JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
5, 2023
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VOL. 82, NO.
ª 2023 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
PUBLISHED BY ELSEVIER
Combination Lipid-Lowering Therapy
in Patients Undergoing Percutaneous
Coronary Intervention
Seung-Jun Lee, MD,a,* Jae Hong Joo, PHD,b,c,* Sohee Park, PHD,c Choongki Kim, MD,d Dong-Woo Choi, PHD,e
Sung-Jin Hong, MD,a Chul-Min Ahn, MD,a Jung-Sun Kim, MD,a Byeong-Keuk Kim, MD,a Young-Guk Ko, MD,a
Donghoon Choi, MD,a Yangsoo Jang, MD,f Chung-Mo Nam, PHD,b Myeong-Ki Hong, MDa
ABSTRACT
BACKGROUND The RACING (randomized comparison of efficacy and safety of lipid-lowering with statin monotherapy
versus statin/ezetimibe combination for high-risk cardiovascular diseases) trial examined the effects of combination
therapy with moderate-intensity statin and ezetimibe in patients with atherosclerotic cardiovascular disease compared
with high-intensity statin monotherapy.
OBJECTIVES This observational study was conducted to evaluate the impact of 2 treatment strategies used in the
RACING trial in clinical practice.
METHODS After stabilized inverse probability of treatment weighting, a total of 72,050 patients who were prescribed
rosuvastatin after drug-eluting stent implantation were identified from a nationwide cohort database: 10,794 patients
with rosuvastatin 10 mg plus ezetimibe 10 mg (combination lipid-lowering therapy) and 61,256 patients with rosuvas-
tatin 20 mg monotherapy. The primary endpoint was the 3-year composite event of cardiovascular death, myocardial
infarction, coronary artery revascularization, hospitalization for heart failure treatment, or nonfatal stroke in accordance
with the RACING trial.
RESULTS Combination lipid-lowering therapy was associated with a lower occurrence of the primary endpoint (11.6% vs
15.2% for those with high-intensity statin monotherapy; HR: 0.75; 95% CI: 0.70-0.79; P < 0.001). Compared with high-
intensity statin monotherapy, combination lipid-lowering therapy was associated with fewer discontinuations of statin
(6.5% vs 7.6%; HR: 0.85; 95% CI: 0.78-0.94: P < 0.001) and a lower occurrence of new-onset diabetes requiring
medication (7.7% vs 9.6%; HR: 0.80; 95% CI: 0.72-0.88; P < 0.001).
CONCLUSIONS In clinical practice, combination lipid-lowering therapy with ezetimibe and moderate-intensity statin
was associated with favorable clinical outcomes and drug compliance in patients treated with drug-eluting stent
implantation. (CONNECT DES Registry; NCT04715594) (J Am Coll Cardiol 2023;82:401–410) © 2023 by the American
College of Cardiology Foundation.
I n patients with atherosclerotic cardiovascular
disease (ASCVD), including those with coronary
artery disease, the optimum management of
dyslipidemia is a cornerstone therapy to prevent
intensity statin monotherapy is strongly recommen-
ded to achieve an adequate reduction of low-density
lipoprotein–cholesterol (LDL-C) levels, particularly
in high-risk patients who have experienced multiple
recurrent adverse' cardiovascular events.1-4 High- adverse cardiovascular events or who have a history
From the aSeverance Hospital, Yonsei University College of Medicine, Seoul, Korea; bDepartment of Preventive Medicine, Yonsei
University College of Medicine, Seoul, Korea; cGraduate School of Public Health, Yonsei University, Seoul, Korea; dEwha Womans
University College of Medicine, Seoul Hospital, Seoul, Korea; eCancer Big Data Center, National Cancer Center, Goyang, Korea; and
the fCHA University College of Medicine, Seongnam, Korea. *Drs Lee and Joo contributed equally to this work.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’
institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information,
visit the Author Center.
Manuscript received April 12, 2023; accepted May 9, 2023.
ISSN 0735-1097/$36.00 https://doi.org/10.1016/j.jacc.2023.05.042
402 Lee et al JACC VOL. 82, NO. 5, 2023

