Stroke

TOPICAL REVIEW

Cilostazol for Secondary Stroke Prevention

History, Evidence, Limitations, and Possibilities
Adam de Havenon , MD, MSCI; Kevin N. Sheth , MD; Tracy E. Madsen , MD, PhD; Karen C. Johnston, MD, MSc;
Tanya N. Turan , MD, MSCR; Kazunori Toyoda , MD, PhD; Jordan J. Elm, PhD; Joanna M. Wardlaw , MD, FRCR;
S. Claiborne Johnston , MD, PhD; Olajide A. Williams , MD; Ashkan Shoamanesh , MD; Maarten G. Lansberg , MD, PhD

ABSTRACT: Cilostazol is a PDE3 (phosphodiesterase III) inhibitor with a long track record of safety that is Food and Drug
Administration and European Medicines Agency approved for the treatment of claudication in patients with peripheral arterial
disease. In addition, cilostazol has been approved for secondary stroke prevention in several Asian countries based on trials
that have demonstrated a reduction in stroke recurrence among patients with noncardioembolic stroke. The onset of benefit
appears after 60 to 90 days of treatment, which is consistent with cilostazol’s pleiotropic effects on platelet aggregation,
vascular remodeling, blood flow, and plasma lipids. Cilostazol appears safe and does not increase the risk of major bleeding
when given alone or in combination with aspirin or clopidogrel. Adverse effects such as headache, gastrointestinal symptoms,
and palpitations, however, contributed to a 6% increase in drug discontinuation among patients randomized to cilostazol in
a large secondary stroke prevention trial (CSPS.com [Cilostazol Stroke Prevention Study for Antiplatelet Combination]). Due
to limitations of prior trials, such as open-label design, premature trial termination, large loss to follow-up, lack of functional
or cognitive outcome data, and exclusive enrollment in Asia, the existing trials have not led to a change in clinical practice or
guidelines in Western countries. These limitations could be addressed by a double-blind placebo-controlled randomized trial
conducted in a broader population. If positive, it would increase the evidence in support of long-term treatment with cilostazol
for secondary prevention in the millions of patients worldwide who have experienced a noncardioembolic ischemic stroke.
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Key Words: aspirin ◼ brain ischemia ◼ follow-up studies ◼ headache ◼ humans

I
n the 1980s, Takao Nishi’s lab at the Japanese phar-
maceutical company Otsuka synthesized the quinolone
derivative cilostamide, which inhibited platelet aggrega-
tion and had vasodilatory properties but caused persistent
tachycardia.1 With modification of an amide side chain,
the Otsuka researchers created cilostazol, which had the
desired effects of cilostamide and a reduced risk of tachy-
cardia (Figure 1). Cilostazol was first marketed in Japan in
1988 as Pletaal and subsequently as Pletal in the United
States in 1999 and the United Kingdom in 2001.2 In the
United States and Europe, cilostazol is only approved for
intermittent claudication in patients with peripheral arterial
disease (PAD). Japanese regulators approved cilostazol
for PAD as well as prevention of recurrent ischemic stroke
in 2003,3 as have several other countries in Asia. At pres-
ent, cilostazol is available worldwide in both branded and
generic formulations, and is available in the United States
as a generic medication for < $10 a month and in Ger-
many for as little as €5 a month.4–6
Cilostazol is a PDE3 (phosphodiesterase III) inhibitor
that is metabolized by the hepatic cytochrome P450 sys-
tem and is independent of the cyclooxygenase (aspirin)
or platelet P2Y12 receptor (clopidogrel) pathways.7,8 The
active metabolites of cilostazol reversibly inhibit PDE3,
which mitigates degradation of cyclic adenosine mono-
phosphate (cAMP) and leads to inhibition of platelet
reactivity and aggregation. Cilostazol also prevents ade-
nosine uptake into cells, further augmenting cAMP.9,10
Cilostazol’s cAMP-mediated inhibition of platelet reactiv-
ity and aggregation is comparable to that of aspirin and
ticlopidine, yet cilostazol has a lower incidence of hemor-
rhagic complications.11–14 Unlike aspirin and ticlopidine,
which block extracellular membrane receptors for their
antiplatelet effect,15 cilostazol functions intracellularly

Correspondence to: Adam de Havenon, MD, MSCI, Department of Neurology, University of Utah, 175 N Medical Dr, Salt Lake City, UT 84132. Email adam.
dehavenon@hsc.utah.edu
For Sources of Funding and Disclosures, see page e642.
© 2021 American Heart Association, Inc.
Stroke is available at www.ahajournals.org/journal/str

Stroke. 2021;52:e635–e645. DOI: 10.1161/STROKEAHA.121.035002 October 2021   e635

 de Havenon et al
Topical Review
Figure 1. The molecular structure of cilostazol.
and does not prolong overall bleeding time.16–20 A com-
parison of the mechanism of action, common and major
adverse events, and out-of-pocket cost of common anti-
platelet medications used in stroke prevention is shown
in Table 1.
In addition to platelet inhibition, cilostazol enhances
vasodilatation, prevents intimal hyperplasia and prolifera-
tion of vascular smooth muscle cells, lowers blood pres-
sure, and may increase cerebral blood flow, improve myelin
repair, and enhance astrocyte-to-neuron energy sup-
ply.21–27 The vasodilatory effects of cilostazol appear to be
mediated by endothelial production of nitrous oxide (which
may be deficient in many patients with stroke, particularly
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lacunar stroke) in response to elevated concentrations of
cAMP,23–25,28 as well as the chronic inhibition of vascular
smooth muscle cell proliferation that leads to more compli-
ant arteries.29–32 This vascular remodeling occurs because
cAMP reduces the activity of platelet-derived growth fac-
tor, which regulates vascular smooth muscle prolifera-
tion.29–31 Cilostazol’s vasodilatory and arterial remodeling
effects lead to a mild (2–4 mm Hg) reduction in systolic
blood pressure,33 but hypotension is seen in <1% of
patients.34 Patients taking cilostazol have an increase in
heart rate, typically on the order of 6 bpm, but the effect
has not been associated with tachyarrhythmia.35,36
Because PDE3 is found throughout the human body,
the effects of cilostazol are not limited to platelets and
endothelial cells.37 Higher levels of intracellular cAMP
reduce the expression of interleukin-6, which can increase
the activity of lipoprotein lipase.38,39 Consequently, cilo-
stazol therapy is associated with a 16% to 29% decrease
in triglycerides and a 12% to 13% increase in high-
density lipoprotein cholesterol.40–42 Additional pleiotro-
pic effects that have been proposed include a decrease
in systemic inflammation, improved stroke recovery,
reduction of amyloid-related neurotoxicity, prevention of
restenosis of cardiac stents, and prevention of diabetic
nephropathy.37,43–53 Another potential role for cilostazol is
in the prevention of dementia or cognitive decline,21,27,54–56
particularly in patients with chronic microvascular disease
e636   October 2021
Cilostazol for Secondary Stroke Prevention
who may benefit from the effects of cilostazol on myelin
repair and astrocyte-to-neuron energy supply.13,26,27
OTHER PHOSPHODIESTERASE
INHIBITORS
Other PDE3 inhibitors include milrinone, vesnarinone,
and amrinone. These drugs have been used to treat
severe congestive heart failure that is refractory to first-
line medications.57,58 Milrinone—the most commonly
used—inhibits both PDE3 and PDE4, increases cardiac
index, has more cardiac side effects than cilostazol, and
has been associated with sudden cardiac death and an
increase in all-cause mortality with chronic use.59,60 Milri-
none is, therefore, only used for short durations and not a
viable alternative to cilostazol for stroke or cardiovascular
disease prevention.61
Cilostazol is sometimes compared with dipyridamole,
which inhibits PDE5 and has been combined with aspi-
rin for secondary stroke prevention.62 While cilostazol
and dipyridamole are both PDE inhibitors with similar
systemic side effects (Table 1), their effects within the
platelet are unique because they inhibit different PDEs.63
For example, inhibition of PDE5 (dipyridamole) increases
cyclic guanosine monophosphate while inhibition of
PDE3 increases cAMP. Outside platelets, the drugs also
have different pleiotropic effects since PDE5 is mainly
expressed by platelets, smooth muscle cells, and the
lung, while PDE3 is more widely expressed throughout
the human body.1 Because of these differences, results
of clinical trials with dipyridamole do not provide insight
into cilostazol’s effect on secondary stroke prevention.
TRIALS OF CILOSTAZOL FOR SECONDARY
STROKE PREVENTION
With the exception of a small trial (n=57) in the United
Kingdom,27 all cilostazol trials for stroke and cardiovascular
disease prevention have been conducted in Asia.13 These
trials have typically used a cilostazol dose of 100 mg 2
times a day (BID). The most important and largest random-
ized clinical trials are CSPS (Cilostazol Stroke Prevention
Study; 2000), CSPS 2 (Cilostazol for Prevention of Sec-
ondary Stroke; 2010), PICASSO (Prevention of Cardiovas-
cular Events in Asian Patients With Ischaemic Stroke at
High Risk of Cerebral Haemorrhage; 2018), and CSPS.
com (Cilostazol Stroke Prevention Study for Antiplatelet
Combination; 2019).33,64,65 In CSPS, 1095 patients (65.6%
men) who had a noncardioembolic stroke in the prior 1
to 6 months were randomized to cilostazol 100 mg BID
or placebo in a double-blind design. The primary outcome
was ischemic stroke, which occurred less frequently in
the cilostazol versus placebo arm (3.37% versus 5.78%
annually; relative risk reduction, 0.42 [95% CI, 0.09–0.63]).
