Journal of the American Heart Association

EDITORIAL

Upfront Combination of Statin and

Ezetimibe for Patients With Acute Coronary
Syndrome: Time for a New Approach?
Lina Ya’Qoub, MD; Hend Mansoor, PharmD, PhD; Islam Y. Elgendy , MD

L
ipid-­lowering therapy (LLT) is a cornerstone in
the management of patients with acute coronary
syndrome (ACS).1 Statins are 3-­hydroxy-­3-­methy
lglutaryl-­coenzyme A reductase inhibitors, which re-
duce low-­density lipoprotein cholesterol (LDL-­C) lev-
els and subsequent cardiovascular events.1 Statins
not only lower LDL-­C levels but also exert beneficial
anti-­inflammatory effects among patients with ACS (ie,
pleiotropic effect).1,2 Statins are linked with subjective
myalgia (ie, muscle pain with normal enzymes), or what
has been described as a nocebo effect,2 which occurs
in up to 30%.1 This leads to dose reduction, switching
to an alternative statin therapy, or adding a nonstatin
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cardiovascular death, nonfatal myocardial infarction,
unstable angina requiring rehospitalization, coronary
revascularization within 30 days after randomization, or
nonfatal stroke) was significantly lower with the combi-
nation of simvastatin–­ezetimibe at 7 years (hazard ratio
[HR], 0.94 [95% CI, 0.89–­0.99]; P=0.016).4 Although
the combination of simvastatin-­ezetimibe significantly
reduced LDL-­C levels by 24% at 1 year (53.2 mg per
deciliter in the combination group versus 69.9 mg per
deciliterin the simvastatin monotherapy group),4 the
clinical benefit observed with the combination of statin
and ezetimibe might not be only attributed to the re-
duction in LDL-­C levels. Indeed, intracoronary imaging

LLT to avoid the risk of nonadherence or discontinua-
tion of therapy, which in turn might affect cardiovascu-
lar outcomes.3
See Article by Lewek et al.
Ezetimibe, a commonly prescribed nonstatin LLT,
targets the NPC1L1 (Niemann–­Pick C1–­like 1) protein,
thus reducing the absorption of cholesterol from the
intestine.4 In the IMPROVE-­ IT (Improved Reduction
of Outcomes: Vytorin Efficacy International Trial) trial,
18 144 patients with recent ACS were randomly as-
signed to a combination of high-­ dose simvastatin–­
ezetimibe (40–­10 mg) versus simvastatin monotherapy
(40 mg).4 The primary end point (ie, composite of
studies have shown greater coronary plaque regres-
sion with the combination of statin and ezetimibe com-
pared with statin monotherapy.5,6
The American College of Cardiology/American
Heart Association 2018 guidelines for management of
blood cholesterol recommend starting high-­intensity or
maximally tolerated statin therapy in patients with ACS
(Class I-­A recommendation) and adding ezetimibe if
LDL-­C level is >70 mg/dL despite maximally tolerated
statin dose or when statins are not tolerated (Class
IIa-­BR recommendation).1 Despite these recommen-
dations, a significant proportion of these high-­risk pa-
tients do not achieve the recommended target LDL-­C
levels in clinical practice. In the DA VINCI study, which
included 5888 patients (2888 patients for secondary
prevention) from 18 countries in Europe, high-­intensity

Key Words: Editorials ■ acute coronary syndrome ■ ezetimibe ■ lipid lowering therapy ■ statin

The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.
Correspondence to: Islam Y. Elgendy, MD, FACC, FAHA, FSCAI, FSVM, FESC, Gill Heart Institute, University of Kentucky, 900 S. Limestone St., Lexington, KY
40536. Email: iyelgendy@gmail.com
This article was sent to Amgad Mentias, Associate Editor, for editorial decision and final disposition.
For Disclosures, see page 3.
© 2023 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley. This is an open access article under the terms of the Creative
Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use
is non-commercial and no modifications or adaptations are made.
JAHA is available at: www.ahajournals.org/journal/jaha