Combination Lipid-Lowering Therapy After PCI AUGUST 1, 2023:401–410

ABBREVIATIONS of percutaneous coronary intervention represent the entire Korean population. 10 Because
AND ACRONYMS (PCI). 1,2,4
However, there have been concerns personal information was strictly masked during
regarding discrepancies between guideline cohort generation according to the guidelines of the
ASCVD = atherosclerotic
cardiovascular disease
recommendations and clinical practice Korean Health Insurance Review and Assessment
because of the adverse effects of high- Service, informed consent was waived. This study
DES = drug-eluting stent
intensity statin treatment in some pa- was approved by the Institutional Review Board of
IPTW = inverse probability of
treatment weights tients. 5,6 In this context, an early or initial our institute. This study was registered at Clinical-
LDL-C = low-density
combination of ezetimibe with a lower- Trial.gov (NCT04715594). Causes of death were ac-
lipoprotein–cholesterol intensity statin, as opposed to maximizing quired from the National Institute of Statistics
MI = myocardial infarction statin potency until the onset of intolerance, of Korea.
NHIS = National Health may offer equal or greater LDL-C reduction
COHORT DESIGN AND STUDY POPULATION. Use of
Insurance Service with fewer side effects, particularly
ezetimibe was only covered by insurance criteria for
PCI = percutaneous coronary myopathy, and increased persistence
patients who did not achieve sufficient LDL-C
intervention (compliance).7
reduction even with use of the high-intensity or
Recently, the RACING (randomized comparison of
maximum dose of statin therapy before 2016 in Korea.
efficacy and safety of lipid-lowering with statin
Therefore, the combination of ezetimibe with
monotherapy versus statin/ezetimibe combination
moderate-intensity statin, which we aimed to vali-
for high-risk cardiovascular diseases) trial demon-
date in this study, was rarely applicable in clinical
strated the noninferiority of combination lipid-
practice before 2016. Therefore, the cohort of this
lowering therapy with moderate-intensity statin and
study comprised patients with ASCVD who had un-
ezetimibe compared with high-intensity statin mon-
dergone PCI and received either combination lipid-
otherapy regarding 3-year adverse cardiovascular
lowering therapy (rosuvastatin 10 mg plus ezetimibe
outcomes in patients with ASCVD. 8 Combination
10 mg daily) or high-intensity statin monotherapy
lipid-lowering therapy was correlated with increased
(rosuvastatin 20 mg daily) between January 2016 and
drug adherence and greater LDL-C reduction than
December 2018. Among the 52 million Korean citizens
high-intensity statin monotherapy. 8
included in the NHIS database, we identified 273,670
The purpose of the present study was to assess the
adult patients (aged $20 years) who underwent drug-
general applicability of the RACING trial results in
eluting stent (DES) implantation between January
patients who underwent PCI in a clinical setting. Us-
2005 and December 2015 (CONNECT DES cohort reg-
ing the Korean nationwide cohort database, we
istry). 9 According to the eligibility criteria of the
assessed the association between combination lipid-
RACING trial, we excluded patients with chronic liver
lowering therapy and the occurrence of the clinical
disease (n ¼ 15,648), solid organ transplant recipients
endpoints of the RACING trial in comparison with
(n ¼ 1,239), and pregnant or potential child-bearing
high-intensity statin monotherapy.
women (n ¼ 199). Furthermore, after the treatment
SEE PAGE 411
strategy of the RACING trial, patients who received
statins other than rosuvastatin (n ¼ 96,784), a rosu-
METHODS
vastatin dosage different from the RACING trial
(n ¼ 70,604), and those without a statin prescription
STUDY DESIGN AND DATA. This study was a
(n ¼ 6,216) were not included in this study. Patients
nationwide retrospective analysis of the National
who died within 7 days after PCI (n ¼ 4,823) or with
Health Claims database established by the National
missing covariates (n ¼ 5,535) were also excluded
Health Insurance Service (NHIS) of Korea, which
from the study. Consequently, this study included
contains claimed medical costs, precise information
the remaining 72,622 patients with DES implantation
on prescribed drugs including the number of pills and
who were treated with rosuvastatin 10 mg plus eze-
drug dosage, and medical history provided as Inter-
timibe 10 mg daily (n ¼ 11,280) or rosuvastatin 20 mg
national Classification of Diseases, Tenth Revision
9 daily (n ¼ 61,342) (Figure 1). The details of the trial
codes. A majority (97.1%) of the Korean population
protocol in comparison with the RACING trial are
mandatorily subscribes to the NHIS, which is the sole
presented in Supplemental Table 1.
insurer managed by the Korean government.
Considering that the NHIS also covers information for STUDY OUTCOMES. In accordance with the random-
the remaining population (2.9%) categorized as ized RACING trial,8 the primary endpoint was the
medical aid subjects, this cohort is considered to composite of cardiovascular death, myocardial
JACC VOL. 82, NO. 5, 2023 Lee et al 403
AUGUST 1, 2023:401–410 Combination Lipid-Lowering Therapy After PCI

F I G U R E 1 Flow Chart of 273,670 Patients Who Underwent PCI With DES Implantation

273,670 patients who underwent PCI with DES implantation

In South Korea from January 2005 to December 2016

17,086 Not meeting the RACING eligibility criteria

15,648 Chronic liver disease
1,239 Solid organ transplantation
199 Pregnant or potential childbearing

256,584 patients who were treated with PCI and met the
eligibility criteria of the RACING trial

96,784 Use of statin other than rosuvastatin

70,604 Use of rosuvastatin dosage different
from the RACING trial
6,216 No statin treatment
4,823 Death within 7 days after PCI
5,535 Missing medical information

72,622 patients who were treated with statin

according to RACING strategy after PCI

Combination lipid-lowering High-intensity statin

therapy (N = 11,280) monotherapy (N = 61,342)

From the Korean National Health Insurance Service database, patients who had undergone PCI and received either combination lipid-lowering
therapy (rosuvastatin 10 mg plus ezetimibe 10 mg daily) or high-intensity statin monotherapy (rosuvastatin 20 mg daily) were enrolled.
DES ¼ drug-eluting stent; PCI ¼ percutaneous coronary intervention; RACING ¼ randomized comparison of efficacy and safety of
lipid-lowering with statin monotherapy versus statin/ezetimibe combination for high-risk cardiovascular diseases.

