10.1161/CIRCULATIONAHA.116.024604
Reductions in Atherogenic Lipids and Major Cardiovascular Events:
A Pooled Analysis of 10 ODYSSEY Trials Comparing Alirocumab to Control
Running Title: Ray et al., Lipid reductions + CV events in ODYSSEY
Kausik K Ray, MD, MPhil1; Henry N Ginsberg, MD2; Michael H Davidson, MD3;
Robert Pordy, MD4; Laurence Bessac, MD5; Pascal Minini, PhD6; Robert H Eckel, MD7;
Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017
Christopher P Cannon, MD8
1
Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Publi
Public
Health,
College,
Heal
lth
th,, IImperial
mper
mp
e iall Co
C
llege, London, UK; 2Columb
Columbia
bia
i University, New York,
York, NY; 3Department of
Medicine
Medicine,
e, Un
Univer
University
e si
er
sity
ty off Ch
Chic
Chicago
icag
ic
a o Me
M
Medicine,
diciine
n ,C
Chicago,
hiccag
ago,
o, IL;
IL; 4Re
Regeneron
Rege
gene
neron Pharmaceuticals,
Phar
Ph
arma
ar
m ceut
utic
ut
ical
ic
a s,
al
Tarrytown,
Taarrytown,
rrr
NY;
Y 5S
Sanofi,
ano
nofi, Paris,
Parris, France;
Pa
e; 6Bios
Biostatistics
staatist
stics an
andd Pr
Pro
Programming,
ograammin
ng, S
Sanofi,
anofi, C
Chilly-Mazarin,
hillyy-Mazzarrin
France;
Fra
Fr
ancee; 7Un
University
Universi
sity
si
ty off Co
C
Colorado,
lo
ora
radoo, An
A
Anschutz
scchu
hutz
tz Med
Medical
edic
ed
i al
ic
a Campus,
Cam
ampu
pus, Aurora,
Aur
urorra, C
CO;
O;
8
Harvard Clinical Research Institute
Institute, Boston
Boston, MA
Address for Correspondence:
Kausik K Ray, MD, MPhil
Imperial Centre for Cardiovascular Disease Prevention
Department of Primary Care and Public Health
School of Public Health, Imperial College
Reynolds Building, St Dunstan’s Road
London, W68RP, UK
Tel.: 44 (0)207 594 0716
Fax.: +44 (0)207 594 0854
Email: [email protected]
Journal Subject Terms: Coronary Artery Disease; Atherosclerosis; Vascular Disease;
Pharmacology; Lipids and Cholesterol
1
10.1161/CIRCULATIONAHA.116.024604
Abstract
Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017
Background— A continuous relationship between reductions in low-density lipoprotein
cholesterol (LDL-C) and major adverse cardiovascular events (MACE) has been observed in
statin and ezetimibe outcomes trials, down to achieved levels of 54 mg/dL. However, it is
uncertain whether this relationship extends to LDL-C levels <50 mg/dL. We assessed the
relationship between additional LDL-C, non-high-density lipoprotein cholesterol (non-HDL-C),
and apolipoprotein B100 (apoB) reductions and MACE among patients within the ODYSSEY
trials that compared alirocumab versus controls (placebo/ezetimibe), mainly as add on to
maximally tolerated statin.
Methods— Data were pooled from 10 double-blind trials (6699 patient-years follow-up).
Randomization was to alirocumab 75/150 mg every 2 weeks or control for 24–104 weeks, added
to background statin therapy in 8 trials. This analysis included 4974 patients (3182 alirocumab,
1174 placebo, 618 ezetimibe). In a post hoc analysis, the relationship between average on
treatment lipid levels and percent reductions in lipids from baseline were correlated with MACE
(coronary heart disease death, non-fatal myocardial infarction [MI], ischemic stroke, or unstable
angina requiring hospitalization) using multivariable
a analyses.
Results— Overall, 33.1% of the pooled cohort achieved average LDL-C <50 mg/
g//dL ((44.7–52.6%
44.7
44
.7–5
.7
–52.
–5
2..6%
6
mg/dL
allocated to alirocumab, 6.5% allocated to ezetimibe, and 0% allocated to placebo). In total, 104
patients experienced MACE (median time to event: 36 weeks). For every 39 mg/dL lower
achieved LDL-C, the risk of MACE appeared to be 24% lower (adjusted hazard ratio [HR] 0.76,
confidence
interval
reductions
95% co
conf
nfid
nf
id
den
ence
c int
ntterval [CI]: 0.63–0.91; P=0.0025).
P=0.00225)
5 . Percent red
duc
u tionns in LDL-C from baseline
wer
were
re iinversely
nversely
y ccorrelated
orrre
r laate
tedd wi
w
with
th
hM
MACE
A E rates
AC
ra (H
(HR
HR 0.71
0.71 [0.57
[0.
0 577 to
to 0.89]
0.89
0.
89]] per
89
per additional
addiiti
tion
onnal
a 50%
% reduction
red
educ
uction
uc
Materially
similar
from
m baseline; P=0.003).
P=0
0.003
033).
) Ma
Mate
terially
te
ly sim
milar strengths
strrengt
gths of association
assoc
ociatiion to those
oc
thos
osee described
os
desccri
ribe
b d for
fo LDL-C
LD
DL-C
were
with
achieved
non-HDL-C
percentage
wer
re observed wi
w
th ac
chieved
ed
d non-HDL
L-C andd aapoB
pooB levels
leeve
vels
ls or
or per
rceentaage
g rreductions.
eductionns.
Conclusions—
post
ODYSSEY
percentage
reductions
Conc
nclu
nc
lusionss— In
lu
n a pos
ost hocc an
aanalysis
alys
ysis
ys
is ffrom
room 100 O
DYSS
DY
SS
SEY trials
triaals greater
tr
greateer pe
gr
erc
rcentag
ag
ge red
ductionns in
LDL-C
LDL-C
with
MACE,
LDL
LD
L-C
C and
d lower
low
ower
err oon-treatment
n-trrea
eatm
tmen
ent LD
DL-C
C were
weree aassociated
s ocia
ss
ocia
i te
tedd wi
ith a llower
ow
werr iincidence
nccid
iden
en
nce ooff MA
MACE
C ,
CE
including
LDL-C
mg/dL). These findings require further validation in the
ncluding very low levels of LDL
C (<50 mg/dL)
ongoing prospective ODYSSEY OUTCOMES trial.
Clinical Trial Registration: clinicaltrials.gov identifiers: NCT01507831, NCT01623115,
NCT01709500, NCT01617655, NCT01644175, NCT01644188, NCT01644474, NCT01730040,
NCT01730053, NCT01709513.
Key-words: PCSK9; low-density lipoprotein cholesterol; apolipoprotein; cardiovascular events;
MACE, ASCVD, Risk reduction, Alirocumab, ODYSSEY
2
10.1161/CIRCULATIONAHA.116.024604
Clinical Perspectives:
What’s new?
x
Cardiovascular benefits of statins and add-on lipid-lowering therapy only extend to LDLC levels of ~54 mg/dL. We investigated whether this relationship extends below 50 mg/dL
using data from ODYSSEY trials of alirocumab (PCSK9 monoclonal antibody) versus
placebo/ezetimibe.
x
About half of alirocumab-treated patients achieved LDL-C <50 mg/dL. For each 39
Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017
mg/dL lower achieved LDL-C, MACE incidence fell by 24%, and 50% reductions in
LDL-C from baseline reduced MACE by
y 29%.
x
Similar associations were observed with non-high-density lipoprotein cholesterol
choleest
sterol
oll aand
nd
apolipoprotein B achieved levels and percentage reductions and MACE.
x
Low
L
ow LD
LDLLDL-C
-C levels were not associated with
wiithh excess treatment
treatme
ment eemergent
mergent adverse events.
What are th
he cli
inicall implications?
implication
i
s??
the
clinical
x
These analyses provide further reassurance about the safety and cardiovascular benefit of
achieving even further reductions in LDL-C with alirocumab beyond what was previously
achieved with statins and ezetimibe.
x
Limitations include the low number of events (104), the limited duration of the studies
(24-104 weeks) and the post hoc nature of this analysis.
x
If the forthcoming outcomes trials of PCSK9 inhibitors such as alirocumab demonstrate
additional reduction in MACE with further LDL-C reduction, then guideline committees
may investigate lower LDL-C goals or a larger reduction in LDL-C from untreated
baseline for those at highest risk of MACE.
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10.1161/CIRCULATIONAHA.116.024604
Introduction
Statins have been the cornerstone of global lipid modification guidelines for the prevention of
major adverse cardiovascular events (MACE).1 With accumulating evidence, each subsequent
iteration of clinical guidelines have extended statin indications and have recommended the
achievement of progressively lower low-density lipoprotein cholesterol (LDL-C) goals2-4 or
most recently percentage reductions in LDL-C using the most potent statins.5 Recently, the
IMPROVE IT trial demonstrated that further reductions in LDL-C to a mean of 54 mg/dL with a
non-statin lipid-lowering therapy (LLT) in statin-treated individuals provided additional
Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017
reductions in MACE,6 supporting the concept that lower LDL-C levels are better, and consistent
with observational data from several statin trials.7-9
Inhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9) offer the prospect of
achievingg even lower LDL-C levels than ezetimibe when added to statins. Data from the phase 3
OD
DYS
Y SEY tria
iall pr
ia
rog
o ra
r m, iin
n wh
whic
icch aver
erage ac
chi
h ev
ved L
DL-C
DL
-C levels
lev
ev
vel
elss of <
50 m
g/dL
g/
dL wer
e e ob
er
obse
serv
se
r ed
ODYSSEY
trial
program,
which
average
achieved
LDL-C
<50
mg/dL
were
observed
en alirocuma
mabb wa
ma
w
ddedd to statin therapy,10-12
th
herapy,10
10-112 allows
allo
al
lows
lo
w for
ws
for the exploration
explo
loraatiion of changes
chan
ch
angges in event
even
when
alirocumab
wass aadded
ates at much
h lower LD
LDL-C levels than previously
previiously analyzed.
rates
In addition, percent reduction in LDL-C has also been cited as being important in some
guidelines 5, 13, 14 and as patients in the ODYSSEY trials have already had their LDL-C reduced
by 30–50% with statins, these trials allow us to explore the relationship between further
percentage reductions in LDL-C and risk. Therefore, we assessed whether the relationship
between LDL-C and risk extends to very low levels of LDL-C (<50 mg/dL) in the ODYSSEY
trial program. We hypothesized that, among patients already receiving maximally tolerated statin
therapy, both lower achieved LDL-C and greater percentage reductions from baseline would
translate into lower rates of MACE. Furthermore, as many guidelines increasingly recommend
4
10.1161/CIRCULATIONAHA.116.024604
non-high-density lipoprotein cholesterol (non-HDL-C) or apolipoprotein B100 (apoB) as potential
alternatives to LDL-C for assessing the efficacy of LLT, we provide similar analyses using these
lipid parameters for comparison.4, 15, 16
Methods
Patient population
The Phase 3 ODYSSEY trial designs have been reported previously.6, 11, 12, 17-22 Briefly, patients
were enrolled if they had established atherosclerotic cardiovascular disease (ASCVD) or high CV
Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017
risk such as heterozygous familial hypercholesterolemia (HeFH) with LDL-C inadequately
controlled on their existing treatment (statin/other LLT/diet). The main exclusionn cr
criteria
rit
iter
eria
er
iaa w
were
eree
er
baseline LDL-C <70 mg/dL for those with ASCVD and very high risk or <100 mg/dL for high
risk
isk patients without ASCVD at screening. Individuals with triglyceride levels >400 mg/dL were
excl
excluded
clud
uded (for fu
furthe
further
her de
he
deta
details
tail
ta
ilss on iinclusion
il
nclu
nc
lusion
lu
on and exclusion
exc
x lu
lusionn criteria
cri
rite
teri
te
r a se
see
ee eT
eeTable1,
able11, on
ab
onli
online
line
li
n Sup
ne
Supplemental
uppl
up
plem
pl
emen
em
e ta
Mat
Material).
ater
at
e ial). For th
er
the present
pressent analysis
an
nalysis dataa w
were
ere ppooled
ooleed fr
from
om 110
0P
Phase
haasee 3 OD
ODYS
ODYSSEY
Y SEY tri
YS
ttrials
rialls (eFigure
(eFigur
ure
1). Patients were rand
randomized
domized to receive alirocumab
b or control (p
((placebo
lacebo or ezetimibe) with double
doubleblind treatment periods of 24–104 weeks. Six of the 10 studies, representing ~80% of the
population, had a minimum study duration of 52 weeks. All study protocols were approved by the
relevant local independent review boards, and all participating patients provided written, informed
consent.
