Atherosclerosis 277 (2018) 211e218

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Atherosclerosis
journal homepage: www.elsevier.com/locate/atherosclerosis

Efficacy and safety of alirocumab in patients with or without prior

coronary revascularization: Pooled analysis of eight ODYSSEY phase 3
trials
Dean J. Kereiakes a, *, Norman E. Lepor b, Robert Gerber c, L. Veronica Lee d, Joe Elassal e,
Desmond Thompson e, C. Michael Gibson f
a
The Christ Hospital, Heart and Vascular Center/The Lindner Research Center, Cincinnati, OH, USA
b
Cedars-Sinai Medical Center/Westside Medical Associates of Los Angeles, Beverly Hills, CA, USA
c
Department of Cardiology, East Sussex Healthcare NHS Trust, Hastings, UK
d
Sanofi, Bridgewater, NJ, USA
e
Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA
f
Beth Israel Deaconess Medical Center, Boston, MA, USA

a r t i c l e i n f o a b s t r a c t

Article history: Background and aims: Patients with atherosclerotic cardiovascular disease (ASCVD) and prior revascu-
Received 29 May 2018 larization are at high risk of further cardiovascular events and may require additional lipid-lowering
Received in revised form therapies beyond maximally tolerated statin therapy. We assessed the efficacy and safety of alir-
29 June 2018
ocumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, in patients with ASCVD, with
Accepted 6 July 2018
Available online 10 July 2018
or without prior coronary revascularization (percutaneous coronary intervention [PCI] or coronary artery
bypass graft [CABG]).
Methods: Data from eight controlled (placebo/ezetimibe) phase 3 ODYSSEY trials were pooled and
Keywords:
PCSK9
stratified by trial design: alirocumab 150 mg or 75 mg with possible dose increase to 150 mg (75/150 mg)
Alirocumab every 2 weeks (Q2W) versus placebo, and alirocumab 75/150 mg Q2W versus ezetimibe. Most patients
Cholesterol-lowering drugs received background maximally tolerated statin therapy.
Low-density lipoprotein cholesterol Results: Among 4629 randomized patients with hypercholesterolemia, 3382 had ASCVD including 2191
Coronary revascularization with prior revascularization. Although baseline characteristics were comparable between alirocumab
Cardiovascular risk and control groups, revascularized patients were more likely to be male, have had prior myocardial
infarction/stroke, have higher lipoprotein (a) and PCSK9 levels, and were more often treated with high-
intensity statin therapy. Alirocumab significantly reduced low-density lipoprotein cholesterol (LDL-C;
primary endpoint; p < 0.0001), lipoprotein (a), non-high-density lipoprotein cholesterol, and apolipo-
protein B levels from baseline to week 24 (vs. control), regardless of stratified treatment group or
revascularization status. On-treatment LDL-C levels with alirocumab ranged from 45.6 to 64.8 mg/dL.
Alirocumab had a similar safety profile regardless of revascularization status, and higher rates of
injection-site reactions versus controls.
Conclusions: Alirocumab is generally well-tolerated and effective with a similar safety profile in high-risk
patients with or without prior revascularization (PCI/CABG).
© 2018 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND
license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

1. Introduction
Patients with atherosclerotic cardiovascular disease (ASCVD)
* Corresponding author. The Christ Hospital Heart and Vascular Center/The
Lindner Research Center, 2123 Auburn Ave, Suite 424, Cincinnati, OH, USA.
E-mail address: Lindner@thechristhospital.com (D.J. Kereiakes).
who have undergone prior revascularization are at very high risk of
further cardiovascular (CV) events and may require additional
lipid-lowering therapy beyond maximally tolerated statins [1]. For
high-risk patients with ASCVD and elevated low-density lipopro-
tein cholesterol (LDL-C) despite treatment with maximally toler-
ated statin therapy in combination with ezetimibe, guidelines/
consensus documents from the European Society of Cardiology
(ESC)/European Atherosclerosis Society (EAS) [2,3] and the

https://doi.org/10.1016/j.atherosclerosis.2018.07.010
0021-9150/© 2018 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
212 D.J. Kereiakes et al. / Atherosclerosis 277 (2018) 211e218