infarction (MI), coronary artery revascularization,
hospitalization for heart failure treatment,
nonfatal stroke that occurred during the 3-year
follow-up period. Cardiovascular death was ascer-
tained from the National Statistical Office of Korea,
which provided death certificates with an accuracy of
92% for a specific cause of death. 10-12 Cardiovascular
death was identified by a death certificate with at
least 1 cardiovascular-related diagnosis (acute MI,
stroke, heart failure, or sudden cardiac death). MI has
been defined by the International Classification of
Diseases, 10th Revision, codes corresponding to acute
MI and satisfaction of 1 or more of the following
conditions: 1) concurrent presence of claims for
coronary angiography; 2) admission via the emer-
or gency department; or 3) cardiac biomarkers tested
more than 4 times. 11 A detailed description of each
efficacy endpoint is presented in Supplemental
Table 2. Secondary endpoints evaluated the clinical
efficacy and safety according to the treatment strat-
egy after PCI. The secondary efficacy endpoints
included the composite of cardiovascular death, MI,
coronary artery revascularization, or stroke, the
composite of all-cause death, MI, coronary artery
revascularization, hospitalization for heart failure, or
stroke, and the individual component of the primary
or secondary endpoint. The secondary safety end-
points included: 1) discontinuation of statin for more
404 Lee et al
Combination Lipid-Lowering Therapy After PCI
than 180 days; and 2) the occurrence of adverse
clinical endpoints including new-onset diabetes
mellitus requiring medication, rhabdomyolysis, gall-
bladder disease requiring cholecystectomy, and a
new diagnosis of cancer. A detailed description of
each safety endpoint is presented in
Supplemental Table 3.
STATISTICAL ANALYSIS. Continuous variables are
reported as mean  SD, and dichotomous variables
are presented as frequency (percentage). We esti-
mated the inverse probability of treatment weights
(IPTW) using the propensity score, which was deter-
mined using logistic regression with factors of age,
sex, history of comorbidities and medications, and
year of PCI, to reduce the impact of confounding bias
(Supplemental Table 4). Stabilization of IPTW was
conducted by multiplying it by the marginal proba-
bility of receiving each treatment. The effect size
difference between the 2 groups for baseline comor-
bidities and medications was calculated using stan-
dardized mean difference and Kernel density plots.
Standardized mean difference values >0.2 were
regarded as representing a potential imbalance be-
tween the 2 groups. Cumulative incidence curves and
the rate of primary and secondary endpoint occur-
rence during the follow-up period were plotted using
the Kaplan–Meier method. The adjusted HR for each
clinical endpoint was calculated using a Cox propor-
tional hazard regression model. A cause-specific
hazard model was used to consider death as a
competing risk when comparing the incidences of
cardiovascular death, MI, stroke, and hospitalization
due to heart failure. Sensitivity analyses were con-
ducted according to baseline characteristics to affirm
the robustness of the main results. A 2-sided
P value <0.05 was considered significant. Statistical
analyses were conducted using SAS version 9.4 (SAS
Institute) and R version 4.0 (The R Foundation).
RESULTS
Patients were followed for 2.9  0.4 years in the
combination lipid-lowering therapy group and 2.9 
0.4 years in the high-intensity statin monotherapy
group. Baseline characteristics including the comor-
bidities, medication history, and procedural infor-
mation of the cohort population before and after
stabilized IPTW are presented in Table 1. After
weighting using the stabilized IPTW, 72,050 patients
who had undergone DES implantation and were
treated with rosuvastatin between 2016 and 2018
were included: 10,794 patients with combination
lipid-lowering therapy and 61,256 patients with high-
intensity statin monotherapy. After the application of
JACC VOL. 82, NO. 5, 2023
AUGUST 1, 2023:401–410
stabilized IPTW, there was no evidence of inequality
in baseline comorbidities, medication history, or
procedural characteristics between the 2 groups (all
standardized mean differences <0.1) (Supplemental
Figures 1 and 2). The temporal trends in change of
statin intensity during the 3-year study period are
presented in Supplemental Figure 3. In the combi-
nation lipid-lowering therapy group, 10,118 patients
(89.7%) continued to receive equivalent intensity of
initial statin therapy; 47,908 patients (78.1%) main-
tained the initial statin intensity in the high-intensity
statin monotherapy group (P < 0.001). The cumula-
tive incidence and relative hazards of primary and
secondary efficacy endpoints are presented in Table 2
and the Central Illustration. The occurrence of the
primary endpoint was significantly lower in the
combination lipid-lowering therapy group (11.6% vs
15.2% in the high-intensity statin monotherapy
group; HR: 0.75; 95% CI: 0.70-0.79; P < 0.001) (Central
Illustration). Similarly, combination lipid-lowering
treatment was associated with a lower incidence of
the composite of cardiovascular death, MI, coronary
revascularization, or stroke (8.7% vs 12.2% in high-
intensity statin monotherapy; HR: 0.73; 95% CI:
0.68-0.78; P < 0.001). The cumulative incidences of
each clinical endpoint are also presented in Table 2.
During the 3-year follow-up of the study period,
compared with high-intensity statin monotherapy,
combination lipid-lowering therapy was associated
with a lower occurrence of cardiovascular death, all-
cause death, MI, coronary artery revascularization,
and nonfatal stroke. Subgroup analyses also demon-
strated a consistently beneficial impact of combina-
tion lipid-lowering therapy vs high-intensity statin
monotherapy regarding the occurrence of the primary
endpoint (Figure 2).
The 3-year occurrence of the secondary safety
endpoint is presented in Table 3. Discontinuation of
statin was significantly lower in the combination
lipid-lowering therapy group (6.5% vs 7.6% in the
high-intensity statin monotherapy group; HR: 0.85;
95% CI: 0.78-0.94; P < 0.001) (Central Illustration,
Supplemental Figure 4). In addition, compared with
high-intensity statin monotherapy, combination
lipid-lowering therapy was associated with a lower
incidence of new-onset diabetes requiring medication
(7.7% vs 9.6%, respectively; HR: 0.80; 95% CI: 0.72-
0.88; P < 0.001) (Central Illustration).
DISCUSSION
In this large nationwide cohort of 273,670 patients
who underwent PCI with DES implantation, 256,584
patients (93.7%) met the RACING enrollment criteria.
JACC VOL. 82, NO. 5, 2023 Lee et al 405
AUGUST 1, 2023:401–410 Combination Lipid-Lowering Therapy After PCI

