Trial Designs

Rationale and design of the effect of

evolocumab in patients at high cardiovascular
risk without prior myocardial infarction or
stroke (VESALIUS-CV) trial
Erin A. Bohula, MD, DPhil a , Nicholas A. Marston, MD, MPH a , Andrea Ruzza, MD, PhD b , Sabina A. Murphy, MPH a ,
Gaetano M. De Ferrari, MD c , Rafael Diaz, MD d , Lawrence A. Leiter, MD e , Mary Elliott-Davey, MSc f ,
Huei Wang, PhD b , Ajay K. Bhatia, MD, PhD b , Robert P. Giugliano, MD, SM a , and Marc S. Sabatine, MD, MPH a
Boston, MA; Thousand Oaks, CA; Turin, Italy; Santa Fe, Argentina; Toronto, Canada; Cambridge, United Kingdom

ABSTRACT
Background The reduction of low-density lipoprotein cholesterol (LDL-C) with evolocumab, a fully human monoclonal
antibody inhibitor of proprotein convertase subtilisin/kexin type 9 (PCSK9i), reduces the risk of major adverse cardiovascular
events in patients with established atherosclerotic cardiovascular disease (ASCVD) with a prior MI, prior stroke, or symp-
tomatic peripheral artery disease, with no offsetting safety concerns. The effect of evolocumab on CV outcomes in lower risk
patients without a history of MI or stroke has not been explored.
Study design VESALIUS-CV is a randomized, double-blind, placebo-controlled, global clinical trial designed to eval-
uate the effect of evolocumab on the risk of major cardiovascular events in patients at high cardiovascular risk but without
a prior ischemic event. The study population consists of 12,301 patients with atherosclerosis or high-risk diabetes mellitus
without a prior MI or stroke; an LDL-C ≥ 90 mg/dL, or non-high-density lipoprotein cholesterol (non-HDL-C) ≥ 120 mg/dL, or
apolipoprotein B ≥ 80 mg/dL; and treated with optimized lipid-lowering therapy. Patients were randomized in a 1:1 ratio to
evolocumab 140 mg subcutaneously every 2 weeks or matching placebo. The primary efficacy objective is to assess whether
evolocumab reduces the risk of the dual primary composite endpoints of coronary heart disease (CHD) death, myocardial
infarction (MI), or ischemic stroke (triple primary endpoint) and of CHD death, MI, ischemic stroke, or ischemia-driven arterial
revascularization (quadruple primary endpoint). Recruitment began in June 2019 and completed in November 2021. The
trial is planned to continue until at least 751 patients experience an adjudicated triple endpoint, at least 1254 experience
an adjudicated quadruple endpoint, and the median follow-up is ≥4.5 years.
Conclusion VESALIUS-CV will determine whether the addition of evolocumab to optimized lipid-lowering therapy re-
duces cardiovascular events in patients at high cardiovascular risk without a prior MI or stroke.
Trial registration NCT03872401. (Am Heart J 2024;269:179–190.)

Background particularly low-density lipoprotein-cholesterol (LDL-C),

Cardiovascular disease is the leading cause of mor- is a modifiable independent cardiovascular risk factor.2
bidity and mortality globally.1 Elevated cholesterol, Mendelian randomization studies of genetic variants
associated with lower LDL-C demonstrated a lower risk
of cardiovascular disease.3 Numerous interventional
From the a TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham
studies have reinforced the consistent cardiovascular
and Women’s Hospital, Harvard Medical School, Boston, MA, b Amgen, Thousand benefit of LDL-C lowering.4 Specifically, data from more
Oaks, CA, c Department of Medical Sciences, University of Turin and Department of Car-
diology, Azienda Ospedaliera Universitaria Città della Salute e della Scienza, Turin, Italy,
than 160,000 patients from randomized clinical trials in
d Estudios Clínicos Latino America, Santa Fe, Argentina, e Li Ka Shing Knowledge Insti- primary and secondary prevention populations treated
tute of St Michael’s Hospital, University of Toronto, Toronto, Ontario, Canada, f Amgen, with statin therapy demonstrated a reduction in the risk
Cambridge, United Kingdom
Submitted September 14, 2023; accepted December 10, 2023 of major cardiovascular events that was proportionate
Reprint requests: Erin A. Bohula, MD, DPhil, TIMI Study Group, Cardiovascular Division, to the absolute magnitude of LDL-C reduction and
Brigham and Women’s Hospital, 60 Fenwood Road, Suite 7022, Boston, MA 02115.
the duration of therapy, translating to an approximate
E-mail address: [email protected].
0002-8703
22% lower risk of major vascular events per 1 mmol
© 2024 Elsevier Inc. All rights reserved. (38.7mg/dL) reduction in LDL-C in patients treated for a
https://doi.org/10.1016/j.ahj.2023.12.004
 American Heart Journal
180 Bohula et al
March 2024