American College of Cardiology [4,5] recommend addition of a
proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor to
further reduce both LDL-C and CV risk.
Alirocumab, a fully human monoclonal antibody to PCSK9, as
add-on to background maximally tolerated statin therapy with or
without other lipid-lowering therapies, has been shown to signif-
icantly reduce LDL-C levels from baseline compared with controls
(placebo or ezetimibe) in high/very high CV risk patients with
insufficiently controlled hypercholesterolemia in the ODYSSEY
clinical trial program [6e12]. High-risk patients included those
with heterozygous familial hypercholesterolemia (HeFH), non-
familial hypercholesterolemia with clinical ASCVD, or patients at
increased risk of ASCVD due to one or more risk factors. Further-
more, alirocumab was generally well tolerated in these high-risk
patient populations compared with controls [6e12].
In this post hoc, pooled analysis of eight phase 3 ODYSSEY trials,
we compared the efficacy and safety of alirocumab in patients with
clinical ASCVD between those with versus those without prior
coronary revascularization (percutaneous coronary intervention
[PCI] or coronary artery bypass graft [CABG]). The efficacy and
safety of alirocumab, on a background of maximally tolerated statin
therapy, has not previously been established in this very high-risk
subgroup of patients with ASCVD and prior coronary
revascularization.
2. Patients and methods
Patient-level data were pooled from eight placebo- or
ezetimibe-controlled, randomized, double-blind, multicenter,
phase 3 ODYSSEY trials of alirocumab ranging from 24 to 104
weeks' duration, involving patients with hypercholesterolemia
receiving background therapy with maximally tolerated statin
therapy (except for two trials that used fixed statin doses) [11,12],
with or without other lipid-lowering therapy (Fig. 1). The trials
enrolled patients with established ASCVD or other factors placing
them at high CV risk; three trials specifically recruited patients with
HeFH [6,8]. The methods and primary results of each trial have been
described previously [6e12]. Individual study protocols were
approved by appropriate institutional review boards and inde-
pendent ethics committees, and were conducted in accordance
with the Declaration of Helsinki and the International Conference
on Harmonization guidelines for Good Clinical Practice. All study
participants provided written, informed consent prior to trial
enrolment.
In six studies, patients received an initial dosage of alirocumab
75 mg every 2 weeks (Q2W) with potential dose increase to 150 mg
Q2W at week 12 (75/150 mg Q2W) based on achievement of pre-
defined ASCVD risk-based LDL-C levels at week 8 (
70 mg/dL in FH
I & II, COMBO I & II, or
70 or
100 mg/dL depending on CV risk in
OPTIONS I & II) [6,9e12]. In two trials (LONG TERM and HIGH FH)
[7,8], alirocumab 150 mg Q2W was used for the study duration.
From these eight trials, only data for patients with clinical
ASCVD (defined as coronary heart disease, ischemic stroke/tran-
sient ischemic attack, or peripheral arterial disease e all presumed
of atherosclerotic origin) [13] were included in the current analysis,
and compared between subgroups with or without prior revascu-
larization (PCI or CABG).
Baseline characteristics of patients with or without prior

Fig. 1. Overview of the eight ODYSSEY trials and treatment pools included in this analysis.
a
Alirocumab dose could be increased in a blinded fashion from 75 to 150 mg Q2W at week 12 if LDL-C was
70 mg/dL at week 8 (or
70 or 100 mg/dL, depending on risk, in the
OPTIONS studies).
b
Maximally tolerated statin dose defined as atorvastatin 40 or 80 mg, rosuvastatin 20 or 40 mg, or simvastatin 80 mg daily; lower doses were allowed with an investigator-approved
reason such as intolerance or local practice. In two trials the statin dose was fixed, i.e., OPTIONS I (atorvastatin 20 or 40 mg) and OPTIONS II (rosuvastatin 10 or 20 mg).
ASCVD, atherosclerotic cardiovascular disease; CABG, coronary artery bypass grafting; CV, cardiovascular; FH, familial hypercholesterolemia; HeFH, heterozygous FH; LDL-C, low-
density lipoprotein cholesterol; LLT, lipid-lowering therapy; PCI, percutaneous coronary intervention; Q2W, every 2 weeks.
Clinicaltrial.gov identifiers: LONG TERM, NCT01507831; HIGH FH, NCT01617655; COMBO I, NCT01644175; FH I, NCT01623115; FH II, NCT01709500; COMBO II, NCT01644188;
OPTIONS I, NCT01730040; OPTIONS II, NCT01730053.
Table 1
Baseline characteristics of patients with ASCVD by history of prior coronary revascularization (CABG or PCI) (randomized population).

