International Journal of

Molecular Sciences

Review
The Role of Cilostazol, a Phosphodiesterase-3 Inhibitor, in the
Development of Atherosclerosis and Vascular Biology: A Review
with Meta-Analysis
Minji Sohn and Soo Lim *

Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University
College of Medicine, Seongnam 13620, Republic of Korea; [email protected]
* Correspondence: [email protected]

Abstract: Atherosclerotic cardiovascular disease (ASCVD) stands as the leading global cause of
mortality. Addressing this vital and pervasive condition requires a multifaceted approach, in which
antiplatelet intervention plays a pivotal role, together with antihypertensive, antidiabetic, and lipid-
lowering therapies. Among the antiplatelet agents available currently, cilostazol, a phosphodiesterase-
3 inhibitor, offers a spectrum of pharmacological effects. These encompass vasodilation, the impedi-
ment of platelet activation and aggregation, thrombosis inhibition, limb blood flow augmentation,
lipid profile enhancement through triglyceride reduction and high-density lipoprotein cholesterol
elevation, and the suppression of vascular smooth muscle cell proliferation. However, the role of
cilostazol has not been clearly documented in many guidelines for ASCVD. We comprehensively
reviewed the cardiovascular effects of cilostazol within randomized clinical trials that compared it to
control or active agents and involved individuals with previous coronary artery disease or stroke,
as well as those with no previous history of such conditions. Our approach demonstrated that the
administration of cilostazol effectively reduced adverse cardiovascular events, although there was
less evidence regarding its impact on myocardial infarction. Most studies have consistently reported
its favorable effects in reducing intermittent claudication and enhancing ambulatory capacity in
patients with peripheral arterial disease. Furthermore, cilostazol has shown promise in mitigating
restenosis following coronary stent implantation in patients with acute coronary syndrome. While
Citation: Sohn, M.; Lim, S. The Role research from more diverse regions is still needed, our findings shed light on the broader implications
of Cilostazol, a Phosphodiesterase-3 of cilostazol in the context of atherosclerosis and vascular biology, particularly for individuals at high
Inhibitor, in the Development of risk of ASCVD.
Atherosclerosis and Vascular Biology:
A Review with Meta-Analysis. Int. J. Keywords: atherosclerosis; cardiovascular diseases; cilostazol; platelet aggregation inhibitors; aspirin
Mol. Sci. 2024, 25, 2593. https://
doi.org/10.3390/ijms25052593

Academic Editor: Antonio Barbato

1. Introduction
Received: 11 January 2024
Revised: 7 February 2024
Cardiovascular diseases (CVDs) [1], including coronary artery disease (CAD), cere-
Accepted: 14 February 2024
brovascular disease, and peripheral artery disease (PAD), are a significant global public
Published: 23 February 2024
health problem [1,2]. Ischemic heart disease is the most common cause of death world-
wide [3]. Moreover, cerebrovascular diseases are more prevalent among Asian ethnicities,
thus becoming a top priority for intervention. Since 2015, stroke has become the lead-
ing cause of death and disability in China, posing a significant public health threat [4].
Copyright: © 2024 by the authors. Atherosclerosis in peripheral arteries is characterized by stenosis or the occlusion of the
Licensee MDPI, Basel, Switzerland. arteries that supply blood to the lower limbs, resulting in symptoms such as intermittent
This article is an open access article claudication and ulceration [2]. PAD is also related to a high risk of atherosclerotic car-
distributed under the terms and diovascular disease ASCVD, including myocardial infarction, stroke, and renovascular
conditions of the Creative Commons disease [5]. About 1–3% patients with intermittent claudication exhibit progression to
Attribution (CC BY) license (https:// severe limb-related complications within 5 years, which may necessitate limb amputation
creativecommons.org/licenses/by/
and result in premature death [5].
4.0/).

Int. J. Mol. Sci. 2024, 25, 2593. https://doi.org/10.3390/ijms25052593 https://www.mdpi.com/journal/ijms

Int. J. Mol. Sci. 2024, 25, 2593 2 of 26

These vascular diseases are mainly caused by atherosclerosis, which starts with the
development of fibrofatty lesions known as atherosclerotic plaques. Several mechanisms
are involved in this process: the accumulation of modified low-density lipoprotein (LDL)
in the intima, the attraction of pro-inflammatory monocytes and T lymphocytes to the
arterial wall, the proliferation and migration of vascular smooth muscle cells (VSMCs), the
aggravation of oxidative stress and the increase in adhesion molecules, and the aggregation
of platelets [1]. The rupture of the fibrous cap in an atherosclerotic plaque can result in the
development of a life-threatening ASCVD, such as myocardial infarction and stroke, both of
which can also lead to various complications that significantly impact the patient’s quality of
life [6,7]. Furthermore, ASCVD is commonly asymptomatic up until the occurrence of acute
coronary syndrome or stroke [8]. Therefore, preventive measures and early interventions
aimed at reducing the risk of these conditions are crucial.
Type 2 diabetes mellitus (T2DM) is closely linked to an increased risk of CAD and cere-
brovascular disease. Patients with T2DM have a 2–4-fold higher CVD risk compared to that
of the general population, regardless of the presence/absence of other risk factors [9]. Thus,
diabetes mellitus is regarded as being equivalent to the risk of CAD. Furthermore, ASCVD
is the principal cause of death and disability among patients with diabetes mellitus [10].
Diabetes mellitus is characterized by insulin resistance, dyslipidemia, inflammation, and
hypercoagulability, which exacerbate the underlying causes of atherosclerosis and heart
failure [11]. To date, the cardiovascular benefit of multifactorial risk-reduction approaches
using antidiabetic agents, antihypertensive drugs, and lipid-lowering therapy has been
proven, thus reducing the incidence of cardiovascular complications [12]. However, the cur-
rent therapeutic strategies are not sufficient for preventing adverse cardiovascular events,
and a substantial number of patients with diabetes mellitus still face a risk of CVD, leading
to the term “residual risk” [12].
For the management of the residual risk, international guidelines from the USA
and Europe recommend the use of antiplatelet agents as a main management strategy
in patients with diabetes and a high CVD risk [13,14]. Hence, antiplatelet agents such
as aspirin, clopidogrel, and cilostazol could be contemplated in the management of the
residual risk, pending additional supportive evidence.
Cilostazol is an antiplatelet agent that inhibits phosphodiesterase-3 (PDE-3) and in-
creases cyclic adenosine monophosphate (cAMP) concentrations, leading to the inhibition
of platelet aggregation and thrombus formation [15]. PDE-3 is expressed in cell populations
such as platelets, VSMCs, cardiac myocytes, and adipocytes [16]. Therefore, cilostazol is
expected to have some effects in these tissues.
Cilostazol has been approved for improving intermittent claudication symptoms
in various countries. In further research, cilostazol treatment reduced the progression of
atherosclerosis in patients with carotid artery stenosis [17,18] and the recurrence of stroke in
patients with cerebrovascular disease [19,20]. In addition, previous studies have shown that
cilostazol therapy is beneficial for CAD when administered immediately after percutaneous
coronary intervention or in addition to other antiplatelet agents [21,22].
In 2015, a critical review of the literature regarding cilostazol and its role against
CVD was reported [23]. Since then, many basic and clinical studies have been published;
however, its role has not been reviewed systematically. Moreover, cilostazol has not been
well documented in the literature with regard to its role in CVD and diabetes mellitus. In
this review, we discuss the mechanism of action of cilostazol and evaluate the efficacy and
safety of the drug based on the results of clinical trials. Furthermore, we comprehensively
explore the role of cilostazol in the prevention and treatment of atherosclerosis.