Lipid measurements
LDL-C was calculated using the Friedewald equation unless triglycerides were >400 mg/dL when
it was determined by beta quantification. ApoB levels in serum were determined using
immunonephelometry by a central laboratory (Medpace Reference Laboratories, Cincinnati, OH,
5
10.1161/CIRCULATIONAHA.116.024604
US, and Leuven, Belgium, except for the LONG TERM study, which used Covance Central
Laboratories, Indianapolis, IN, USA, and Geneva, Switzerland) and non-HDL-C via subtraction
of HDL-C from total cholesterol.
MACE definitions
MACE was defined as per the primary endpoint of the ODYSSEY OUTCOMES study:23
coronary heart disease (CHD) death, non-fatal myocardial infarction [MI], ischemic stroke, or
unstable angina (UA) requiring hospitalization. Cardiovascular events were adjudicated by a
central Clinical Events Committee12 (the same Committee is involved in the ODYSSEY
Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017
OUTCOMES trial23). UA cases considered here were limited to those with definite evidence of
he ischemic condition, i.e., small proportion of UAs qualified (see definition of UA
UA in
n the
the
the
Supplemental Material).
Statistical Analysis
Baseline
Base
selline characteristics
se
chara
ra
acter
eristi
t cs and
ti
a d distribution
an
dist
di
stri
st
ribu
ri
uti
tion of lipid
lipiid parameters
li
paara
rame
mete
me
terss
te
Baseline
Base
seli
se
l ne data we
w
were
ree poo
pooled
ooled fo
for all random
randomized
omized pati
patients
ienntss and
and presented
prresen
nteed st
stratified
traatiifi
fied accor
according
o diing to
or
whether the studies were placebo-controlled
placebo-controllled
d or ezetimibe-controlled. For continuous variables,
the data are reported as means and standard deviations or median and interquartile range if they
were not normally distributed. The distribution of LDL-C, non-HDL-C and apoB levels at
baseline and average “on treatment” levels or average percentage reductions in these parameters
during the study treatment period are depicted graphically and analyzed using descriptive
statistics comparing treatment groups (alirocumab versus placebo, or versus ezetimibe). These
include only patients in the safety population i.e. patients randomized and who received at least 1
dose or part of a dose of study treatment.
6
10.1161/CIRCULATIONAHA.116.024604
Lipid changes and risk of MACE
Irrespective of treatment allocation patients were pooled into one overall cohort and the
relationship between LDL-C and MACE during the treatment period was assessed using 1)
achieved LDL-C levels during treatment and 2) percentage reductions in LDL-C from baseline.
Average on-treatment LDL-C or the mean percentage reduction during the treatment period were
determined from the area under the curve (using trapezoidal method), taking into account all
LDL-C values up to end of treatment period or occurrence of MACE, whichever came first.
Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017
The relationship between on treatment LDL-C and MACE was assessed using a
priiorr hhistory
isto
is
to
ory of
of MI
M
multivariable Cox regression model with adjustment for age, gender, diabetes, prior
or stroke, baseline LDL-C and smoking status as previously published.24 Hazard ratios (HR) and
95% confidence intervals (CI) were calculated for every 39 mg/dL lower LDL-C to provide a
2
comparison
comp
mparison wit
mp
with
ithh th
it
the
he Ch
Chol
Cholesterol
oles
ol
esteero
roll T
Treatment
r atme
re
m nt Tri
Trialist
rial
ri
a istt (CT
(CTT)
CT
TT) me
m
meta-regression
taa-re
regr
re
gresssi
s on lline.
inee.25
in
Similar
Sim
millar
analyses
anal
alyyses were cconducted
al
o ducteed fo
on
for
or the percent
percentage
ntage re
reduction
educttionn in L
LDL-C
DL-C from
DL
from baseline
baseeline andd ssubsequent
ba
ubsequen
ub
nt
risk
isk of MACE
M CE
MA
C with
h HR and 95% C
CII expressed for
for each 50% reduction in
i LD
LDL-C.
DL-C
C.
To assess the shape of association, the adjusted rates of MACE and associated 95% CI
were determined from a multivariate Poisson model and depicted graphically as a function of
average LDL-C levels or average percentage reduction during treatment. Instead of using all
available lipid measurements (average LDL-C levels or reductions) sensitivity analyses were
conducted using only LDL-C values and percentage reduction at Week 4 and subsequent events
after excluding events that occurred prior to Week 4. Finally, similar analyses to those described
above were conducted for non-HDL-C or apoB. All analyses were generated using SAS version
9.4 and all tests and confidence intervals were two-sided.
7
10.1161/CIRCULATIONAHA.116.024604
Safety analysis
For safety, treatment-emergent adverse events (TEAEs) were defined as those events occurring
from the first dose of study treatment and up to 70 days after the last dose. The principal analyses
compared randomized treatment to alirocumab versus control. We also explored the strength of
association between any TEAE and LDL-C levels or percentage reductions in LDL-C using
multivariable logistic regression, after adjustment for the same covariates included in the MACE
analyses. Data are reported as odds ratio (OR) and 95% CI per 39 mg/dL difference or 50%
reduction in LDL-C. The shape of the association was also depicted graphically using adjusted
Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017
TEAE rate and associated 95% CI plotted against average LDL-C levels or percentage LDL-C
eductions derived from multivariate logistic regression models.
reductions
Results
Base
selline characteristics
se
chara
ra
acter
eristi
t css
ti
Baseline
Thee bbaseline
aseline characteristics
cha
haraacterristicss ooff individua
ual studies
studdie
ies are
ar sh
show
own in
ow
in eT
Table22 iin
n th
he online
n S
ne
upplem
menta
individual
shown
eTable2
the
Supplemental
material
l, andd the pool
led
d summary of placebo and ezetimibe comparator trials are shown in Table
T bl
Ta
be
material,
pooled
1. In the placebo-controlled trials, 2318 patients were treated with alirocumab and 1174 were
treated with placebo; in the ezetimibe-controlled trials, 864 were treated with alirocumab and 618
were treated with ezetimibe. Hence, a total of 4974 patients were included in the lipid and MACE
analyses described below. Overall the average age was ~60 years, with patients being mostly
white and having an average body mass index of ~30 kg/m2. Approximately two thirds were
male, one third had diabetes, two thirds had a prior history of ASCVD, and about one-fifth were
smokers. One third of participants in the placebo-controlled trials had HeFH.
8
10.1161/CIRCULATIONAHA.116.024604
Baseline lipids
Baseline lipid values for individual studies are reported in eTable 3 in the Supplement. Pooled
mean baseline LDL-C levels ranged from 123.2 to 126.8 mg/dL, non HDL-C between 154.2 to
156.9 mg/dL, and apoB between 101.8 to 104.3 mg/dL (Table 1). As expected, the distribution of
baseline lipids at randomization was fairly similar between alirocumab and the control groups
(eFigure 2 in the Supplement).
Lipid levels during treatment
Figure 1 illustrates the distribution of different lipid parameters during treatment. The mean LDLDownloaded from http://circ.ahajournals.org/ by guest on June 16, 2017
C levels achieved during treatment were: in placebo-controlled studies, 56.9 and 126.5 mg/dL
among those treated with alirocumab and placebo, and in ezetimibe-controlled stu
udi
dies
es, 64.0
es
64 0 and
and
n
studies,
100.9 mg/dL with alirocumab and ezetimibe, respectively (Table 2; individual trial dataa in eTable
eTabl
4). Correspo
p nding values for non-HDL-C and apoB shown in Table 2. Similar results were
Corresponding
obta
ain
ined usingg Week
Wee
eek 4 ac
achi
h ev
hi
ved llipids
ipid
ip
i s in
iinstead
steadd of
o av
veraage levels
lev
evelss throughout
thro
th
rouggho
h utt the
the entire
ent
n iree duration
dura
du
rati
ra
tion
ti
o of
on
obtained
achieved
average
he study
stt
(eTab
ab
ble
l 5).
5)).
the
(eTable
O erall, 33.
Ov
3 1%
% of patients achieved an average LD
DL-C
C <500 mg/d
/ L during treatment. In
Overall,
33.1%
LDL-C
mg/dL
placebo-controlled studies, 52.6% of alirocumab and 0% of placebo treated patients achieved
LDL-C levels <50 mg/dL. In the ezetimibe-controlled studies, the corresponding figures were
44.7% for alirocumab and 6.5% for ezetimibe arms, respectively. Thus when all patients were
pooled, the overall distribution of each lipid parameter during treatment largely reflected the
greater proportion of patients achieving very low levels of LDL-C, non-HDL-C and apoB in the
alirocumab group (eFigure 3).
Percent reductions in lipids from baseline
Figure 2 depicts the distribution of the average percentage change from baseline in LDL-C, non-
9
10.1161/CIRCULATIONAHA.116.024604
HDL-C, and apoB during the trials. The average percentage change in LDL-C from baseline
during treatment was -55.4% for alirocumab and +2.7% for placebo; and -48.1% with alirocumab
and -18.0% with ezetimibe, respectively, in placebo- and ezetimibe-controlled trials (Table 2,
individual trial data in eTable 4). Corresponding results for non-HDL-C and apoB are shown in
Table 2 and eTable 4. When Week 4 percentage reductions were assessed rather than the average
reductions over the course of the trial similar values were observed (eTable 5). The combined
distribution plot (eFigure 3) mainly reflected the greater reductions in lipids achieved with
alirocumab versus the relatively modest reductions observed with ezetimibe and with placeboDownloaded from http://circ.ahajournals.org/ by guest on June 16, 2017
treated patients largely remaining unchanged from baseline.
On treatment lipid levels and MACE
A total of 104 first MACE were reported: 20 CHD deaths, 64 non-fatal
f
MI, 16 ischemic strokes,
and 4 unstable angina episodes occurred (median time to event: 36 weeks), among 4974 patients
treated
reaateed during a tot
total
o al
ot
a ooff 66
6699
99 ppatient-years
a ie
at
ient
n -ye
nt
year
a s of ffollow-up.
o lo
ol
ow-uup. A lower
lowe
lo
werr ri
rrisk
sk of MA
MACE
ACE was
w s ob
wa
obse
observed
serv
se
rvved
with
th
h lower
lower achi
achieved
h eved LD
hi
LDL-C
C levels ((Figure
Figu
gure 3; aad
adjusted
dju
usted
dH
HR
R 0.
00.76,
76, 95
95% CI
CI: 0.
00.63–0.91
63–0.991 perr 39 m
mg/dL
g/dL
lower
ower achieved LDL
LDL-C;
DL-C
C; P=0.0025; Table 2). Sim
Similar
i il
i ar results were obtained using a single Week
k4
LDL-C measurement instead of average levels throughout the trial (eTable 5).
In pairwise comparisons of LDL-C, non-HDL-C, and apoB, there was a strong and
significant correlation between levels of each lipid parameter (all correlation coefficients >0.9;
P<0.0001; eTable 6). As with achieved average LDL-C, lower (average) achieved non-HDL-C
and apoB levels were associated with a lower risk of MACE (Figure 3). A 39 mg/dL difference in
LDL-C corresponds to a 42 mg/dL difference in non-HDL-C and 27 mg/dL difference in apoB in
the present pooled datasets. For each 42 mg/dL lower non-HDL-C the HR was 0.77 (CI 0.65–
10
10.1161/CIRCULATIONAHA.116.024604
0.93; P=0.0056; Table 2). The corresponding HR for each 27 mg/dL lower apoB was 0.72 (CI
0.60–0.86 ; P=0.0002; Table 2).
