OnyxAVMPhysicianTrainingPresentationInt 'l

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Onyx™ Liquid Embolic System

Physician Orientation ReviewInternational

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Materials and Indications

• This presentation is intended for the purpose of didactic review with physicians regarding the use of the Onyx LD Embolic System– Model #’s 105-7000-060, 065, 080 (Onyx 18, 20, 34)

• Indications for Use: Embolization of lesions in the peripheral and neurovasculature, including arteriovenous malformations and hypervasculartumors.

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Onyx Development

• Ongoing research since 1993

• Human clinical studies commenced 1997

• Name change 1999: Embolyx to Onyx (LES)

• CE Mark received for AVM indication, July 1999– Regularly used since then in Europe

• Estimated worldwide procedures: 15,000+

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Onyx Liquid Embolic System

• Ethylene-vinyl alcohol copolymer– EVOH

• Dimethyl Sulfoxide Solvent– DMSO

• Micronized tantalum powder– Ta

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Onyx Embolization Process

• Onyx is a pre-mixed, radiopaque, injectable embolic fluid.

• Polymer precipitation occurs upon contact with aqueous solution.

• Contact with blood = “Precipitation”

• Solvent diffuses away

• Forms a spongy polymeric cast

• Forms a skin - solidifies from the outside in

• Liquid center continues to flow

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Characteristics

• Onyx delivers in a cohesive manner• Analogy of “lava” demonstrates characteristics of

behavior).

Onyx PrecipitateExternal Surface

Onyx PrecipitateInternal Surface

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Device Components

• 1.5 ml vial of Onyx– Onyx 18, 105-7000-060– Onyx 20, 105-7000-065– Onyx 34, 105-7000-080

• 1.5 ml vial of DMSO• MTI 1 ml luer-lock delivery syringes

– 2 white for Onyx, 1 yellow for DMSO

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Onyx Relative Viscosity

Onyx HD - Aneurysm Therapy

Onyx AVM v. HD for Aneurysms –

Entirely Different Viscosity

0

100

200

300

400

500

600

6% 6.50% 8% 20%Viscosity doubles between

Onyx 18 (6%) to Onyx 34 (8%)

Onyx LD - AVM Formulations

0

5

10

15

20

25

30

35

40

Water HumanBlood

25%nBCA

6% 6.5 8%

Scale = centistokes VS.

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DMSO (Dimethyl Sulfoxide Solvent)

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DMSO Study Review

• In ‘90 - ‘91 Taki and Terada successfully described embolization with EVAL dissolved in DMSO

• Safety concerns emerged

• Chaloupka and Viñuela conducted early UCLA study - showed severe vasospasm and angionecrosis

• Subsequent studies show safety of the Onyx delivery protocol– Dr. Chaloupka (1999)– UCLA (1998)

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Chaloupka et, al., UCLA, AJNR, June 1994

• 1st study: DMSO intra-arterial injections in volumes – 0.5 mL and 0.8 mL – Injected over a timeframe of 15 seconds or less

• Rete mirabile of 29 swine

• When injected over relatively rapid timeframes– DMSO was reported to cause moderate to severe

vasospasm– Sub arachnoid hemorrhage (SAH), stroke or death

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Murayama, (et al) UCLA, Neurosurgery, November 1998

• Embolyx E (now Onyx) and its solvent DMSO– 44 rete mirabile in 22 swine

• Study showed two important factors influencing vascular toxicity:– Contact time with arterial wall– Volume of DMSO

• Fast delivery (0.5 mL in 5-15 seconds) – Caused severe vasospasm and histological endothelial

necrosis• Slow delivery (0.5 mL in 30-120 seconds)

– Showed no vasospasm, minimal inflammation and no complications

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Chaloupka, (et al) AJNR, March 1999

• At MTI’s request, Dr. Chaloupka agreed to conduct a 2nd study reexamination DMSO angiotoxicity

• Purpose was to evaluate the effects of intra-arterial DMSO injections at slower rates of 30, 60 and 90 seconds

• Rete of 26 swine• No acute hemodynamic alterations• No infarction or SAH

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Chaloupka, (et al) AJNR, March 1999

• No significant changes in arterial blood pressure

• No alterations in heart rate or ECG

• Conclusion: – Found that lower dose rates of superselectively infused DMSO

are associated with a more acceptable safety and histotoxicity profile than previously reported