2. Limitations of Aspirin Therapy for Atherosclerotic CVD

Aspirin, which inhibits COX-1 and prevents the formation of thromboxane, thereby ex-
erting antiplatelet effects, remains the most commonly used antiplatelet agent [24]. Recently,
controversy has arisen regarding the effectiveness of aspirin in the primary prevention of
CVD. Both Asian and European studies that investigated the primary preventive effect of
Int. J. Mol. Sci. 2024, 25, 2593 3 of 26

aspirin for CVD in patients with T2DM reported an absence of significant differences in the
incidence of CVD between the aspirin treatment group and the non-aspirin group [25,26]. A
meta-analysis of several clinical studies in which aspirin was administered for the primary
prevention of CVD also showed that aspirin did not reduce the incidence of CVD in patients
with diabetes [27]. The six-year follow-up of the primary preventive effect of aspirin against
CVD in more than 14,000 Japanese elderly patients also failed to demonstrate the beneficial
effect of aspirin on the incidence of CVD [28].
Moreover, it was reported that the use of aspirin not only increased the number of
adverse events, such as major bleeding and gastrointestinal discomfort, but also did not
reduce the risk of cardiovascular events in primary prevention (Table 1) [25,26,28–34].
There is some evidence from basic studies suggesting that aspirin might not be suffi-
cient to reduce abnormal platelet activation. The platelet multidrug resistance protein 4
(MRP4) is upregulated after aspirin administration, which could represent one of the
mechanisms underlying the high residual platelet reactivity after aspirin intake [35]. Impor-
tantly, patients with persistent high platelet reactivity while on aspirin therapy exhibited
an increased risk of recurrent cardiovascular events [36].
Based on these findings, the role of aspirin in this context has changed drastically
since 2018. The US Preventive Services Task Force did not recommend the initiation of low-
dose aspirin among patients aged 60 years or older [37]. The American Heart Association
(AHA) and American College of Cardiology (ACC) Foundation’s statement on aspirin
for the primary prevention of cardiovascular events in individuals with diabetes suggests
that low-dose aspirin should not be administered to those with a low risk for ASCVD
(10-year risk < 5%), but can be considered in patients with an increased cardiovascular risk
(10-year risk > 10%) [38,39]. Unfortunately, no direct evidence from a clinical trial supports
these risk-based treatment recommendations, resulting in controversy in the primary
prevention among patients with a high CVD risk. Moreover, the primary preventive effect
of aspirin was not clearly demonstrated, even for high-risk patients, such as those with
T2DM (Table 1).
In contrast, the guidelines for the secondary prevention of diabetes recommend aspirin
therapy (75–162 mg daily) for individuals with diabetes and a history of ASCVD [13].
Nevertheless, concerns regarding the side effects of this therapy remain unaddressed.
In the Aspirin in Reducing Events in the Elderly (ASPREE) study, cancer-related death
occurred in 3.1% of the participants in the aspirin group and in 2.3% of those in the placebo
group (hazard ratio: 1.31; 95% confidence interval (CI): 1.10–1.56), indicating a higher
cancer mortality rate in the aspirin therapy compared with that of the placebo group [33].
Although the risk of cancer development was not confirmed in other studies (Table 1),
concerns regarding this issue remain.
Int. J. Mol. Sci. 2024, 25, 2593 4 of 26

Table 1. Randomized controlled studies with aspirin for preventing primary cardiovascular events since 2000.

Patient’s
Trial Information * Efficacy and Safety Outcomes
Bibliographic Characteristics
Information Patients’ Men (%)/Age Diabetes Cardiovascular
Population Duration ** Bleeding Risks Cancer Risks
Number (Years) Comorbidity Events ***
No difference in
RR of 3P-MACE a Severe bleedings more
Participants with at least cancer risks with
with aspirin vs. frequent in the aspirin
PPP study [29] one already known major 5 years 4495 42.5/64.4 16.5% aspirin vs.
no-aspirin: group (1.1% vs. 0.3%;
cardiovascular risk factor no-aspirin
0.71 (0.48–1.04) p < 0.0008)
(3.9% vs. 3.5%)
Female health Any gastrointestinal
RR of 3P-MACE a
professionals, aged ≥45 bleeding: RR
with aspirin vs.
WHS study [30] and without a history of mean 10.1 years 39,876 0/54.6 2.6% 1.22 (1.10–1.34) Not reported
placebo: 0.91
cardiovascular disease Requiring transfusion:
(0.80–1.03)
or cancer RR 1.40 (1.07–1.83)
No difference in
HR of atherosclerotic significant
Patients with events b with aspirin gastrointestinal
JPAD study [25] mean 4.37 years 2539 54.6/64 100% Not reported
type 2 diabetes vs. no-aspirin: bleeding with aspirin
0.80 (0.58–1.10) vs. no-aspirin
(1.0% vs. 0.3%)
Participants aged ≥40
with type 1 or type 2 No difference in No difference in
No difference in
diabetes and an ankle atherosclerotic events gastrointestinal
POPADAD median 6.7 years c with aspirin vs. malignancy with
brachial pressure index of 1276 44.1/60.3 100% bleeding with aspirin
study [26] (4.5~8.6 years) aspirin vs. placebo
0.99 or less but no no-aspirin: vs. no-aspirin:
(8.3% vs. 10.7%)
symptomatic 0.98 (0.76–1.26) 0.90 (0.53–1.52)
cardiovascular disease
Participants aged 60 to Major gastrointestinal
85 years, presenting with HR of 3P-MACE a and extracranial
hypertension, 6 years (median with aspirin vs. bleedings more
JPPP study [28] 14,658 42.3/70.5 33.9% Not reported
dyslipidemia, or diabetes 5.02 years) no-aspirin: frequent in the aspirin
mellitus without 0.94 (0.77–1.15) group (0.1% vs. 0.07%;
cardiovascular disease p < 0.001)
Int. J. Mol. Sci. 2024, 25, 2593 5 of 26

Table 1. Cont.

Patient’s
Trial Information * Efficacy and Safety Outcomes
Bibliographic Characteristics
Information Patients’ Men (%)/Age Diabetes Cardiovascular
Population Duration ** Bleeding Risks Cancer Risks
Number (Years) Comorbidity Events ***
RR of serious vascular
Patients with type 2 RR of any major
ASCEND at least 7 years events d with aspirin RR of any cancer:
diabetes without 15,480 62.6/63.3 100% bleeding:
study [31] (mean 7.4 years) vs. placebo: 1.01 (0.92–1.11)
cardiovascular disease 1.29 (1.09–1.52)
0.88 (0.79–0.97)
Participants aged
≥55 years (men) or
HR of 3P-MACE a No difference in
≥60 years (women) and HR of gastrointestinal
ARRIVE study 6 years (mean with aspirin vs. cancer with aspirin
had moderate 12,546 70.4/63.9 0% bleeding:
[32] 5 years) no-aspirin: vs. placebo (not
cardiovascular risk, 2.11 (1.39–3.28)
0.79 (0.61–1.02) sufficient events)
without at high risk of
bleeding or diabetes
HR of ischemic HR of major
Elderly participants who HR of cancer-related
events-related deaths hemorrhage-related
ASPREE did not have 6 years (median deaths with aspirin
19,114 43.6/median 74 10.8 with aspirin vs. deaths with aspirin vs.
study [33] cardiovascular disease, 4.7 years) vs. placebo:
placebo: placebo:
dementia, or disability 1.31 (1.10–1.56)
0.82 (0.62–1.08) 1.13 (0.66–1.94)
Participants without No difference in major
HR of 3P-MACE a by HR of cancer with
Yusuf S. et al., cardiovascular disease 6 years (mean bleeding with aspirin
5713 47.1/63.9 36.7% aspirin vs. placebo: aspirin vs. placebo:
2021 [34] who had an elevated 4.6 years) vs. placebo
0.86 (0.67–1.10) 0.83 (0.54–1.27)
INTERHEART Risk Score (1.5% vs. 1.3%)
Abbreviations: 3P-MACE, 3-point major adverse cardiovascular events; HR, hazard ratio; and RR, risk ratio. * Aspirin (100 mg) was compared to placebo or control therapy. ** Study
drug was administered during the whole study period. *** Definition of cardiovascular events were different between the groups: a 3P-MACE: cardiovascular death, non-fatal,
myocardial infarction, and stroke. b Composite of sudden death; death from coronary, cerebrovascular, and aortic causes; non-fatal acute myocardial infarction; unstable angina; newly
developed exertional angina; nonfatal ischemic and hemorrhagic stroke; transient ischemic attack; or nonfatal aortic and peripheral vascular disease (arteriosclerosis obliterans, aortic
dissection, mesenteric arterial thrombosis). c Death from coronary heart disease or stroke, non-fatal myocardial infarction or stroke, or above ankle amputation for critical limb ischemia.
d Composite of nonfatal myocardial infarction, nonfatal stroke (excluding confirmed intracranial hemorrhage) or transient ischemic attack, or death from any vascular cause (excluding

confirmed intracranial hemorrhage).