Percentage reductions in lipids and MACE
LDL-C percent reduction was inversely correlated with MACE rates (Figure 3; HR 0.71 [0.57–
0.89] per additional 50% reduction in LDL-C; P=0.003; Table 2). Similarly the risk of MACE
was also lower with greater percent reductions from baseline in both non-HDL-C (Figure 3, HR
0.71 [0.52–0.97] per 50% reduction; P=0.0323) and apoB (Figure 3, HR 0.68 [0.54–0.85] per
50% reduction; P=0.0008; Table 2). Qualitatively similar results were observed using a single
Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017
Week 4 measurement of LDL-C or non-HDL-C and Week 12 apoB instead of using average
values throughout the trial (eTable 5)
Safety
Overall incidence of TEAEs, serious TEAEs, deaths, and discontinuations due to TEAEs were
similar
imi
mila
lar between
la
betweeen al
alirocumab
lirroccum
mab and
and control
con
ontrol
ol patient
patients
n s within
nt
wi n the
the pools
poo
ools
lss of
of placebop ac
pl
aceboo- and
and ezetimibee ettimi
ez
mibe
bebe
controlled
cont
ntro
nt
r lled studies
ro
studi
d es (eTable
di
(eeTabble 7)
7).. A high
higher
g err rrate
ate off in
injection
njec
ection
on si
site
t reactions,
te
reactio
ions, mo
m
mostly
stly mildd inn intensity
st
intensity
y and
an
self-limiting,
elff limiting, were observed with alirocumabb compared with controls. Analyses
A alyses comparing the
An
h
relationship between a 39 mg/dL lower LDL-C and odds of any TEAE were not significant (OR
1.02, 95% CI: 0.96–1.09, eFigure 4). Nor was there any significant association between a 50%
lowering of LDL-C and odds of any TEAE (OR 1.02, 95% CI: 0.93–1.13; eFigure 4).
Results
Currently all global guidelines for ASCVD risk reduction focus on optimization of statin therapy
as the first option for reducing LDL-C for those at high risk.4, 5, 13 The therapeutic limits of
statins and the clinical scenarios in which they have been tested have therefore established the
11
10.1161/CIRCULATIONAHA.116.024604
boundaries of contemporary clinical guidelines and the recommendations they have set, whether
that be a LDL-C goal or a percentage reduction in LDL-C. Based on randomized clinical trial data
of intensive versus standard statin therapy7, 8, 25 knowledge of the distribution of LDL-C levels
in general populations26, 27 and what it is achievable on average with the most potent statins,
guidelines such as the updated Adult Treatment Panel III and those from the European Society of
Cardiology/European Atherosclerosis Society recommended pragmatic goals for LDL-C of <70
mg/dL for those at highest ASCVD risk.2, 4
More recently, the ACC/AHA guidelines and the UK NICE guidelines have argued that
Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017
most statin trials have tested whether a certain percentage reduction in LDL-C translates into a
reduction
eduction in clinical events rather than a LDL-C goal, and thus recommended LD
LDL-C
DL--C re
reductions
edu
duct
ctio
ct
ions
io
of at least 30–50% for those at elevated risk, again based on what is achievable using the most
potent statins.5, 13 Until recently, it was uncertain based on trials data whether consistently
achi
achieving
hiev
eving LDL
ev
LDL-C
L-C levels
leeveels <70
<70
7 m
mg/dL,
g/ddL,
g/
L orr achiev
achieving
vin
ing ffurther
urthe
herr pe
he
perc
percentage
rcen
rc
ntage
tage
g red
reductions
educti
tion
ti
onss in LDL
on
LDL-C
DL--C af
DL
afte
after
t r
maxi
maximizing
ximi
xi
m zing statins,
staati
t ns,, would
wo
translate
traanslate into
tr
to a lower
low
werr risk
ris
isk of M
MACE.
ACE
AC
E.
T
Th
Thee IM
IIMPROVE
PR
ROV
OVE
E IT trial extendedd our evidence-base beyondd stati
statins,
ins, de
ddemonstrating
monstrating that
LDL-C levels on average 54 mg/dL with ezetimibe plus statins further reduced MACE as
compared with the achievement of an LDL-C of ~70 mg/dL with statins alone.6 The risk
reduction observed in the IMPROVE IT trial was also entirely consistent with the absolute
reduction in LDL-C that would have been predicted by the CTT statin derived regression line,
supporting the notion that LDL-C reduction by statins and ezetimibe confer similar benefits and
that the real determinant of the relative risk reduction is the magnitude of the change in LDL-C
rather than the mechanism by which this is achieved. If the findings of IMPROVE-IT are
considered as a further percentage reduction in LDL-C, then they support the notion that starting
12
10.1161/CIRCULATIONAHA.116.024604
with a baseline LDL-C of ~70 mg/dL, a further 20% reduction in LDL-C translates into a 6–7%
lower risk of MACE. However, the question remains as to whether the additional percentage
reduction in LDL-C (of 50–60%) and even lower on-treatment LDL-C level (<50 mg/dL) that can
be achieved by adding a PCSK9 inhibitor to a statin will be associated with a lower risk of
MACE.
The present analysis reports data from 10 randomized trials in the ODYSSEY trial
program, providing information on 6699 patient-years of exposure and suggests that there is
continuous relationship between average on-treatment LDL-C and MACE with no evidence of
Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017
discernable attenuation even at low achieved levels of LDL-C (<50 mg/dL). Furthermore, for
every additional 39 mg/dL lower LDL-C achieved with either alirocumab or ezetimibe
ezetiimi
mibe
be (on
(on ttop
op of
maximally tolerated statins in most patients), there was a further 24% lower risk of MACE (HR
0.76, 95% CI: 0.63–0.91). This is remarkably similar to the CTT point estimate of a 22% risk
reduction
eduuction (ratee rratio
atiio 0.
0.78,
.78
78,, 95%
9 % CI 0.76–0.80)
95
0.7
. 6–
6–0.80) for
fo every
ev y 39 m
mg/dL
g dL
g/
L reduction
red
educ
ucti
t onn in
in LDL-C
LD C achieved
achi
ac
h ev
hi
eved
e
with
th
h statins.25
statins.255
Similarly,
S
Si
miilarly, we observed
obbserved an inverse
i verse relationship
in
rela
l tionshhip with addi
additional
d tional percentage reductions iinn
LDL-C and MACE, without evidence of attenuation of benefit for greater percentage reductions
in LDL-C. In multivariable regression analyses, each 50% incremental reduction in LDL-C on top
of statins was associated with a further 29% reduction in the risk of MACE (HR 0.71, 95% CI
0.57 to 0.89).
There was a significant correlation between LDL-C and non-HDL-C, between LDL-C and
apoB and between non-HDL-C and apoB (all P<0.0001). As with LDL-C, we observed a
continuous relationship between lower achieved levels of both non-HDL-C and apoB with lower
rates of MACE (HR 0.77 [95% CI 0.65–0.93] per 42 mg/dL difference and HR 0.72 [0.60–0.86]
13
10.1161/CIRCULATIONAHA.116.024604
per 27 mg/dL difference, respectively), with no discernable evidence of attenuation at lower
levels. Furthermore, greater percentage reductions in non-HDL-C and apoB were also both
associated with a lower risk of MACE with no evidence of attenuation of benefit.
Our findings are consistent with epidemiological studies in statin naïve populations which
have suggested a continuous relationship between LDL-C, non-HDL-C and apoB and risk28 with
no apparent attenuation of the relationship as well as the data from the statin trials where a
continuous relationship between on-treatment LDL-C, non-HDL-C and MACE29 have been
observed without evidence of a threshold. Although LDL-C continues to be the main target of
Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017
lipid lowering strategies, levels of non-HDL-C and apoB have been shown to more closely
correlate with risk of MACE, as these parameters more accurately reflect the actu
actual
uall nnumber
umbe
um
berr of
be
circulating atherogenic particles or their cholesterol content, particularly in patients with elevated
TGs that likely have elevations in non-LDL atherogenic particles.30 Our findings showed
materially
mate
terrially sim
te
similar
mil
ilar
a benefit
ben
nef
efit
it w
with
itth reductions
redu
re
ducction
du
ons in each
eac
a h parameter
ac
p rame
pa
mete
me
teer in
i ppart
art du
art
dduee to the
he cco-linearity
o-li
ol near
li
a it
ar
ityy of tthe
h
he
parameters
para
ameters andd the
thee relatively
rellativelly small number
numb
m er off eevents.
ven
ents..
Prior
P
Pr
ior workk bby
y Ro
R
Robinson
binson et al.31, 32 have
h ve ddemonstrated
ha
emonstratedd that the bbenefit
eneffit off LLT
T is also
related to the percentage reduction in LDL-C and non-HDL-C with consistent benefits between
statins. While high-intensity statins have offered us the scope of a 50% reduction in LDL-C, the
addition of a PCSK9 inhibitor to statin therapy offers us a further 50–60% reduction in these
parameters on top of statins, or ~75–80% total reduction from the patient’s untreated baseline
LDL-C level. Consistent with this rationale is the recent 2016 ACC pathway for the addition of
non-statin therapies for those individuals with high absolute risk and high LDL-C levels despite
maximally tolerated statin therapy.14 Our observation that high-risk patients with LDL-C levels
14
10.1161/CIRCULATIONAHA.116.024604
between 120–130 mg/dL, despite maximally tolerated statin, derive benefit from a further 50%
reduction in LDL-C or lower achieved absolute levels lends support to the consensus statement.
As we approach the possibility of achieving lower LDL-C levels consistently with PCSK9
inhibition, concerns have been raised about the potential safety of achieving very low levels of
LDL-C (e.g. <50 mg/dL). The present Phase 3 clinical trial analyses provide further data
regarding the overall safety of alirocumab and lower LDL-C levels not being associated with an
increase in total adverse events (AEs). These findings add to earlier observations from highintensity statin trials which have also failed to demonstrate any relationship adverse events and
Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017
lower achieved LDL-C levels.24, 33, 34
Limitations
The limitations of the present analysis merit consideration. Importantly, although adverse
consequences of very low LDL-C were not identified in these trials, the long-term effects of very
low
ow
w le
levels of LD
LDLLDL-C
L C in
Lindu
induced
duce
du
c d by P
PCSK9
C K9 inhib
CS
inhibitors
bit
itorrs aree un
unkn
unknown.
know
kn
o n. Mo
ow
M
Moreover,
reover
re
err, while
whil
wh
ilee these
il
th
hesse data
data are
derived
deri
riive
v d from rrandomized
ando
an
domi
mized co
controlled
ontrolled trials,
triials, thee aanalyses
naaly
ysees ar
aaree ob
observ
observational
rvaationa
nal in naturee and
andd derive
derived
ed
from a relativ
relatively
i ely smal
small
ll number of events and
d as such we cannot therefore
the
h refore exclude
d the potenti
potential
iall for
fo
confounding as an explanation for the observed associations. We have attempted to take these into
account via statistical adjustment and conducting sensitivity analyses using alternative
methodology which have produced materially similar findings. Furthermore, the 10 studies
pooled differed most notably in prevalence of HeFH, diabetes, age, prior history of MI or stroke
and baseline LDL-C. Studies derived principally from HeFH patients tended to be a decade
younger, have fewer patients with diabetes and higher baseline LDL-C levels. Similarly, in trials
without background statin therapy baseline LDL-C was higher. Therefore, a potential critique of
the analyses of achieved LDL-C and MACE could be that patients that achieve lower LDL-C had
15
10.1161/CIRCULATIONAHA.116.024604
lower baseline LDL-C and lower risk than patients at higher baseline LDL-C levels. However, we
controlled for baseline LDL-C in all analyses and thus we do not believe that baseline LDL-C
levels accounted for our findings. Furthermore, we also assessed percentage reductions in LDL-C
which provided similar quantitative findings. Further reassurance of our methodology arises from
the magnitude of the association observed between a 39 mg/dL difference in LDL-C and MACE,
which is similar to the point estimate derived from the CTT meta-regression line and lies within
its confidence intervals. For the safety analysis, we only looked at overall TEAE rates to
maximize power, and more sophisticated analyses looking at specific TEAEs would be more
Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017
informative in larger trials with longer follow up than the present pooled data.
