Early Initiation of Tafolecimab for Patients With Acute Coronary Syndromeundergoing Percutaneous Coronary Intervention in Chinese Population (EMPACT): A Randomized Controlled Trial
Phase: NA
Conditions: Acute Coronary Syndrome, Non ST Segment Elevation Acute Coronary Syndrome
Sponsor: China National Center for Cardiovascular Diseases

A Randomized Controlled Trial of Early Initiation of Intensive Lipid-Lowering Therapy for Patients
with Acute Coronary Syndrome undergoing Percutaneous Coronary Intervention _20230825
A Randomized Controlled Trial of Intensive
Lipid-Lowering
Therapy
to
Improve
Prognosis in Patients with Acute Coronary
Syndrome and Establishment of A Model
for Evaluating Risk for Residual Serum
Lipid
-- A Randomized Controlled Trial of Early
Initiation
of
Intensive
Lipid-Lowering
Therapy for Patients with Acute Coronary
Syndrome
undergoing
Percutaneous
Coronary Intervention
Research protocol
Version Number: V2.0
Version Date: 20230705
Project source: Chinese Academy of Medical Sciences
Principle Investigator: Zhou Zhou
Affiliation Department: Center of Clinical Laboratory, Fu Wai
Hospital, Chinese Academy of Medical Sciences
Contact: Na-qiong Wu
Tel: +86 13501139869
Project implementation period: December 2023 to December 2025

A Randomized Controlled Trial of Early Initiation of Intensive Lipid-Lowering Therapy for Patients
with Acute Coronary Syndrome undergoing Percutaneous Coronary Intervention _20230825
Contents
1. Research Background............................................................................................. 1
2. Research Purpose.................................................................................................... 6
3. Research Method..................................................................................................... 6
3.1 Research Design Method............................................................................. 6
3.2 Research Object........................................................................................... 7
3.3 Selection and validation of research indicators or outcome indicators....... 9
3.4 Early termination of study........................................................................... 9
4. Sample size estimation.......................................................................................... 10
5. Data management.................................................................................................. 10
6. Principle of confidentiality................................................................................... 11
7. Quality control of research................................................................................... 11
8. Ethical principles................................................................................................... 11
8.1 Ethical approval................................................................................................. 11
8.2 The process of informed consent....................................................................... 11
8.3 Risk minimization.............................................................................................. 12
9. Organization and management of the research.................................................. 12
10. References............................................................................................................ 12

A Randomized Controlled Trial of Early Initiation of Intensive Lipid-Lowering Therapy for Patients
with Acute Coronary Syndrome undergoing Percutaneous Coronary Intervention _20230825
1
1. Research background
Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death
worldwide, and its incidence is increasing yearly in China, which has not yet reached
the inflection point [1]. Acute coronary syndrome (ACS) is a severe form of ASCVD,
and lipid-lowering and antithrombotic therapy are the two core therapies. In the latest
ESC/EAS guidelines for lipid management [2], for ACS patients, the target LDL-C is
<1.4 mmol/L and ≥50% reduction from baseline, and specific initiatives to achieve
this target are proposed, emphasizing the timing of clinical application and status of
the
novel
lipid-lowering
agent-proprotein
convertase
subtilisin/kexin
type
9
monoclonal antibody (PCSK9) (hereafter referred to as PCSK9 antibody). In recent
years, large-scale randomized controlled trials and outcomes of PCSK9 antibodies
have demonstrated that PCSK9 antibodies further reduce adverse cardiovascular
events by significantly lowering LDL-C levels under the background statin ( ±
cholesterol absorption inhibitor ) therapy [3-5]. The introduction of PCSK9 antibodies
allowed for the reduction of LDL-C to unprecedented levels. From the "cholesterol
principle" perspective, it is theoretically reasonable to add a PCSK9 inhibitor to
statins as soon as possible during hospitalization for ACS patients. Still, there is no
clear evidence from large RCTs. Current evidence supports that for ACS patients,
PCSK9 antibodies could be used only when LDL-C is still not up to standard based
on treatment with the maximum tolerable dose of statins during the first 2-3 months.
However, the immediate initiation of PCSK9 antibodies during the acute phase of
ACS (before hospital discharge) has yet to be studied.
1.1 Evidence-based evidence of cardiovascular benefit from early initiation of
intensive lipid-lowering for ACS patients
Previous
statins-related
studies
have
found
that
the
MIRACL
study
(Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering) initiated
treatment with atorvastatin 80 mg/day or placebo four days after hospitalization in
3,086 patients with ACS for four months [6]. Mean LDL-C at four months were
72 and 135 mg/dl, respectively, and the incidence of MACE was 14.8% and 17.4%
(RR, 0.84; 95% CI, 0.70-1.00; P=0.048)[7]. The PROVE-IT trial (Pravastatin or
Atorvastatin Evaluation and Infection Therapy) compared 4,162 patients with ACS
after ten days with atorvastatin 80 mg/day and pravastatin 40 mg/day given for a
median duration of two years, with a median LDL-C of 62 mg/dl and 95 mg/dl,
respectively [8]. In the early benefit analysis in the PROVE-IT trial, the incidence of
MACE was lower in the early initiation of atorvastatin 80 mg group after ACS,
with a 30-day post-randomization group primary endpoint (3.0% vs. 4.2%; HR, 0.72;
95% CI, 0.52-0.99; P=0.046) and triple primary composite endpoint -defined as death,
myocardial infarction, or recurrent ACS with rehospitalization (9.6% vs. 13.1%; HR,

