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 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 Echoes Technically Difficult Background Large Body Habitus Chest Wall Deformities Severe Chronic Lung Disease

Non Contrast Contrast

Background Before 1997 Phase III Studies 1700 Patients No Safety Concerns UCA FDA Approval Black Box Warning On Optison & Definity

Over 2 million Doses Administered 11 Deaths Overall 4 Deaths Within 30 min.

Black box Warning New Contraindications R L, bi-directional, or transient R L 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 R L, bi-directional, or transient R L 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 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 Characteristics Retrospectively Analyzed Consecutive Patients with resting Echo From Saint Louis University and University of Nebraska Short Term Follow-Up 24 Hrs. Non-Fatal Myocardial Infarctions & Death From All Causes 30 Min.

Patient Characteristics N=23659

Results Retrospectively Analyzed Consecutive Patients CONTRAST Resting Echo From Saint Louis University and University of Nebraska Short Term Follow-Up 30 Min.24 Hrs. No Events 3 Non-Fatal MI and 1 Death

Results: Contrast Echo Short Term Follow up N= 23659

Results Retrospectively Analyzed 5900 Consecutive Patients NON CONTRAST Resting Echo From Saint Louis University and University of Nebraska Short Term Follow-Up 30 Min.24 Hrs. No Events 7 Non-Fatal MI and 1 Death

Baseline Demographics Resting Echo Quality Contrast NonDiagnostic N=23659 No Contrast Diagnostic N=5900 P Male66.4%60.2 %NS Hypertension59%54.3%NS DM38%32%NS Hyperlipidemia54%51%NS Smoking49%41%NS Previous MI16%12%NS Previous CABG9%7%NS Previous PTCA18%14%NS

Results: NonContrast Echo Short Term Follow up N= 5900

DSE CONTRAST vs. NON CONTRAST 4011 Patients Who Received Contrast for Suboptimal Images Versus Specificity Sensitivity Angiography Accuracy Angiography 1923 Matched Patients With Optimal Image Quality Without Contrast

Baseline Demographics DSE Quality Contrast NonDiagnostic No Contrast Diagnostic P Male61.4%58.2 %NS Hypertension56%52%NS DM32%29%NS Hyperlipidemia48%54%NS Smoking39%36%NS Previous MI14%10%NS Previous CABG10%7%NS Previous PTCA16%12%NS

DSE Data DSE Image Quality Contrast NonDiagnostic No Contrast Diagnostic P Normal61.7%63.8%NS Fixed10.8%9.8%NS Ischemia13.8%12.1%NS Fixed & Isch14.1%12.8%NS Target HR84.2%83.7%NS Rest EF % %NS Chest Pain12.6%13.7%NS Dyspnea6.8%7.6%NS

Angiographic Data DSE Image Quality Contrast NonDiagnostic No Contrast Diagnostic P Stenosis Severity %70+14 %NS Single Vessel58%54%NS 2 Vessel21%25%NS 3 Vessel12%11%NS LAD49%54%NS CX24%19%NS RCA22%20%NS

Results DSE Image Quality Contrast NonDiagnostic No Contrast Diagnostic P Sensitivity81 %73 %NS Single Vessel74 %68 %NS Multivessel85 %83 %NS Accuracy82 %76 %NS

Myocardial Perfusion 6075 Patients Analyzed to Determine Added Benefit Of Myocardial Perfusion Imaging With Respect to Long Term Follow-Up

Results Long Term Follow-Up 6075 Patients 2-92 Months 237 Non-Fatal MI 273 Deaths

Results 6075 Patients Analyzed to Determine Added Benefit Of Myocardial Perfusion Imaging With Respect to Long Term Follow-Up 4251 Normal Studies 1824 Abnormal Studies Adverse Events N=133(3.7%) Adverse Events N=377(20.6%)

510 EVENTS Results 133 Normal WM Normal MP 291 Abnormal WM Abnormal MP 86 Normal WM Abnorm MP

5 Year Event Free Survival Stress Contrast Myocardial Perfusion * * * *p<0.05

Univariate Predictors Multivar. Predictors Variables RR(95%CI)pRR(95%p Age>70 1.5( )0.05NS Hyperlipid 0.6( )0.31NS Hyperten. 0.8( )0.12NS DM 1.2( )0.92NS Pre CABG 2.2( )0.001NS Pre MI 2.1( ) ( )0.01 EF< ( ) ( )0.01 Abn WM 3.9( )0.001NS Abn MP 5.0( ) ( )0.001

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.

Summary 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

Summary 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

Summary 4.Myocardial perfusion assessment with contrast echo –Adds significant prognostic value 4.Myocardial perfusion assessment with contrast echo –Adds significant prognostic value

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

THANK YOU FOR YOUR ATTENTION