: the impact of scaffold design and materials on reducing thrombogenicity Michael Joner, MD Deutsches Herzzentrum München und Deutsches Zentrum für Herz-Kreislaufforschung e.v.
Potential conflicts of interest Speaker's name: Michael Joner I have the following potential conflicts of interest to report: Receipt of honoraria or consultation fees: Boston Scientific, Biotronik, OrbusNeich, Coramaze, Astra Zeneca, Bristol-Myers Squibb
Definite/Probable Scaffold Thrombosis (in %) Definite/Probable Scaffold Thrombosis (in %) Definite/Probable Scaffold Thrombosis (in %) Scaffold thrombosis in ABSORB BVS Recent studies show increased thrombosis tendency in BVS vs DES. Thrombosis in general however has multifactorial causes, thick strut design being one of them ABSORB II 3-year data 1 ABSORB III 2-year data 2 AIDA 2-year data 3 4.0% P=0.03 4.0% P=NS 4.0% P<0.001 3.5% 3.5% 3.5% 3.5% 3.0% 2.8% 3.0% 3.0% 2.5% 2.5% 2.5% 2.0% 2.0% 1.9% 2.0% 1.5% 1.5% 1.5% 1.0% 1.0% 0.8% 1.0% 0.9% 0.5% 0.5% 0.5% 0.0% Absorb 0.0% Xience 0.0% Absorb Xience 0.0% Absorb Xience 1) Adapted from Serruys P. et al., The Lancet 2016; 388(10059):2479-2491 2) Adapted from Ellis S.G.oral abstract presentation at ACC 2017 3) Adapted from Wykrzykowska J.J. et al., New England Journal of Medicine 2017, published online ahead of print
Scaffold thrombosis in DREAMS-1G BIOSOLVE-I 36-month follow-up Definite/Probable Scaffold Thrombosis BIOSOLVE-II 24-month follow-up Definite/Probable Scaffold Thrombosis BIOSOLVE-III 6-month follow-up Definite/Probable Scaffold Thrombosis 0.0% 0.0% 0.0% 1) BIOSOLVE-I data from Haude M. et al., EuroIntervention 2016;12:e160-e166 2) BIOSOLVE-II data from Haude M., oral abstract presentation, EuroPCR 2017 3) BIOSOLVE-III data from Haude M., oral abstract presentation, EuroPCR 2017
Scaffold Thrombosis Factors Stent geometry Stent geometry Late-aquired incomplete device apposition Delayed or incomplete endothelialisation of device struts Hypersensitivity or inflammatory reactions to device components Modified from : Capodanno D, et al., EuroIntervention, 2015;11 Suppl V:V181-4
Scaffold Thrombosis Factors Stent geometry Stent geometry Late-aquired incomplete device apposition Delayed or incomplete endothelialisation of device struts Hypersensitivity or inflammatory reactions to device components Modified from : Capodanno D, et al., EuroIntervention, 2015;11 Suppl V:V181-4
Computed flow dynamics aims to explain how strut thickness may influence device thrombogenicity Greater strut thickness is associated with increased platelet activation due to higher shear stress. In addition, platelet aggregation is increased due to larger areas of regional flow reverse and stasis. 1) 2) 3) 1) Foin, N., et al. IJCA. 2014;143 (09), 2) Tolentino, A. Cardiov.Nurse/Tech. Symp. 2016, 3) Koskinas K., J Am Coll Cardiol. 2012 Apr 10;59(15):1337-49
Computed flow dynamics suggest accelerated endothelialization in relative to Absorb The backbone design was found to optimize the wall shear stress compared to the Absorb design. High WSS in between strut crowns (green areas) is physiologic and is associated with accelerated endothelialization. low high Absorb IIB(R)03_2017_Entwurf BIOTRONIK data on file
Evaluation of acute thrombogenicity in a well established porcine arteriovenous shunt model Stent geometry, coating and backbone composition impact on acute thrombogenicity Thicker stent struts show greater thrombus deposition as compared with thinner stent struts
Evaluation of acute thrombogenicity in vs. Absorb vs. Orsiro Shunt study 1: Comparison of acute thrombogenicity of Absorb vs vs. Orsiro Detection of platelets and inflammatory cells by immunofluorescence Estimation of thrombus deposition by SEM Shunt model AV-shunt with a sylgard tube (inner diameter 2.70mm) 1h blood flow or until >50% reduction of blood flow Target blood activated clotting times (ACT) were kept between 150-190s by i.v. Administration of heparin (low heparin model) No antiplatelet agents (e.g. Aspirin, clopidogrel) were used Otsuka et al., JACC Cardiovasc Interv. 2015 Aug 17;8(9):1248-60. Waksman R. et al., In press Circulation Intervention