T A B L E 1 Baseline Characteristics and Medications

Before Stabilized IPTW After Stabilized IPTW

(N ¼ 72,622) (N ¼ 72,050)

Combination High-Intensity Combination High-Intensity

Lipid-Lowering Statin Lipid-Lowering Statin
Therapy Monotherapy Therapy Monotherapy
(n ¼ 11,280) (n ¼ 61,342) SMD (n ¼ 10,794) (n ¼ 61,256) SMD

Age, y 61.9  11.1 63.0  11.5 0.096 62.3  10.9 62.8  11.5 0.048
Female 3,085 (27.4) 16,486 (26.9) 0.011 2,927 (27.1) 16,527 (27.0) 0.003
Comorbidity
Hypertension 8,720 (77.3) 46,080 (75.1) 0.051 8,242 (76.4) 46,246 (75.5) 0.020
Chronic kidney disease with severe renal impairmenta 504 (4.5) 2,892 (4.7) 0.012 523 (4.9) 2,877 (4.7) 0.007
Diabetes mellitus 5,244 (46.5) 26,967 (44.0) 0.051 5,007 (46.4) 27,215 (44.4) 0.039
Charlson comorbidity index 3.4  2.3 3.3  2.3 0.040 3.4  2.3 3.3  2.3 0.020
Statin therapy before rosuvastatin treatmentb 0.202 0.055
High-intensity statin 1,930 (17.1) 12,474 (20.3) 2,193 (20.3) 12,246 (20.0)
Low-intensity to moderate-intensity statin 5,810 (51.5) 25,462 (41.5) 4,892 (45.3) 26,396 (43.1)
None 3,540 (31.4) 23,406 (38.2) 3,709 (34.4) 22,614 (36.9)
Atherosclerotic cardiovascular disease
Prior MI 2,648 (23.5) 13,438 (21.9) 0.037 2,360 (21.9) 13,500 (22.0) 0.004
Acute MI 2,491 (22.1) 17,285 (28.2) 0.141 2,584 (23.9) 16,680 (27.2) 0.076
Prior coronary bypass graft surgery 114 (1.0) 632 (1.0) 0.002 119 (1.1) 632 (1.0) 0.007
Prior ischemic stroke 1,802 (16.0) 9,483 (15.5) 0.014 1,747 (16.2) 9,552 (15.6) 0.016
Peripheral artery disease 711 (6.3) 3,227 (5.3) 0.045 625 (5.8) 3,332 (5.4) 0.015
Medication before PCI
Aspirin 8,814 (78.1) 36,319 (59.2) 0.417 7,049 (65.3) 37,845 (61.8) 0.073
Clopidogrel 7,533 (66.8) 26,526 (43.2) 0.487 5,247 (48.6) 28,565 (46.6) 0.040
b-blocker 5,855 (51.9) 24,243 (39.5) 0.251 4,579 (42.4) 25,251 (41.2) 0.024
RAAS blockade 5,411 (48.0) 22,885 (37.3) 0.217 4,223 (39.1) 23,728 (38.7) 0.008
Procedural information
Number of stents 1.3  0.6 1.3  0.6 0.008 1.3  0.6 1.3  0.6 0.010
Type of drug-eluting stent 0.031 0.091
First-generationc 1,811 (16.1) 9,169 (15.0) 2,011 (18.6) 9,325 (15.2)
Next-generation 9,469 (83.9) 52,173 (85.0) 8,783 (81.4) 51,931 (84.8)
Duration of dual antiplatelet therapy 0.061 0.005
<365 d 5,089 (45.1) 25,830 (42.1) 4,611 (42.7) 26,004 (42.4)
$365 d 6,191 (54.9) 35,512 (57.9) 6,183 (57.3) 35,252 (57.6)
Year of PCI 0.194 0.096
2005-2009 2,180 (19.3) 11,163 (18.2) 2,413 (22.4) 11,327 (18.5)
2010-2014 2,862 (25.4) 20,900 (34.1) 3,380 (31.3) 20,173 (32.9)
2015-2016 6,238 (55.3) 29,279 (47.7) 5,002 (46.3) 29,756 (48.6)

Values are mean  SD or n (%). aChronic kidney disease with advanced stage requiring intensive medical therapy and financial assistance from health insurance. bThe intensity
of prior statin treatment was categorized based on the 2013 American College of Cardiology/American Heart Association guideline for blood cholesterol treatment. cFirst-
generation drug-eluting stent indicates Cypher and Taxus.
IPTW ¼ inverse probability of treatment weighting; MI ¼ myocardial infarction; PCI ¼ percutaneous coronary intervention; RAAS ¼ renin-angiotensin-aldosterone-system;
SMD ¼ standardized mean difference.

