Ultrasound enhancing agents (UEAs) are widely used in transthoracic and stress echocardiography (TTE/SE) to improve diagnostic clarity, particularly in patients with poor endocardial border definition. Despite their benefits, recent reports have raised concerns about the safety of these agents. To assess the validity of these concerns, a large-scale retrospective analysis was conducted using nationwide data. A study evaluated the incidence of serious adverse events within two days of UEA administration, comparing outcomes across different agents and timeframes.
Evaluating Nationwide Safety Outcomes
The study reviewed claims data from over 11.4 million insured adults in the United States between 2018 and 2022, focusing on more than 500,000 cases in which UEAs were used during TTE/SE. A propensity score-matched cohort analysis was conducted to control for baseline differences between patients who received UEAs and those who did not. The results indicated that individuals who received UEAs had significantly lower odds of death within two days of the procedure compared to those who did not. Importantly, rates of other serious complications, such as anaphylaxis, myocardial infarction, ventricular tachycardia and cardiac arrest, were similar between the two groups.
Across the three commercially available agents—Definity, Lumason and Optison—no significant differences in death rates or secondary outcomes were observed. These findings held consistent across the study years, including both the pre-COVID and post-COVID vaccination periods. The data showed no temporal increase in adverse events, undermining concerns that COVID-19 vaccination might influence hypersensitivity to UEAs.
Balancing Risk with Clinical Utility
UEAs remain a cornerstone of modern echocardiographic practice, with their ability to enhance image clarity contributing to improved diagnosis and more efficient care. Their established benefits include reductions in the need for additional imaging, faster decision-making and overall cost efficiency. The rate of serious adverse events, such as anaphylaxis, was estimated at approximately 1 in 10,000, aligning with previous literature and confirming that such events are exceedingly rare.
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Although certain reports had suggested that specific agents might pose higher risks—particularly in the context of prior COVID-19 vaccination or polyethylene glycol hypersensitivity—this large-scale analysis found no evidence to support those claims. Instead, it suggested that prior findings of variability in safety may be attributed to differences in patient populations, healthcare settings and agent usage patterns rather than to the agents themselves.
Continued Vigilance and Practical Implications
While the data support the safety of UEAs, they also underscore the need for appropriate risk management. All echocardiography laboratories should maintain protocols to quickly recognise and respond to anaphylactoid reactions, however rare. UEAs, unlike other contrast media, do not impact renal or thyroid function, and their safety profile remains one of the most favourable among imaging agents. However, as with any medical intervention, continuous monitoring through pharmacovigilance systems is essential.
The underuse of UEAs, particularly in some demographic groups such as women, remains a concern. Addressing these disparities could enhance diagnostic equity and improve outcomes. Moreover, the results of this study reaffirm the importance of including UEA safety data in clinical guidelines and institutional policies, particularly as new contrast applications emerge, such as in molecular imaging and therapeutic ultrasound techniques.
This comprehensive nationwide analysis of over 11 million patients offers robust evidence that ultrasound enhancing agents are safe for use in transthoracic and stress echocardiography. Serious adverse events within two days of administration are uncommon, and the use of UEAs is associated with lower odds of death. These findings are consistent across different agents, years and patient subgroups, reinforcing the role of UEAs as a valuable and safe diagnostic tool in modern cardiology. Continued use, guided by clinical need and supported by appropriate safety protocols, remains well justified.
Source: Journal of the American Heart Association
Image Credit: iStock