– Chaloupka confirmed Murayama’s results

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DMSO Overview

• Enters the bloodstream and is absorbed into tissues

• Metabolized to dimethyl sulfone (DMSO2) and dimethyl sulfide (DMS)– 80% of these metabolites are eliminated via the kidneys in

urine within a week

– Also eliminated via the skin or lungs which causes a garlic odor to the breath

• Complete elimination: 13-18 days

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Procedure Guidelines

Please refer to the Instructions for Use for full prescribing details

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Onyx Animation

Onyx AVM Animation available

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Shake Onyx Vials

• Place vials on mixer

• Set mixer to maximum setting

• Shake for a minimum of 20 minutes

• Maintain shaking of vials until ready to use

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Superselective Contrast Injection

• Confirm micro catheter placement

• Contrast agent per institutional procedure

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Flush Microcatheter

• Flush contrast from micro catheter

• IFU state 10ml of saline

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Prime Catheter with DMSO

• Aspirate 0.8 mL DMSO into the yellow MTI DMSO 1 mL syringe

• Inject DMSO to sufficiently fill dead space of delivery catheter– Marathon = 0.23mL – UltraFlow HPC = 0.26mL

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Prepare Onyx Delivery Syringe

• Remove prepared vial from shaker

• Aspirate 1 mL Onyx into the white MTI Onyx 1 mL syringe– Using an 18 or 20 gauge

needle

• Clear any air bubbles within the syringe and hub

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• When ready to deliver Onyx, remove DMSO syringe

• Hold the micro catheter hub in a vertical position

• Overfill hub of the catheter with the balance of DMSO

Overfill Hub with DMSO

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Onyx Delivery Syringe

• Connect Onyx syringe to the hub.

• For optimal fluoroscopic visualization, quickly point vertically to create an interface between DMSO and Onyx.

• While holding the syringe vertically, begin injection Onyx to displace DMSO.

• Inject Onyx at the recommended slow, steady rate of:0.25ml over 90 seconds, (approx. 0.1 mL/min)

IFU states: “Do not exceed a 0.3 mL/min”

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Continue Injecting Onyx

• Continue holding the syringe vertically until Onyx passes through the hub

• Once Onyx passes through the hub, the syringe may be held in a comfortable (horizontal) position

• Begin fluoroscopic imaging just prior to delivering catheter dead space:

– Marathon = 0.23mL – UltraFlow HPC = 0.26mL

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Detachment of Catheter

• After completion of Onyx injection, slightly aspirate syringe: Only 0.1ml is needed

• Gently, slowly and “incrementally” pull the catheter a few centimeters at a time.

• Tension will increase in catheter– Hold when sufficient tension is

reached– Gradually increase

• Catheter will release

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Onyx Preparation

1. Shake Vials 20 minutes

6. Displace DMSO 0.25ml / 90 secs

3. Load dead space with DMSO

4. Overwashcatheter hub

5. Connect Onyx Syringe vertically

2. Flush Catheter

7. Fluoro just prior to filling deadspace

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Onyx AVM

Technique

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“Plug and Push” Technique

• Create a “plug” around catheter tip

• Allow use of “Flow Arrest” to promote distal movement

• Use a “waiting technique” to create change in pressure

• Can help improve penetration

• Must balance with cautions and risks

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Hints for Plug and Push Technique

• Re- road map after each “injection” cycle (wait time)– This will help monitor deposition and movement of “new” material

• May be necessary to repeat cycle multiple times during an injection– When material first begins to reflux…– wait :30 seconds to break the motion…– upon re-injection again the material should move distally

– As a full circumferential plug forms…– wait up to 2:00min to solidify flow arrest…

• When beginning injection… SLOW gentle injection will help control new deposition

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Technique Decision Tree

Begin Slow OnyxInjection

Reflux (laminar/plug) ?

Pause

:30 SecondsMomentum Break

2:00 MinutesSolidify Plug

ContinueConstant Slow Rate

Forward Penetration

Re-InjectRepeat Process

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Potential Risks

• Using Plug and Push can create conditions that should be monitored closely.