median of 4-5 years.5 More recently, LDL-C lowering with We randomized 12,301 patients in a 1:1 ratio to re-
proprotein convertase subtilisin/kexin type 9 (PCSK9) ceive either evolocumab 140 mg subcutaneously every
inhibitors was shown to reduce the risk of cardiovascular 2 weeks or matching placebo with stratification by LDL-
events in secondary prevention populations with stable C level (<160 mg/dL [4.14 mmol/L] vs ≥160 mg/dL) and
atherosclerotic cardiovascular disease (ASCVD) with a by geographical region. Randomization was performed
prior MI, prior stroke or symptomatic PAD or with a in a double-blind fashion using a central computerized,
recent history of acute coronary syndrome (ACS).6 , 7 The web-based system. All patients are to be followed for clin-
effect of PCSK9 inhibition on cardiovascular events has ical endpoints and selected adverse events until the end
not been studied in lower risk populations without a of the study.
prior cardiovascular ischemic event. The study is being performed in accordance with
Here we describe the design of the effect of ethical principles consistent with the Declaration of
EVolocumab in PatiEntS at High CArdiovascuLar Helsinki 2013, ICH good clinical practice guidelines,
RIsk WithoUt Prior Myocardial Infarction or Stroke and applicable regulatory requirements. The study pro-
(VESALIUS)-CV trial. This global phase III trial is de- tocol and informed consent were reviewed and ap-
signed to evaluate the impact of evolocumab on major proved by the corresponding health authorities and
cardiovascular events in patients without a prior MI or ethics boards/institutional research boards for all partic-
stroke at high risk for a first cardiovascular event. ipating study sites. Enrolled patients gave informed con-
sent for participation in the study.
Study design and population
VESALIUS-CV (TIMI 66) is a randomized, double-blind, Treatment protocol and follow-up procedures
parallel-group, placebo-controlled, global trial evaluat- Study drug
ing evolocumab in 12,301 patients at high risk for a Study drug is dispensed as evolocumab 140 mg in a pre-
first cardiovascular event. The primary hypothesis is that filled autoinjector to be self-administered subcutaneously
evolocumab will reduce the risk of major adverse cardio- every 2 weeks or matching placebo. Dose titrations or
vascular events. adjustments are not permitted.
Eligible patients must meet study criteria for (1) age, Background lipid-lowering therapy
(2) qualifying lipid parameters, (3) disease category, and Eligibility with respect to qualifying lipid parameter
(4) presence of at least one high-risk criteria (Table 1). criteria was assessed in patients on at least 2 weeks of
Specifically, study patients must be age 50 (men) or 55 stable, optimized background lipid-lowering therapy.
(women) to 79 years old with an LDL-C ≥ 90 mg/dL Background lipid-lowering therapy was encouraged to
(≥2.3 mmol/L), non-HDL-C ≥ 120 mg/dL (≥3.1 mmol/L), be established jointly by the patient and their health
or apolipoprotein B (ApoB) ≥ 80 mg/dL (≥1.56 µmol/L) care providers and to be consistent with local pro-
on at least 2 weeks of stable, optimized lipid-lowering fessional society guidelines. As eligible patients are at
therapy. Patients must meet study criteria for at least 1 high cardiovascular risk, it was anticipated that the
of the following 4 disease categories: coronary artery majority of patients in the trial would be treated with
disease, atherosclerotic cerebrovascular disease, pe- a high-intensity background lipid-lowering regimen that
ripheral artery disease, or high-risk diabetes mellitus. would be anticipated to reduce LDL-C by ≥50% from
The latter refers to patients with diabetes that is either the untreated baseline level. While patients on any statin
long-standing (≥10 years), is treated with daily insulin, intensity with or without ezetimibe were eligible for
or is complicated by microvascular disease. Additionally, the trial, it was encouraged, as per local guidelines
eligible patients must have at least 1 high-risk criterion and standard of care, that patients be on a maximally
listed in Table 1. Patients with an MI or stroke prior to tolerated regimen prior to screening. In patients not able
randomization are excluded. A complete list of inclusion to tolerate high-intensity statin, the addition of ezetimibe
and exclusion criteria are detailed in Tables 1 and 2, was encouraged. Patients with statin intolerance were
respectively. eligible provided they had demonstrated intolerance
Enrollment was targeted to achieve approximately 30% to at least 2 different statins, including at least 1 at the
of the total population without known significant AS- lowest approved dose. Background lipid-lowering ther-
CVD (ie, meeting protocol-specified criteria for high-risk apy was to remain unchanged throughout the follow up
diabetes without meeting protocol-specified criteria for period unless a change was deemed clinically necessary.
vascular disease). To this end, enrollment criteria were Concomitant use of nonstudy investigational products
modified in December 2020 to limit further recruitment and commercially available PCSK9 inhibitor therapies
of patients with diabetes mellitus and no significant AS- were prohibited.
CVD to those with very elevated lipid values (LDL-C Lipid monitoring
≥ 130 mg/dL [≥3.36 mmol/L], non-HDL-C ≥ 160 mg/dL Investigators and staff involved in the study were
[≥4.14 mmol/L], or apolipoprotein B ≥ 120 mg/dL [≥2.3 prohibited from performing nonprotocol lipid panel
μmol/L]) to meet recruitment targets. testing during a patient’s study participation until at
American Heart Journal
Bohula et al 181
Volume 269

Table 1. Inclusion criteria.

1. Age from ≥50 years (men) or ≥55 years (women) to <80 years (either sex).
2. Lipid parameters of LDL-C ≥ 90 mg/dL (≥2.3 mmol/L) or non-HDL-C ≥ 120 mg/dL (≥3.1 mmol/L), or apolipoprotein B ≥ 80 mg/dL
(≥1.56 µmol/L).∗
3. Diagnostic evidence of at least 1 of the following disease categories (A-D) at screening:
A. Significant coronary artery disease meeting at least 1 of the following criteria:
1. History of coronary revascularization with multivessel coronary disease as evidenced by any of the following:
a. percutaneous coronary intervention (PCI) of 2 or more vessels, including branch arteries,
b. PCI or coronary artery bypass grafting (CABG) with residual ≥50% stenosis in a separate, unrevascularized vessel, or
c. multivessel CABG 5 years or more prior to screening.
2. Significant coronary disease without prior revascularization as evidenced by either a ≥70% stenosis of at least 1 coronary
artery, ≥50% stenosis of 2 or more coronary arteries, or ≥50% stenosis of the left main coronary artery.
3. Coronar y arter y calcium score ≥ 100 in patients without a coronar y arter y revascularization prior to randomization.
B. Significant atherosclerotic cerebrovascular disease meeting at least 1 of the following criteria:
1. Prior transient ischemic attack with ≥50% carotid stenosis.
2. Internal or external carotid artery stenosis of ≥70% or 2 or more ≥50% stenoses.
3. Prior internal or external carotid artery revascularization.
C. Significant peripheral arterial disease meeting at least 1 of the following criteria:
1. ≥50% stenosis in a limb artery.
2. History of abdominal aorta treatment (percutaneous or surgical) due to atherosclerotic disease.
3. Ankle brachial index < 0.85.
D. High-risk diabetes mellitus with at least 1 of the following:
1. Known microvascular disease, defined by diabetic nephropathy or treated retinopathy. Diabetic nephropathy defined as
persistent microalbuminuria (urinary albumin to creatinine ratio ≥30 mg/g) and/or persistent estimated glomerular filtration
rate (eGFR) <60 mL/min/1.73 m2 that is not reversible due to an acute illness.
2. Chronic daily treatment with an intermediate or long-acting insulin.
3. Diabetes diagnosis ≥10 years ago.
4. At least 1 of the following high-risk criteria:
A. Polyvascular disease, defined as coronary, carotid, or peripheral artery stenosis ≥ 50% in a second distinct vascular location in a
patient with coronary, cerebral or peripheral arterial disease (inclusion criterion 3A-C).
B. Presence of either diabetes mellitus or metabolic syndrome in a patient with coronary, cerebral, or peripheral artery disease
(inclusion criterion 3A-C).
C. At least 1 coronary, carotid, or peripheral artery residual stenosis ≥ 50% in a patient with diabetes meeting inclusion criterion 3D.
D. LDL-C ≥ 130 mg/dL (≥3.36 mmol/L), or non-HDL-C ≥ 160 mg/dL (≥4.14 mmol/L), or apolipoprotein B ≥ 120 mg/dL (≥2.3
µmol/L) if available.
E. Lipoprotein (a) > 125 nmol/L (50 mg/dL).
F. Familial hypercholesterolemia.
G. Family history of premature coronary artery disease defined as an MI or CABG in the patient’s father or brother at age < 55 years
or an MI or CABG in the patient’s mother or sister at age < 60 years.
H. High-sensitivity C-reactive protein ≥3.0 mg/L in the absence of an acute illness.
I. Current tobacco use.
J. ≥65 years of age.
K. Menopause before 40 years of age.
L. eGFR from 15 to <45 mL/min/1.73 m2 .
M. Coronar y arter y calcification score ≥ 300 in a patient without a coronar y revascularization prior to randomization
5. Informed consent prior to initiation of any study specific activities/procedures.

