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Drug Drug Eluting Eluting BalloonsBalloonsBackground and Background and RationaleRationale

Pieter R. Stella, MDDept. of Interventional CardiologyUniversity Medical Centre UtrechtThe Netherlandsp.stella@umcutrecht.nl

Glimpse into the Future Glimpse into the Future –– May 21May 21

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Disclosure Statement of FinancialDisclosure Statement of Financial InterestInterest

Member Advisory Board Eurocor GmbH

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Why do we want a DEB in a DESWhy do we want a DEB in a DES--era?era?A: we unfortunately still have DESA: we unfortunately still have DES--restenosisrestenosis

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AndAnd . . we have economic & health issues :

stentcoststentcost and (life ?)and (life ?)--long dual long dual antiplateletantiplatelet therapy ??therapy ??

StillStill . . persisting safety issue due to absence of neointimal coverage and late malapposition: patient compliance ?

late & very late stent thrombosis !late & very late stent thrombosis !

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Why do we want a DEB ?Why do we want a DEB ?

1. Small Vessels

2. Bifurcations

3. Diabetics

4. Acute Myocardial infarction

DES: still not perfect in ;

““Late Late malappositionmalapposition””

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Potential Advantages DEB

Local drug delivery over very short period of time : not weeks / months

Avoid chronic inflammation due to absence polymers

Better re-endothelialization : reduced dual antiplatelet therapy

No distortion of original vessel anatomy (BIF)

No double / triple metal layers in case of ISR or BIF

Easy lesion crossing / deliverability by balloon only

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MethodsMethods & Techniques & Techniques

• lipophylic drug (rapid absorption) for short inflation times

• sustained retention into tissue (microtubuli / cytoskeleton)

• prevention of drug release before landing at ‘ target ‘ (“wash-off”)

• increased profile compared to non-coated balloon

• 3 3 μgμg paclitaxel / mm2 balloon paclitaxel / mm2 balloon surfacesurface

Several techniques and methods however common properties:

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WhyWhy PaclitaxelPaclitaxel ?*?*

1. The ideal drug needs to inhibit cell proliferation without killing the cells. 

2. Paclitaxel has a dose dependant effect associated with a large therapeuticwindow.

CytostaticCytostatic Cytotoxic !!

* Axel et al: Circulation. 1997; 96:636-645; Sollot et al; J. Clin.Invest. 1995; 95: 1869-1876;

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How How doesdoes itit workwork ??

Restenosis is a complex mechanism involving many actors

Restenosis // Healing

RestenoticRestenotic Cascade*Cascade*

Inflammatory Cells

SMC Proliferation

SMC Migration

ECM

Platelet Aggregation

Endothelialization

0–2Days

2–4Days

4–10 Days

10–14 Days

2–4 Weeks

* Table adapted from Ferns et al: International Journal of Experimental Pathology,2000; 81:63-88

Paclitaxel release from PEB

Paclitaxel release from PES

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MethodsMethods & Techniques & Techniques

Paccocath Technology € : matrix coating with ‘hydrophylic spacer’ which leads to high contact surface, more uniform and complete release between the lipophilic drug molecules and the vessel wall. High tissue concentration > 450 µM/L

Invatec FreePac Technology € : separates Paclitaxel molecules and balances hydrophilic and lipophilic properties. Facilitates Paclitaxel elution into the vessel wall. Total drug elution time to 30 – 60 seconds. Tissue concentration ?

Lutonix Coating Technology: active agent and additives which prevents premature release from the balloon surface and facilitates rapid release of drug from the balloon. Tissue concentration ?