In summary, these analyses provide further reassurance about the safety and
and
cardiovascular benefit of achieving even further reductions in LDL-C, non-HDL-C and apoB
beyond what was previously achieved with statins alone. The results of the large cardiovascular
outc
outcomes
comes studi
studies
diees w
di
with
ithh PC
PCSK
PCSK9
SK99 inhibitors
SK
inhi
in
hibi
hi
b to
ors such as
a O
ODYSSEY
DY
YSS
SSEY
EY OUT
OUTCOMES
UTCO
UT
COME
M S are
are as
asse
assessing
s ssin
ingg whether
in
whet
wh
e her
et
PCSK
PCSK9
SK9 inhibition
SK
inhibiti
tioon with
ti
withh alirocumab
aliroc
ocumab on top
oc
to of m
maximally
axim
imal
ally
al
ly tolerated
tol
olerrated
d statin
statinn therapy
th
herapy
err
reduces
redu
d cess MACE.
du
MACE
CE. If
these
hese trials
tria
i ls demonstrate
demonstrate effectiveness of further LD
LDL-C
DL-C reducti
reduction,
ion, then guideline committees ma
may
investigate lower targets or a larger reduction in LDL-C from untreated baseline for those at
highest risk of MACE.
Acknowledgments
The following individuals from the study sponsors were involved in critical review of the
manuscript: Carol Hudson, BPharm, and William Sasiela, PhD (Regeneron Pharmaceuticals,
Inc.); L. Veronica Lee, MD, and Michael Howard, MBA (Sanofi). Medical writing support was
16
10.1161/CIRCULATIONAHA.116.024604
provided by Rob Campbell, PhD, Prime Medica, Knutsford, UK, funded by Sanofi and
Regeneron Pharmaceuticals, Inc.
Sources of Funding
This analysis was funded by Sanofi and Regeneron Pharmaceuticals, Inc.
Disclosures
KK Ray: Personal fees (data safety monitoring board) from AbbVie, Inc., consultant
Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017
fees/honoraria from Aegerion, Algorithm, Amgen, AstraZeneca, Boehringer Ingelheim, Cerenis,
Eli Lily and Company, Ionis Pharmaceuticals, Kowa, Medicines Company, MSD,
Novartis,
D, N
ovar
ov
arti
ar
tis,
ti
s,
Pfizer, Regeneron, Reservlogix, Sanofi, and Takeda, and research grants from Kowa, Pfizer, and
Regeneron.
HN
NG
Ginsberg:
insberg: G
Grants
raant
n s an
and
nd pe
ppersonal
rson
rs
onal
on
al ffees
eess from S
Sanofi,
a of
an
ofi, ggrants
rant
ra
ntss fr
nt
ffrom
om
mR
Regeneron,
egen
eg
eneronn, co
cons
consultant
nsultaantt ffor
ns
or
Amgen
Pfizer.
Am
mge
gen and forr Pf
P
izer.
iz
MH Davidson: Consultant/advisory board fees from Merck, Sanofi
Sanofi,
f , Regeneron, Amgen and
Lipimedix.
R Pordy: Employee and stockholder, Regeneron.
L Bessac and P Minini: Employees and stockholders, Sanofi.
RH Eckel: Personal fees from Sanofi/Regeneron, Ionis Pharmaceuticals, UniQure, and Merck.
CP Cannon: Grants from Arisaph, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim,
GlaxoSmithKline, Janssen, Merck and Takeda; consulting fees from Alnylam, Amgen, Arisaph,
Boehringer Ingelheim, Boehringer Ingelheim/Eli Lilly, BMS, GlaxoSmithKline, Kowa, Merck,
Takeda, Lipimedix, Pfizer, Regeneron and Sanofi.
17
10.1161/CIRCULATIONAHA.116.024604
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20
10.1161/CIRCULATIONAHA.116.024604
Table 1. Baseline characteristics
Placebo-controlled trials
Ezetimibe-controlled trials*
Alirocumab
(n=2324)
Placebo
(n=1175)
Alirocumab
(n=864)
Ezetimibe
(n=620)
58.7 (11.6)
58.8 (11.4)
61.9 (9.4)
62.1 (9.5)
1415 (60.9)
712 (60.6)
581 (67.2)
388 (62.6)
2139 (92.0)
1072 (91.2)
745 (86.2)
548 (88.4)
30.1 (5.6)
30.3 (5.6)
30.2 (6.0)
30.0 (5.7)
838 (36.1)
419 (35.7)
40 (4.6)
43 (6.9)
699 (30.1)
355 (30.2)
283 (32.8)
192 (31.0)
1615 (69.5)
834 (71.0)
651 (75.3)
411 (66.3)
1454 (62.6)
766 (65.2)
611 (70.7)
390 (62.9)
199 (8.6)
86 (7.3)
67 (7.8)
42
4 (6.8)
(6.8))
97 (4.2)
56 (4.8)
33 (3.8)
199 (3.1)
(3.
3 1)
453 (19.5)
231 (19.7)
146 (16.9)
118 (19.0)
High
Hi
gh‡
1327 (57.1)
682 ((58.0)
58.0)
430
43 (49
(49.8)
9.8)
265 (42.7)
Moderate
M
oderate§
65
650
50 ((28.0)
28.0
28
.0))
.0
314
31 ((26.7)
26.7
7)
208
208 (24.1)
(24
4.1
. )
1522 (24.5)
(24.5
5)
Low
L
ow‫ۅ‬
344 (14.8)
34
177
17 ((15.1)
15.1))
47
47 (5.
(5.4)
.4)
277 (4.4)
0
0
17
178
78 ((20.6)
20
0.6)
1176
766 (28.4)
3 (0.1)
2 (0.2)
1 (0.1)
0
non-HDL-C
126.8 (46.3)
155.7 (49.6)
126.8 (44.8)
155.5 (48.5)
123.2 (51.5)
154.2 (57.2)
125.5 (56.9)
156.9 (64.1)
apoB
104.3 (29.0)
104.0 (28.5)
101.8 (30.7)
102.5 (32.2)
Age, years, mean (SD)
Sex, male, n (%)
Race, white, n (%)
2
BMI, kg/m , mean (SD)
HeFH, n (%)
Diabetes, n (%)
ASCVD, n (%)†
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CHD
Ischemic
stroke/TIA
PAD
Current smoker, n (%)
Statin intensity, n (%)
No sstatins
tatiins
Missing
Baseline lipids, mg/dL,
mean (SD)
LDL-C
Pooled data of all randomized patients from the 10 trials included in this analysis.
*In combination with statins or not.
†
Patients may be in more than one category.
‡
Atorvastatin 40 to 80 mg, rosuvastatin 20 to 40 mg or simvastatin 80 mg.
§
Atorvastatin 20 to <40 mg, rosuvastatin 10 to <20 mg or simvastatin 40 to <80mg.
‫ۅ‬
Atorvastatin <20 mg, rosuvastatin <10 mg or simvastatin <40 mg.
ASCVD, atherosclerotic cardiovascular disease; BMI, body mass index; CHD, coronary heart
disease, HeFH, heterozygous familial hypercholesterolemia, non-HDL-C, non-high-density
lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; PAD, peripheral artery
disease, SD, standard deviation, TIA, transient ischemic attack.
21
10.1161/CIRCULATIONAHA.116.024604
Table 2. Achieved lipid levels and percentage reductions during treatment and relationship to MACE
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Placebo-controlled trials
Average achieved,
mg/dL
LDL-C
Ezetimibe-controlled trials
Alirocumab
Placebo
Alirocumab
(n=2318)
(n=1174)
(n=864)
56.9 (38.8) 126.5 (43.9) 64.0 (42.4)
MACE versus average achieved level
(pool of all patients from the trials)
Category
N
Hazard ratio (95% CI)
P-value
Ezetimibe
(n=618)
100.9 (50.8) Per 39 mg/dL 4972
0.76 (0.63 to 0.91)
0.0025
difference
128.5 (55.2) Per 42 mg/dL 4974
0.77 (0.65 to 0.93)
0.0056
difference
89.2 (31.0) Per 27 mg/dL 4871
0.72 (0.60 too 0.86)
0 866)
0.
0 000
0.
0.0002
difference
MACE versus % change in
in average
a errag
av
agee level
leve
le
vell
ve
non-HDL-C
82.0 (41.8)
156.0 (47.2)
91.1 (45.6)
apoB
57.1 (29.1)
104.1 (28.1)
64.9 (28.1)
Average
age % change
from baseline
LDL-C
C
-55.4 (23.5)
2.7 (25.7)
-48.1 (23.8)
-18.0 (28.9)
non-HDL-C
HDL-C
-46.9 (20.7)
2.6 (21.1)
-40.3 (20.1)
-16.8 (20.5)
apoB
--45.5
45.5 ((22.8)
45
22.8)
22
2.2 (24.0)
-35.9 (20.9)
-12.0 ((20.1)
20.1)
Per 50%
reduction
Per 50%
reduction
Per 50%
redu
re
duct
du
c ionn
reduction
4972
0.71 (0.57 to 0.89)
0.003
0.0030
4974
0.71 (0.52 to 0.97)
0.032
0.0323
48711
0.68 (0.54 to 0.85)
0.000
0.0008
Lipidss aree m
mean
ean (SD). Ha
Haza
Hazard
ardd rat
ratio,
atio
o, 95%
% cconfidence
onfiden
nce in
interval
nteerval (C
(CI)
CI) an
and
nd P-va
P-value
vallue determined
va
deteerm
mined
ed from
mam
multivariate
ultivariate C
Cox
ox m
model.
odel.
Multivariate
variate
te aanalysis
naly
na
lysi
ly
siss ad
si
adj
adjusted
justed
d onn bbaseline
aselinee ccharacteristics
hara
ha
raact
cter
eristiics ((age,
er
age,
ag
e, ssex,
ex
x, ddiabetes,
iaabet
ettes,
ess, pr
prio
prior
iorr hi
io
hist
history
storyy of
st
o M
MI/stroke,
I/sstroke
ke, ba
ke
base
baseline
seli
se
line
li
ne LDL
LDL-C
DL-C and smoking
sm
mok
status).
). Average LDL
LDL-C
DL-C during the treatment peri
period
iod determinedd from
f om the area under the
fr
th curve (using trapezoidal m
method),
ethod),
t
taki
taking
ing into
account
unt all LDL
LDL-C
C values up to end of treatment period or occurrence of MACE
MACE, whichever comes first
first. For patients with no post
postbaseline LDL-C, LDL-C at baseline was used.
Note: 2 patients with missing baseline LDL-C and 3 with missing baseline apoB were excluded from the multivariate analysis.
Non-HDL-C, non-high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; MACE major adverse
cardiovascular events.
22
10.1161/CIRCULATIONAHA.116.024604
Figure Legends
Figure 1. Distribution of achieved levels of LDL-C (A), non-HDL-C (B) and apoB (C) during
treatment, stratified by control group.For patients with no post-baseline lipid measurement,
baseline values were used. Non-HDL-C, non-high-density lipoprotein cholesterol; LDL-C, lowdensity lipoprotein cholesterol.
Figure 2. Distribution of the percentage reductions in LDL-C (A), non-HDL-C (B) and apoB (C)
Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017
from baseline during treatment stratified by control group. For patients with no post-baseline
ipid measurement, baseline values were used. Two patients with missing baseline
ne L
DL-C
DL
-C and
and
lipid
LDL-C
hree patients with missing baseline apoB were excluded from the analysis.Non-HDL-C, nonthree
high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol.
Figu
gure
gu
r 3. Relationship
Relaatio
i ns
nshipp between
betw
ween on-trea
atment llipids
ipids
ds aand
nd rreductions
educ
ed
uctionns in llipid
ip
pid
d levels with
w th
wi
h MACE.
MACE.
E.
Figure
on-treatment
M
CE
E rate by
b achieved levels of LDL-C,
LDLL C, non-HDL-C, and
d
Panels A
A,, B and C show adjusted MA
MACE
apoB, respectively, during follow up. Corresponding results for percent reductions are shown in
panels D, E and F, respectively. Multivariate analysis adjusted on baseline characteristics (age,
sex, diabetes, prior history of MI/stroke, baseline LDL-C and smoking status). Non-HDL-C,
non-high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; MACE
major adverse cardiovascular events.