∗
Based on most recent value in the 3 months prior to screening, reflecting ≥2 weeks of stable, optimized background lipid lowering therapy.HDL-C, high-density lipoprotein
cholesterol; LDL-C, low-density lipoprotein cholesterol; MI, myocardial infarction.

least 12 weeks after the last administration of investiga- patients return for study visits at 4-month intervals un-
tional product (to avoid potential unblinding). Nonstudy til the end of the study. During follow up visits, patients
clinicians were permitted to monitor lipid values dur- are assessed for adverse and potential endpoint events.
ing study participation as deemed clinically necessary; All patients are to undergo a safety follow-up assessment
however, patients and study staff were instructed to after permanently or temporarily discontinuing therapy.
remain blinded to lipid results performed from ran- Vital status assessment will be attempted in all patients
domization through 12 weeks after the last study drug at the end of the trial.
administration. Procedural modifications in the context of COVID-
Visit schedule and follow-up 19
The anticipated duration of the trial is approximately With the onset of the coronavirus disease 2019
6 years; the actual duration of the trial will be based on (COVID-19) pandemic, sites could utilize remote and vir-
accrual of a predetermined number of events and achiev- tual study visits as well as site-to-patient shipment of
ing a median follow up of at least 4.5 years. Randomized study drug. Later protocol iterations expanded the use of
 American Heart Journal
182 Bohula et al
March 2024

Table 2. Exclusion criteria.

Disease related

• Myocardial infarction or stroke prior to randomization.

• Coronar y arter y bypass graft surger y <3 months prior to screening.
• Uncontrolled or recurrent ventricular tachycardia in the absence of an implantable-cardioverter defibrillator.
• Atrial fibrillation or atrial flutter not on anticoagulation therapy
• Last measured left-ventricular ejection fraction < 30% or New York Heart Association Functional Class III/IV.
• Planned arterial revascularization.

Diagnostic assessments

• Triglycerides ≥ 500 mg/dL (≥5.7 mmol/L) measured up to 3 months prior to screening.

• End stage renal disease, defined as an estimated glomerular filtration rate < 15 mL/min/1.73 m2 or receiving dialysis, up to 6
months prior to screening.

Other medical conditions

• Malignancy (except nonmelanoma skin cancers, cervical in situ carcinoma, breast ductal carcinoma in situ, or stage 1 prostate
carcinoma) within the last 5 years prior to day 1.
• History or evidence of clinically significant disease (eg, malignancy, respiratory, gastrointestinal, renal or psychiatric disease) or
unstable disorder that, in the opinion of the investigator(s), Amgen physician or designee would pose a risk to the patient’s safety or
interfere with the study assessments, procedures, completion, or result in a life expectancy of less than 1 year.
• Persistent acute liver disease or hepatic dysfunction, defined as Child Pugh score of C.

Prior/concomitant therapy

• Previously received a cholesterol ester transfer protein inhibitor (ie, anacetrapib, dalcetrapib, evacetrapib), mipomersen, lomitapide,
or has undergone LDL-apheresis in the last 12 months prior to LDL-C screening.
• Previously received or receiving any other therapy to inhibit PCSK9 in the following timeframe prior to screening:
◦ Bococizumab at any time.
◦ Evolocumab, alirocumab, or any other monoclonal antibody against PCSK9 within 3 months.
◦ Inclisiran within 12 months.

Prior/concurrent clinical study experience

• Currently receiving treatment in another investigational device or drug study, or less than 30 days since ending treatment on another
investigational device or drug study(ies).

Other exclusions

• Female patients of childbearing potential unwilling to use 1 acceptable method of effective contraception during treatment and for an
additional 15 weeks after the last dose of investigational product.
• Patient has known sensitivity to any of the products or components to be administered during dosing.
• Patient likely to not be available to complete all protocol-required study visits or procedures, and/or to comply with all required study
procedures to the best of the patient and investigator’s knowledge.
• Patient is staff personnel directly involved with the study or is a family member of the investigational study staff.
• Female patient is pregnant, had a positive pregnancy test at screening (by a serum pregnancy test and/or urine pregnancy test),
breastfeeding, or planning to become pregnant or breastfeed during treatment and for an additional 15 weeks after the last dose of
investigational product.

LDL, low-density lipoprotein; PCSK-9, proprotein convertase subtilisin/kexin type 9.

site-to-patient shipment of study drug for circumstances endpoint). Ischemia-driven arterial revascularization is
unrelated to COVID-19. Adverse event assessment and defined as revascularization of any vascular bed, includ-
data capture was modified to allow for collection of ing coronary, cerebrovascular or peripheral, performed
COVID-19 specific details, including source material to in the presence of ischemia of the relevant end-organ.
support adjudication of the contribution of COVID-19 to The secondary efficacy endpoints, which will be tested
death events. in the following hierarchical order, are: the composites
of MI, ischemic stroke, or any IDR; CHD death, MI, or
Study end points IDR; cardiovascular (CV) death, MI, or ischemic stroke;
The dual primary efficacy endpoints of the trial are a CHD death or MI; and the individual endpoints of MI,
composite of coronary heart disease (CHD) death, MI, or IDR, CHD death, CV death, all-cause death, and ischemic
ischemic stroke (triple primary endpoint) and a compos- stroke (Appendix A, Figure A1). Prespecified exploratory
ite of CHD death, MI, ischemic stroke, or any ischemia- endpoints include the change in LDL-C from baseline
driven arterial revascularization (IDR; quadruple primary with evolocumab in a subset of patients with central lipid
American Heart Journal
Bohula et al 183
Volume 269

