Safety of Contrast Agents during Stress Echocardiography: A Cohort Study from a Single Center , 4 Years Experience With 26,774 Patients

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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

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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

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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
   contrast-related side effects

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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

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Methods

• Identification of Outcomes
• Death
• Cross matching of the stress echo database with
  the Death Database of the Mayo Clinic
• Individual chart review to confirm occurrence and
  timing, in relation to contrast administration
• Cardiac death within 30 days was also determined
• Myocardial Infarction
• ICD-9 for MI (410) including cardiac
  infarction, infarction of heart, myocardium, or
  ventricle, ST elevation (STEMI) and non-ST
  elevation (NSTEMI) myocardial infarction
• Individual chart review to confirm occurrence and
  timing, in relation to contrast administration

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Methods

• Statistical Analysis Plan
• Numbers () presented for categorical variables
  and differences between contrast groups were
  tested using the Pearson chi-square or Fischers
  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).
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Study Flow Chart
November 2003 - December 2007
26,774 SE pts DSE 12,760 Exercise 14,014
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Clinical characteristics of 26,774 SE patients
November 2003 - December 2007
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Short term Safety of Contrast Stress
Echocardiography
November 2003 - December 2007
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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

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MI within 72 hours of Contrast Stress
Echocardiography
3 cases of MI (1 with Definity, and 2 with
Optison)
Demographics Indication for SE and result Outcome
65 yo male DM, HTN, high lipids Preoperative dobutamine-SE Marked positive SE in LAD territory VF during recovery (defibrillation) Troponin T was elevated (0.05ng/ml) 3 hours post SE Urgent coronary angiography Stenting of LAD (100 stenosis)
73 yo female Smoker, DM, HTN, high lipids Preoperative dobutamine-SE Negative SE and stress ECG Hip surgery same day of SE Postoperative day 2 , she developed chest pain Troponin T was elevated (0.23ng/ml) NSTEMI was diagnosed Coronary angiography and stenting of 90 OM was done
68 yo male Renal cell carcinoma Dobutamine-SE for assessment of suspected CAD Negative SE and stress ECG Patient developed chest pain during the SE Troponin T was elevated (0.08ng/ml) 3 hours post SE NSTEMI was diagnosed Coronary angiography showed 60 Cx stenosis and 50 RCA
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Arrhythmias During Contrast Stress
Echocardiography

• Supraventricular tachycardia
• Contrast cohort 30 patients (0.28)
• Reference cohort 34 patients (0.21)
• Ventricular tachycardia
• Contrast cohort 11 patients (0.10)
• Reference cohort 7 patients (0.04)

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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

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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

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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 and dobutamine study
(as it had higher risk patients)
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The annualized event rate for combined (death
MI) events

• Dobutamine SE cohort
• Contrast
• 9.6 (8.9, 10.3)
• 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)

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Contrast Related Adverse Events (AE)

• AEs were consistently documented by unique
  statements in EMR starting in January 2007
• In year 2007 3,071 contrast SE (1,819
  dobutamine-SE 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 310,000 patients)
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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, n3071)
  however paper recording for previous 3 years
  showed same rate of AEs.
• 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

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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