With prior PCI/CABG Without prior PCI/CABG p-valuea

Alirocumab (n ¼ 1416) Control (n ¼ 775) Overall (n ¼ 2191) Alirocumab (n ¼ 779) Control (n ¼ 412) Overall (n ¼ 1191)

Age, years, mean (SD) 61.3 (9.7) 61.3 (9.6) 61.3 (9.7) 62.0 (9.8) 62.3 (9.6) 62.1 (9.8) 0.0222
Gender, male, n (%) 1061 (74.9%) 581 (75.0%) 1642 (74.9%) 443 (56.9%) 223 (54.1%) 666 (55.9%) <0.0001
Race, White, n (%) 1288 (91.0%) 709 (91.5%) 1997 (91.1%) 708 (90.9%) 378 (91.7%) 1086 (91.2%) 0.9701
Body mass index, kg/m2, mean (SD) 30.1 (5.2) 30.6 (5.7) 30.2 (5.3) 30.1 (5.9) 29.9 (4.7) 30.0 (5.5) 0.2685
HeFH, n (%) 254 (17.9%) 144 (18.6%) 398 (18.2%) 126 (16.2%) 66 (16.0%) 192 (16.1%) 0.1346
Total PCSK9, ng/mL, mean (SD)b

D.J. Kereiakes et al. / Atherosclerosis 277 (2018) 211e218

692.7 (246.1) 693.3 (260.2) 692.9 (250.9) 643.4 (222.1) 658.0 (520.3) 648.3 (350.9) 0.0006
Free PCSK9, ng/mL, mean (SD)b 312.3 (119.8) 314.6 (119.0) 313.1 (119.5) 284.8 (113.0) 279.7 (106.7) 283.1 (110.9) <0.0001
Diabetes, n (%) 380 (26.8%) 211 (27.2%) 591 (27.0%) 236 (30.3%) 124 (30.1%) 360 (30.2%) 0.0445
Hypertension, n (%) 1057 (74.6%) 595 (76.8%) 1652 (75.4%) 608 (78.0%) 328 (79.6%) 936 (78.6%) 0.0366
C-reactive protein, mg/dL, mean (SD) 0.3 (0.6) 0.3 (0.6) 0.3 (0.6) 0.4 (0.8) 0.4 (1.1) 0.4 (0.9) 0.0004
Background statin treatment, n (%)
High-intensity 885 (62.5%) 502 (64.8%) 1387 (63.3%) 414 (53.1%) 215 (52.2%) 629 (52.8%) <0.0001
Moderate-intensity 365 (25.8%) 196 (25.3%) 561 (25.6%) 253 (32.5%) 134 (32.5%) 387 (32.5%) <0.0001
Low-intensity 163 (11.5%) 77 (9.9%) 240 (11.0%) 111 (14.2%) 63 (15.3%) 174 (14.6%) 0.0019
Lipid parameters, mg/dL, mean (SD)
LDL-C (calculated) 115.0 (39.1) 114.0 (40.0) 114.6 (39.4) 120.5 (41.8) 121.9 (47.4) 121.0 (43.8) <0.0001
Non-HDL-C 144.2 (43.1) 143.9 (44.3) 144.1 (43.5) 150.6 (45.3) 151.4 (52.4) 150.9 (47.8) <0.0001
HDL-C 48.2 (12.9) 47.4 (12.2) 47.9 (12.7) 50.6 (12.9) 51.1 (13.3) 50.8 (13.0) <0.0001
Triglycerides, mg/dL, median (Q1:Q3) 128.0 (92.0:182.0) 134.0 (100.0:180.5) 129.6 (94.0:181.4) 132.7 (99.0:179.6) 128.2 (93.0:181.9) 131.9 (96.0:180.0) 0.4881
ApoB 98.4 (26.2) 97.8 (26.2) 98.2 (26.2) 99.7 (26.0) 101.0 (30.8) 100.2 (27.7) 0.0447
Lp(a), mg/dL, median (Q1:Q3) 31.6 (10.0:83.2) 27.5 (9.7:77.7) 30.1 (9.9:81.7) 21.0 (7.5:58.1) 20.1 (7.0:59.0) 20.7 (7.1:58.2) <0.0001
Any cardiovascular history/risk factor 1416 (100.0%) 775 (100.0%) 2191 (100.0%) 585 (75.1%) 327 (79.4%) 912 (76.6%) <0.0001
Prior history of MI/stroke 937 (66.2%) 498 (64.3%) 1435 (65.5%) 445 (57.1%) 233 (56.6%) 678 (56.9%) <0.0001
Acute MI 826 (58.3%) 458 (59.1%) 1284 (58.6%) 265 (34.0%) 156 (37.9%) 421 (35.3%) <0.0001
Silent MI 58 (4.1%) 24 (3.1%) 82 (3.7%) 38 (4.9%) 10 (2.4%) 48 (4.0%) 0.6777
Unstable angina 305 (21.5%) 184 (23.7%) 489 (22.3%) 100 (12.8%) 59 (14.3%) 159 (13.4%) <0.0001
Other clinically significant CHD 554 (39.1%) 319 (41.2%) 873 (39.8%) 338 (43.4%) 180 (43.7%) 518 (43.5%) 0.0395
Congestive heart failure 56 (4.0%) 30 (3.9%) 86 (3.9%) 15 (1.9%) 11 (2.7%) 26 (2.2%) 0.0068