testing as well as the effect of evolocumab on the inci- The target sample size was based on the dual primary
dence of new or worsening aortic stenosis and the in- endpoints of the study. Using conservative projections
cidence of new or recurrent venous thromboembolism. for LDL-C lowering and incorporating a treatment lag as
Analyses will be conducted in prespecified subgroups, has been seen with statins and PCSK9 inhibitors, the
including according to disease category and baseline anticipated hazard ratios over the duration of the study
LDL-C. were 0.77 for the triple primary endpoint and 0.80 for
The safety and tolerability of evolocumab, compared the quadruple primary endpoint. Assuming an annual-
with placebo, will be assessed for treatment-emergent ad- ized event rate in the placebo arm of approximately 1.6%
verse events leading to investigational product discontin- for the triple endpoint and 2.7% for the quadruple end-
uation and treatment-emergent serious adverse events. point,10 , 11 a 1% annual rate of loss to follow-up and a
Adjudication of the dual primary and secondary effi- study duration of 63 months, a total of 12,000 patients
cacy endpoints is performed according to prespecified experiencing 751 triple endpoint events provides >90%
definitions based on the 2017 guidance document for power to demonstrate superiority of evolocumab over
clinical trial endpoints8 by the Thrombolysis in Myocar- placebo using a 2-sided 0.025 level of significance for
dial Infarction (TIMI) Clinical Endpoints Committee, con- the triple composite endpoint. Using the same assump-
sisting of specifically trained physicians with board cer- tions, 1254 quadruple endpoint events provide a power
tification in cardiovascular medicine or neurology (de- of >95% to demonstrate superiority.
pending on the event type), and who are blinded to ran-
domized treatment assignment.
Genetic, biomarker, and lipid substudies
Genetic, biomarker, and lipid substudies are being con-
Statistical considerations
ducted as a part of the VESALIUS-CV study. Patients
The primary efficacy analyses of VESALIUS-CV are
provided written informed consent for participation in
based on the time from randomized treatment assign-
the substudies. DNA samples are being collected with
ment to the first occurrence of any element of the dual
the intent of assessing the relationship between ge-
primary efficacy endpoint being tested and assessed for
netic variants and the efficacy, safety, and tolerability
superiority of evolocumab to placebo according to the
of evolocumab as well as cardiovascular events. Serum
intention-to-treat principle in all randomized patients.
and plasma samples for assessment of cardiovascular
This final analysis will be conducted after all 3 of the
biomarkers are obtained at baseline and once during the
following are met: (1) ≥751 patients have experienced
treatment period (in all patients), and at the end of study
the triple primary endpoint, (2) ≥1254 patients have ex-
(in a subset of consented participants). The aim of the
perienced the quadruple primary endpoint, and (3) the
biomarker substudy is to evaluate the relationships be-
median follow up is ≥4.5 years (Figure 1). All secondary
tween biomarkers and the efficacy, safety, and tolerabil-
objectives will also be assessed at the time of the pri-
ity of evolocumab as well as between biomarkers and
mary analysis according to the intention-to-treat princi-
cardiovascular events. Centralized lipid testing is being
ple. The primary analysis of all time-to-event endpoints
conducted at baseline, years 1 and 2 and end of study in
will be the log-rank test stratified by the randomization
a subset of ∼2,000 patients randomly selected to approx-
stratification factors. In addition, HR and 95% CI will be
imate the overall study population.
estimated from a Cox model stratified by the randomiza-
tion stratification factors.
In order to preserve the overall type 1 error rate at an Study organization
alpha of 0.05 in the primary analysis of the dual primary The executive committee, composed of members of
efficacy endpoints and secondary efficacy endpoints, a the TIMI Study Group, other leading academic experts,
parallel gatekeeping strategy will be applied using a trun- and the sponsor (Amgen), oversees all aspects of the
cated Hochberg procedure (Appendix A).9 This proce- trial (Appendix B). The executive committee is respon-
dure allows unused alpha from the dual primary end- sible for the scientific content of the protocol and its
point testing to be passed to the secondary endpoint test- implementation. An independent DMC reviews available
ing if at least 1 of the primary tests are successful. Addi- accumulating safety data approximately every 6 months
tional details of the gatekeeping strategy are described in as well as a single prespecified assessment of efficacy as
Appendix A. noted above. A CEC blinded to study treatment adjudi-
The data monitoring committee (DMC) will only re- cates the elements of the dual primary and secondary
view unblinded cardiovascular endpoint data to consider endpoints. Centrally measured on-treatment lipid data
a recommendation for early termination based on effi- (LDL-C) will be reviewed during the trial by an indepen-
cacy at a single, prespecified interim analysis after ac- dent, unblinded lipid monitoring committee in order to
crual of 75% of the targeted number of each of the pri- evaluate compliance with study drug use (ie, to assess
mary endpoints and median duration of follow-up of at whether LDL-C reductions are as expected in the subset
least 3.5 years. of patients who remain on study drug). This committee
 American Heart Journal
184 Bohula et al
March 2024

Figure 1

Trial schema. ApoB, apolipoprotein B; CAD, coronar y arter y disease; CHD, coronar y heart disease; CVD, cerebrovascular disease; HDL-C,
high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; MI, myocardial infarction; PAD, peripheral arterial disease;
Q2W, every 2 weeks; Q 4 mos, every 4 months.

