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JAMA Cardiol
. 2025 Aug 30:e253460.
doi: 10.1001/jamacardio.2025.3460. Online ahead of print. High-Dose vs Standard-Dose Influenza Vaccine and Cardiovascular Outcomes in Older Adults: A Prespecified Secondary Analysis of the DANFLU-2 Randomized Clinical Trial
Niklas Dyrby Johansen 1 2 , Daniel Modin 1 2 , Matthew M Loiacono 3 4 , Rebecca C Harris 5 , Marine Dufournet 6 , Carsten Schade Larsen 7 8 , Lykke Larsen 9 , Lothar Wiese 10 , Michael Dalager-Pedersen 11 12 , Brian L Claggett 13 , Kira Hyldekær Janstrup 1 2 , Katja Vu Bartholdy 1 2 , Katrine Feldballe Bernholm 1 2 , Julie Inge-Marie Helene Borchsenius 1 2 , Filip Soeskov Davidovski 1 2 , Lise Witten Davodian 1 2 , Maria Dons 1 2 , Lisa Steen Duus 1 2 , Caroline Espersen 1 2 , Frederik Holme Fussing 1 2 , Anne Marie Reimer Jensen 1 2 , Nino Emanuel Landler 1 2 , Adam Cadovius Femerling Langhoff 1 2 , Mats Christian Højbjerg Lassen 1 2 , Anne Bjerg Nielsen 1 2 , Camilla Ikast Ottosen 1 2 , Morten Sengeløv 1 2 , Kristoffer Grundtvig Skaarup 1 2 , Manan Pareek 1 2 , Scott D Solomon 13 , Martin J Landray 14 , Gunnar H Gislason 1 15 16 , Lars Køber 15 17 , Pradeesh Sivapalan 15 18 , Cyril Jean-Marie Martel 19 , Jens Ulrik Stæhr Jensen 15 18 , Tor Biering-Sørensen 1 2 17 20
Affiliations
Importance: The high-dose inactivated influenza vaccine (HD-IIV) has demonstrated superior protection against laboratory-confirmed influenza infection vs standard-dose IIV (SD-IIV); however, data regarding its effectiveness against cardiovascular (CV) outcomes are mainly from observational studies or specific high-risk groups.
Objective: To investigate the relative vaccine effectiveness (rVE) of HD-IIV vs SD-IIV against CV outcomes in the general older adult population in Denmark.
Design, setting, and participants: This was a prespecified secondary analysis of DANFLU-2, a pragmatic, open-label, individually randomized clinical trial (RCT) using nationwide administrative health registries in Denmark during the 2022/2023 to 2024/2025 influenza seasons. Older adults (age ≥65 years) were eligible for inclusion regardless of comorbidity. The trial design specified that if the primary end point was neutral, no hypothesis testing would be performed for secondary or exploratory end points. Data were analyzed from June 29 to August 12, 2025.
Interventions: Individual-level 1:1 randomization to HD-IIV or SD-IIV. Participants re-enrolling in additional seasons were rerandomized.
Main outcomes and measures: Severe CV outcomes were prespecified secondary and exploratory end points in the trial, occurring from 14 days after vaccination through May 31 the following year.
Results: A total of 332 438 participants (170 900 [51.4%] male; mean [SD] age, 73.7 [5.8] years) were randomized (166 218 to HD-IIV and 166 220 to SD-IIV), of whom 91 026 (27.4%) had a history of CV disease. HD-IIV did not significantly reduce the trial's primary end point of hospitalization for influenza or pneumonia. The incidence of hospitalization for any cardiorespiratory disease was lower in the HD-IIV group than the SD-IIV group (rVE, 5.7% [95% CI, 1.4% to 9.9%]; absolute difference, -0.13 [95% CI, -0.24 to -0.03] percentage points), and rVE did not differ by history of CV disease compared with no CV disease at baseline. Hospitalization for any CV disease occurred in fewer participants in the HD-IIV group than the SD-IIV group (rVE, 7.5% [95% CI, 1.5% to 12.5%]; absolute difference, -0.10 [95% CI, -0.18 to -0.02] percentage points) as did hospitalization for heart failure (rVE, 19.5% [95% CI, 3.3% to 33.1%]; absolute difference, -0.03 [95% CI, -0.06 to -0.01] percentage points).
Conclusions and relevance: This study found reduced incidence of cardiorespiratory hospitalization among those who received HD-IIV vs SD-IIV, driven by a lower incidence of CV hospitalizations, and particularly heart failure hospitalizations. These differences should be interpreted as exploratory findings in the setting of a large RCT with a neutral primary outcome.
Trial registration: ClinicalTrials.gov Identifier: NCT05517174.