Bleeding complications were similar in both arms.65 The
Stroke. 2021;52:e635–e645. DOI: 10.1161/STROKEAHA.121.035002
 de Havenon et al
Table 1. Comparison of the Mechanism of Action, Common and Major Adverse Events, and Out-of-Pocket Cost of Common
Antiplatelet Medications Used in Stroke Prevention
Medication Mechanism of action
Cilostazol Reversible intracellular PDE3 inhibition
Dipyridamole Reversible intracellular PDE5 inhibition
Aspirin Irreversible inhibition of COX
Clopidogrel Irreversible extracellular inhibition of
P2Y12
Ticagrelor Irreversible extracellular inhibition of
P2Y12
Prasugrel Irreversible extracellular inhibition of
P2Y12
COX indicates cyclooxygenase; and PDE, phosphodiesterase III.
*According to Lexicomp (online.lexi.com).
†According to goodrx.com, in the United States, without insurance, at Walmart.
PICASSO trial of 1534 ischemic stroke patients with a his-
tory of intracerebral hemorrhage or imaging evidence of
≥2 cerebral microbleeds also found that cilostazol did not
increase the risk of intracerebral hemorrhage.66
In CSPS 2, 2672 patients who had a noncardioem-
bolic stroke within the prior 26 weeks were randomized
to cilostazol 100 mg BID or aspirin 81 mg daily in a dou-
ble-blind design and followed for a mean of 29 months.
The majority of patients (65%) had a lacunar stroke as
the index event, and 72% were men.64 The primary out-
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come in CSPS 2 was stroke, including intraparenchymal
and subarachnoid hemorrhage, which occurred less fre-
quently in the cilostazol arm (2.8%) compared with the
aspirin arm (3.7%), with a hazard ratio (HR) for cilostazol
of 0.74 (95% CI, 0.56–0.98).
The CSPS.com trial enrolled 1879 high-risk patients
(cervical/intracranial artery stenosis or multiple vascular
risk factors) with a noncardioembolic stroke in the prior
8 to 180 days. The trial was unblinded and randomized
patients who were receiving standard-of-care treatment
with aspirin or clopidogrel to cilostazol 100 mg BID ver-
sus no additional medication.33 The primary outcome was
first recurrence of a symptomatic ischemic stroke, and the
median follow-up duration was 1.4 years. In CSPS.com,
cilostazol was highly effective at preventing recurrent
stroke when added to aspirin or clopidogrel monother-
apy (HR, 0.49 [95% CI, 0.31–0.76]). Subgroup analyses
showed relatively equal efficacy among all major patient
subgroups, with the exception of sex. Female patients
experienced less benefit (HR, 0.82 [95% CI, 0.37–1.84])
than men (HR, 0.40 [95% CI, 0.23–0.68]), but this differ-
ence was not significant (interaction term sex×treatment
P=0.13). Since women only represented 30% of the
cohort, this could have been due to low power. Cilo-
stazol had a nearly identical risk reduction in the 547
patients with intracranial artery stenosis (HR, 0.48 [95%
CI, 0.27–0.86]) and the 1177 patients without (HR, 0.47
Stroke. 2021;52:e635–e645. DOI: 10.1161/STROKEAHA.121.035002
Cilostazol for Secondary Stroke Prevention
Topical Review
Most common adverse events* Major adverse events Monthly cost†
Headache, diarrhea, palpitation, dizzi- Contraindicated in patients with heart $9.00
ness, tachycardia failure
Headache, dizziness, abdominal dis- Major bleeding (when combined with $73.54
tress, angina pectoris, nausea aspirin)
Dyspepsia, rash, minor bleeding, Major bleeding, upper gastrointestinal $2.47
epistaxis ulcers
Bruising, minor bleeding, epistaxis Major bleeding $15.00
Dyspnea, ventricular pause, nausea, Major bleeding, bradyarrhythmia, $373.90
dizziness, transient creatinine increase, thrombotic thrombocytopenic purpura
minor bleeding
Hypertension, headache, nausea, Fatal bleeding, thrombotic thrombocy- $32.36
minor bleeding, epistaxis topenic purpura
[95% CI, 0.23–0.95]; P for interaction, 0.95). In the sub-
group of patients with lacunar stroke (n=925), cilostazol
had an HR of 0.41 (95% CI, 0.21–0.81).
The most recent and comprehensive meta-analysis of
cilostazol for the prevention of ischemic stroke and major
adverse cardiovascular events (MACE) in stroke survivors
showed that “cilostazol reduced recurrent ischemic stroke,
recurrent hemorrhagic stroke, death, and MACE compared
with control, in the presence or absence of aspirin, or when
compared directly with aspirin.”13 (Figure 2) An important
finding from this meta-analysis is that cilostazol was most
beneficial in trials that treated patients for ≥6 months. This
is consistent with the Kaplan-Meier analysis for the pre-
vention of any stroke in CSPS 2 and ischemic stroke in
CSPS.com (Figure 3), which shows that the curves for the
cilostazol and control arms separate 60 to 90 days after
randomization. It is also consistent with the neutral results
of the ADS trial (Acute Aspirin Plus Cilostazol Dual Ther-
apy for Non‐Cardiogenic Stroke Patients Within 48 Hours
of Symptom Onset), which randomized 1201 patients with
noncardioembolic stroke within 48 hours of symptom onset
to cilostazol plus aspirin versus aspirin alone and followed
patients for 3 months.67 During this relatively short follow-
up period, cilostazol did not reduce stroke recurrence. The
delayed onset of benefit is likely a result of an accumula-
tion of the pleiotropic effects of cilostazol over time.
CILOSTAZOL ADVERSE EVENTS,
INTERACTIONS, AND CONTRAINDICATIONS
A meta-analysis of 8 randomized, placebo-controlled tri-
als of cilostazol among patients with intermittent clau-
dication (n=2702) identified headache, diarrhea, and
abnormal stools as the most common side effects of cilo-
stazol 100 mg BID, which were increased over the pla-
cebo arm rates by 19%, 10%, and 10%, respectively.42
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 de Havenon et al Cilostazol for Secondary Stroke Prevention
Topical Review
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Figure 2. Meta-analysis combinations13 of cilostazol (CLZ) vs controls.

Shown for the outcomes of ischemic stroke (top), major adverse cardiovascular events (middle), and hemorrhagic stroke (bottom), showing
odds ratios (ORs) below 1, consistent with the benefit of CLZ. ASA indicates aspirin; and CLP, clopidogrel.

Palpitations, dizziness, and tachycardia were also com-
mon.68 The adverse events of cilostazol reported in a
meta-analysis of secondary stroke prevention trials are
listed in Table 2.13 These side effects likely contributed
to the increased rate of drug discontinuation in the cilo-
stazol arm of the CSPS.com trial (9.8%) compared with
the control arm (3.5%).69 A suggested approach to mini-
mize cilostazol discontinuation is to begin therapy with a
lower dose (50 mg BID) and titrate to the full 100 mg
BID dose after 2 to 4 weeks.70
Cilostazol has potential drug interactions with medi-
cations that affect the hepatic P450 enzymes CYP3A4
and CYP2C19. In the US Food and Drug Administration
(FDA), labeling for cilostazol, CYP3A4 and CYP2C19
inhibitors, which decrease cilostazol clearance, such
as macrolide antibiotics, diltiazem, azoles, omeprazole,
fluoxetine, and sertraline, are identified as having a drug-
drug interaction.34 A reasonable approach for patients on
these medications would be to decrease the cilostazol
dose to 50 mg BID, which is consistent with the labeling
for patients with PAD.34 Although atorvastatin, fluvastatin,
lovastatin, and simvastatin could theoretically decrease
cilostazol levels by inhibiting CYP2C19, the effect is not
clinically significant.34 Cilostazol has a half-life of 14 to 15
hours and needs to be dosed BID. Cilostazol’s absorption
is increased with high-fat meals, which almost doubles
the peak effect and reduces the half-life to 5 hours, so it
should not be taken within 2 hours of a meal.71

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 de Havenon et al
Figure 3. Separation of stroke event rates in patients receiving cilostazol vs controls.
Kaplan-Meier curves for CSPS 2 (left) and CSPS.com (right), showing the failure rate for stroke events in the first year of follow-up and lower
rate for patients randomized to cilostazol (CLZ).
