Please Note: Due to technical difficulties the medical contrast images will not be in motion, the images will appear as still pictures. For medical images.

Please Note:

Due to technical difficulties the medical contrast images will not be in motion, the images will appear as still pictures.

For medical images please refer to the transcript, Part 2, beginning on page 101 for the description of the image that was provided by the presenter.

OPTISON™GE Healthcare

FDA Cardiovascular and Renal Drugs Advisory

Committee

June 24, 2008

June 24, 2008 OPTISON 3

Optison Presentation OverviewIntroductions

Larry Bell, MDGlobal Head Regulatory Affairs GE

HealthcarePre-Clinical

Morten Eriksen. M.D., Ph.D. Senior Scientist, PhysiologistGE Healthcare

ClinicalSteven B. Feinstein, M.D., F.A.C.C.Professor of MedicineDirector - Echocardiography LabRush University Medical Center Chicago, IL

OPTISON™ CMC and Pre-clinical Data

Morten Eriksen, MD, PhDSenior Scientist

GE Healthcare


Content

Chemistry, Manufacturing and Control (CMC)

Pre-Clinical data

Animal Models


Optison constituents

Structure of the Optison microsphere: Octafluoropropane encapsulated by a 15 nm thick shell of heat denatured human albumin.

Except from the gas, Optison is essentially identical to Albunex.

Optison contains:Perflutren (octafluorpropane) gas (2.8% v/v)Human albumin as shell materialHuman albumin (1%) in vehicle


Optison size distribution and lung capillaries

Size Distribution of Optison microspheres as administered compared to size distribution of lung capillaries (cumulative percentage smaller than stated size) and theoretical distribution of Optison after passage through the lungs. The number of particles from a clinical dose retained in the lungs is very small compared to the number of lung capillaries.

0

2

4

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0 5 10 15Diameter (um)

Mil

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en

t sm

all

er

than

giv

en

siz

e

Optison - as injected

Optison - post lung

Capillary size (cumulative)

Capillary size

Optison size


Size stability in blood plasma

0.000

0.001

0.002

0.003

0.004

0.005

0.006

0.007

0.008

1 10 100

Diameter (um)

Vo

lum

e co

nce

ntr

atio

n (

% v

/v)

3 sec

6 sec

12 sec

60 s

Volume concentration and size distribution of Optison at various time points during incubation in plasma at 37°C with 85-95% gas saturation. The data shows that Optison bubbles decrease in size.

Theory: A bubble containing Perflutren (or any other heavy gas) suspended in blood plasma might potentially increase in size by a net inward gas diffusion of N2, O2, or CO2

Optison in blood plasma

Pre-Clinical


Absorption Distribution Metabolism Excretion (ADME)

• 125I-Optison microspheres are cleared from the blood pool in rats during the first few minutes following dosing.

• The liver is the major organ of uptake of albumin.

• Perflutren is cleared via exhaled air with an elimination t1/2 of 40 seconds in dogs. Almost 100% is recovered from exhaled air in 15 minutes.


General toxicology (1)

NOAEL HED Safety factor*

Single dose 20 mL/kg (rats & dogs)

10 mL/kg (monkeys)

3.2 mL/kg (rats), 11.2 (dogs)

3.2 mL/kg (monkeys)

26x (rats), 89x (dogs)

26x (monkeys)

Repeat dose

29 - 31 days

5 mL/kg/day (rats)

< 0.25 mL/kg (dog) **

0.8 mL/kg/day (rats)

-

6x (rats)

-

Repeat dose, 3 times per week for 3 weeks

5 mL/kg (rats)

20 mL/kg (dogs)

0.8 mL/kg (rats)

11.1 mL/kg (dogs)

6x (rats)

92x (dogs)

Teratology, embryonic effects

> 10 mL/kg/day (rats)

0.25 mL/kg/day (rabbits)

- -

NOAEL = No Observable Adverse Effect Level HED = Human Equivalent Dose* Relative to the highest approved human dose**not established, effects were observed at the lowest dose


General toxicology (2)

• No toxicity or local irritation after intravascular, perivascular, intramuscular, topical dermal and ocular administration of Optison.

• No genotoxicity.• In-vitro human blood compatibility of

Optison without ultrasound exposure: No hemolysis.


