
multivariate modelling adjusting for baseline factors
associated with achieved LDL-C and randomised treatment arm. Cognition was assessed using the Cambridge
Neuropsychological Test Automated Battery [Giugliano
RP et al. N Engl J Med. 2017] and a patient survey of
everyday cognition.
Of the 25,982 patients analysed, the proportions of
patients who achieved LDL-C values < 0.5, 0.5-1.3, 1.3-1.8,
1.8-2.6, and ≥ 2.6 mM were 10%, 31%, 13%, 29%, and
17%, respectively. Patients achieving the lowest LDL-C
values were more likely to have received evolocumab.
They also had lower baseline LDL-C, total cholesterol,
and lipoprotein(a) levels and were more likely older,
male, and non-white.

0.20
0.18

LDL-C (mM)

Adj HR (95% CI)

< 0.5

0.76 (0.64-0.90)

0.5-1.3

0.85 (0.76-0.96)

1.3-1.8

0.94 (0.82-1.09)

1.8-2.6

0.97 (0.86-1.09)

≥2.6

P = .0012

referent

0.16
0.14
0.12
0.10
0

0.5

0.1

1.5

2.0

2.5

3.0

3.5

4.0

4.5

LDL-C (mM) at 4 weeks

LDL-C, low-density lipoprotein cholesterol.
Reproduced with permission from RP Giugliano, MD, SM.

There was no significant association between
achieved LDL-C and safety outcomes, either for all SAEs
or other AEs of interest (adjusted P values for trend > .10
for each). Cognition as assessed by the CANTAB tool did
not differ across the groups and the patient survey of
everyday congition showed similar to slightly improved
results with lower achieved LDL-C levels.
An exploratory analysis showed that patients with
LDL-C < 0.26 mM at 4 weeks (n = 504) had the best outcomes (primary outcome: adjusted HR, 0.69; 95% CI,
0.49 to 0.97; P = .03; secondary outcome: adjusted HR,
0.59; 95% CI, 0.37 to 0.92; P = .02) with no difference in
SAEs or AEs leading to drug discontinuation.
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