A Randomized Controlled Trial of Early Initiation of Intensive Lipid-Lowering Therapy for Patients
with Acute Coronary Syndrome undergoing Percutaneous Coronary Intervention _20230825
2
0.72; 95%CI, 0.58-0.89; P=0.003) was significantly different between groups. Besides,
the four months primary composite endpoint was different between groups (8.2% vs.
10.2%; HR, 0.81; 95 CI%, 0.65-0.98; P=0.03) [9]. The above findings suggest that in
the statin times, compared with conventional lipid-lowering therapy, early
treatment (Days 4-10 after ACS) with intensive lipid-lowering (high-intensity
statins) has more clear cardiovascular benefits, which appear as early as the 30th
day and most significantly at four months for ACS patients.
1.2 Evidence-based evidence of more cardiovascular benefit in ACS patients by
achieving lower LDL-C
A recent meta-analysis that included 19 studies (15 for statins, 3 for PCSK9
antibodies, and 1 for ezetimibe, n=152,507) comparing intensive lipid-lowering
(n=76,679) with conventional lipid-lowering (n=75,829) found that intensive LDL-
C-lowering further reduced adverse cardiovascular events (RR, 0.81; 95% CI,
0.77-0.86) [10]. Evidence indicated that most ACS patients can achieve very low
LDL-C to less than 1.0 mmol /L with PCSK9 antibodies in combination with statin ±
ezetimibe, which has confirmed safety. Among these studies, the FOURIER study, as
well as the ODESSEY OUTCOME study, have confirmed that in ACS patients with
sub-standard LDL-C, the addition of PCSK9 antibodies results in lower LDL-C levels,
which leads to more cardiovascular benefits and a lower incidence of MACE [3-5].
The latest study, FOURIER-OLE (open-label extension), suggested that ASCVD
patients applied evolocumab for up to 8.4 years (median five years), with a median
LDL-C level of 30 mg/dL. Still, the incidence of adverse events such as serious
adverse events, muscle-related events, new-onset diabetes mellitus, hemorrhagic
strokes, and neurocognitive events was not increased by long-term use of evolocumab
compared with the placebo group. Besides, long-term maintenance of <20 mg/dl
(<0.5 mmol/L) by evolocumab was associated with a lower risk of cardiovascular
outcomes [11-12]. The ODSSEY OUTCOME study found a trend toward a decrease
in all-cause deaths in the Alirocumab group, with a four months LDL-C of up to 30
mg/dl (linear trend-adjusted P=0.017) [13]. The evidence from the above studies
confirmed that lower LDL-C levels resulted in more cardiovascular benefits
without increasing the incidence of additional adverse events.
1.3 Delayed benefitss and memory effects of applying intensive lipid-lowering
therapy in ACS patients
The delayed benefits, or memory effects of intensive lipid-lowering therapy
have been defined as the benefit obtained after a specific duration of intensive lipid-
lowering treatment has been applied that persists for a more extended period after the
cessation of the trial (discontinuation of the medication) to examine the long-term
clinical benefits of the pharmacologic intervention. The memory effect of intensive

