Peri-interventional Triple Therapy With Dabigatran Improves Vasomotion and Promotes Endothelialization in Porcine Coronary Stenting Model

Abstract

Objective: We evaluated the short and long-term effect of peri-interventional dabigatran therapy on vasomotion, endothelialization, and neointimal formation in a porcine coronary artery stenting model.Background: Stenting of coronary arteries induces local inflammation, impairs vasomotion and delays endothelialization.Methods: Twenty-eight animals underwent percutaneous coronary intervention (PCI) with drug eluting stents. Sixteen pigs started dabigatran therapy 4 days prior to PCI and continued for 4 days post-stenting, while 12 animals served as controls. Post-stenting dual antiplatelet therapy (75 mg clopidogrel and 100 mg aspirin) was continued in both groups until termination. Immediately post-stenting and at day 3 optical coherence tomography (OCT) was performed in all animals, followed by euthanasia of 8 dabigatran and 4 control animals. The remaining pigs (8 of each group) were followed up for 1 month, with control angiography and OCT. Tissue burden (degree of peri-strut structure—thrombus and/or fibrin) was evaluated. After euthanasia coronary arteries were harvested for in-vitro myometry and histology.Results: Thrombin generation was lower (p < 0.001) and tissue burden (0.83 ± 0.98 vs. 3.0 ± 2.45; p = 0.031) was significantly decreased in dabigatran treated animals. After 3 days post-PCI endothelium-dependent vasodilation was significantly improved (77 ± 40% vs. 41 ± 31%, p = 0.02) in dabigatran animals. Neither quantitative angiography nor histomorphometry showed differences between the groups. Endothelialization was faster in the dabigatran group as compared with controls (p = 0.045).Conclusion: Short-term peri-interventional triple therapy with dabigatran, aspirin, and clopidogrel led to an enhanced endothelium dependent vasodilation and faster endothelialization. However, neointimal formation 1-month after stent implantation was comparable between groups.

Peri-Interventional Triple Therapy with Dabigatran Modifies Vasomotion after Bare-Metal Stent Implantation in a Pig Coronary Artery Model

“…Of note, in dabigatran-treated animals, BMS implantation resulted in upregulation of the proinflammatory MCP-1 in the stented tissue as compared with animals not treated with dabigatran. This pattern is different from the previously described downregulation of MCP-1 in DES-implanted tissue of dabigatran-treated animals [ 5 ]. However, in both scenarios—after BMS or DES implantation—peri-strut inflammation as evaluated on histopathology did not significantly differ between dabigatran-treated and control animals.…”

“…In agreement with previous reports, we found with BMS that histological markers of inflammation did not differ significantly between dabigatran-treated and control animals. In the same vein, in our previous experiment with a Biolimus A9–eluting DES [ 5 ], histological inflammatory markers did not significantly change with use of dabigatran. However, the downregulation of MCP-1 in dabigatran-treated animals – and most probably the favorable vasomotor reaction, as a result—may be explained by the additional use of a novel DES platform.…”

“…In our previous experiment using the Nobori Biolimus A9–eluting DES, treatment with dabigatran resulted in enhanced endothelium-dependent vasodilatation without relevant effects on vasoconstriction or on endothelium-independent vasodilatation [ 5 ]. Given this finding, in the absence of Biolimus A9, i.e., when using a BMS, dabigatran treatment has different effects on vasomotion.…”

“…To perform OCT measurements, we used LightLab Imaging software, as previously described [ 15 ]. To quantify the peri-strut tissue burden, i.e., structures on the struts most likely to be a thrombus and/or fibrin, we used a semi-quantitative score [ 5 ].…”

“…We hypothesized that a dabigatran-related reduction in thrombin levels would lead to dampened inflammatory activation after local vascular injury. Using a pig coronary artery model, we previously showed that initiating triple anticoagulant therapy with aspirin, clopidogrel, and dabigatran just before DES implantation and continuing the therapy for a short time afterward resulted in improved endothelium-dependent vasodilatation, faster strut endothelialization, and reduced expression of MCP-1 [ 5 ]. However, the short-term periprocedural triple therapy showed no effect on neointimal proliferation in the longer term, at one month.…”