A scientific rationale for the CREST trial results: evidence for the mechanism of action of cilostazol in restenosis.
The Cilostazol for RESTenosis (CREST) clinical trial was initiated to evaluate the efficacy of cilostazol, an antiplatelet drug, in inhibiting restenosis after stent implantation in a native coronary artery as evaluated by quantitative coronary angiography. Preliminary results suggest that cilostazol reduces restenosis by 36% over standard therapy alone. Restenosis after coronary stenting is primarily attributed to neointimal formation. Cilostazol decreases the activity of phosphodiesterase type 3, leading to the accumulation of cyclic adenosine monophosphate, which initiates a cascade of events including upregulation of anti-oncogenes p53 and p21 and upregulation of hepatocyte growth factor (HGF). The increase in p53 protein blocks cell cycle progression and induces apoptosis in vascular smooth muscle cells (VSMCs), leading to an antiproliferative effect. Upregulation of local HGF stimulates rapid regeneration of endothelial cells, which inhibits neointimal formation via two mechanisms: inhibition of abnormal VSMC growth and improvement of endothelial function. These mechanisms may be responsible for the improvement in restenosis shown in the CREST trial and a number of other trials in patients who underwent percutaneous transluminal coronary angioplasty. These effects, in addition to antithrombotic and vasodilatory attributes of cilostazol, make it a potentially viable treatment option for preventing restenosis following coronary stenting.
Morishita
Ryuichi
R
Division of Clinical Gene Therapy, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita 565-0871, Osaka 565, Japan. morishit@cgr.med.osaka-u.ac.jp
D000077407:Cilostazol; D023903:Coronary Restenosis / Q000473:pathology / Q000517:prevention & control*; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000473:pathology; D010975:Platelet Aggregation Inhibitors / Q000627:therapeutic use*; D016032:Randomized Controlled Trials as Topic; D013777:Tetrazoles / Q000627:therapeutic use*; D016896:Treatment Outcome
D010975:Platelet Aggregation Inhibitors; D013777:Tetrazoles; D000077407:Cilostazol