€: comercially available

paclitaxelpaclitaxel + ‘additives’+ ‘additives’

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MethodsMethods & Techniques& Techniques

matrix coating: paclitaxel + hydrophilicspacer (iopromide)pure paclitaxel

Paclitaxel Paclitaxel + separator molecule

Paccocath Technology

FreePac Technology

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MethodsMethods & Techniques & Techniques

Eurocor Dior Technology € : shellac® coating and balloon folds to prevent wash-off. Drug delivery by simple diffusion. Medium tissue concentration 50>x< 200 µM/L

Aachen Resonance Elutax Technology € : drug encased in the surface, 20 % release by diffusion after each inflation. Tissue concentration ??

Acrostak Genie Technology € : liquid drug delivery by operators discretion. Dosage ? Tissue concentration ??

paclitaxelpaclitaxel withoutwithout ‘additives’‘additives’

€ Comercially available

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DIORDIOR™™ TechnologyTechnology::• Paclitaxel balloon surface: 3 µg/mm²

• Coating method is a 1:1 mixture of Paclitaxel (Ph Eur.) and Shellac (Ph Eur.)

• Additional protection of wash off effect: drug hidden within the balloon folds

• Delivery by simple diffusion (Paclitaxel = lipofylic)

• The Coating is CE marked

• Shellac is well established in Cosmetics, as food coating and Tablet coating.

• Balloon inflation time recommended: 20-30 sec. @ nominal balloon pressure

- No additional drug release after 45 sec.

The optical refraction of Shellac gives balloon a shiny appearance

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Inflation time-dependent tissue concentrations of paclitaxel from the Dior balloon N=29*

0

50

100

150

200

250

300

15 sec 20 sec 30 sec 45 sec

Prox. Ref Balloon Dist.Ref

(µM/L)

Arterial tissue paclitaxel concentration

*Gyöngyösi et al

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ClinicalClinical Data IData I

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ClinicalClinical Data IIData II

By :Scheller etal.

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ClinicalClinical Data IIIData III

Presented by Bruno Scheller @ JIM 09

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ClinicalClinical Data IVData IV

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DDrug rug EEluting luting BBalloon in alloon in bbIIffUUrcationrcation TTrialrial“ DEBIUT “ DEBIUT --registry“ 6 mo clinical FUregistry“ 6 mo clinical FU

Medina classification Medina classification type:type:(proximal main (proximal main branch, distal main branch, distal main branch, and side branch, and side branch branch involvementinvolvement

Number of patients Number of patients ((nn = 20)= 20)

(n (n [[%%]]))

1.1.11.1.1 12 (60)12 (60)

1.1.01.1.0 2 (10)2 (10)

1.0.11.0.1 4 (20)4 (20)

0.1.10.1.1 2 (10)2 (10)

QCAQCA Main branch Side branch

Lesion length (mm)

15.5 +/- 5.0 4.2 +/- 2.8

Stent length (mm)

19.0 +/- 6.0 -

Reference vessel

diameter (mm)

3.0 +/- 0.6 2.4 +/- 0.4

100 % successful100 % successful

No MACE , no SATNo MACE , no SATBy:Fanggiday et al, CCI vol 71- 529-5352008

Clinical Data V

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BifurcationBifurcation interventionintervention withwith DIOR DIOR balloonballoon: DEBIUT : DEBIUT studystudy

index

baseline

6 month FU

1. Predilatation with DEB, followed by one BMS (prov. T –technique)

2. Only 3 months of DAPT

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BifurcationBifurcation interventionintervention withwith DIOR DIOR balloonballoon: DEBIUT : DEBIUT studystudy

index index

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TherapeuticTherapeutic WindowWindow **

1. The ideal drug needs to inhibit cell proliferation without killing the cells. 

2. Paclitaxel has a dose dependant effect associated with a large therapeuticwindow.

CytostaticCytostatic Cytotoxic !!

Highest average peak tissue concentration (0,3µg/ml)  observed with DIORTM PEB

* Axel et al: Circulation. 1997; 96:636-645; Sollot et al; J. Clin.Invest. 1995; 95: 1869-1876;

Is this important ??Is this important ??