23
Figure 1A
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Figure 1B
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Figure 1C
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Figure 2A
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Figure 2B
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Figure 2C
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Figure 3A
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Figure 3B
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Figure 3C
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Figure 3D
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Figure 3E
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Figure 3F
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Reductions in Atherogenic Lipids and Major Cardiovascular Events: A Pooled Analysis of 10
ODYSSEY Trials Comparing Alirocumab to Control
Kausik K. Ray, Henry N. Ginsberg, Michael H. Davidson, Robert Pordy, Laurence Bessac, Pascal
Minini, Robert H. Eckel and Christopher P. Cannon
Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017
Circulation. published online October 24, 2016;
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 2016 American Heart Association, Inc. All rights reserved.
Print ISSN: 0009-7322. Online ISSN: 1524-4539
The online version of this article, along with updated information and services, is located on the
World Wide Web at:
http://circ.ahajournals.org/content/early/2016/10/21/CIRCULATIONAHA.116.024604
Free via Open Access
Data Supplement (unedited) at:
http://circ.ahajournals.org/content/suppl/2016/10/24/CIRCULATIONAHA.116.024604.DC1
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Dr. Carolyn Lam:
Welcome to Circulation on the Run, your weekly podcast summary and
backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, associate
editor from the National Heart Center and Duke National University of
Singapore. Today we will be discussing the pooled analysis results of the 10
ODYSSEY Trials with important implications for the reduction of lipids in major
cardiovascular events. But first, here's your summary of this week's journal.
The first paper provides experimental data on vascular disease that brings into
focus the critical roles of transcription factors such as GATA2 in the
maintenance of endothelial cell function, as well as the role of selected
microRNAs as a novel player of vascular regulation. In this study by first author
Dr. Hartman, corresponding author Dr. Thum from Hanover Medical School, and
colleagues, authors used GATA2 gain and loss of function experiments in human
umbilical vein endothelial cells to identify a key role of GATA2 as a master
regulator of multiple endothelial functions, and this via microRNA-dependent
mechanisms.
Global microRNA screening identified several GATA2-regulated microRNAs,
including miR-126 and miR-221. GATA2 deficiency led to vascular abnormalities,
whereas supplementation with miR-126 normalized vascular function. In a
mouse model of carotid injury, GATA2 was reduced and systemic
supplementation of miR-126-coupled nanoparticles enhanced miR-126
availability in the carotid artery and improved reendothelialization of injured
carotid arteries in vivo.
In summary, GATA2-mediated regulation of miR-126 and miR-221 has an
important impact on endothelial biology. Thus, modulation of GATA2 and its
targets miR-126 and miR-221 represents a promising therapeutic strategy for
the treatment of vascular diseases.
The next study is the first to show that current smokers from the general
population have lower levels of circulating cardiac troponin I, a seemingly
paradoxical observation given the known detrimental cardiovascular impact of
cigarette smoking.
First author Dr. Lyngbakken, corresponding author Dr. Omland, and colleagues
from the University of Oslo used data from the large population-based HUNT
study, in which cardiac troponin I was measured in 3,824 never smokers, 2,341
former smokers, and 2,550 current smokers. Current smokers had significantly
lower levels of cardiac troponin I than never smokers and former smokers, an
association that remains significant even after adjustment for potential
confounders.
The authors also found an association between increasing concentrations of
troponin I and clinical endpoints, namely acute myocardial infarction, heart
COTR134_24
Page 2 of 8
failure, and cardiovascular death in the total cohort. However, this association
was attenuated in current smokers and was significantly weaker than in never
or former smokers with a p for interaction of 0.003. The prognostic accuracy of
troponin I as assessed by C-statistics was lower in current smokers than in never
smokers. Troponin I provided no incremental prognostic information to the
Framingham Cardiovascular Disease risk score in the current smokers.
Together, these results suggest that mechanistic pathways other than those
involving subclinical myocardial injury may be responsible for the cardiovascular
risk associated with current smoking. Future studies are needed to determine
whether a lower cardiac troponin I threshold should be considered for exclusion
of myocardial infarction in smokers or whether prognostic tools other than
measurement of cardiac troponins should be utilized when evaluating risk of
future events in current smokers.
The next study contributes to our understanding of cardiomyocyte signaling in
response to ischemic injury. In the study by first author Dr. [Wool 00:05:04],
corresponding author Dr. [Ju 00:05:04] from Tongji University School of
Medicine in Shanghai, and colleagues, authors sought to understand the role of
low-density lipoprotein receptor-related proteins 5 and 6 as well as beta-catenin
signaling in the heart. They did this using conditional cardiomyocyte-specific
knockout mice who had surgically induced myocardial infarction. They found
that deletion of lipoprotein receptor-related proteins 5 and 6 promoted cardiac
ischemic insults. Conversely, deficiency of beta-catenin, a downstream target,
was beneficial in ischemic injury. Interestingly, although both insulin-like growth
factor-binding protein 4 and Dickkopf-related protein 1 are secreted betacatenin pathway inhibitors, the former protected the ischemic heart by
inhibiting beta-catenin, whereas the latter enhanced the injury response mainly
through inducing lipoprotein-related protein 5 and 6 endocytosis and
degradation.
These findings really add to our understanding of the beta-catenin signaling
pathway in ischemic injury and suggests that new therapeutic strategies in
ischemic heart disease may involve fine-tuning these signaling pathways.
The next paper from the International Consortium of Vascular Registries is the
first study allowing an assessment of variations in repair of abdominal aortic
aneurysms in 11 countries over 3 continents represented by the Society of
Vascular Surgery and European Society for Vascular Surgery. Dr. Beck from
University of Alabama-Birmingham School of Medicine, and colleagues, looked
at registry data for open and endovascular abdominal aortic aneurysm repair
during 2010 to 2013, collected from 11 countries. These were Australia,
Denmark, Hungary, Iceland, New Zealand, Norway, Sweden, Finland,
Switzerland, Germany, and the United States.
Among more than 51,000 patients, utilization of endovascular aortic repair for
intact aneurysms varied from 28% in Hungary to 79% in the United States, and
COTR134_24
Page 3 of 8
for ruptured aneurysms from 5% in Denmark to 52% in the United States. In
addition to the between-country variations, significant variations were present
between centers within each country in terms of endovascular aortic repair use
and rate of small aneurysm repair. Countries that more frequently treated small
aneurysms tended to use the endovascular approach more frequently.
Octogenarians made up 23% of all patients, with a range of 12% in Hungary to
29% in Australia. In countries with a fee for service reimbursement systems,
such as Australia, Germany, Switzerland, and the United States, the proportion
of small aneurysms and octogenarians undergoing intact aneurysm repair was
higher compared to countries with a population-based reimbursement model.
In general, center-level variation within countries in the management of
aneurysms was as important as variation between counties. Hence, this study
shows that despite homogeneous guidelines from professional societies, there
is significant variation in the management of abdominal aortic aneurysms, most
notably for intact aneurysm diameter at repair, utilization of endovascular
approaches, and the treatment of elderly patients. These findings suggest that
there is an opportunity for further international harmonization of treatment
algorithms for abdominal aortic aneurysms. This is discussed in an
accompanying editorial entitled, Vascular Surgeons Leading the Way in Global
Quality Improvement, by Dr. Fairman.
The final paper from Dr. Gibson at Beth Israel Deaconess Medical Center and
Harvard Medical School and colleagues, presents the results of the apoAI event
reducing in ischemic syndromes I, or AEGIS-I, trial, which was a multicenter,
randomized, doubleblind, placebo-controlled dose-ranging phase 2b trial of
CSL112, which is an infusible, plasma-derived apoAI that has been studied in
normal subjects and those with stable coronary artery disease, but now studied
in the current study in patients with acute myocardial infarction.
The trial showed that among patients with acute myocardial infarction, four
weekly infusions of a reconstituted, infusible, human apoAI, CSL112, was
associated with a dose-dependent elevation of circulating apoAI and cholesterol
efflux capacity without adverse hepatic or renal outcomes. The potential benefit
of CSL112 to reduce major adverse cardiovascular events will need to be
assessed in an adequately powered phase 3 trial.
Now for our future discussion. Today I am delighted to have with us Dr. Kausik
Ray from Imperial College London, who's the first and corresponding author of a
new paper regarding the pooled analysis of the 10 ODYSSEY Trials. To discuss it
with us is Dr. Carol Watson, associate editor from UCLA. Kausik, just let me start
by congratulating you on this paper. I believe this is the first data that allows us
to look under the 50 mg/dL mark of LDL and really ask if the LDL MACE
relationship extends below this level.
Dr. Kausik Ray:
COTR134_24
Yes, the reason for looking at this is that the IMPROVE-IT trial really looked at
people down to an average LDL cholesterol of about 54, and with the new
Page 4 of 8
PCSK9 inhibitors, which instead of giving you a 20% further reduction LDL, they
give you the opportunity for a further 50 to 60% reduction. We actually get the
chance to get people down to levels like 25 mg/dL, and the question is, does the
benefit continue at that level?
We did a pooled analysis of 10 of the ODYSSEY Trials, really in some ways to try
and help predict what you might see in ODYSSEY outcomes, what you might see
in the [Fuliay 00:12:00] trial, and to also manage expectations as well, because
there's probably been a lot of hype around the two New England Journal papers
about 50, 60% reductions of all potential reductions based on small numbers of
events. So the question is, if you reduce LDL by 39 mg/dL, how might that
reduce your risk, and is the relationship continuous? So those were the aims.
Dr. Carolyn Lam:
That's great, and maybe could you give us an idea of the number of patients you
are looking at and the number of events?
Dr. Kausik Ray:
Yeah. In the 10 pool studies, we had just under 5,000 individuals, and we had
just about 6,700 person years' worth of followup. In total, we had 104 first
MACE events. To put this into context, it's about one third of the number of
events that the first [framing 00:12:53] of analysis had. It's an observation
analysis rather than randomized trial data, so you got to bear that in mind with
the usual caveats that go with observational data. But the same endpoints that
were adjudicated, this is [inaudible 00:13:10] heart disease death, non-fatal MI,
ischemic stroke, and unstable angina requiring hospitalization. This is the same
endpoint that is in the ODYSSEY Outcomes Trial, so it's interesting in that regard.
Dr. Carolyn Lam:
Yeah, it sure is. So what's the bottom line? What did you find?
Dr. Kausik Ray:
What we found was that there was a continuous relationship all the way down
to LDL cholesterol levels of about 25 mg/dL, that every 39 mg/dL lower on
treatment LDL, your risk went down by about 24%. If you looked at [apo-like
00:13:48] approaching be on non-HDL cholesterol, again, you found the same
continuous relationship with a similar point estimate for a similar standardized
difference in LDL cholesterol. We also looked at many of the guidelines, talk
about percentage reduction. We actually looked at percentage reductions. If
you start with a baseline LDL of X and you achieve a 50% further reduction in
LDL, how much further benefit does that give you? A 50% further reduction
gave you a 29% further lower risk of MACE. So we didn't find any threshold or
limit all the way down to LDLs of about 25.
Dr. Carolyn Lam:
That's really a key, novel finding that you contributed, so congratulations once
again. I suppose the question will always be, you're talking about relative risk
reductions here. At such low levels, can you give us an idea of the absolute risk
reductions?
Dr. Kausik Ray:
Yes. You've got to remember that the relative risk reductions are what you can
apply to population differences. If you pick a high-risk patient population, you
COTR134_24
Page 5 of 8
would expect to see a much bigger absolute risk reduction than maybe this
study or another study. Similarly, if you pick a low-risk group, you are going to
see a much smaller absolute benefit. I always try to advise a little bit of caution
that if you basically look at the range ... If you start with let's say an LDL of 150
and you go down to let's say an LDL of 25, you are talking about a 1.25%
absolute risk reduction. Remember, these patients are possibly going to be a
slightly lower risk than the ones that are recruited into the ODYSSEY Outcomes
and into the [Fuliay 00:15:46] trial, for example.
Dr. Carolyn Lam:
I think you mentioned what I was going to just ask you about. This is
observational. You had 104 events, and I suppose another limitation might be
that your followup was two years at max, if I'm not wrong? What do you say
about that, and are there plans for future analyses?
