ARTICLES

Formulary Forum

Cilostazol: Treatment of Intermittent Claudication

Muredach P Reilly and Emile R Mohler III

OBJECTIVE:
To review the pharmacology and clinical utility of cilostazol, an antiplatelet and vasodilator agent approved for the
management of intermittent claudication.
DATA SOURCES: Primary literature on cilostazol was identified from a comprehensive MEDLINE literature search (1980–February
2000). Selected meeting abstracts and manufacturer literature were also used as source material. Indexing terms included
cilostazol, intermittent claudication, platelet inhibitors, and restenosis.
STUDY SELECTION: Human clinical, pharmacokinetic and randomized comparative trials performed in the US and Asia were
reviewed. Selected in vitro, ex vivo, and animal studies were evaluated when human data were not available.
DATA SYNTHESIS: Intermittent claudication, defined as reproducible discomfort of a muscle group induced by exercise and relieved
by rest, is the most common clinical manifestation of peripheral arterial disease (PAD). Cilostazol, a specific inhibitor of cyclic
adenosine monophosphate phosphodiesterase in platelets and vascular smooth-muscle cells, is a potent antiplatelet agent and
vasodilator that reduces vascular proliferation and has lipid-lowering effects in vivo. Recent multicenter, randomized, placebo-
controlled trials have led to approval of cilostazol by the Food and Drug Administration for relief of intermittent claudication in patients
with stable PAD. Cilostazol doubled walking distances and improved quality of life compared with placebo in these studies. One trial
found that cilostazol was more effective than pentoxifylline, the only alternative pharmacologic therapy for claudication. Although
frequent (~50%) minor adverse effects, including headache, diarrhea, and palpitations, may occur in clinical practice, cilostazol has
not been associated with major adverse events or increased mortality. Small, nonblind studies suggest that cilostazol may prove
useful in preventing thrombosis and restenosis following percutaneous coronary interventions, although these remain unlabeled
uses.
CONCLUSIONS: The unique combination of antiplatelet, vasodilatory, and antiproliferative effects of cilostazol appear to make it an
attractive agent for use in patients with PAD. Clinical trials demonstrating a significant improvement in walking distances with
cilostazol therapy suggest that it will be an important tool in improving symptoms and quality of life in patients with intermittent
claudication.
KEY WORDS: cilostazol, intermittent claudication, peripheral arterial disease, antiplatelet, vasodilator, restenosis.
Ann Pharmacother 2001;35:48-56.
ACPE UNIVERSAL PROGRAM NUMBER: 407-000-01-001-H01

ntermittent claudication is defined as reproducible dis-
Ilieved
comfort of a muscle group induced by exercise and re-
by rest. Symptoms develop because of reduced blood
supply, which fails to meet the metabolic demands of the
muscle group. Peripheral arterial obstructive disease
Author information provided at the end of the text.
Cilostazol (Pletal, Otsuka America Pharmaceutical).
(PAD) is by far the most common cause of intermittent
claudication. However, up to 40% of people with PAD are
asymptomatic, and many patients with claudication do not
seek medical attention.1 The clinical importance of PAD,
which often goes unrecognized and may affect up to 5% of
elderly patients in the US, is highlighted by an associated
sixfold increased risk of death from cardiac and cere-
brovascular causes. Improved detection of PAD through
more widespread use of the ankle–brachial index (ABI;