A Randomized Controlled Trial of Early Initiation of Intensive Lipid-Lowering Therapy for Patients
with Acute Coronary Syndrome undergoing Percutaneous Coronary Intervention _20230825
3
statins therapy has been demonstrated. A systematic review studying the legacy
effects of treating hypertriglyceridemia included 13 RCTs of lipid-lowering drugs
compared with placebo or conventional lipid-lowering therapy with follow-up at the
end of the trial. All of these demonstrated that lipid-lowering therapy produces a
legacy effect of preventing both fatal and nonfatal events, which showed that early
treatment leads to more profound clinical effects [14]. The 20-year follow-up of the
WOSCOPS trial about the memory effect of statins therapy has confirmed [15] that
compared with the control group, the cardiovascular risk-benefit for five years of
lipid-lowering therapy with pravastatin application persisted for 20 years. These
benefits were also evident across outcomes (mortality and hospitalization) and did not
diminish over time. However, previous studies of memory effects have not indicated
whether these benefits were unique to intensive statin therapy or due to statin
lowering serum lipid profile levels. In a post hoc analysis of the ODYSSEY
OUTCOMES trial comparing the efficacy of a PCSK9 inhibitor (alirocumab) to
placebo, both groups were used for high-intensity or maximally tolerated doses of
statin therapy. Patients with two consecutive LDL-C levels <0.39 mmol/L (15 mg/dL)
on alirocumab, then alirocumab was discontinued. Over a median follow-up of 2.8
years, the incidence of MACE in alirocumab group that reached the target LDL-C was
significantly lower than that in placebo group (6.4% vs. 8.4%; HR, 0.72; 95% CI,
0.51-0.997; P=0.047). These suggested that after the use of intensive lipid-lowering
therapy (statin + alirocumab) to achieve limited duration with an LDL-C level of
<0.39 mmol /L, followed by statin monotherapy was associated with a lower risk of
MACE compared with statin monotherapy. This clinical benefit persisted for several
years after discontinuation of PCSK9 inhibitors [16].
1.4 PCSK9 and platelet functions
In vitro studies, in vivo animal studies, and human studies have confirmed that
PCSK9 levels correlate with platelet reactivity [17-20]. One study found that plasma
levels of sP-selectin, a biomarker of platelet and endothelial activation, was
significantly lower in PCSK9-/- mice than in control mice, suggesting that platelet
function is impaired in PCSK9-/- mice [17]. Increases in thrombotic events of
relevance have been detected in mice transfected with the PCSK9 adenovirus, and
human studies have confirmed a positive correlation between PCSK9 levels and
platelet reactivity [20].
A prospective observational study consecutively enrolled ACS patients
receiving prasugrel or ticagrelor and undergoing PCI [21] used a multiplate analyzer
to determine adenosine diphosphate (ADP)-induced platelet aggregation. Major
adverse cardiovascular events (MACE) were defined as a composite of cardiovascular
death,
myocardial
infarction,
unstable
angina,
stent
thrombosis,
repeat

A Randomized Controlled Trial of Early Initiation of Intensive Lipid-Lowering Therapy for Patients
with Acute Coronary Syndrome undergoing Percutaneous Coronary Intervention _20230825
4
revascularization, and ischemic stroke with a 12-month follow-up. A direct
association was found between elevated PCSK9 serum levels and platelet reactivity
(r=0.30; p=0.004). Platelet reactivity was assessed according to tertiles of PCSK9
levels and was found to be significantly higher in those located in the highest tertile
than in the lowest tertile (p=0.02). In patients with PCSK9 levels located in the
highest tertile, 13/59 (22.03%) developed MACE within one year, whereas in the
lowest tertile of PCSK9, 2/59 (3.39%) did so. At one-year follow-up, PCSK9 was
independently associated with an increase in ischemic MACE: the risk ratio for the
occurrence of MACE at high PCSK9 levels versus low PCSK9 levels was 2.62%. The
risk ratio for the occurrence of MACE was 2.62 (95% CI 1.24-5.52; p = 0.01).
Figure 1 Cited in Navarese EP, Kolodziejczak M, Kereiakes DJ, Tantry US, O'Connor C, Gurbel PA. Proprotein Convertase
Subtilisin/Kexin Type 9 Monoclonal Antibodies for Acute Coronary Syndrome: a Narrative Review. annals of internal medicine
2016;164:600-7.
Plasma PCSK9 levels are elevated in the acute phase in ACS patients.
Evidence confirms that elevated PCSK9 levels are associated with atherosclerotic
plaque instability, inflammatory response, and platelet reactivity [22-23].
PCSK9 inhibitors can potentially deplete cholesterol from platelet membranes
by significantly reducing LDL-C levels; its inhibitory effect on platelet activation may
also be mediated by decreasing the ability of platelets to oxidize LDL, thereby
decreasing the latter's ability to stimulate platelet activity via the CD36 and LOX- 1
receptor pathways; in addition, PCSK9 inhibitors reduce levels of lipoprotein(a)
[Lp(a)] ( a primary carrier of oxidized phospholipids), thereby potentially impairing
its ability to activate platelets via toll-like receptor 2 (TRL2); PCSK9 inhibitors also
increase high-density lipoprotein (HDL), reduce platelet activation acting on apoER2