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*Sequent Please – Paccocath technique

24By Dr. Echevarri –Solaci 2008 Cancun

Coronary Aneurisms AfterPaclitaxel – Coated Balloon in PigsAneurisms in High Dose PEB Group

Restenosis Inhibition Restenosis Inhibition -- TherapeuticTherapeutic WindowWindow

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to Summarize: to Summarize: Where would we want a DEB ?Where would we want a DEB ?

•• In stent In stent restenosisrestenosis : avoid double/triple metal layer: avoid double/triple metal layer

•• Small vesselsSmall vessels : DES not perfect, better ‘: DES not perfect, better ‘crossabilitycrossability’’

•• BifurcationsBifurcations : avoid uncontrolled drug release by (mini: avoid uncontrolled drug release by (mini--) ) crushing polymers, SB is small vessel, ease of procedure, crushing polymers, SB is small vessel, ease of procedure, no distortion of original BIFno distortion of original BIF--anatomyanatomy

• Acute coronary syndromes : local plaque stabilization, avoid late malapposition DES

• Below the Knee : no stent fractures

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ConclusionsConclusions

1. Early results very promising – especially for ISR and BTK

2. Limited Results on Long term clinical effects de novo lesions

3. Reduction of dual antiplatelet therapy icw. BMS (3ms) seems safe

4. Clinical trials ongoing in bifurcatons (DEBIUT), AMI (DEB-AMI), small vessels and de novo lesions (DILATATION) and . . . . soon much more

5. We need to establish the tissue concentration as a We need to establish the tissue concentration as a meaningful value and understand which dosage is effective meaningful value and understand which dosage is effective andand safe !safe !

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Heart Lung Centre Utrecht Heart Lung Centre Utrecht -- UMCUUMCU

20092009

1800 PCI 1800 PCI

20 ASD / PFO20 ASD / PFO

25 25 Percut.ValvePercut.Valve

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ClinicalClinical Data VIData VI

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0

0,5

1

1,5

2

2,5

3

3,5

Lumen area Neointima Area IEL Area Media Area EEL Area

Dior Non-coated balloon

mm2

p<0.001

p=0.045

0

10

20

30

40

50

60

70

%Area stenosis

Dior Non-coated balloon

0

0,05

0,1

0,15

0,2

0,25

0,3

0,35

0,4

0,45

0,5

max. neoint. Thickness

Dior Non-coated balloon

%AreaArea stenosisstenosis

Max. Max. neointneoint. . thicknessthickness

P<0.001

p=0.039

%

mm

Quantitative Quantitative histologicalhistological resultsresults in in overstretchoverstretch pocinepocine arteriesarteries ––FU @ 14 FU @ 14 daysdays (N=12) **(N=12) **

**Gyöngyösi et al

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NonNon--coatedcoated balloonballoon Dior II balloonDior II balloon

Study design **(Randomized N=12)

Porcine coronary arteries were dilated (1.3:1 balloon/artery ratio) with either

Dior balloon (3 µg/mm2 paclitaxel balloon surface) or noncoated balloon

Follow-up angiography and obdution: 14 days post-balloon dilatation

**Gyöngyösi et al

EurocorEurocor DiorDior™™ TechnologyTechnology::Medium Dose ReleaseMedium Dose Release

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2h post-dilatation

0± 0

0.81± 0.389

2.642± 2.157

4.342± 0.734

9.778± 6.65

5.862± 2.094

1.84± 1.963

5.779± 3.064

1.219± 0.4

1.227± 0.367

0± 0

0.49± 0.195

0.647± 0.322

0.315± 0.151

12h post-dilatation

baseline kissing final

ArterialArterial tissuetissue paclitaxelpaclitaxel concentrationconcentration

DIOR in MB DIOR in SB

µg/gµg/gGyöngyösi et al., Coron Artery Dis. 2008 Jun;19(4):243-7

BifurcationBifurcation interventionintervention withwith DIOR I DIOR I balloonballoon