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Doppler-determined ankle/arm blood pressure ratio of
<0.9 is diagnostic of PAD) and more aggressive secondary
preventive measures are expected to improve cardiovascu-
lar outcomes in this population.
Intermittent claudication is associated with a reduced
quality of life, and there are limited treatment options for
this often debilitating symptom.1,2 Cilostazol, an agent em-
ployed in the treatment of PAD in Japan for over a decade,
was recently approved by the Food and Drug Administra-
tion (FDA) for the management of intermittent claudica-
tion.3-7 Although its precise mechanism of action is not ful-
ly understood, cilostazol is a type-III phosphodiesterase in-
hibitor with antiplatelet, vasodilatory, and antiproliferative
actions.8-10 Preliminary clinical data11,12 indicate that cilo-
stazol may be useful as an antithrombotic and antiprolifer-
ative agent following percutaneous coronary interventions,
although these remain unlabeled uses. In this article, we re-
view the current understanding of the pharmacology and
clinical utility of cilostazol.
Pharmacology
At least nine distinct genes for phosphodiesterases
(PDEs I–IX) have been identified in mammalian tis-
sues.13,14 Cyclic adenosine monophosphate (cAMP), a sec-
ond messenger generated by adenylate cyclase in response
to a variety of extracellular stimuli, undergoes degradation
by specific phosphodiesterases. PDE-III (cyclic guanosine
monophosphate [GMP]–inhibited cAMP-PDE) is one of a
number of isozymes present in platelets, vascular smooth-
muscle cells, cardiomyocytes, and endothelial cells.8,10,14
cAMP mediates many of the known agonist-induced
platelet inhibitory, vasodilatory and vascular
antiproliferative responses in vivo.14,15
Cilostazol (6-[4-(1-cyclohexyl-1H-tetrazol-
5-yl) butoxy]-3- 4-dihydro-2(1H)-quinolone)
is a potent, reversible PDE-III isozyme–selec-
tive inhibitor. All available evidence points to-
ward increased responsiveness to cAMP-stim-
ulating agents as its mechanism of action.8-10
Cilostazol has minimal inhibitory effects on
other PDEs, demonstrates no significant activ-
ity against calcium-calmodulin–activated PDEs,
and does not modulate the guanylate cyclase/
cyclic GMP–signaling pathway.8-10
ANTIPLATELET EFFECT
Cilostazol inhibits both primary and sec-
ondary phases of platelet aggregation induced
by adenosine diphosphate, collagen, epineph-
rine, arachidonic acid, and thrombin (Figure
1).8,16-19 Platelet cAMP concentrations and
platelet inhibitory responses to agonists that
stimulate adenylate cyclase were greatly in-
creased in the presence of cilostazol.8,10,20 In-
creased platelet cAMP concentrations attenu-
ate activation by many agonists through en-
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hanced protein kinase A– dependent substrate phosphory-
lation and sequestration of calcium.21 Endothelial cells,
probably through the release of prostacyclin, an activator
of adenylate cyclase, enhance the antiplatelet activity of
cilostazol in vitro.18 This suggests that increased sensitivity
to adenylate cyclase stimuli may contribute to the anti-
platelet effect of cilostazol at the blood vessel wall.
In a double-blind, crossover study19 of three antiplatelet
agents, cilostazol was a more potent inhibitor of adenosine
diphosphate, collagen, and arachidonic acid–induced plate-
let aggregation ex vivo than aspirin or ticlopidine.17 Cilo-
stazol suppressed thrombin-induced platelet calcium in-
creases, thromboxane A2 formation, and platelet factor- 4
release, in addition to inhibition of platelet aggregation and
agonist-induced procoagulant activity.19 Cilostazol, but not
aspirin, also inhibits high shear-stress–induced platelet ag-
gregation both in vitro and in vivo.20 Shear-stress during
exercise is believed to be an important mechanism of plate-
let activation at points of arterial bifurcation in patients
with atherosclerosis,22 and thus may be of particular rele-
vance to the reported benefits of cilostazol in patients with
intermittent claudication.
VASODILATORY/HEMODYNAMIC EFFECTS
Inhibition of smooth-muscle cell PDE-III with resultant
arterial vasodilation is thought to play a role in the benefi-
cial effects of cilostazol in intermittent claudication.23 In
whole organ studies,24 cilostazol produced vasodilation of
human coronary and renal arteries. Intravenous infusion in
a canine coronary reperfusion model resulted in a 25% de-
crease in mean blood pressure at plasma concentrations
Figure 1. Intracellular mechanism of the antiplatelet and vasodilatory effects of cilostazol.
Phosphodiesterase III inhibition results in increased cyclic adenosine monophosphate in
response to adenylate cyclase agonists. This leads to attenuation of calcium-mediated
platelet activation and smooth-muscle cell contraction. Solid line = stimulation; broken line
= inhibition; AC = adenylate cyclase; ADP = adenosine diphosphate; AMP = adenosine
monophosphate; ATP = adenosine triphosphate; DAG = diacyl glycerol; insP = inositol phos-
phate; PDE III = phosphodiesterase III; PGE2 = prostaglandin E2; PGI2 = prostacyclin; PKC
= protein kinase C; PLC = phospholipase C; SMC = smooth muscle cell; TxA2 = thrombox-
ane A2.
The Annals of Pharmacotherapy ■ 2001 January, Volume 35 ■ 49
MP Reilly and ER Mohler III
similar to those in human clinical studies.25 Chronic oral
administration (6 mo) of cilostazol in human clinical trials6
resulted in a small increase in heart rate (<10 beats/min).
This observation, in addition to animal studies26 demon-
strating a sustained hemodynamic response after two
weeks of cilostazol therapy, suggests that cilostazol thera-