Int. J. Mol. Sci. 2024, 25, x FOR PEER REVIEW 7 of 29

Int. J. Mol. Sci. 2024, 25, 2593 6 of 26

3. Beneficial RoleRole
3. Beneficial of Cilostazol in the
of Cilostazol in Development of Atherosclerosis
the Development of Atherosclerosis
3.1. 3.1.
Antiplatelet Activity
Antiplatelet Activity
Cilostazol inhibits
Cilostazol platelet
inhibits function
platelet by inhibiting
function PDE-3
by inhibiting and increasing
PDE-3 cAMPcAMP
and increasing levels lev-
[40]els
(Figure 1). Platelet
[40] (Figure reactivity
1). Platelet is mediated
reactivity by the
is mediated byintracellular calcium
the intracellular levels,
calcium which
levels, which
induce a molecular
induce a molecular cascade including
cascade cAMP,
including cAMP,resulting in platelet
resulting degranulation,
in platelet degranulation, confor-
confor-
mational
mational changes,
changes, and and aggregation
aggregation [41]. [41]. Elevated
Elevated cAMPcAMP levels levels upregulate
upregulate the activity
the activity of
of protein
protein kinase A kinase
(PKA),A which
(PKA),phosphorylates
which phosphorylates key intermediary
key intermediary moleculesmolecules that are
that are essen-
essential
tial for plateletforaggregation
platelet aggregation
[42]. PKA [42]. PKA
has also hastied
been alsotobeen tied to the downregulation
the downregulation of platelet of
platelet
adhesion adhesion
through the through the phosphorylation
phosphorylation of the GP-Ib-IXof the GP-Ib-IX
complex, thecomplex,
inhibitionthe
of inhibition
intracel- of
lularintracellular
calcium store calcium storethromboxane
release, release, thromboxane
receptor receptor desensitization,
desensitization, and theand the inhibition
inhibition of
of the phosphorylation
the phosphorylation of myosin
of myosin light kinase
light chain chain kinase
[43]. [43].

Figure 1. Mechanisms of action of cilostazol. Cilostazol inhibits phosphodiesterase-3 in various cell

Figure 1. Mechanisms of action of cilostazol. Cilostazol inhibits phosphodiesterase-3 in various cell
types including platelets, vascular cells, myocytes, and adipocytes, which affects several pathways
types including platelets, vascular cells, myocytes, and adipocytes, which affects several pathways
resulting
resulting in vasodilation
in vasodilation and and enhanced
enhanced blood
blood perfusion.
perfusion. Cilostazol
Cilostazol induces
induces nitricnitric
oxide oxide
(NO)(NO) release
release
fromfrom endothelial
endothelial cells
cells andand activates
activates calcium-dependentpotassium
calcium-dependent potassiumchannels
channels inin vascular
vascular smooth
smoothmus-
cle cells,
muscle cells, leading
leadingtotovasodilation.
vasodilation.ThisThisaction
actionleads
leadstotothe
theupregulation
upregulation of of
thethe
protein kinase
protein kinaseA (PKA),
A
(PKA),
andand eventually
eventually causing
causing arterial
arterial dilatation
dilatation and platelet
and platelet inactivation.
inactivation. Furthermore,
Furthermore, cilostazol
cilostazol attenuates
attenuates the activation
the activation of platelets,
of platelets, thus facilitating
thus facilitating blood perfusion.
blood perfusion. 5′ AMP,
Abbreviations:
Abbreviations: 5′ -adenosine
5′AMP, 5′-
adenosine monophosphate; cAMP, cyclic adenosine monophosphate; eNOS, endothelial
monophosphate; cAMP, cyclic adenosine monophosphate; eNOS, endothelial nitric oxide synthase; nitric ox-
ide synthase;
JAK2, Janus JAK2, Janus
kinase 2; kinase
PDE-3,2;phosphodiesterase-3;
PDE-3, phosphodiesterase-3; PKA, kinase
PKA, protein proteinA;kinase
PPARγ,A; PPARγ,
peroxisome
peroxisome proliferator-activated receptor gamma; STAT3, signal transducer and activator of tran-
proliferator-activated receptor gamma; STAT3, signal transducer and activator of transcription 3; TG,
scription 3; TG, triglycerides; and TXA2, thromboxane A2.
triglycerides; and TXA2, thromboxane A2.

Recent evidence
Recent hashas
evidence suggested
suggesteda role forfor
a role cilostazol in in
cilostazol thethe
inhibition
inhibitionofof
MRP4
MRP4 [44]
[44]and
and in
in overcoming a high on-aspirin-treatment residual platelet reactivity in a
overcoming a high on-aspirin-treatment residual platelet reactivity in a cAMP-independent cAMP-inde-
pendent manner
manner [45]. MRP4,
[45]. MRP4, which which is expressed
is expressed in platelets
in platelets primarily
primarily in theinmembranes
the membranesof dense
of dense granules [46], promotes platelet aggregation by transporting
granules [46], promotes platelet aggregation by transporting cyclic nucleotides, cyclic nucleotides,
including
including
cAMP cAMP and cGMP,
and cGMP, outside outside of platelets
of platelets [47]. MRP4
[47]. MRP4 has also
has also beenbeen
shown shown to de-
to desensitize
sensitize platelets
platelets to thetoinhibitory
the inhibitory effects
effects of endothelial-derived
of endothelial-derived nitric
nitric oxide
oxide andand sensitize
sensitize them
them to ADP-mediated activation [44]. Thus, the inactivation of MRP4 and
to ADP-mediated activation [44]. Thus, the inactivation of MRP4 and the inhibition of the inhibition
of phosphodiesterase-4
phosphodiesterase-4by bycilostazol
cilostazolare
arereported
reported toto
have
have synergistic and
synergistic andpotent
potenttherapeu-
therapeutic
tic antiplatelet effects [46].
antiplatelet effects [46].
Int. J. Mol. Sci. 2024, 25, 2593 7 of 26

The clinical findings of decreased platelet reactivity after cilostazol treatment have
been described in various populations, including patients with acute coronary syndrome
and ischemic stroke [40,48], and even when administered in addition to aspirin and clopido-
grel [49]. Cilostazol is likely to be more effective in inhibiting platelet activation, especially
in patients with diabetes mellitus. Platelets themselves have insulin receptors which, when
activated, initiate a molecular cascade, leading to increased cAMP levels and platelet inhi-
bition [50]. Insulin resistance is associated with an attenuated P2Y1 response caused by
low cAMP levels, which may explain the observation that patients with T2DM are at an
increased risk of thrombosis [50]. Another study further established a relatively higher
degree of platelet inhibition by cilostazol in patients with diabetes compared with those
without this condition [51].

3.2. Increase in Nitric Oxide Secretion

Cilostazol has a potent vasodilatory effect. Cilostazol treatment leads to PKA phos-
phorylation and the activation of endothelial nitric oxide synthase (eNOS), which increases
nitric oxide levels [52]. The vasodilatory effect of cilostazol therapy includes the PKA-
mediated phosphorylation of G-protein-coupled receptor kinase 2, the inactivation of
G-alpha-q-mediated signaling, and the hyperpolarization of smooth muscle cell mem-
branes through the potentiation of calcium-activated potassium currents [53,54].
Because of its PDE-3-inhibitory function, cilostazol administration resulted in the
accumulation of cAMP, thus inducing vasodilation [55]. This process was mediated by
the cAMP-dependent secretion of nitrogen oxide (NO) by vascular endothelial cells [56].
The other signaling pathway is endothelium-independent and involves the direct effect of
cilostazol on VSMCs. cAMP build-up in these cells induces the PKA-dependent activation
of the calcium-dependent potassium channel, leading to vasorelaxation [57]. In addition,
cilostazol was shown to inhibit cGMP-specific PDE or PDE-5 [58], which may contribute to
its vasorelaxant properties by promoting the accumulation of cGMP in VSMCs [58]. Further-
more, cilostazol treatment attenuated adenosine uptake by several types of cells, thereby
leading to adenosine build-up in the interstitial fluid and vascular circulation [59]. The
increase in extracellular adenosine potentiates adenosine receptor A2 activity in endothelial
cells, causing arterial dilatation [60].