Dr. Kausik Ray:
Within the context of these studies, I think that the whole of this data will
eventually become dwarfed by what we see with the big CDOTs, because you've
got 18, 27,000 people, 3 years' worth of exposure and followups, so you are
going to have many, many more events. That is a limitation, but I think what is
interesting is that we know that the baseline LDL cholesterol level is around
about 90 mg/dL. We don't actually know what the actual baseline ... because
the baseline [characters 00:16:43] haven't been published for ODYSSEY
Outcomes, but the [Fuliays 00:16:46] around about 89. What it tells you is what
the point estimate is likely to be. It's likely to be in the 24 to 32% ballpark
because that's what your baseline LDL is and that's what we'd predict in the
regression lines that we observed here.
I think that we're not going to get many more events in these studies because
largely the randomized period of followup is now over. Many of these people
are now into open labels, extensions for safety, so we won't get many more
events from this. In terms of, I think, the way people should maybe look at this
is possibly as a taster for what's to come in the next 18 months or so. I think for
the time being it answers two questions. Is lower likely to be better? And it is. I
think the other question it tells is how might you get people down to LDLs below
50?
One of the important things was that if you were just on statins, in this
population, if you were recruited on the basis of a high baseline LDL, you got no
additional people down to LDLs below 50. You got under 10% with add-on
[inaudible 00:18:05], but you got around about 50% when you used the PCSK9
inhibitor as an add-on to existing therapy. It tells you about how to get to such
low levels as well. I think that's the other key thing that it actually gives you.
We did an analysis of safety [inaudible 00:18:23], and I think that's really
important. Once you see the efficacy, or if you see the MACE events continue to
go down ... If you looked at treatment-emergent adverse events ... and I
completely take the fact that it's every side effect reported altogether, which
may or may not be linked to LDL levels specifically, but when we did that, the
COTR134_24
Page 6 of 8
relationship actually was just a horizontal line, so there was no relationship with
percentage reduction or on treatment LDL, so it gave us a nice idea of both
safety and efficacy that we might experience in the big outcome studies.
Dr. Carolyn Lam:
All right. Obviously the big outcome studies are going to be game changers, and
I'd really love to invite [Carol Scotts 00:19:09] here, because there's a whole lot
of other things that need to be considered if this becomes the case, isn't it?
Carol, I really appreciated that you invited an editorial, and the editorial is by
Neil Stone who entitles it, Looking Beyond Statins: Will the Dollars Make Cents?
Please tell us about the discussions about this paper that occurred.
Dr. Carol :
I would again like to congratulate Dr. Ray on a fantastic paper, and I would like
to reiterate exactly what he said. I think it really does give us some comfort
about this class of medication and its relative safety. I think that's very
important, because I can't tell you how many patients I get and how many
referring physicians I get who worry when their patients come back with LDLs of
20 or below. I think that gave us some comfort, and I do also think it was very
important to show that this would fall along the same regression line that
statins perhaps would fall.
As with all the caveats that Dr. Ray said, I agree with all of them, but I do say this
is a tasty little taster, and I appreciate and congratulate you for publishing this.
The editorial by Dr. Neil Stone was quite interesting. As you said, he subtitled it,
Will the Dollars Make Cents? C E N T S or S E N S E, sort of a play on words there.
Will the relative benefits that we can achieve with this class of medications
make sense for the cost of these drugs?
That's obviously a very separate issue from what was discussed in the
manuscript, but it's something to think about. We understand that there are
additional patients that will be helped if they can get their LDL down, and we
hope that that will translate into the outcomes. Again, just as Dr. Ray
mentioned, we will have to wait for the cardiovascular outcomes trials to be
completed. When they are, if they do show the benefits that we hope, will their
price point make them accessible to enough patients for this to be a widely
applied, utilized therapy? Or will they not? That's part of what was discussed in
Dr. Stone's editorial.
Dr. Kausik Ray:
When we were writing the manuscript and stuff like that, and we were doing
this and everybody's like, "Oh, wow, look at the graphs." I said, "Look, we need
to balance all of these bits and reassure ... We've got an opportunity." So I
suggested them giving those additional analyses, and you saw how big the
online supplement was. There was a ton of work that we put into this, and to
format it into a concise ... I really want to just thank the editorial board for
giving us the chance and actually being able to help us and work with us on this,
because it's really important. I hope people look at all of those things because it
will help people also that question the LDL. They all talk about the hypothesis
COTR134_24
Page 7 of 8
and the safety of really low LDLs, and people come off statins as a result. I think
this will help.
Dr. Carolyn Lam:
COTR134_24
You're listening to Circulation on the Run. Thank you so much for being with us,
and don't forget to tune in next week.
Page 8 of 8
Supplemental Material
1
Definition of unstable angina used in the ODYSSEY studies
A diagnosis of an unstable angina (new ACS event without elevation in cardiac
biomarkers) that meets the primary endpoint requires the following:
 Admission to hospital or emergency room (until at least next calendar day) with
symptoms presumed to be caused by myocardial ischemia with an accelerating
tempo in the prior 48 hours. and/or prolonged (at least 20 minutes) rest chest
discomfort
AND
 New high-risk ECG findings consistent with ischemia (or presumed new if no prior
ECG available), as defined below:
– New or presumed new ST depression >0.5mm in 2 contiguous leads or T wave
inversion >1mm in leads with prominent R wave or R/S >1 in 2 contiguous
leads
– New or presumed new ST elevation at the J point in >2 contiguous leads
>0.2mV in V2 or V3 in men or >0.15 mV in women in V2 or V3 or >0.1mV in
other leads
– LBBB (new or presumed new)
AND
 Definite contemporary* evidence of angiographically significant coronary disease
as demonstrated by:
2
– Need for coronary revascularization procedure (PCI or CABG) excluding those
performed to treat only restenosis lesion(s) at previous PCI site(s)
OR
– Angiographic evidence of at least 1 significant (> 70%) epicardial coronary
stenosis not due to restenosis at previous PCI site.
*The coronary revascularization procedure or the diagnostic angiography must have
been performed during the hospitalization for that event.
3
eTable 1. Key inclusion and exclusion criteria for trials included in this
analysis
Study
Inclusion criteria
LDL-C exclusion
criteria
FH I, FH II1
Patients with HeFH not adequately
controlled with a maximally-tolerated
stable daily dose of statin* for ≥4
weeks prior to screening ± other LLT
LDL-C <70 mg/dL (for
patients with
documented clinical
ASCVD) or LDL-C
<100 mg/dL (for
patients with no
documented ASCVD)
HIGH FH2
As above
LDL-C <160 mg/dL.
COMBO I,3 COMBO II4
Patients with hypercholesterolemia
(non-FH), not adequately controlled
with a maximally-tolerated stable
daily dose of statin* for ≥4 weeks
prior to screening (± other LLT in
COMBO I; no other LLT allowed in
COMBO II)
LDL-C <70 mg/dL (for
patients with
documented clinical
ASCVD) or LDL-C
<100 mg/dL (for
patients with no
documented ASCVD)
LONG TERM5
Included both HeFH and non-FH
patients, otherwise inclusion criteria
as for the FH studies above
LDL-C <70 mg/dL.
OPTIONS I,6 OPTIONS II7
Patients with HeFH or non-FH,
receiving either atorvastatin 20 or 40
mg (OPTIONS I) or rosuvastatin 10
or 20 mg (OPTIONS II) ± other LLT
(apart from ezetimibe as it was used
as a comparator)
LDL-C <70 mg/dL (for
patients with
documented clinical
ASCVD) or LDL-C
<100 mg/dL (for
patients with no
documented ASCVD)
ALTERNATIVE8
Patients with HeFH or non-FH and
documented statin intolerance† and
moderate to very high
cardiovascular risk;‡ patients were
not receiving a statin but other LLT
(apart from ezetimibe) were allowed
LDL-C <70 mg/dL for
very-high risk, LDL-C
<100 mg/dL for
moderate or high risk
MONO9
Subjects with 10-year risk of fatal CV
events of ≥1% and 5% based on the
European Systematic Coronary Risk
10
Evaluation (SCORE) not receiving
statin or other LLT (history of CHD
or HeFH was an exclusion criterion
for this study)
LDL-C <70 mg/dL or
>190 mg/dL
Exclusion criteria common to
all studies

Age <18 years

Use of fibrates, other than fenofibrate
4

Fasting serum triglycerides >400 mg/dL

Estimated glomerular filtration rate (eGFR) <60
mL/min/1.73 m2
Clinicaltrials.gov identifiers: LONG TERM, NCT01507831; FH I NCT01623115; FH II, NCT01709500;
HIGH FH, NCT01617655; COMBO I, NCT01644175; COMBO II, NCT01644188; MONO,
NCT01644474; OPTIONS I, NCT01730040; OPTIONS II, NCT01730053; ALTERNATIVE,
NCT01709513.
ASCVD, atherosclerotic cardiovascular disease; LLT, lipid-lowering therapy.
*
Maximally tolerated statin dose = the highest tolerable registered dose of daily statin currently
administered to the patient, i.e. rosuvastatin 20 or 40 mg, atorvastatin 40 or 80 mg; or simvastatin 80
mg. Lower doses could be used e.g. in the case of intolerance or local practice according to the
investigator’s judgment.
†
Inability to tolerate 2 or more statins because of muscle-related symptoms.
‡
Moderate risk = 10-year risk of fatal CV events of ≥1% and 5% (SCORE); high risk = SCORE ≥5%;
eGFR 30 to <60 mL/min/1.73 m2; type 1 or 2 diabetes mellitus without target organ damage; or HeFH;
very-high risk = CHD, ischemic stroke, peripheral artery disease, transient ischemic attack, abdominal
aortic aneurysm, or carotid artery occlusion >50% without symptoms; carotid endarterectomy or
carotid artery stent procedure; renal artery stenosis or renal artery stent procedure; or type 1 or type 2
diabetes mellitus with target organ damage.
References
1.
2.
3.
Kastelein JJ, Ginsberg HN, Langslet G, Hovingh GK, Ceska R, Dufour R, Blom D, Civeira F,
Krempf M, Lorenzato C, Zhao J, Pordy R, Baccara-Dinet MT, Gipe D, Geiger MJ, Farnier M.
ODYSSEY FH I and FH II: 78 week results with alirocumab treatment in 735 patients with
heterozygous familial hypercholesterolaemia. Eur Heart J. 2015;36:2996-3003.
Ginsberg HN, Rader DJ, Raal FJ, Guyton JR, Baccara-Dinet MT, Lorenzato C, Pordy R,
Stroes E. Efficacy and Safety of Alirocumab in Patients with Heterozygous Familial
Hypercholesterolemia and LDL-C of 160 mg/dl or Higher. Cardiovasc Drugs Ther.
2016;30:473-483.
Kereiakes DJ, Robinson JG, Cannon CP, Lorenzato C, Pordy R, Chaudhari U, Colhoun HM.
Efficacy and safety of the PCSK9 inhibitor alirocumab among high cardiovascular risk patients
on maximally tolerated statin therapy: the ODYSSEY COMBO I study. Am Heart J.
2015;169:906-915.e913.
5
4.
5.
6.
7.
8.
9.
10.
Cannon CP, Cariou B, Blom D, McKenney JM, Lorenzato C, Pordy R, Chaudhari U, Colhoun
HM. Efficacy and safety of alirocumab in high cardiovascular risk patients with inadequately
controlled hypercholesterolaemia on maximally tolerated doses of statins: the ODYSSEY
COMBO II randomized controlled trial. Eur Heart J. 2015;36:1186-1194.
Robinson JG, Farnier M, Krempf M, Bergeron J, Luc G, Averna M, Stroes ES, Langslet G,
Raal FJ, El Shahawy M, Koren MJ, Lepor NE, Lorenzato C, Pordy R, Chaudhari U, Kastelein
JJ. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J
Med. 2015;372:1489-1499.
Bays H, Gaudet D, Weiss R, Ruiz JL, Watts GF, Gouni-Berthold I, Robinson J, Zhao J,
Hanotin C, Donahue S. Alirocumab as add-on to atorvastatin versus other lipid treatment
strategies: ODYSSEY OPTIONS I randomized trial. J Clin Endocrinol Metab. 2015:31403148.