py may not induce tachyphylaxis to its pharmacologic ef-
fect.
VASCULAR EFFECTS
Cilostazol inhibits vascular smooth-muscle cell PDE-III
and attenuates proliferative response to a variety of growth
factors including platelet-derived growth factor and in-
sulin-like growth factor-I.27,28 Cilostazol-induced increases
in cAMP may inhibit cell growth by inhibition of mitogen-
activated protein kinase activity,28 induction of nitric oxide
synthesis,29 and suppression of platelet-derived growth fac-
tor expression.30 It is noteworthy that increased PDE-III ac-
tivity and reduced cAMP concentrations have been de-
scribed in studies of atherosclerosis31 and that PDE-III in-
hibitors, including cilostazol, have been shown to suppress
neointimal formation in a rat vascular injury model.15,32
LIPOPROTEIN EFFECTS
Cilostazol has beneficial effects on lipid metabolism in
patients with intermittent claudication and diabetes.5,6,33
The mechanism of this activity is unclear, but may be relat-
ed to cAMP-mediated enhancement of peripheral lipopro-
tein lipase activity or attenuation of hepatic triglyceride se-
cretion.34,35 In a randomized, placebo-controlled trial33 of
189 patients with PAD, cilostazol 200 mg/d for 12 weeks
resulted in a 15% reduction in plasma triglycerides and
10% increase in high-density cholesterol without a signifi-
cant change in low-density cholesterol. Effects appeared to
be greatest in patients with the highest baseline triglyceride
concentrations. It is unclear whether cilostazol has benefi-
cial effects on lipid parameters when used in conjunction
with aggressive lipid-lowering agents (including hydroxy-
methyl gluataryl coenzyme A reductase inhibitors), which
is advocated in patients with PAD.
Pharmacokinetics
Pharmacokinetic studies36-38 in humans showed that sin-
gle oral doses of cilostazol resulted in peak plasma concen-
trations after three to four hours and an elimination half-
life of 11–13 hours. Steady-state concentrations are achieved
by day 4 following multiple oral dosing of 100 mg twice
daily in adults.38 In the presence of a fatty meal, the rate of
absorption and AUC (bioavailability) were increased com-
pared with the fasting state.39 In vitro studies40 suggest that
95% of cilostazol is plasma protein bound, particularly to
albumin.
Cilostazol undergoes extensive hepatic metabolism in
humans by CYP3A4, to a lesser extent by CYP2C19, and
to a relatively minor extent by CYP1A2.8,40,41 The major
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metabolites found in human plasma are the dehydrocilo-
stazol derivative, OPC-13015, and the monohydroxycilo-
stazol, OPC-13213.39-41 Both are active metabolites and
produce threefold more and threefold less platelet inhibi-
tion, respectively, than cilostazol. Cilostazol and OPC-
13015 are excreted in the liver; urinary excretion of OPC-
13213 and conjugated glucuronide metabolites account for
approximately 30% of the orally administered dose. The
plasma concentration (5–10 µM) produced by standard
doses of cilostazol in humans is similar to the concentra-
tion required to inhibit platelet and vascular smooth-mus-
cle cell PDE-III activity in vitro and ex vivo.10,16,37 The
pharmacologic activity of cilostazol and its metabolites
was similar in subjects with mild hepatic disease and mild
to moderate renal impairment compared with healthy con-
trols.42 Severe renal impairment increases serum cilostazol
concentrations, but pharmacologic activity appeared to be
little changed.
Clinical Studies
INTERMITTENT CLAUDICATION
The primary medical management of patients with PAD
should be aimed at reducing the risk of cardiovascular
complications including myocardial infarction and stroke.1
This includes smoking cessation, antiplatelet therapy, and
aggressive management of lipid concentrations and other
risk factors. However, there are few medical options for
the management of stable but sometimes debilitating inter-
mittent claudication.2 Most clinical trials have used stan-
dardized treadmill testing to assess the effect of interven-
tions on initial claudication distance (ICD), the walking
distance before the onset of claudication pain, or absolute
claudication distance (ACD), the total walking distance be-
fore intolerable claudication pain. Smoking cessation and
supervised exercise programs can result in small but sig-
nificant improvement in walking distances. Pentoxifylline,
a rheologic agent thought to improve skeletal muscle oxy-
gen delivery, also increases walking distances, but the clin-
ical significance of these small improvements has been
questioned. Clinical studies9 conducted in Japanese pa-
tients with PAD suggested that cilostazol increased dermal
blood flow and could improve claudication. A series of
multicenter clinical trials4-7,33 in the US (Table 1) has led to
FDA approval of cilostazol for the relief of intermittent
claudication in patients with PAD.
Money et al.4 assessed the effect of cilostazol 100 mg
twice daily for 16 weeks in a multicenter, randomized, dou-
ble-blind, placebo-controlled trial on treadmill walking
distance, functional status, and ABIs in 239 patients with
intermittent claudication. The ACD improved significantly
in cilostazol-treated patients (47% vs. 12.9%; p < 0.001)
compared with those who received placebo after 16 weeks.
Subjective functional status measures and ABIs were also
significantly better in cilostazol-treated patients. Thus,
findings were consistent across all end points, although im-
provements in ABIs have not generally been associated
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 Cilostazol

