Cilostazol: Action, Dosage and Notes on Peripheral Arterial Disease
Cilostazol is a prescription-only active ingredient from the group of phosphodiesterase-3 inhibitors (PDE3 inhibitors). It is used in patients with peripheral arterial disease (PAD) to improve walking distance and to relieve the complaints associated with the condition. In the EU, cilostazol is available under the brand name Pletal.
Peripheral arterial disease is a chronic circulatory disorder of the limbs, usually the legs, caused by atherosclerotic deposits in the arteries. The leading symptom of PAD in Fontaine stage II is intermittent claudication: exertion-dependent pain in the calf or thigh that subsides at rest (shop window disease). Cilostazol acts at two sites: it improves blood flow properties and has a vasodilatory effect.
Mechanism of Action
Cilostazol selectively inhibits the enzyme phosphodiesterase 3 (PDE3) in platelets and smooth vascular muscle cells. PDE3 is responsible for the breakdown of cyclic adenosine monophosphate (cAMP). By inhibiting PDE3, the intracellular cAMP level rises, producing two essential effects:
Antithrombotic effect: In platelets, an elevated cAMP level leads to inhibition of platelet aggregation. The platelets are less prone to clumping together, which reduces the risk of blood clot formation in atherosclerotic vessels. Cilostazol also inhibits the release of thromboxane A2, a potent vasoconstrictor and activator of platelet aggregation.
Vasodilatory effect: In smooth vascular muscle cells, an elevated cAMP level leads to relaxation and thus dilation of blood vessels. This promotes peripheral blood flow, particularly in leg vessels, and can extend walking distance.
Cilostazol is rapidly absorbed after oral intake. Bioavailability is increased by fatty meals. The active ingredient is extensively metabolised via the cytochrome P450 system (mainly CYP3A4 and CYP2C19) in the liver. The half-life of the parent compound is 11 to 13 hours.
Indications
Cilostazol is approved in the EU for improving maximum and pain-free walking distance in patients with intermittent claudication without rest pain and without peripheral tissue necrosis (PAD Fontaine grade IIa and IIb).
It is therefore a symptomatic therapy that does not affect the underlying atherosclerosis. Cilostazol should always be used in combination with non-pharmacological measures:
- Regular structured walking training (vascular exercise programme)
- Smoking cessation as the most important single measure
- Treatment of cardiovascular risk factors (hypertension, diabetes, hyperlipidaemia)
- Platelet function inhibition with aspirin or clopidogrel (separately)
Cilostazol is not suitable for patients with critical limb ischaemia (rest pain, necrosis, gangrene). In these cases, interventional or surgical procedures (angioplasty, bypass) are required.
Dosage and Administration
Cilostazol is prescription-only. Dosage is determined by the treating physician.
The recommended standard dose is 100 mg twice daily as a film-coated tablet, taken 30 minutes before or two hours after breakfast and the evening meal. Intake together with fatty meals should be avoided, as this increases bioavailability and raises the risk of side effects (e.g. tachycardia).
In patients who are concurrently taking CYP3A4 inhibitors (e.g. erythromycin, diltiazem, omeprazole), a reduction to 50 mg twice daily is recommended, as these substances can increase cilostazol levels.
Effect does not occur immediately. A clinically relevant improvement in walking distance is expected at the earliest after 2 to 4 weeks. Full efficacy is generally only seen after 12 weeks. If no adequate response is established after 3 months, therapy should be discontinued.
Side Effects
Cilostazol has a characteristic side effect profile, mainly caused by its vasodilatory and antithrombotic effect.
Very common (more than 10 in 100 patients): Headaches are the most common side effect and affect up to a third of all patients, particularly at the start of therapy. They arise from vasodilation and diminish in most patients over the course of therapy.
Common (1 to 10 in 100 patients): Diarrhoea, nausea and soft stools have been reported. Palpitations and tachycardia (increased heart rate) are explained by the positive chronotropic effect of PDE3 inhibitors. Dizziness and peripheral oedema also occur.
Bleeding risk: Through inhibition of platelet aggregation, the risk of bleeding is increased. Particularly with concurrent use of anticoagulants (e.g. warfarin, phenprocoumon, DOACs) or other platelet function inhibitors (aspirin, clopidogrel), the risk of relevant bleeding increases. Patients should discontinue intake in good time before planned surgical procedures.
Cardiac effects: As a PDE3 inhibitor, cilostazol has a positive inotropic and positive chronotropic effect. In patients with heart failure, this effect can worsen the prognosis (analogy to other PDE3 inhibitors such as milrinone, which increased mortality in heart failure). Cilostazol is contraindicated in heart failure.
Drug Interactions
Cilostazol is metabolised predominantly via CYP3A4 and CYP2C19. Inhibitors of these enzymes considerably increase cilostazol plasma levels:
- CYP3A4 inhibitors: ketoconazole, itraconazole, erythromycin, clarithromycin, diltiazem, verapamil, grapefruit juice
- CYP2C19 inhibitors: omeprazole, esomeprazole, fluvoxamine
With these substances, a dose reduction to 50 mg twice daily is recommended. Strong CYP3A4 inducers such as rifampicin, carbamazepine or St John's Wort can weaken the effect of cilostazol.
Combination with other platelet function inhibitors (aspirin, clopidogrel, ticagrelor) or anticoagulants significantly increases bleeding risk. Such a combination should only take place after careful medical assessment and under regular monitoring.
Special Notes
Heart failure: Cilostazol is contraindicated in heart failure of any severity. PDE3 inhibitors can increase mortality in heart failure. Cardiac function must be assessed before starting therapy.
Cardiac arrhythmias: Patients with known cardiac arrhythmias, particularly atrial fibrillation, ventricular fibrillation or long QT syndrome, and patients taking QT-prolonging medications should not receive cilostazol, or only under very close cardiological monitoring.
Hepatic insufficiency: Cilostazol is contraindicated in severe hepatic insufficiency, as metabolism can be significantly impaired and plasma levels may rise in an uncontrolled manner.
Pregnancy and breastfeeding: Animal studies have yielded indications of harmful effects on the foetus. Cilostazol should not be used during pregnancy. During breastfeeding, use should be discouraged, as cilostazol passes into breast milk.
Frequently Asked Questions
How long must cilostazol be taken?
With good response, cilostazol is used as a long-term medication. If no clinically relevant improvement in walking distance is established after twelve weeks, therapy should be reviewed and generally discontinued.
Can cilostazol be combined with aspirin?
This combination is possible but increases bleeding risk. It should only take place after medical assessment, and patients should watch for signs of bleeding (e.g. increased tendency to bleed, blood in urine or stool, unusual bruising).
Can I drink grapefruit juice during therapy?
Grapefruit juice inhibits CYP3A4 and can increase cilostazol levels. It is recommended to avoid large quantities of grapefruit juice during therapy and to discuss this with the physician or pharmacist.
References
- European Medicines Agency (EMA): Pletal Summary of Product Characteristics (current version)
- German Society for Angiology: S3 Guideline PAD (current version)
- Dawson DL et al.: A comparison of cilostazol and pentoxifylline for treating intermittent claudication. Am J Med. 2000;109(7):523-530
- Regensteiner JG et al.: Oral treprostinil and cilostazol improve claudication in peripheral arterial disease. Ann Intern Med. 2002;136(7):544-548
- ABDA Database: Monograph Cilostazol (current version)