Journal Reading

Effects of Cilostazol on Arterial

Wound
Healing: A Retrospective Analysis
Taufan H Dewangga,dr
131621130506

Introduction
1980s

in Japan a drug for the treatment of critical limb

ischemia
A phosphodiesterase-3 inhibitor to increased intracellular
levels of cAMP, by promoting activation of protein kinase
vascular smooth muscle relaxation and vasodilation of the
peripheral arterial circulation.
Induce dilation of the pedal arteries and increase limb blood
flow in humans with peripheral arterial disease (PAD)
Increases in ankle pressures and more rapid recovery of
ankle pressures after exercise

Introduction
Thermographic

studies show that cilostazol therapy

increases lower extremity skin temperature in subjects
with PAD
Other effects include :
inhibition of platelet aggregation,
reduction of risk for thrombotic stroke, and
inhibition of myointimal hyperplasia after coronary
artery stenting

Introduction
Cilostazol was approved by the United States Food and

Drug Administration (FDA) in 1999 for treating

intermittent claudication secondary to PAD,
And in managing critical limb ischemia including ulcers
and wounds induced by arterial insufficiency

Introduction
Over

the last decade, cilostazol treated >500 subjects

with PAD, of which 20% had tissue loss or ulcers.
Dramatic improvements and healing in wounds of both
the upper and lower extremities
To figure out efficacy of cilostazol in promoting arterial
wound healing, we have retrospectively analyzed the
clinical records of patients with wounds who received
cilostazol

 (A) A 60 y.o Caucasian male in August

2001 with a 4-month history of a

nonhealing ulcer on the medial
aspect of the right ankle.
(B) Three years earlier, he undergone
suprageniculate
femoropopliteal
bypass with a polytetrafluorethylene
conduit that was thrombosed. The
ABI was 0.61.

 Physical

examination

venous

insufficiency
Started on compression therapy with
multiple-layer dry bandages and topical
silvadene.
The wound showed no change in size
after 2 months, and he was scheduled
for repeat lower extremity bypass.
He was started on cilostazol. Marked
wound healing was evident at follow-up
a week later,
Surgery was subsequently deferred as
complete wound healing was achieved
within
4
weeks
with
continued
compression

MATERIALS AND METHODS

A

list of all patients for whom cilostazol was dispensed

between August 2000 and September 2010 was provided
by the pharmacy service, and their charts were reviewed
In each case, we confirmed that the medication had been
dispensed and that with prolonged therapy refills had been
provided based on pharmacy records.
Subjects were started on 50-mg cilostazol twice daily for 2
to 4 weeks
Increased to 100 mg twice daily unless significant adverse
effects were observed (e.g., diarrhea and tachycardia).

MATERIALS AND METHODS

Inclusion:

Only patients with full-thickness wounds or ulcers

Subjects with failed revascularization before cilostazol initiation
Nonhealing incisions after previous surgery or amputation (wound
dehiscence)
Nonhealing wounds after thrombosis of previously patent arterial
reconstructions

Exclusion:

If refills should have been provided but were not documented, or if

we could not confirm that cilostazol had been taken by a patient
Subjects who had undergone successful revascularization within 6
months of starting cilostazol or immediately after starting cilostazol

MATERIALS AND METHODS

Heal :

Operative surgical debridement without amputation was not a

marker of therapeutic failure
Wounds completely healed without arterial reconstruction, primary
closure, or amputation,
In patients with bilateral limb involvement, both limbs had to
experience complete healing

Not Heal

Patients who were lost to follow-up or died without evidence for

healing,
Who underwent revascularization, primary closure, or skin grafting,
Who underwent amputation of the wounded portion of a limb

MATERIALS AND METHODS

561 subjects had prescriptions for cilostazole
8 never took medication
435 didnt have significant extremity wounds
29
had extremity wound develop after
commencing cilostazole not included
89
7

82

started cilostazol therapy

CR not sufficiently
CR sufficient

MATERIALS AND METHODS

110 limbs

cilostazole therapy

6 upper ext
104 lower ext

9 not adequate
101 efficacy

to determine a response

MATERIALS AND METHODS

Demographic parameter analized

- Age
- Weight
- Height
- Body mass index
- Diabetes
- Tobacco use
- Renal failure requiring hemodialysis - Congestive
heart failure
- Albumin
- Creatinin
- Duration of theraphy

MATERIALS AND METHODS

Limb and wound characters analyzed :

ankle-brachial index (ABI),

largest wound size per extremity,
number of wounds per extremity,
Chronicity of the wound before starting cilostazol,
Presence of gangrene, and
presence of exposed bone, tendon, or joint

In

the analysis by patient, if both limbs were

wounded, the lower ABI was used.