• Waiting time– Catheter occlusion/pressure build up

• Possible reflux– Catheter Removal

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Fundamentals of AVM Embolization…

Imaging/Working Projection

Microcatheter Position

Microcatheter RetrievalPedicle Selection Size

Contribution / Flow

Onyx Technique

Are Critical to Onyx PerformanceAre Critical to Onyx Performance

Injection Speed Delivery Rate

Waiting Time / Pressures

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Imaging/Working Projection

• Always work with Reference Image and Working Projection

• A reference image becomes very useful during long Onyx injections – Catheter distal shaft – Nidal Angioarchitecture– Primary venous drainage

• Optimize working projection: – Separation of catheter tip, minimal foreshortening of catheter – Allows to recognize, measure and manage reflux– Instructions for Use recommends a maximum of 1cm reflux– Modifications based on anatomy

• Distal turn or bend in catheter tip• Select a point on catheter (a turn or bend) to use as a reference and

reflux limit

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Reference Images

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Feeder Selection

• Larger contributing feeders seem to promote penetration:

– Generally easier to reach nidal position– Generally provide a greater pressure

gradient– Therefore can capitalize on Onyx

characteristics for better penetration.

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Feeder Selection

• Small pedicles can have limited penetration

– Especially if proximal – because of change in pressure as feeder fills… can cause limited nidal penetration.

– Must inject very slowly, control reflux, and expect possibly limited nidal delivery from small feeders.

– Risk of delayed catheter retrieval can occur… because of potential spasm / reflux build up quickly.

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Microcatheter Position

• Intra-nidal (or wedged) position seems optimal– Or as close as possible to nidus – Especially because Onyx performs best when “pushed” into the

lesion

• Proximal positions:– May result in minimal nidal deposition and a “feeder” injection

– As Onyx is delivered into feeder, the pressure gradient changes.As feeder closes, the path of least resistance becomes retrograde reflux occurs.

– “Plug and Push” may not achieve same results as nidal position

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Injection Rate

• The Slower… The Better – Better Control and Better

penetration overall– More penetration before

reflux and more control when reflux occurs

• Rate must be constant and slow– Any change in injection rate

will create reflux– If rate is too fast, reflux will

occur quickly

• Using the “DMSO Displacement” rate as a reference– 0.25ml over 90 seconds

= 0.16ml / minute – Continue this rate (or

slower)– Case examples: 0.10 -

0.15 ml / minute

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Consider all the Consider all the factors that can factors that can affect affect difficult difficult catheter removal:catheter removal:

Length of Reflux

Distal 2cm (loop, hook)

Potential for Spasm

Time of Injection

Size of Feeder

Tortuosity

Difficult CatheterRetrieval

••Evaluating these parameters prior to injection can determine howEvaluating these parameters prior to injection can determine how much reflux will be acceptedmuch reflux will be accepted

Catheter Retrieval

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Retrieval Techniques: Two Paths

Two Techniques ProvideVersatile, Effective Use

Slow “Traction”Technique

Quick “Wrist Snap”Technique

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Slow “Traction” Technique

• Slowly, and incrementally (cm by cm), withdraw the catheter

• Tension will slowly increase creating retrieval force directly to the catheter tip

• Sustain “moderate” tension (hold for a moment)

• Catheter tip will “release” from Onyx cast

• Completely withdrawal catheter

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Quick “Wrist Snap” Technique

• Remove all “slack” from catheter. Withdraw catheter 3 – 5 cm.

• This will create a slight tension throughout the catheter

• Quickly move wrist from left to right (about 10 – 20cm)– No need to move the entire arm– This is NOT like a glue technique

• This provides a “spark” of energy through the catheter– Without stretching the catheter too much and risking breakage

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Step #2: Assess risk of spasm or vessel

damage

Is the catheter tip beginning to release

from Onyx cast?``

Is the vasculature straightening ?

Is the Onyx cast retracting?

Step #2a: Sustain Traction and Monitor Tip Release

Step #1: Apply gentle, incremental traction to catheter (cm by cm)

Step #3: Release Traction and Repeat Decision Tree

Applying Intermittent Traction As Necessary

Catheter Retrieval Management

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Quick Wrist Snap - Steps

Create slight tension

•Remove all “slack” from the catheter –•By pulling a few cm.

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Quick Wrist Snap - Steps

NOTE: It is not necessary to move the entire arm (such as a glue technique). This technique can risk catheter separation.

