Background
Blockages in the arteries to the legs - peripheral arterial disease - affect 20% of people aged over 70 years and 4% to 12% of people aged 55 to 70 years. Approximately 40% of those with peripheral arterial disease complain of pain in the legs or buttocks that occurs with exercise and subsides with rest. This is known as intermittent claudication and these symptoms are an indicator for the development of blocked arteries elsewhere in the body. People with intermittent claudication have a three- to six-fold increased chance of dying as a result of cardiovascular events compared to people of the same age without intermittent claudication.
People with intermittent claudication are treated with best medical management which includes modifying risk factors, such as stopping smoking, and doing structured exercise. Further cardiovascular risk modification includes treatment for high blood pressure, diabetes and cholesterol reduction. In practice, compliance with best medical treatment is poor and most people continue to have symptoms of intermittent claudication. Some drug therapies, such as cilostazol, are used to help improve symptoms of intermittent claudication and so we examined the evidence to see if cilostazol improved walking distance, quality of life and other important outcomes compared to placebo (dummy pill) or other drugs used for intermittent claudication.
Study characteristics and key results
We included 16 double-blind, randomised controlled trials, with 3972 adults (search up to 9 November 2020). Participants taking cilostazol for three to six months could walk approximately 26 metres further before calf pain and 40 metres further in total compared to participants taking placebo. However, participants taking cilostazol had nearly three times the odds of experiencing headache related to study medication. There is currently not enough information about the effectiveness of cilostazol for serious events such as amputation, revascularisation and cardiovascular events. Despite its importance, only four studies reported quality of life, using different tools and ways of reporting. Very limited data indicated no difference between cilostazol and pentoxifylline for improving walking distance, and there was not enough information comparing cilostazol with pentoxifylline, for any other outcomes.
Certainty of the evidence
We judged the evidence to be 'very low' to 'low-certainty' for all outcomes except headaches, which were 'moderate-certainty'. All studies were downgraded because we strongly suspected publication bias from drug company involvement.
Conclusion
Cilostazol can increase the distance walked both in total and before the onset of pain, compared to placebo. Cilostazol was associated with increased headaches and there was a lack of evidence for other important outcomes such as amputation, revascularisation and cardiovascular events.
Cilostazol has been shown to improve walking distance in people with intermittent claudication. However, participants taking cilostazol had higher odds of experiencing headache. There is insufficient evidence about the effectiveness of cilostazol for serious events such as amputation, revascularisation, and cardiovascular events. Despite the importance of QoL to patients, meta-analysis could not be undertaken because of differences in measures used and reporting. Very limited data indicated no difference between cilostazol and pentoxifylline for improving walking distance and data were too limited for any conclusions on other outcomes.
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 (exercise-induced lower limb pain relieved by rest). These patients have a three- to six-fold increase in cardiovascular mortality. Cilostazol is a drug licensed for the use of improving claudication distance and, if shown to reduce cardiovascular risk, could offer additional clinical benefits. This is an update of the review first published in 2007.
To determine the effect of cilostazol on initial and absolute claudication distances, mortality and vascular events in patients with stable intermittent claudication.
The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase, CINAHL, and AMED databases, and the World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials registries, on 9 November 2020.
We considered double-blind, randomised controlled trials (RCTs) of cilostazol versus placebo, or versus other drugs used to improve claudication distance in patients with stable intermittent claudication.
Two authors independently assessed trials for selection and independently extracted data. Disagreements were resolved by discussion. We assessed the risk of bias with the Cochrane risk of bias tool. Certainty of the evidence was evaluated using GRADE. For dichotomous outcomes, we used odds ratios (ORs) with corresponding 95% confidence intervals (CIs) and for continuous outcomes we used mean differences (MDs) and 95% CIs. We pooled data using a fixed-effect model, or a random-effects model when heterogeneity was identified. Primary outcomes were initial claudication distance (ICD) and quality of life (QoL). Secondary outcomes were absolute claudication distance (ACD), revascularisation, amputation, adverse events and cardiovascular events.
We included 16 double-blind, RCTs (3972 participants) comparing cilostazol with placebo, of which five studies also compared cilostazol with pentoxifylline. Treatment duration ranged from six to 26 weeks. All participants had intermittent claudication secondary to PAD. Cilostazol dose ranged from 100 mg to 300 mg; pentoxifylline dose ranged from 800 mg to 1200 mg. The certainty of the evidence was downgraded by one level for all studies because publication bias was strongly suspected. Other reasons for downgrading were imprecision, inconsistency and selective reporting.
Cilostazol versus placebo
Participants taking cilostazol had a higher ICD compared with those taking placebo (MD 26.49 metres; 95% CI 18.93 to 34.05; 1722 participants; six studies; low-certainty evidence). We reported QoL measures descriptively due to insufficient statistical detail within the studies to combine the results; there was a possible indication in improvement of QoL in the cilostazol treatment groups (low-certainty evidence). Participants taking cilostazol had a higher ACD compared with those taking placebo (39.57 metres; 95% CI 21.80 to 57.33; 2360 participants; eight studies; very-low certainty evidence). The most commonly reported adverse events were headache, diarrhoea, abnormal stools, dizziness, pain and palpitations. Participants taking cilostazol had an increased odds of experiencing headache compared to participants taking placebo (OR 2.83; 95% CI 2.26 to 3.55; 2584 participants; eight studies; moderate-certainty evidence).Very few studies reported on other outcomes so conclusions on revascularisation, amputation, or cardiovascular events could not be made.
Cilostazol versus pentoxifylline
There was no difference detected between cilostazol and pentoxifylline for improving walking distance, both in terms of ICD (MD 20.0 metres, 95% CI -2.57 to 42.57; 417 participants; one study; low-certainty evidence); and ACD (MD 13.4 metres, 95% CI -43.50 to 70.36; 866 participants; two studies; very low-certainty evidence). One study reported on QoL; the study authors reported no difference in QoL between the treatment groups (very low-certainty evidence). No study reported on revascularisation, amputation or cardiovascular events. Cilostazol participants had an increased odds of experiencing headache compared with participants taking pentoxifylline at 24 weeks (OR 2.20, 95% CI 1.16 to 4.17; 982 participants; two studies; low-certainty evidence).