Results Shunt Study 1: vs. Absorb vs. Orsiro Shunt study 1: Comparison of acute thrombogenicity of Absorb vs Orsiro and Detection of platelets and inflammatory cells by immunofluorescence Estimation of thrombus deposition by SEM Absorb Orsiro Photo SEM IF Waksman R. et al., In press Circulation Cardiovascular Intervention
Results Shunt Study 1: vs. Absorb vs. Orsiro Scanning Electron Microscopy Significantly less thrombus deposition in compared to Absorb Less inflammatory cells in compared to Absorb Arrows: thrombus deposition, arrowhed: inflammatory cells Waksman R. et al., In press Circulation Cardiovascular Intervention
Results Shunt Study 1: vs. Absorb vs. Orsiro Immunoflurescence Significantly less platelet coverage in and Orsiro compared to Absorb Waksman R. et al., In press Circulation Cardiovascular Intervention
Evaluation of acute thrombogenicity in vs. 316L-Equivalent Shunt study 2: Effect of magnesium backbone on acute thrombogenicity of vs scaffold design in stainless steel (316L-equivalent): Detection of platelets and inflammatory cells by immunofluorescence Estimation of thrombus deposition by SEM Shunt model AV-shunt with a sylgard tube (inner diameter 2.70mm) 1h blood flow or until >50% reduction of blood flow Target blood activated clotting times (ACT) were kept between 150-190s by i.v. Administration of heparin (low heparin model) No antiplatelet agents (e.g. Aspirin, clopidogrel) were used Otsuka et al., JACC Cardiovasc Interv. 2015 Aug 17;8(9):1248-60. Waksman R. et al., In press Circulation Intervention
Results Shunt Study 2: vs 316L-Equivalent Shunt study 2: Effect of magnesium backbone on acute thrombogenicity of vs 316L- Equivalent: Detection of platelets and inflammatory cells by immunofluorescence Estimation of thrombus deposition by SEM 316L-Equivalent Photo SEM IF
Results Shunt Study 2: vs 316L-Equivalent Scanning Electron Microscopy Significantly less thrombus deposition in compared to 316L-Equivalent Less inflammatory cells in SEM 316L-Equivalent Arrows: thrombus deposition, arrowhed: inflammatory cells
Results Shunt Study 2: vs 316L-Equivalent Immunofluorescence Significantly less platelet coverage in compared to stainless steel P<0.0001 stainless steel 316L-Equivalent
Scaffold Thrombosis Factors Stent geometry Stent geometry Late-aquired incomplete device apposition Delayed or incomplete endothelialisation of device struts Hypersensitivity or inflammatory reactions to device components Modified from : Capodanno D, et al., EuroIntervention, 2015;11 Suppl V:V181-4
Computed flow dynamics aims to explain how late recoil may cause malapposition which in turn may influence device thrombogenicity 1 Absorb Absorb showed no recoil increase, whereas Absorb diameter decreased >20% within 1st hour in a bench test. 1 Therefore, the polymeric scaffold struts are less apposed to the vessel wall which causes disturbances in the laminar blood flow. 2,3,4 Disturbances activate platelets which play an important role of the thrombus formation cascade. 2 The impact of recoil on the laminar blood flow was simulated using computational flow dynamics. 1) Schmidt W et al. In vitro performance investigation of bioresorbable scaffolds - Standard tests for vascular stents and beyond.cardiovascular Revascularization Medicine. 2016; 17(6):375-383. 2) Foin N et al. Incomplete Stent Apposition Causes High Shear Flow Disturbances and Delay in Neointimal Coverage as a Function of Strut to Wall Detachment Distance, DOI: 10.1161/CIRCINTERVENTIONS.113.000931 3) Kolandaivelu K et al. Stent Thrombogenicicty Early in High-Risk Interventional Settings Is Drive by Stent design and Deployment and Protected by Polymer-Drug Coatings DOI:10.1161/CIRCULTATIONAHA.100.003210 4) Jiménez J.M., Davies P.F. Hemodynamically Driven Stent Strut Design. Annals of Biomedical Engineering. 2009
