Bracco’s perspective on recent publications reporting LUMASON^® (sulfur hexafluoride lipid-type A microspheres) for injectable suspension, for intravenous use or intravesical use safety information

The core results were based on a retrospective assessment of data sets from four health systems in the U.S. (Mayo Clinical Enterprise, Avera Health System, Northwell Health, and Wellstar Health) that had recently observed an increase in the incidence of “severe” and “critical” adverse events (SAEs) at a minority of sites in their systems. The study also retrospectively analyzed data that had been prospectively collected during stress echocardiography procedures conducted at the Mayo Clinic. Finally, the authors conducted a nested case-control study to assess for an association with COVID-19 vaccination status in those patients who had a UEA-associated adverse drug reaction (ADR) after the approval of COVID-19 vaccination in the USA (December 2020) at any Mayo Clinic site.

The review found that a significantly higher rate of severe and critical cardiopulmonary reactions was reported for LUMASON UEA. Moreover, the paper reported that the frequency of serious adverse events following exposure to LUMASON UEA had increased in the last few years, suggesting a possible link with the massive COVID-19 vaccination campaign, and especially with one of the mRNA vaccines.

While the focus of the analysis was on systems that observed an increase in the incidence of SAEs, a comprehensive review of our own safety data from the four systems included in the study shows that only a minority of sites (<15%) experienced SAEs.³ The overall rarity of SAEs occurring within these systems, along with the general limitations of retrospective analyses makes it challenging to draw firm conclusions from the review.

This is the first published review where an increase in the reporting of adverse event frequency for LUMASON UEA has been reported and we are reviewing these findings with the utmost consideration as we work to better understand the methodology used for the review and subsequently any conclusions that can be drawn from the results.

Retrospective chart review at all sites

• The investigation was conducted at four health systems, comprising a total of 81 hospitals. As the adverse events were also reported to Bracco’s pharmacovigilance database, we know that only a minority of hospitals (12/81, 15%) experienced one or more adverse events.³
• The majority of the data from this review derives from a retrospective assessment of different types of medical records. However, it is well known that retrospective studies depend on data entered into a clinical database during routine clinical practice and are not collected for research.
• The review indicates that the included hospitals had different documentation practices calling into question whether patient information was harmonized, i.e.:
  • Among the critical information that had to be collected was the occurrence of complications within the first 30 minutes of contrast administration. However, when discussing review limitations, the authors mention uncertainty about the ability to categorize the timing of post-contrast events.
  • The Authors also report the inability to identify specific symptoms and to categorize the severity of complications.
  • Moreover, certain variables that had the potential to impact the outcome of the review might not have been recorded at all. The retrospective nature of the analysis did not make it possible to account for possible differences in baseline patient characteristics and clinical use of the products across the different health systems, and individual hospitals.
  • Qualification, training and monitoring of operators in charge of extracting information from the relevant databases is not mentioned which can lead to inconsistencies when making comparisons across these databases.
  • Finally, it is unclear whether data abstractors were blind to the purpose of the review and the research questions the review was aimed to address (to avoid reviewers’ bias).
• Among the limitations, it is also mentioned that the frequency of adverse events may have been underestimated. This might have been more likely with an agent like Definity^®, in clinical use at various institutions for a long time, longer than that of LUMASON UEA, where this was observed. The researchers also declared back pain and/or headache to not be allergic and not a major focus of the review further reducing calculated adverse event rates for UEA that may be more prone to these adverse drug reactions, such as Definity^®4.
• Immediate-type (i.e., within 30 minutes) reactions to ultrasound contrast agents are believed to be a consequence of direct activation of the complement system (complement activation-related pseudo-allergy (CARPA) reactions). CARPA reactions resemble true allergic reactions; however, in contrast to immunoglobulin E-mediated type 1 hypersensitivity reactions, in CARPA reactions no prior exposure is necessary, the reaction is typically milder or absent upon repeated exposure, spontaneous resolution often occurs, and there is a higher reaction rate among the general population.⁴ Women and "atopic" individuals (those with pre-existing allergies) may be at higher risk.⁵
• In evaluating the review discussion and listing of individual serious adverse events in the Supplemental Table, a proportion of serious adverse events do not appear to be CARPA reactions (non-CARPA events), especially following exposure to LUMASON UEA (19 cases with Definity^®, 44 with LUMASON UEA). In these cases, a possible association with the administration of the contrast agent is more difficult to suggest. Of note, the conditions of the patients developing non-CARPA events were not reported nor discussed.
• The different administration schemes were a major confounding factor, especially considering that the dilution and infusion for Definity^® was introduced to improve safety and the researchers offered no comparison of CARPA rates with Definity^® dilution/bolus vs further dilution/infusion.⁶

Mayo Clinic Rochester stress echocardiographic database

• Retrospective review of data from a reliable database, composed of prospectively collected information about patients undergoing stress-echo exams.
• The LUMASON UEA and Definity^® cohorts showed several major and significant differences (type of stress procedure, patient populations, administration scheme, etc.), which make them difficult to compare.

In summary, given the limitations and currently available information surrounding the methodology it is difficult to draw firm conclusions from the review by Ali et al.

• No detrimental effects of LUMASON UEA on cardiac electrophysiology were observed in patients with coronary artery disease, and no significant effects on pulmonary hemodynamics were noted in patients with pulmonary hypertension or congestive heart failure.
• Similarly, no effects on several assessments of pulmonary function were observed in patients with chronic obstructive pulmonary disease, and no clinically meaningful changes in oxygen saturation or other safety parameters were observed after administration of LUMASON UEA to patients with diffuse interstitial pulmonary fibrosis.
• The retrospective study of critically ill patients revealed a reduction of in-hospital mortality between patients administered LUMASON UEA for echocardiography versus those who had undergone echocardiography without a contrast agent.
• Post-marketing surveillance revealed very low reporting rates for all serious adverse events (<1 every 10,000 exposures), of which part were due to hypersensitivity to the agent.²