EMA Recommends Restricting Cilostazol Use for PAD

March 22, 2013

The European Medicines Agency has recommended restricting the use of cilostazol-containing medicines in the treatment of intermittent claudication to a narrower patient population in which there are clear signs of clinical benefits with minimal risks. Cilostazol-containing medicines are available in the European Union under the names Pletal  and Ekistol.

Intermittent claudication is a symptomatic form of peripheral arterial disease, where poor blood supply to the leg muscles causes pain and limits exercise.

The recommendation follows a review of current evidence, which indicates that the modest benefits of these cilostazol-containing medicines — ie, their ability to increase the distance patients are able to walk — are only greater than their risks of certain cardiovascular side effects or serious bleeding in a limited subgroup of patients.

The Spanish Agency for Medicines and Health Products (AEMPS) asked EMA's Committee on Medicinal Products for Human Use (CHMP) to carry out a review of these medicines following a number of reports of such suspected side effects, the agency says. These included fatal heart attacks, angina, and arrhythmias as well as cases of serious bleeding, including bleeding in the brain.

The CHMP recommendation will now be sent to the European Commission for the adoption of a legally binding decision throughout the European Union.

In the US, cilostazol is approved for intermittent claudication but is used less than it is in Europe. In Asia, the drug is more widely used — for example, in stroke patients or added to aspirin and clopidogrel as triple therapy after stent implantation for coronary heart disease.

Review Cilostazol Use at Next Routine Appointment

EMA says cilostazol should now only be used for intermittent claudication when lifestyle changes (including smoking cessation and exercise programs) and other appropriate interventions alone have not produced adequate benefit. Treatment should only be started by physicians experienced in the management of intermittent claudication and should be reviewed after three months, at which point therapy should be stopped in those who have not shown clinically relevant benefit.

Cilostazol should not be given to patients who have unstable angina or who have had a myocardial infarction (MI) or percutaneous coronary intervention (PCI) within the past six months or to those with a history of severe tachyarrhythmia. The product should not be given to patients receiving both aspirin and clopidogrel or any other combination of 2 or more additional antiplatelet or anticoagulant medicines. Prescribers also need to be aware of the risk of interactions with cilostazol; its dose should be reduced in patients concurrently taking strong inhibitors of CYP3A4 or CYP2C19 enzymes.

Doctors should review their patients at their next routine appointment and assess the continued suitability of cilostazol treatment, the EMA notes, and other healthcare professionals should refer patients to the prescribing physician as appropriate.

For patients, EMA has this advice: "If you are taking cilostazol-containing medicines, you should make a nonurgent appointment with your doctor to review your treatment. Your doctor will advise you whether you should continue taking cilostazol, stop taking cilostazol, or change the dose that you are taking. The advice will vary for each patient depending on factors such as lifestyle options that could improve your condition, whether your walking symptoms have improved since you started cilostazol, whether you have had recent heart problems, and which other medicines you are taking."

Current Evidence Reassuring on CV Side Effects

The CHMP review of cilostazol examined safety data from nearly 14,000 suspected adverse-drug-reaction reports (in the context of over 6 million patient-years of exposure worldwide) and 4000 events in noninterventional studies and confirmed the known adverse-effect profile of cilostazol from clinical trials. Cases of hemorrhage represented about 8% of the spontaneous reports. The most common cardiovascular events reported were palpitations and tachycardia (each about 5% of total spontaneous reports).

Analysis of available data suggests an increased risk of hemorrhage when cilostazol is given to patients also taking both aspirin and clopidogrel. However, the evidence suggests that cilostazol alone or in combination with 1 other antiplatelet drug does not increase the risk of bleeding, says the CHMP.

There is some comfort, however, on long-term cardiovascular safety of cilostazol from the CASTLE postmarketing study, it adds. Testing cilostazol against placebo, the trial was terminated early because of a high dropout rate in both groups and a much lower mortality rate than expected. There were 49 deaths in the cilostazol group, of which 12 were due to cardiac disorders, and 52 in the placebo group (13 cardiac). When a composite end point of cardiac morbidity (coronary and cerebrovascular events) and mortality was considered, there were 135 events with cilostazol and 153 with placebo.

"Although the design and early termination of the study limit the conclusions that can be drawn, these results provide some reassurance with regard to cardiovascular safety of cilostazol," the EMA notes.

"In conclusion, the CHMP considered that although on average the efficacy of cilostazol is modest, there is a small group of patients in whom it is of clinical relevance, not least in helping them to begin exercise programs. Although suspected adverse-drug-reaction reports have raised some safety concerns, these have not been substantiated in the clinical-trial data (including the CASTLE study), and it remains possible to exclude high-risk patients in clinical practice."