Apo, apolipoprotein; ASCVD, atherosclerotic cardiovascular disease; CABG, coronary artery bypass graft; CHD, coronary heart disease; control, placebo or ezetimibe; HDL-C, high-density lipoprotein cholesterol; HeFH, het-
erozygous familial hypercholesterolemia; LDL-C, low-density lipoprotein cholesterol; Lp(a), lipoprotein (a); MI, myocardial infarction; PCI, percutaneous coronary intervention; PCSK9, proprotein convertase subtilisin/kexin
type 9; SD, standard deviation.
a
p-values for overall cohort with prior PCI/CABG versus overall cohort without prior PCI/CABG were derived from the t-test for normally distributed continuous variables (comparing the mean difference of the two specified
groups) or Chi-Square test for categorical variables.
b
PCSK9 levels were analyzed only in COMBO II, FH I, and LONG TERM.

213
214 D.J. Kereiakes et al. / Atherosclerosis 277 (2018) 211e218

revascularization were compared in groups by treatment with alirocumab versus control (placebo or ezetimibe; p < 0.0001 for all,
alirocumab (150 mg Q2W or 75/150 mg Q2W pooled) versus control Fig. 2A). Significant reductions in LDL-C from baseline to week 24
(placebo/ezetimibe), and overall cohorts with and without prior were generally consistent between patients with and without prior
revascularization. p-values comparing the overall cohorts with revascularization across the treatment pools. LDL-C levels achieved
versus without prior PCI/CABG were derived by t-test for normally at week 24 are shown in Fig. 2B. Regardless of revascularization
distributed continuous variables (comparing the mean difference of status, alirocumab-treated patients achieved on-treatment LDL-C
the two specified groups) or chi-square test for categorical variables. levels of 45.6e64.8 mg/dL. Furthermore, at week 24, a higher pro-
Efficacy data were compared between patients with versus portion of patients who received alirocumab achieved LDL-C
without prior coronary revascularization in three pools stratified by <70 mg/dL (64.0%e85.5% across the pooled groups) than placebo
alirocumab dose received and study control (placebo/ezetimibe; (4.3%e8.2%) or ezetimibe (48.4% and 53.9%), regardless of prior
Fig. 1): pool 1, alirocumab 150 mg Q2W versus placebo; pool 2, revascularization status.
alirocumab 75/150 mg Q2W versus placebo; and pool 3, alirocumab In the trials that permitted dose increase, in pool 2 (alirocumab
75/150 mg Q2W versus ezetimibe. 75/150 vs. placebo) the alirocumab dose was increased from 75 to
The primary efficacy endpoint in this analysis was the per- 150 mg Q2W at week 12 in 22.7% and 37.4% of patients with and
centage change in LDL-C (calculated using the Friedewald formula) without prior revascularization, respectively, and in pool 3
from baseline to week 24 (the primary endpoint of each individual
trial). All data were assessed using an intent-to-treat (ITT) analysis
whereby all data were included regardless of adherence to treat-
ment; missing data were accounted for using a mixed-effect model
with repeated measures (MMRM) approach. Least squares means,
standard errors, and p-values were taken from the MMRM analysis.
Interaction p-values for the comparison of the difference between
alirocumab and control in percentage change for lipid endpoints
observed in subgroups of ASCVD patients, with or without prior
revascularization, were derived according to the same mixed-effect
model as for the primary analysis.
Secondary efficacy endpoints assessed included the effect of
alirocumab on change from baseline to week 24 in other pro-
atherogenic lipoproteins including non-HDL-C, apolipoprotein
(apo) B, and lipoprotein (a) [Lp(a)], in subgroups with and without
prior revascularization (ITT analysis). Achievement of lipid goals
was assessed in the modified ITT population (including only on-
treatment lipid data).
Safety was assessed in the safety population, defined as all
randomized patients who received at least one full or partial dose
of study treatment. All treatment-emergent adverse events (TEAEs)
that occurred during the period from the first dose of study treat-
ment up to 70 days after the patient's last dose are reported and
compared by descriptive statistics in patients with or without prior
revascularization by treatment with alirocumab (regardless of
dose) versus control (placebo/ezetimibe) in the individual trials.