3.3. Antiproliferative Activity, Including Alterations in Adhesion Molecules

Cilostazol exhibited an antiproliferative effect on the vasculature by reducing neoin-
tima formation in animal models [61,62]. This antiproliferative effect of cilostazol is likely
mediated by its effects on cAMP elevation and PKA inhibition, which are responsible for
the decrease in the transcription of genes encoding cellular adhesion molecules and the
proliferation of VSMCs [63] (Figure 1). The administration of cilostazol also decreased
the levels of the vascular cell adhesion molecule, intercellular adhesion molecule, and
E-selectin [64,65]. A decrease in the expression of these cellular adhesion molecules dis-
rupts neointimal proliferation through the reduction in inflammatory cell invasion into
the damaged intima [66]. In addition, cilostazol therapy downregulates growth factors,
such as the vascular endothelial growth factor and platelet-derived growth factor [62,65].
Furthermore, cilostazol plays a favorable role in the transition to smooth muscle cells from
a de-differentiated state [67].

3.4. Improvement in Vascular Endothelial Function

Cilostazol has beneficial effects on endothelial function, which is linked to NO pro-
duction (Figure 1). Cilostazol treatment increased cAMP levels in endothelial cells, which
led to NO production [68]. In aged Wistar rats, endothelial dysfunction was restored
by cilostazol treatment [69]. This protective effect of cilostazol could be attributed to its
favorable actions on arterial walls, including a reduction in oxidative stress and an increase
in NO bioavailability [69]. Another study proved that cilostazol treatment decreased in-
timal thickening and improved the vasodilation capacity [70]. Cilostazol stimulates the
Int. J. Mol. Sci. 2024, 25, 2593 8 of 26

production of hepatocyte growth factor, which is known for its favorable role in attenuating
the malformation and apoptosis of endothelial cells [71].
Also, in a clinical setting, a three-month intervention using cilostazol improved en-
dothelial function, as measured by flow-mediated dilation, compared with aspirin in
patients with stroke (1.0% vs. 0.8%) [72]. Moreover, a six-month treatment with cilosta-
zol improved vasomotor reactivity, as evidenced by an increase in the coronary luminal
diameter following the administration of N-monomethyl-L-arginine [73].

3.5. Anti-Inflammatory Effect

In an animal study, cilostazol deactivated the nucleotide-binding domain-like re-
ceptor protein 3 (NLRP3) inflammasome [74], which is associated with atherosclerosis
and CVD [75,76]. This anti-inflammatory potential was mediated by the downregu-
lation of p65 NF-κB and the enhancement of sirtuin-1, leading to the downregulation
of NLRP3, an apoptosis-associated speck-like protein, active caspase-1, and interleukin-
1β [74]. In an animal study of hypercholesterolemic rats, cilostazol treatment protected
against hypercholesterolemia-induced cardiac damage via molecular mechanisms targeting
the crosstalk between Nrf2 induction and NF-κB inhibition in the heart [77]. Another study
using the mouse models of myocardial ischemia–reperfusion showed that cilostazol treat-
ment attenuated multiple inflammatory markers through the activation of the peroxisome
proliferator-activated receptor-γ (PPARγ), Janus kinase 2 (JAK2), and the signal transducer
and activator of transcription 3 (STAT3) pathways [78].
Similar findings were obtained in human studies. In a randomized controlled trial
(RCT), treatment with cilostazol (100 mg twice daily) significantly decreased the hsCRP
levels by 23.6%, erythrocyte sedimentation rate by 38.7%, and plasma malondialdehyde
concentration by 17.6% [79]. Our group also found that treatment with cilostazol (200 mg
once daily) decreased hsCRP levels significantly compared with aspirin in patients with
T2DM and coronary artery stenosis [80]. It is suggested that the greater anti-inflammatory
potency of cilostazol, when added to the standard dual antiplatelet therapy of aspirin and
clopidogrel, may have contributed to the inhibition of the progression of carotid intima–
media thickness, without raising the risk of hemorrhage [81]. These data are indicative of
the deactivation of inflammation by cilostazol therapy.

3.6. Antioxidative Stress Effect

Cilostazol treatment is related to the activation of endothelial nitric oxide synthase
(eNOS), which is implicated in the maintenance of endothelial function and the reduction
in superoxide-radical-induced injury [52]. Cilostazol upregulates eNOS activity through
multiple pathways. The inhibition of adenosine reuptake increases the activation of an
adenosine-mediated signaling mechanisms involving the “survival” kinase Akt, which sub-
sequently activates eNOS via phosphorylation [52]. The cilostazol-mediated inhibition of
the phosphatase and tensin homolog also upregulates phosphotadidylinositol-3-phosphate,
which in turn activates Akt. The cAMP-mediated activation of PKA has also been shown
to activate eNOS through phosphorylation at a site distinct from Akt [52].
Through these basic mechanisms, cilostazol has been shown to attenuate ischemia–
reperfusion injury in models of myocardial, hepatic, and spinal cord reperfusion in-
jury [82,83]. The administration of cilostazol prior to coronary occlusion and reperfusion
was associated with a significantly smaller infarct size in a rabbit model compared with
that of the controls [84].
Oxidative stress was also decreased in a clinical trial involving individuals with T2DM
and hypertension [79]. Plasma malondialdehyde and blood glutathione markers were
improved after a one-month treatment with cilostazol, indicating its potential antioxidative
effects in humans [79].
Int. J. Mol. Sci. 2024, 25, 2593 9 of 26

3.7. Improvement in the Lipid Profile

Cilostazol seems to induce this favorable alteration in lipid metabolism through the
upregulation of lipoprotein lipase in adipose tissue [85]. The administration of cilostazol
increased lipolysis by inhibiting PDE-3 in adipocytes [86] (Figure 1). In an animal study,
the administration of cilostazol enhanced LDL receptor-related protein 1 (LRP1) expression
in the liver by activating PPARγ through the peroxisome proliferator-responsive elements
present in the LRP1 promoter [87]. This upregulation of hepatic LRP1 may play an impor-
tant role in improving HDL-cholesterol and triglycerides [88]. In the studies of animals fed
with a high-cholesterol diet, the administration of cilostazol decreased the triglyceride and
cholesterol content in the vascular system [89,90].
It Is noteworthy that the Increase In cAMP triggered by cilostazol treatment affects
norepinephrine, thus increasing fat metabolism and exothermic reactions, and consequently
increasing energy consumption. Cilostazol can increase uncoupling protein 1 (UCP1) in
adipocytes [91]. Regulating the expression of UCP1 and PGC1α through cAMP-responsive
element binding (CREB) and increasing free fatty acid release through lipolysis are used as
fuel for thermogenesis in mitochondria [92].
Several clinical trials that examined the effects of cilostazol on lipid profiles have
reported similar findings [80,93,94]. In these studies, the triglyceride levels decreased
by 15–34% in patients with PAD or T2DM. In contrast, HDL-cholesterol was reported to
increase by 7–20% [18]. Cilostazol therapy reduced the remnant lipoprotein level, which is
associated with an increased risk of CVD [94]. Furthermore, cilostazol treatment reduced
apolipoprotein B levels, which are an indirect indicator of LDL particle number [95]. These
improvements in lipid profiles afforded by cilostazol therapy help prevent the development
and progression of atherosclerosis.