with improved walking distance in other claudication tri-
als. Dawson et al.5 demonstrated that cilostazol 100 mg
twice daily for 12 weeks improved ICD and ACD by 35%
(p < 0.01) and 41% (p < 0.005), respectively, compared
with placebo in 81 patients. Patient and physician assess-
ment of improvement corroborated the measured improve-
ments in walking performance observed in cilostazol-treat-
ed patients. In this relatively small study, significant differ-
ences between cilostazol and placebo became apparent
only after 12 weeks of treatment.
A multicenter study conducted by Beebe et al.6 random-
ized 516 patients with moderately severe, stable intermit-
tent claudication in a double-blind study to receive cilosta-
zol 50 mg, 100 mg, or placebo twice daily for 24 weeks.
Improvements in ICD and ACD with cilostazol compared
with placebo were seen as early as four weeks and contin-
ued throughout the study. By week 24, there was a 51%
improvement in maximal walking distance in patients tak-
ing cilostazol 100 mg twice daily compared with a 15%
improvement in the placebo group (p < 0.001). Improved
global and disease-specific quality-of-life assessments were
observed with both doses of cilostazol.
In a placebo-controlled study lasting 24 weeks, Dawson
et al.7 compared the effect of cilostazol 100 mg twice daily
and pentoxifylline 400 mg three times daily in 698 patients
with stable intermittent claudication. Despite a large place-
bo effect (a feature seen in many claudication studies), sig-
nificant improvements in ICD and ACD were seen with
cilostazol, but not pentoxifylline. This is an important find-
ing given the modest impact of pentoxifylline on the relief
of claudication seen in clinical practice.2 The small in-
creases in walking distances with pentoxifylline relative to
placebo in this trial were similar to those reported in previ-
ous studies of this agent.2
Cilostazol produced modest but highly consistent in-
creases in walking distances in all claudication trials pub-
lished to date, which have included over 1500 patients in
the US. In one trial,33 cilostazol produced greater benefit
than pentoxifylline, the only alternative pharmacologic
therapy for intermittent claudication. Furthermore, in three
of these studies,4-6 subjective quality-of-life assessments
by patients and physicians corroborated the measured im-
provements in walking performance. This suggests that
cilostazol will indeed produce clinically meaningful im-
provement in the quality of life of PAD patients with inter-
mittent claudication. Cilostazol had no effect on the cardio-
vascular system in these trials, but they were not designed
to examine this end point. The effect of cilostazol on limb
salvage in patients with critical limb ischemia is unknown,
as only patients with chronic stable PAD were included in
these studies. The major criticisms of the claudication trials
include the relatively small numbers of patients and their
short duration in addition to the withholding of optimal
medical therapies for PAD — antiplatelet agents including
aspirin were disallowed in all studies4-7,33 and lipid-lower-
ing therapy was discontinued in one.33
UNLABELED USES
Coronary Stenting
The use of high-pressure balloon inflation and the com-
bination of aspirin and ticlopidine therapy markedly re-
duced the incidence of thrombotic complications following
coronary stenting.43 However, serious adverse events relat-