A Randomized Controlled Trial of Early Initiation of Intensive Lipid-Lowering Therapy for Patients
with Acute Coronary Syndrome undergoing Percutaneous Coronary Intervention _20230825
5
and SRB1 receptors, and remove cholesterol from platelet membranes. By both
intracellular and extracellular mechanisms, PCSK9 inhibitors enhance the hepatic
LDLR expression and possibly LRP-1 expression, potentially enhancing FVIII
internalization and degradation and reducing FVIII plasma levels. In addition, PCSK9
inhibitors may also reduce the activity of circulating tissue factor (TF) by accelerating
its clearance.
Several studies have shown that PCSK9 antibodies' application in ACS
patients significantly reduced major adverse cardiovascular events (MACE) in post-
ACS patients by plaque modification, interfering with lipid metabolism, platelet
aggregation and ultimately improving endothelial function [24-25]. Therefore, this
may justify earlier initiation of PCSK9 monotherapy.
1.5 Evidence that early initiation of intensive lipid-lowering with PCSK9i results
in earlier achievement of lower LDL-C levels
The risk of major adverse cardiovascular events in the first year after ACS is
very high. Early initiation of PCSK9 monotherapy after ACS reduces the incidence of
MACE. In the newly completed EVACS (Evolocumab in Acute Coronary Syndrome)
study, Evolocumab resulted in 90% of patients with LDL-C < 55 mg/dL compared to
11% of patients receiving statins only [26]. In the EVOPACS study (Evolocumab for
Early Reduction of LDL-cholesterol Levels in Patients With Acute Coronary
Syndromes), Evolocumab resulted in 95.7% of patients achieving LDL-C levels < 55
mg/dL [27].
Taking the above evidence into account (Figure 2), we hypothesize that the
early initiation of lipid-lowering therapy including PCSK9 antibodies for ACS
patients undergoing PCI as soon as possible to achieve lower LDL-C levels, is
predicted to reduce the incidence of major adverse cardiovascular events in patients
after discontinuation of the drug compared with the conventional lipid-lowering
therapy. Thus we propose the optimization strategy of "intensive lipid-lowering with
PCSK9 antibodies can be initiated as early as possible in ACS patients undergoing
PCI.

A Randomized Controlled Trial of Early Initiation of Intensive Lipid-Lowering Therapy for Patients
with Acute Coronary Syndrome undergoing Percutaneous Coronary Intervention _20230825
6
Figure 2 Evidence supporting the New Strategy for Acute Coronary
Syndromes
2. Research purpose
In ACS patients undergoing PCI, early initiation of intensive lipid-lowering
with PCSK9 antibodies, namely achieving lower LDL-C levels as soon as possible, is
expected to reduce the incidence of major adverse cardiovascular events in patients
after discontinuation of the drug compared with conventional lipid-lowering therapy.
Therefore, an optimization strategy of "early initiation of intensive lipid-lowering
with PCSK9 antibodies in ACS patients undergoing PCI " is proposed.
3. Research method
3.1 Research design method
This is a national, multicenter, randomized controlled study with Fu Wai Hospital
as the group leader and at least 7 sub-centers. Patients eligible for enrollment will be
randomized into: group 1 (G1, experimental group): intensive lipid-lowering (statins
+ PCSK9 antibodies); group 2 (G2, control group) conventional lipid-lowering
(statins + cholesterol absorption inhibitor).

