Abstract
Background and Aims
The aim was to evaluate and compare the relative vaccine effectiveness (rVE) of high-dose (HD-IIV) vs. standard-dose inactivated influenza vaccination (SD-IIV) on respiratory and cardiovascular outcomes in persons with or without pre-existing atherosclerotic cardiovascular disease (ASCVD).
Methods
A prespecified exploratory analysis of a pragmatic, open-label, individually randomized trial conducted in Denmark during three influenza seasons. Adults ≥65 years were randomized 1:1 to HD-IIV or SD-IIV. Baseline and outcome data were collected through nationwide registries. The primary outcome was hospitalization for influenza or pneumonia. Major adverse cardiovascular events (MACE) was defined as a composite of cardiovascular death, hospitalization for myocardial infarction, or hospitalization for stroke. Heterogeneity in rVE among participants with vs. without ASCVD was assessed.
Results
The incidence of all outcomes was higher in participants with pre-existing ASCVD (n = 46 825) vs. those without (n = 285 613). rVE was consistent among participants with and without ASCVD (all Pinteraction ≥ .05). The rVE for the primary outcome was 6.87% [95% confidence interval (CI), −2.52 to 15.42] among individuals without ASCVD and 4.71% (95% CI, −11.58 to 18.63) in those with (Pinteraction = .80). For influenza hospitalizations, the rVE was 42.88% (95% CI, 22.07–58.44) vs. 45.73% (95% CI, 16.68–65.16) in those without vs. with ASCVD (Pinteraction = .84). For MACE, the rVE was 4.29% (95% CI, −6.50 to 14.00) in participants without, and 0.30% (95% CI, −17.56 to 15.44) in participants with, pre-existing ASCVD (Pinteraction = .68).
Conclusions
Among individuals ≥65 years, the rVE of HD-IIV vs. SD-IIV against respiratory and cardiovascular outcomes was similar among those with vs. without pre-existing ASCVD.
Keywords: Atherosclerosis, Cardiovascular diseases, Influenza, Randomized controlled trial, Registries, Vaccination
Structured Graphical Abstract
Structured Graphical Abstract.
See the editorial comment for this article ‘Respiratory viruses, vaccines, and the heart: lessons from DANFLU-2, DAN-RSV, and beyond’, by B. Heidecker and T.F. Lüscher, https://doi.org/10.1093/eurheartj/ehaf697.
Introduction
Influenza infection increases the risk of fatal and nonfatal cardiovascular events, including myocardial infarction and stroke.1–5 Underlying cardiovascular disease is also a risk factor for influenza infection and its complications.6,7 Data from both observational studies and small randomized trials suggest that influenza vaccination decreases the risk of cardiovascular morbidity and mortality.8–11 The absolute degree of benefit may be greater among individuals at higher a priori risk, e.g. older subjects and those with cardiovascular disease.12
Yet, these same persons are also more likely to exhibit weaker and less durable antibody responses after receiving standard influenza vaccines.13–16 The high-dose inactivated influenza vaccine contains four times the amount of haemagglutinin antigen and results in significantly more pronounced serological responses in older individuals and in those with high-risk cardiovascular disease as compared with standard-dose vaccines.17–19 The high-dose inactivated influenza vaccine also significantly reduces the risk of laboratory-confirmed influenza illness and may potentially lower the risk of hospitalization and death.20,21 However, it remains unclear whether the improved humoral response translates to a lowering of respiratory and cardiovascular outcomes in persons with atherosclerotic cardiovascular disease.19
Therefore, the main purpose of this prespecified exploratory analysis of the DANFLU-2 trial (A Pragmatic Randomized Trial to Evaluate the Effectiveness of High-Dose Quadrivalent Influenza Vaccine vs. Standard-Dose Quadrivalent Influenza Vaccine in Older Adults) was to evaluate and compare the relative effectiveness of high-dose vs. standard-dose inactivated influenza vaccine on severe respiratory and cardiovascular outcomes, including atherosclerotic cardiovascular disease outcomes, in persons ≥65 years of age, with or without pre-existing atherosclerotic cardiovascular disease.