0cm 20cm

Quick but Short

Wrist Motion

•Quickly move wrist 10 – 15cm to the right•Making a “wrist snap” motion

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Onyx Delivery Microcatheters

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Onyx Delivery Systems

Rebar

Mirage

X-pedion, SilverSpeed

Guidewires

Marathon & Ultraflow Echelon 10 and 14

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Onyx Catheters

Onyx Delivery Catheter

Flow Directed CatheterOver The Wire

Benefits• Reinforced• High Tensile Strength• Burst Profile

Uses• Coils• Liquid Embolics• Particles

UltraFlow

Marathon

Apollo, 2009

Benefits • Soft Supple Tip• No Guidewire• Superior Navigation

UsesAVM embo (nBCA)

• Soft Supple Tip• Superior Navigation• High Tensile Strength• Burst Pressure

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Embolic Injection Pressure v. Burst

• Onyx injection requires very low pressure of approximately 20psi injected at a rate of (0.1 ml / min)

• Marathon provides a robust tolerance between Onyx injection pressure and Onyx burst pressure and is more than 2x in UltraFlow

Source: TR 03-106, UltraFlow TR01-116Test Method: TM0090, Onyx Plug & Push: 1 hour Onyx injections, repeated pressurization to intentional failure.Engineering Note: Test results show that when catheter is intentionally ruptured, the UltraFlow fails between the fuse joint and distal tip, while Marathon fails in the distal

7cm.

psi

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50

100

150

200

250

300

350

400

Onyx 18Injection

UltraFlow Marathon

0.1 ml / min

18x tolerance

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Pressure to Re-inject v. Wait Time

0

20

40

60

80

100

120

140

160

0 30 secs 1min 1.5min 2min 3min 5min

PSI

Wait Time

• Recommendation: Limit “Wait” time less than 2 min.– Onyx mass can precipitate in 3 - 5 minutes.– The increased injection pressure (after a long wait) can approach this limit.

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Summary: Burst Performance

• Recognize occluded catheter if Onyx is not exiting catheter tip – Occlusion may occur after extended wait period during Onyx injection

• Do not interrupt Onyx injection more than 2 minutes

• If Onyx is not exiting tip, do not inject more than 0.05 ml into a potentially occluded catheter.

• Static Pressure to burst the UltraFlow or Marathon should be “recognizable”to identify resistance.

– If resistance is felt, stop Onyx injection.

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Detachment Force – from Onyx Cast

• Marathon design requires 25% less force to retrieve from a cast of Onyx (see test method) than UltraFlow

Source:, Marathon TR 03-106, UltraFlow TR01-116Test Method: TM 0090: Flow model, 3cm Onyx reflux, 1 hour dwell time, at body temperature, slow pull technique

0

10

20

30

40

50

60

70

UltraFlow Marathon

Retrieval Force

Gra

ms

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Distal Tensile Strength

0

100

200

300

400

500

600

Magic 1.2 Magic 1.5 Spinnaker UltraFlow Marathon 1.3

Distal Tensile Strength

• Marathon braiding provides significant tensile strength for excellent catheter retrieval

Source: UltraFlow TR01-116, Marathon TR 03-106, Other Catheters: TR02-088Test Method: TM0080 – test a 1” distal segment gauge length, stretch to break at 20” / min

Gra

ms

130%130%

71%

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FD Catheter Stretch Profile

• Recommended Traction Limit should be < 20cm– Note: If catheter is trapped at distal tip - recommendation offers safety

margin to minimize risk of catheter separation.

0

100

200

300

400

500

600

1cm 3cm 5cm 10cm 15cm 20cm 43cm

Recommended Traction Limit < 20cm

Distance of catheter ‘traction’ (cm)

Stretch Point to Breakage

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Access Summary

• Tip shaping: – It is not necessary to “overshape”

• Guidewire technique: – Some clinicians recommend keeping the guidewire placed just past the

distal tip marker during navigation. This helps maintain a patent lumen and minimize risk of catheter prolapse

• Angiographic technique – Some physicians suggest using a gentle, low volume “puff” of contrast to

confirm catheter patency.

• Less Magnification / Larger Field of View– Prior to embolic delivery, it is suggested to deliver a small volume contrast

injection – While viewing the entire distal catheter segment to verify catheter integrity.

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Onyx™ Liquid Embolic System

Physician Orientation ReviewInternational

CAUTION: Federal (USA) law restricts this device to sale by or on the order of a physician. A complete statement of indications, contraindications, warnings and instructions can be found in the product labeling supplied with each device. WARNINGS: Serious, including fatal, consequences could result with the use of the Onyx LES without adequate training. Contact your ev3 Sales Representative for information on training courses. Onyx is a registered trademark of ev3.