Safety and Efficacy of Commercially Available Ultrasound Contrast Agents in the Clinical Setting Melda S. Dolan, MD; Simil Gala, MD; Saritha Dodla, MD;

Safety and Efficacy of Commercially Available

Ultrasound Contrast Agents in the Clinical Setting

Safety and Efficacy of Commercially Available

Ultrasound Contrast Agents in the Clinical Setting

Melda S. Dolan, MD; Simil Gala, MD; Saritha Dodla, MD; Feng Xie, MD; David Cloutier, MD;

Thomas Porter, MD; Arthur J. Labovitz, MD.

Melda S. Dolan, MD; Simil Gala, MD; Saritha Dodla, MD; Feng Xie, MD; David Cloutier, MD;

Thomas Porter, MD; Arthur J. Labovitz, MD.

ACC DisclosureACC Disclosure

Melda S. Dolan, MD Nothing to disclose

Simil Gala, MD Nothing to disclose

Saritha Dodla, MD Nothing to disclose

Feng Xie, MD Grant

David Cloutier, MD Nothing to disclose

Thomas Porter, MD Grant, Consultant

Arthur J. Labovitz,MD Nothing to disclose

Melda S. Dolan, MD Nothing to disclose

Simil Gala, MD Nothing to disclose

Saritha Dodla, MD Nothing to disclose

Feng Xie, MD Grant

David Cloutier, MD Nothing to disclose

Thomas Porter, MD Grant, Consultant

Arthur J. Labovitz,MD Nothing to disclose

Up To 20-30% of EchoesTechnically Difficult

BackgroundBackground

LargeBody

Habitus

ChestWall

Deformities

SevereChronic

LungDisease

Non Contrast ContrastNon Contrast Contrast

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BackgroundBackground

Before 1997

Phase III Studies1700 Patients

No Safety Concerns

UCAFDA Approval

1997 2007

Black Box Warning

OnOptison & Definity

Over 2 million Doses Administered

11 Deaths Overall

4 Deaths Within 30 min.

Black box WarningNew Contraindications

Black box WarningNew Contraindications

RL, bi-directional, or transient RL cardiac shunts

Clinically unstable or recent worsening congestive heart failure

Acute Coronary Syndrome Serious ventricular arrhythmias or at high risk for

arrhythmias due to QT prolongation Respiratory failure Severe emphysema, pulmonary emboli or other

conditions that compromise pulmonary arterial vasculature

RL, bi-directional, or transient RL cardiac shunts

Clinically unstable or recent worsening congestive heart failure

Acute Coronary Syndrome Serious ventricular arrhythmias or at high risk for

arrhythmias due to QT prolongation Respiratory failure Severe emphysema, pulmonary emboli or other

conditions that compromise pulmonary arterial vasculature

Aim of StudyAim of Study Define overall incidence

of events after contrast administration in the short and longer term.

Outline risk versus benefits profile of contrast use during echocardiograpic exams transthoracic and stress.

Define overall incidence of events after contrast administration in the short and longer term.

Outline risk versus benefits profile of contrast use during echocardiograpic exams transthoracic and stress.