4. Clinical Results of Cilostazol Treatment for Preventing Cardiovascular Events

4.1. Methods for Meta-Analysis of Major Adverse Cardiovascular Outcomes
For clinical interpretation, we systematically reviewed the effects of cilostazol on
cardiovascular outcomes, as registered in PROSPERO CRD42023444959. We searched
PubMed, Embase, and the Cochrane databases for English-language studies published
up to July 2023. The search terms included keywords such as ‘cilostazol’ for the study
intervention; ‘major adverse cardiovascular event’, ‘cardiovascular disease’, ‘cardiovascular
event’, ‘myocardial infarction’, and ‘stroke’ for the outcomes; and ‘randomized controlled
trial’ for the study design. The full list of search terms can be found in Supplementary
Table S1. Using this process, we selected the studies to be included in the present analysis
based on the following inclusion criteria: studies that (1) compared cilostazol with placebo,
control, aspirin, or clopidogrel; (2) reported composite major adverse cardiovascular events
(MACEs); and (3) were RCTs. We excluded studies with a follow-up duration of less than
3 months.
The primary outcome was MACE. Secondary outcomes Included individual cardio-
vascular events, such as fatal or non-fatal MI, fatal or non-fatal stroke, cardiovascular death,
and all-cause mortality. Other adverse events, including major bleeding, discontinuation,
headache, and palpitation, were also analyzed.
Study selection and data collection were confirmed by both authors. Logarithmic
hazard ratios (HRs) were used to calculate combined estimates with a random-effects
model. Random-effects risk ratios were calculated for studies that provided only the event
numbers. The included trials were assessed for the risk of bias using the Cochrane Risk of
Bias 2 tool (see Supplementary Figure S3). The I2 statistic was employed to evaluate the
overall heterogeneity of all comparisons. Publication bias was assessed using a funnel plot
and Egger’s test. Sensitivity analyses were performed focusing on the regions of the trials.
The meta-analysis was conducted using the ‘metafor’ statistical package in R software
(version 4.1.0; R Development Core Team, Vienna, Austria).
Int. J. Mol. Sci. 2024, 25, x FOR PEER REVIEW 11 of 29
Int. J. Mol. Sci. 2024, 25, 2593 10 of 26

4.2. Meta‐Analysis Results of Major Adverse Cardiovascular Outcomes

4.2. Meta-Analysis Results of Major Adverse Cardiovascular Outcomes
Out of 496 articles, 34 were selected [18,20,95–125] (Figure 2), with five trials targeting
Out of
patients 496diabetes
with articles, 34 were selected
(patients [18,20,95–125]
with diabetes (Figure
included, 2), with
ranging from five trials
8.8% totargeting
56.0% in
patients with diabetes (patients with diabetes included, ranging from 8.8%
non-targeted trials) (Table 2). A total of 29 studies were conducted for secondary preven- to 56.0% in
non-targeted trials) (Table 2). A total of 29 studies were conducted for
tion among patients suffering from CAD, stroke, or PAD. Cilostazol was concurrentlysecondary prevention
among patients
used with suffering
aspirin in 19 from CAD,
studies, stroke,
and or PAD.
as part of a Cilostazol was concurrently
triple regimen used with
including aspirin and
aspirin in 19 studies, and as part of a triple regimen including aspirin and
clopidogrel in 13 studies. The bias of the meta-analyses is reported in Supplementary Fig- clopidogrel in
13 studies. The
ures S2 and S3. bias of the meta-analyses is reported in Supplementary Figures S2 and S3.

Figure2.2.PRISMA
Figure PRISMAflow
flowdiagram
diagramfor
forstudies
studiesincluded
includedin
inthe
thecurrent
currentmeta-analysis.
meta-analysis.

All 33
All 33 studies
studies mentioned
mentionedabove abovewerewereincluded
includedin the meta-analysis
in the meta-analysis of cilostazol ther-
of cilostazol
apy for for
therapy thethe
prevention
prevention of of
composite
compositeMACE.
MACE.The Thedefinition
definitionofof MACE
MACE varied among among thethe
trials, which might be attributed to differences in patient characteristics
trials, which might be attributed to differences in patient characteristics (Supplementary (Supplementary
TableS2).
Table S2).Cilostazol
Cilostazoladministration
administrationeffectively
effectivelyreduced
reducedthetherisk
riskofofMACE
MACEcompared
comparedwithwith
boththe
both thecontrol
control(risk
(riskratio
ratio(RR):
(RR):0.62;
0.62;95%
95%CI:
CI:0.52–0.73)
0.52–0.73)(Figure
(Figure3A)3A) and
and aspirin
aspirin (RR:
(RR: 0.74;
0.74;
95% CI:
95% CI: 0.63–0.87) treatments
treatments (Figure
(Figure3B).
3B).Cilostazol
Cilostazolexhibited
exhibited a superior
a superior efficacy over
efficacy overas-
pirin forfor
aspirin secondary
secondary prevention,
prevention, whereas
whereasfurther
furtherevidence
evidenceis needed
is neededto draw a solid
to draw con-
a solid
clusion regarding
conclusion regardingits efficacy in primary
its efficacy in primaryprevention
prevention(Figure 3B).3B).
(Figure OurOurresults confirmed
results confirmedthe
favorable
the effects
favorable of of
effects cilostazol onon
cilostazol stroke,
stroke,which
whichareareeven
evenbetter
better than
than those of aspirin
aspirin [126]
[126]
(Figure
(Figure4B).
4B).The beneficial
The efficacy
beneficial of cilostazol
efficacy in reducing
of cilostazol the risk of
in reducing themyocardial infarction
risk of myocardial
and cardiovascular death was not demonstrated (Figure 4A,C). The distinction in responses
Int. J. Mol. Sci. 2024, 25, 2593 11 of 26

between ischemic stroke and myocardial infarction might lie in their differing associations
with underlying etiologies [127]. Ischemic stroke is primarily associated with the clogging
of blood vessels. In contrast, in myocardial infarction, multiple blood vessels may be
involved, and other risk factors often play a significant role before an attack occurs.
Cilostazol therapy yielded a reduced bleeding risk compared with aspirin (Figure 4E).
However, its usage was limited because of adverse events, leading to therapy discontin-
uation (Figure 4F), such as headache and palpitation (Supplementary Figure S3). This
suggests the need for improvements in this medication to address its side effects.

4.3. Coronary Artery Disease (CAD)

To date, the effect of cilostazol on CAD has not been fully elucidated, particularly as
a primary prevention. In the ESCAPE study, we investigated the efficacy and safety of
cilostazol and aspirin as the primary prevention of CAD in patients with T2DM. This in-
vestigation comprehensively evaluated CAD by assessing coronary artery stenosis, plaque
composition, and calcium deposition using up-to-date computed tomography angiogra-
phy [80]. A sustained-release form of cilostazol treatment (200 mg/day) for 12 months
reduced the progression of coronary artery stenosis in patients with diabetes compared
with aspirin (−3.1% vs. 1.7%). Notably, the noncalcified plaque component was the main
portion of atheromatous plaques that was reduced by cilostazol treatment [80].
We extended this observation to investigate the long-term effect of cilostazol and
aspirin (ESCAPE-extension study) [123]. In this extension study, we found that cilostazol
treatment reduced the incidence of cardiovascular events in the patients with T2DM
compared with aspirin over a median follow-up of 5.2 years (hazard ratio: 0.24; 95% CI:
0.07–0.83). This benefit of cilostazol therapy was maintained together with age, sex, blood
pressure, LDL-cholesterol, and coronary artery calcium score, without serious adverse
events [123].
A previous study that compared cilostazol with aspirin for primary prevention in
patients with T2DM failed to observe favorable effects for cilostazol [118]. The overall
cardiovascular event rate was very small (<3% in both the aspirin and cilostazol groups),
which may have hampered the detection of any significant differences in this population.
The overall data suggest the potential beneficial role of cilostazol treatment in the primary
prevention of CVD, although additional evidence is still needed.