Table 1. Randomized, Controlled Trials of Cilostazol in Patients with Intermittent Claudication

No. ICD (meters) ACD (meters)

Dose Pts. D ▲ p ▲ p ABI Functional
Reference Design (mg/d) (n) (wk) Pre Post (%) Valuea Pre Post (%) Valuea Pre Post p Valuea Status

Money RCT placebo 120 16 NR 244.3 281.1 12.9 0.68 0.69 NS SF-36 +
et al. CLZ 200 119 236.9 332.6 47 <0.001 0.64 0.70 0.0125 WIQ +
(1998)4
Dawson RCT placebo 25 12 77.7 84.6 –2.5 NS 244.3 152.1 –9.3 NR Pat/Phy +/+
et al. CLZ 200 52 71.2 112.5 31.7 <0.01 141.9 231.7 30.5 <0.005
(1998)5

Beebe RCT placebo 170 24 72.4 95.5 20 147.8 174.6 15 SF-36 +

et al. CLZ 100 171 66.5 115.1 48 <0.001 131.5 198.8 38 <0.001 NR WIQ +
(1999)6 CLZ 200 175 70.4 137.9 59 <0.001 129.7 258.8 51 <0.001 COM +
Pat/Phy +/+
Dawson RCT placebo 239 24 55.1 33.5
et al. PTX 1200 232 68.4 NS 30.4 NS NR NR
(1998)7 CLZ 200 227 98.3 <0.05 53.9 <0.05
Elam et al. RCT placebo 94 12 NR 244 304 24.3 0.65 0.65 NS NR
(1998)33 CLZ 200 95 262 335 35.5 <0.004 0.66 0.73 <0.001

+ = significant improvement in measure of functional status; ▲ = percent change in geometric means between baseline and follow-up; ABI = ankle–
brachial index; ACD = absolute claudication distance; CLZ = cilostazol; COM = Claudication Outcome Measures; D = duration; ICD = initial claudication
distance; NR = not reported; Pat/Phy = subjective assessment of improvement by patient and physician; PTX = pentoxifylline; RCT = randomized,
controlled trial; SF-36 = Medical Outcomes Scale Short Form-36; WIQ = Walking Impairment Questionnaire.
a
p Value for comparison between active treatment and placebo.

