What Should Be the Safety Profile of Drug Eluting Stents Suitable for Short DAPT
Renu Virmani CVPath Institute, Inc. Gaithersburg, MD, USA Disclosure
Within the past 12 months, I or my spouse/partner have had a financial interest/arrangement or affiliation with the organization(s) listed below.
Grant/Research/Clinical Trial Support R01 HL141425 Leducq Foundation Grant; 480 Biomedical; 4C Medical; 4Tech; Abbott; Accumedical; Amgen; Biosensors; Boston Scientific; Cardiac Implants; Celonova; Claret Medical; Concept Medical; Cook; CSI; DuNing, Inc; Edwards LifeSciences; Emboline; Endotronix; Envision Scientific; Lutonix/Bard; Gateway; Lifetech; Limflo; MedAlliance; Medtronic; Mercator; Merill; Microport Medical; Microvention; Mitraalign; Mitra assist; NAMSA; Nanova; Neovasc; NIPRO; Novogate; Occulotech; OrbusNeich Medical; Phenox; Profusa; Protembis; Qool; Recor; Senseonics; Shockwave; Sinomed; Spectranetics; Surmodics; Symic; Vesper; W.L. Gore; Xeltis.
Speaker’s Bureau Abbott Vascular; Biosensors; Boston Scientific; Celonova; Cook Medical; CSI; Lutonix Bard; Sinomed; Terumo Corporation.
Consultant/Advisory Boards Amgen; Abbott Vascular; Boston Scientific; Celonova; Cook Medical; Lutonix Bard; Sinomed.
Owner of a healthcare company: No Stockholder of a healthcare company: No Short-term DAPT: What stent characteristics are needed? ➢Thrombo-resistance is essential for all coronary stents because it will allow flexibility in DAPT duration (minimum duration of DAPT for DES is 30 days)
➢Thrombo-resistant DES requires two important characteristics:
✓Stent coating must be thromboresistant – therefore allowing for shorter DAPT as struts may remain uncovered >30 days
✓ Should induce minimal inflammation and thrombus while enhancing endothelial proliferation and functional recovery. Relationship between Medical device and thrombogenicity -Blood material interaction- Complement activation
Inflammation Thrombin Kalikrein
Platelet Fibrin activation formation Platelet aggregation Platelet attachment ↑ Platelet Factor XII • Fibrinogen adhesion activation • Fibronectin Thrombus • vWF Platelet attachment ↓ Protein adsorption • Albumin
Medical device (e.g. stent strut) surface
Jaffer IH, et al. J Thromb Haemost. 2015 Jun;13 Suppl 1:S72-81. Background of the pre-clinical study
➢ The Resolute-Onyx-ZES uses a mixture of hydrophobic C10 polymer, hydrophilic C19 polymer, and polyvinyl pyrolidine polymers (PVP) (called BioLinx polymer).
➢ The relative suitability BioLinx for short-term DAPT was tested in vitro against BMS (CoCr) and Biofreedom-DES (SS316L)
➢ Similarly in vivo testing was performed for the determination of thromboresistance and endothelial functional healing between the Resolute Onyx-DES , an identically designed BMS, and BioFreedom-DES. LEADERS FREE TRIAL
BF-DES vs. BMS Stent thrombosis 2.0% vs. 2.2% p=0.75
P Urban et al. NEJM 2015; 373:2038-2047 Thromboresistance An Ex Vivo Carotid to Jugular Arteriovenous Porcine Shunt Model Porcine AV shunt: carotid-jugular Arterialized flow using Sylgard tube Thrombus formation after 1 hour using customized sheath
Proximal Middle Distal
Artery ▪ All shunts running for 60 minutes Vein ▪ No anti-platelet treatment ▪ Target ACT 150-200 seconds Proximal Middle Distal
Bisected longitudinally
Immunofluorescent staining for platelet (CD61/42b) and assessed by CM
SEM Otsuka F, et al JACC Cardiovasc Interv 2015;8:1248 Platelet Aggregation
Onyx-DES Onyx-BMS BioFreedom
(%) 2 5 0 P<0.01 P=0.06 2 0 0
P<0.01 1 5 0
1 0 0
5 0
0 Onyx-DES Onyx-BMS BioFreedom (n=17) (n=10) (n=9) Inflammation Number of Neutrophils PM-1 (Neutrophils) CD14 (Monocytes) (n) P=0.17 1200 P=0.02 P=0.18
1000
DES
DES - - 800
600
Onyx Onyx 400
200
0 Onyx-DES Onyx-BMS BioFreedom
(n=17) (n=10) (n=8)
BMS
BMS
- - (n) Number of Monocytes
P=0.21 Onyx Onyx 1000 P<0.01 P=0.02 800
600
400
PM-1 CD14 200
DAPI DAPI BioFreedom
BioFreedom 0 CD61 CD61 Onyx-DES Onyx-BMS BioFreedom (n=17) (n=10) (n=8) In Vitro Flow Loop Model: Platelet aggregation Stent and Slide Preparation Platelet Preparation