Platelet Shear Number (PSN) Computed flow dynamics predicted the impact of recoil on the risk of platelet activation and platelet aggregation Platelet Convection Number (PCN) Platelet Aggregation Number (PAN) was simulated with a stable 5% recoil. Absorb was simulated with a 5% and 8% recoil at acute and 1 hour postimplantation respectively 1. Only the results 1-hour post-implantation are shown here. Computed flow dynamic simulation predicts the lowest risk of platelet activation for and the highest for Absorb. 2 The activated platelets are transported to the vessel wall. The transport is represented by the platelet convection number, which resulted lowest for. 2 Finally, the transported platelets aggregate. The risk of platelet aggregation is lowest for compared to Absorb. 2 0.3 0.25 0.2 0.15 0.1 0.11 0.27 3.5 3 2.5 2 1.5 1 2.34 3.05 15 10 5 12.6 14.1 0.05 0.5 0 Absorb 0 Absorb 0 Absorb 1) Schmidt W. et al, Cardiovasc Revasc Med 2016;17(6):375-83 2) IIB(R)03_2017_Entwurf BIOTRONIK data on file, 3) Pictures from: http://ib.bioninja.com.au/standard-level/topic-6-human-physiology/63-defence-against-infectio/clotting.html
Scaffold Thrombosis Factors Stent geometry Stent geometry Late-aquired incomplete device apposition Delayed or incomplete endothelialisation of device struts Hypersensitivity or inflammatory reactions to device components Modified from : Capodanno D, et al., EuroIntervention, 2015;11 Suppl V:V181-4
vs Absorb endothelialisation in rabbit model at 28 days Vessel surface coverage of BRS struts determines pace of re-endothelialisation PLLA BRS p<0.004 p = 0.007 PLLA BRS Waksman R. et al., EuroIntervention 2017; published online ahead of print
Scaffold Thrombosis Factors Stent geometry Stent geometry Late-aquired incomplete device apposition Delayed or incomplete endothelialisation of device struts Hypersensitivity or inflammatory reactions to device components Modified from : Capodanno D, et al., EuroIntervention, 2015;11 Suppl V:V181-4
Results Shunt Study 1: vs. Absorb vs. Orsiro Immunoflurescence (2) Significantly less Neutrophil (PM1 + ) adherence in and Orsiro compared to Absorb Significantly less Monocyte (CD14 + ) adherence in compared to Absorb PM1+ Neutrophil staining: green, CD14+ Monocyte staining: green, DAPI nuclei staining: blue, CD42b/CD61 platelelt staining: red Waksman R. et al., In press Circulation Cardiovascular Intervention
Results Shunt Study 2: vs 316L-Equivalent Immunofluorescence Neutrophil Attachment Significantly less Neutrophil (PM1 + ) adherence in compared to 316L-Equivalent P<0.001 316L-Equivalent 316L-Equivalent
Results Shunt Study 2: vs 316L-Equivalent Immunofluorescence Monocyte Attachment Significantly less Monocyte (CD14 + ) adherence in compared to 316L-Equivalent P<0.0001 316L-Equivalent 316L-Equivalent
Conclusions Geometric design of impacts favorably on acute thrombogenicity relative to Absorb and Orsiro Endothelialization is advanced in relative to Absorb in a rabbit model at 28 days hemodynamic flow properties and biocompatible coating seem to have favorable effects on platelet aggregation and endothelialisation 1 Decreased inflammatory cell attachment in relative to Absorb and Orsiro is observed 1 hour following AV shunt flow The BIOlute coating showed reproducible hemocompatibility on various designs The backbone Magnesium material seems to have a beneficial effect on acute thrombosis risk 1) Malek A.M. et al., Hemodynamic sheer stress and its role in atherosclerosis, JAMA 1999;282:2035-2042