4.4. Carotid Artery Stenosis and Cerebrovascular Disease

Cilostazol decreased the carotid intima–media thickness (IMT), which is a surrogate
indicator of CVD. In the Diabetic Atherosclerosis Prevention by Cilostazol study, which
was conducted in patients with T2DM accompanied by arteriosclerosis obliterans, the
carotid IMT was increased in the aspirin group (+0.048 mm), whereas the cilostazol group
exhibited a decrease in this parameter (–0.024 mm), resulting in a statistically significant
difference in carotid IMT within 2 years [18].
The Cilostazol Stroke Prevention Study compared the secondary stroke preventive
effects by dividing patients with a history of stroke into a cilostazol group and an aspirin
group. As a result, the frequency of stroke recurrence was about 26% lower in the cilostazol
group vs. the aspirin group [20]. Moreover, dual antiplatelet therapy using cilostazol
together with aspirin or clopidogrel reduced the incidence of ischemic stroke recurrence
in patients at high risk of this condition [119]. In that study, the risk of severe or life-
threatening bleeding was similar between the cilostazol with aspirin or clopidogrel therapy
and the aspirin or clopidogrel alone therapy.
In a network meta-analysis comparing 11 antiplatelet medications, cilostazol monother-
apy yielded the most favorable results in stroke recurrence and bleeding risk over other
agents in the patients who had experienced a stroke or transient ischemic attack (TIA) [128].
Further studies are needed for directly comparing cilostazol with a therapeutic agent other
than aspirin.
Int. J. Mol. Sci. 2024, 25, 2593 12 of 26

Table 2. Randomized controlled studies of cilostazol for preventing cardiovascular outcomes.

Bibliographic Duration Patients’ Men (%)/Age

Population Intervention * Diabetes
Information (Intervention/Observation) Number (Years)
Patients who had cerebral infarction within
Gotoh F. et al., 2000 [95] cilostazol 200 mg/day vs. placebo 1 year/3 years 1052 65.6/65.1 24.7%
the previous 1–6 months
Patients with angina or silent myocardial
cilostazol 200 mg/day + clopidogrel +
CREST study [96] ischemia undergoing coronary 6 months/6 months 526 74.2/60 25.7%
aspirin vs. placebo + aspirin + clopidogrel
stent implantation
Patients undergoing bare metal cilostazol 200 mg/day + clopidogrel +
Chen Y.D. et al., 2006 [97] 6 months/9 month 106 61.7/58 29.2%
stent implantation aspirin vs. placebo + aspirin + clopidogrel
DECLARE-LONG Patients with angina pectoris and/or cilostazol 200 mg/day + clopidogrel +
6 months/9 month 500 64.2/61.1 33.2%
study [98] positive stress test aspirin vs. aspirin + clopidogrel
Patients with clinical diagnosis of PAD and cilostazol 200 mg/day (or 100 mg/day)
CASTLE study [99] 3 years/3 years 1435 65.5/66.2 35.7%
symptoms of claudication vs. placebo
Patients who had ischemic stroke within cilostazol 200 mg/day vs. aspirin
CASISP study [100] 12–18 months/18 months 719 68.7/60.2 18.2%
the previous 1–6 months 100 mg/day
Patients with diabetes and angina pectoris
DECLARE-DIABETES cilostazol 200 mg/day + clopidogrel +
or positive stress test and a native 6 months/9 month 400 58/60.9 100%
study [101] aspirin vs. aspirin + clopidogrel
coronary lesion
Patients who had ischemic stroke during
Guo J.J. et al., 2009 [102] cilostazol 200 mg/day vs. aspirin 100 mg 1 year/1 year 68 35.3/60.8 8.8%
the recent 1–6 months
Patients with acute coronary syndromes cilostazol 200 mg/day + clopidogrel +
Han Y. et al., 2009 [103] 6 months/1 year 1212 73.3/59.9 21.7%
undergoing PCI aspirin vs. aspirin + clopidogrel
cilostazol 200 mg/day + aspirin 81 or
Patients with intermittent claudication
Soga Y. et al., 2009 [104] 100 mg/day vs. aspirin 81 mg or 2 years/2 years 78 83.3/70.7 35.9%
undergoing endovascular therapy
100 mg/day
cilostazol 100 mg or 200 mg/day vs.
DAPC study [18] Patients with T2D suspected of PAD 2 years/2 years 297 52.2/63.5 100%
aspirin 81 mg or 100 mg/day
Patients who had cerebral infarction within cilostazol 200 mg/day vs. aspirin
CSPS 2 study [20] 1–5 years/5 years 2672 71.7/63.5 29.0%
the previous 26 weeks 81 mg/day
Patients with acute symptomatic stenosis in
TOSS-2 study [105] the middle cerebral artery or the cilostazol 200 mg/day vs. clopidogrel 7 months/7 months 457 51.2/65.5 42.5%
basilar artery
Int. J. Mol. Sci. 2024, 25, 2593 13 of 26

Table 2. Cont.

Bibliographic Duration Patients’ Men (%)/Age

Population Intervention * Diabetes
Information (Intervention/Observation) Number (Years)
Patients with stable angina or acute
DECLARE-LONG II cilostazol 200 mg/day + clopidogrel +
coronary syndrome and a native long 8 months/1 year 499 70.6/61.5 35.3%
study [106] aspirin vs. placebo + aspirin + clopidogrel
coronary lesion
Patients who had ischemic stroke with cilostazol 200 mg/day vs. aspirin
CAIST study [107] 90 days/90 days 458 61.4/63 34.7%
neurological deficits 300 mg/day
cilostazol 200 mg/day + clopidogrel +
CILON-T study [108] Patients undergoing drug-eluting stent 6 months/6 months 915 70.7/64.4 33.6%
aspirin vs. aspirin + clopidogrel
STOP-IC study [109] Patients with symptomatic PAD cilostazol 200 mg/day + aspirin vs. aspirin 12 months/12 months 191 68.6/73 56.0%
Obese patients undergoing cilostazol 200 mg/day + clopidogrel +
Gao W. et al., 2013 [110] 1 year/1 year 428 80.4/56.5 17.8%
coronary stenting aspirin vs. aspirin + clopidogrel
Youn Y.J. et al., Patients with CAD implanting cilostazol 200 mg/day + clopidogrel +
3 months/1 year 615 63.6/64.6 31.7%
2014 [111] drug-eluting stent aspirin vs. aspirin + clopidogrel
CATHARSIS study [112] Patients with intracranial arterial stenosis cilostazol 200 mg/day + aspirin vs. aspirin 2 years/2 years 163 65.6/68.3 36.8%
Patients with stable CAD or acute
CATS-I study [113] cilostazol 200 mg/day + aspirin vs. aspirin 2 year/2 year 514 74.7/69 39.9%
coronary syndrome
Zheng X.-T. et al., Patients with complex lesions cilostazol 100 mg/day + clopidogrel +
3 months/1 year 127 70.9/64.6 37.0%
2016 [114] undergoing PCI aspirin vs. aspirin + clopidogrel
cilostazol 200 mg/day + aspirin +
CREATIVE study [115] Patients undergoing PCI clopidogrel vs. aspirin + clopidogrel (75 mg 12 months/18 months 1076 59.9/58.4 33.2%
or 150 mg)
cilostazol 200 mg/day + aspirin +
DECREASE PCI Patients undergoing drug-eluting stents
clopidogrel vs. placebo + aspirin 1 year/1 year 404 71.3/62.2 30.9%
study [116] for CAD
+ clopidogrel
Patients with ischemic stroke with
At least 1 year/median
PICASSO study [117] intracerebral hemorrhage or cilostazol 200 mg/day vs. aspirin 1512 62/65.7 32.1%
1.9 years
multiple microbleeds
Patients with T2D without
Hong S et al., 2019 [118] cilostazol 200 mg/day vs. aspirin 3 years/3 years 415 50.4/59.6 100%
macrovascular complications
Int. J. Mol. Sci. 2024, 25, 2593 14 of 26

Table 2. Cont.