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MP Reilly and ER Mohler III

ing to ticlopidine use44 have prompted an examination of
potentially safer antiplatelet agents such as clopidogrel, an
agent with a similar mode of action but less serious adverse
effects than ticlopidine.45 The recent report46 of an extreme-
ly rare association between clopidogrel and thrombotic
thrombocytopenic purpura supports ongoing efforts to dis-
cover new, safe, and effective antiplatelet regimens for
coronary stenting. Given its broad range of antiplatelet ac-
tivity, cilostazol is a potential alternative in poststenting an-
tiplatelet regimens. In two small, prospective, nonrandom-
ized Japanese studies,47,48 cilostazol 200 mg/d appeared to
be as safe and efficacious as aspirin 243 mg/d following
stent implantation. Park et al.11 compared the effects of
cilostazol 200 mg/d for six months with ticlopidine 500
mg/d for four weeks in a randomized, controlled trial in
490 patients undergoing elective stent implantation. All pa-
tients received aspirin 200 mg/d and treatment was started
two days prior to the procedure. At 30 days follow-up,
rates of stent thrombosis (0.8% vs. 0.4%; p = NS) and my-
ocardial infarction (0.8% vs. 0.4%; p = NS) were similar
with cilostazol and ticlopidine, respectively. No deaths oc-
curred in either group, and there were no serious adverse
events in cilostazol-treated patients. Currently, aspirin/
cilostazol has not been directly compared with aspirin/
clopidogrel, the presently favored antiplatelet regimen fol-
lowing coronary stenting.
nosis with cilostazol following coronary angioplasty at six
months in a study of 68 patients compared with ticlopidine
(n = 8) or aspirin (n = 25). In a randomized study of 35 pa-
tients (43 lesions) undergoing elective Palmaz–Schatz stent
implantation, Yamasaki et al.52 showed reduced late lumen
loss at six months in patients receiving cilostazol 200 mg/d
compared with aspirin 243 mg/d. Tsuchikane et al., in a se-
ries of distinct percutaneous transluminal coronary angiog-
raphy (n = 211; 273 lesions),12 directional coronary
atherectomy (n = 39),50 and stent implantation (n = 29; 41
stents)49 studies at a single center, reported reduced reste-
nosis rates in patients randomized to receive cilostazol 200
mg/d compared with aspirin 250 mg/d. In a four-armed
study of cilostazol 200 mg/d, probucol 500 mg/d, the com-
bination of both drugs, and placebo in 126 patients (165 le-
sions) undergoing elective stenting, Sekiya et al.51 found
significantly lower rates of restenosis at six months in the
combination therapy and cilostazol-treated patients com-
pared with those who received probucol alone or placebo.
The effect of cilostazol on restenosis has not yet been test-
ed in a large, randomized, double-blind trial, and its effica-
cy in the setting of concomitant glycoprotein IIβ/IIIα an-
tagonism, which may also reduce restenosis,54 is presently
unknown.
Safety and Adverse Events

RESTENOSIS
Given its antiproliferative properties and promising re-
sults in animal models of vascular injury, cilostazol has
been tested for its efficacy in preventing restenosis follow-
ing coronary interventions in a series of small, nonblind
studies (Table 2).12,49-53 Take et al.53 reported reduced reste-
Minor adverse effects occurred more frequently (~50%
vs. 25%) with cilostazol than placebo during clinical trials.4-7
The most common adverse effects reported included head-
ache (25–35% vs. 10–16%), diarrhea (25–30% vs. 5–8%),
dizziness (10–13% vs. 2–6%), and palpitations (11–18%
vs. 0 –3%). In most cases, these symptoms were mild or
transient, responded to symptomatic treatment or dose re-

Table 2. Trials Examining the Effect of Cilostazol on Restenosis Following Percutaneous Coronary Interventions
Dose No. D Restenosis p MLD p TLR p
Reference Design Intervention (mg/d) Pts./Lesions (mo) (%) Valuea (mm ± SD) Valuea (%) Valuea

Tsuchikane et al. ORCT PTCA ASA 250 99/129 3 39.5 1.37 ± 0.58 28.7
(1999)12 CLZ 200 94/123 17.9 <0.001 1.65 ± 0.55 <0.0001 11.4 <0.001
Nakamura et al. ORCT P–S stent ASA 250 /14 6 NAb –31.81% NR
(1998)49 CLZ 200 /15 NAb –21.85% <0.05
Tsuchikane et al. ORCT DCA ASA 250 19/19 6 26 1.81 ± 0.68 16
(1998)50 CLZ 200 20/20 0 0.02 2.33 ± 0.6 0.016 0 NS
Sekiya et al. ORCT Wiktor–Stent (106) control 32/41 6 31.7 1.92 ± 0.73 NR
(1998)51 P–S stent (59) PRB 500 31/42 16.7 NS 2.19 ± 0.83 NS
CLZ 200 31/40 12.5 <0.05 2.38 ± 0.7 <0.05
PRB/CLZ 32/42 9.5 <0.05 2.62 ± 0.66 <0.01
Yamasaki et al. ORCT P–S stent ASA 243 17/21 6 NR 1.99 ± 0.51 NR
(1998)52 CLZ 200 18/22 2.49 ± 0.4 <0.05
Take et al. ORCT PTCA ASA or TCL 33/40 4–6 40 1.5 ± 0.9 NR
(1997)53 CLZ 100 35/42 16.7 <0.05 1.7 ± 0.8 <0.05

ASA = aspirin; CLZ = cilostazol; D = duration; DCA = directional coronary atherectomy; MLD = minimal lumen diameter; NR = not reported; ORCT =
open-label, randomized, controlled trial; PRB = probucol; PRB/CLZ = combination of probucol and cilostazol; P–S stent = Palmaz–Shatz stent; PTCA
= percutaneous coronary balloon angioplasty; TCL = ticlopidine; TLR = target lesion revascularization.
a
p Value for comparison between active treatment and placebo.
b
Neointimal area (%) at intravascular ultrasound.