We were able to investigate the clinical impact of
combination lipid-lowering therapy vs high-intensity
statin monotherapy in patients with DES implanta-
tion in a clinical setting using the distinct traits of the
Korean NHIS database, which accurately tracks all
prescription drug information throughout the entire
follow-up period. The principal findings of our study
are as follows: 1) among the patients with DES im-
plantation, combination lipid-lowering therapy was
associated with a reduction in the primary and
secondary efficacy endpoints as compared with high-
intensity statin monotherapy (these results were
consistent across all subgroups after sensitivity ana-
lyses); 2) in accordance with the findings of the
RACING trial, the risk of drug cessation was signifi-
cantly reduced in the combination lipid-lowering
therapy group; and 3) in addition, combination
lipid-lowering therapy was related to a decreased
incidence of new-onset diabetes requiring
medication.
406 Lee et al JACC VOL. 82, NO. 5, 2023

Combination Lipid-Lowering Therapy After PCI AUGUST 1, 2023:401–410

T A B L E 2 Risks of Primary and Secondary Efficacy Endpoints for 3 Years After Stabilized Inverse Probability of Treatment Weighting

Combination
Lipid-Lowering High-Intensity
Therapy Statin Monotherapy Risk Difference
(n ¼ 10,794) (n ¼ 61,256) (95% CI)a HR (95% CI)b P Value

Primary endpoint
Composite of cardiovascular death, MI, coronary artery 1y 665 (6.2) 4,471 (7.3) –1.1 (–1.7 to –0.6) 0.84 (0.78-0.92) <0.001
revascularization, or hospitalization for heart failure or stroke 2y 1,080 (10.0) 7,702 (12.6) –2.6 (–3.3 to –1.9) 0.80 (0.75-0.85) <0.001
3y 1,248 (11.6) 9,337 (15.2) –3.6 (–4.4 to –2.9) 0.75 (0.70-0.79) <0.001
Secondary efficacy endpoint
Composite of cardiovascular death, MI, coronary artery 1y 469 (4.3) 3,172 (5.2) –0.8 (–1.3 to –0.4) 0.84 (0.76-0.92) <0.001
revascularization, or stroke 2y 790 (7.3) 5,502 (9.0) –1.7 (–2.3 to –1.1) 0.81 (0.75-0.88) <0.001
3y 937 (8.7) 7,474 (12.2) –3.5 (–4.2 to –2.8) 0.73 (0.68-0.78) <0.001
Composite of all-cause death, MI, coronary artery revascularization, or 1y 729 (6.8) 4,943 (8.1) –1.3 (–1.9 to –0.7) 0.84 (0.77-0.90) <0.001
hospitalization for heart failure or stroke 2y 1,230 (11.4) 8,598 (14.0) –2.6 (–3.4 to –1.9) 0.81 (0.76-0.86) <0.001
3y 1,446 (13.4) 10,598 (17.3) –3.9 (–4.7 to –3.1) 0.77 (0.73-0.82) <0.001
Individual clinical endpoint
Cardiovascular death 1y 104 (1.0) 766 (1.3) –0.3 (–0.5 to –0.1) 0.80 (0.68-0.92) <0.001
2y 227 (2.1) 1,663 (2.7) –0.6 (–0.9 to –0.3) 0.77 (0.67-0.89) <0.001
3y 295 (2.7) 2,240 (3.7) –0.9 (–1.3 to –0.5) 0.74 (0.66-0.84) <0.001
All-cause death 1y 175 (1.6) 1,243 (2.0) –0.4 (–0.7 to 0.1) 0.82 (0.70-0.97) 0.004
2y 394 (3.6) 2,667 (4.4) –0.7 (–1.1 to –0.3) 0.83 (0.75-0.93) <0.001
3y 522 (4.8) 3,734 (6.1) –1.3 (–1.8 to –0.8) 0.79 (0.72-0.86) <0.001
MI 1y 70 (0.7) 711 (1.2) –0.5 (–0.7 to –0.3) 0.56 (0.43-0.71) <0.001
2y 95 (0.9) 1,057 (1.7) –0.8 (–1.1 to –0.6) 0.51 (0.41-0.63) <0.001
3y 108 (1.0) 1,330 (2.2) –1.2 (–1.5 to –0.9) 0.46 (0.38-0.56) <0.001
Coronary artery revascularization 1y 182 (1.7) 1,199 (2.0) –0.3 (–0.6 to 0.0) 0.86 (0.72-1.03) 0.108
2y 298 (2.8) 2,168 (3.5) –0.8 (–1.2 to –0.4) 0.78 (0.68-0.89) 0.003
3y 339 (3.1) 2,710 (4.4) –1.3 (–1.7 to –0.9) 0.71 (0.62-0.80) <0.001
Hospitalization for heart failure 1y 251 (2.3) 1,499 (2.4) –0.1 (–0.4 to 0.2) 0.95 (0.82-1.11) 0.535
2y 400 (3.7) 2,400 (3.9) –0.2 (–0.6 to 0.2) 0.94 (0.84-1.07) 0.358
3y 469 (4.3) 2,813 (4.6) –0.2 (–0.7 to 0.2) 0.95 (0.86-1.04) 0.267
Nonfatal stroke 1y 136 (1.3) 1,000 (1.6) –0.4 (–0.6 to –0.1) 0.77 (0.63-0.94) 0.010
2y 233 (2.2) 1,549 (2.5) –0.4 (–0.7 to 0.0) 0.85 (0.73-0.99) 0.046
3y 272 (2.5) 1,921 (3.1) –0.6 (–1.0 to –0.3) 0.80 (0.69-0.92) 0.002