3. Results

Among all randomized patients (n ¼ 4629) with hypercholes-

terolemia in the eight trials (Fig. 1), 73.1% (n ¼ 3382) had ASCVD
and 47.3% (n ¼ 2191) had undergone prior revascularization. Base-
line characteristics of the patients with ASCVD, with or without
prior revascularization, are presented in Table 1.
Baseline characteristics were generally comparable between the
alirocumab and control groups, although there were some differ-
ences according to revascularization status (Table 1). Compared
with the overall pooled group of patients (i.e., all alirocumab and
control recipients) without prior revascularization, patients with
prior revascularization were significantly more likely to be younger,
male, have a prior history of myocardial infarction (MI) or stroke,
acute MI, unstable angina, or congestive heart failure, and be using
high-intensity background statin therapy. Additionally, patients
Fig. 2. Percentage change from baseline in (A) LDL-C and (B) achieved LDL-C level at
with prior revascularization had statistically significantly higher Week 24 in patients with or without prior coronary revascularization (PCI/CABG; ITT
mean total and free baseline PCSK9 (313.1 vs. 283.1 ng/mL) and analysis).
median Lp(a) (30.1 vs. 20.7 mg/dL) levels as well as lower mean **p < 0.0001 versus control.
a
LDL-C (114.6 vs. 121.0 mg/dL) and non-HDL-C (144.1 vs. 150.9 mg/ Interaction p-value for percentage reduction in LDL-C (alirocumab minus control) for
patients with versus without prior revascularization.
dL) levels (p < 0.0001 for all). CABG, coronary artery bypass graft; ITT, intent-to-treat; LDL-C, low-density lipoprotein
In both patients with or without prior revascularization, LDL-C cholesterol; LS, least squares; PCI, percutaneous coronary intervention; Q2W, every 2
was significantly reduced from baseline to week 24 with weeks; SE, standard error.
 D.J. Kereiakes et al. / Atherosclerosis 277 (2018) 211e218 215

Fig. 3. Change from baseline to week 24, LS mean (%), in (A) non-HDL-C, (B) ApoB, and (C) Lp(a) in patients with or without prior revascularization (PCI/CABG; ITT analysis).
*p < 0.01.
**p < 0.0001 versus control.
a
Interaction p-value for percentage reduction in lipid parameter (alirocumab minus control) for patients with versus without prior revascularization.
ApoB, apolipoprotein B; CABG, coronary artery bypass graft; ITT, intent-to-treat; Lp(a), lipoprotein (a); LS, least squares; non-HDL-C, non-high-density lipoprotein cholesterol; PCI,
percutaneous coronary intervention; Q2W, every 2 weeks; SE, standard error.