Farnier M, Jones P, Severance R, Averna M, Steinhagen-Thiessen E, Colhoun HM, Du Y,
Hanotin C, Donahue S. Efficacy and safety of adding alirocumab to rosuvastatin versus
adding ezetimibe or doubling the rosuvastatin dose in high cardiovascular-risk patients: the
ODYSSEY OPTIONS II randomized trial. Atherosclerosis. 2016;244:138-146.
Moriarty PM, Thompson PD, Cannon CP, Guyton JR, Bergeron J, Zieve FJ, Bruckert E,
Jacobson TA, Kopecky SL, Baccara-Dinet MT, Du Y, Pordy R, Gipe DA. Efficacy and safety
of alirocumab versus ezetimibe in statin-intolerant patients, with a statin-re-challenge arm:
The ODYSSEY ALTERNATIVE randomized trial. J Clin Lipidol. 2015;9:758-769.
Roth EM, Taskinen MR, Ginsberg HN, Kastelein JJ, Colhoun HM, Robinson JG, Merlet L,
Pordy R, Baccara-Dinet MT. Monotherapy with the PCSK9 inhibitor alirocumab versus
ezetimibe in patients with hypercholesterolemia: results of a 24 week, double-blind,
randomized Phase 3 trial. Int J Cardiol. 2014;176:55-61.
Reiner Z, Catapano AL, De Backer G, Graham I, Taskinen MR, Wiklund O, Agewall S, Alegria
E, Chapman MJ, Durrington P, Erdine S, Halcox J, Hobbs R, Kjekshus J, Filardi PP, Riccardi
G, Storey RF, Wood D. ESC/EAS Guidelines for the management of dyslipidaemias: the Task
Force for the management of dyslipidaemias of the European Society of Cardiology (ESC)
and the European Atherosclerosis Society (EAS). Eur Heart J. 2011;32:1769-1818.
6
eFigurre 1. Overv
view of stu
udies included in th
his analys
sis
ALI, alirocumab; CV, cardiovascular
c
r; EZE, ezetimibe; HeFH, he
eterozygous fa
amilial hyperch
holesterolemia
a; LLT,
ering therapy; PBO, placebo
o; Q2W, everyy 2 weeks.
lipid-lowe
ALI 75/15
50 indicates sttudies using a dose titration
n strategy, whe
ereby ALI 75 mg
m Q2W was increased to 150
1 mg
Q2W at Week
W
12 if LDL-C at Week 8 was ≥70 mg
g/dL (or, in OP
PTIONS I, OPT
TIONS II, and ALTERNATIV
VE, ≥70
or 100 mg/dL, dependiing on CV riskk). ALI 150 ind
dicates studiess where patien
nts received 15
50 mg Q2W frrom the
n all but two sttudies, patients also receive
ed background
d statin therapy ± other LLT (EZE was nott allowed
outset. In
as background LLT in EZE-controlle
ed studies). Th
he statin was at
a maximally to
olerated dose in 6 studies (8
85% of all
es were performed without background statin
patients in the 10 trialss). Under “additional populattions”, 2 studie
NATIVE, in pattients with doccumented stattin intolerance
e, and MONO, a monotherapy study perfo
ormed
(ALTERN
without background
b
LL
LT). OPTIONS
S studies included patients at
a high CV riskk receiving mo
oderate to high
h doses
of potent statins.
*No other non-statin LL
LT allowed in COMBO II. †Concomitant
C
statin and dose
es were atorva
astatin 20 or 40
4 mg in
S I and rosuva
astatin 10 or 20
2 mg in OPTIONS II.
OPTIONS
7
eTable 2. Baseline characteristics in Phase 3 ODYSSEY trials (randomized
population)
Study
Group
Age,
years,
mean
(SD)
Male,
n (%)
Race,
white
n (%)
BMI,
kg/m2,
mean
(SD)
HeFH, n
(%)
ALI 150
(n = 1553)
60.4
(10.4)
983
(63.3)
1,441
(92.8)
30.2
(5.7)
276
(17.8)
545 (35.1)
1,187
(76.4)
PBO
(n = 788)
60.6
(10.4)
474
(60.2)
730
(92.6)
30.5
(5.5)
139
(17.6)
269 (34.1)
612
(77.7)
ALI 150
(n = 72)
49.8
(14.2)
35
(48.6)
64 (88.9)
28.8
(5.2)
72 (100)
9 (12.5)
32 (44.4)
PBO
(n = 35)
52.1
(11.2)
22
(62.9)
30 (85.7)
28.9
(4.2)
35 (100)
6 (17.1)
22 (62.9)
ALI 75/150
(n = 209)
63.0
(9.5)
131
(62.7)
170
(81.3)
32.6
(6.3)
0
94 (45.0)
179
(85.6)
PBO
(n = 107)
63.0
(8.8)
77
(72.0)
88 (82.2)
32.0
(7.1)
0
42 (39.3)
87 (81.3)
ALI 75/150
(n = 323)
52.1
(12.9)
180
(55.7)
300
(92.9)
29.0
(4.6)
323
(100)
32 (9.9)
154
(47.7)
PBO
(n = 163)
51.7
(12.3)
94
(57.7)
144
(88.3)
30.0
(5.4)
163
(100)
25 (15.3)
81 (49.7)
ALI 75/150
(n = 167)
53.2
(12.9)
86
(51.5)
164
(98.2)
28.6
(4.6)
167
(100)
7 (4.2)
63 (37.7)
PBO
(n = 82)
53.2
(12.5)
45
(54.9)
80 (97.6)
27.7
(4.7)
82 (100)
3 (3.7)
32 (39.0)
ALI 75/150
(n = 479)
61.7
(9.4)
360
(75.2)
404
(84.3)
30.0
(5.4)
0
145 (30.3)
461
(96.2)
EZE
(n = 241)
61.3
(9.2)
170
(70.5)
206
(85.5)
30.3
(5.1)
0
76 (31.5)
224
(92.9)
ALI 75/150
(n = 104)
63.1
(10.2)
64
(61.5)
91
(87.5)
31.2
(6.9)
12
(11.5)
58
(55.8)
59
(56.7)
EZE
(n = 102)
64.8
(9.6)
67
(65.7)
91
(89.2)
31.2
(5.9)
4
(3.9)
45
(44.1)
66
(64.7)
ALI 75/150
(n = 103)
59.9
(10.2)
59
(57.3)
87
(84.5)
31.0
(6.9)
14
(13.6)
37
(35.9)
60
(58.3)
Type 2
diabetes,
n (%)
ASCVD,
n (%)
Placebocontrolled
LONG TERM
(MTD statin)
HIGH FH
(MTD statin)
COMBO I
(MTD statin)
FH I
(MTD statin)
FH II
(MTD statin)
Ezetimibecontrolled
COMBO II
(MTD statin)
OPTIONS I
(atorvastatin 2040 mg)
OPTIONS II
(rosuvastatin 1020 mg)
8
Study
ALTERNATIVE
(no statin)
MONO
(no statin)
Male,
n (%)
Race,
white
n (%)
BMI,
kg/m2,
mean
(SD)
HeFH, n
(%)
Type 2
diabetes,
n (%)
ASCVD,
n (%)
61.8
(10.3)
57
(56.4)
88
(87.1)
31.1
(6.4)
14
(13.9)
44
(43.1)
63
(61.8)
ALI 75/150
(n = 126)
64.1
(9.0)
70
(55.6)
117
(92.9)
29.6
(6.6)
14 (11.1)
36 (28.6)
71 (56.3)
EZE
(n = 125)
62.8
(10.1)
67
(53.6)
116
(92.8)
28.4
(4.9)
25 (20.0)
24 (19.2)
58 (46.4)
ALI 75/150
(n = 52)
60.8
(4.6)
28
(53.8)
46 (88.5)
30.1
(5.9)
0
3 ( 5.8)
0
EZE
(n = 51)
59.6
(5.3)
27
(52.9)
47 (92.2)
28.4
(6.7)
0
1 ( 2.0)
0
Group
Age,
years,
mean
(SD)
EZE
(n = 101)
ALI = alirocumab; ASCVD = atherosclerotic cardiovascular disease; atorva = stoarvastatin; BMI = body mass
index; EZE = ezetimibe; LDL-C = low-density lipoprotein cholesterol; MTD, maximally tolerated dose of statin;
PBO = placebo; Q2W = every 2 weeks: rosuva = rosuvastatin; SD = standard deviation.
9
eTable 3. Baseline lipid values in individual studies (randomized population)
Trial
LONG TERM
HIGH FH
COMBO I
FH I
FH II
COMBO II
OPTIONS I
OPTIONS II
ALTERNATIVE
MONO
ALI
PBO
ALI
PBO
ALI
PBO
ALI
PBO
ALI
PBO
ALI
EZE
ALI
EZE
ALI
EZE
ALI
EZE
ALI
EZE
n=1550
n=788
n=72
n=35
n=207
n=107
n=322
n=163
n=167
n=81
n=479
n=241
n=104
n=101
n=103
n=101
n=126
n=124
n=52
n=51
122.7
121.9
196.3
201.0
100.2
106.0
144.8
144.4
134.6
134.0
108.6
104.6
109.6
99.7
113.1
111.1
191.1
193.5
141.1
138.3
(42.6)
(41.4)
(57.9)
(43.4)
(29.5)
(35.3)
(51.1)
(46.8)
(41.1)
(41.4)
(36.5)
(34.1)
(36.4)
(29.2)
(30.0)
(45.7)
(72.7)
(70.9)
(27.1)
(24.5)
Group
LDL-C
non-
152.6
152.0
223.9
231.5
130.0
133.4
170.3
169.6
159.0
157.5
139.1
136.8
137.3
126.7
142.1
140.8
230.0
229.8
167.4
164.0
HDL-C
(46.6)
(45.8)
(58.8)
(47.6)
(34.0)
(39.8)
(54.6)
(50.6)
(44.8)
(43.7)
(40.4)
(40.4)
(39.3)
(35.1)
(37.1)
(49.8)
(80.4)
(82.7)
(0.3)
(29.7)
101.9
101.4
138.2
146.6
90.8
91.4
114.4
113.4
107.9
107.7
94.3
93.5
93.1
86.5
95.8
95.1
141.7
138.2
104.3
104.3
(27.7)
(27.3)
(32.0)
(28.3)
(21.4)
(24.1)
(30.8)
(28.5)
(27.4)
(23.9)
(23.2)
(23.1)
(23.7)
(20.3)
(21.5)
(26.4)
(39.5)
(37.4)
(18.4)
(19.1)
apoB
ALI, alirocumab; EZE, ezetimibe; non-HDL-C, non-high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; PBO, placebo. Lipids are
means (SD), mg/dL.
10
eFigurre 2. Distriibution of lipid levels at base
eline in pooled treatment grou
ups
accord
ding to control used
d in the OD
DYSSEY trials
t
and overall dis
stributions for
all gro
oups comb
bined
11
12
Two pattients with miissing baseline LDL-C an
nd 3 patientss with missing
g apo B were
e excluded frrom the
analysiss.
Non-HD
DL-C, non-hig
gh-density lip
poprotein cho
olesterol; LDL-C, low-den
nsity lipoprote
ein cholesterrol.
13
eFigurre 3. Distriibution of average achieved
a
l
lipid
levels
s and perc
cent reduc
ction
in lipid
ds from ba
aseline du
uring treatment for all
a treatme
ent groups
s combine
ed
14
Non-HD
DL-C, non-hig
gh-density lip
poprotein cho
olesterol; LDL-C, low-den
nsity lipoprote
ein cholesterrol.