Ultrasound related studies

• In-vivo rabbit blood compatibility of Optison with US exposure:

− No hemolysis− Reductions in WBCs comparable to latex particle

controls

• Cardiovascular effects in dogs, 0.25 mL/kg (groups of 3 animals dosed with vehicle, Optison and Optison + dipyramidole):

− No effects related to Optison at 5 min. interval measurements

• Endothelial damage studied in dogs, 0.72 mL/kg Optison and local high power ultrasound (MI = 0.8 and 1.8):

− No endothelial damage (HE staining and albumin in tissue by immunohistochemical staining) in jugular vein wall, aortic wall, myocardium and kidney compared to non-exposed control tissue.


Optison in the microcirculation

Muscle capillary intravital fluorescence microscopy studies in rat and mouse muscle with i.v. and i.a. injections of Optison:•Optison particles move with same speed as RBCs, but

adhere to inflamed endothelium without causing blockage of blood flow.[Yasu et al.]

•No alterations in arterial pressure and microvascular blood flow were observed. Large microparticles or aggregates were not seen in vessels.[Dittrich et al. 1995]

•Rat spinotrapezius muscle with arterial injections of Optison showed occasional blockage of capillaries caused by large bubbles. This was consistent with finding of prolonged contrast in dog myocardium observed after direct intracoronary injections.[Skyba et al. 1996]

Optison does not block systemic capillaries after i.v. injection

Animal Models


Dog modelsHemodynamic effects of particles

Anaesthetized dogs can be instrumented for simultaneous measurements of hemodynamic variables. Pressure can be measured in:

−systemic arteries −left ventricle of the heart−central veins−pulmonary artery

Blood flow in arteries and cardiac output can be measured by implanted flowmeters, ultrasound Doppler or thermodilution, and the ECG can be recorded and analyzed.

The preparations can be combined with acute disease, such as myocardial ischemia, infarction or reperfusion injury.

Direct effects of mechanical blockage of the pulmonary circulation cannot be studied in the intact animal, since the number of lung capillaries (≈ 1011) is much larger than the number of particles (≈ 108) dosed.


Pigs as experimental animals for evaluation of particle-based drugs

• Animals from the Artiodactyla order (pig, goat, sheep and cow) have intravascular pulmonary macrophages.

• These macrophages react to particles in the bloodstream by activation, phagocytosis and thromboxane A2 release.

• The resulting pulmonary vasoconstriction can be severe.

• Release of thromboxane and the pulmonary hypertension response can be abolished by indomethacine.

• Phagocytosis persists after treatment with indomethacine, causing substantial first-pass extraction of particles which adversely impacts ability to study ADME, general toxicity and efficacy.


Effect of indomethacine in pigs given Albunex.

Source: Østensen et al. 1992

0.2 mL Albunex i.v.; 27 kg pig

3.2 mL Albunex i.v. to same pig after indomethacine.


Pulmonary macrophages in different species.

Organ distribution of particles cleared from blood in different species.Source: The Pulmonary Intravascular Macrophage, ed. N.C.

Staub, 1989

Pulmonary artery pressure response to liposomes in different species.

Cat

Calf

Sheep

Goat

Pig

NewbornPig

Rabbit

Dog

Guinea Pig

Rat

Mouse

0 4020 60 80 100Clearanceof

Blood - BorneParticles(in % of RecoveredDose)

LungLiver/Spleen

Cat

Calf

Sheep

Goat

Pig

NewbornPig

Rabbit

Dog

Guinea Pig

Rat

Mouse

0 4020 60 80 100Clearanceof

Blood - BorneParticles(in % of RecoveredDose)

LungLiver/Spleen

10-2 10-1 1 10210

10-2 10-1 1 10210

sheepgoatcow

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Pul

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H2O

)

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60

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Doses of liposomes(mol of total lipids/kg)

dogcatrat

10-2 10-1 1 10210

10-2 10-1 1 10210

sheepsheepgoatgoatcowcow

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Doses of liposomes(mol of total lipids/kg)

dogdogcatcatratrat


The pig is an inappropriate model for screening of ultrasound contrast agents• It has abundant intravascular lung macrophages,

not detected in humans, and the acute hemodynamic response to i.v. injected particles is atypical of human response.

• The response might mask other acute effects with relevance for human safety.

• The biodistribution of ultrasound contrast agents is predominantly to the lungs and the first-pass arterial concentration is reduced, this impacts the ability to study ADME, general toxicity and efficacy.