(alirocumab 75/150 vs. ezetimibe) 15.8% and 22.7%, respectively.
Compared with controls, alirocumab significantly reduced non-
HDL-C, apoB (p < 0.0001 for both), and Lp(a) levels (p < 0.01) from
baseline to week 24 in patients with or without prior revasculari-
zation with consistency across each dose pool (Fig. 3).
Alirocumab was generally well tolerated compared with con-
trols, regardless of revascularization status (Table 2). The overall
frequency of TEAEs in patients with and without prior revascular-
ization was 82% and 75%, respectively. A higher frequency of
injection-site reactions (mostly mild and transient) was observed
with alirocumab.
4. Discussion
In this pooled analysis of 3382 high CV risk patients with ASCVD
and hypercholesterolemia despite maximally tolerated statin
therapy, alirocumab significantly reduced LDL-C and other
atherogenic lipoproteins and was generally well tolerated,
regardless of prior revascularization (PCI or CABG) status. Almost
half (47.3%) of all patients (64.8% of those with ASCVD) in the eight
ODYSSEY trials included in this analysis had undergone prior cor-
onary revascularization. At week 24, across the three treatment
pools stratified by trial design, a higher proportion of patients
treated with alirocumab (64.0%e85.5%) than controls (4.3%e53.9%)
achieved ESC/EAS [2] and National Lipid Association [14] recom-
mended LDL-C goals for patients at very-high ASCVD risk (<70 mg/
dL), regardless of prior revascularization status.
Notably, potentially important differences between patients
with and without prior revascularization were observed at base-
line. Baseline levels of LDL-C and non-HDL-C were lower and PCSK9
levels were higher in patents with versus without prior revascu-
larization. These differences may reflect the increased use of high-
intensity statin therapy in the prior revascularization group, as
statins have been associated with increases in both hepatic LDL-C
receptors as well as PCSK9 levels [15]. Additionally, statins have
little effect on Lp(a) levels [16], which were higher in patients with
216 D.J. Kereiakes et al. / Atherosclerosis 277 (2018) 211e218

Table 2
Safety analysis (safety population).

Patients, n (%) Placebo-controlled studies Ezetimibe-controlled studies

With prior PCI/CABG Without prior PCI/CABG With prior PCI/CABG Without prior PCI/CABG

ALI (n ¼ 1004) PBO (n ¼ 522) ALI (n ¼ 607) PBO (n ¼ 312) ALI (n ¼ 410) EZE (n ¼ 252) ALI (n ¼ 170) EZE (n ¼ 100)