15
eTable 4. Average achieved lipid levels and percentage reductions during treatment in individual trials (safety population)
Trial
LONG TERM
HIGH FH
COMBO I
FH I
FH II
COMBO II
OPTIONS I
OPTIONS II
ALTERNATIVE
MONO
ALI
PBO
ALI
PBO
ALI
PBO
ALI
PBO
ALI
PBO
ALI
EZE
ALI
EZE
ALI
EZE
ALI
EZE
ALI
EZE
n=1550
n=788
n=72
n=35
n=207
n=107
n=322
n=163
n=167
n=81
n=479
n=241
n=104
n=101
n=103
n=101
n=126
n=124
n=52
n=51
49.8
120.5
111.5
183.9
52.2
102.2
76.3
153.4
68.2
138.7
53.5
82.4
58.7
78.1
67.9
89.3
103.3
160.7
68.3
111.7
(34.6)
(39.0)
(65.0)
(47.0)
(25.6)
(34.9)
(41.0)
(49.1)
(35.9)
(41.5)
(31.4)
(33.3)
(33.4)
(32.2)
(33.1)
(42.4)
(68.0)
(58.3)
(20.5)
(22.6)
75.1
151.1
137.5
213.8
80.1
130.4
99.7
181.0
91.0
163.2
80.6
110.2
83.4
103.3
93.1
116.5
135.5
191.6
91.1
135.8
(38.1)
(42.7)
(65.1)
(50.2)
(31.2)
(38.6)
(44.3)
(52.4)
(39.2)
(46.3)
(34.2)
(38.2)
(36.8)
(36.5)
(38.2)
(44.3)
(70.4)
(64.2)
(20.3)
(26.6)
51.5
101.0
90.5
136.4
59.5
91.2
71.4
118.9
64.4
107.6
59.0
79.6
58.3
76.3
67.0
83.8
90.2
121.5
65.9
92.8
(28.4)
(26.3)
(36.2)
(30.1)
(20.3)
(25.8)
(27.0)
(29.6)
(23.7)
(23.4)
(22.5)
(24.2)
(25.9)
(25.7)
(27.3)
(26.5)
(38.0)
(32.2)
(14.6)
(17.2)
-59.9
2.3
-42.9
-7.2
-46.8
-1.6
-45.8
8.6
-48.6
5.0
-50.1
-19.4
-45.8
-21.4
-40.2
-13.5
-47.5
-15.7
-51.1
-18.7
Group
Average
achieved,
mg/dL
LDL-C
non-HDL-C
apoB*
Average %
change from
baseline
†
LDL-C
16
(22.1)
(27.6)
(27.4)
(21.5)
(23.7)
(17.5)
(23.8)
(23.8)
(22.2)
(16.5)
(24.6)
(26.3)
(27.1)
(20.3)
(24.7)
(51.7)
(19.0)
(16.0)
(13.0)
(11.0)
-50.5
2.0
-38.0
-6.3
-37.7
-0.5
-39.9
8.5
-42.1
4.6
-41.0
-18.0
-38.3
-18.2
-34.4
-13.8
-41.9
-15.7
-44.9
-16.7
(19.4)
(22.1)
(24.4)
(20.0)
(20.3)
(15.8)
(21.4)
(20.7)
(20.1)
(16.0)
(20.8)
(22.2)
(23.5)
(18.0)
(21.4)
(28.9)
(14.5)
(11.8)
(11.3)
(11.2)
-50.1
2.0
-33.6
-5.6
-34.2
1.5
-36.3
6.2
-39.6
0.8
-36.9
-13.9
-36.4
-12.2
-29.4
-9.2
-36.9
-11.1
-36.7
-10.2
(22.6)
(26.4)
(24.4)
(18.5)
(20.3)
(18.8)
(19.9)
(19.2)
(18.2)
(12.3)
(20.6)
(19.8)
(24.7)
(20.5)
(25.1)
(28.9)
(15.9)
(12.3)
(13.4)
(11.8)
non-HDL-C
apoB
‡
ALI, alirocumab; EZE, ezetimibe; non-HDL-C, non-high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; PBO, placebo. Lipids are
means (SD), mg/dL.
For patients with no post-baseline lipid values, baseline values were used. *Two patients with missing baseline and no post-baseline apoB were excluded
from the analysis. †Two patients with missing baseline LDL-C were excluded from the analysis. ‡103 patients with missing baseline apoB were excluded from
the analysis.
17
eTable 5. Week 4* achieved lipid levels and percentage reductions in individual trials (safety population)
LONG
TERM
Trial
Group
ALI
PBO
HIGH FH
COMBO I
FH I
FH II
COMBO II
OPTIONS I OPTIONS II
ALTERN.
MONO
ALI
PBO
ALI
PBO
ALI
PBO
ALI
PBO
ALI
EZE
ALI
EZE
ALI
EZE
ALI
EZE
ALI
EZE
n=1550 n=788 n=72
n=35
n=207
n=107
n=322
n=163
n=167
n=81
n=479
n=241
n=104
n=101
n=103
n=101
n=126
n=124
n=52
n=51
Achieved
mg/dL
LDL-C
MACE vs achieved level
(pool of all patients from the
trials)
Category
47.9 120.1 100.4 181.7 52.2 101.6 77.8 146.5 76.2 134.3 52.4 76.6 50.4 72.7 62.5 79.0 107.1 156.4 68.0 112.1
(37.1) (42.5) (74.3) (51.5) (33.0) (36.0) (43.3) (53.8) (37.8) (43.9) (34.4) (31.3) (30.6) (30.6) (33.9) (36.4) (69.8) (55.9) (20.6) (24.7)
N
HR
P(95% CI) value
Per 39
0.79
mg/dL 4972 (0.67 to 0.0092
difference
0.94)
0.81
non-HDL- 71.0 149.5 124.6 209.9 78.3 128.0 100.6 173.5 97.4 156.8 78.2 103.8 73.7 96.8 86.8 104.6 138.8 189.7 91.6 136.5 Per 42
mg/dL 4974 (0.68 to 0.0141
(39.6) (46.5) (73.0) (57.6) (37.6) (41.3) (47.8) (57.5) (43.6) (46.8) (38.2) (35.7) (32.9) (36.8) (39.7) (38.9) (79.2) (67.0) (23.1) (29.2)
C
decrease
0.96)
apoB
†
% change
from
baseline
LDL-C‡
48.8 99.5 84.4 131.7 61.4 93.2 75.8 115.6 73.6 105.7 58.6 76.8 60.4 73.3 66.7 81.1 91.2 121.4 66.3 92.1
(30.9) (27.6) (36.2) (29.3) (25.5) (31.7) (30.0) (29.5) (30.2) (24.9) (24.8) (22.8) (26.7) (23.2) (27.9) (25.5) (37.9) (33.1) (18.4) (17.8)
Per 27
0.79
mg/dL 4871 (0.67 to 0.0072
decrease
0.94)
MACE vs % change
0.74
-61.6 1.3 -50.7 -9.4 -48.7 -1.7 -46.1
3.5
-43.7 1.2
-52.0 -24.9 -53.4 -26.4 -45.4 -23.7 -45.9 -18.3 -51.5 -18.6 Per 50%
4972 (0.60 to 0.0030
(24.3) (30.1) (27.2) (19.3) (25.3) (25.0) (22.9) (33.3) (20.2) (16.0) (26.3) (23.7) (25.4) (22.6) (23.8) (46.4) (18.2) (11.8) (12.8) (12.2) reduction
0.90)
0.71
non-HDL- -53.4 0.5 -45.1 -9.0 -40.3 -2.4 -40.4 4.0 -39.2 0.3 -43.4 -22.3 -45.3 -23.1 -39.5 -22.9 -41.2 -16.9 -45.1 -16.3 Per 50%
4974 (0.54 to 0.0147
(20.1)
(24.0)
(23.9)
(19.0)
(21.0)
(20.8)
(20.9)
(29.5)
(18.8)
(15.2)
(22.5)
(21.4)
(21.7)
(19.4)
(20.5)
(24.4)
(15.0)
(11.0)
(10.5)
(12.1)
reduction
C
0.94)
apoB§
0.75
-52.8 0.4 -38.1 -9.1 -32.9
3.2
-32.8
2.9
-31.9 -1.0 -37.7 -16.5 -34.4 -15.0 -29.4 -12.1 -35.3 -11.2 -35.8 -11.1 Per 50%
4871 (0.61 to 0.0064
(2.54) (30.5) (24.4) (16.6) (22.9) (21.1) (20.4) (18.3) (20.1) (15.1) (21.8) (19.9) (23.8) (16.8) (25.9) (26.4) (19.2) (13.5) (16.7) (13.9) reduction
0.92)
18
ALI, alirocumab; ALTERN., ALTERNATIVE; EZE, ezetimibe; non-HDL-C, non-high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol;
PBO, placebo. Lipids are means (SD), mg/dL. *Week 12 data shown for apoB as no Week 4 values were collected.
For patients with no lipid values at Week 4 (or Week 12 for apoB), baseline values were used. †14 patients with missing baseline apoB and no Week 12 apoB
were excluded from the analysis. ‡Two patients with missing baseline LDL-C were excluded from the analysis. §103 patients with missing baseline apoB were
excluded from the analysis.
19
eTable 6. Correlation between average LDL-C, non-HDL-C and apoB during the
treatment period
Average
Average
LDL-C
non-HDL-C
Average LDL-C during the
treatment period
-
Average non-HDL-C during
the treatment period
0.973
Average apoB during the
treatment period
(P<0.0001)
Average apoB
0.973
0.922
(P<0.0001)
(P<0.0001)
-
0.922
0.948
(P<0.0001)
(P<0.0001)
0.948
(P<0.0001)
-
Pearson correlation coefficient
Non-HDL-C, non-high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol.
20
eTable 7. Safety summary for the 10 Phase 3 trials used in this analysis*
Placebo-controlled trials
Ezetimibe-controlled trials
Alirocumab
Placebo
Alirocumab
Ezetimibe
(n=2318)
(n=1174)
(n=864)
(n=618)
TEAEs
1851 (79.9)
954 (81.3)
657 (76.0)
457 (73.9)
Treatment-emergent SAEs
385 (16.6)
202 (17.2)
147 (17.0)
86 (13.9)
16 (0.7)
13 (1.1)
6 (0.7)
9 (1.5)
144 (6.2)
67 (5.7)
84 (9.7)
66 (10.7)
Nasopharyngitis
291 (12.6)
142 (12.1)
52 (6.0)
41 (6.6)
Injection site reaction
167 (7.2)
62 (5.3)
25 (2.9)
13 (2.1)
infection
162 (7.0)
94 (8.0)
62 (7.2)
40 (6.5)
Influenza
147 (6.3)
63 (5.4)
37 (4.3)
23 (3.7)
Urinary tract infection
128 (5.5)
65 (5.5)
21 (2.4)
25 (4.0)
Back pain
123 (5.3)
70 (6.0)
33 (3.8)
26 (4.2)
Diarrhoea
123 (5.3)
57 (4.9)
30 (3.5)
21 (3.4)
Headache
119 (5.1)
64 (5.5)
43 (5.0)
24 (3.9)
n (%)
TEAEs leading to death
TEAEs leading to
discontinuation
TEAEs in ≥5% of patients
Upper respiratory tract
21
Arthralgia
118 (5.1)
76 (6.5)
42 (4.9)
26 (4.2)
Myalgia
111 (4.8)
46 (3.9)
62 (7.2)
48 (7.8)
Accidental overdose
30 (1.3)
17 (1.4)
54 (6.3)
24 (3.9)
SAE, serious adverse event; TEAE, treatment-emergent adverse event.
*Placebo-controlled studies: Phase 3 (LONG TERM, FH I, FH II, HIGH FH, COMBO I); ezetimibecontrolled studies: Phase 3 (COMBO II, OPTIONS I, OPTIONS II, ALTERNATIVE, MONO).
Originally published by Elsevier and reproduced under STM Permissions Guidelines from: Gaudet D,
Watts GF, Robinson JG, et al. Effect of Alirocumab on Lipoprotein(a) Over ≥1.5 Years (From the
Phase 3 ODYSSEY Program). Am J Cardiol. 2016;(epub ahead of print). DOI:
http://dx.doi.org/10.1016/j.amjcard.2016.09.010. 22
eFigurre 4. Adjus
sted rate of
o any TEA
AE by ave
erage LDL--C during treatmentt
period
d: (A) achie
eved LDL--C during treatmentt, (B) perc
centage re
eduction in
n LDLC from
m baseline
e (multivarriate analy
ysis adjustted on bas
seline cha
aracteristics;
pool o
of Phase 3 studies)
A
B
LDL-C, llow-density lipoprotein ch
holesterol; TEAE, treatme
ent-emergen
nt adverse evvent.
23