Optison / Albunex In Other Species • Albunex has been injected in dog preparations at

single doses up to 20 ml without any effects on pulmonary arterial pressure [Walker et al 1992]

• The effects of Optison on pulmonary arterial pressure in dogs is none or minimal.

• Optison does not affect pulmonary arterial pressure in man measured during CABG surgery [Erb et al 2001]

• Optison has been injected in ≈1 million doses without serious events that can be attributed to pulmonary vascular effects.Data from the pig is not a good predictor of clinical

side effects.dog models are better!


Clinical Overview

Steven B. Feinstein, M.D., F.A.C.C.

Professor of Medicine

Director of the Echocardiography Lab

Rush University Medical Center, Chicago, IL


Clinical Outline

Introduction to clinical applications

Optison NDA Clinical Safety Data

Optison Post-Marketing Surveillance

Optison Clinical Literature

Future uses of Contrast - Vascular


American Society of Echocardiography Guidelines for use of U/S contrast 2000

ASE Position PaperTask Force on Standards and Guidelines for the Use of Ultrasonic Contrast in Echocardiography: S. L. Mulvagh, MD Chair, A. N. DeMaria MD, Co chair, S. B. Feinstein MD, P. N. Burns, PhD et al., Contrast Echocardiography: Current and Future Applications, J Am Soc Echocardiogr, 2000 13(4):331-342

At present, it is the position of this guideline committee that intravenous contrast agents demonstrate substantial value in the difficult-to-image patient with comorbid conditions limiting an ultrasound evaluation of the heart. For such patients, the use of intravenous contrast agents should be encouraged as a means to provide added diagnostic information and to streamline early detection and treatment of underlying cardiac pathophysiology.


Left ventricular endocardial border detection


1

2

3?

4?

5?

6

3

2

11

4

5

6

Left ventricular endocardial border detection (6 apical segments as defined by the American Society of Echocardiography)


Left ventricular opacification (LVO) following intravenous injection of Optison

NDA Clinical Safety Data


U/S contrast compositionProduct Shell Material Encapsulated Gas

Albunex

Protein/Albumin

Air

Optison Octafluoropropane/Perflutren

Definity

PhospholipidsSonoVue Sulphur-hexafluoride

Sonazoid Perfluorobutane

AirAlbumin

Perflutren

Optison1 mil doses, 1998-2008

Albunex~ 63,000 doses, 1994 - 1997

-Inert-Device/ISPAN -Intra-ocular use

- vaccines, blood vol. replacement- PulmoliteR _ macroaggregated albumin 150µ - 700 000 proc. p.a.


Overview of Clinical Investigations (1995-1996)

Study No.

Study Description Dose

Individual/accumulated

No. subjec

ts

FS-1000 Safety, dose-ranging, preliminary efficacy 0.5 40.0 mL

44.0 mL

40

FS-1250 Safety: Evaluate immunologic response to re-challenge – 1 year later (Patients from FS-1000)

20.0 mL

0.02 mL *

5

FS-1500 Mass Balance: Measure PFP in blood and expired air as a measure of clearance; half-life;

recovery in expired air

20.0 mL 10

FS-6000 Single Blind Safety and immunological response in healthy volunteers and in subjects with cardiac, hepatic and respiratory diseases.

Comparison to 1% HSA

20.0 mL 50

FS-3000 Comparative: Evaluate safety and efficacy for endocardial border delineation and left

ventricular chamber opacification vs. Albunex and enhancement of Doppler signals vs.

baseline, non-contrast signal

0.2 5.0 mL

8.7 mL

101

FS-3500 Comparative: Evaluate safety and efficacy for endocardial border delineation and left

ventricular chamber opacification vs. Albunex and enhancement of Doppler signals vs.

baseline, non-contrast signal

0.2 5.0 mL

8.7 mL

102

* Intra-dermal injection


Clinical Safety Parameters – all studies

Criteria FS-1000*(n=40)

F5-1500*(n=10)

FS-6000**(n=50)

FS-1250*(n=5)

FS-3000/FS-3500

***(n=203)

12-lead ECG X X X X X

Physical examination

X X X X X

Neurological examination

X

Spirometry X X

Vital Signs X X X X X

O2 Saturation X X X X X

Chemistry Panel X X X X X*Baseline, 2h, 24h** Baseline, 2h, 48h *** Baseline, 30 min, 48h (up to 10 days) Vital signs 5 to 20 min intervals. Min 48h and max 10 days between each test agentsO2 sat at -2, 2, 4, 6, 8, 10, 20 and 40 min