will provide feedback to study leadership if any cohorts fying criteria for ASCVD. The median baseline LDL-C of
(eg, countries) appeared to have suboptimal compliance. 122 mg/dL (interquartile range from 104 to 149 mg/dL)
The study was designed by the TIMI Study Group in is higher than might be expected for an unselected pop-
conjunction with the executive committee and the trial ulation with a similar risk profile due to the inclusion re-
sponsor. Data analysis will be conducted by the TIMI quirement for an LDL-C of at least 90 mg/dL. A majority
Study Group with validation by the trial sponsor. The of patients (68%) are on high-intensity statin therapy at
TIMI Study Group will have free and complete access to baseline. Thirteen percent of patients are not on a statin
all trial data and will submit the results of the study for at baseline. Twenty percent are on ezetimibe. The DMC
publication in a peer-reviewed medical journal. has met approximately every 6 months and has recom-
The VESALIUS-CV study is supported by a research mended continuing as planned at each meeting.
grant from Amgen. The trial has been registered un-
der number NCT03872401. Qualified researchers may re-
quest data from Amgen clinical studies. For details, visit Discussion
http://www.amgen.com/datasharing. Intensive LDL-C lowering therapy with statins has been
shown to reduce the risk of major adverse cardiovascu-
lar events across a range of patient populations, including
Current status both primary and secondary prevention.5 Nonstatin LDL-
The VESALIUS-CV study enrolled patients in 33 coun- C lowering therapy, such as ezetimibe, PCSK9 inhibitors,
tries and 774 sites. Recruitment began in June 2019 and and bempedoic acid, have resulted in lower rates of
was completed in November 2021, after a pause from major adverse cardiovascular events in high-risk, sec-
April to May 2020 during the early phase of the COVID- ondary prevention populations.4 , 6 , 7 , 12 , 13 Of particular
19 pandemic. The baseline characteristics are presented relevance, in the Further Cardiovascular Outcomes Re-
in Table 3 for the overall trial cohort (N = 12,301) and search with PCSK9 Inhibition in Subjects with Elevated
stratified by qualifying disease category. The mean age Risk (FOURIER) trial, the PCSK9 inhibitor, evolocumab,
is 65 years and 42% of patients are women. Approxi- significantly reduced the risk of the primary endpoint of
mately two-thirds of patients meet criteria for at least cardiovascular death, myocardial infarction, stroke, hos-
one of the qualifying ASCVD categories, including 45% pitalization for unstable angina, or coronary revascular-
with CAD, 10% with CVD, and 17% with PAD. Approx- ization by 15% and the risk of the secondary endpoint of
imately half of the patients have high-risk diabetes and CV death, MI, or stroke by 20%. This was seen in patients
one-third have high-risk diabetes without meeting quali- with a prior MI, prior stroke or PAD, and after a median
American Heart Journal
Bohula et al 185
Volume 269

Table 3. Baseline characteristics.

Overall cohort Stratified by qualifying disease category at study inclusion∗

All CAD CVD PAD High-risk DM
N = 12,301 N = 5,563 N = 1,207 N = 2,134 N = 6,026
(100%) (45%) (9.8%) (17%) (49%)

Demographics
Age (years, mean ± standard deviation) 65 ± 7 66 ± 7 66 ± 7 65 ± 7 66 ± 7
Female 42 32 51 38 50
Caucasian 93 91 98 97 92
Hispanic/Latino 17 11 8.6 23 22
Region
North America 11 11 6.1 5.7 14
Europe 69 70 85 72 64
Asia/Pacific 5.1 9.5 1.4 1.0 2.9
Latin America/South America 15 9.3 7.2 21 20
Comorbidities
Hypertension 87 86 92 85 90
Any diabetes mellitus (DM) 58 37 31 44 100
Qualifying disease categories for inclusion∗
CAD without prior myocardial infarction 45 100 19 15 21
Revascularization w/multivessel disease 33 73 14 12 18
Significant CAD without prior 5.2 11 3.4 1.6 2.1
revascularization
Coronar y arter y calcium score ≥ 100 in 8.2 18 1.5 1.1 2.2
the absence of prior revascularization,
where available†
Cerebrovascular disease (CVD) without prior 10 4.1 100 7.9 4.3
stroke
Peripheral arterial disease (PAD) 17 5.7 14 100 11
High-risk diabetes mellitus 49 23 21 31 100
High-risk criteria for inclusion (where known)
LDL-C ≥ 130, non-HDL-C ≥ 160, or ApoB ≥ 51 43 54 47 55
120 mg/dL
Any DM or metabolic syndrome with 30 44 40 50 33
qualifying CAD, CVD, or PAD
High-risk DM w/≥1 arterial stenosis of ≥50% 9.5 12 18 16 19
Polyvascular disease 5.4 8.6 26 20 2.9
Lipoprotein(a) > 125 nmol/L (50 mg/dL), 3.4 4.6 3.1 4.9 2.1
where available†
Familial hypercholesterolemia 8.7 10 6.8 6.9 6.9
Family history of premature CAD 22 26 21 16 19
High sensitivity C-reactive protein ≥ 3 mg/L, 4.2 3.7 5.2 4.1 4.7
where available†
Current tobacco use 28 22 31 42 26
Age ≥ 65 years 56 58 55 56 57
Menopause before 40 years 3.1 1.8 3.3 3.2 4.1
eGFR 15-<45 ml/min/1.73m2 6.9 5.9 6.7 7.0 10
Coronar y arter y calcium score ≥ 300 in the 4.4 10 1.0 0.7 1.2
absence of prior revascularization, where
available†
Background lipid-lowering therapy
Any statin 87 86 92 91 86
High-intensity statin 68 66 80 76 67
Moderate-intensity statin 17 17 10 14 18
Ezetimibe 20 27 14 16 16
High-intensity lipid-lowering regimen‡ 73 73 83 79 71
Baseline lipid values in mg/dL, median (Q1,
Q3)
(continued on next page)
 American Heart Journal
186 Bohula et al
March 2024

Table 3. (continued)

Overall cohort Stratified by qualifying disease category at study inclusion∗

All CAD CVD PAD High-risk DM
N = 12,301 N = 5,563 N = 1,207 N = 2,134 N = 6,026
(100%) (45%) (9.8%) (17%) (49%)

Low-density lipoprotein-cholesterol 122 (104, 149) 116 (101, 141) 126 (106, 157) 120 (103, 149) 125 (104, 151)
In patients not on ao statin 139 (116, 167) 139 (116, 166) 150 (115, 184) 142 (119, 169) 137 (115, 163)
In patients on non-high-intensity statin 116 (101, 139) 112 (100, 132) 120 (101, 148) 116 (102, 143) 116 (101, 140)
In patients on high-intensity statin 121 (103, 148) 114 (101, 138) 125 (106, 156) 119 (101, 148) 125 (105, 151)
Non-high-density lipoprotein-cholesterol 153 (130, 183) 146 (126, 174) 155 (130, 190) 149 (128, 182) 158 (135, 187)
Total cholesterol 202 (178, 233) 194 (174, 224) 208 (182, 246) 198 (177, 232) 205 (182, 237)
Triglycerides 153 (111, 218) 146 (106, 204) 142 (104, 198) 146 (106, 211) 170 (122, 241)
Apolipoprotein-B 101 (89, 122) 98 (85, 115) 101 (88, 116) 100 (88, 121) 105 [92, 126)

