High-Dose vs Standard-Dose Influenza Vaccine and Cardiovascular Outcomes in Older Adults: A Prespecified Secondary Analysis of the DANFLU-2 Randomized Clinical Trial.

Background

To investigate the relative vaccine effectiveness (rVE) of HD-IIV vs SD-IIV against CV outcomes in the general older adult population in Denmark.

本研究旨在调查丹麦普通老年群体中，HD-IIV与SD-IIV对心血管结果的相对疫苗有效性（rVE）。

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.

这是DANFLU-2的预定次要分析，DANFLU-2是一项实用的、开放标签的、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性的行政健康登记系统。

Older adults (age ≥65 years) were eligible for inclusion regardless of comorbidity.

年龄≥65岁的老年人，无论是否有合并症，都有资格纳入研究。

The trial design specified that if the primary end point was neutral, no hypothesis testing would be performed for secondary or exploratory end points.

试验设计规定，如果主要终点结果为中性，则不对次要或探索性终点进行假设检验。

Data were analyzed from June 29 to August 12, 2025.

数据分析时间为2025年6月29日至8月12日。

Methods

Individual-level 1:1 randomization to HD-IIV or SD-IIV.

个体水平上的1:1随机分配到高剂量流感灭活疫苗(HD-IIV)或标准剂量流感灭活疫苗(SD-IIV)。

Participants re-enrolling in additional seasons were rerandomized.

重新参加额外季节的参与者被重新随机分配。

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.

严重心血管（CV）结局是试验中预先设定的次要和探索性终点，从接种疫苗后14天开始，直至次年5月31日。

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.

共有332,438名参与者（170,900名[51.4%]为男性；平均[标准差]年龄为73.7[5.8]岁）被随机分配（166,218名接受高剂量流感疫苗（HD-IIV），166,220名接受标准剂量流感疫苗（SD-IIV）），其中91,026名（27.4%）有心血管疾病史。

HD-IIV did not significantly reduce the trial's primary end point of hospitalization for influenza or pneumonia.

HD-IIV并未显著降低试验的主要终点，即因流感或肺炎住院的风险。

The incidenceof 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.

与SD-IIV组相比，HD-IIV组因任何心肺疾病住院的发生率较低（rVE，5.7% [95% 置信区间，1.4% 至 9.9%]；绝对差异，-0.13 [95% 置信区间，-0.24 至 -0.03] 百分点），并且与无心血管疾病史的患者相比，有心血管疾病史的患者rVE没有差异。

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).

与SD-IIV组相比，HD-IIV组的任何心血管疾病住院人数较少（相对风险降低，7.5% [95% 置信区间，1.5% 至 12.5%]；绝对差异，-0.10 [95% 置信区间，-0.18 至 -0.02] 百分点），心力衰竭住院人数也较少（相对风险降低，19.5% [95% 置信区间，3.3% 至 33.1%]；绝对差异，-0.03 [95% 置信区间，-0.06 至 -0.01] 百分点）。

conclusions_and_relevance

This study found reduced incidenceof cardiorespiratory hospitalization among those who received HD-IIV vs SD-IIV, driven by a lower incidenceof CV hospitalizations, and particularly heart failure hospitalizations.

该研究发现，与SD-IIV相比，接受HD-IIV治疗的患者的心肺住院发生率降低，这是由于心血管住院发生率，特别是心力衰竭住院发生率的降低所驱动的。

These differences should be interpreted as exploratory findings in the setting of a large RCT with a neutral primary outcome.

在主要结果为中性的大型随机对照试验（RCT）背景下，这些差异应被视为探索性发现。

trial_registration

ClinicalTrials.gov Identifier: NCT05517174.

ClinicalTrials.gov 注册号：NCT05517174。