Cilostazol (Pletal): risks of cardiovascular and bleeding events

Indication restricted to second-line treatment and contraindicated with some cardiovascular conditions and medicines Furthermore, cilostazol is now contraindicated in patients with any of the following: Unstable angina, recent myocardial infarction or coronary intervention (within 6 months) a history of severe tachyarrhythmia those receiving two or more other antiplatelet or anticoagulant treatments For patients starting cilostazol, prescribers should assess benefit after 3 months of treatment, and should stop treatment if patients have not made clinically relevant improvements in walking distance. All patients who are currently receiving long-term treatment should be reassessed at a routine appointment, in light of the new advice.

Article date: April 2013

Cilostazol (Pletal) is a phosphodiesterase type 3 inhibitor indicated for the improvement of walking distances in patients with intermittent claudication, who do not have rest pain and who do not have evidence of peripheral tissue necrosis (Fontaine stage II). The effects of cilostazol include antiplatelet activity and vasodilation.

A review of the benefits and risks of cilostazol was triggered by reports of adverse reactions (mainly cardiac and haemorrhagic), and by the potential for drug interactions.

Efficacy of cilostazol

In clinical trials, cilostazol provided an average improvement in maximum walking distance of 87 m (approximately 66% increase) compared with 44 m for placebo; average baseline walking distance was 133 m. The studies measured walking distance using a graded treadmill test, and therefore the actual improvement on flat ground is expected to be greater.

Safety review of cilostazol

Safety data from the efficacy trials and a phase IV long-term safety study (CASTLE) were reviewed. The most commonly reported reactions were relatively minor (headaches, diarrhoea, palpitations, dizziness), and the clinical trials did not raise serious safety concerns. However cilostazol has been shown to increase heart rate by about 5 to 7 beats per minute, and this may put some patients at increased risk of cardiac events (eg, those with stable coronary disease). Contraindications have been revised to exclude patients at greatest risk of cardiac adverse events.

The CASTLE trial had a primary endpoint of all-cause mortality and included more than 1400 patients. Although the trial was terminated early due to a low event rate and high drop-out, it was considered to provide some reassurance on cardiovascular safety. No increase in bleeding risk was found with cilostazol alone or combined with one other antiplatelet treatment (clopidogrel or aspirin). However, there was a higher frequency of bleeding events when cilostazol was combined with both clopidogrel and aspirin.

Cilostazol is mainly metabolised via CYP3A4 and CYP2C19. Exposure to cilostazol is increased if it is taken concomitantly with medicines that inhibit these enzymes.

Pharmacokinetic data from interaction studies has been reviewed and a dose reduction (to 50 mg twice a day) is now recommended when cilostazol is taken with strong inhibitors of these enzymes. The increase in overall pharmacological activity when cilostazol is taken with ketoconazole or erythromycin is around 35%; when taken with omeprazole it is increased by about 47%.

Conclusions of the review

The benefit provided by cilostazol is clinically relevant in some patients and the risks associated with treatment in these patients are manageable. However, in patients with some cardiovascular conditions or those receiving two or more other antiplatelet or anticoagulant treatments, the risks of cilostazol outweigh the benefits.

Advice for healthcare professionals:

  • cilostazol is restricted to second-line treatment where lifestyle modifications (eg, smoking cessation and exercise regimens) and other appropriate interventions have failed to provide sufficient improvement. Lifestyle changes should continue during treatment
  • cilostazol is contraindicated in patients with:
    • unstable angina
    • recent myocardial infarction
    • coronary intervention (within 6 months)
    • history of severe tachyarrhythmia
    • those receiving 2 or more other antiplatelet or anticoagulant treatments
  • advise patients to take cilostazol 30 minutes before breakfast and evening meal
  • reassess patients after 3 months of starting cilostazol and consider stopping treatment if there is no clinically relevant improvement in walking distance
  • adose reduction to 50 mg twice a day is recommended when cilostazol is taken in combination with any of the following:
    • erythromycin
    • clarithromycin
    • ketoconazole
    • itraconazole; omeprazole
    • any strong inhibitors of CYP3A4 or CYP2C1
  • reassess patients currently receiving long-term treatment with cilostazol at a routine appointment, in order to advise on treatment continuation, dose change, or cessation

Further information

EMA press release and link to agreed product information

BNF section 2.6.4: Peripheral vasodilators and related drugs

Article citation: Drug Safety Update April 2013, vol 6, issue 9: A2.

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