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duction (50 mg twice daily), and rarely required discontin-
uation of the drug (<5%). In contrast to ticlopidine, an
agent with somewhat similar antiplatelet effects as cilosta-
zol, there have been no reports of significant liver function
test abnormality, neutropenia, or thrombocytopenia with
cilostazol. Cilostazol has not been associated with any sig-
nificant bleeding complications.
The use of oral milrinone or vesnarinone, distinct PDE-
III inhibitors, in clinical trials of patients with severe con-
gestive heart failure55,56 has been associated with increased
cardiac mortality (primarily due to arrhythmias). The effect
of cilostazol on mortality in patients with a history of con-
gestive heart failure is unknown due to the exclusion of
this patient population from claudication clinical trials.
There was no evidence of increased mortality in eight pla-
cebo-controlled clinical trials3 involving >2200 patients re-
ceiving cilostazol for periods of up to six months. Howev-
er, the calculated relative risk of death of 1.2 has a wide
95% confidence interval (0.5 to 3.1), and there are no data
on the long-term risk or the risk in patients with more se-
vere underlying heart disease. This may be particularly im-
portant in patients with intermittent claudication given the
prevalence of concomitant coronary artery disease1 and the
likelihood of prolonged cilostazol treatment. In one study,6
cilostazol was associated with significant increases in heart
rate (5.1 beats/min with 50 mg and 7.4 beats/min with 100
mg) and reductions in PR, QRS, and QT intervals on elec-
trocardiographs compared with placebo, consistent with
inhibition of cardiac PDE-III in vivo. It is worth noting that
the FDA has required the manufacturer to perform Phase
IV studies examining the long-term safety of and drug in-
teractions with cilostazol.
Cilostazol is contraindicated in patients with heart fail-
ure. Patients with arrhythmias or a recent history of myo-
cardial infarction, myocardial revascularization, or unsta-
ble angina were excluded from the intermittent claudica-
tion clinical trials. Therefore, caution should be exercised
when using cilostazol in subjects with established coronary
artery disease, as the long-term effects of this agent in this
population, in which asymptomatic left-ventricular dys-
function is prevalent, is unknown. Cilostazol has not been
studied in patients with moderate to severe hepatic impair-
ment or in patients on dialysis and therefore should be
avoided in these situations. The use of this agent in pedi-
atric populations has not been studied. Geriatric popula-
tions have been included in cilostazol studies,4-7,38 and nei-
ther the pharmacokinetic characteristics nor clinical effects
were affected by age.
Drug Interactions
Significant interactions have been reported9,40,57,58 between
cilostazol and drugs that inhibit CYP3A4 and CYP2C19,
the predominant metabolic pathways for cilostazol. Coad-
ministration of cilostazol with diltiazem or erythromycin,
moderate inhibitors of CYP3A4, led to increased plasma
concentrations of cilostazol (by 53% and 47%, respective-
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Cilostazol
ly) and its active metabolites in humans.40,57 The combination
of cilostazol and more potent CYP3A4 inhibitors, such as
ketoconazole, itraconazole, fluconazole, and grapefruit
juice, has not been studied in humans. Distinct CYP3A4
inhibitors that could potentially interact with cilostazol in-
clude cimetidine, ranitidine, clarithromycin, danazole, flu-
oxetine, metronidazole, quinidine, indinavir, and related
antiretroviral agents.59 Omeprazole, a CYP2C19 inhibitor,
produced a modest increase (18%) in plasma cilostazol
concentrations.58 Other drugs that inhibit CYP2C19 and
therefore could interact with cilostazol include amio-
darone, clopidogrel, ketoprofen, fluvastatin, and sulfon-
amides.59 Thus, a reduced dose of 50 mg twice daily is rec-
ommended when using cilostazol with agents known to in-
hibit these cytochrome isoforms; grapefruit juice should be
avoided during cilostazol therapy. Cilostazol does not ap-
pear to inhibit CYP3A4 in humans, as there was no in-
crease in plasma concentrations of lovastatin or its metabo-
lites following cilostazol coadministration. It is not known
whether cilostazol affects P-glycoprotein transport in the
gastrointestinal tract or kidney. No significant change in
platelet aggregation or bleeding time was observed follow-
ing concomitant administration of cilostazol and aspirin.
Furthermore, there was no apparent increase in hemor-
rhagic events in patients (n = 201) taking cilostazol who
required aspirin therapy in randomized, controlled trials.4-7
A single dose of warfarin showed no interaction with
cilostazol with respect to the effect on platelet aggregation,
bleeding time, or prothrombin time.40
Pharmacoeconomics
To date, cilostazol and pentoxifylline are the only two
drugs approved for the relief of intermittent claudication in
the US.2,3 Although improvement in walking distances with
pentoxifylline has been demonstrated,2,7 the clinical rele-
vance of the small increases in walking distances that it
produces remains unclear and the benefit appears to be less
than with cilostazol. When cilostazol is used for intermit-
tent claudication, recommended doses (100 mg twice dai-
ly) cost approximately $95/month compared with $60/
month for pentoxifylline 400 mg three times daily.60 No
studies examining the cost-effectiveness of cilostazol in
clinical practice have been reported.
Dosing, Administration, and Patient Counseling
Cilostazol is available in 50- or 100-mg tablets. The
recommended dosage of cilostazol for intermittent claudi-
cation is 100 mg twice daily taken at least half an hour be-
fore or two hours after meals. No dose titration is neces-
sary and no limit to the duration of treatment has been rec-
ommended, although clinical trials lasted a maximum of
six months. Patients should be advised to avoid drinking
grapefruit juice while taking cilostazol. A reduced cilosta-
zol dose of 50 mg twice daily should be considered during
coadministration of CYP3A4 and CYP2C19 inhibitors. A
reduced dose can also be used if minor adverse effects per-
The Annals of Pharmacotherapy ■ 2001 January, Volume 35 ■ 53
MP Reilly and ER Mohler III
sist despite the institution of preventive measures such as
the use of simple analgesics for headache. Patients with in-
termittent claudication may respond as early as two to four
weeks after initiation, but treatment for up to 12 weeks
may be needed before a beneficial effect is experienced.
Patients should be instructed about the possibility of minor
adverse reactions including headache, diarrhea, dizziness,
and palpitations.
Formulary Recommendations
Cilostazol represents a useful addition to the formulary.
Based on limited data, cilostazol offers an advantage over
pentoxifylline, the only alternative drug for the treatment
of intermittent claudication. However, the everyday clini-
cal importance of the moderate improvement in walking
distances and quality-of-life scores in the clinical trials will
only be determined with more extensive clinical experi-
ence. The fact that cilostazol is well tolerated and has not
been associated with any serious complications should fa-
cilitate more widespread use.
Summary
PAD may affect up to 5% of Americans over age 55, of-
ten goes unrecognized, and carries a sixfold increased risk
of death from cardiovascular events, predominantly my-
ocardial infarction and stroke.1 Cilostazol, a specific in-
hibitor of cAMP–PDE-III activity in platelets and vascular
smooth-muscle cells, is a potent antiplatelet agent and va-