Methods
Trial design, participants, and procedures
The rationale, design, baseline characteristics, and primary results of the DANFLU-2 trial are reported elsewhere.22–24 In brief, DANFLU-2 was a pragmatic, registry-based, open-label, active-controlled, individually randomized trial conducted at more than 500 sites across Denmark during the 2022/2023, 2023/2024, and 2024/2025 influenza seasons. The trial enrolled adults ≥65 years, irrespectively of comorbidity. Participants were mainly recruited using electronic invitation letters sent through the Danish governmental digital mail system, Digital Post. Up to 1 000 000 randomly selected Danish citizens ≥65 years of age were invited during each influenza season. There were no formal exclusion criteria; vaccines were simply to be administered in accordance with routine clinical practice guidelines.
Participants were individually randomized 1:1 to either a high-dose inactivated influenza vaccine (Fluzone® High-Dose Quadrivalent/Efluelda®/Efluelda Tetra®; Sanofi) or a quadrivalent standard-dose inactivated influenza vaccine (VaxigripTetra; Sanofi). The high-dose inactivated influenza vaccine contained 60 μg of haemagglutinin antigen for each strain, while the standard-dose inactivated influenza vaccine contained 15 μg. Only one study visit was needed for randomization and vaccine delivery. All participants provided written informed consent, either online or in person. Participants re-enrolling in subsequent seasons were re-randomized and treated as unique observations. Co-administration with other seasonal vaccines was allowed according to local recommendations and included COVID-19 vaccines/boosters. The trial was approved by the Danish Medical Research Ethics Committees and the Danish Medicines Agency and further conducted in accordance with the Declaration of Helsinki and the International Council for Harmonization Good Clinical Practice guidelines.
Baseline evaluation and atherosclerotic cardiovascular disease
Baseline data were collected through linkage to the nationwide administrative health registries. International Classification of Diseases, Tenth Revision (ICD-10) codes and/or Anatomical Therapeutic Chemical (ATC) codes were used to define baseline conditions, medications, and vaccination status.22 Pre-existing atherosclerotic cardiovascular disease was defined as a history of ischaemic heart disease, cerebrovascular disease, or peripheral artery disease.
Outcomes
Outcome data were also collected through linkage to the nationwide health registries.22 During each study season, participants were followed for clinical outcomes from Day 15 after the initially booked vaccination date through May 31 (both included) the following year. The primary outcome was hospitalization for influenza or pneumonia. The first secondary outcome was hospitalization for any cardiorespiratory disease. Subordinate secondary outcomes were all-cause hospitalization, all-cause mortality, and the individual components of the primary outcome. All cardiovascular outcomes were exploratory. The main major adverse cardiovascular events outcome for this analysis was defined as a composite of death from cardiovascular causes, hospitalization for myocardial infarction, or hospitalization for stroke. Any hospitalization-based events with an associated COVID-19 ICD-10 discharge diagnosis code were not considered as outcomes.
Statistical analysis
Baseline characteristics were displayed according to the absence or presence of pre-existing atherosclerotic cardiovascular disease overall and with additional stratification by randomization group. Continuous variables were presented as means and standard deviations. Categorical variables were presented as number (%). Between-group comparisons were performed using the Mann-Whitney U test or Pearson’s χ2 test, respectively.
All analyses were performed according to the intention-to-treat principle. All effectiveness outcomes were examined using relative vaccine effectiveness (rVE) and based on first events only. rVE was calculated as (1 − relative risk) * 100%, and 95% confidence intervals (CI) were constructed using the exact Clopper–Pearson method for binomial proportions. rVE is the proportion of residual disease remaining after the control vaccine regimen that is prevented by the intervention vaccine regimen. For example, an rVE of 10% is mathematically equal to a relative risk of 0.90 for the intervention vs. control. An rVE = 0 signifies a null effect, an rVE >0 favours the intervention regimen, and an rVE <0 favours the control regimen. Event rates and rVE were displayed in the groups described above.