Clinical SafetyThere were no safety concerns based on physical & neurological exams, spirometry & chemistry

CriteriaPhysical examinationNeurological examinationSpirometryChemistry Panel

No clinically significant changes after Optison, or between Optison and Albunex or 1% HSA

Demo

PFP


Clinical ECGsThere were no changes in 12 lead ECG

Protocol

Results

FS- 1000

No changes

FS- 1500

3 subjects with minor rhythm changes

FS- 6000

No changes

FS- 1250

1 subject had irregularities at baseline which reverted to NSR

FS- 3000

No changes

FS- 3500

No changes



Clinical Vital SignsBased on body temperature, heart rate, respiratory rate & BP

• No changes for FS-1000, FS-1250, FS-6000, FS- 3000 and FS-3500

• FS-1500 (PK study, N=10) Individual changes:– One patient elevated respiration rate of 22

breaths/min– One patient had increase in HR and multiple AEs –

uncertain relationship


Clinical Oxygen Saturation for OptisonProtocol Results

FS- 1000

Statistically, but no clinically significant changes

(at 6 min one patient tried to minimize breathing & coughed: O2 Sat. changed from 96 to 87% but recovered to 96% at 8 min)

FS- 1500

No changes

FS- 6000

No changes –vol 20mL - 1 liver (HPS) subj. remained stable at 76%

FS- 1250

No changes

One lung patient declined 8.25% after 1% HSA at 10 min.

FS- 3000

3,636 oxygen measurements, 13 measurements changed (0.4%) in 5 patients.

FS- 3500

3,672 oxygen measurements, 7 measurements changed (0.2%) in 4 patients .


1000&

6000


Transient changes ( ) in Oxygen Saturation Protocol

Agent Patient # with decreased Oxygen Saturation

Patient # with increased Oxygen Saturation

Comments

FS- 3000

Optison

3117 COPD, MI, HTN, smoker

3121 275 lbs, DM, MI, nicotine and alcohol use

3416 Nicotine and alcohol use, valve dx, HTN, MI

3113 228 lbs, pleural effusion

Albunex

3118

FS- 3500

Optison

5319 COPD, pneumonia

5111 221 lbs, sleep apnea, DM

5305 83 years of age

5410 Chronic bronchitis, pneumonia, CAD

3000&

3500

• None of the changes were symptomatic• Change defined as > 7.5% from baseline• All changes were transient in nature• Changes are considered random fluctuations, or related to undiagnosed OSA or variability of oxygen saturation measurements in subjects required to rest in supine position for over 2 hours.


Clinical Immunological Responses: NoneProtocol

# Subjects Optison

# Subjects1% HSA

Intra-dermal & i.V. inj.

Blood samples

Blood analysis - ELISA

Cytokines & complement activation

FS- 1000

16 X -24 h, -1h

2h

1,2,3 wk

IgG, IgA, IgM, IgD & IgE

-

FS- 1250

5* (from FS-

1000)

X Interleukin-1 alpha, interleukin-2, TNF-α. iC3b & SC56-9

FS- 6000

25 25 X

FS- 1000 FS- 1250 FS- 6000No immunological response

1 subject: mild skin reaction after intra-dermal inj., and did not receive i.v. inj. None of the subjects developed antibodies to Optison or had any cytokine release or complement activation.

1 subject had total CPK at 2h of 157 U/L (Normals 26-140 U/L). Returned to normal within 24h. Subject had several AEs – all resolved. No other responses.

No specific antibodies to Optison. No significant increases above normal ranges of cytokine release or complement activation* Intra-dermal approx 1 year after first i.v.

inj.


Optison NDA includes adverse events only

Adverse Events: Any event happening within the study period,- temporally related but not necessarily casual related

Adverse Reactions: Reactions (events) within the study period with a causal or unknown relationships to the product


All AEs were mild/moderate, transient and frequently unrelated to OptisonAdverse Events in All Participants Exposed to Optison

Body System Phase III Trials All Trials (Ph. I, II & III)