TEAEs 834 (83.1%) 440 (84.3%) 465 (76.6%) 231 (74.0%) 332 (81.0%) 192 (76.2%) 118 (69.4%) 76 (76.0%)
Treatment-emergent SAEs 224 (22.3%) 119 (22.8%) 97 (16.0%) 49 (15.7%) 97 (23.7%) 50 (19.8%) 32 (18.8%) 21 (21.0%)
TEAEs leading to death 9 (0.9%) 6 (1.1%) 4 (0.7%) 6 (1.9%) 4 (1.0%) 7 (2.8%) 2 (1.2%) 2 (2.0%)
TEAEs leading to discontinuation 67 (6.7%) 35 (6.7%) 38 (6.3%) 17 (5.4%) 31 (7.6%) 25 (9.9%) 15 (8.8%) 4 (4.0%)
TEAEs in
5% of patients
Nasopharyngitis 141 (14.0%) 60 (11.5%) 66 (10.9%) 33 (10.6%) 22 (5.4%) 12 (4.8%) 8 (4.7%) 6 (6.0%)
Upper respiratory tract infection 74 (7.4%) 40 (7.7%) 47 (7.7%) 31 (9.9%) 40 (9.8%) 21 (8.3%) 5 (2.9%) 4 (4.0%)
Injection-site reaction 72 (7.2%) 26 (5.0%) 33 (5.4%) 10 (3.2%) 11 (2.7%) 2 (0.8%) 3 (1.8%) 1 (1.0%)
Arthralgia 66 (6.6%) 36 (6.9%) 21 (3.5%) 15 (4.8%) 24 (5.9%) 8 (3.2%) 3 (1.8%) 5 (5.0%)
Diarrhea 61 (6.1%) 26 (5.0%) 27 (4.4%) 16 (5.1%) 13 (3.2%) 8 (3.2%) 3 (1.8%) 3 (3.0%)
Influenza 59 (5.9%) 26 (5.0%) 25 (4.1%) 8 (2.6%) 12 (2.9%) 15 (6.0%) 11 (6.5%) 3 (3.0%)
Myalgia 58 (5.8%) 21 (4.0%) 25 (4.1%) 8 (2.6%) 21 (5.1%) 13 (5.2%) 5 (2.9%) 2 (2.0%)
Back pain 55 (5.5%) 33 (6.3%) 25 (4.1%) 17 (5.4%) 20 (4.9%) 11 (4.4%) 5 (2.9%) 1 (1.0%)
Urinary tract infection 51 (5.1%) 20 (3.8%) 34 (5.6%) 22 (7.1%) 10 (2.4%) 8 (3.2%) 2 (1.2%) 5 (5.0%)
Bronchitis 50 (5.0%) 31 (5.9%) 28 (4.6%) 9 (2.9%) 13 (3.2%) 8 (3.2%) 6 (3.5%) 4 (4.0%)
Headache 45 (4.5%) 20 (3.8%) 31 (5.1%) 20 (6.4%) 23 (5.6%) 11 (4.4%) 6 (3.5%) 2 (2.0%)
Hypertension 43 (4.3%) 20 (3.8%) 23 (3.8%) 14 (4.5%) 25 (6.1%) 11 (4.4%) 9 (5.3%) 5 (5.0%)
Pain in extremity 38 (3.8%) 28 (5.4%) 18 (3.0%) 13 (4.2%) 13 (3.2%) 8 (3.2%) 2 (1.2%) 0 (0.0%)
Dizziness 37 (3.7%) 24 (4.6%) 19 (3.1%) 12 (3.8%) 24 (5.9%) 17 (6.7%) 7 (4.1%) 5 (5.0%)
Osteoarthritis 27 (2.7%) 11 (2.1%) 19 (3.1%) 13 (4.2%) 13 (3.2%) 5 (2.0%) 1 (0.6%) 6 (6.0%)
Accidental overdosea 13 (1.3%) 5 (1.0%) 8 (1.3%) 6 (1.9%) 32 (7.8%) 13 (5.2%) 15 (8.8%) 6 (6.0%)

ALI, alirocumab; CABG, coronary artery bypass graft; EZE, ezetimibe; PBO, placebo; PCI, percutaneous coronary intervention; SAE, serious adverse event; TEAE, treatment-
emergent adverse event.
a
Accidental overdose was an event suspected by the investigator or spontaneously notified by the patient (not based on systematic injection/capsule counts) and defined as
at least twice the intended dose within the intended therapeutic interval.