Risks

Benefits

Patient CharacteristicsPatient CharacteristicsRetrospectively

Analyzed

23659 Consecutive Patients with resting EchoFrom Saint Louis University and University of Nebraska

Short TermFollow-Up

24 Hrs.

Non-Fatal Myocardial Infarctions&

Death From All Causes

30 Min.

Patient Characteristics Patient Characteristics

N=23659

59%

54%

49%

38%

9%

66%

56%

0% 20% 40% 60% 80%

Age >50

Male

Diabetes ty 1

Diabetes type 2

Smoking

Hyperlipidemia

Hypertension

ResultsResultsRetrospectively

Analyzed

23659 Consecutive PatientsCONTRAST Resting Echo

From Saint Louis University and University of Nebraska

Short TermFollow-Up

30 Min. 24 Hrs.

No Events 3 Non-Fatal MI and 1 Death

Results: Contrast Echo Short Term Follow up

Results: Contrast Echo Short Term Follow up

23655

3

10

5000

10000

15000

20000

25000

Death

Events

MI

No Events

EventsMINo Events

N= 23659

ResultsResultsRetrospectively

Analyzed

5900 Consecutive PatientsNON CONTRAST Resting Echo

From Saint Louis University and University of Nebraska

Short TermFollow-Up

30 Min. 24 Hrs.

No Events 7 Non-Fatal MI and 1 Death

Baseline DemographicsBaseline DemographicsResting Echo

Quality

ContrastNonDiagnostic

N=23659

No ContrastDiagnostic

N=5900P

Male 66.4% 60.2 % NS

Hypertension 59% 54.3% NS

DM 38% 32% NS

Hyperlipidemia 54% 51% NS

Smoking 49% 41% NS

Previous MI 16% 12% NS

Previous CABG 9% 7% NS

Previous PTCA 18% 14% NS

Results: NonContrast Echo Short Term Follow up

Results: NonContrast Echo Short Term Follow up

5892

7

10

2000

4000

6000

Events

Death

MI

No Events

DeathMINo Events

N= 5900

DSECONTRAST vs. NON CONTRAST

DSECONTRAST vs. NON CONTRAST

4011 Patients Who Received

Contrast for SuboptimalImages

Versus

SpecificitySensitivity Angiography

Accuracy

Angiography

1923Matched Patients

With Optimal Image Quality Without Contrast

Baseline DemographicsBaseline DemographicsDSEQuality

ContrastNonDiagnostic

No ContrastDiagnostic P

Male 61.4% 58.2 % NS

Hypertension 56% 52% NS

DM 32% 29% NS

Hyperlipidemia 48% 54% NS

Smoking 39% 36% NS

Previous MI 14% 10% NS

Previous CABG 10% 7% NS

Previous PTCA 16% 12% NS

DSE DataDSE DataDSEImage Quality

ContrastNonDiagnostic

No ContrastDiagnostic P

Normal 61.7% 63.8% NS

Fixed 10.8% 9.8% NS

Ischemia 13.8% 12.1% NS

Fixed & Isch 14.1% 12.8% NS

Target HR 84.2% 83.7% NS

Rest EF 56.9+ 10.2% 58.2+8.7% NS

Chest Pain 12.6% 13.7% NS

Dyspnea 6.8% 7.6% NS

Angiographic DataAngiographic DataDSEImage Quality

ContrastNonDiagnostic

No ContrastDiagnostic P

Stenosis Severity

74+ 10 % 70+14 % NS

Single Vessel 58% 54% NS

2 Vessel 21% 25% NS

3 Vessel 12% 11% NS

LAD 49% 54% NS

CX 24% 19% NS

RCA 22% 20% NS

ResultsResults

DSEImage Quality

ContrastNonDiagnostic

No ContrastDiagnostic P

Sensitivity 81 % 73 % NS

Single Vessel 74 % 68 % NS

Multivessel 85 % 83 % NS

Accuracy 82 % 76 % NS

Myocardial PerfusionMyocardial Perfusion

6075Patients Analyzed to

Determine Added BenefitOf Myocardial Perfusion Imaging

With Respect to Long Term Follow-Up

ResultsResults

Long TermFollow-Up

6075 Patients

2-92 Months

237 Non-Fatal MI273 Deaths

ResultsResults

6075Patients Analyzed to

Determine Added BenefitOf Myocardial Perfusion Imaging

With Respect to Long Term Follow-Up

4251 Normal Studies

1824 Abnormal Studies

AdverseEventsN=133(3.7%)

AdverseEventsN=377(20.6%)

510 EVENTS

ResultsResults

133Normal WMNormal MP

291 Abnormal WM Abnormal MP

86Normal WMAbnorm MP

95%

80%

69%

0%

20%

40%

60%

80%

100%

Normal MP and WM

Abn. MP and Normal WM

Abn. MP and Abn. WM

5 Year Event Free Survival

Stress Contrast Myocardial Perfusion

*

**

*p<0.05

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Univariate Predictors

Multivar.

Predictors

Variables RR(95%CI) p RR(95% p

Age>70 1.5(1.0-2.4) 0.05 NSHyperlipid 0.6(0.5-1.0) 0.31 NSHyperten. 0.8(0.5-1.0) 0.12 NSDM 1.2(0.9-1.6) 0.92 NSPre CABG 2.2(1.3-3.8) 0.001 NSPre MI 2.1(1.2-3..4) 0.001 0.6(0.4-0.9) 0.01EF<50 1.6 (0.7-4.1) 0.001 1.4(1.0-1.8) 0.01Abn WM 3.9(2.9-5.7) 0.001 NSAbn MP 5.0(3.4-8.7) 0.001 2.4(1.0-5.9) 0.001

Summary Summary

1. The risk of both short-term and long-term events, defined as non-fatal myocardial infarction and death, following contrast administration during resting echo is very low.

• Not different from non-contrast studies.

1. The risk of both short-term and long-term events, defined as non-fatal myocardial infarction and death, following contrast administration during resting echo is very low.

• Not different from non-contrast studies.

SummarySummary

2. In patients undergoing DSE, the risk of an adverse event in a patient that received contrast was comparable to patients that did not receive contrast

2. In patients undergoing DSE, the risk of an adverse event in a patient that received contrast was comparable to patients that did not receive contrast

SummarySummary

3. The benefits of contrast use in patients with suboptimal images are significant and outweigh the possible risks.

– Making suboptimal studies equivalant to optimal studies

– Preventing additional costly tests

3. The benefits of contrast use in patients with suboptimal images are significant and outweigh the possible risks.

– Making suboptimal studies equivalant to optimal studies

– Preventing additional costly tests

SummarySummary

4. Myocardial perfusion assessment with contrast echo

– Adds significant prognostic value

4. Myocardial perfusion assessment with contrast echo

– Adds significant prognostic value

ConclusionConclusion

In light of these findings regarding safety and benefits, the FDA should reconsider the black box warning placed on contrast agents used during echocardiography.

In light of these findings regarding safety and benefits, the FDA should reconsider the black box warning placed on contrast agents used during echocardiography.

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