Please Note:Please Note:

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

For these images, please refer to the For these images, please refer to the transcript, Part 3 pages 210 through transcript, Part 3 pages 210 through 225, for the description of the image 225, for the description of the image provided by the presenter.provided by the presenter.

Presentation to the Cardiovascular Presentation to the Cardiovascular and Renal Drugs Advisory and Renal Drugs Advisory

Committee Regarding Safety Committee Regarding Safety Considerations in the Development Considerations in the Development

of Ultrasound Contrast Agentsof Ultrasound Contrast Agents

June 24June 24thth 2008 2008

Who We AreWho We Are

Michael L. Main MDMichael L. Main MDSaint Luke’s Saint Luke’s

Mid America Heart Institute Mid America Heart Institute Kansas City, MOKansas City, MO

Jonathan H. Goldman MDJonathan H. Goldman MDUniversity of CaliforniaUniversity of California

San Francisco, CASan Francisco, CA

Paul A. Grayburn MDPaul A. Grayburn MDBaylor University Baylor University

Medical CenterMedical CenterDallas TXDallas TX

Steven B. Feinstein MD, Steven B. Feinstein MD, Rush UniversityRush University

Chicago, ILChicago, IL

Who We RepresentWho We Represent

An international grass-roots organization An international grass-roots organization (14 countries)(14 countries)

Cardiologists, sonographers, radiologists, Cardiologists, sonographers, radiologists, vascular medicine specialists, and other vascular medicine specialists, and other health care professionalshealth care professionals

All with extensive clinical experience with All with extensive clinical experience with ultrasound contrast agentsultrasound contrast agents

Timeline Timeline

Letter from grassroots organization to Letter from grassroots organization to FDA Medical Imaging Division on FDA Medical Imaging Division on November 10, 2007November 10, 2007

Met with FDA Medical Imaging Division Met with FDA Medical Imaging Division on December 11, 2007on December 11, 2007

Signed confidentiality agreements with Signed confidentiality agreements with sponsors, reviewed data, designed and sponsors, reviewed data, designed and conducted safety studiesconducted safety studies

…we do not believe that these new "black box" warnings reflect the proven efficacy of ultrasound contrast agents, their established safety record, the potential risks ofalternative procedures, and the likely confounding effect of "pseudocomplication."

Main ML, Goldman JH, Grayburn PA. J Am Coll Cardiol 2007;50:2434-7.

Current Paradigm for Imaging Current Paradigm for Imaging Agent EvaluationAgent Evaluation

““Nobody needs to die from a diagnostic Nobody needs to die from a diagnostic test” (threshold for approval and test” (threshold for approval and persistence is 100% safety)persistence is 100% safety)

No cardiovascular test (except No cardiovascular test (except possibly the stethoscope) meets possibly the stethoscope) meets this standardthis standard

Event Rates for Commonly Performed Event Rates for Commonly Performed Cardiovascular ProceduresCardiovascular Procedures

Procedure Event Rate Event

CoronaryAngiography

1:1000 Death

Exercise TreadmillTesting

1:2500 MI or Death

SPECT Exam orRadionuclideVentriculography

1:1000 to1:10,000

Fatal Malignancy

ContrastEchocardiography

1:500,000 Death

Complete List of Contraindications to Complete List of Contraindications to Ultrasound Contrast AgentsUltrasound Contrast Agents

Right-to-left, bi-directional, or transient right-to-left cardiac shuntsRight-to-left, bi-directional, or transient right-to-left cardiac shunts Worsening or clinically unstable heart failureWorsening or clinically unstable heart failure Acute myocardial infarction or acute coronary syndromesAcute myocardial infarction or acute coronary syndromes Serious ventricular arrhythmias or high risk for arrhythmias due to Serious ventricular arrhythmias or high risk for arrhythmias due to

prolongation of the QT intervalprolongation of the QT interval Respiratory failure, as manifest by signs or symptoms of carbon Respiratory failure, as manifest by signs or symptoms of carbon

dioxide retention or hypoxemiadioxide retention or hypoxemia Severe emphysema, pulmonary emboli or other conditions that Severe emphysema, pulmonary emboli or other conditions that

cause pulmonary hypertension due to compromised pulmonary cause pulmonary hypertension due to compromised pulmonary arterial vasculaturearterial vasculature

Hypersensitivity to perflutrenHypersensitivity to perflutren

Complete List of Contraindications to Complete List of Contraindications to Ultrasound Contrast AgentsUltrasound Contrast Agents