RESULTS
101

limbs

41 (40,6%) healed
60 did not heal

2 wounded (33%) healed

4 did not heal

39 (41.1%) healed
56 (58.9%) did not heal

30 (36.6%) complete healing

52 non healed

upper ext (6)

Lower ext (95)

82 patients amenable to analysis :

DISCUSSION
101 limbs with ischemic tissue loss or ulceration

41 limbs (40.6%) complete healing

30 (36.6%) from82 patients complete healing
of all extremity wounds
Healing was less likely in subjects with gangrene,
diabetes and active smokers at the time therapy
was initiated
Subjects who were treated with cilostazol tended
to have long courses of therapy before complete
healing (mean: 9.7 months).

DISCUSSION
Weakness :

Review of small number of patients and limbs and

is underpowered to detect significant differences

between the healed and nonhealed limbs
Ideally should have a control group of patients,
who are managed without cilostazol, with
comparable ischemia
we did not directly confirm compliance with the
prescribed cilostazol regimen by counting tablets
or using diaries

DISCUSSION
Nonetheless despite these
methodological problems, in several
cases, we saw dramatic healing soon
after starting cilostazol

DISCUSSION
The

Healing of Ischemic Foot Ulcers with

Cilostazol
Trial
(HEAL-IT)
:
multicenter,
prospective, placebo-controlled, double-blind,
randomized trial to evaluate cilostazols effect on
marginally ischemic ulcers
Designed to select subjects with borderline
arterial perfusion
The goal to assess the efficacy of cilostazol in
promoting healing in wounds where perfusion
was likely to be borderline

DISCUSSION

Transcutaneous

PO2 measurements at
the foot or toe pressures had to be
between 20 and 40 mm Hg
Pressures >40 mmHg, healing rates are
>90%
Pressures <20mmHg, healing rates are
<20%.

DISCUSSION

Enroll 300 subjects but was terminated

early because of poor enrollment.

The final number of subjects with
complete data was 54
The main outcome, complete healing at
6 months, was virtually identical in the
2 treatment groups, being almost 70%

DISCUSSION

At 3 months, the difference in complete

healing between the cilostazol and

placebo groups was significant (52%
vs. 18%, P 0.01)
At 6 months, the ulcer healing was
greater in the cilostazol group and the
time to complete healing was shorter
with cilostazol

 The

DISCUSSION

authors concluded that cilostazol may

have a role in healing ischemic ulcers.
The HEAL-IT study was halted because of
low enrollment and that only 95 subjects
were randomized rather than the 300
anticipated.
As a consequence, the study was
underpowered, and its results should be
regarded as inconclusive

DISCUSSION

retrospective analysis from the

University of North Carolina of the
natural history of arterial wound healing
without arterial reconstruction reported
limb salvage rates of 25% at 6 months
and 52% at 1 year
Successful limb salvage was highly
correlated with ABI and initial wound size

 Extensive

DISCUSSION

tissue loss (i.e., Wagner grade

4) or necrotizing infection, led to
exclusion from analysis
Toe amputations and other footsparing
procedures were performed in 28% of
subjects who were deemed successfully
salvaged, led to the judgment that wound
healing had not occurred with cilostazol

DISCUSSION
It cannot be discerned from this article whether

any of the patients were treated with cilostazol,

but according to the lead author they were not.
As a consequence, the high level of limb
salvage without arterial surgery reported in the
University of North Carolina article cannot
easily be compared with our results, and should
not, in our opinion, be used to argue that
cilostazol is without benefit for ischemic wound
healing

DISCUSSION
Of

note, if the 9 limbs that were observed to heal after

primary closure, skin grafting, or footsparing amputation
in our series are combined with the 41 limbs that healed
without any surgical interventions
We observed an overall rate of 49.5% limb salvage with
cilostazol therapy (rising to 50.5% when just lower
extremity wounds are considered).
Our subjects had more severe wounds than the group
analyzed in the University of North Carolina article, our
data indicate that cilostazol may improve arterial wound
outcomes when revascularization is not an option.

Conclusions

Although our results are limited by their

retrospective
nature
and
small
numbers, they indicate that for patients
with ischemic tissue loss who are not
good
candidates
for
arterial
reconstruction, adjunctive therapy with
cilostazol may be beneficial.

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