1. Collect human blood (total 60ml, using citrate 0.32%) 2. 200g 10 min centrifuge (first spin) 3. Collect supernatant. 4. 700g 17min centrifuge (second spin) 5. Lower 1/3 PRP and upper 2/3 PPP. Collect PRP. 6. Resuspend PRP 7. Label platelet (using CMFDA) 45min 8. 1300g 10 min centrifuge (third spin) 9. Collect only pellet. And resuspend it using PPP (2-3ml) Final volume is usually about 20-25ml 10. Confocal Out of Confocal Microscopy In Confocal Microscopy
Stents
Tube Serum with albumin or platelets Slide Pump Human Platelet Aggregation in an in vitro flow model 60min
30 min In Vitro Flow Loop Model: Albumin binding and retention
A B
Lumen Slide
Stent Laser and camera Cover glass from the bottom side C D Albumin Binding Washing (30min) (30min)
Stents Stents
Pump Slide Pump Slide Tube Tube Laser and camera Fluorescent albumin from the bottom side DMEM Human Albumin Retention in an in vitro flow model 30min Human Albumin Retention in an in vitro flow model
Onyx-DES (mm2) Albumin positive area
10 P<0.01 P<0.01
Onyx-BMS 5 P<0.01
0 Onyx-DES Onyx-BMS BioFreedom (n=10) (n=4) (n=6) BioFreedom Endothelial Functional Healing Evaluation of Healing by SEM (28days)
Onyx-DES Onyx-BMS BioFreedom % Tissue coverage ns (%) P=0.03 P=0.03 1 0 0
5 0
0 Onyx-DES Onyx-BMS BioFreedom (n=12) (n=7) (n=6) Vascular Health Requires Good Endothelial Function
• Dysfunction of the endothelium is the initial inciting event in atherogenesis • VE-cadherin regulates endothelial barrier function via binding to p120 (red arrow). Impaired endothelial barrier function because of dissociation of VE-cadherin and p120 interaction (blue arrow) • Return of functional endothelial cells is necessary for complete healing
Confocal Microscopy Scanning Electron Microscopy Confocal Microscopy Scanning Electron Microscopy
Functional Functional Functional Functional
Dysfunctional Dysfunctional Dysfunctional X200 Dysfunctional X600 Evaluation of Healing by Confocal Microscopy
VE-Cadherin P-120 Onyx-DES Onyx-BMS BioFreedom
(%) 1 0 0 ns
ns ns
localization -
5 0
cad/p120 cad/p120 co - 0 Onyx-DES Onyx-BMS PF-BES % VE % (n=12) (n=7) (n=6) Evaluation of Endothelial Permeability by Evans Blue Dye Onyx-DES Onyx-BMS BioFreedom % Evans Blue positive area (%) 1 0 0 Evans blue uptake (%)8 0 ns(%)
P=0.03 ns ns P=0.02 6 0
4 0
2 0
0 Onyx-DES Onyx-BMS BioFreedom (n=12) (n=7) (n=6) Resolute DES: CVPath autopsy registry Stent thrombosis 2 / 294 sections (0.7 %) (1/39 cases)
Movat Movat H&E 1mm 66-yo white female 76-yo white female 74-yo white male Severe CAD, post-CABG, post-PCI Severe CAD, post-CABG, post-PCI VLST case (in LCX ostium) Resolute case case Integrity, 3.0*22mm) 3-y post Resolute implantation 2-y post Resolute implantation 4-y post implantation (1-yr Asprin RCA; Resolute Integrity 3.0*18mm LCX; Resolute Integrity 3.0*30mm +Ticagrelor, followed by Asprin 81 mg) LAD ostium: Resolute Integrity BIONYX Trial: Onyx Versus Orsiro
Resolute Onyx vs. Orsiro Stent Thrombosis 1 (0.1%) vs. 9 (0.7%) P=0.0112
VON BIRGELEN C, ET AL. LANCET. 2018;392:1235-1245. Summary Thromboresistance Resolute Onyx-DES showed superior thromboresistance relative to Onyx-BMS and BioFreedom in porcine shunt model. Albumin (human) retention was significantly higher in Resolute Onyx-DES as compared to Onyx-BMS and BioFreedom. . Endothelial Functional Healing Onyx-DES showed comparable healing function to BF-BES. Conclusion • Taken together these results demonstrate the thromboresistance and early healing of Resolute-Onyx-DES. These properties are essential for patients who may need to interrupt or discontinue DAPT shortly after stent placement. • These preclinical data are supported by the recent Bionyx Trial in which Onyx had a ST rate of 0.1%. • 1-month DAPT after Onyx-DES maybe promising and this question will be answered by the results of the Onyx One Trial. Onyx ONE Global Randomized Trial Acknowledgments
CVPath Institute Hiroyuki Jinnouchi, MD Atsushi Sakamoto, MD Rika Kawakami, MD Masayuki Mori, MD Yu Sato, MD Anne Cornelissen, MD Liang Guo, PhD Robert Kutyz, MS Russ Jones Ed Acampado, DVM Abebe Atiso, HT Jinky Beyer Washington DC Lila Adams, HT Frank D Kolodgie, PhD Aloke V Finn, MD