Because other oral phosphodiesterase inhibitors (eg,
milrinone and vesnarinone; see paragraph above on phos-
phodiesterase inhibitors for more detail) have caused
increased mortality in patients with severe heart failure,60,72
the FDA placed a boxed warning on cilostazol that contra-
indicates its use in patients with heart failure, which is con-
sistent with a similar contraindication from the European
Medicines Agency.34,73 However, the increase in mortality
with milrinone or similar drugs was relatively small (relative
risk in a Cochrane Review, 1.17 [95% CI, 1.06–1.30]),60,74,75
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an analysis of the Cilostazol Safety Database did not find
an increase in mortality with cilostazol in patients with
heart failure, and other studies of administrative claims
have likewise failed to show an association between cilo-
stazol and mortality among patients with heart failure.74,76,77
Cilostazol’s pharmacokinetics do not appear to be
meaningfully altered by patient age or sex,78,79 and data
from PAD patients do not suggest that race or ethnicity
impacts the effectiveness of cilostazol for reducing claudi-
cation symptoms.68,80,81 Genetic polymorphisms in hepatic
P450 enzymes can affect cilostazol pharmacokinetics
but not to the degree seen with platelet P2Y12 receptor
inhibitors such as clopidogrel.82–84 Although mild hepatic
impairment has little effect on cilostazol levels,34 more
severe hepatic impairment warrants caution as cilostazol
has not been studied in that patient population and its
metabolism could be reduced, leading to elevated serum
levels.85 Dose adjustment is not recommended in patients
with renal impairment, and dialysis is unlikely to affect lev-
els given the high (≥95%) protein binding of cilostazol.85
CLINICAL GUIDELINE RECOMMENDATIONS
REGARDING THE USE OF CILOSTAZOL
A 2014 Cochrane review of 15 double-blind randomized
trials with a total of 3718 PAD patients showed that cilo-
stazol 100 mg BID increased walking distance before clau-
dication compared with both placebo and cilostazol 50 mg
Stroke. 2021;52:e635–e645. DOI: 10.1161/STROKEAHA.121.035002
Cilostazol for Secondary Stroke Prevention
Topical Review
BID.68 The American Heart Association/American College
of Cardiology guideline on PAD states that “cilostazol is an
effective therapy to improve symptoms and increase walk-
ing distance in patients with claudication” (class IA recom-
mendation).86 Based off this robust and consistent data,
cilostazol has an indication for symptomatic treatment of
intermittent claudication in the United States, Japan, Korea,
China, the United Kingdom and many other countries.5
In Japan, cilostazol was recommended as a first-line
antiplatelet agent for the prevention of recurrent ischemic
stroke in 2015.87 In the upcoming 2021 Japan Stroke
Society prevention guideline, the addition of cilostazol to
treatment with either aspirin or clopidogrel will be recom-
mended as a reasonable option for patients with noncar-
dioembolic stroke or transient ischemic attack who have
cervical/intracranial artery stenosis or multiple vascular
risk factors. Secondary stroke prevention guidelines in
Asia give a high level of evidence recommendation for
cilostazol in all subtypes of noncardioembolic stroke.88 In
the United States, the 2021 American Heart Association
secondary stroke prevention guideline gives cilostazol a
class IIb (Level of Evidence C-LD) recommendation spe-
cific to patients with “stroke or TIA attributable to 50% to
99% stenosis of a major intracranial artery,” which states
that “the addition of cilostazol 200 mg/day to aspirin or
clopidogrel might be considered to reduce recurrent
stroke risk.”89 The guideline also states that in patients
with “ischemic stroke related to small vessel disease, the
usefulness of cilostazol for secondary stroke prevention is
uncertain.” The European Stroke Organization guidelines
do not mention cilostazol for secondary prevention.90
CILOSTAZOL PRESCRIPTION PATTERNS
FOR STROKE PREVENTION IN WESTERN
COUNTRIES
To understand whether, despite the lack of guideline
endorsement, neurologists in the United States were
October 2021   e639
 de Havenon et al
Table 2. Adverse Events in Patients Taking Cilostazol Compared With Controls Taking
Antiplatelet Therapy
Topical Review
Adverse event Cilostazol, n (%)
Major bleeding 79/4211, 1.9%
Headache 743/4804, 15.5%
Dizziness 349/3419, 10.2%
Palpitations 281/4566, 6.2%
Diarrhea 303/2434, 12.5%
Constipation 189/2334, 8.1%
Nausea 76/1548, 4.9%
prescribing cilostazol, we performed a retrospective
analysis of the publicly available Medicare Part D Pre-
scriber Files from 2017 to 2018.91 We included provid-
ers designated as Neurology and calculated how many
prescribed cilostazol and, as a comparator, clopidogrel. In
2017, only 76 of 12 995 (0.6%) neurologists prescribed
cilostazol at least once to a Medicare Part D beneficiary,
while 4601of 12 995 (35.4%) prescribed clopidogrel
at least once. In 2018, the number of neurologists who
prescribed cilostazol was even lower at 65 of 13 206
(0.5%), while 4491 of 13 206 (34.0%) prescribed clopi-
dogrel at least once.
To explore whether patients in the United States with
ischemic stroke are being prescribed cilostazol more fre-
quently since CSPS.com, we used data from TriNetX—
a global federated health research network providing
access to electronic medical records from ≈69.5 million
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patients.92 The TriNetX platform only uses aggregated
counts and statistical summaries of deidentified informa-
tion. No protected health information or personal data are
made available, and Institutional Review Board approval
is not required. This analysis included patients diagnosed
with ischemic stroke (ICD-10-CM I63)93 from 2017 to the
end of 2020. In 2017-2018, there were 249 621 patients
diagnosed with ischemic stroke, of whom 2490 received
cilostazol (1.0%) and 81 455 received clopidogrel (32.6%).
In 2019-2020, 255 514 patients were diagnosed with
ischemic stroke, of whom 2516 received cilostazol (1.0%)
and 88 759 received clopidogrel (34.7%). Though this
sample is not fully representative, these data suggest that
cilostazol prescriptions in the US stroke survivors have not
increased since the positive results of the CSPS.com trial
were presented in February 2019.
In Europe, the European Medicines Agency has only
recommended cilostazol for claudication symptoms in
PAD patients and in 2013 further restricted the indica-
tion to patients who had failed lifestyle changes and do
not have comorbid cardiovascular disease.73 A study of 5
European health agency databases from 2002 to 2012
examined new off-label prescriptions of cilostazol. In the
United Kingdom, only 1% of off-label cilostazol prescrip-
tions were for cerebrovascular disease; in Spain, it was
0.3% to 2.1%; in Sweden, it was 0.3%; and in Germany,
it was 4.8%.94 These data suggest that in Europe, like in
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Cilostazol for Secondary Stroke Prevention
Control, n (%) Odds ratio (95% CI)
102/4176, 2.4% 0.73 (0.54–0.99)
413/4778, 8.6% 2.00 (1.76–2.28)
292/3418, 8.5% 1.22 (1.04–1.44)
124/4581, 2.7% 2.29 (1.87–2.80)
126/2403, 5.2% 2.42 (1.99–2.96)
268/2330, 11.5% 0.68 (0.56–0.82)
53/1547, 3.4% 1.47 (1.02–2.11)
the United States, cilostazol is not widely used in patients
with cerebrovascular disease.
BARRIERS TO CILOSTAZOL FOR STROKE
PREVENTION IN THE UNITED STATES
AND EUROPE
The fact that the major cilostazol trials conducted thus far
have not led to a change in practice patterns or guideline
recommendations in Western countries might be because
of limitations in their design, surprisingly large effect sizes,
and the patients who were studied (exclusively Asians
and predominantly male participants). Another factor that
might give physicians pause before adopting long-term
dual antiplatelet therapy (DAPT) with cilostazol is that
prior trials of long-term DAPT after ischemic stroke have
not shown an acceptable risk/benefit profile. The MATCH
trial (Management of Atherothrombosis With Clopidogrel
in High-Risk Patients), which randomized 7599 patients
with recent ischemic stroke or transient ischemic attack
to either DAPT (aspirin plus clopidogrel) or clopidogrel
monotherapy, showed no reduction in the primary MACE
outcome (ischemic stroke, myocardial infarction, vascular
death, or rehospitalization for acute ischemia including
transient ischemic attack, angina pectoris, or worsening of
PAD) during a mean follow-up of 18 months.95 While there
was a nonsignificant 7.1% (95% CI, −8.5 to 20.4) relative
risk reduction in ischemic stroke, the rate of life-threaten-
ing bleeding was 1.3% higher in the DAPT arm compared
with the clopidogrel monotherapy arm (P<0.001).