A Randomized Controlled Trial of Early Initiation of Intensive Lipid-Lowering Therapy for Patients
with Acute Coronary Syndrome undergoing Percutaneous Coronary Intervention _20230825
7
Methods of randomization: All eligible patients entering the appropriate
group are randomly grouped using IRT to obtain a random number, which is
automatically assigned to a random number by the system. The planned time to
complete enrollment of all patients was at most one year, with a maximum follow-up
of two years. Safety assessments included monitoring of all adverse events (AEs),
serious adverse events (SAEs), and regular monitoring of vital signs and clinical
laboratory tests.
3.2 Research object
3.2.1 Criteria for inclusion, exclusion, and withdrawal
A total of 3684 patients will be enrolled. Inclusion criteria: Patients 18 to 75
years of age with acute non-ST elevation myocardial infarction (NSTEMI),
completing PCI and 1.8mmol/L< Baseline LDL-C level <3.4mmol/L. NSTE-ACS
includes non-ST-segment elevation myocardial infarction and unstable angina.
Exclusion criteria: 1) Severe heart failure (Killip class Ⅲor Ⅳ) or cardiogenic
shock; 2) Known hemorrhagic stroke at any time; 3) Uncontrolled or recurrent
arrhythmic events; 4) Uncontrolled hypertension; 5)Severe hepatic and renal
dysfunction, or CK >5 times the ULN; 6) Malignant tumor; 7) Intolerant to statins or
cholesterol absorption inhibitor; 8) Intolerant to injections; 9) Life expectancy < 1
year; 10) Poor compliance. Withdrawal criteria: Patients may withdraw from the
study at any time.
3.2.2 Grouping of research subjects
Randomization: 1842 cases in each group. Group 1 (G1, experimental group,
n=1842): intensive lipid-lowering (statin + PCSK9 antibodies). Group 2 (G2, control
group, n=1842): conventional lipid-lowering (statin + cholesterol absorption inhibitor).
The PCSK9 antibodies in this study are toleucizumab 150 mg q2w i.h. In terms of
lipid-lowering therapy for both groups, lipid-related guidelines are followed to ensure
that, as far as possible, lipid-lowering therapy other than PCSK9 antibodies remained
unchanged throughout the study period, provided that no serious safety issues
occurred. In terms of lipid compliance, the baseline LDL-C range of 1.8-3.4 mmol/L
in the enrollment criteria has excluded the population with high baseline LDL-C
levels that are not easy to comply with, and lipid-lowering drugs other than PCSK9
antibodies can satisfy the guideline requirement of LDL-C compliance level. In
addition, concerning the ODYSSEY OUTCOMES study, LDL-C <0.4 mmol/L (15
mg/dL) was selected as the safety threshold (discontinuation criterion) for the
application of PCSK9 monoclonal antibody to achieve very low levels of LDL-C [16].
SCREENING PERIOD: patients 18 to 75 years of age with acute non-ST
elevation myocardial infarction (NSTEMI), completing PCI and 1.8mmol/L<
Baseline LDL-C level <3.4mmol/L will be screened at each subcenter.

A Randomized Controlled Trial of Early Initiation of Intensive Lipid-Lowering Therapy for Patients
with Acute Coronary Syndrome undergoing Percutaneous Coronary Intervention _20230825
8
Random Grouping: All eligible patients are grouped using randomization,
and the system generates a random list, automatically assigning patient numbers to
random numbers.
BLINDED AND UNBLINDED: This study utilized an unblinded design.
Enrolled patients, researchers, academic research center staff, and treating physicians
know the treatment.
Visit 0 (V0): is the day of enrollment. Patients will sign informed consent. We
will complete all baseline data collection and give appropriate treatment therapy
according to groups.
Visit 1 (V1): is the day at the end of 1 month after enrollment. We use routine
laboratory tests to determine the patients' tolerance of the treatment therapy (safety
assessment).
Visit 2 (V2): is the day at the end of 6 months after enrollment. We use blood
for routine laboratory tests, record major adverse cardiovascular events (MACEs), and
follow patients' tolerance (safety assessment) and compliance with the therapy.
Visit 3 (V3): is the day at the end of year 1 after enrollment. We use blood for
routine laboratory tests, record the secondary key observational endpoint (the
occurrence of major adverse cardiovascular and cerebrovascular events (MACCE) at
the end of year 1), and follow up on the patients' tolerance (safety assessment) and
compliance with the therapy.
Visit 4 (V4): is the day at the end of year 2 after enrollment. We use blood for
routine laboratory tests and record the primary observation endpoint (the occurrence
of MACCE at the end of year 2).
Figure 3: Flow chart of the study

A Randomized Controlled Trial of Early Initiation of Intensive Lipid-Lowering Therapy for Patients
with Acute Coronary Syndrome undergoing Percutaneous Coronary Intervention _20230825
9
3.3 Selection and validation of study or outcome indicators
Primary Observational Endpoint: The primary observational endpoint is 2-
year MACCE (Major adverse cardiovascular and cerebrovascular events, including
cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, hospitalization
for unstable angina, and coronary revascularization). Coronary revascularization
included undergoing coronary intervention (PCI) and coronary artery bypass grafting
(CABG).
Secondary key observational endpoints: Key secondary observational
endpoints include MACEs (major adverse cardiovascular events,
defined as
cardiovascular death, nonfatal myocardial infarction, hospitalization for unstable
angina, and coronary revascularization) at the end of 2 years.
Secondary Observational Endpoints: Secondary observational endpoints
include MACCE at the end of 1 year (Major adverse cardiovascular and
cerebrovascular
events,
defined
as
cardiovascular
death,
nonfatal
myocardial
infarction,
nonfatal
stroke,
hospitalization
for
unstable
angina,
coronary
revascularization, and bleeding-related events)
Additional Observational Endpoints: Additional observational endpoints
include the individual observational endpoints that make up the MACCE at the end of
2 years.
3.4 Early termination of study
Early termination of the study means terminating the study due to efficacy or
safety. If safety concerns pose unexpected risks to patients, the study may be
suspended or terminated early when necessary. Suppose this study is brought up for
termination. In that case, the Clinical Coordinating Center will provide a written
statement to the Collaborative Principal Investigators, so that each Collaborative
Principal Investigator can notify their respective Ethics Committees and patients. The
Clinical Coordinating Center will also notify the appropriate authorities. The Clinical
Coordinating Center may terminate the enrollment of the Collaboration or may no
longer allow the Investigator or Collaboration to participate in the study if there is
evidence that the Investigator has failed to conduct appropriate clinical standards or
has failed to comply with the study protocol. Notification of suspension or
termination of the study or the study collaborative's/investigator's participation in the
study will be sent to the investigator and the Ethics Committee. Once the study is
terminated early, patients will be notified according to the process and receive a
routine lipid-lowering regimen established by the clinician.