Bibliographic Duration Patients’ Men (%)/Age

Population Intervention * Diabetes
Information (Intervention/Observation) Number (Years)
Patients with high-risk non-cardioembolic cilostazol 200 mg/day + aspirin or At least 1 year/median
CSPS.com study [119] 1879 70.3/69.7 37.3%
ischemic stroke clopidogrel vs. aspirin or clopidogrel 1.4 years
Chen Y.-C. et al., cilostazol 200 mg/day + clopidogrel +
Patients undergoing PCI 6 months/2 years 211 69.7/65.7 25%
2019 [120] aspirin vs. aspirin + clopidogrel
Uchiyama S. et al., cilostazol 200 mg/day + aspirin or At least 1 year/median
Patients with intracranial arterial stenosis 547 67.1/70 39.5%
2021 [121] clopidogrel vs. aspirin or clopidogrel 1.4 years
Kalantzi K. et al., Patients with T2D exhibiting symptomatic cilostazol 200 mg/day + clopidogrel
12 months/3 years 794 64/67.8 100%
2021 [122] lower extremity arterial disease vs. clopidogrel
ESCAPE-Extension: Patients with T2D and mild to moderate At least 1 year/median
cilostazol 200 mg/day vs. aspirin 88 63/61 100%
Sohn M. et al., 2022 [123] coronary artery stenosis 5.2 years
Patients with CAD or at a high risk of mean 2.9 years/mean
Lin J.-L. et al., 2022 [124] cilostazol 200 mg/day vs. placebo 266 73.3/65.8 39.5%
cardiovascular disease 2.9 years
cilostazol 200 mg/day ± isosorbide
LACI-2 study [125] Patients who had lacunar stroke mononitrate vs. isosorbide mononitrate or 12 months/12 months 363 69.1/64.3 22.0%
no study drug
Patients who had ST-elevation cilostazol 200 mg/day + aspirin or
Park S. et al., 2023 [129] 1 or 6 months/12 months 948 81.5/61.6 26.6%
myocardial infarction clopidogrel vs. aspirin or clopidogrel
* The standard dosage of other interventions was not specified: aspirin, 100 mg, and clopidogrel, 75 mg. CAD, coronary artery disease; PAD, peripheral arterial disease; PCI, percutaneous
coronary intervention; and T2D, type 2 diabetes.
 Int. J. Mol. Sci. 2024, 25, x FOR PEER REVIEW
Int. J. Mol. Sci. 2024, 25, 2593 15 of 26

(A)

(B)

(C)

Figure
Figure 3. Forest plots of3.cilostazol
Forest plots of cilostazolmajor
in composite in composite
adversemajor adverse cardiovascular
cardiovascular events (MACEs)events (MAC
compared with thepared with (A)
following: thethe
following:
control, (A) the control,
(B) aspirin, (B) clopidogrel.
and (C) aspirin, andCI,
(C)confidence
clopidogrel. CI, confidence
interval;
RR, risk ratio. RR, risk ratio.
Int.Int. J. Mol.
J. Mol. Sci.
Sci. 2024,
2024, 25,25, x FOR PEER REVIEW
2593 1816ofof29
26

(A) (B)

(C) (D)

(E) (F)

Figure4.4.Forest
Figure Forestplots
plotsof
ofcilostazol
cilostazolin
incardiovascular
cardiovascular and
and safety
safety events: (A) myocardial
events: (A) myocardial infarction,
infarction,
(B)
(B)stroke,
stroke,(C)
(C)cardiovascular
cardiovasculardeath,
death,(D)
(D)all-cause
all-causedeath,
death, (E)
(E) bleeding, and (F) discontinuation
discontinuation of
of the
the
studydrug.
study drug.

4.5.
4.5.Peripheral
PeripheralArtery
ArteryDisease
Disease(PAD)
(PAD)
The
The clinical excellence ofcilostazol
clinical excellence of cilostazolisissufficient
sufficienttotorecommend
recommendit it asas
a first-line
a first-linedrug
drugin
PAD, because it increases NO in vascular endothelial cells in a dose-dependent
in PAD, because it increases NO in vascular endothelial cells in a dose-dependent manner, manner, to
dilate blood vessels [130]. A meta-analysis of 16 RCTs reported that intermittent
to dilate blood vessels [130]. A meta-analysis of 16 RCTs reported that intermittent clau- claudica-
tion was significantly
dication improved
was significantly by cilostazol
improved therapy
by cilostazol (100–300
therapy mg per
(100–300 mgday) compared
per day) comparedwith
the placebo [131]. An RCT including 698 patients with moderate-to-severe
with the placebo [131]. An RCT including 698 patients with moderate-to-severe claudica- claudication
symptoms
tion symptomsreported that that
reported a 6-month
a 6-monthcilostazol
cilostazol therapy
therapy improved
improvedthe themaximal walking
maximal walking
distance by 54%, compared with pentoxifylline therapy (30% increase)
distance by 54%, compared with pentoxifylline therapy (30% increase) [132]. Another [132]. Another study
including 394 patients with intermittent claudication showed that cilostazol
study including 394 patients with intermittent claudication showed that cilostazol treat- treatment for
6 ment
months improved the maximal walking distance compared with the
for 6 months improved the maximal walking distance compared with the placebo placebo [133]. A 2021
Cochrane Systematic
[133]. A 2021 CochraneReview and Meta-analysis
Systematic Review and including
Meta-analysis16 double-blind
including 16RCTs reported
double-blind
that
RCTsparticipants
reported that taking cilostazol
participants hadcilostazol
taking a higher had initial claudication
a higher distance, by
initial claudication 26.5 m
distance,
(95% CI: 18.9–34.1 m), compared with those taking the placebo [131].
by 26.5 m (95% CI: 18.9–34.1 m), compared with those taking the placebo [131]. Cilostazol Cilostazol exerted
beneficial effects regarding
exerted beneficial the primary
effects regarding the prevention of diabetic
primary prevention of foot ulcers
diabetic viaulcers
foot a lowering
via a
effect on MMP-9 levels [134].
lowering effect on MMP-9 levels [134].
Recently, a prospective study with 794 participants showed that the adjunctive ad-
ministration of cilostazol to clopidogrel-treated patients with T2DM with symptomatic
Int. J. Mol. Sci. 2024, 25, 2593 17 of 26

PAD lowered the risk of ischemic events and improved intermittent claudication symp-
toms, without increasing the bleeding risk [122]. Based on this evidence, the ACC/AHA
guidelines provided a class I recommendation for the use of cilostazol in the treatment of
intermittent claudication in 2016 and thereafter [135].

5. Potential Benefits of Cilostazol Therapy

Neuroprotective Effect
There is evidence supporting the benefits of cilostazol in neuroprotection. Several stud-
ies reported that cilostazol was helpful in preventing symptomatic cerebral vasospasm and
in reducing cerebral infarction and intracranial hemorrhage in patients with stroke [136,137].
These effects depended mainly on the anti-inflammatory and antiapoptotic effects of cilosta-
zol, which are mediated by scavenging hydroxyl radicals, decreasing the formation of
tumor necrosis factor-α (TNF-α), and inhibiting adenosine diphosphate-ribose polymerase
activity [138]. Moreover, cilostazol treatment improved neuronal survival by promoting
the Akt and CREB, as well as brain-derived neurotrophic factor content in a rat model [74].
The production of NO triggered by cilostazol therapy via the activation of endothelial NO
synthase also contributed to neuroprotection via endothelial protection [139].
It is known that cilostazol reduces blood–brain barrier permeability and the degree
of intracerebral cell death via mechanisms involving the inhibition of collagenase [140].
Cilostazol treatment also prevented endothelial cell death and protected collagen type 4,
laminin, and vascular endothelial and N-cadherins from collagenase injury, and attenuated
blood–brain barrier leakage, resulting in intracranial hemorrhage [141].
In addition, cilostazol had a neuroprotective effect against hypoperfusion and perma-
nent cerebral ischemia [142,143]. Cilostazol treatment in Wistar rats with bilateral carotid
artery occlusion decreased apoptosis by downregulating TNF-α, suppressed overly acti-
vated astroglia and microglia in the white matter, and increased oligodendrocytes [142].
The protection mechanism was multifactorial in reducing oxidative stress [143].
In a multicenter and double-blind RCT, the administration of cilostazol to participants
with moderate or severe white matter changes (WMC), which demonstrates small-vessel
disease in the brain, and at least one lacunar infarction significantly reduced the risk
of ischemic vascular events compared with aspirin (HR: 0.11; 95% CI: 0.02–0.89) [144].
However, there was no significant difference between the effects of cilostazol and those
of aspirin on WMC progression in patients with cerebral small-vessel disease [144]. In a
systematic review and meta-analysis of RCTs for stroke and cognitive decline, cilostazol
therapy reduced recurrent ischemic stroke; however, the authors failed to prove its efficacy
on cognitive dysfunction [126].