Right-to-left, bi-directional, or transient right-to-left cardiac shuntsRight-to-left, bi-directional, or transient right-to-left cardiac shunts Worsening or clinically unstable heart failureWorsening or clinically unstable heart failure Acute myocardial infarction or acute coronary syndromesAcute myocardial infarction or acute coronary syndromes Serious ventricular arrhythmias or high risk for arrhythmias due to Serious ventricular arrhythmias or high risk for arrhythmias due to

prolongation of the QT intervalprolongation of the QT interval Respiratory failure, as manifest by signs or symptoms of carbon Respiratory failure, as manifest by signs or symptoms of carbon

dioxide retention or hypoxemiadioxide retention or hypoxemia Severe emphysema, pulmonary emboli or other conditions that Severe emphysema, pulmonary emboli or other conditions that

cause pulmonary hypertension due to compromised pulmonary cause pulmonary hypertension due to compromised pulmonary arterial vasculaturearterial vasculature

Hypersensitivity to perflutrenHypersensitivity to perflutren

Event Rates for Commonly Performed Event Rates for Commonly Performed Cardiovascular ProceduresCardiovascular Procedures

Procedure Event Rate Event

CoronaryAngiography

1:1000 Death

Exercise TreadmillTesting

1:2500 MI or Death

SPECT Exam orRadionuclideVentriculography

1:1000 to1:10,000

Fatal Malignancy

ContrastEchocardiography

1:500,000 Death

Complete List of Absolute Complete List of Absolute Contraindications to Cardiac Contraindications to Cardiac

CatheterizationCatheterization

“The only absolute contraindication to cardiac catherization is refusal of a

mentally competent patient to consent to the procedure”

Grossman W. Current practice standards. In: Baim DS and Grossman W, editors. Cardiac Catheterization, Angiography and Intervention. Baltimore, MD: Williams and Wilkins, 1996:9-16

ACC/AHA/ASE 2003 Guidelines Update for the ACC/AHA/ASE 2003 Guidelines Update for the Clinical Application of EchocardiographyClinical Application of Echocardiography

Complications of Transesophageal Complications of Transesophageal EchocardiographyEchocardiography

Seward JB et al. J Am Soc Echocardiogr 1992;5:228

Complications of Transesophageal Complications of Transesophageal EchocardiographyEchocardiography

Mortality rate = 1/10,000

Daniel WG et al. Circulation 1991;83:17-821

ACC/AHA/ASE 2003 Guidelines Update for the ACC/AHA/ASE 2003 Guidelines Update for the Clinical Application of EchocardiographyClinical Application of Echocardiography

“Echocardiographic contrast agents may improve diagnosis in free wall rupture and in identifying intracardiac thrombus.”

Current Paradigm for Imaging Current Paradigm for Imaging Agent EvaluationAgent Evaluation

““The risk benefit analysis is different for The risk benefit analysis is different for diagnostic than for life-saving drugs”diagnostic than for life-saving drugs”

Accurate diagnosis and appropriate Accurate diagnosis and appropriate treatment are inextricably linked; failure to treatment are inextricably linked; failure to make a correct diagnosis leads to make a correct diagnosis leads to administration of the wrong therapy and/or administration of the wrong therapy and/or withholding the correct therapy. In withholding the correct therapy. In cardiovascular disease this can be fatal.cardiovascular disease this can be fatal.

Apical mural thrombus or not?Apical mural thrombus or not?

45 year-old man 45 year-old man with known with known coronary artery coronary artery diseasedisease

Percutaneous Percutaneous coronary coronary intervention in 2003intervention in 2003

Apical 4-chamber

Contrast Enhanced ExaminationContrast Enhanced Examination

Contrast enhanced image reveals a large left Contrast enhanced image reveals a large left ventricular apical mural thrombusventricular apical mural thrombus

Apical 4-chamber

Recent Anterior Myocardial Infarction and Recent Anterior Myocardial Infarction and Possible Apical ThrombusPossible Apical Thrombus

Contrast Enhanced ImageContrast Enhanced Image

Baseline Image Contrast Enhanced Image

Left Ventricular PseudoaneurysmLeft Ventricular Pseudoaneurysm

Baseline Contrast Enhanced

LV Rupture/PseudoaneurysmLV Rupture/Pseudoaneurysm

500,000 STEMI per year in US*500,000 STEMI per year in US* 1-6% have LV rupture*1-6% have LV rupture*

Immediate deathImmediate death Pseudoaneurysm formation (high death risk)Pseudoaneurysm formation (high death risk) Treatment is immediate surgeryTreatment is immediate surgery

Echo without contrast is only 26% sensitive**Echo without contrast is only 26% sensitive** Contrast is diagnosticContrast is diagnostic If only 1% have pseudoaneurysm (5000 pts per If only 1% have pseudoaneurysm (5000 pts per

year) contrast could potentially save 3750 lives year) contrast could potentially save 3750 lives per year***per year***

* ACC/AHA Guidelines** Frances et al, JACC 1998***Grayburn PA. Am J Cardiol 2008;101:892-3.

