Type 3 phosphodiesterase inhibitors may be protective against cerebrovascular events in patients with claudication

J Stroke Cerebrovasc Dis. 2008 May-Jun;17(3):129-33. doi: 10.1016/j.jstrokecerebrovasdis.2007.12.005.


Objective: The risk of cerebrovascular events in patients with mild to moderate peripheral vascular disease is significant. Cilostazol is a phosphodiesterase type 3 (PDE3) inhibitor that is effective in the treatment of symptoms of peripheral arterial occlusive disease. The method of action includes antithrombotic, vasodilatory, and antiproliferative effects.

Methods: The Cilostazol: A Study in Long-Term Effects (CASTLE) trial was a prospective randomized double-blinded trial to establish the safety of this PDE3 inhibitor use in 1435 patients with mild to moderate peripheral arterial occlusive disease. A post hoc analysis of the CASTLE trial was undertaken to evaluate cilostazol use on cerebrovascular events. Blinded adjudication of all cerebrovascular events (stroke, transient ischemic attack, and carotid revascularization) in this trial was performed. Kaplan-Meier analysis was used for statistical evaluation.

Results: The overall rate of cerebrovascular events was 4.6% (67 of 1435 patients) with a mean follow-up of 515 days. Ischemic vascular events were more common (2.5%) than hemorrhagic events (0.3%; P < .05). The placebo group demonstrated a greater risk for events (6.1%; 43 of 718 patients) versus the cilostazol treated group (3.2%; 24 of 717 patients; P < .05). Cerebrovascular risk factors were similar in both groups.

Conclusion: The risk of cerebrovascular events in patients with mild to moderate peripheral arterial occlusive disease is 4.6% with a mean follow-up of 515 days. Treatment with PDE3 inhibitors may reduce this risk. Further evaluation of the use of PDE3 inhibitors for prevention of cerebrovascular events should be considered.

Publication types

  • Clinical Trial, Phase IV
  • Multicenter Study
  • Randomized Controlled Trial

MeSH terms

  • Aged
  • Cardiovascular Agents / pharmacology
  • Cardiovascular Agents / therapeutic use*
  • Cerebrovascular Disorders / enzymology
  • Cerebrovascular Disorders / etiology
  • Cerebrovascular Disorders / prevention & control*
  • Cilostazol
  • Cyclic Nucleotide Phosphodiesterases, Type 3 / metabolism
  • Double-Blind Method
  • Female
  • Humans
  • Intermittent Claudication / drug therapy*
  • Intermittent Claudication / enzymology
  • Intermittent Claudication / etiology
  • Male
  • Middle Aged
  • Peripheral Vascular Diseases / complications
  • Peripheral Vascular Diseases / drug therapy*
  • Peripheral Vascular Diseases / enzymology
  • Phosphodiesterase 3 Inhibitors*
  • Phosphodiesterase Inhibitors / pharmacology
  • Phosphodiesterase Inhibitors / therapeutic use*
  • Prospective Studies
  • Risk Assessment
  • Severity of Illness Index
  • Tetrazoles / pharmacology
  • Tetrazoles / therapeutic use*
  • Time Factors
  • Treatment Outcome


  • Cardiovascular Agents
  • Phosphodiesterase 3 Inhibitors
  • Phosphodiesterase Inhibitors
  • Tetrazoles
  • Cyclic Nucleotide Phosphodiesterases, Type 3
  • Cilostazol