N= 199 N= 279

No. % No. %Body as a whole 13/199 6.5 47/279 16.8

Cardiovascular System 8/173 4.6 11/182 6.0

Digestive System 6/70 8.6 14/85 16.5

Endocrine System 3/73 4.1 3/77 3.9

Hemic and Lymphatic System

1/17 5.9 2/20 10.0

Musculoskeletal System 5/55 7.3 15/78 19.2

Nervous System 4/34 11.8 6/39 15.4

Respiratory System 8/79 10.1 14/92 15.2

Skin and Appendages 3/30 10.0 7/36 19.4

Special Senses 4/50 8.0 19/72 26.4

Urogenital System 2/56 3.6 9/74 12.2

One patient can have multiple events and are recorded as such


AEs in patient with impaired cardiac function is lower than for not impaired patientsAdverse Events in Patients with Impaired Functions Exposed to

Optison

Body System

Phase III Trials All Trials (Ph. I, II & III)Impaired Not Impaired Impaired Not Impaired

No. % No. % No. % No. %

CARDIAC IMPAIRMENT

Body as a whole 1/34 2.9 12/165 7.3 1/34 2.9 46/245 18.8

Cardiovascular System 1/32 3.1 7/141 5.0 1/32 3.1 10/150 6.7

Digestive System 0/15 0.0 6/55 10.9 0/15 0.0 14/70 20.0

Endocrine System 1/16 6.3 2/57 3.5 1/16 6.3 2/61 3.3


0/6 0.0 1/11 9.1 0/6 0.0 2/14 14.3

Musculoskeletal System 0/13 0.0 4/42 9.5 0/13 0.0 15/65 23.1

Nervous System 0/8 0.0 4/26 15.4 0/8 0.0 6/31 19.4

Respiratory System 1/30 3.3 7/49 14.3 1/30 3.3 13/62 21.0

Skin and Appendages 0/5 0.0 3/25 12.0 0/5 0.0 7/31 22.6

Special Senses 1/11 0.0 4/39 10.3 0/11 0.0 19/61 31.1

Urogenital System 0/10 0.0 2/46 4.3 0/10 0.0 9/64 14.1Significant cardiac disease as documented by medical history; EF< 40%:


AEs in patient with impaired pulmonary function are lower or same level as for not impaired patients

Adverse Events in Patients with Impaired Functions Exposed to Optison

Body System

Phase III Trials All Trials (Ph. I, II & III)Impaired Not Impaired Impaired Not Impaired

No. % No. % No. % No. %

PULMONARY IMPAIRMENT

Body as a whole 2/47 4.3 11/152 7.2 5/53 9.4 42/226 18.6

Cardiovascular System 2/47 4.3 6/126 4.8 2/49 4.1 9/133 6.8

Digestive System 1/17 5.9 5/53 9.4 3/19 15.8 11/66 16.7

Endocrine System 2/22 9.1 1/51 2.0 2/24 8.3 1/53 1.9


N/A N/A 1/17 5.9 0/1 0.0 2/19 10.5

Musculoskeletal System 0/10 0.0 4/45 8.9 3/15 20.0 12/63 19.0

Nervous System 1/9 11.1 3/25 12.0 1/10 10.0 5/29 17.2

Respiratory System 2/21 9.5 6/58 10.3 5/27 18.5 9/65 13.8

Skin and Appendages 0/8 0.0 3/22 13.6 0/10 0.0 7/26 26.9

Special Senses 0/10 0.0 4/40 10.0 3/13 23.1 16/59 27.1

Urogenital System 0/13 0.0 2/43 4.7 2/18 11.1 7/56 12.5Respiratory diseases – COPD, emphysema, pulmonary hypertension, bronchiectasis

Optison Post-Marketing Surveillance


Spontaneously Serious Adverse Reports 1998 – 200812 reports in 10 years with ~1million doses administered < 0.001%

Patient no.

Event Comments Cause*

0206s-000225 Jan’ 01

Chest pain with abnormal ECG

1h post Optison Unknown

0206s-00038 Feb’01

Decreased HR 175 71 bpm. Chest pain. Abnormal ECG

Dobutamine peak dose 40 mg/kg. Possible paradoxical response to dobutamine? (8% occurrence –JACC 1997,29(5):994. Responded to atropine.

Unknown

0207s-000912 Aug’98

Convulsion. ER visit for chest pain and ventricular tachycardia; status post cardioversion. Recovered.

Unknown

0207s-001024 Feb’00

Bradycardia Treated with fluids, 1mg atropine. Continued stress test without symptoms.

