Cilostazol as a noninferiority pharmacologic option to paclitaxel in early intimal hyperplasia inhibition after venous balloon angioplasty in a rabbit model: a preliminary study

The development of venous intimal hyperplasia (VIH) has not been fully studied. At present, there are no drugs approved for VIH inhibition; to investigate such alternatives, we aimed to compare paclitaxel with cilostazol in VIH early inhibition in a preliminary experimental model of balloon angioplasty. Twenty-eight male New Zealand rabbits were randomly divided into two groups: cilostazol (A) and paclitaxel (B), which underwent femoral vein barotrauma by a 4 mm balloon angioplasty. The VIH model was previously tested in controls obtaining an 80% increase of subintimal area (SIA) compared with veins without injury (from 0.12 mm(2) [standard deviation (SD), 0.05] to 0.86 mm(2) [SD, 0.08]). Group A received 20 mg/kg twice daily; group B angioplasty was performed with a single-dose paclitaxel-coated balloon. Seven days later rabbits were euthanized, and vein tissue samples were taken for histological analysis. The primary end point was SIA measure expressed in mm(2), and the anticipated difference between treatments was 0.21 mm(2). Other measurements were immunohistochemistry expression of hypoxia inducible factor-1 alpha, platelet derived growth factor, and smooth muscle actin, as surrogates of cell migration and oxidative stress. SIA of group A was 0.33 mm(2) (SD, 0.15; 95% CI, 0.24-0.42 mm(2)), and that of group B was 0.31 mm(2) (SD, 0.14; 95% CI, 0.22-0.40 mm(2)). Both drugs showed a reduction of 61% and 63%, respectively, in SIA, compared with controls. The difference between both drugs was 0.0193 mm(2) (95% CI, −0.1175 to 0.156 mm(2)); the statistical difference was found in hypoxia inducible factor-1 alpha expression between both groups. CLINICAL RELEVANCE: Although veins have a thinner middle layer compared with arteries, smooth muscle cells appear to play an important role in venous stenosis after angioplasty. The study of smooth muscle cell response after barotrauma may have clinical applications in the endovascular treatment of venous stenosis, because at the moment, there is no medication indicated to prolong patency after venous endovascular procedures, for example in May Thurner syndrome. Paclitaxel and cilostazol seem to have a promising role. Finally, the present study could inspire a research line to reduce stent placement and increase patency after venous angioplasty.