A Randomized Controlled Trial of Early Initiation of Intensive Lipid-Lowering Therapy for Patients
with Acute Coronary Syndrome undergoing Percutaneous Coronary Intervention _20230825
10
4.Sample size estimation
Refer to previous studies, the application of PCSK9 antibodies based on statin
therapy significantly reduced the incidence of MACEs (defined as coronary heart
disease death, non-fatal infarction, re-hospitalization for unstable angina, or ischemic
stroke events) compared with placebo (OR=0.72) [16], and this benefit was more
evident in the high-risk ASCVD population. Evidence from previous studies suggests
[5] that the 2-year event rate of MACEs (definition: cardiovascular death, myocardial
infarction, stroke, hospitalization for unstable angina, and coronary revascularization)
in the control group (G2, conventional lipid-lowering) was approximately 13.6%,
presupposing that the OR of the intensive lipid-lowering group with early initiation of
PCSK9i in the present study relative to that of the conventional lipid-lowering group
= 0.70, and the 2-year MACEs (defined as: cardiovascular death, myocardial
infarction, stroke, hospitalization for unstable angina, and coronary revascularization)
event rate in the test group (G1, intensive lipid-lowering) 2-year MACCE incidence
was 9.52%, and the 1:1 ratio of enrollment according to the overall test level of two-
sided α=0.05, test efficacy β=0.80, would result in a single-group sample size of 1,749
cases, a total sample size of 3,498 cases, and a total of 3,684 patients would be needed
to account for a 5% dropout rate.to account for a 5% dropout rate.
5.Data management
To ensure the accuracy and authenticity of data collection, the research team
unified data quality control training. The data come from the baseline and follow-up
data collected by the investigators, and the collected baseline and follow-up data are
organized to establish the database. The database will be stored separately by the
investigator of this study to ensure that the database is not leaked to the public. During
the follow-up survey, the designated study doctor will be responsible for the
collection and entry of follow-up data. The data will be entered in pairs, and the
results of the entry will be used to identify issues such as missing values, outliers, and
logical errors, effectively avoiding mistakes during data entry and merging the
databases through the software data comparison function. In order to strengthen the
management and quality control of clinical endpoint events, a Clinical Endpoint Event
Committee (CEC) will be established to determine the expected endpoint events of
the trial under the unified evaluation criteria during and at the end of the trial, so as to
more accurately evaluate the results of the trial.

A Randomized Controlled Trial of Early Initiation of Intensive Lipid-Lowering Therapy for Patients
with Acute Coronary Syndrome undergoing Percutaneous Coronary Intervention _20230825
11
6.The principle of confidentiality
All the data of this study, are stored in Fu Wai Hospital. The researcher strictly
abides by the principle of confidentiality in accordance with the regulations. Data
desensitization technology is applied to de-identify personal information, protect
private data, ensure information security, and collect, extract, and analyze information
in the background. All data will be appropriately kept as the basis of the study and
will not be used as evidence for other purposes, and only the researcher, the research
authority, and the Ethics Committee will be allowed to access the relevant data of the
study. The identity of the enrollees and the privacy of their personal data will not be
mentioned in any study report. The data and results of this study may be published or
made public in paper or electronic form in domestic or foreign medical journals or
other media, but the researcher will maintain the confidentiality of the identity of the
study participants in accordance with the legal requirements to ensure that the
personal information of the study participants will not be disclosed.
7.Quality control of research
Quality control of the main aspects of the study, assessment of whether the
collaborating unit has the facilities and conditions required for the study before the
investigation is initiated, quality control during the clinical research process,
laboratory processes, quality control of data management, division of labor,
clarification of duties and authorization of the participating researchers, unified
training and monitoring plan for the study protocol and the corresponding operations,
and so on.
8. Ethical principle
8.1 Ethical approval
This study protocol will comply with relevant laws and regulations and be
approved by the Ethics Committee. In the execution of all aspects of the study, all
specifications set forth in the protocol will be strictly followed; the investigator will
not modify or change the operating procedures described in this protocol. If any
modification of the study protocol and informed consent is required during the study,
it will be re-submitted to the Ethics Committee for approval.
8.2 The process of informed consent
Before each subject is enrolled in the study, the investigator will provide
him/her or his/her legal representative with the content and instructions of a complete,
comprehensive,
easy-to-understand,
and
Ethics
Committee-approved
informed
consent form in written text and give the subject or his/her legal representative
sufficient time to consider whether or not to participate in the study. Entry into the
study is allowed only after the informed consent is signed by the subject or his/her
legal representative. During the study, if new safety information results in a

