Safety of Contrast Agents during
Stress Echocardiography:
A Cohort Study from a Single
Center , 4 Years Experience With
26,774 Patients
Sahar S. Abdelmoneim, M.D., M.S.; Mathieu Bernier, M.D.;
Christopher G. Scott, M.S.; Abhijeet Dhoble, M.D.;
Sue Ann C. Ness, R.N; Mary E. Hagen, R.N, R.D.C.S; Stuart Moir, M.D.;
Robert B. McCully, M.D.; Patricia A. Pellikka, M.D.;
Sharon L. Mulvagh, M.D
Mayo Clinic , Rochester –MN
Disclosure Information
Sharon L. Mulvagh, M.D.
Safety of Contrast Agents during Stress Echocardiography: a
Cohort Study from a Single Center Experience Spanning 4 years
and 26,774 Patients
FINANCIAL DISCLOSURE:
•Research Grants- Lantheus Medical Imaging, GE Healthcare
•No conflicts of interest to disclose for remaining authors
UNLABELED/UNAPPROVED USES DISCLOSURE:
•None
Specific Aims
1.
To evaluate the safety (short- and long-term) of
contrast agents during stress echocardiography
(SE) using endpoints of death and myocardial
infarction (MI)
2.
To compare annualized rates of combined events
(death and MI) in patients receiving contrast and
those not
3.
To determine nature and frequency of contrastrelated side effects
Methods
Research Design
 A retrospective cohort study
Study Population
 November 1, 2003 and December 31, 2007
 Stress Echo Database: electronic, clinical & demographic info,
prospectively collected, indexed and stored
 2 Cohorts : contrast vs. non contrast
 Contrast Cohort: clinically indicated contrast study for LVO
 Contrast agents: Definity and Optison
Outcomes of Interest
 Short term safety within 72 hours and 30 days after SE
 Long term safety of contrast use up to 4.5 years after SE
 Endpoints: death & MI
 Arrhythmias
 Contrast related side effects
Methods
Identification of Outcomes
Death :
1. Cross matching of the stress echo database with the Death
Database of the Mayo Clinic
2. Individual chart review to confirm occurrence and timing,
in relation to contrast administration
3. Cardiac death within 30 days was also determined
Myocardial Infarction :
1.
ICD-9 for MI (410) including: cardiac infarction,
infarction of heart, myocardium, or ventricle, ST elevation
(STEMI) and non-ST elevation (NSTEMI) myocardial
infarction
2. Individual chart review to confirm occurrence and timing,
in relation to contrast administration
Methods
Statistical Analysis Plan*
 Numbers (%) presented for categorical variables and
differences between contrast groups were tested using the
Pearson chi-square or Fischer’s Exact test
 For continuous variables, mean and standard deviation are
presented and differences between groups were tested using
the two-sample T-test
 Survival was estimated using the Kaplan Meier (KM) method
 Multivariable Cox proportional hazards regression models
were used to test for differences in long term outcomes after
adjusting for known confounders
 Contrast-related side effects were reported as percentage of
the total documented side effects starting in year 2007
 Annualized rates of combined death and MI events in both
cohorts were reported
* SAS Version 9.1 (SAS Institute Inc, Cary, North Carolina, USA).
Study Flow Chart
November 2003 - December 2007
26,774 SE pts
DSE: 12,760
Exercise: 14,014
Clinical characteristics of 26,774 SE patients
November 2003 - December 2007
Short term Safety of Contrast Stress Echocardiography
November 2003 - December 2007
Deaths within 72 hours of Contrast Stress Echocardiography
1 case with contrast agent Definity