Values are n (%) unless otherwise indicated. aA 95% CI for absolute risk reduction attributed to each treatment was calculated. bCox proportional hazard models were used to obtain adjusted HR, 95% CI, and
P values by defining high-intensity statin monotherapy as the reference arm.
Abbreviation as in Table 1.

In patients with documented
lowering therapy is a cornerstone of secondary pre-
vention management, and more intense LDL-C
reduction lowers the risk of recurrent adverse car-
diovascular events.13 In addition, because the thera-
peutic benefit of LDL-C lowering is more pronounced
in patients with ASCVD at high risk, contemporary
guidelines emphasize the attainment of treatment
goals based on the patient’s risk.2,4 The 2019 Euro-
pean guidelines on lipid management identified pa-
tients with a prior PCI as a very high-risk population
and strongly advocated for intensive lipid-lowering
therapy with an LDL-C target of 55 mg/dL and $50%
decrease from baseline.4 In the 2018 American
guidelines on lipid management, prior PCI is one of
the high-risk conditions constituting the defining
criterion for a very high-risk ASCVD necessitating an
ASCVD, lipid- initial high-intensity statin therapy.2 Taken together,
patients who underwent PCI are regarded to have a
particularly greater risk of recurrent adverse cardio-
vascular events among patients with ASCVD. In these
high-risk subjects, high-intensity statin monotherapy
should be initially prescribed up to the highest
tolerated dose to achieve sufficient LDL-C lowering.
However, despite the generally acknowledged effi-
cacy of high-intensity statin therapy in the secondary
prevention of ASCVD in patients who underwent DES
implantation, substantial underuse of high-intensity
statin is observed globally. 7,14,15 One of the plausible
explanations for low prescribing rates could be the
occurrence or potential concerns about side effects
associated with high-intensity statin.7,8,16 Supporting
this notion, >30% of all patients in this nationwide
cohort of patients with a history of PCI were not
JACC VOL. 82, NO. 5, 2023 Lee et al 407
AUGUST 1, 2023:401–410 Combination Lipid-Lowering Therapy After PCI

C ENTR AL I LL U STRA T I O N Combination Lipid-Lowering Therapy in Practice: Assessing RACING

Generalizability

Combination Lipid-Lowering Therapy in Patients Treated With Percutaneous Coronary

Intervention in Practice: Assessing RACING Generalizability

3-Year Composite Events of Cardiovascular Death, MI, Discontinuation

Coronary Artery Revascularization, Heart Failure, or Stroke of Statin (%)
10 P = 0.001
18
8
15.2% 7.6
HR: 0.75 (95% CI: 0.70-0.79); P < 0.001 6
Cumulative Incidence (%)

6.5
4
12 11.6% 2
0

New-Onset Diabetes
6
Requiring Medication (%)

P < 0.001
10
0 9.6
8
7.7
0 1 2 3 6
Years 4
61,256 56,785 53,554 51,919 2
10,794 10,129 9,714 9,546
0
High-Intensity Statin Monotherapy
Combination Lipid-Lowering Therapy
Lee S-J, et al. J Am Coll Cardiol. 2023;82(5):401–410.

Combination lipid-lowering therapy with ezetimibe and moderate-intensity statin was associated with a more favorable 3-year composite outcome than
high-intensity statin monotherapy in clinical practice. Compared with high-intensity statin monotherapy, combination lipid-lowering therapy was
associated with fewer discontinuations of statin and a lower occurrence of new-onset diabetes requiring medication. MI ¼ myocardial infarction;
RACING ¼ randomized comparison of efficacy and safety of lipid-lowering with statin monotherapy versus statin/ezetimibe combination for high-risk
cardiovascular diseases.

receiving statin therapy at the time of study enroll-
ment. Moreover, the proportion of patients previ-
ously receiving low-intensity or moderate-intensity
statin therapy was higher in the combination lipid-
lowering therapy group, indicating a preference for
the ezetimibe combination to ongoing statin therapy
over maximizing statin intensity in the clinical prac-
tice. These findings highlight the need for improved
statin adherence and tailored treatment strategies for
high-risk patients with ASCVD.
Recently, the RACING trial demonstrated the non-
inferiority of combination lipid-lowering therapy vs
high-intensity statin monotherapy regarding the
occurrence of adverse cardiovascular outcomes. 8
Furthermore, drug compliance and LDL-C lowering
effects were shown to be greater in the combination
lipid-lowering therapy group. Among the 3,780 pa-
tients with documented ASCVD in the RACING trial,
2,497 (66%) had a history of prior PCI. In accordance
with the results of the RACING trial, combination
lipid-lowering therapy was significantly related to
fewer discontinuations of statin than high-intensity
statin monotherapy in this study. Given that the
achievement of lower LDL-C by the addition of
408 Lee et al JACC VOL. 82, NO. 5, 2023