A Randomized Controlled Trial of Early Initiation of Intensive Lipid-Lowering Therapy for Patients
with Acute Coronary Syndrome undergoing Percutaneous Coronary Intervention _20230825
12
significant change in the risk/benefit assessment, the subject or his/her legal
representative will be provided with all the updated new information, and a new
informed consent form will be re-signed.
8.3 Risk minimization
This study firmly adheres to the principle of minimization of risk to subjects
regarding informed consent, benefits to subjects (personal and societal benefits)
versus risk, confidentiality, and conflict of interest.
9. Organizational management of the study
The project source of this study is the Chinese Academy of Medical Sciences,
and it is an investigator-initiated study. The Cardiovascular Metabolism Center of Fu
Wai Hospital, as the group leader, and Naqiong Wu, as the specific implementer of
this study, are responsible for the overall operation of the study, including the
management of the participating collaborators and the monitoring analysis and
reporting of the collaborators. Naqiong Wu are responsible for the treatment grouping
of eligible subjects, acceptance and processing of data collected by the leader unit (Fu
Wai Hospital) and the collaborating units, quality control, and statistical analysis and
reporting.
10. References
[1]. Joint Committee on Revision of Guidelines for Prevention and Control of
Dyslipidemia in Chinese Adults. Chinese Guidelines for Prevention and Control
of Dyslipidemia in Adults (2016 Revision). Chinese Journal of Circulation, 2016,
31: 937-953.
[2]. 2019 ESC/EAS guidelines for the management of dyslipidaemias: Lipid
modification to reduce cardiovascular risk. Atherosclerosis. 2019;290:140-205.
[3]. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N
Engl J Med. 2017 May 4;376(18):1713-1722.
[4]. Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome.N
Engl J Med. 2018 ;379(22):2097-2107.
[5]. Sabatine MS, De Ferrari GM, Giugliano RP, et al. Clinical Benefit of
Evolocumab by Severity and Extent of Coronary Artery Disease: Analysis From
FOURIER. Circulation. 2018;138(8):756-766.
[6]. Schwartz GG, Olsson AG, Ezekowitz MD, et al. Effects of atorvastatin on early
recurrent ischemic events in acute coronary syndromes: the MIRACL study: a
randomized controlled trial. JAMA 2001; 285:1711-8
[7]. Kinlay S, Schwartz GG, Olsson AG, et al. High- dose atorvastatin enhances the
decline in inﬂammatory markers in patients with acute coronary syndromes in the

