Efficacy of the Direct Thrombin Inhibitor Ximelagatran in Maintaining Small-Diameter Vascular Graft Patency.
Authors: Schmidt Steven P. , Evancho-Chapman Michelle , Deeken Amy , Van Giezen Hans , Carlsson Stefan C. 
Published: October 2019

Abstract
Objective: A clinically successful small-diameter prosthetic vascular graft has yet to be developed. Improved performance outcomes are also needed with larger-diameter prosthetic vascular grafts for arterial bypass. Ximelagatran (ExantaTM), a fixed-dose, oral direct thrombin inhibitor, is under investigation for thromboprophylaxis in various clinical settings. We hypothesized that ximelagatran could be successful in promoting patencies of small-diameter prosthetic vascular bypass grafts. We hypothesized that ximelagatran could be successful in promoting patencies of small-diameter prosthetic vascular bypass grafts. This 6-month study compared the performances of grafts implanted in carotid arteries in dogs treated with ximelagatran, aspirin, or ximelagatran + aspirin vs non-treated controls.
Methods: Dogs (n=6 per group) received bilateral 6-cm long surgical implants of 4 mm internal diameter standard-walled ePTFE vascular grafts. Grafts were interpolated with end-to-end anastomoses as interposition grafts into the common carotid arteries. Ximelagatran administration (200 mg BID p.o.) began 4 hours post graft-implantation. Aspirin (325 mg QD p.o.) was initiated 3 days pre surgery. Medications were continued until study end point. Vascular graft patencies were assessed by non-invasive ultrasound studies 2 weeks post graft-implantation, then monthly. Study end points were bilateral graft failure or 6 months of implantation, whichever was first. A pathologist performed blinded evaluations of the retrieved grafts through calculations of thrombus-free surface areas (TFSA) and histological analyses of healing.
Results: One ximelagatran- and one aspirin-treated dog were excluded from the study owing to surgical complications. Ximelagatran was well tolerated. There were no deviations from canine blood norms other than expected elevated PTs and APTTs in ximelagatran-treated animals. Graft Patency: At 6 months, mean graft patencies were similar for the ximelegatran and the ximelagatran + aspirin groups, but both groups were significantly different compared to the aspirin alone and control groups.1TFSA: Mean TFSA of grafts from both the ximelagatran and ximelagatran + aspirin groups were similar but were significantly different from the aspirin alone group.2Intimal Hyperplasia: Statistical differences between groups were not evident between specific locations. However, grafts from the control and aspirin alone groups had more intimal hyperplasia overall than the ximelagatran and ximelagatran + aspirin groups.
Conclusions: Ximelagatran-treated dogs had small-diameter vascular graft implants with higher patencies, greater TFSAs and a trend toward less intimal hyperplasia compared with dogs medicated with aspirin alone or controls. We believe that further investigation is warranted in defining the potential use of ximelagatran in maintaining small-diameter vascular graft patencies.
Study Group Drug Dose(s) Patency* TFSA % 1 Month 3 Months 6 Months *ratio of number of grafts open to the flow of blood to the total number of evaluable grafts at each time period Ximelagatran 200 mg BID 100% (10/10) 100% (10/10) 88%1 (7/8) 63.4%2 Aspirin 325 mg QD 70% (7/10) 40% (4/10) 30% (3/10) 22.4 Ximelagatran + Aspirin 200 mg BID + 325 mg QD 83% (10/12) 66% (8/12) 66%1 (8/12) 55.0%2 Control - 17% (2/12) 0 (0/12) 0 (0/12) 0