The SPS3 trial (Secondary Prevention of Small Sub-
cortical Strokes Trial) compared DAPT (aspirin plus
clopidogrel) to aspirin monotherapy in 3020 patients
with recent symptomatic lacunar ischemic stroke.96 The
primary outcome was recurrent stroke, including hem-
orrhagic stroke, and patients were followed for a mean
of 3.4 years. Like MATCH, SPS3 showed a nonsignifi-
cant lower rate of recurrent ischemic stroke with DAPT
(HR, 0.82 [95% CI, 0.63–1.09]) that was offset by
almost twice the rate of major hemorrhage and death
with DAPT. The ESPRIT trial (Aspirin Plus Dipyridamole
Versus Aspirin Alone After Cerebral Ischaemia of Arte-
rial Origin) compared aspirin plus dipyridamole to aspirin
Stroke. 2021;52:e635–e645. DOI: 10.1161/STROKEAHA.121.035002
 de Havenon et al
alone (30–325 mg daily) in 2739 patients with recent
ischemic stroke who were followed for a mean of 3.5
years.97 The primary outcome in ESPRIT was a MACE
composite, which was reduced by 20% (HR, 0.80 [95%
CI, 0.66–0.98]). The PRoFESS trial (Prevention Regimen
for Effectively Avoiding Second Strokes) compared aspi-
rin plus dipyridamole to clopidogrel in 20 332 patients
with recent ischemic stroke who were followed for a
mean of 2.5 years.62 In PRoFESS, aspirin plus dipyri-
damole was not associated with a significant reduction
in recurrent stroke (HR, 1.01 [95% CI, 0.92–1.11]) and
resulted in an increase in major hemorrhagic events (HR,
1.15 [95% CI, 1.00–1.32]).
Given the failure of long-term DAPT in large ran-
domized controlled secondary stroke prevention trials,
there has been reluctance to test novel long-term DAPT
combinations. In recent years, clinical trials have instead
focused on short-term DAPT therapy started within days
after stroke onset, to balance the secondary stroke pre-
vention benefit with hemorrhagic risk (CHANCE [Clopi-
dogrel in High-Risk Patients With Acute Nondisabling
Cerebrovascular Events], POINT [Platelet-Oriented
Inhibition in New TIA and Minor Ischemic Stroke], and
THALES [The Acute Stroke or Transient Ischemic Attack
Treated With Ticagrelor and Aspirin for Prevention of
Stroke and Death]).98–100
While these trials have demonstrated benefit from
short-term DAPT after ischemic stroke, they do not
address the risk of recurrent ischemic events that are
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experienced by patients beyond the first month. The
PRoFESS and MATCH trials show that patients with
stroke continue to accumulate MACE events at a nearly
linear rate of 4% to 8% per year during long-term fol-
low-up (Figure 4). Cilostazol could reduce this rate by
34% based on the results of a recent meta-analysis or
48% based on the results of CSPS.com.13,33 Long-term
cilostazol combined with aspirin or clopidogrel does not
increase bleeding risk beyond that of either aspirin or
clopidogrel alone and has considerably less risk than
the long-term combination of aspirin and clopidogrel.13,95
Figure 4. The rate of major adverse cardiovascular events (MACE) during follow-up in the PRoFESS (Prevention Regimen for
Effectively Avoiding Second Strokes) and MATCH (Management of Atherothrombosis With Clopidogrel in High-Risk Patients) trials.
Stroke. 2021;52:e635–e645. DOI: 10.1161/STROKEAHA.121.035002
Cilostazol for Secondary Stroke Prevention
Thus, the safety and efficacy profile of cilostazol could
complement current poststroke DAPT strategies. After
Topical Review
completion of a short (3 weeks to 3 months) course of
DAPT with aspirin and clopidogrel or ticagrelor, cilostazol
could subsequently be added indefinitely to single anti-
platelet treatment.
ONGOING AND FUTURE TRIALS OF
CILOSTAZOL
There is ongoing research with cilostazol. The LACI-2
trial (Lacunar Intervention Trial; ISRCTN 14911850,
EudraCT 2016-002277-35) is studying long-term
cilostazol and isosorbide mononitrate in a partial fac-
torial PROBE (Prospective Randomized Open, Blinded
End-Point) design after lacunar ischemic stroke in the
United Kingdom (target n=400),70 and the COMCID
trial (Trial of Cilostazol in Patients With Mild Cognitive
Impairment) in Japan is evaluating cilostazol’s effects on
cognitive function in patients with mild cognitive impair-
ment at baseline (target n=200).54,91 However, there are
no ongoing trials that will provide level 1 evidence of
cilostazol for preventing recurrent stroke and MACE.
Positive results of a large placebo-controlled trial con-
ducted outside of Asia and with adequate enrollment of
both women and men and careful stroke subtyping are
needed to change guidelines in Western countries and
determine whether cilostazol should become the stan-
dard of care for secondary prevention after noncardio-
embolic stroke.
An alternative to a large RCT is an observational study
that compares outcomes between patients who are pre-
scribed cilostazol and those who are not. The limitation of
such a design is that there are only small numbers of post-
stroke patients who are prescribed cilostazol and that pre-
scription patterns are likely confounded by indication.101
Another alternative is an open-label cluster randomized
trial, but such a design would still be costly while not provid-
ing the highest level evidence that is lacking. In contrast, a
October 2021   e641
 de Havenon et al
well-designed randomized placebo-controlled trial of cilo-
stazol could provide this evidence. To be most informative,
Topical Review
such a trial should have the following features: (1) broad
inclusion criteria in terms of stroke etiology, (2) stratified
randomization (eg, according to stroke etiology, sex, race/
ethnicity, and duration since index stroke), (3) a relatively
long follow-up duration (median of at least 2 years) to
assess both early and long-term effects, (4) assessment
of multiple patient-centric outcomes (eg, recurrent stroke,
dependency, MACE, cognition, and death), and (5) a large
enough sample to have sufficient power to detect a rela-
tively modest treatment effect (eg, a 20% risk reduction
for recurrent stroke or MACE would be a clinically relevant
finding even though a meta-analysis of prior studies sug-
gests that cilostazol reduces the rate of MACE by 34%).
Because cilostazol is currently generic and inexpensive,
industry is unlikely to fund such a trial.
The cost of cilostazol may increase dramatically if a
pharmaceutical company pursues a branded formulation
and is granted market exclusivity by the FDA.102 A cau-
tionary tale is the anti-inflammatory medication colchi-
cine, which is derived from the autumn crocus plant and
was used by ancient Egyptians for rheumatism and joint
swelling as far back as 1500 BC and as a tablet extract in
19th century Europe.103,104 Generic colchicine continued
to be prescribed and was endorsed in guidelines for gout
and other indications until in 2009, the FDA granted a
Philadelphia pharmaceutical company market exclusivity
for a branded form (Colcrys) based off improved labeling
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and a small trial with 185 gout patients.105–107 The result
was an overnight 5289% price increase, a subsequent
decrease in the use of colchicine, and 50-fold increase in
the cost of colchicine for Medicare.105,108,109 A 2010 edi-
torial in the New England Journal of Medicine aptly stated
“an alternative solution, probably much less expensive,
would be for the FDA or the National Institutes of Health
to fund trials that address outstanding questions related
to widely available drugs such as colchicine,”107 and we
would argue, cilostazol.
CONCLUSIONS
Cilostazol is a PDE3 inhibitor with a long track record of
safety. In Asian populations, its long-term use has been
shown to reduce recurrent stroke and MACE when used
alone or in combination with aspirin or clopidogrel for
secondary stroke prevention. Cilostazol has a delayed
onset of benefit for stroke prevention, which is consistent
with its pleiotropic effects on platelet aggregation, vascu-
lar remodeling, vasoreactivity, and the plasma lipid profile.
Given the low cost of cilostazol and the encouraging data
from Asian trials, which suggest a robust treatment effect,
it is imperative that a confirmatory trial be conducted in a
Western population to demonstrate generalized efficacy.
If positive, it would provide the required evidence to sup-
port the long-term use of cilostazol for secondary stroke
e642   October 2021
Cilostazol for Secondary Stroke Prevention
prevention in the millions of patients worldwide who have
experienced a noncardioembolic stroke.
ARTICLE INFORMATION
Affiliations
Department of Neurology, University of Utah (A.d.H.). Department of Neurology,
Yale University (K.N.S.). Department of Emergency Medicine, Brown University
(T.E.M.). Department of Neurology, University of Virginia (K.C.J.). Department of
Neurology, Medical University of South Carolina (T.N.T., J.J.E.). Department of
Cerebrovascular Medicine, National Cerebral and Cardiovascular Center, Ja-
pan (K.T.). Center for Clinical Brain Sciences, UK Dementia Research Institute,
University of Edinburgh (J.M.W.). Dell Medical School (S.C.J.). Department of
Neurology, Columbia University (O.A.W.). Department of Medicine (Neurology),
McMaster University/Population Heath Research Institute (A.S.). Department of
Neurology, Stanford University (M.G.L.).
Sources of Funding
Dr de Havenon is funded by National Institutes of Health (NIH)-National Insti-
tute of Neurological Disorders and Stroke (NINDS) K23NS105924; Dr John-
ston by NIH-NCATS UL1TR003015, NIH-NCATS KL2TR00316, NIH-NINDS
U01 NS086872; Dr Sheth by NIH-NINDS U01NS106513, R01NS11072,
R01NR018335, R03NS112859, U24NS107215, U24NS107136, and the
American Heart Association 17CSA33550004; Dr Toyoda by the Japan
Agency for Medical Research and Development 20lk0201094h0002 and
20lk0201109h0001. Dr Wardlaw is funded by the UK Dementia Research Insti-
tute (funded by the UK Medical Research Council, Alzheimer’s Research UK and
Alzheimer’s Society) and the Fondation Leducq (16 CVD 05). The research report-
ed in this publication was supported, in part, by the National Center for Advancing
Translational Sciences of the National Institutes of Health under award number
UL1TR002538. The content is solely the responsibility of the authors and does
not necessarily represent the official views of the National Institutes of Health.