(vs without) prior revascularization, and may reflect residual risk in
this population. Although LDL-C is the primary treatment target for
ASCVD risk reduction, further improvements in the lipid/lipopro-
tein profile of high-risk patients with ASCVD, with or without prior
revascularization, were seen with significant reductions from
baseline to week 24 in apoB, non-HDL-C, and Lp(a) levels following
alirocumab treatment compared with control.
As coronary atherosclerotic plaque distribution is multicentric
and multivessel, clinical events following PCI may be related to
either stented or non-stented coronary segments. In fact, beyond
the first year after coronary stent deployment, most ischemic
events are related to non-stented coronary segments [17,18]. In this
regard, the reduction in atherogenic lipid components by PCSK9
inhibition has been associated with a reduction in plaque volume,
plaque stabilization, and a reduction in subsequent revasculariza-
tion procedures over time [19e21]. Indeed, a large-scale meta-
analysis of randomized controlled clinical trials suggests that the
clinical impact of coronary plaque burden reduction and plaque
stabilization by PCSK9 inhibition may manifest clinically as a
reduction in all-cause and cardiac-related death, and MI [22].
Epidemiological and genome-wide association studies suggest
that elevated levels of Lp(a) are an independent risk factor for the
development of ASCVD [23], and are associated with aortic valve
stenosis [24e26]. In our study, Lp(a) was reduced with alirocumab,
which may lead to reduced CV risk; however, there is currently no
evidence that pharmacological reduction in Lp(a) leads to reduced
ASCVD events. Furthermore, although it has been shown that PCSK9
inhibitors reduce Lp(a) levels by up to 29%, versus a negligible effect/
increase with statins [16,27], the mechanism for the reduction in
Lp(a) levels with PCSK9 inhibitors is currently unclear; both LDL
receptor and non-LDL-receptor pathways may be involved. A recent
study of another PCSK9-targeted approach showed that inhibiting
intrahepatocyte PCSK9 synthesis with a small interfering RNA also
resulted in LDL-C and Lp(a) reductions [28].
In this analysis of very high-risk patients, alirocumab was
generally well tolerated with a similar safety profile in patients
with and without prior revascularization. As seen in a previous
pooled safety analysis of alirocumab trials [29], a higher frequency
of injection-site reactions was observed with alirocumab versus
controls, regardless of revascularization status.
The efficacy and safety results of the present analysis in patients
with prior PCI/CABG (who are at very high risk for a recurrent
event) [2e5] are consistent with prior pooled/subgroup analyses in
high-risk individuals across the Phase 3 ODYSSEY clinical trial
program, including those with HeFH and diabetes mellitus [30e32],
which suggests that alirocumab may provide a valuable treatment
option for high-risk patients with ASCVD who require additional
LDL-C lowering beyond that achieved with maximally tolerated
statin therapy and ezetimibe.
Limitations of this analysis include its post hoc design and the
fact that the individual trials included were not adequately pow-
ered to assess clinical CV endpoints. However, results from a
recently completed large (n ¼ 18,924) clinical outcomes study of
alirocumab in a high-risk population of patients with recent acute
coronary syndrome, ODYSSEY OUTCOMES (NCT01663402), showed
that alirocumab significantly reduced CV events compared with
placebo [33]. Finally, although patients with prior revascularization
were clearly identified in the constituent trial case-report forms,
the mode of revascularization (PCI vs CABG) was not specified.
Although some differences in clinical outcomes have been observed
between revascularization modalities in randomized trials of
treatment strategy, those observations are not pertinent to the
specific endpoints and time course for evaluation in the present
study.
In conclusion, consistent with findings from other subgroup
analyses in high CV risk patients, alirocumab significantly reduces
LDL-C and other atherogenic lipoproteins and is generally well
tolerated in patients with ASCVD, with or without prior revascu-
larization. The increased levels of Lp(a) in patients with prior
revascularization observed in the present analysis may reflect re-
sidual atherothrombotic risk in this population and potentially
identifies an additional therapeutic target.
 D.J. Kereiakes et al. / Atherosclerosis 277 (2018) 211e218
Conflicts of interest
Dr Kereiakes reports no disclosures. Dr Lepor reports he has
received research grant support from Regeneron Pharmaceuticals,
Inc. and participated in speaker's bureau for Regeneron Pharma-
ceuticals, Inc. and Sanofi. Dr Gerber reports no disclosures. Dr Lee
reports she is an employee and stockholder in Sanofi. Dr Elassal
reports he was an employee and stockholder in Regeneron Phar-
maceuticals, Inc. at the time of this analysis. Dr Thompson reports
he is a Consultant to Medical Affairs at Regeneron Pharmaceuticals,
Inc. Dr Gibson reports no disclosures.
Financial support
This analysis was funded by Sanofi and Regeneron Pharmaceu-
ticals, Inc.
Author contributions
DJ Kereiakes, NE Lepor, R Gerber, LV Lee, J Elassal and CM Gibson
contributed to the study concept, data analysis and interpretation,
and in drafting the manuscript. D Thompson was involved in sta-
tistical analysis and interpretation. All authors provided critical
review of drafts and approved the final version for submission.
Acknowledgments
The authors thank the patients, their families, and all in-
vestigators involved in this analysis. The following people from the
study sponsors provided editorial comments on the manuscript:
Michael Howard, MBA, and Corinne Hanotin, MD (Sanofi), and
Robert Pordy, MD, Carol Hudson, MS, and Eva-Lynne Greene, MS
(Regeneron Pharmaceuticals, Inc.). Medical writing support, under
the direction of the authors, was provided by Nila Bhana, MSc, of
Prime (Knutsford, UK), supported by Sanofi and Regeneron Phar-
maceuticals, Inc., according to Good Publication Practice guidelines
(Link). The sponsors were involved in the study design, collection,
analysis, and interpretation of data, as well as data checking of
information provided in the manuscript. The authors were
responsible for all content and editorial decisions, and received no
honoraria related to the development of this publication.
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