Johansen Niklas Dyrby, Modin Daniel, Loiacono Matthew M, Harris Rebecca C, Dufournet Marine, Larsen Carsten Schade, Larsen Lykke, Wiese Lothar, Dalager-Pedersen Michael, Claggett Brian L, Janstrup Kira Hyldekær, Bartholdy Katja Vu, Bernholm Katrine Feldballe, Borchsenius Julie Inge-Marie Helene, Davidovski Filip Soeskov, Davodian Lise Witten, Dons Maria, Duus Lisa Steen, Espersen Caroline, Fussing Frederik Holme, Jensen Anne Marie Reimer, Landler Nino Emanuel, Langhoff Adam Cadovius Femerling, Lassen Mats Christian Højbjerg, Nielsen Anne Bjerg, Ottosen Camilla Ikast, Sengeløv Morten, Skaarup Kristoffer Grundtvig, Pareek Manan, Solomon Scott D, Landray Martin J, Gislason Gunnar H, Køber Lars, Sivapalan Pradeesh, Martel Cyril Jean-Marie, Jensen Jens Ulrik Stæhr, Biering-Sørensen Tor
Department of Cardiology, Copenhagen University Hospital - Herlev and Gentofte, Copenhagen, Denmark.
Center for Translational Cardiology and Pragmatic Randomized Trials, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
JAMA Cardiol. 2025 Aug 30. doi: 10.1001/jamacardio.2025.3460.
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.
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.
Individual-level 1:1 randomization to HD-IIV or SD-IIV. Participants re-enrolling in additional seasons were rerandomized.
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.
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).
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.
ClinicalTrials.gov Identifier: NCT05517174.
高剂量灭活流感疫苗（HD-IIV）已证明与标准剂量灭活流感疫苗（SD-IIV）相比，对实验室确诊的流感感染具有更好的保护作用；然而，关于其对心血管（CV）结局有效性的数据主要来自观察性研究或特定高危人群。
调查HD-IIV与SD-IIV在丹麦普通老年人群中预防心血管结局的相对疫苗有效性（rVE）。
设计、设置和参与者：这是对DANFLU-2进行的预先指定的二次分析，DANFLU-2是一项务实、开放标签、个体随机临床试验（RCT），在2022/2023至2024/2025流感季节期间使用丹麦全国行政卫生登记系统。年龄≥65岁的老年人无论是否合并症均符合纳入条件。试验设计规定，如果主要终点为中性，则不对次要或探索性终点进行假设检验。数据于2025年6月29日至8月12日进行分析。
个体层面1:1随机分配至HD-IIV或SD-IIV。重新参加后续季节的参与者重新进行随机分组。
严重心血管结局是试验预先指定的次要和探索性终点，发生在接种疫苗后14天至次年5月31日期间。
共有332438名参与者（170900名[51.4%]男性；平均[标准差]年龄73.7[5.8]岁）被随机分组（166218名分配至HD-IIV，166220名分配至SD-IIV），其中91026名（27.4%）有心血管疾病史。HD-IIV并未显著降低试验的主要终点——流感或肺炎住院率。HD-IIV组任何心肺疾病的住院发生率低于SD-IIV组（rVE为5.7%[95%CI，1.4%至9.9%]；绝对差值为-0.13[95%CI，-0.24至-0.03]个百分点），且与基线时无心血管疾病相比，rVE在有无心血管疾病史的人群中无差异。HD-IIV组任何心血管疾病的住院参与者少于SD-IIV组（rVE为7.5%[95%CI，1.5%至12.5%]；绝对差值为-0.10[95%CI，-0.18至-0.02]个百分点），心力衰竭住院情况也是如此（rVE为19.5%[95%CI，3.3%至33.1%]；绝对差值为-0.03[95%CI，-0.06至-0.01]个百分点）。
本研究发现，与SD-IIV相比，接受HD-IIV者中心血管呼吸住院发生率降低，这是由心血管住院率降低，尤其是心力衰竭住院率降低所致。在主要结局为中性的大型RCT背景下，这些差异应作为探索性结果来解读。
ClinicalTrials.gov标识符：NCT05517174。
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