Unknown

0207s-001113 Apr’00

ECG change Reporting physician felt the recorded EKG changes were not symptomatic or caused by Optison

Unrelated

0507s 00526 July ‘05

Pericardial rupture post MI, death

Angina x 1 week. Admitted with acute inferior MI. Two days later Dobuamine stress echo.

Unrelated*Defined by the reporter of event

Optison 1998-2005, 2007 to present


Spontaneously Serious Adverse Reports 1998 – 200812 reports in 10 years total administered doses~1 mill ~0.001%

Patient no.

Event Comments Cause*

0206s-0001 19 June’02

Anaphylactic shock. Hypoxia. Chest pain

Hypotension, nausea began within 5 min Related

0402s-000217 Fed’04

Anaphylactic reaction Multiple allergies. Previous blood transfusion without reactions. Possibly related?

Unknown

0207s-00276 Aug’99

Urticaria, facial edema Patient on ACE-inhibitor (Lisinopril). Treated with anti-histamins and steroids

Unknown

0206s-0006 8 Feb’01

Shortness of breath. Baseline hypoxia with Ox sat ~70% post 10 days C-section.

30 y old, 388lbs (176 kg)

Heparin used and patient recovered

Unknown

0402s-000325 Feb’04

Hypoxia Hypoventilation prior to Optison and 1 day post-op CABG

Unrelated

0508s-0006

31 Aug’05

Dyspnea exacerbation Multiple co-morbidities and multiple drug sensitivities. Underwent dobutamine stress echo resulted in increased shortness of breath

Unknown

*Defined by the reporter of event


One reported death unrelated to Optison * July 18, 2005, Acute inferior MI (1 week of

angina) July 21, 2005, low dose dobutamine stress

echo (10mcg/kg/min) Approximately 1 h later, found

unresponsive in electromechanical dissociation (EMD)

CPR unsuccessful, urgent 2-D echo, new pericardial effusion noted

Diagnosis: Post MI myocardial rupture* Occurred in the United Kingdom


“In conclusion, it appears from the report of Dr. Hillis that is highly

likely that the death of this unfortunate patient occurred as a

result of spontaneous cardiac rupture and is not likely to be

related to the procedures that were carried out prior to the incident.”

Dr. Roxy SeniorConsultant Cardiologist

Optison Literature


Review of clinical literature 1998-2008

• 975 ICU patients: chest pain & no ST-elevation

• 3 ml Optison

• No AEs related to Optison. No serious cardiopulmonary reactions or deaths

• 105 patients with continuous ECG, O2 Sat. & hemodynamic measurements

• No significant changes after Optison

Variable Pre-Optison

Post-Optison

P-value

Heart rate 72±14 72±14 0.62

sDB 135±27 133±28 0.35

dBP 72±15 76±16 0.66

O2 Sat 97±2 98±2 0.3

PR Interval 165±26 167±25 0.41

QRS interval

98±22 99±23 0.56

QT interval 403±53 407±43 0.20

QTc interval

434±64 437±33 0.79

56 clinical studies: ~9250 patients received Optison

Patient population: 8670 cardiac ( incl. 2159 ICU patients) & 578 non-cardiac

No concerns about Optison AEs or changes in any safety parameters

Tong 2005/Wei 2008*: ICU patients with chest pain and non-diagnostic ECG

* Report on safety data not previously published


Erb et al, JASE 2001, vol 14: 595-600Intraoperative Contrast Echocardiography with IV Optison Does Not Cause Hemodynamic Changes During Cardiac Surgery

• 35 heart surgery patients (CABG, ASA class IV), received 97 total injections of 0.3ml bolus doses of Optison delivered via a central venous catheter

•No statistically significant differences in ST-segment changes, HR, arterial and central venous pressure, peripheral O2 saturation, cardiac index, LVEF and regional wall motion were seen 5 and 10 min after Optison in all patients undergoing concurrent use of anesthetics, high oxygen content and positive end expiratory pressure (PEEP).