LV PseudoaneurysmLV Pseudoaneurysm

4 deaths with Definity over 6 years4 deaths with Definity over 6 years Contraindication of Definity in acute MI Contraindication of Definity in acute MI

would potentially lead to the loss of would potentially lead to the loss of 22,500 lives (3750 X 6) over 6 years 22,500 lives (3750 X 6) over 6 years from undiagnosed left ventricular from undiagnosed left ventricular pseudoaneurysmpseudoaneurysm

Grayburn PA. Am J Cardiol 2008;101:892-3.

Current Paradigm for Imaging Current Paradigm for Imaging Agent EvaluationAgent Evaluation

In 2007, the FDA developed a list of In 2007, the FDA developed a list of “risk factors” for cardiovascular “risk factors” for cardiovascular collapse in patients receiving collapse in patients receiving ultrasound contrast agents which ultrasound contrast agents which included the new contraindications of included the new contraindications of November, 2007November, 2007

This approach equates association This approach equates association with causation and is not validwith causation and is not valid

PseudocomplicationPseudocomplication

Complication occurring after anyComplication occurring after any

medical procedure may be attributable to medical procedure may be attributable to the procedure itselfthe procedure itselfprogression of underlying disease progression of underlying disease

state (pseudocomplication)state (pseudocomplication)

Pseudocomplication in Cardiac Pseudocomplication in Cardiac CatheterizationCatheterization

Event -24 hour to cath Cath +72 hour

SAE 0.81% 0.81%

Death 0.24% 0%

Hildner et al. Pseudocomplications of cardiac catheterization. Chest 1973;63:15-17

Serious adverse events are relatively common in patients who are “sick enough” to warrant invasive testing

Data Necessary to Determine Adverse Data Necessary to Determine Adverse Event Rates of Medical Procedures Event Rates of Medical Procedures

Number of patients undergoing procedureNumber of patients undergoing procedure Number of adverse eventsNumber of adverse events Ambient rate of adverse events in patients Ambient rate of adverse events in patients

with the same disease state not with the same disease state not undergoing procedureundergoing procedure

Kusnetzky LL et al. J Am Coll Cardiol 2008;51:1704-5

18,671 patients18,671 patients 12,475 12,475

unenhancedunenhanced 6,196 Definity6,196 Definity

In-patient In-patient echocardiography echocardiography between January between January 2005 and October 2005 and October 20072007

Vital status at 24 Vital status at 24 hours available for hours available for all patientsall patients

ResultsResults

0

0.2

0.4

Definity Non Contrast

p-value=0.60

Kusnetzky LL et al. J Am Coll Cardiol 2008;51:1704-5

Percent Mortality at 24 hours

46 deaths26 deaths

Acute Mortality in Hospitalized Patients Undergoing Echocardiography with and without an ultrasound contrast agent: multicenter

results in 4,300,966 Consecutive Patients

Main ML et al. J Am Coll Cardiol 2008; under review

Acute Mortality in Hospitalized Patients Undergoing Echocardiography with and without an Ultrasound Contrast Agent:

Multicenter Results in 4,300,966 Consecutive Patients

1.05

1.055

1.06

1.065

1.07

1.075

1.08

Definity Non Contrast

One Day Mortality

p-value=0.613

Multivariable logistic regression analysis: patients receiving Definity were 24% less likely to die within 1-day than patients not receiving a contrast agent (adjusted odds ratio=0.76 (95% CI =0.70-0.82).

Main ML et al. J Am Coll Cardiol 2008; under review

ConclusionsConclusions

Ultrasound contrast agents improve diagnostic accuracy Ultrasound contrast agents improve diagnostic accuracy and enable proper therapeutic interventionand enable proper therapeutic intervention

Pseudocomplication is likely responsible for many of the Pseudocomplication is likely responsible for many of the adverse events attributed to ultrasound contrast agentsadverse events attributed to ultrasound contrast agents

Known risks of alternative testing are much greater than the Known risks of alternative testing are much greater than the perceived risk associated with ultrasound contrast agentsperceived risk associated with ultrasound contrast agents

Large scale outcome studies in hospitalized patients Large scale outcome studies in hospitalized patients undergoing echocardiography show no increase in all undergoing echocardiography show no increase in all cause mortality in patients receiving ultrasound contrast cause mortality in patients receiving ultrasound contrast agents; risk adjusted mortality is much (24%) lower in the agents; risk adjusted mortality is much (24%) lower in the contrast echocardiography groupcontrast echocardiography group

RecommendationsRecommendations Removal of the Black Box warning for the Removal of the Black Box warning for the

perflutren containing compoundsperflutren containing compounds Clearly define criteria for issuance of Clearly define criteria for issuance of

warnings and contraindications for future warnings and contraindications for future agents and new applicationsagents and new applications

Complete adjudication of all previous and Complete adjudication of all previous and future serious adverse events and deaths future serious adverse events and deaths which have been associated with ultrasound which have been associated with ultrasound contrast agentscontrast agents