Disclosures
Drs de Havenon, Sheth, and Lansberg report having submitted a concept syn-
opsis to the NINDS of a randomized controlled trial of cilostazol for secondary
stroke prevention. Dr de Havenon has investigator-initiated funding from AMAG,
AMGEN and Regeneron pharmaceuticals, consulting fees from Integra and
royalities from Up-to-Date. Dr Johnston has investigator-initiated funding from
Rivanna Medical, LLC, is on data safety monitoring boards for Biogen, and is
a consultant to Diffusion Pharmaceuticals, Neurotrauma Science LLC, and the
Food and Drug Administration. Dr Johnston reports research support from As-
traZeneca and receives Drub Placebo for NIH-sponsored randomized trial from
Sanofi. Dr Sheth reports funding from Biogen, Novartis, Bard, Hyperfine, Astro-
cyte, Alva Health, and NControl and is DSMB Chair for Zoll. Dr Toyoda reports
personal fees from Daiichi Sankyo, Bayer Yakuhin, Bristol Myers Squibb, Takeda,
and Nippon Boehringer-Ingelheim. Dr Shoamanesh reports funding from Bayer
AG, Daiichi Sankyo, Servier Canada, Portola Pharmaceuticals, and Bristol Myers
Squibb. Dr Wardlaw reports being the primary investigator of the LACI-2 trial
(Lacunar Intervention-1), which is funded by the British Heart Foundation. The
other authors report no conflicts.
REFERENCES
1. Nishi T, Kimura Y, Nakagawa K. [Research and development of cilostazol:
an antiplatelet agent]. Yakugaku Zasshi. 2000;120:1247–1260. doi:
10.1248/yakushi1947.120.12_1247
2. Kambayashi J, Liu Y, Sun B, Shakur Y, Yoshitake M, Czerwiec F. Cilostazol as
a unique antithrombotic agent. Curr Pharm Des. 2003;9:2289–2302. doi:
10.2174/1381612033453910
3. Otsuka Pharmaceutical Co. Ltd. Pharmaceutical business products
[Internet]. Accessed February 26, 2021. https://www.otsuka.co.jp/en/
pharmaceutical-business/products/.
4. GoodRx. Cilostazol prices, coupons & savings tips [Internet]. Accessed
August 28, 2021. https://www.goodrx.com/cilostazol.
5. UpToDate. Cilostazol: Drug information - UpToDate [Internet]. Accessed
February 26, 2021. https://www.uptodate.com/contents/cilostazol-drug-
information?search=pletal&source=panel_search_result&selectedTitle=
1~33&usage_type=panel&kp_tab=drug_general&display_rank=1.
6. www.shop-apotheke.com. Cilostazol-Elpen 100 mg 56 St - shop-apotheke.
com [Internet]. Accessed April 13, 2021. https://www.shop-apotheke.com/
arzneimittel/10941689/cilostazol-elpen-100-mg.htm.
Stroke. 2021;52:e635–e645. DOI: 10.1161/STROKEAHA.121.035002
 de Havenon et al
7. Hiratsuka M, Hinai Y, Sasaki T, Konno Y, Imagawa K, Ishikawa M, Mizugaki
M. Characterization of human cytochrome p450 enzymes involved in the
metabolism of cilostazol. Drug Metab Dispos. 2007;35:1730–1732. doi:
10.1124/dmd.107.016758
8. PubChem. Cilostazol [Internet]. Accessed October 1, 2020. https://pub-
chem.ncbi.nlm.nih.gov/compound/2754.
9. Liu Y, Fong M, Cone J, Wang S, Yoshitake M, Kambayashi J. Inhibition of
adenosine uptake and augmentation of ischemia-induced increase of inter-
stitial adenosine by cilostazol, an agent to treat intermittent claudication.
J Cardiovasc Pharmacol. 2000;36:351–360. doi: 10.1097/00005344-
200009000-00011
10. Sun B, Le SN, Lin S, Fong M, Guertin M, Liu Y, Tandon NN, Yoshitake
M, Kambayashi J. New mechanism of action for cilostazol: interplay
between adenosine and cilostazol in inhibiting platelet activation. J Car-
diovasc Pharmacol. 2002;40:577–585. doi: 10.1097/00005344-
200210000-00011
11. Ikeda Y, Kikuchi M, Murakami H, Satoh K, Murata M, Watanabe K, Ando Y.
Comparison of the inhibitory effects of cilostazol, acetylsalicylic acid and
ticlopidine on platelet functions ex vivo. Randomized, double-blind cross-
over study. Arzneimittelforschung. 1987;37:563–566.
12. Goto S. Cilostazol: potential mechanism of action for antithrombotic effects
accompanied by a low rate of bleeding. Atheroscler Suppl. 2005;6:3–11. doi:
10.1016/j.atherosclerosissup.2005.09.002
13. McHutchison C, Blair GW, Appleton JP, Chappell FM, Doubal F, Bath PM,
Wardlaw JM. Cilostazol for secondary prevention of stroke and cogni-
tive decline. Stroke. 2020;51:2374–2385. doi: 10.1161/STROKEAHA.
120.029454
14. Panchal HB, Shah T, Patel P, Albalbissi K, Molnar J, Coffey B, Khosla S,
Ramu V. Comparison of on-treatment platelet reactivity between triple anti-
platelet therapy with cilostazol and standard dual antiplatelet therapy in
patients undergoing coronary interventions: a meta-analysis. J Cardiovasc
Pharmacol Ther. 2013;18:533–543. doi: 10.1177/1074248413495971
15. Rondina MT, Weyrich AS. Targeting phosphodiesterases in anti-platelet
therapy. Handb Exp Pharmacol. 2012;210:225–238. doi: 10.1007/978-3-
642-29423-5_9
16. Smith JB, Araki H, Lefer AM. Thromboxane A2, prostacyclin and aspirin:
effects on vascular tone and platelet aggregation. Circulation. 1980;62(6 pt
2):V19–V25.
Downloaded from http://ahajournals.org by on May 31, 2024
17. Dobesh PP, Stacy ZA, Persson EL. Pharmacologic therapy for intermittent clau-
dication. Pharmacotherapy. 2009;29:526–553. doi: 10.1592/phco.29.5.526
18. Yasunaga K, Mase K. Clinical effects of oral cilostazol on suppression of
platelet function in patients with cerebrovascular disease. Arzneimittelforsc-
hung. 1985;35(7A):1186–1188.
19. Igawa T, Tani T, Chijiwa T, Shiragiku T, Shimidzu S, Kawamura K, Kato S,
Unemi F, Kimura Y. Potentiation of anti-platelet aggregating activity of cilo-
stazol with vascular endothelial cells. Thromb Res. 1990;57:617–623. doi:
10.1016/0049-3848(90)90079-r
20. Tani T, Sakurai K, Kimura Y, Ishikawa T, Hidaka H. Pharmacological manipu-
lation of tissue cyclic AMP by inhibitors. Effects of phosphodiesterase inhib-
itors on the functions of platelets and vascular endothelial cells. Adv Second
Messenger Phosphoprotein Res. 1992;25:215–227.
21. Sakurai H, Hanyu H, Sato T, Kume K, Hirao K, Kanetaka H, Iwamoto T.
Effects of cilostazol on cognition and regional cerebral blood flow in patients
with Alzheimer’s disease and cerebrovascular disease: a pilot study. Geriatr
Gerontol Int. 2013;13:90–97. doi: 10.1111/j.1447-0594.2012.00866.x
22. Lee SJ, Lee JS, Choi MH, Lee SE, Shin DH, Hong JM. Cilostazol improves
endothelial function in acute cerebral ischemia patients: a double-blind
placebo controlled trial with flow-mediated dilation technique. BMC Neurol.
2017;17:169. doi: 10.1186/s12883-017-0950-y
23. Ikeda U, Ikeda M, Kano S, Kanbe T, Shimada K. Effect of cilostazol, a
cAMP phosphodiesterase inhibitor, on nitric oxide production by vas-
cular smooth muscle cells. Eur J Pharmacol. 1996;314:197–202. doi:
10.1016/s0014-2999(96)00551-1
24. Nakamura T, Houchi H, Minami A, Sakamoto S, Tsuchiya K, Niwa Y,
Minakuchi K, Nakaya Y. Endothelium-dependent relaxation by cilostazol, a
phosphodiesteras III inhibitor, on rat thoracic aorta. Life Sci. 2001;69:1709–
1715. doi: 10.1016/s0024-3205(01)01258-9
25. Hashimoto A, Miyakoda G, Hirose Y, Mori T. Activation of endothelial nitric
oxide synthase by cilostazol via a cAMP/protein kinase A- and phos-
phatidylinositol 3-kinase/Akt-dependent mechanism. Atherosclerosis.
2006;189:350–357. doi: 10.1016/j.atherosclerosis.2006.01.022
26. Bath PM, Wardlaw JM. Pharmacological treatment and prevention of cere-
bral small vessel disease: a review of potential interventions. Int J Stroke.
