Cilostazol for intermittent claudication.
Author(s): Bedenis R(1), Stewart M, Cleanthis M, Robless P, Mikhailidis DP, Stansby G.
Affiliation(s): Author information:
(1)Centre for Population Health Sciences, University of Edinburgh, Edinburgh, UK,
EH8 9AG.
Publication date & source: 2014, Cochrane Database Syst Rev. , 10:CD003748
BACKGROUND: Peripheral arterial disease (PAD) affects between 4% and 12% of
people aged 55 to 70 years, and 20% of people over 70 years. A common complaint
is intermittent claudication, characterised by pain in the legs or buttocks that
occurs with exercise and which subsides with rest. Compared with age-matched
controls, people with intermittent claudication have a three- to six-fold
increase in cardiovascular mortality. Symptoms of intermittent claudication,
walking distance, and quality of life can be improved by risk factor
modification, smoking cessation, and a structured exercise programme.
Antiplatelet treatment is beneficial in patients with intermittent claudication
for the reduction of vascular events but has not previously been shown to
influence claudication distance. This is an update of a review first published in
2007.
OBJECTIVES: To determine the effect of cilostazol (an antiplatelet treatment) on
improving initial and absolute claudication distances, and in reducing mortality
and vascular events in patients with stable intermittent claudication.
SEARCH METHODS: For this update, the Cochrane Peripheral Vascular Diseases Group
Trials Search Co-ordinator searched the Specialised Register (last searched
October 2013) and CENTRAL (2013, Issue 9).
SELECTION CRITERIA: Double-blind, randomised controlled trials (RCTs) of
cilostazol versus placebo, or versus other antiplatelet agents in patients with
stable intermittent claudication.
DATA COLLECTION AND ANALYSIS: Two authors independently assessed trials for
selection and independently extracted data. Disagreements were resolved by
discussion. We performed the meta-analysis as a fixed-effect model with weighted
mean differences (WMDs) and 95% confidence intervals (CIs) for continuous data,
and odds ratios (ORs) with 95% CIs for dichotomous data.
MAIN RESULTS: We included fifteen double-blind, RCTs comparing cilostazol with
placebo, or medications currently known to increase walking distance e.g.
pentoxifylline. There were a total of 3718 randomised participants with treatment
durations ranging from six to 26 weeks. All participants had intermittent
claudication secondary to PAD. Comparisons included cilostazol twice daily, with
dosages of 50 mg, 100 mg and 150 mg compared with placebo, and cilostazol 100 mg,
twice daily, compared with pentoxifylline 400 mg, three times daily. The
methodological quality of the trials was generally low, with the majority being
at an unclear risk for selection bias, performance bias, detection bias and other
bias. Attrition bias was generally low, but reporting bias was high or unclear in
the majority of the studies. For eight studies data were compatible for
comparison by meta-analysis, but data for seven studies were too heterogenous to
be pooled. For the studies included in the meta-analysis, for initial
claudication distance (ICD - the distance walked on a treadmill before the onset
of calf pain) there was an improvement in the cilostazol group for the 100 mg and
50 mg twice daily, compared with placebo (WMD 31.41 metres, 95% CI 22.38 to 40.45
metres; P < 0.00001) and WMD 19.89 metres, 95% CI 9.44 to 30.34 metres; P =
0.0002), respectively. ICD was improved in the cilostazol group for the
comparison of cilostazol 150 mg versus placebo and cilostazol 100 mg versus
pentoxifylline, but only single studies were used for these analyses. Absolute
claudication distance (ACD - the maximum distance walked on a treadmill) was
significantly increased in participants taking cilostazol 100 mg and 50 mg twice
daily, compared with placebo (WMD 43.12 metres, 95% CI 18.28 to 67.96 metres; P =
0.0007) and WMD 32.00 metres, 95% CI 14.17 to 49.83 metres; P = 0.0004),
respectively. As with ICD, ACD was increased in participants taking cilostazol
150 mg versus placebo, but with only one study an association cannot be clearly
determined. Two studies comparing cilostazol to pentoxifylline had opposing
findings, resulting in an imprecise CI (WMD 13.42 metres (95% CI -43.51 to 70.35
metres; P = 0.64). Ankle brachial index (ABI) was lowered in the cilostazol 100
mg group compared with placebo (WMD 0.06, 95% CI 0.04 to 0.08; P < 0.00001). The
single study evaluating ABI for the comparison of cilostazol versus
pentoxifylline found no change in ABI.There was no association between treatment
type and all-cause mortality for any of the treatment comparisons, but there were
very few events, and therefore larger, adequately powered studies will be needed
to assess if there is a relationship. Only one study evaluated individual
cardiovascular events, and from this study there is no clear evidence of a
difference between any of the treatment groups and risk of myocardial infarction
or stroke. We evaluated adverse side effects, and in general cilostazol was
associated with a higher odds of headache, diarrhoea, abnormal stool, dizziness
and palpitations. We only reported quality of life measures descriptively as
there was insufficient statistical detail within the studies to combine the
results, although there was a possible indication in improvement of quality of
life in the cilostazol treatment groups.
AUTHORS' CONCLUSIONS: Cilostazol has been shown to be of benefit in improving
walking distance in people with intermittent claudication secondary to PAD.
Although there is an increase in adverse side effects, they are generally mild
and treatable. There is currently insufficient data on whether taking cilostazol
results in a reduction of all-cause mortality and cardiovascular events or an
improvement in quality of life. Future research into the effect of cilostazol on
intermittent claudication should carefully consider comparability, sample size
and homogeneity when designing a study.
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