Background
Influenza causes substantial morbidity and mortality worldwide, particularly among individuals with cardiovascular disease (CVD), who face increased risks of cardiovascular events during and after influenza infection. Despite unequivocal recommendations by health authorities for annual influenza vaccination, overall vaccination rates remain suboptimal in the United States, particularly among populations vulnerable to cardiovascular complications. Prior evidence from Denmark demonstrated that electronic messaging highlighting the cardiovascular benefits of influenza vaccination increased vaccine uptake. Whether this targeted communication strategy is effective in a diverse and large U.S. population, characterized by broader demographic heterogeneity and healthcare access challenges, remains unclear.
Study Design
Bhatt et al. conducted a prospective, randomized, open-label trial with blinded end point assessment embedded within a multiregional U.S. healthcare system. The study enrolled 3,668,428 adults across three states and Washington, DC. Participants were randomized equally (1:1:1:1) into four groups based on two electronic messaging interventions at separate time points: (1) two cardiovascular-focused messages, (2) cardiovascular-focused message followed by usual care message, (3) usual care message followed by cardiovascular-focused message, or (4) two usual care messages. Usual care messaging referred to standard vaccine promotion communications without specific emphasis on cardiovascular benefits. The primary endpoint was influenza vaccination receipt by January 1, 2025. Six coprimary comparisons assessed the impact of messaging sequences on vaccination uptake.
Key Findings
The cohort comprised a mean age of 48.36 years, with a slight female predominance (52.87%), 10.53% were Black, and 19.15% had preexisting cardiovascular disease. Overall influenza vaccination uptake was 32.46%, reflecting a relatively low baseline rate.
The trial’s primary analysis comparing participants receiving cardiovascular-focused messages at any time point against those receiving two rounds of usual care messaging revealed no significant difference: 32.41% vs. 32.60% vaccination rates, respectively (absolute difference -0.19 percentage points; 99.2% confidence interval, -0.34 to -0.04). Time to vaccination, an important metric of early uptake, also did not differ significantly between groups. No subgroup analyses demonstrated improved uptake with cardiovascular-focused messaging, including among participants with existing cardiovascular disease.
This contrasts with prior Danish data, suggesting that contextual factors such as demographic diversity, baseline vaccination attitudes, healthcare system integration, or message delivery modality may influence responsiveness to cardiovascular framing. The study importantly confirmed feasibility of large-scale, individual-level randomization embedded within routine health system operations.
Expert Commentary
This comprehensive trial highlights critical considerations for behavioral interventions aiming to improve vaccine uptake via targeted messaging. Despite biologically plausible and epidemiologically supported cardiovascular benefits of influenza vaccination, conveying these in an electronic letter format did not produce measurable changes in vaccine acceptance in a diverse U.S. population with generally low uptake rates.
Possible explanations include message saturation amid competing health information, variations in health literacy, mistrust of medical messaging in certain populations, or insufficient emotional salience of cardiovascular risk framing to motivate behavior change. Additionally, structural barriers such as access and convenience likely remain dominant determinants of vaccination uptake beyond motivational nudges. Future research may explore multimodal, culturally tailored education combined with system-level access improvements.
A limitation is the trial’s reliance on electronic communication alone, which may not engage all sociodemographic groups equally. Engagement metrics such as message open rates or qualitative assessments of message perception were not reported but might elucidate underlying mechanisms of null effect.
Conclusion
Cardiovascular-focused electronic messaging, though conceptually appealing and effective in prior European settings, failed to augment influenza vaccine uptake in a large, racially and regionally diverse U.S. cohort within routine care. These findings underscore the complexity of vaccine promotion efforts in populations with heterogeneous barriers and highlight the need for multifaceted interventions beyond message framing alone. Furthermore, the trial exemplifies the potential of embedded randomized designs for rapid, scalable evaluation of behavioral strategies in real-world health systems. Ongoing initiatives should consider integrating personalized, culturally sensitive communication with enhanced vaccine access to optimize immunization rates, particularly among cardiovascular patients at high risk for influenza-related complications.
References
Bhatt AS, Berry NC, Parikh RV, et al. Cardiovascular-Focused Messaging to Improve Influenza Vaccination Rates. NEJM Evidence. 2025 Oct;4(10):EVIDoa2500208. doi:10.1056/EVIDoa2500208. Epub 2025 Aug 30. PMID: 40884406.
CDC. Influenza (Flu): People with Certain Medical Conditions. Centers for Disease Control and Prevention. Updated 2024. https://www.cdc.gov/flu/highrisk/index.htm
Udell JA, Zawi R, Bhatt DL, et al. Association between influenza vaccination and cardiovascular outcomes in high-risk patients: a meta-analysis. JAMA. 2013;310(16):1711-1720.
Vaccination Coverage Among Adults in the United States, 2023: Data Summary. CDC, National Center for Immunization and Respiratory Diseases. 2024.