Cardiovascular Hospitalizations Lower With High-Dose Flu Vaccine, Analysis Suggests

A prespecified secondary analysis of the DANFLU-2 pragmatic randomized trial found that the incidence of cardiorespiratory hospitalization was lower among older adults who received a high-dose versus a standard-dose influenza vaccine, regardless of cardiovascular disease (CVD) history.

"The high-dose inactivated influenza vaccine has demonstrated superior protection against laboratory-confirmed influenza infection versus standard-dose inactivated influenza vaccine; however, data regarding its effectiveness against cardiovascular outcomes are mainly from observational studies or specific high-risk groups," noted Tor Biering-Sørensen, MD, PhD, of Copenhagen University in Denmark, and co-authors.

Overall, 332,438 participants from DANFLU-2 were included in the analysis; 51.4% were men, mean age was 73.7 and 27.4% had a history of CVD. Relative vaccine effectiveness (rVE) was calculated as 1 minus the crude relative risk of the end point and expressed as a percentage.

• The incidence of hospitalization for any cardiorespiratory disease was lower in the high-dose (2.25%) than the standard-dose group (2.38%; rVE 5.7%, 95% CI 1.4%-9.9%). The absolute difference was −0.13 percentage points (95% CI −0.24 to −0.03). The rVE did not differ by history of CVD versus with no baseline CVD.
• Hospitalization for any CVD occurred in fewer participants in the high-dose group than the standard-dose group (rVE 7.2%, 95% CI 1.5%-12.5%), with an absolute difference of −0.10 percentage points (95% CI −0.18 to −0.02).
• Hospitalization for heart failure also was lower in the high-dose group (rVE 19.5%, 95% CI 3.3%-33.1%) with an absolute difference of −0.03 percentage points (95% CI −0.06 to −0.01).

The findings were presented at the European Society of Cardiology Congress in Madrid and published in JAMA Cardiology.

DANFLU-2 was a pragmatic, open-label, randomized trial assessing influenza vaccine efficacy in high and standard doses. The trial design specified that if the primary end point was neutral, no hypothesis testing would be performed for secondary or exploratory end points.

"The trial did not meet its primary end point and the findings reported here should be considered hypothesis-generating; however, the trial was adequately powered to evaluate cardiorespiratory hospitalizations," Biering-Sørensen and colleagues noted. "These findings, while not subject to formal type I error control, provide potentially important clinical insights."

Severe CV outcomes were prespecified secondary and exploratory end points. The high-dose vaccine did not significantly reduce the DANFLU-2 end point of hospitalization for influenza or pneumonia compared with the standard dose.

Data were from Denmark’s national administrative health registries for the 2022-2023 to 2024-2025 influenza seasons. Adults ages 65 or older were eligible, regardless of comorbidity. Participants were randomized to high-dose (n=166,218) or standard-dose (n=166,220) vaccination.

"The DANFLU-2 trial represents a paradigm shift in evidence generation for the effectiveness of vaccines against severe outcomes. By combining criterion-standard individual-level randomization with pragmatic design elements, including digital recruitment, online informed consent, and comprehensive use of routine health data, this streamlined trial provides causal inference within a general-population vaccination setting, all while imposing minimal participation burden," Biering-Sørensen and co-authors noted.

"This secondary analysis of DANFLU-2 demonstrates the utility of the large-scale data generated by the trial beyond its primary analysis: to deliver insights from secondary and exploratory analyses for cardiovascular outcomes and for high-risk populations (e.g., patients with heart failure) with much larger sample sizes than seen in previous trials," they stated.

In an accompanying editorial, Robert Califf, MD, of Duke University in Durham, North Carolina, noted that the analysis clarified small differences between two doses of influenza vaccine.

"More importantly, though, it highlights what we need to do to understand the most effective interventions. Better health outcomes would ensue if health systems, insurance companies, and federal agencies worked together to build a learning health system for better patient outcomes, vs the current obsession with financialization of every transaction. We now have the technology and methods to clarify the road ahead on the health care highway — let’s use them," Califf pointed out.

"In the longer term, the methods applied in this trial may prove more important than its specific findings," Califf observed. "Particularly in the U.S., we are operating a ’nonlearning health system’ in which we have a plethora of digital data but are unwilling or unable to marshal our massive talent and computational capability to optimize the production of usable knowledge from that data. Across different clinical practice guidelines in specialties including cardiology, general surgery, oncology, and pediatrics, less than 15% of major recommendations are based on high-quality evidence, and progress toward a system that rapidly generates evidence to guide practice continues to be modest at best."

Influenza vaccination is a high-level recommendation in clinical practice guidelines for patients with acute coronary syndromes, but standard doses often fail to elicit a sufficient immune response in older people and in people with medical conditions including CVD.

Although DANFLU-2 was open-label, the "risk of bias was considered low, as knowledge of treatment assignment was not expected to have a substantial effect on severe hospitalization-based events, and participants received clinical treatment by health care practitioners not involved in the trial," Biering-Sørensen and colleagues wrote. Assessments relied on national registry data which may introduce misclassification, they added.

The study was funded by Sanofi.

Biering-Sørensen reported receiving grants from Sanofi during the conduct of the study and grants from AstraZeneca, Bayer, Boston Scientific, GE Healthcare, GSK, Novartis, Novo Nordisk Pfizer, and Sanofi-Pasteur and personal fees from Amgen, AstraZeneca, Bayer, CSL Seqirus, GE Healthcare, GSK, IQVIA, Novartis, Parexel, and Sanofi outside the submitted work.

Califf reported no conflicts of interest.

Johansen ND, et al "High-dose vs standard-dose influenza vaccine and cardiovascular outcomes in older adults: a prespecified secondary analysis of the DANFLU-2 randomized clinical trial" JAMA Cardiol 2025; DOI: 10.1001/jamacardio.2025.3460.

Califf RM "Evidence about benefits and risks of vaccines: challenges in science, medicine, public health, and culture" JAMA Cardiol 2025; DOI: 10.1001/jamacardio.2025.3521.