Cilostazol

Some of the views expressed in the following notes on newly approved products should be regarded as preliminary, as there may have been limited published data at the time of publication, and little experience in Australia of their safety or efficacy. However, the Editorial Executive Committee believes that comments made in good faith at an early stage may still be of value. Before new drugs are prescribed, the Committee believes it is important that more detailed information is obtained from the manufacturer's approved product information, a drug information centre or some other appropriate source.

Pletal (Pharmalink)
50 mg and 100 mg tablets
Approved indication: intermittent claudication
Australian Medicines Handbook section 6.8.1

Cilostazol is a phosphodiesterase III inhibitor. It is indicated for intermittent claudication in patients with peripheral arterial disease who do not have rest pain or evidence of peripheral tissue necrosis. Intermittent claudication is characterised by pain in the legs or buttocks during exercise which subsides with rest. These patients are usually managed by lifestyle modification, including stopping smoking and a supervised exercise program, plus drug therapy to reduce cardiovascular risk.

It is not clear exactly how cilostazol improves the symptoms of intermittent claudication. Its main physiological effects are vasodilation and inhibition of platelet aggregation. Other antiplatelet treatments with similar effects may reduce vascular events in peripheral artery disease, but they have not been shown to improve walking distance in patients with intermittent claudication.

A meta-analysis (seven trials involving 1500 patients) of cilostazol found that 50 mg and 100 mg cilostazol doses (given twice daily for 12-24 weeks) significantly increased absolute walking distance (maximum distance walked on a treadmill) from baseline by 32 m and 50 m more than placebo. A higher dose of cilostazol (150 mg twice daily) also increased walking distance, but the effect was not statistically significant.¹ Exclusion criteria varied between the trials but many excluded patients with ischaemic rest pain, hypertension, obesity and bleeding disorders. Patients taking antiplatelet, anticoagulant or anti-inflammatory drugs were also excluded from some of the trials.¹

Only one of the studies in the meta-analysis compared cilostazol to an active comparator, pentoxifylline (400 mg three times daily). In this study, 698 patients with moderate to severe claudication received treatment for 24 weeks. Absolute walking distance increased by an average of 107 m for patients taking cilostazol, 64 m for pentoxifylline and 65 m for placebo.²

Cilostazol has not been directly compared to lifestyle interventions. However, a meta-analysis of supervised exercise programs found that after three months patients with intermittent claudication could walk 150 m further than those following an unsupervised exercise program. Before treatment, these patients could walk 300 m.³

The most common adverse events in the clinical trials were headache (more than 30% of patients), diarrhoea, palpitations and abnormal stools (more than 15%). Oedema resulted in some patients discontinuing cilostazol treatment.⁴

Phosphodiesterase inhibitors have previously been associated with increased mortality in patients with heart failure.⁵ When cilostazol was approved in the USA, the Food and Drug Administration requested an additional long-term safety trial to assess all-cause mortality. Consequently, a postmarketing study followed 1435 patients with peripheral artery disease on cilostazol for up to 3.5 years. Patients taking aspirin, clopidogrel, pentoxifylline, anticoagulants, or who had had heart failure in the past, were allowed in the trial. It is important to note that patients with clinical evidence of current heart failure were excluded from this trial. From the data obtained, the number of deaths (from any cause or cardiovascular) and serious bleeding events were similar for cilostazol and placebo. There seemed to be no increase in bleeding events in patients taking aspirin, clopidogrel or anticoagulants.⁴ However, long-term adherence in this study was low, with more than 60% of patients discontinuing before the end of the trial. This resulted in the study being underpowered to meet its primary end point - all-cause mortality - and limits the interpretation of the safety data.

After oral administration, cilostazol is readily absorbed and steady-state concentrations are reached after four days. A high fat meal increases the absorption of this drug and the recommendation is to take it at least half an hour before or two hours after breakfast and the evening meal. Smoking decreases exposure to cilostazol by approximately 20%.

Cilostazol is extensively metabolised mainly by CYP3A4 but also by CYP2C19 and CYP2D6, and is contraindicated in patients with moderate or severe hepatic impairment. The majority of metabolites are excreted in the urine so cilostazol is also contraindicated in severe renal impairment. Cilostazol may lead to increased plasma concentrations of drugs that are substrates of CYP3A4 or CYP2C19, such as midazolam, nifedipine and verapamil, so caution is recommended during co-administration.

Patients who are predisposed to bleeding, including those with active peptic ulceration, recent haemorrhagic stroke, surgery within the last three months, or proliferative diabetic retinopathy, should not take cilostazol. Cilostazol is also contraindicated in patients with congestive heart failure, prolonged QT_cinterval, multifocal ventricular ectopic beats or a history of ventricular tachycardia or ventricular fibrillation.

Haematological abnormalities (including thrombocytopenia, leucopenia, agranulocytosis, pancytopenia and aplastic anaemia) have occurred with cilostazol. Some of these were fatal so patients should have their blood counts monitored closely. Patients should be advised to report any signs of blood dyscrasia such as fever or sore throat, and if infection is suspected a full blood count should be done. Treatment should be stopped immediately if any haematological abnormalities develop. For patients having elective surgery, cilostazol should be stopped five days before the procedure.

Caution is urged when giving cilostazol with drugs that lower blood pressure as cilostazol may have an additive hypotensive effect with reflex tachycardia. Caution is also recommended when giving cilostazol to patients with atrial or ventricular ectopy or with atrial fibrillation or flutter.

Patients already taking anticoagulant or antiplatelet drugs should be monitored for bleeding events. Cilostazol has not been assessed in patients who are taking clopidogrel and have a high risk for bleeding such as coronary stent insertion. Cilostazol could potentiate the effects of nitric oxide donors such as sildenafil and should be used with caution in patients taking these drugs.

Cilostazol helps with the symptoms of intermittent claudication, however the overall gains were modest and show little advantage over supervised exercise programs.3 Cilostazol should not be used in patients with congestive heart failure.

manufacturer provided the clinical evaluation

The Transparency Score () is explained in New drugs: transparency', Vol 37 No 1, Aust Prescr 2014;37:27.

Note on references

At the time the comment was prepared, information about this drug was available on the web site of the Food and Drug Administration in the USA (www.fda.gov).