2015;10:469–478. doi: 10.1111/ijs.12466
Stroke. 2021;52:e635–e645. DOI: 10.1161/STROKEAHA.121.035002
Cilostazol for Secondary Stroke Prevention
27. Blair GW, Appleton JP, Flaherty K, Doubal F, Sprigg N, Dooley R, Richardson
C, Hamilton I, Law ZK, Shi Y, et al. Tolerability, safety and intermediary
pharmacological effects of cilostazol and isosorbide mononitrate, alone
Topical Review
and combined, in patients with lacunar ischaemic stroke: the LACunar
Intervention-1 (LACI-1) trial, a randomised clinical trial. EClinicalMedicine.
2019;11:34–43. doi: 10.1016/j.eclinm.2019.04.001
28. Tanaka T, Ishikawa T, Hagiwara M, Onoda K, Itoh H, Hidaka H. Effects of
cilostazol, a selective cAMP phosphodiesterase inhibitor on the contrac-
tion of vascular smooth muscle. Pharmacology. 1988;36:313–320. doi:
10.1159/000138400
29. Hayashi S, Morishita R, Matsushita H, Nakagami H, Taniyama Y, Nakamura
T, Aoki M, Yamamoto K, Higaki J, Ogihara T. Cyclic AMP inhibited prolif-
eration of human aortic vascular smooth muscle cells, accompanied by
induction of p53 and p21. Hypertension. 2000;35(1 pt 2):237–243. doi:
10.1161/01.hyp.35.1.237
30. Takahashi S, Oida K, Fujiwara R, Maeda H, Hayashi S, Takai H,
Tamai T, Nakai T, Miyabo S. Effect of cilostazol, a cyclic AMP phos-
phodiesterase inhibitor, on the proliferation of rat aortic smooth mus-
cle cells in culture. J Cardiovasc Pharmacol. 1992;20:900–906. doi:
10.1097/00005344-199212000-00009
31. Hadrava V, Kruppa U, Russo RC, Lacourcière Y, Tremblay J, Hamet P.
Vascular smooth muscle cell proliferation and its therapeutic modula-
tion in hypertension. Am Heart J. 1991;122(4 pt 2):1198–1203. doi:
10.1016/0002-8703(91)90939-f
32. Lacolley P, Regnault V, Nicoletti A, Li Z, Michel JB. The vascular smooth
muscle cell in arterial pathology: a cell that can take on multiple roles. Car-
diovasc Res. 2012;95:194–204. doi: 10.1093/cvr/cvs135
33. Toyoda K, Uchiyama S, Yamaguchi T, Easton JD, Kimura K, Hoshino H,
Sakai N, Okada Y, Tanaka K, Origasa H, et al; CSPS.com Trial Investiga-
tors. Dual antiplatelet therapy using cilostazol for secondary prevention
in patients with high-risk ischaemic stroke in Japan: a multicentre, open-
label, randomised controlled trial. Lancet Neurol. 2019;18:539–548. doi:
10.1016/S1474-4422(19)30148-6
34. Drugs.com. Cilostazol - FDA prescribing information, side effects and uses
[Internet]. Accessed February 26, 2021. https://www.drugs.com/pro/cilo-
stazol.html.
35. Kwon BJ, Lee SH, Kim DB, Park HJ, Jang SW, Ihm SH, Kim HY, Seung
KB. A randomized comparison study assessing the impact of cilostazol on
the heart rate and arrhythmias by 24-hour ambulatory holter electrocardio-
graphic monitoring after drug-eluting stent implantation for coronary artery
disease. J Atheroscler Thromb. 2015;22:152–164. doi: 10.5551/jat.25577
36. Appleton JP, Blair GW, Flaherty K, Law ZK, May J, Woodhouse LJ, Doubal
F, Sprigg N, Bath PM, Wardlaw JM. Effects of isosorbide mononitrate
and/or cilostazol on hematological markers, platelet function, and hemo-
dynamics in patients with Lacunar Ischaemic Stroke: safety data from
the Lacunar Intervention-1 (LACI-1) trial. Front Neurol. 2019;10:723. doi:
10.3389/fneur.2019.00723
37. Asal NJ, Wojciak KA. Effect of cilostazol in treating diabetes-associ-
ated microvascular complications. Endocrine. 2017;56:240–244. doi:
10.1007/s12020-017-1279-4
38. Trujillo ME, Sullivan S, Harten I, Schneider SH, Greenberg AS, Fried SK.
Interleukin-6 regulates human adipose tissue lipid metabolism and leptin
production in vitro. J Clin Endocrinol Metab. 2004;89:5577–5582. doi:
10.1210/jc.2004-0603
39. Zitnik RJ, Zheng T, Elias JA. cAMP inhibition of interleukin-1-induced inter-
leukin-6 production by human lung fibroblasts. Am J Physiol. 1993;264(3 pt
1):L253–L260. doi: 10.1152/ajplung.1993.264.3.L253
40. Lee TM, Su SF, Hwang JJ, Tseng CD, Chen MF, Lee YT, Wang SS. Dif-
ferential lipogenic effects of cilostazol and pentoxifylline in patients with
intermittent claudication: potential role for interleukin-6. Atherosclerosis.
2001;158:471–476. doi: 10.1016/s0021-9150(01)00457-9
41. Elam MB, Heckman J, Crouse JR, Hunninghake DB, Herd JA, Davidson
M, Gordon IL, Bortey EB, Forbes WP. Effect of the novel antiplate-
let agent cilostazol on plasma lipoproteins in patients with intermittent
claudication. Arterioscler Thromb Vasc Biol. 1998;18:1942–1947. doi:
10.1161/01.atv.18.12.1942
42. Thompson PD, Zimet R, Forbes WP, Zhang P. Meta-analysis of results from
eight randomized, placebo-controlled trials on the effect of cilostazol on
patients with intermittent claudication. Am J Cardiol. 2002;90:1314–1319.
doi: 10.1016/s0002-9149(02)02869-2
43. da Motta NAV, de Brito FCF. Cilostazol exerts antiplatelet and anti-inflam-
matory effects through AMPK activation and NF-kB inhibition on hyper-
cholesterolemic rats. Fundam Clin Pharmacol. 2016;30:327–337. doi:
10.1111/fcp.12195
October 2021   e643
 de Havenon et al
44. Motta NAV, Autran LJ, Brazão SC, Lopes RO, Scaramello CBV, Lima GF,
Brito FCF. Could cilostazol be beneficial in COVID-19 treatment? Thinking
about phosphodiesterase-3 as a therapeutic target. Int Immunopharmacol.
Topical Review
2021;92:107336. doi: 10.1016/j.intimp.2020.107336
45. Chattipakorn SC, Thummasorn S, Sanit J, Chattipakorn N. Phosphodies-
terase-3 inhibitor (cilostazol) attenuates oxidative stress-induced mito-
chondrial dysfunction in the heart. J Geriatr Cardiol. 2014;11:151–157. doi:
10.3969/j.issn.1671-5411.2014.02.014
46. Tang WH, Lin FH, Lee CH, Kuo FC, Hsieh CH, Hsiao FC, Hung YJ. Cilostazol
effectively attenuates deterioration of albuminuria in patients with type 2
diabetes: a randomized, placebo-controlled trial. Endocrine. 2014;45:293–
301. doi: 10.1007/s12020-013-0002-3
47. Douglas JS, Holmes DR, Kereiakes DJ, Grines CL, Block E, Ghazzal ZMB,
Morris DC, Liberman H, Parker K, Jurkovitz C, et al. Coronary stent reste-
nosis in patients treated with cilostazol. Circulation. 2005;112:2826–2832.
doi: 10.1161/CIRCULATIONAHA.104.530097
48. Godinho J, de Oliveira JN, Ferreira ED, Zaghi GG, Bacarin CC, de Oliveira
RM, Milani H. Cilostazol but not sildenafil prevents memory impairment
after chronic cerebral hypoperfusion in middle-aged rats. Behav Brain Res.
2015;283:61–68. doi: 10.1016/j.bbr.2015.01.026
49. Matsumoto S, Shimodozono M, Miyata R, Kawahira K. Effect of cilo-
stazol administration on cerebral hemodynamics and rehabilitation out-
comes in poststroke patients. Int J Neurosci. 2011;121:271–278. doi:
10.3109/00207454.2010.551431
50. Zeller T, Trenk D. Cilostazol. Circulation. 2013;127:2261–2263. doi:
10.1161/CIRCULATIONAHA.113.003284
51. Ono K, Tsuji M. Pharmacological potential of cilostazol for Alzheimer’s
disease. Front Pharmacol. [Internet]. Accessed March 1, 2021. https://
www.frontiersin.org/articles/10.3389/fphar.2019.00559/full.
52. Tanaka M, Saito S, Inoue T, Satoh-Asahara N, Ihara M. Potential therapeutic
approaches for cerebral amyloid angiopathy and Alzheimer’s disease. Int J
Mol Sci . 2020;21:1992.