Female 76 years old

Diabetes Mellitus

Preoperative evaluation of mycotic aneurysm
repair

Preoperative contrast dobutamine SE was
negative for myocardial ischemia

No reported immediate side effects from
contrast

Postoperative day 2 (48 hours of SE) , patient
expired from multiorgan failure
MI within 72 hours of Contrast Stress Echocardiography
3 cases of MI (1 with Definity, and 2 with
Optison)
Demographics Indication
for SE and
Outcome
• 65 yo male
• DM, HTN, high lipids
•73 yo female
• Smoker, DM, HTN, high
lipids
• 68 yo male
• Renal cell carcinoma
result
• Preoperative dobutamine-SE
• Troponin T was elevated
(0.05ng/ml) 3 hours post SE
• Marked positive SE in LAD
territory
• Urgent coronary angiography
• VF during recovery
Stenting of LAD (100% stenosis)
(defibrillation)
• Preoperative dobutamine-SE
• Postoperative day 2 , she
developed chest pain
• Negative SE and stress ECG
• Troponin T was elevated
• Hip surgery same day of SE
(0.23ng/ml)
• NSTEMI was diagnosed
• Coronary angiography and
stenting of 90% OM was done
• Dobutamine-SE for
• Patient developed chest pain
assessment of suspected CAD
during the SE
• Negative SE and stress ECG
• Troponin T was elevated
(0.08ng/ml) 3 hours post SE
• NSTEMI was diagnosed
• Coronary angiography showed
60% Cx stenosis and 50% RCA
Arrhythmias During Contrast Stress Echocardiography
Supraventricular tachycardia
 Contrast cohort:
30 patients (0.28%)
P =0.31
 Reference cohort: 34 patients (0.21%)
Ventricular tachycardia
 Contrast cohort: 11 patients (0.10%)
 Reference cohort: 7 patients (0.04%)
P =0.09
Long term Safety of Contrast Stress Echocardiography
(A) Survival free of death
 Kaplan-Meier survival curves Presenting Survival Free of Major Cardiovascular Events Including Death
and Myocardial Infarction over 4 years followup for the dobutamine SE and exercise SE subgroups.
Patients in the contrast cohort received contrast agents during SE and patients in the noncontrast cohort
did not
 P values are reported from the unadjusted model. After adjustment for known confounders, no
differences in the hazard ratios for the events were observed between the contrast and noncontrast
cohorts. SE, stress echocardiography
Long term Safety of Contrast Stress Echocardiography
(B) Survival free of MI
 Kaplan-Meier survival curves Presenting Survival Free of Major Cardiovascular Events Including Death
and Myocardial Infarction over 4 years followup for the dobutamine SE and exercise SE subgroups.
Patients in the contrast cohort received contrast agents during SE and patients in the noncontrast cohort
did not
 P values are reported from the unadjusted model. After adjustment for known confounders, no
differences in the hazard ratios for the events were observed between the contrast and noncontrast
cohorts. SE, stress echocardiography
Long term Safety of Contrast Stress Echocardiography

After adjustment for known confounders*, no differences in
events were observed between contrast-SE and non
contrast-SE cohorts
*Known confounders: Age , gender, BMI, EF, DM, previous CAD, positive SE
risk patients)
and dobutamine study (as it had higher
The annualized event rate for
combined (death & MI) events

Dobutamine –SE cohort
Contrast
9.6% (8.9, 10.3)
P =NS
Non contrast
10.9% (10.2, 11.6)

Exercise –SE cohort
Contrast
2.2% (1.8, 2.6)
Non contrast
1.9% (1.6, 2.1)
P =NS
Contrast Related Adverse Events (AE)

AE’s were consistently documented by unique
statements in EMR starting in January 2007

In year 2007: 3,071 contrast SE (1,819 dobutamineSE and 1,252 exercise-SE) were performed

AE from contrast: “possible” in 68 /3071 (2.2%)

Of 68 patients, a “definite” relation to contrast was
established in 41/3071 (1.3%) patients:
 Backache alone in 19
 Headache alone in 16
 Backache and headache in 4
 Transient wheezing in 1
 Urticaria with mouth swelling in 1
Acute anaphylactoid
reaction in our study was
in 0.03%
(in ~3:10,000 patients)
Limitations and Strengths
Limitations
 Retrospective
 Use of ICD codes for outcomes retrieval
 Contrast related side effects were consistently documented
in the EMR for 1 year (2007, n=3071); however paper
recording for previous 3 years showed same rate of AE’s.
Strengths
 Large sample size
 Cohort design
 Detailed demographic information and assessment of
known confounders allowed thorough evaluation of the
association between contrast use and the endpoint events
using multivariate, and cox regression analysis
Conclusions

The use of FDA-approved contrast agents during
Stress Echocardiography IS NOT associated with
an increased risk of death or myocardial
infarction in either the short-term (within 72 hrs,
and 30 days) or long- term (up to 4.5 years)

Contrast related side effects occur at an
acceptable rate, comparable to contrast agents
used in other imaging modalities

This large single center study provides further
evidence supporting the safety of contrast use in
ultrasound in general, and stress
echocardiography, in particular