. 2025 Aug 30:e253460.
doi: 10.1001/jamacardio.2025.3460. Online ahead of print. High-Dose vs Standard-Dose Influenza Vaccine and Cardiovascular Outcomes in Older Adults: A Prespecified Secondary Analysis of the DANFLU-2 Randomized Clinical Trial
Niklas Dyrby Johansen 1 2 , Daniel Modin 1 2 , Matthew M Loiacono 3 4 , Rebecca C Harris 5 , Marine Dufournet 6 , Carsten Schade Larsen 7 8 , Lykke Larsen 9 , Lothar Wiese 10 , Michael Dalager-Pedersen 11 12 , Brian L Claggett 13 , Kira Hyldekær Janstrup 1 2 , Katja Vu Bartholdy 1 2 , Katrine Feldballe Bernholm 1 2 , Julie Inge-Marie Helene Borchsenius 1 2 , Filip Soeskov Davidovski 1 2 , Lise Witten Davodian 1 2 , Maria Dons 1 2 , Lisa Steen Duus 1 2 , Caroline Espersen 1 2 , Frederik Holme Fussing 1 2 , Anne Marie Reimer Jensen 1 2 , Nino Emanuel Landler 1 2 , Adam Cadovius Femerling Langhoff 1 2 , Mats Christian Højbjerg Lassen 1 2 , Anne Bjerg Nielsen 1 2 , Camilla Ikast Ottosen 1 2 , Morten Sengeløv 1 2 , Kristoffer Grundtvig Skaarup 1 2 , Manan Pareek 1 2 , Scott D Solomon 13 , Martin J Landray 14 , Gunnar H Gislason 1 15 16 , Lars Køber 15 17 , Pradeesh Sivapalan 15 18 , Cyril Jean-Marie Martel 19 , Jens Ulrik Stæhr Jensen 15 18 , Tor Biering-Sørensen 1 2 17 20
Affiliations
- PMID: 40884442
- PMCID: PMC12398768
- DOI: 10.1001/jamacardio.2025.3460
Importance: The high-dose inactivated influenza vaccine (HD-IIV) has demonstrated superior protection against laboratory-confirmed influenza infection vs standard-dose IIV (SD-IIV); however, data regarding its effectiveness against cardiovascular (CV) outcomes are mainly from observational studies or specific high-risk groups.
Objective: To investigate the relative vaccine effectiveness (rVE) of HD-IIV vs SD-IIV against CV outcomes in the general older adult population in Denmark.
Design, setting, and participants: This was a prespecified secondary analysis of DANFLU-2, a pragmatic, open-label, individually randomized clinical trial (RCT) using nationwide administrative health registries in Denmark during the 2022/2023 to 2024/2025 influenza seasons. Older adults (age ≥65 years) were eligible for inclusion regardless of comorbidity. The trial design specified that if the primary end point was neutral, no hypothesis testing would be performed for secondary or exploratory end points. Data were analyzed from June 29 to August 12, 2025.
Interventions: Individual-level 1:1 randomization to HD-IIV or SD-IIV. Participants re-enrolling in additional seasons were rerandomized.
Main outcomes and measures: Severe CV outcomes were prespecified secondary and exploratory end points in the trial, occurring from 14 days after vaccination through May 31 the following year.
Results: A total of 332 438 participants (170 900 [51.4%] male; mean [SD] age, 73.7 [5.8] years) were randomized (166 218 to HD-IIV and 166 220 to SD-IIV), of whom 91 026 (27.4%) had a history of CV disease. HD-IIV did not significantly reduce the trial's primary end point of hospitalization for influenza or pneumonia. The incidence of hospitalization for any cardiorespiratory disease was lower in the HD-IIV group than the SD-IIV group (rVE, 5.7% [95% CI, 1.4% to 9.9%]; absolute difference, -0.13 [95% CI, -0.24 to -0.03] percentage points), and rVE did not differ by history of CV disease compared with no CV disease at baseline. Hospitalization for any CV disease occurred in fewer participants in the HD-IIV group than the SD-IIV group (rVE, 7.5% [95% CI, 1.5% to 12.5%]; absolute difference, -0.10 [95% CI, -0.18 to -0.02] percentage points) as did hospitalization for heart failure (rVE, 19.5% [95% CI, 3.3% to 33.1%]; absolute difference, -0.03 [95% CI, -0.06 to -0.01] percentage points).
Conclusions and relevance: This study found reduced incidence of cardiorespiratory hospitalization among those who received HD-IIV vs SD-IIV, driven by a lower incidence of CV hospitalizations, and particularly heart failure hospitalizations. These differences should be interpreted as exploratory findings in the setting of a large RCT with a neutral primary outcome.
Trial registration: ClinicalTrials.gov Identifier: NCT05517174.