sodilator, and reduces vascular proliferation in vivo. Re-
cent multicenter, randomized, placebo-controlled trials
have shown its benefit in improving intermittent claudica-
tion in patients with stable PAD compared with placebo
and pentoxifylline. There is no evidence that cilostazol re-
duces cardiovascular events in patients with PAD, al-
though clinical trials were not designed to address this hy-
pothesis. More importantly, cilostazol has not been shown
to increase cardiovascular mortality, which is a concern
with distinct phosphodiesterase inhibitors. Despite the lack
of serious adverse events from cilostazol to date, its long-
term safety, particularly in patients with more severe un-
derlying heart disease, remains unknown. Frequent minor
adverse effects, particularly headache, palpitations, and di-
arrhea, may occur in clinical practice. In conclusion, the
unique combination of antiplatelet, vasodilatory, antiprolif-
erative, and lipid-modifying effects of cilostazol make it an
attractive agent for use in PAD patients with intermittent
claudication.
Muredach P Reilly MB, Cardiovascular Division, Department of
Medicine, School of Medicine, University of Pennsylvania, Philadel-
phia, PA
Emile R Mohler III MD, Director of Vascular Medicine, Cardiovas-
cular Division, Department of Medicine, School of Medicine, Uni-
versity of Pennsylvania
Reprints: Emile R Mohler III MD, Department of Medicine, School
of Medicine, University of Pennsylvania, 432 PHI Bldg., 51 North
39th St., Philadelphia, PA 19104-2699, FAX 215/662-9866, E-mail
emmd@mail.med.upenn.edu
54 ■ The Annals of Pharmacotherapy ■ 2001 January, Volume 35
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EXTRACTO
OBJETIVO: Repasar la farmacología y la utilidad clínica de cilostazol, un
agente antiplaquetario y vasodilatador aprobado recientemente para el
manejo de claudicación intermitente.
FUENTES DE INFORMACIÓN: Búsqueda de la literatura primaria de
cilostazol en MEDLINE de enero de 1980 a febrero de 2000. Extractos
seleccionados de presentaciones y literatura del fabricante se usaron
también como fuente. Los términos de catalogar utilizados incluyen
cilostazol, claudicación intermitente, inhibidor de plaquetas, y restenosis.
SELECCIÓN DE ESTUDIOS: Se revisaron estudios clínicos,
farmacocinéticos, y comparativos aleatorios llevados a cabo en Estados
Unidos y Asia. También se examinaron estudios selectos in vitro, ex
vivo, y en animales cuando no habían disponibles datos humanos.
SÍNTESIS: Claudicación intermitente, definido como una molestia
repetitiva de un grupo de músculos inducida por ejercicio y aliviada con
descanso, es la manifestación clínica más común de enfermedad de
arterias periféricas (PAD, por sus siglas en inglés). Cilostazol, un
inhibidor específico de la fosfodiesterasa de monofosfato de adenosina
cíclica (PDE-III, por sus siglas en inglés) en plaquetas y en las células
del músculo liso vascular, es un agente antiplaquetario y vasodilatador
potente, reduce la proliferación vascular y tiene efectos reductores en
■ 2001 January, Volume 35 ■ 55
MP Reilly and ER Mohler III
lípidos in vivo. Estudios aleatorios, controlado por placebo,
contribuyeron a la aprobación de cilostazol por la Administración de
Alimentos y Fármacos para el alivio de claudicación intermitente en
pacientes con PAD estable. Cilostazol permite que se duplique las
distancias caminadas y mejora la calidad de vida en comparación con
placebo. Uno de los estudios encontró que cilostazol es más efectivo que
pentoxifilina, la única alternativa en terapia farmacológica para
claudicación. A pesar de que en la práctica clínica pueden ocurrir efectos
adversos menores, incluyendo dolor de cabeza, diarrea y palpitaciones,
con frecuencia (casi un 50%), cilostazol no ha sido asociado a eventos
adversos mayores o a un aumento en mortalidad. Estudios pequeños, no
ciegos, sugieren que cilostazol puede ser de utilidad en prevenir
trombosis y estenosis recurrente después de intervenciones coronarias
percutáneas, aunque éstas no están incluidas en la etiqueta.
CONCLUSIONES: La combinación única de efectos antiplaquetarios,
vasodilatadores y antiproliferativos de cilostazol lo hacen un agente
atractivo para usar en pacientes con PAD. Los estudios clínicos que
demuestran una mejoría significativa en distancia caminada con
cilostazol sugieren que éste se convertirá en una herramienta importante
para mejorar los síntomas y la calidad de vida de los pacientes con
claudicación intermitente.
Sonia I Lugo
RÉSUMÉ
OBJECTIF: Réviser la pharmacologie et l’utilité clinique du cilostazol, un
agent antiplaquettaire et un vasodilatateur récemment approuvé dans le
traitement de la claudication intermittente.
REVUE DE LITTÉRATURE: Une recherche exhaustive dans la banque de
données MEDLINE (janvier 1980 à février 2000) a permis d’identifier
la littérature primaire pertinente concernant le cilostazol. De
l’information additionnelle a été extraite des résumés présentés lors de
conférences scientifiques et de la documentation du manufacturier. Les
mot-clés utilisés étaient: cilostazol, claudication intermittente, inhibiteurs
plaquettaires, et resténose.
SÉLECTION DES ÉTUDES: Les études humaines cliniques et
pharmacocinétiques, de même que les études comparatives et
56 ■ The Annals of Pharmacotherapy ■ 2001 January, Volume 35
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randomisées réalisées aux États-Unis et en Asie ont été évaluées.
Lorsque certaines données chez l’humain n’étaient pas disponibles, des
études animales, in vivo et ex vivo choisies ont aussi été examinées.
RÉSUMÉ: La claudication intermittente se définit comme un inconfort
reproductible au niveau d’un groupe de muscles, induit par l’exercice et
soulagé par le repos. Elle constitue la manifestation la plus fréquente de
la maladie vasculaire périphérique (MVP). Le cilostazol, un inhibiteur
spécifique de l’adénosine monophosphate cyclique phosphodiestérase
(PDE-III) contenue dans les plaquettes et dans le muscle lisse vasculaire,
est un agent antiplaquettaire puissant et un vasodilatateur. De plus, il
réduit la prolifération vasculaire et possède un effet hypolipémiant in
vivo. De récentes études multicentriques, randomisées, et contrôlées par
placebo ont conduit à son approbation par l’Administration des Drogues
et Alimentaires, pour le traitement de la claudication intermittente chez
les patients atteints de MVP stable. Comparativement au placebo, ces
études ont démontré que le cilostazol permet de doubler la distance
parcourue à la marche et d’améliorer la qualité de vie des sujets. Une
étude a démontré que le cilostazol était plus efficace que la
pentoxifylline, la seule alternative actuellement disponible pour le
traitement pharmacologique de la claudication intermittente. Malgré
l’apparition clinique de fréquents effets secondaires mineurs
(approximativement 50%), incluant les céphalées, la diarrhée, et les
palpitations, le cilostazol n’a pas été associé à aucun effet indésirable
majeur, ni à un accroissement de la mortalité. De petites études ouvertes
suggèrent que le cilostazol pourrait être utile dans la prévention de la
thrombose et de la resténose à la suite d’interventions coronariennes
percutanées (ICP), une indication qui demeure non approuvée.
CONCLUSIONS: La combinaison unique des effets antiplaquettaire,
vasodilatateur, et antiprolifératif du cilostazol en fait un agent attrayant
pour le traitement des patients atteints de MVP. Comme les études
cliniques ont démontré qu’il procure une amélioration significative de la
distance parcourue à la marche, le cilostazol deviendra un outil
important pour améliorer les symptômes et la qualité de vie des patients
atteints de claudication intermittente.
Pierre Martineau
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