53. Maki T, Okamoto Y, Carare RO, Hase Y, Hattori Y, Hawkes CA, Saito S,
Yamamoto Y, Terasaki Y, Ishibashi-Ueda H, et al. Phosphodiesterase III
inhibitor promotes drainage of cerebrovascular β-amyloid. Ann Clin Transl
Neurol. 2014;1:519–533. doi: 10.1002/acn3.79
54. Saito S, Kojima S, Oishi N, Kakuta R, Maki T, Yasuno F, Nagatsuka K,
Yamamoto H, Fukuyama H, Fukushima M, et al. A multicenter, randomized,
Downloaded from http://ahajournals.org by on May 31, 2024
placebo-controlled trial for cilostazol in patients with mild cognitive impair-
ment: the COMCID study protocol. Alzheimers Dement (N Y). 2016;2:250–
257. doi: 10.1016/j.trci.2016.10.001
55. Lee JY, Lee H, Yoo HB, Choi JS, Jung HY, Yoon EJ, Kim H, Jung YH, Lee HY,
Kim YK. Efficacy of cilostazol administration in Alzheimer’s disease patients
with white matter lesions: a positron-emission tomography study. Neuro-
therapeutics. 2019;16:394–403. doi: 10.1007/s13311-018-00708-x
56. Tai SY, Chien CY, Chang YH, Yang YH. Cilostazol use is associated with
reduced risk of dementia: a nationwide cohort study. Neurotherapeutics.
2017;14:784–791. doi: 10.1007/s13311-017-0512-4
57. Zimmerman J, Lee JP, Cahalan M. 25 - Vasopressors and Inotropes
[Internet]. In: Hemmings HC, Egan TD, editors. Pharmacology and Physi-
ology for Anesthesia. 2nd ed. Elsevier;2019: pp. 520–534. Accessed
February 26, 2021. https://www.sciencedirect.com/science/article/pii/
B9780323481106000259.
58. Amsallem E, Kasparian C, Haddour G, Boissel JP, Nony P. Phospho-
diesterase III inhibitors for heart failure. Cochrane Database Syst Rev.
2005;1:CD002230. doi: 10.1002/14651858.CD002230.pub2
59. Shakur Y, Fong M, Hensley J, Cone J, Movsesian MA, Kambayashi J,
Yoshitake M, Liu Y. Comparison of the effects of cilostazol and milrinone on
cAMP-PDE activity, intracellular cAMP and calcium in the heart. Cardiovasc
Drugs Ther. 2002;16:417–427. doi: 10.1023/a:1022186402442
60. Packer M, Carver JR, Rodeheffer RJ, Ivanhoe RJ, DiBianco R, Zeldis
SM, Hendrix GH, Bommer WJ, Elkayam U, Kukin ML. Effect of oral
milrinone on mortality in severe chronic heart failure. The PROMISE
Study Research Group. N Engl J Med. 1991;325:1468–1475. doi:
10.1056/NEJM199111213252103
61. Ayres JK, Maani CV. Milrinone [Internet]. In: StatPearls. StatPearls Pub-
lishing; 2021. Accessed February 27, 2021. http://www.ncbi.nlm.nih.gov/
books/NBK532943/.
62. Sacco RL, Diener HC, Yusuf S, Cotton D, Ounpuu S, Lawton WA, Palesch
Y, Martin RH, Albers GW, Bath P, et al; PRoFESS Study Group. Aspirin and
extended-release dipyridamole versus clopidogrel for recurrent stroke. N
Engl J Med. 2008;359:1238–1251. doi: 10.1056/NEJMoa0805002
63. Gresele P, Momi S, Falcinelli E. Anti-platelet therapy: phosphodiesterase
inhibitors. Br J Clin Pharmacol. 2011;72:634–646. doi: 10.1111/j.1365-
2125.2011.04034.x
e644   October 2021
Cilostazol for Secondary Stroke Prevention
64. Shinohara Y, Katayama Y, Uchiyama S, Yamaguchi T, Handa S, Matsuoka K,
Ohashi Y, Tanahashi N, Yamamoto H, Genka C, et al; CSPS 2 Group. Cilo-
stazol for prevention of secondary stroke (CSPS 2): an aspirin-controlled,
double-blind, randomised non-inferiority trial. Lancet Neurol. 2010;9:959–
968. doi: 10.1016/S1474-4422(10)70198-8
65. Gotoh F, Tohgi H, Hirai S, Terashi A, Fukuuchi Y, Otomo E, Shinohara Y, Itoh
E, Matsuda T, Sawada T, et al. Cilostazol stroke prevention study: a placebo-
controlled double-blind trial for secondary prevention of cerebral infarction.
J Stroke Cerebrovasc Dis. 2000;9:147–157. doi: 10.1053/jscd.2000.7216
66. Kim BJ, Lee EJ, Kwon SU, Park JH, Kim YJ, Hong KS, Wong LKS, Yu S,
Hwang YH, Lee JS, et al; PICASSO Investigators. Prevention of cardiovas-
cular events in Asian patients with ischaemic stroke at high risk of cerebral
haemorrhage (PICASSO): a multicentre, randomised controlled trial. Lancet
Neurol. 2018;17:509–518. doi: 10.1016/S1474-4422(18)30128-5
67. Aoki J, Iguchi Y, Urabe T, Yamagami H, Todo K, Fujimoto S, Idomari K,
Kaneko N, Iwanaga T, Terasaki T, et al; ADS Investigators. Acute aspirin
plus cilostazol dual therapy for noncardioembolic stroke patients within
48 hours of symptom onset. J Am Heart Assoc. 2019;8:e012652. doi:
10.1161/JAHA.119.012652
68. Bedenis R, Stewart M, Cleanthis M, Robless P, Mikhailidis DP, Stansby G.
Cilostazol for intermittent claudication. Cochrane Database Syst Rev [Inter-
net]. 2014. Accessed October 1, 2021. https://www.cochranelibrary.com/
cdsr/doi/10.1002/14651858.CD003748.pub4/full.
69. Hankey GJ. CSPS.com trial of adding cilostazol to antiplatelet therapy
to reduce recurrent stroke. Stroke. 2020;51:696–698. doi: 10.1161/
STROKEAHA.119.028409
70. Wardlaw J, Bath PMW, Doubal F, Heye A, Sprigg N, Woodhouse LJ, Blair
G, Appleton J, Cvoro V, England T, et al; LACI-2 Trial Investigators. Protocol:
the Lacunar Intervention Trial 2 (LACI-2). A trial of two repurposed licenced
drugs to prevent progression of cerebral small vessel disease. Eur Stroke J.
2020;5:297–308. doi: 10.1177/2396987320920110
71. Bramer SL, Forbes WP. Relative bioavailability and effects of a high fat
meal on single dose cilostazol pharmacokinetics. Clin Pharmacokinet.
1999;37(suppl 2):13–23. doi: 10.2165/00003088-199937002-00002
72. Cohn JN, Goldstein SO, Greenberg BH, Lorell BH, Bourge RC, Jaski BE,
Gottlieb SO, McGrew F, DeMets DL, White BG. A dose-dependent increase in
mortality with vesnarinone among patients with severe heart failure. N Engl J
Med. 1998;339:1810–1816. doi: 10.1056/NEJM199812173392503
73. Anonymous. Cilostazol-containing medicines [Internet]. European Medicines
Agency. 2018. Accessed April 10, 2021. https://www.ema.europa.eu/en/
medicines/human/referrals/cilostazol-containing-medicines.
74. Hiatt WR, Money SR, Brass EP. Long-term safety of cilostazol in patients with
peripheral artery disease: the CASTLE study (cilostazol: a study in long-term
effects). J Vasc Surg. 2008;47:330–336. doi: 10.1016/j.jvs.2007.10.009
75. www.heart.org. Classes of heart failure [Internet]. Accessed February 27, 2021.
https://www.heart.org/en/health-topics/heart-failure/what-is-heart-failure/
classes-of-heart-failure.
76. Wu C-K, Lin J-W, Wu L-C, Chang C-H. Risk of heart failure hospitalization
associated with cilostazol in diabetes: a nationwide case–crossover study.
Front Pharmacol [Internet]. 2019. Accessed February 27, 2021. https://
www.ncbi.nlm.nih.gov/pmc/articles/PMC6330376/.
77. Pratt CM. Analysis of the cilostazol safety database. Am J Cardiol.
2001;87(12A):28D–33D. doi: 10.1016/s0002-9149(01)01719-2
78. Jung YS, Chae D, Park K. Population pharmacodynamics of cilostazol in
healthy Korean subjects. Transl Clin Pharmacol. 2018;26:93–98. doi:
10.12793/tcp.2018.26.2.93
79. Lee D, Lim LA, Jang SB, Lee YJ, Chung JY, Choi JR, Kim K, Park JW, Yoon
H, Lee J, et al. Pharmacokinetic comparison of sustained- and immediate-
release oral formulations of cilostazol in healthy Korean subjects: a ran-
domized, open-label, 3-part, sequential, 2-period, crossover, single-dose,
food-effect, and multiple-dose study. Clin Ther. 2011;33:2038–2053. doi:
10.1016/j.clinthera.2011.10.024
80. Kalantzi K, Tentolouris N, Melidonis AJ, Papadaki S, Peroulis M, Amantos
KA, Andreopoulos G, Bellos GI, Boutel D, Bristianou M, et al. Efficacy
and safety of adjunctive cilostazol to clopidogrel-treated diabetic patients
with symptomatic lower extremity artery disease in the prevention of
ischemic vascular events. J Am Heart Assoc. 2021;10:e018184. doi:
10.1161/JAHA.120.018184
81. Money SR, Herd JA, Isaacsohn JL, Davidson M, Cutler B, Heckman J,
Forbes WP. Effect of cilostazol on walking distances in patients with inter-
mittent claudication caused by peripheral vascular disease. J Vasc Surg.