Column percentage depicted unless otherwise indicated. Data based on interim snapshot taken in February 2022 after completion of enrollment but during ongoing trial
and data cleaning.
∗
Cohorts not mutually exclusive as patients may meet criteria for more than one qualifying disease category.
†
Based on local testing done for routine clinical purposes. Percentage reflects proportion meeting criteria in overall population, rather than in the population with
nonmissing data. Data available for 2,600, 3,078, and 1,214 patients for lipoprotein(a), hs-CRP and coronary artery calcium score, respectively. Therefore, among those
with available data, the proportions who met the criteria were 16.0%, 16.8%, and 44.6% (for coronary artery calcium score ≥ 300), respectively.
‡
High-intensity regimen is defined as either a high intensity statin (eg, atorvastatin ≥ 40 mg daily or rosuvastatin ≥ 20 mg daily) or a combination of any statin at any
approved daily dose and ezetimibe daily.ASCVD, atherosclerotic cardiovascular disease; CAD, coronary artery disease; eGFR, estimated glomerular filtration rate.

follow-up of only 2.2 years.6 Patients with higher bur- The VESALIUS-CV study is designed to explore
den of atherosclerotic disease, such as residual multives- whether LDL-C lowering with evolocumab will improve
sel disease or multiple prior MIs, tended to have greater cardiovascular outcomes in a lower risk population than
relative and absolute benefit with evolocumab.14 , 15 No previously studied in the pivotal cardiovascular outcome
significant safety concerns, including muscle symptoms trials of PCSK9 inhibitor therapy. We hypothesize that
and neurocognitive deficits, were observed in the over- lower risk patients will benefit from aggressive lipid-
all trial population or in those achieving very low LDL-C lowering therapy with nonstatin agents both based on
values.6 , 16 , 17 Similarly, in ODYSSEY Outcomes, another trials in primary prevention population with statins and
PCSK9 inhibitor, alirocumab, resulted in a significant 15% on genetic/Mendelian randomization studies in general
relative risk reduction in the primary endpoint of CHD populations showing a lower risk of major adverse car-
death, MI, ischemic stroke, or unstable angina requiring diovascular events in patients with lower LDL-C levels
hospitalization in patients with a history of ACS, without as a means of preventing both development and pro-
significant safety concerns.7 gression of ASCVD. To this end, VESALIUS-CV includes
In the open-label extension study of the FOURIER trial a lower risk population compared with other PCSK9 in-
(FOURIER-OLE), 6,635 patients completing the parent hibitor trials to date, including (1) patients with evidence
trial at participating sites were transitioned to open-label of ASCVD but without a prior ischemic event and (2) pa-
evolocumab.18 Patients originally randomized in the par- tients without known significant ASCVD, but who are at
ent trial to evolocumab vs placebo had lower rates of ma- high risk of incident cardiovascular events in the pres-
jor adverse cardiovascular events for an additional several ence of diabetes and additional high-risk factors (approx-
years, again without safety concerns,18 and with lower imately one-third of the trial population). Although lower
rates of cardiovascular events in those who achieved the risk than prior trials, these patients could still largely be
lowest LDL-C levels.19 Notably, with longer term follow- classified as very high risk in some guidelines, such as the
up of up to 8.7 years, significant reductions in cardiovas- ESC 2019 Dyslipidemia guidelines.22 Importantly, there
cular and in CHD death were observed.18 is relatively limited data on intensive LDL-C lowering in
Based on the findings of FOURIER, evolocumab is ap- the latter population with diabetes without known AS-
proved for use by the US Food and Drug Administration CVD.23 Notably, VESALIUS-CV represents the first cardio-
and the European Medicines Agency to reduce the risk of vascular outcomes study of a PCSK9 inhibitor in such a
myocardial infarction, stroke and coronary revasculariza- primary prevention population. Since the inception of
tion in patients with established cardiovascular disease VESALIUS-CV, a second cardiovascular outcomes study,
with a prior MI, stroke, or peripheral arterial disease.20 , 21 VICTORION-1 PREVENT (NCT05739383), was designed
Additionally, evolocumab is approved for use in primary to evaluate the effect of another PCSK9 inhibitor, in-
hyperlipidemia, including heterozygous familial hyperc- clisiran, on cardiovascular outcomes in patients without
holesterolemia (FH), and in homozygous FH to reduce a prior major ASCVD event at increased risk for a first
LDL-C. major cardiovascular event. In addition to evaluating ef-
American Heart Journal
Bohula et al 187
Volume 269

