Comparative Safety of Ultrasound Enhancing Agents: A Systematic Review and Bayesian Network Meta-Analysis

Ultrasound enhancing agents (UEAs), including Optison, DEFINITY, and LUMASON, enhance the diagnostic performance of echocardiography, particularly, in patients with suboptimal acoustic windows. However, there remains a paucity of comparative safety assessments among the Food and Drug Administration-approved UEAs. A Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-guided systematic literature review performed in August 2023 searched Medline, Embase, Cochrane Library, and gray literature. Randomized and nonrandomized comparative evidence on safety of contrast-enhanced procedures were included. A feasibility assessment ensured homogeneity across studies by comparing patient characteristics and outcomes. Bayesian hierarchical network meta-regression was used to indirectly compare published safety outcomes across different UEAs. In addition, adverse events (AEs) between 2019 and 2023 for each UEA were retrieved from the Food and Drug Administration Adverse Events Reporting System (FAERS), and comparative safety outcomes were derived using annual UEA administration in the United States. The screening of 4,146 records rendered 19 studies for inclusion in the indirect comparison analysis after feasibility assessment. Optison demonstrated favorable safety in direct comparisons with DEFINITY and LUMASON across the majority of investigated AEs. Network meta-regression results on serious AEs within 30 minutes revealed odds ratios (ORs) of 0.59 (95% confidence interval 0.27 to 1.23) and 0.63 (0.29 to 1.33) for Optison versus LUMASON and DEFINITY, respectively, indicating a decreased risk of serious AEs for Optison versus LUMASON and DEFINITY, further supported by statistically significant ORs within FAERS: 0.01 (0 to 0.02), p <0.001 and 0.15 (0.05 to 0.48), p = 0.001 for Optison versus LUMASON and DEFINITY, respectively. In conclusion, our results restate the favorable comparative safety profile of Optison, providing new evidence to inform clinical decision-making.