Combination Lipid-Lowering Therapy After PCI AUGUST 1, 2023:401–410

F I G U R E 2 Subgroup Analysis Regarding the Primary Endpoint Between the 2 Treatment Strategies

Combination Lipid-Lowering High-Intensity Statin

Therapy Monotherapy
HR P for
Covariates
(95% CI) Interaction
Primary Primary
Patient N Patient N
Endpoint Endpoint
Age
<65 years 6,204 586 (9.5) 33,879 4,247 (12.5) 0.74 (0.68-0.81)
0.66
≥65 years 4,590 662 (14.4) 27,377 5,090 (18.6) 0.76 (0.70-0.83)
Sex
Male 7,867 838 (10.7) 44,729 6,558 (14.7) 0.71 (0.66-0.77)
0.07
Female 2,927 410 (14.0) 16,527 2,779 (16.8) 0.83 (0.75-0.92)
Hypertension
No 2,552 216 (8.5) 15,010 1,902 (12.7) 0.65 (0.57-0.75)
0.08
Yes 8,242 1,032 (12.5) 46,246 7,435 (16.1) 0.77 (0.72-0.82)
Diabetes Mellitus
No 5,787 571 (9.9) 34,041 4,516 (13.3) 0.73 (0.67-0.80)
0.66
Yes 5,007 677 (13.5) 27,215 4,821 (17.7) 0.75 (0.69-0.81)
Prior statin intensity
High-intensity 2,193 213 (9.7) 12,246 1,601 (13.1) 0.82 (0.73-0.92)
Low to moderate-intensity 4,892 612 (12.5) 26,396 3,972 (15.0) 0.76 (0.71-0.81) 0.12
None 3,709 423 (11.4) 22,614 3,764 (16.6) 0.70 (0.64-0.77)
Prior myocardial infarction
No 8,434 952 (11.3) 47,756 7,128 (14.9) 0.74 (0.69-0.79)
0.70
Yes 2,360 296 (12.6) 13,500 2,209 (16.4) 0.76 (0.68-0.86)
Acute myocardial infarction
No 8,210 1,039 (12.7) 44,576 7,369 (16.5) 0.77 (0.72-0.82)
0.82
Yes 2,584 209 (8.1) 16,680 1,968 (11.8) 0.68 (0.60-0.76)
DAPT duration
<365 days 4,611 517 (11.2) 26,004 3,681 (14.2) 0.78 (0.72-0.86)
0.16
≥365 days 6,183 731 (11.8) 35,252 5,656 (16.0) 0.72 (0.67-0.78)

0.5 1 2
Favors Combination Favors High-Intensity
Lipid-Lowering Therapy Statin Monotherapy

Subgroup analyses showed a consistently beneficial impact of combination lipid-lowering therapy vs high-intensity statin monotherapy regarding the occurrence of the
primary endpoint. Numbers and percentages show the number of patients at risk and the incidence of the primary endpoint. DAPT ¼ dual antiplatelet therapy

nonstatin lipid-lowering agents was associated with However, there was no statistically significant dif-
better clinical outcomes in patients treated with ference in the incidence of the primary endpoint be-
PCI,17-19 combination lipid-lowering therapy could tween the 2 groups in the RACING trial. Compared
lead to better clinical outcomes in those patients. with the FOURIER (Further cardiovascular OUtcomes

T A B L E 3 Secondary Safety Endpoint

Combination High-Intensity
Lipid-Lowering Therapy Statin Monotherapy Risk Difference
(n ¼ 10,794) (n ¼ 61,256) (95% CI)a HR (95% CI)b P Value

Discontinuation of statin 703 (6.5) 4,667 (7.6) –1.1 (–1.7 to –0.5) 0.85 (0.78-0.94) 0.001
New-onset diabetes requiring medicationsc 445/5,787 (7.7) 3,262/34,041 (9.6) –1.9 (–2.7 to –1.0) 0.80 (0.72-0.88) <0.001
Rhabdomyolysis 36 (0.3) 255 (0.4) –0.1 (–0.3 to 0.1) 0.86 (0.61-1.22) 0.397
Cholecystectomy 113 (1.1) 622 (1.0) 0.0 (–0.2 to 0.2) 1.03 (0.85-1.26) 0.746
Cancer diagnosis 406 (3.8) 2,359 (3.9) –0.1 (–0.5 to 0.3) 0.98 (0.88-1.09) 0.677