ficacy, VESALIUS-CV will assess the long-term safety of ing. Huei Wang: Conceptualization, Data curation, For-
evolocumab with an anticipated median follow up of mal analysis, Methodology, Supervision, Validation, Writ-
≥4.5 years. ing – review & editing. Ajay K. Bhatia: Conceptualiza-
In summary, the VESALIUS-CV trial of 12,301 patients tion, Investigation, Methodology, Supervision, Writing –
with long-term follow-up should provide a definitive as- review & editing. Robert P. Giugliano: Conceptualiza-
sessment of efficacy and safety of evolocumab in patients tion, Investigation, Methodology, Supervision, Writing –
at high risk for a first major cardiovascular event. review & editing. Marc S. Sabatine: Conceptualization,
Investigation, Methodology, Supervision, Writing – re-
Disclosures view & editing.
Drs. Bohula, Giugliano, Marston, Murphy and Saba-
tine are members of the TIMI Study Group. The TIMI Acknowledgements
Study Group reports grant support through Brigham and The study leadership thanks Andrew Hamer MBChB
Women’s Hospital from Abbott, Amgen, Anthos Thera- and Armando Lira Pineda MD for their role in trial design
peutics, ARCA Biopharma, Inc., AstraZeneca, Boehringer and start up during their tenure with Amgen, Inc.
Ingelheim, Daiichi-Sankyo, Eisai, Intarcia, Ionis Pharma-
ceuticals, Inc., Merck, Novartis, Pfizer, Regeneron Phar-
maceuticals, Inc., Roche, Siemens Healthcare Diagnos- Supplementary materials
tics, Inc., Softcell Medical Limited, Verve Therapeutics, Supplementary material associated with this article can
Zora Biosciences. Dr. Bohula reports personal fees from be found, in the online version, at doi:10.1016/j.ahj.
Kowa, Novo Nordisk, Servier and Esperion. Dr. Marston 2023.12.004.
reports no personal fees. Dr. Leiter reports personal fees
from Amarin, Amgen, AstraZeneca, HLS, Kowa, Merck, Appendix A. Sequential parallel
Pfizer, and Sanofi. Dr. Bhatia, Dr. Wang and Ms. Elliott-
Davey are employees and stockholders of Amgen. Dr. gatekeeping procedure
Ruzza is former Amgen employee and stockholder, has The multiplicity adjustment procedure used within the
a pending patent application PCT/US2021/034489 on primary endpoints is the truncated Hochberg procedure.
PCSK9 inhibitors and methods of use thereof to treat The truncated Hochberg procedure is based on the 2-
cholesterol-related disorders, and is currently GSK em- sided alpha level of 0.05. The truncated Hochberg pro-
ployee and stockholder. Dr. Giugliano reports personal cedure can pass the unused alpha from the primary end-
fees from Amgen, Daiichi-Sankyo, Dr. Reddy’s Labora- points to the secondary endpoints if at least 1 of the
tories, Inventiva Pharma, Medical Education Resources, primary endpoints is successful (Figure A1). The fol-
Pfizer, Sanofi, SUMMEET. Dr. Sabatine reports personal lowing endpoint-specific alpha levels for the truncated
fees from Amgen; Anthos Therapeutics; AstraZeneca; Hochberg are constructed by combining the endpoint-
Beren Therapeutics; Boehringer Ingelheim; Dr. Reddy’s specific alpha levels of the conventional Hochberg
Laboratories; Fibrogen; Intarcia; Merck; Moderna; Novo method with the prespecified truncation fraction of 0.5.
Nordisk; Precision BioSciences; Silence Therapeutics. • The first test from the primary endpoints (ie, the
larger P-value for the primary endpoints) for the
CRediT authorship contribution truncated Hochberg test is performed at alpha
statement level of 0.0375. If the first test is successful, then
the remaining test is also considered successful.
Erin A. Bohula: Conceptualization, Investigation, • The remaining test from the primary endpoints, af-
Methodology, Writing – original draft, Writing – re- ter the first test is not successful, is performed at
view & editing. Nicholas A. Marston: Conceptualiza- alpha level of 0.025.
tion, Investigation, Methodology, Writing – review & The multiplicity adjustment procedure used within the
editing, Supervision. Andrea Ruzza: Conceptualization, secondary endpoints is fixed sequence testing proce-
Investigation, Methodology, Writing – review & editing. dure. The specific 2-sided alpha level (α ∗ ) is used for the
Sabina A. Murphy: Conceptualization, Data curation, secondary endpoints depending on the statistically sig-
Investigation, Methodology, Writing – review & editing. nificant results of the primary endpoints as follows:
Gaetano M. De Ferrari: Conceptualization, Investiga-
tion, Writing – review & editing. Rafael Diaz: Concep- • α ∗ = 0.05, if the first test from the primary end-
tualization, Investigation, Writing – review & editing. points (ie, the larger P-value for the primary end-
Lawrence A. Leiter: Conceptualization, Investigation, points) is successful. Note: If the first test is suc-
Writing – review & editing. Mary Elliott-Davey: Con- cessful, then the remaining test is also considered
ceptualization, Data curation, Formal analysis, Investiga- successful. In this case, each of the secondary end-
tion, Methodology, Validation, Writing – review & edit- points are tested at an alpha level of 0.05 in the
 American Heart Journal
188 Bohula et al
March 2024

Figure A1

Sequential parallel gatekeeping procedure.

fixed sequential order the secondary endpoints are Nicholas A. Marston, MD, MPH, Investigator
listed in Figure A1. M. Polly Fish, Director of Operations
• α ∗ = 0.0125, if the first test from the primary end- Alexandra Pricken, MS, Senior Project Manager
points is not successful (ie, the larger P-value for Robin Striar, Lead Clinical Trial Coordinator
the primary endpoints > 0.0375) and the remain- Gina Heller, Clinical Trial Coordinator
ing test from the primary endpoints is successful Sabina A. Murphy, MPH, Director of Statistics
(ie, the smaller P-value in the primary endpoints Julia F. Kuder, MA, Director of Statistical Programming
≤ 0.025). In this case, each of the secondary end-
points are tested at an alpha level of 0.0125 in the Amgen/sponsor leadership
fixed sequential order the secondary endpoints are Narimon Honarpour, MD, SVP Global Development
listed in Figure A1 Magnus Ohman, MD, VP Global Development
• α ∗ = 0, if both tests from the primary endpoints Gabriel Paiva da Silva Lima, MD, Executive Medical Di-
are not successful. rector
Ajay Bhatia, MD, PhD, Clinical Research Medical Direc-
tor
Appendix B. Committees and Marcoli Cyrille, MD, Clinical Research Medical Director
leadership Natasha Hambley, Director Global Clinical Program
TIMI Study Group Mgt
Marc S. Sabatine, MD, MPH, Chair Giles Harding, Senior Manager Global Clinical Program
Robert P. Giugliano, MD, SM, Principal Investigator Huei Wang, Director Global Statistical Lead
Erin A. Bohula, MD, DPhil, Investigator Mary Elliott-Davey, MSc, Study Lead Statistician
American Heart Journal
Bohula et al 189
Volume 269