6. Considerations in Using Cilostazol Therapy

6.1. Adverse Effects of Cilostazol Therapy
Cilostazol has been reported to cause more headaches, palpitations, and gastroin-
testinal disorders when compared with a placebo [145]. Headaches were the primary
reason for the discontinuation of this medication. Cilostazol significantly increased the
cerebral blood flow in patients with chronic cerebral infarction [95]; therefore, the cerebral
blood vessels dilated, which may have caused headaches, although the patients would
acclimate to it within 1 week. Currently, a sustained-release formulation that reduces the
incidence of headache by introducing a technology with controlled dissolution is available
in several countries [146].
It is important to understand that cilostazol has the potential to increase the heart
rate by about 3–5 beats/min [23,145]. Although this side effect will not necessarily be
present in all patients, and the extent of its impact may vary according to the dosage
and individual physiological responses, further research is needed to investigate how this
outcome may affect the progression of CVDs. Thus, cilostazol is contraindicated in patients
with established heart failure [147].
Int. J. Mol. Sci. 2024, 25, 2593 18 of 26

6.2. Effects of Cilostazol Therapy by Regional Background

Although numerous studies have been published on cilostazol’s protective effects
against atherosclerosis, it is evident that most of these studies have been conducted in
Asia (Figure 5). Studies have demonstrated that cilostazol improves major adverse car-
diovascular events (MACE) and stroke outcomes, affirming its efficacy. However, limited
studies make it hard to interpret its effects in other regions (Figure 5A,C). Moreover, as
recent
Int. J. Mol. Sci. 2024, 25, x FOR PEER studies have not shown favorable results for myocardial infarction [125,129],
REVIEW 21 offurther
29
investigation is needed to determine its efficacy in Asian populations as well (Figure 5B).

(A) (B)

(C) (D)

Figure
Figure 5. 5. Forest
Forest plots
plots of cilostazol’s
of cilostazol’s effect
effect on composite
on composite majormajor adverse
adverse cardiovascular
cardiovascular eventsevents
(MACEs)
(MACEs)
and and individual
individual components components
categorizedcategorized by regional
by regional background:
background: (A) MACE,
(A) MACE, (B) myocar-
(B) myocardial infarc-
dial infarction (MI), (C) stroke, and (D) cardiovascular death. CI, confidence interval; RR, risk ratio.
tion (MI), (C) stroke, and (D) cardiovascular death. CI, confidence interval; RR, risk ratio.
7. Conclusions
Cilostazol has multifaceted beneficial effects through various mechanisms, including
platelet inhibition, vasodilation via NO production, protective effects on vascular endo-
thelial cells, antiproliferative effects on VSMCs, and favorable changes in lipid profiles
(Figure 6). These beneficial effects of cilostazol are attributable to its pleiotropic properties,
Int. J. Mol. Sci. 2024, 25, 2593 19 of 26

7. Conclusions
Cilostazol has multifaceted beneficial effects through various mechanisms, includ-
Int. J. Mol. Sci. 2024, 25, x FOR PEERing
REVIEW inhibition, vasodilation via NO production, protective effects on 22
platelet of 29
vascular
endothelial cells, antiproliferative effects on VSMCs, and favorable changes in lipid profiles
(Figure 6). These beneficial effects of cilostazol are attributable to its pleiotropic properties,
including
includingits
itsanti-inflammatory
anti-inflammatory and antioxidative actions.AAneuroprotective
antioxidative actions. neuroprotective effect
effect waswas
also found in a few clinical studies of cilostazol.
also found in a few clinical studies cilostazol.

Figure 6. Anti-atherosclerotic effect of cilostazol.

Figure 6. Anti-atherosclerotic effect of cilostazol.

Basedon
Based onthe
therecent
recentresults
resultsofoflarge
largeclinical
clinicalstudies
studiessuggesting
suggestingthat
thataspirin
aspirinshould
shouldnotnotbe
be recommended in primary prevention settings, cilostazol treatment may
recommended in primary prevention settings, cilostazol treatment may be a viable option be a viable op-
tion
for for preventing
preventing the development
the development and progression
and progression of vascular
of vascular diseases.
diseases. Obviously,
Obviously, ci-
cilostazol
lostazol is effective in PAD, and recent evidence supports its effectiveness in CAD
is effective in PAD, and recent evidence supports its effectiveness in CAD as well as ischemic as well
as ischemic stroke. Notably, recent studies reported that cilostazol treatment was effica-
stroke. Notably, recent studies reported that cilostazol treatment was efficacious in reducing
cious in reducing atheromatous plaque progression in coronary arteries and decreasing
atheromatous plaque progression in coronary arteries and decreasing cardiovascular events
cardiovascular events compared with aspirin in patients with diabetes and subclinical
compared with aspirin in patients with diabetes and subclinical CAD. Thus, cilostazol
CAD. Thus, cilostazol might be helpful in the comprehensive vascular management of
might be helpful in the comprehensive vascular management of patients with a high risk
patients with a high risk of CV. However, it is noteworthy that these results were mainly
of CV. However, it is noteworthy that these results were mainly derived from East-Asian
derived from East-Asian populations. Additional trials including other ethnic groups are
populations. Additional trials including other ethnic groups are needed to generalize
needed to generalize the beneficial effects of this drug. Adverse events occurring after ci-
the beneficial effects of this drug. Adverse events occurring after cilostazol therapy, such
lostazol therapy, such as headache and heart rate increase, have not been completely re-
as headache and heart rate increase, have not been completely resolved; therefore, the
solved; therefore, the development of more-advanced PDE-3 inhibitors that do not exhibit
development of more-advanced PDE-3 inhibitors that do not exhibit these unwanted effects
these unwanted effects is warranted. Longer-term studies with a robust outcome are
is warranted. Longer-term studies with a robust outcome are needed to confirm the efficacy
needed to confirm the efficacy and safety of cilostazol therapy.
and safety of cilostazol therapy.
Supplementary Materials: The following supporting information can be downloaded at:
Supplementary Materials: The following supporting information can be downloaded at: https://www.
www.mdpi.com/xxx/s1.
mdpi.com/article/10.3390/ijms25052593/s1.
Author Contributions: Conceptualization, M.S. and S.L.; methodology, M.S. and S.L.; validation,
Author
M.S. andContributions: Conceptualization,
S.L.; formal analysis, M.S. and S.L.;M.S. and S.L.; M.S.
investigation, methodology, M.S. and M.S.
and S.L.; resources, S.L.; and
validation,
S.L.;
M.S.
dataand S.L.; formal
curation, analysis,
M.S. and M.S. and S.L.; investigation,
S.L.; writing—original M.S. and
draft preparation, M.S.S.L.;
andresources, M.S. and S.L.;
S.L.; writing—review
andcuration,
data editing, M.S.
M.S.andandS.L.;
S.L.;visualization, M.S. and
writing—original S.L.;
draft supervision,
preparation, S.L.;and
M.S. project
S.L.;administration,
writing—review S.L.
and
All authors
editing, M.S. have read visualization,
and S.L.; and agreed to M.S.
the published
and S.L.; version of theS.L.;
supervision, manuscript.
project administration, S.L. All
authors
Funding:have read
This and agreed
research to the
received published
no external version of the manuscript.
funding.
Funding: ThisReview
Institutional researchBoard
received no external
Statement: funding.
This is not applicable as this project did not involve humans
or animals.
Informed Consent Statement: Not applicable.
Data Availability Statement: The supporting data for the findings can be obtained from the corre-
sponding author upon a reasonable request.
Int. J. Mol. Sci. 2024, 25, 2593 20 of 26

Institutional Review Board Statement: This is not applicable as this project did not involve humans
or animals.
Informed Consent Statement: Not applicable.
Data Availability Statement: The supporting data for the findings can be obtained from the corre-
sponding author upon a reasonable request.
Conflicts of Interest: The authors declare no conflicts of interest.

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