A Randomized Controlled Trial of Early Initiation of Intensive Lipid-Lowering Therapy for Patients
with Acute Coronary Syndrome undergoing Percutaneous Coronary Intervention _20230825
13
MIRACL study. Circulation 2003; 108:1560-6.
[8]. Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus moderate lipid
lowering with statins after acute coronary syndromes. N Engl J Med 2004;350.
1495-504.
[9]. Ray KK, Cannon CP, McCabe CH, et al. Early and late beneﬁts of high-dose
atorvastatin in patients with acute coronary syndromes: results from the PROVE
IT- TIMI 22 trial. J Am Coll Cardiol 2005;46: 1405-10
[10].
Koskinas KC, Siontis GCM, Piccolo R et al. Effect of statins and non-statin
LDL-lowering medications on cardiovascular outcomes in secondary prevention:
a meta-analysis of randomized trials. Eur Heart J. 2018 Apr 7;39(14):1172-1180.
[11].
O'Donoghue ML, Giugliano RP, Wiviott SD, et al. Long-Term Evolocumab in
Patients with Established Atherosclerotic Cardiovascular Disease. Circulation.
2022;146(15):1109-1119.
[12].
Gaba P, O'Donoghue ML, Park JG, et al. Association Between Achieved Low-
Density Lipoprotein Cholesterol Levels and Long-Term Cardiovascular and
Safety
Outcomes:
an
Analysis
of
FOURIER-OLE.
Circulation.
2023;10.1161/CIRCULATIONAHA.122.063399.
[13].
Steg PG, Szarek M, Bhatt DL, et al. Effect of Alirocumab on Mortality After
Acute Coronary Syndromes. Circulation. 2019 Jul 9;140(2):103-112.
[14].
Kostis JB, Shetty M, Chowdhury YS, Kostis WJ. The Legacy Effect in
Treating Hypercholesterolemia. J Cardiovasc Pharmacol Ther. 2020;25(4):291-
298.
[15].
Kashef MA, Giugliano G. Legacy effect of statins: 20-year follow up of the
West of Scotland Coronary Prevention Study (WOSCOPS). Glob Cardiol Sci
Pract. 2016;2016(4):e201635. Published 2016 Dec 30.
[16].
Schwartz GG, Szarek M, Bhatt DL, et al. Transiently achieved very low LDL-
cholesterol levels by statin and alirocumab after acute coronary syndrome are
associated with cardiovascular risk reduction: the ODYSSEY OUTCOMES trial.
eur Heart J. 2023;ehad144.
[17].
Wang H, Wang Q, Wang J, et al. Proprotein convertase subtilisin/ kexin type 9
(PCSK9) deﬁciency is protective against venous thrombosis in mice. Sci Rep
2017;7(01):14360
[18].
Camera M, Rossetti L, Barbieri SS, et al. PCSK9 as a positive modulator of
platelet activation. J Am Coll Cardiol 2018;71(08): 952-954
[19].
Navarese EP, Kolodziejczak M, Winter MP, et al. Association of PCSK9 with
platelet reactivity in patients with acute coronary syndrome treated with prasugrel
or ticagrelor: the PCSK9- REACT study. Int J Cardiol 2017;227:644-649
[20].
Song L, Zhao X, Chen R, et al. Association of PCSK9 with inflammation and

A Randomized Controlled Trial of Early Initiation of Intensive Lipid-Lowering Therapy for Patients
with Acute Coronary Syndrome undergoing Percutaneous Coronary Intervention _20230825
14
platelet activation markers and recurrent cardiovascular risks in STEMI patients
undergoing primary PCI with or without diabetes. Cardiovasc Diabetol.
2022;21(1):80. Published 2022 May 20.
[21].
Navarese EP, Kolodziejczak M, Kereiakes DJ, Tantry US, O'Connor C, Gurbel
PA. Proprotein Convertase Subtilisin/Kexin Type 9 Monoclonal Antibodies for
Acute Coronary Syndrome: a Narrative Review. annals of internal medicine
2016;164:600-7.
[22].
Cariou B, Guérin P, Le May C, et al. Circulating PCSK9 levels in acute
coronary syndrome: results from the PC-SCA-9 prospective study. Diabetes
Metab 2017 ;43(06):529-535
[23].
Fitzgerald DJ, Roy L, Catella F, FitzGerald GA. Platelet activation in unstable
coronary disease. N Engl J Med 1986;315(16):983-989
[24].
Gresele
P,
Falcinelli
E,
Loffredo
F,
et
al.
Platelets
release
matrix
metalloproteinase-2 in the coronary circulation of patients with acute coronary
syndromes:
possible
role
in
sustained
platelet
activation.
Eur
Heart
J
2011;32(03):316-325
[25].
De Servi S, Crimi G, Calabrò P, et al. Relationship between diabetes, platelet
reactivity, and the SYNTAX score to one-year clinical outcome in patients with
non-ST-segment elevation acute coronary syndrome undergoing percutaneous
coronary intervention. EuroIntervention 2016;12(03):312 -318
[26].
Iannuzzo G, Gentile M, Bresciani A, et al. Inhibitors of Protein Convertase
Subtilisin/Kexin 9 (PCSK9) and Acute Coronary Syndrome (ACS): The State-of-
the-Art.
J
Clin
Med.
2021;10(7):1510.
published
2021
Apr
5.
doi:10.3390/jcm10071510. the-Art. J Clin Med. 2021;10(7):1510. Published 2021
Apr 5.
[27].
Koskinas KC, Windecker S, Buhayer A, Gencer B, Pedrazzini G, Mueller C,
Cook S, Muller O, Matter CM, Räber L, Heg D, Mach F; EVOPACS
Investigators. Design of the randomized, placebo-controlled evolocumab for early
reduction of LDL-cholesterol levels in patients with acute coronary syndromes
(EVOPACS) trial. Clin Cardiol. 2018 Dec;41(12):1513-1520.
[28].
Kim JS, Kim JH, Shin DH, et al. Effect of High-Dose Statin Therapy on Drug-
Eluting Stent Strut Coverage. Arterioscler Thromb Vasc Biol. 2015;35(11):2460 -
2467.