Executive Committee Marc Bonaca, MD, MPH

Marc S. Sabatine, MD, MPH, Chair Matthew Roe, MD (withdrew from role during trial)
Robert P. Giugliano, MD, SM
Rafael Diaz, MD (withdrew from role during study) Independent Data Monitoring Committee
Lawrence Leiter, MD Charles H. Hennekens, MD, Chairman
Gaetano DeFerrari, MD Felicita Andreotti, MD
Jose C. Nicolau (added in role during study) W. Virgil Brown, MD
Barry R. Davis, MD
Steering Committee includes Members of the Ex- Jamie Hoel, Independent Statistical Data Analysis Cen-
ecutive Committee and the following Investigators tre Member
and National Lead Investigators∗ :
∗
Country of National Lead Investigators shown in Clinical Endpoints Committee
parentheses. Christian Ruff, MD, MPH, Chairman
Rafael Diaz, MD (Argentina; withdrew from role during Cheryl Lowe, CEC Operations Director
study) Elaine Gershman, CEC VESALIUS-CV Sr. Project Man-
Alberto Lorenzatti (Argentina; added in role during ager
study) Eva Moy, CEC VESALIUS-CV Coordinator
Stephen Nicholls, MD, MBBS, PhD (Australia) Cliff Berger, MD, FACC
Christoph Ebenbichler, MD (Austria) David Leeman, MD
Peter Sinnaeve, MD, PhD (Belgium) Carolyn Ho, MD
Jose Carlos Nicolau, MD (Brazil) Frederick Ruberg, MD
Assen Goudev, MD (Bulgaria) Eric Awtry, MD
Subodh Verma, MD (Canada) Kevin Croce, MD, PhD
Lawrence Leiter, MD Akshay Desai, MD, MPH
Ma Changsheng, MD, PhD Eli Gelfand, MD
Vladimir Blaha, MD (Czech Republic) Garrick Stewart, MD, MPH, MMSc
Jindrich Spinar, MUDr, PhD (Czech Republic) Natalia Rost, MD, MPH
Henrik Kjaerulf Jensen, MD (Denmark) Scott Silverman, MD
Margus Viigimaa, MD, PhD (Estonia) Andrew Norden, MD, MPH, MBA
Johanna Kuusisto, MD, PhD (Finland) Aneesh Singhal, MD
Gilles Montalescot, MD (France) Sanjay Divakaran, MD
Ioanna Gouni-Berthold, MD (Germany) Yuri Kim, MD, PhD
Konstantinos Tsioufis, MD (Greece) Ashvin Pande, MD
Robert Kiss, MD (Hungary)
Axel Sigurdsson, MD, PhD (Iceland) References
Gaetano DeFerrari, MD (Italy) 1. Organization WH. Cardiovascular disease (CVDs) fact sheet.
Andrejs Erglis, MD (Latvia) 2021. https://www.who.int/news- room/fact- sheets/detail/
Rimvydas Slapikas, MD, PhD (Lithuania) cardiovascular- diseases- (cvds) [accessed 26 February 2023].
Enrique Morales Villegas, MD (Mexico) 2. Ference BA, Ginsberg HN, Graham I, et al. Low-density
J. H. Cornel, MD (Netherlands) lipoproteins cause atherosclerotic cardiovascular disease. 1.
Andrzej Budaj, MD, PhD (Poland) Evidence from genetic, epidemiologic, and clinical studies. A
Jorge Ferreira, MD (Portugal) consensus statement from the European Atherosclerosis Society
consensus panel. Eur Heart J 2017;38:2459–72.
Dragos Vinereanu, MD, PhD, FRCP (Romania)
3. Ference BA, Yoo W, Alesh I, et al. Effect of long-term exposure to
Oleg Averkov, MA (Russian Federation)
lower low-density lipoprotein cholesterol beginning early in life
Daniel Pella, MD, PhD (Slovakia) on the risk of coronary heart disease: a Mendelian
Hyo-soo Kim, MD, PhD (South Korea) randomization analysis. J Am Coll Cardiol 2012;60:2631–9.
Jose Lopez-Sendon, MD (Spain) 4. Silverman MG, Ference BA, Im K, et al. Association between
Jacob Odenstedt, MD (Sweden) lowering LDL-C and cardiovascular risk reduction among different
Min-Ji Charng, MD (Taiwan) therapeutic interventions: a systematic review and meta-analysis.
Lale Tokgozoglu, MD JAMA 2016;316:1289–97.
Naveed Sattar, MD (United Kingdom) 5. Cholesterol Treatment Trialists C, Mihaylova B, Emberson J, et al.
Alexandr Parkhomenko, MD (Ukraine) The effects of lowering LDL cholesterol with statin therapy in
Robert Giugliano, MD, SM (USA) people at low risk of vascular disease: meta-analysis of individual
data from 27 randomised trials. Lancet 2012;380:581–90.
Erin Bohula, MD, DPhil (USA)
6. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and
Ron Blankstein, MD
clinical outcomes in patients with cardiovascular disease. N Engl
Jeffery Saver, MD J Med 2017;376:1713–22.
 American Heart Journal
190 Bohula et al
March 2024

7. Schwartz GG, Steg PG, Szarek M, et al. Alirocumab and 16. Giugliano RP, Pedersen TR, Park JG, et al. Clinical efficacy and
cardiovascular outcomes after acute coronary syndrome. N Engl safety of achieving very low LDL-cholesterol concentrations with
J Med 2018;379:2097–107. the PCSK9 inhibitor evolocumab: a prespecified secondary
8. Hicks KA, Mahaffey KW, Mehran R, et al. 2017 Cardiovascular analysis of the FOURIER trial. Lancet 2017;390:1962–71.
and stroke endpoint definitions for clinical trials. Circulation 17. Giugliano RP, Mach F, Zavitz K, et al. Cognitive function in a
2018;137:961–72. randomized trial of evolocumab. N Engl J Med
9 US Department of Health and Human Services FaDAF, Center for 2017;377:633–43.
Drug Evaluation and Research (CDER), Center for Biologics 18. O’Donoghue ML, Giugliano RP, Wiviott SD, et al. Long-term
Evaluation and Research (CBER). Multiple endpoints in clinical evolocumab in patients with established atherosclerotic
trials (guidance for industry). 2017. https://www.fda.gov/ cardiovascular disease. Circulation 2022;146:1109–19.
downloads/drugs/guidancecomplianceregulatoryinformation/ 19. Gaba P, O’Donoghue ML, Park JG, et al. Association between
guidances/ucm536750.pdf [accessed 1 November 2003]. achieved low-density lipoprotein cholesterol levels and long-term
10. Bhatt DL, Steg PG, Miller M, et al. Cardiovascular risk reduction cardiovascular and safety outcomes: an analysis of
with icosapent ethyl for hypertriglyceridemia. N Engl J Med FOURIER-OLE. Circulation 2023;147:1192–203.
2019;380:11–22. 20. Agency EM. Repatha: EPAR product information. 2023. https:
11. Steg PG, Bhatt DL, Simon T, et al. Ticagrelor in patients with //www.ema.europa.eu/en/medicines/human/EPAR/repatha
stable coronary disease and diabetes. N Engl J Med [accessed November 1 2023].
2019;381:1309–20. 21. Administration UFaD. Repatha prescribing information. 2017.
12. Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added https://www.accessdata.fda.gov/drugsatfda_docs/label/
to statin therapy after acute coronary syndromes. N Engl J Med 2017/125522s014lbl.pdf [accessed November 1 2023].
2015;372:2387–97. 22. Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS
13. Nissen SE, Lincoff AM, Brennan D, et al. Bempedoic acid and guidelines for the management of dyslipidaemias: lipid
cardiovascular outcomes in statin-intolerant patients. N Engl J modification to reduce cardiovascular risk. Eur Heart J
Med 2023;388:1353–64. 2020;41:111–88.
14. Sabatine MS, De Ferrari GM, Giugliano RP, et al. Clinical Benefit 23. Colhoun HM, Betteridge DJ, Durrington PN, et al. Primary
of evolocumab by severity and extent of coronary artery disease: prevention of cardiovascular disease with atorvastatin in type 2
analysis from FOURIER. Circulation 2018;138:756–66. diabetes in the Collaborative Atorvastatin Diabetes Study
15. Schwartz GG, Giugliano RP. Proprotein convertase (CARDS): multicentre randomised placebo-controlled trial. Lancet
subtilisin/kexin type 9 inhibition after acute coronary syndrome 2004;364:685–96.
or prior myocardial infarction. Curr Opin Lipidol
2022;33:147–59.