Sub-groups Time of measurements

PAs mmHg

PAd mmHg

CO2 comments

97 injections

(n=35 patients, ASA class

IV**)

5 min vs baseline 1.3 ± 2.4 0.6 ± 2.4 0.2 ± 2.3 NS

10 min vs baseline

0.7 ± 5.0 0.9 ± 3.0 -0.5 ± 2.0

NS

** Patients have severe systemic disease that limits activity and is a constant threat to life.


Herzog, JAMA 2008, vol 299; 2023-2025 Incidence of adverse events associated with use of perflutren contrast agents for echocardiography• 112 776 Echo studies from Hennepin County Medical Center, Minneapolis, Minnesota

• 16 025 received ultrasound contrast Optison: 3051 patients (Feb1998 – Feb 2002) Definity: 12 974 patients (Feb 2002 – Oct 2007)

• All patients receiving contrast were routinely observed for at least 30 min

• Patient groups were similar

• Methods of identifying adverse events were comparable

• No adverse events after Optison

• 20 Adverse events after Definity of which 4 were serious:

- 65% had history of allergy- 65% were women- Causal relationship uncertain

Patient population Definityn=1297481%

Optisonn=305119%

Indication for resting echo:

LV function

WM abnormalities

Right heart function/ pulmonary hypertension

Valvular disease

10764

2522

1768

1304

2447

558

377

334

ICU patients 2431 520

Estimated Pulmonary artery pressure > 35 mmHg

1882 440

Overall rate of Adverse Events was low

Future Use of ContrastVascular


• More than 79 million American adults have CVD

• 1.2 million Heart Attacks

• 700,000 strokes

• 240,000 TIAs

• CVD is no 1 reason in hospital discharges

Anterior difficult w/o contrast

Anterior walls w/ contrast

*Heart Disease and Stroke Statistics – 2007 Update. Circulation 2007

Need for improved management and non-invasive diagnosis of cardiovascular disease


Nearly 1/3 of Americans (73 Million) have diabetes or are at risk• 58 million people die each year from CV disease

• DM and HTN are the primary predisposing factors

• Over 90% of type II DM is linked with excessive weight

• 147 million people have impaired glucose tolerance and will increase to 420 million by year 2025; most notably in developing countries 84M to 228M

• > 65 years of age = 15.8% with diabetes

• USA Prevalence of diabetes = 9.3% (6.5% diagnosed and 2.8 undiagnosed)

• USA = 26% of the population have impaired fasting glucose

N Engl J Med. 2007 Jan 18;356(3):213-5


Future use of vascular U/S contrast could play a significant role in CVD management1. Enhancement of the carotid

artery luminal morphologyin patients with known or suspected carotid artery stenosis

2. Improved resolution of c-IMT for CV risk assessment in patients with riskfactors…monitoring of treatment

3. Identification of arterial wall neo-vascularization (vasa vasorum) in patientswith known stenosis

Anterior difficult w/o contrast

Anterior walls w/ contrast


Enhancement of the carotid artery luminal morphology


Identification of arterial wall neo-vascularization (vasa vasorum)


Identification of arterial wall neo-vascularization (vasa vasorum)

Courtesy:Hans-Peter Weskott, Hannover, Germany


U/S contrast expected to be safe and effective in subjects at risk of vascular diseaseDose of U/S contrast: Same range as approved indication

MI carotid imaging: 0.06 – 0.40

Safety parameters: Vitals, O2 saturation, 12-lead ECG, AEs

Study population:

Phase 2: Subjects with known or suspected carotid artery disease

Stable cerebrovascular and cardiovascular disease

Phase 3/clin.practice:Include more unstable patients representing patients in clinical practice (dependent on phase 2)


Summary: Optison has an excellent safety profileBased on pre-clinical, clinical and post-marketing experience• Pre-clinical studies indicate Optison is safe

- The pig is an inappropriate model for safety of ultrasound contrast agents and the canine may be a more appropriate model

•Clinical NDA studies show no serious safety concerns -Extensive safety monitoring (ECG, vital signs, O2 saturations,

immunological, cytokine, complement) revealed no significant findings

• Post-marketing experience in ~1 million patients: excellent safety profile

- 45 post marketing non-serious reports- 12 SAE’s- One reported death; follow up information revealed death by cardiac

rupture unrelated to Optison usage (adjudicated by Dr. Roxy Senior, external reviewer)

• Literature survey patients no safety concerns- ~60 studies and > 9200 Optison patients including > 2100 ICU patients

- Erb et al 2001: No pulmonary artery pressure changes in critically ill ventilated patents with catheters in place receiving Optison bolus injection

- Herzog 2008 (N=16,025): No Optison adverse events in 3051 patients

Please Note: Due to technical difficulties the medical contrast images will not be in motion, the images will appear as still pictures. For medical images.

Documents

optison cmc

mlkg dogs

optison bubbles

mlkgday rats

preclinical slide

blood plasma slide

mlkg monkeys

il slide