J Am Heart Assoc. 2023;12:e031615. DOI: 10.1161/JAHA.123.0316151

 Ya’Qoub et al
statin monotherapy was used in 20% and 38% of very
high-­risk primary and secondary prevention patients,
respectively. Corresponding LDL-­C goal was achieved
in only 22% and 45% for very high-­risk primary and sec-
ondary prevention patients, respectively. Importantly,
combination of moderate to high-­ intensity statins
with ezetimibe was used only in 9%.7 In the GOULD
(Getting to an Improved Understanding of Low-­Density
Lipoprotein Cholesterol and Dyslipidemia Management)
registry, which was a prospective study of 5006 pa-
tients with atherosclerotic cardiovascular disease in
the United States, 67% who were on maximally toler-
ated statins had elevated LDL-­C levels. Ezetimibe was
added in only 6.8% of patients with LDL-­C≥100 mg/dL
and in 4.5% of patients with LDL-­C 70 to 99 mg/dL.8
The low uptake of ezetimibe in these real-­world studies
might be a reflection of the evidence base during that
time, because the IMPROVE-­IT trial tested ezetimibe in
combination with high-­dose simvastatin (40 mg); thus,
a knowledge gap had existed on the potential benefit
of ezetimibe in combination with lower doses of statins.
The RACING (Randomized Comparison of Efficacy
and Safety of Lipid-­Lowering With Statin Monotherapy
Versus Statin/Ezetimibe Combination for High-­ Risk
Cardiovascular Diseases) trial has challenged the
concept of the add-­on ezetimibe and introduced the
approach of upfront treatment with a combination
therapy. The trial randomized 3780 patients with ath-
erosclerotic cardiovascular disease (only 1% with ACS)
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to a combination of ezetimibe with moderate-­intensity
statin (rosuvastatin 10 mg) versus high-­ intensity sta-
tin monotherapy (rosuvastatin 20 mg). Combination
of rosuvastatin-­ezetimibe significantly reduced LDL-­C
levels at 1, 2, and 3 years (73%, 75%, and 72% in the
combination therapy versus 55%, 60%, and 58% in the
rosuvastatin monotherapy group, respectively), and
the incidence of drug discontinuation was significantly
lower with combination therapy (4.8% versus 8.2%).
The primary end point (ie, cardiovascular death, major
cardiovascular events or nonfatal stroke) occurred
in 9.1% in the combination group versus 9.9% in the
rosuvastatin monotherapy group (absolute difference
−0.78% [90% CI, −2.39 to 0.83]) achieving noninferior-
ity.9 A recent observational analysis of 72 050 patients
after percutaneous coronary intervention with drug-­
eluting stents from Korea also demonstrated that the
combination of moderate-­intensity rosuvastatin (10 mg)
with ezetimibe was associated with a lower incidence
of the cardiovascular death, major cardiovascular
events, or nonfatal stroke at 3 years, compared with
high-­intensity rosuvastatin (20 mg) monotherapy after
inverse probability weighing (11.6% versus 15.2%; HR,
0.75 [95% CI, 0.70–­0.79]). Similarly, the incidence of
drug discontinuation was significantly lower with com-
bination therapy (6.5% versus 7.6%; HR, 0.85 [95% CI,
0.78–­0.94]).10
J Am Heart Assoc. 2023;12:e031615. DOI: 10.1161/JAHA.123.0316152
Combination of Ezetimibe and Statin in ACS
In this issue of the Journal of the American Heart
Association (JAHA), Lewek et al extended our knowl-
edge by focusing exclusively on a secondary preven-
tion population with recent ACS. Using data from a
large observational multicenter registry of consecutive
ACS hospitalizations in Poland, the authors identified
38 023 patients who had data on LDL-­C levels and
were discharged on statin therapy. Propensity score
matching was used to match 768 patients who re-
ceived an upfront combination of statin (any dose of
atorvastatin or rosuvastatin)-­ezetimibe to 768 patients
who received statin monotherapy. Upfront combina-
tion was associated with a lower incidence of all-­cause
mortality at 1 year (5.9% versus 3.5%, P=0.04), 2 years
(7.8% versus 4.3%, P=0.02), and 3 years (10.2% versus
5.5%, P=0.02).11
On a quick glance, the findings from the study by
Lewek et al are in line with other studies9,10 and sup-
port an upfront combination of statin-­ezetimibe for
patients with ACS, but a few issues deserve closer
consideration. First, the study showed a strong sur-
vival benefit with combination therapy, a finding
that was not seen in the RACING trial. However, it
is important to note that the RACING trial included
only a minority of patients with recent ACS (~1%).
Observational studies are prone to selection bias,
which is relevant in this study because only 2% of
patients were discharged on ezetimibe. Further, a
considerable number of patients were excluded due
to lack of data on LDL-­C levels. Second, the registry
captures data on medications upon discharge but not
on admission, so some patients might have been on
combination therapy before admission. To adequately
compare the effectiveness of 2 pharmacological strat-
egies, including only new users would have provided
better insights.12 Notably, the prevalence of hyperlip-
idemia and prior cardiovascular events was higher in
the combination therapy group supporting the notion
that this group was likely on a more intensive LLT be-
fore admission. Third, the registry does not capture
data on the statin dose, which is an important factor
in assessing the impact of moderate-­intensity versus
high-­intensity statin on outcomes and discontinua-
tion of therapy. Fourth, several high-­risk ACS features
were more prevalent in the statin monotherapy group,
for example, New York Heart Association class III/ IV
and Killip class III/IV, which potentially affect mortal-
ity. Although the authors accounted for these factors
in the propensity model, there are likely other resid-
ual confounding factors such as cardiogenic shock
that were unmeasured. This potential for unmeasured
confounding is also supported by the early separation
of the Kaplan–­Meyer curves. Notwithstanding these
issues, the authors should be applauded for their
work, which proposes a new LLT approach for the
management of patients with ACS.
 Ya’Qoub et al
In conclusion, the study by Lewek et al11 and other
studies9,10 suggest that an upfront combination of
statin-­ezetimibe might be associated with improved
clinical outcomes and lower rates of drug discontinu-
ation compared with statin monotherapy. Perhaps the
widespread availability of a polypill combining statin-­
ezetimibe might also improve patient adherence.13,14
Collectively, these findings support a pragmatic clinical
trial including patients with ACS and high-­risk athero-
sclerotic cardiovascular disease ensuring adequate
representation of racial and ethnic groups to assess
the impact of combination of low-­to moderate-­intensity
statin-­ezetimibe versus high-­dose statin monotherapy.
ARTICLE INFORMATION
Affiliations
Department of Cardiology, Saint Mary’s Regional Medical Center, Reno, NV
(L.Y.); Department of Pharmacy, Practice and Science, College of Pharmacy,
University of Kentucky, Lexington, KY (H.M.); and Division of Cardiovascular
Medicine, Gill Heart Institute, University of Kentucky, Lexington, KY (I.Y.E.).
Disclosures
None.
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