1998;27:267–274. doi: 10.1016/s0741-5214(98)70357-x
82. Damman P, Woudstra P, Kuijt WJ, de Winter RJ, James SK. P2Y12 platelet
inhibition in clinical practice. J Thromb Thrombolysis. 2012;33:143–153. doi:
10.1007/s11239-011-0667-5
Stroke. 2021;52:e635–e645. DOI: 10.1161/STROKEAHA.121.035002
 de Havenon et al
83. Yoo HD, Cho HY, Lee YB. Population pharmacokinetic analysis of cilostazol
in healthy subjects with genetic polymorphisms of CYP3A5, CYP2C19
and ABCB1. Br J Clin Pharmacol. 2010;69:27–37. doi: 10.1111/j.1365-
2125.2009.03558.x
84. Lee HI, Byeon JY, Kim YH, Lee CM, Choi CI, Jang CG, Bae JW, Lee YJ, Lee
SY. Effects of CYP2C19 and CYP3A5 genetic polymorphisms on the phar-
macokinetics of cilostazol and its active metabolites. Eur J Clin Pharmacol.
2018;74:1417–1426. doi: 10.1007/s00228-018-2522-5
85. Chapman TM, Goa KL. Cilostazol: a review of its use in intermit-
tent claudication. Am J Cardiovasc Drugs. 2003;3:117–138. doi:
10.2165/00129784-200303020-00006
86. Gerhard-Herman MD, Gornik HL, Barrett C, Barshes NR, Corriere MA, Drachman
DE, Fleisher LA, Fowkes FGR, Hamburg NM, Kinlay S, et al. 2016 AHA/ACC
guideline on the management of patients with lower extremity peripheral artery
disease: executive summary: a report of the American College of Cardiology/
American Heart Association task force on clinical practice guidelines. Circula-
tion. 2017;135:e686–e725. doi: 10.1161/CIR.0000000000000470
87. Toyoda K, Inoue M, Koga M. Small but steady steps in stroke medicine in Japan.
J Am Heart Assoc. 2019;8:e013306. doi: 10.1161/JAHA.119.013306
88. Kim JS, Kwon SU, Uchiyama S. Cilostazol research in Asia: can it be applied
to European and American patients? Int J Stroke. 2015;10(suppl 1):1–9.
doi: 10.1111/ijs.12460
89. Kleindorfer DO, Towfighi A, Chaturvedi S, Cockroft KM, Gutierrez J, Lombardi-
Hill D, Kamel H, Kernan WN, Kittner SJ, Leira EC, et al. 2021 guideline for
the prevention of stroke in patients with stroke and transient ischemic attack:
a guideline from the American Heart Association/American Stroke Associa-
tion. Stroke. 2021;52:e364–e467. doi: 10.1161/STR.0000000000000375
90. European Stroke Organisation. ESO guideline directory [Internet]. Accessed
April 9, 2021. https://eso-stroke.org/guidelines/eso-guideline-directory/.
91. CMS. Medicare provider utilization and payment data: part D pre-
scriber | [Internet]. Accessed January 20, 2021. https://www.cms.gov/
Research-Statistics-Data-and-Systems/Statistics-Trends-and-Reports/
Medicare-Provider-Charge-Data/Part-D-Prescriber.
92. Datasets [Internet]. TriNetX. Accessed August 28, 2021. https://trinetx.
com/datasets/.
93. McCormick N, Bhole V, Lacaille D, Avina-Zubieta JA. Validity of diagnos-
tic codes for acute stroke in administrative databases: a systematic review.
PLoS One. 2015;10:e0135834. doi: 10.1371/journal.pone.0135834
Downloaded from http://ahajournals.org by on May 31, 2024
94. Castellsague J, Perez-Gutthann S, Calingaert B, Bui C, Varas-Lorenzo C, Arana
A, Prados-Torres A, Poblador-Plou B, Gonzalez-Rubio F, Giner-Soriano M, et al.
Characterization of new users of cilostazol in the UK, Spain, Sweden, and Ger-
many. Pharmacoepidemiol Drug Saf. 2017;26:615–624. doi: 10.1002/pds.4167
95. Diener HC, Bogousslavsky J, Brass LM, Cimminiello C, Csiba L, Kaste M,
Leys D, Matias-Guiu J, Rupprecht HJ; MATCH Investigators. Aspirin and
clopidogrel compared with clopidogrel alone after recent ischaemic stroke
or transient ischaemic attack in high-risk patients (MATCH): randomised,
double-blind, placebo-controlled trial. Lancet. 2004;364:331–337. doi:
10.1016/S0140-6736(04)16721-4
Stroke. 2021;52:e635–e645. DOI: 10.1161/STROKEAHA.121.035002
Cilostazol for Secondary Stroke Prevention
96. SPS3 Investigators, Benavente OR, Hart RG, McClure LA, Szychowski JM,
Coffey CS, Pearce LA. Effects of clopidogrel added to aspirin in patients
with recent lacunar stroke. N Engl J Med. 2012;367:817–825. doi:
Topical Review
10.1056/NEJMoa1204133
97. ESPRIT Study Group; Halkes PH, van Gijn J, Kappelle LJ, Koudstaal
PJ, Algra A. Aspirin plus dipyridamole versus aspirin alone after cerebral
ischaemia of arterial origin (ESPRIT): randomised controlled trial. Lancet.
2006;367:1665–1673. doi: 10.1016/S0140-6736(06)68734-5
98. Johnston SC, Easton JD, Farrant M, Barsan W, Conwit RA, Elm JJ, Kim
AS, Lindblad AS, Palesch YY; Clinical Research Collaboration, Neurological
Emergencies Treatment Trials Network, and the POINT Investigators.
Clopidogrel and aspirin in acute ischemic stroke and high-risk TIA. N Engl
J Med. 2018;379:215–225. doi: 10.1056/NEJMoa1800410
99. Johnston SC, Amarenco P, Denison H, Evans SR, Himmelmann A, James
S, Knutsson M, Ladenvall P, Molina CA, Wang Y; THALES Investigators.
Ticagrelor and aspirin or aspirin alone in acute ischemic stroke or TIA. N
Engl J Med. 2020;383:207–217. doi: 10.1056/NEJMoa1916870
100. Wang Y, Wang Y, Zhao X, Liu L, Wang D, Wang C, Wang C, Li H, Meng X,
Cui L, et al; CHANCE Investigators. Clopidogrel with aspirin in acute minor
stroke or transient ischemic attack. N Engl J Med. 2013;369:11–19. doi:
10.1056/NEJMoa1215340
101. Kyriacou DN, Lewis RJ. Confounding by indication in clinical research.
JAMA. 2016;316:1818–1819. doi: 10.1001/jama.2016.16435
102. Sahragardjoonegani B, Beall RF, Kesselheim AS, Hollis A. Repurposing ex-
isting drugs for new uses: a cohort study of the frequency of FDA-granted
new indication exclusivities since 1997. J Pharm Policy Pract. 2021;14:3.
doi: 10.1186/s40545-020-00282-8
103. Graham W, Roberts JB. Intravenous colchicine in the management of gouty
arthritis. Ann Rheum Dis. 1953;12:16–19. doi: 10.1136/ard.12.1.16
104. Nuki G, Simkin PA. A concise history of gout and hyperuricemia and their
treatment. Arthritis Res Ther. 2006;8(suppl 1):S1. doi: 10.1186/ar1906
105. Meyer H. The high price of FDA approval [Internet]. Kaiser Health News.
2009. Accessed March 2, 2021. https://khn.org/news/fda-approval/
106. Research C for DE and. Colchicine (marketed as Colcrys) Information. FDA
[Internet]. 2018. Accessed March 2, 2021. https://www.fda.gov/drugs/
post mar ket -dr ug-safet y-inf or mat ion-pat ient s-and-pr oviders/
colchicine-marketed-colcrys-information.
107. Kesselheim AS, Solomon DH. Incentives for drug development — the
curious case of Colchicine. N Engl J Med. 2010;362:2045–2047. doi:
10.1056/NEJMp1003126
108. Bloomberg.com. 2,000% Drug price surge is a side effect of FDA safety
program [Internet]. 2015. Accessed March 2, 2021. https://www.bloom-
berg.com/news/articles/2015-10-06/2-000-drug-price-surge-is-a-side-
effect-of-fda-safety-program.
109. Kesselheim AS, Franklin JM, Kim SC, Seeger JD, Solomon DH. Reductions
in use of colchicine after FDA enforcement of market exclusivity in a com-
mercially insured population. J Gen Intern Med. 2015;30:1633–1638. doi:
10.1007/s11606-015-3285-7
October 2021   e645