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Magmaris: the impact of scaffold design and materials on reducing

thrombogenicity

Michael Joner, MD

Deutsches Herzzentrum München und Deutsches Zentrum für Herz-Kreislaufforschung e.V.

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

Potential conflicts of interest

2.8%

0.0%0.0%

0.5%

1.0%

1.5%

2.0%

2.5%

3.0%

3.5%

4.0%

Absorb Xience

Def

init

e/P

rob

able

Sca

ffo

ld T

hro

mb

osi

s (i

n %

)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

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

ABSORB II – 3-year data1 ABSORB III – 2-year data2

P=0.03

1.9%

0.8%

0.0%

0.5%

1.0%

1.5%

2.0%

2.5%

3.0%

3.5%

4.0%

Absorb Xience

Def

init

e/P

rob

able

Sca

ffo

ld T

hro

mb

osi

s (i

n %

)

P=NS

AIDA – 2-year data3

3.5%

0.9%

0.0%

0.5%

1.0%

1.5%

2.0%

2.5%

3.0%

3.5%

4.0%

Absorb XienceD

efin

ite/

Pro

bab

le S

caff

old

Th

rom

bo

sis

(in

%)

P<0.001

Scaffold thrombosis in Magmaris

BIOSOLVE-I36-month follow-up

Definite/Probable Scaffold Thrombosis

0.0%

BIOSOLVE-II24-month follow-up


0.0%

BIOSOLVE-III6-month follow-up


0.0%

1) BIOSOLVE-I data from Haude M. et al., EuroIntervention 2016;12:e160-e1662) BIOSOLVE-II data from Haude M., oral abstract presentation, EuroPCR 20173) BIOSOLVE-III data from Haude M., oral abstract presentation, EuroPCR 2017

DREAMS-1G Magmaris

Scaffold Thrombosis Factors

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

Stent geometry

Computed flow dynamics aims to explain how strut thickness may influence device

thrombogenicityGreater 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) 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

1) 2)

3)

Computed flow dynamics suggest accelerated endothelialization in Magmaris relative to Absorb

IIB(R)03_2017_Entwurf BIOTRONIK data on file

Magmaris

Absorb

The Magmaris 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.

highlow

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 Magmaris vs. Absorb vs. Orsiro

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

Shunt study 1: Comparison of acute thrombogenicity of Absorb vs Magmaris vs. Orsiro

Detection of platelets and inflammatory cells by immunofluorescence

Estimation of thrombus deposition by SEM

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:Magmaris vs. Absorb vs. Orsiro

Shunt study 1: Comparison of acute thrombogenicity of Absorb vs Orsiro and Magmaris



Photo

IF

SEM

Absorb Orsiro Magmaris

Waksman R. et al., In press Circulation Cardiovascular Intervention

Results Shunt Study 1: Magmaris vs. Absorb vs. OrsiroScanning Electron Microscopy

Significantly less thrombus deposition in Magmaris compared to Absorb

Less inflammatory cells in Magmaris compared to Absorb

Arrows: thrombus deposition, arrowhed: inflammatory cells


Results Shunt Study 1: Magmaris vs. Absorb vs. Orsiro

Immunoflurescence Significantly less platelet coverage in Magmaris and Orsiro compared to Absorb


Evaluation of acute thrombogenicity in Magmaris vs. 316L-Equivalent

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

Shunt study 2: Effect of magnesium backbone on acute thrombogenicity of Magmaris vs Magmaris scaffold design in stainless steel (316L-equivalent):



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: Magmaris vs 316L-Equivalent

Shunt study 2: Effect of magnesium backbone on acute thrombogenicity of Magmaris vs 316L-Equivalent:



Photo

IF

SEM

Magmaris 316L-Equivalent

Results Shunt Study 2: Magmaris vs 316L-EquivalentScanning Electron Microscopy

Significantly less thrombus deposition in Magmaris compared to 316L-Equivalent

Less inflammatory cells in SEM

Magmaris 316L-Equivalent

Arrows: thrombus deposition, arrowhed: inflammatory cells


Immunofluorescence Significantly less platelet coverage in Magmaris compared to stainless steel Magmaris

P<0.0001

316L-Equivalent

Magmaris

stainless steel Magmaris


Stent geometry





Stent geometry

Computed flow dynamics aims to explain how late recoil may cause malapposition which in turn may influence device thrombogenicity

Magmaris 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.113.0009313) 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.100.0032104) Jiménez J.M., Davies P.F. Hemodynamically Driven Stent Strut Design. Annals of Biomedical Engineering. 2009

Magmaris MagmarisAbsorb Absorb

1

Computed flow dynamics predicted the impact of recoil on the risk of platelet activation

and platelet aggregation Magmaris was simulated with a stable 5% recoil. Absorb was simulated with a 5% and 8% recoil at acute and 1 hour post-

implantation respectively1. Only the results 1-hour post-implantation are shown here.

Computed flow dynamic simulation predicts the lowest risk of platelet activation for Magmaris 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 Magmaris.2

Finally, the transported platelets aggregate. The risk of platelet aggregation is lowest for Magmaris compared to Absorb.2

1) Schmidt W. et al, Cardiovasc Revasc Med 2016;17(6):375-832) 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

0.11

0.27

0

0.05

0.1

0.15

0.2

0.25

0.3

Magmaris Absorb

Pla

tele

t Sh

ear

N

um

ber

(P

SN)

12.6

14.1

0

5

10

15

Magmaris AbsorbP

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let

Agg

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n

Nu

mb

er (

PAN

)2.34

3.05

0

0.5

1

1.5

2

2.5

3

3.5

Magmaris Absorb

Pla

tele

t C

on

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ion

N

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(P

CN

)


Stent geometry





Stent geometry

Magmaris vs Absorb endothelialisation in rabbitmodel at 28 days

Vessel surface coverage of BRS struts determines pace of re-endothelialisation

Magmaris PLLA BRS

Waksman R. et al., EuroIntervention 2017; published online ahead of print

PLLA BRSMagmaris

p<0.004

p = 0.007


Stent geometry





Stent geometry

Results Shunt Study 1: Magmaris vs. Absorb vs. Orsiro

Immunoflurescence (2) Significantly less Neutrophil (PM1+) adherence in Magmaris and Orsiro compared to Absorb

Significantly less Monocyte (CD14+) adherence in Magmaris compared to Absorb

PM1+ Neutrophil staining: green, CD14+ Monocyte staining: green, DAPI nuclei staining: blue, CD42b/CD61 platelelt staining: red



Immunofluorescence – Neutrophil Attachment Significantly less Neutrophil (PM1+) adherence in Magmaris compared to 316L-Equivalent

P<0.001

Magmaris

316L-Equivalent

316L-Equivalent


Immunofluorescence – Monocyte Attachment Significantly less Monocyte (CD14+) adherence in Magmaris compared to 316L-Equivalent

Magmaris

P<0.0001

316L-Equivalent

316L-Equivalent

Conclusions

Geometric design of Magmaris impacts favorably on acutethrombogenicity relative to Absorb and Orsiro

Endothelialization is advanced in Magmaris relative to Absorb in a rabbitmodel at 28 days

Magmaris hemodynamic flow properties and biocompatible coating seemto have favorable effects on platelet aggregation and endothelialisation1

Decreased inflammatory cell attachment in Magmaris relative to Absorband Orsiro is observed 1 hour following AV shunt flow

The BIOlute coating showed reproducible hemocompatibility on variousdesigns

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

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