Values are n (%) or n/N (%), unless otherwise indicated. aA 95% CI for absolute risk reduction attributed to each treatment was calculated. bCox proportional hazard models
were used to obtain adjusted HR, 95% CI, and P values by defining high-intensity statin monotherapy as the reference arm. cIncidence of new-onset diabetes requiring
medication was assessed for participants without prior diabetes history at enrollment.
JACC VOL. 82, NO. 5, 2023
AUGUST 1, 2023:401–410
Research with PCSK9 Inhibition in subjects with
Elevated Risk) study that investigated the effect of
proprotein convertase subtilisin-kexin type 9 inhibi-
tor in 27,564 ASCVD patients for 3 years 20 or the
IMPROVE-IT (IMProved Reduction of Outcomes:
Vytorin Efficacy International Trial) that enrolled
18,144 patients with acute coronary syndrome and
tested the efficacy of ezetimibe combination in addi-
tion to simvastatin for 7 years, 21 the RACING study
followed 3,840 patients with ASCVD for 3 years.
Therefore, it may be presumed that a smaller number
of study patients and a shorter duration of follow-up
in the RACING trial failed to demonstrate a statisti-
cally significant difference in clinical outcomes in the
combination lipid-lowering therapy group. The cur-
rent nationwide cohort study enrolled 72,622 patients
treated with DES implantation, outnumbering the
total population of the RACING trial by 18 times, and
demonstrated a clearly favorable effect of combina-
tion lipid-lowering therapy vs high-intensity statin
monotherapy with regard to the primary and sec-
ondary efficacy endpoints of the RACING trial.
Notably, the upper 95% CI for the risk difference be-
tween the 2 treatment strategies for the primary
outcome in this study was –2.9%, which did not sur-
pass the noninferiority margin of the RACING trial
(2.0%). This finding verifies the principal result of the
RACING trial, which was aimed to demonstrate that
combined lipid-lowering therapy is not inferior to
high-intensity statin monotherapy in patients with
ASCVD. In addition, the P value of the superiority test
was <0.001, reinforcing the considerable benefit of
combination lipid-lowering therapy in high-risk pa-
tients with ASCVD.
Among the several side effects related to high-
intensity statin therapy, the occurrence or wors-
ening of diabetes is a major concern. 16 In particular,
the administration of high-intensity rosuvastatin
(20 mg daily) is known to significantly increase the
risk of diabetes.22,23 In the current analysis of real-
world practice emulating the RACING trial, early
ezetimibe combination therapy with moderate-
intensity statin was associated with a lower inci-
dence of new-onset diabetes compared with
high-intensity statin monotherapy. Furthermore, the
clinical efficacy of combination lipid-lowering ther-
apy was consistently maintained in a prespecified
subgroup of patients with diabetes in the RACING
trial. 24 This nationwide cohort analysis imitating the
RACING trial provides significant support for the su-
perior safety of an initial ezetimibe combination with
moderate-intensity statin, even in patients with
ASCVD at a higher risk.
Lee et al 409
Combination Lipid-Lowering Therapy After PCI
STUDY LIMITATIONS. First, in this nationwide
cohort based on claims data, the serial changes of
lipid profiles during the follow-up period between
the 2 treatment strategies were not analyzed. Sec-
ond, because the NHIS only contains information
about claims data and does not provide medical
records, the reasons for discontinuing statin are
unknown. Third, although significant differences
were adjusted by using the stabilized IPTW method,
there were distinct differences between the 2 groups
in terms of prior medication status or comorbidities,
implying an inherent difference in the characteristics
of patients receiving each treatment strategy in
clinical practice. Finally, due to the nature of the
retrospective cohort based on the claims, the results
of this study cannot be used to prove causal
relationships, and residual confounding factors may
persist even after stabilized IPTW. To further mini-
mize the errors, we adopted a very stringent defi-
nition for clinical endpoints, particularly for the
secondary safety endpoint.
CONCLUSIONS
In this nationwide cohort study, combination lipid-
lowering therapy with moderate-intensity statin and
ezetimibe was associated with a lower occurrence of
adverse cardiovascular events, statin discontinua-
tion, and diagnosis of new-onset diabetes requiring
medication than high-intensity statin monotherapy
in patients who underwent PCI with DES implanta-
tion. These results not only strengthen the general-
izability of the randomized RACING trial in clinical
practice but also provide new insight into the efficacy
and safety of combination lipid-lowering therapy.
FUNDING SUPPORT AND AUTHOR DISCLOSURES
This work was supported by the Cardiovascular Research Center,
Seoul, Korea. The funder had no role in the design and conduct of the
study; data collection, management, statistical analysis, and inter-
pretation of the data; preparation, review, or approval of the manu-
script; and decision to submit the manuscript for publication. All
authors have reported that they have no relationships relevant to the
contents of this paper to disclose.
ADDRESS FOR CORRESPONDENCE: Dr Myeong-Ki
Hong, Division of Cardiology, Severance Hospital,
Yonsei University College of Medicine, 50-1
Yonsei-ro, Seodaemun-gu, Seoul 03722, Korea.
E-mail: mkhong61@yuhs.ac. OR Dr Chung-Mo Nam,
Department of Preventive Medicine, Yonsei
University College of Medicine, 50-1 Yonsei-ro,
Seodaemun-gu, Seoul 03722, Korea. E-mail:
cmnam@yuhs.ac.
410 Lee et al
Combination Lipid-Lowering Therapy After PCI
PERSPECTIVES
COMPETENCY IN PATIENT CARE AND
PROCEDURAL SKILLS: A combination of moderate-
intensity statin and ezetimibe therapy reduces the inci-
dence of adverse cardiovascular events compared with
high-intensity statin monotherapy during a period of 3
years after PCI.
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KEY WORDS coronary artery disease,
dyslipidemia, statin
A PPE NDI X For supplemental tables and
figures, please see the online version of this
paper.