Heterogeneity in rVE among participants with vs. without atherosclerotic cardiovascular disease was assessed using the Cochran–Mantel–Haenszel test for homogeneity. Moreover, a sensitivity analysis was conducted in which participants with pre-existing heart failure or atrial fibrillation were included in the atherosclerotic cardiovascular disease group. A two-sided P-value <.05 was considered statistically significant. While a formal testing hierarchy was established for the primary analysis, the results from this analysis, although prespecified, are to be considered exploratory. Statistical analysis was performed using SAS Software, version 9.4 (SAS Institute, Cary, NC, USA); Stata MP, version 19.5 (StataCorp, College Station, TX, USA); and R, version 4.3.3 (R Foundation for Statistical Computing, Vienna, Austria).
Results
Baseline characteristics
A total of 332 438 participants were randomized to either the high-dose inactivated influenza vaccine (n = 166 218) or to the standard-dose inactivated influenza vaccine (n = 166 220). Overall, 46 825 (14.1%) participants had a history of atherosclerotic cardiovascular disease, of whom 31 112 (9.4%) had ischaemic heart disease, 16 381 (4.9%) cerebrovascular disease, and 2979 (0.9%) peripheral artery disease. A total of 3516 (1.1%) individuals had atherosclerotic cardiovascular disease affecting more than one vascular bed. Baseline characteristics in participants with and without pre-existing atherosclerotic cardiovascular disease are shown in Table 1 and with further stratification for randomization group in Supplementary data online, Table S1. Persons with atherosclerotic cardiovascular disease were fundamentally different from those without atherosclerotic cardiovascular disease; they were older, more often men, and had a higher prevalence of all reported cardiovascular and non-cardiovascular comorbidities. However, when considering individuals with or without pre-existing atherosclerotic cardiovascular disease separately, characteristics were well-balanced among those randomized to high-dose vs. standard-dose inactivated influenza vaccine. Baseline characteristics of the study participants in the sensitivity analysis are displayed in Supplementary data online, Table S2.
Table 1.
Baseline characteristics in DANFLU-2 participants with and without a history of atherosclerotic cardiovascular disease
| Characteristic | No history of ASCVD n = 285 613 |
History of ASCVD n = 46 825 |
P-value |
|---|---|---|---|
| Age (years), mean (standard deviation) | 73.4 (5.7) | 75.2 (6.1) | <.001 |
| Men, n (%) | 139 743 (48.9%) | 31 157 (66.5%) | <.001 |
| Hypertension, n (%) | 43 605 (15.3%) | 20 302 (43.4%) | <.001 |
| Diabetes, n (%) | 33 513 (11.7%) | 10 368 (22.1%) | <.001 |
| Ischaemic heart disease, n (%) | 0 | 31 112 (66.4%) | N/A |
| Prior myocardial infarction, n (%) | 0 | 9405 (20.1%) | N/A |
| Cerebrovascular disease, n (%) | 0 | 16 381 (35.0%) | N/A |
| Peripheral artery disease, n (%) | 0 | 2979 (6.4%) | N/A |
| ASCVD in >1 vascular bed, n (%) | 0 | 3516 (7.5%) | N/A |
| Heart failure, n (%) | 5072 (1.8%) | 5338 (11.4%) | <.001 |
| Atrial fibrillation, n (%) | 24 421 (8.6%) | 9664 (20.6%) | <.001 |
| Valvular heart disease, n (%) | 10 297 (3.6%) | 4826 (10.3%) | <.001 |
| Chronic lung disease, n (%) | 21 057 (7.4%) | 6095 (13.0%) | <.001 |
| Chronic kidney disease, n (%) | 34 969 (12.2%) | 11 819 (25.2%) | <.001 |
| Chronic liver disease, n (%) | 4014 (1.4%) | 974 (2.1%) | <.001 |
| Cancer, n (%) | 38 530 (13.5%) | 7388 (15.8%) | <.001 |
| Immunodeficiency, n (%) | 11 880 (4.2%) | 2435 (5.2%) | <.001 |
| Co-administration with COVID-19 vaccine, n (%) | 176 306 (61.7%) | 28 417 (60.7%) | <.001 |
ASCVD, atherosclerotic cardiovascular disease; COVID-19, Coronavirus disease 2019; DANFLU-2, A Pragmatic Randomized Trial to Evaluate the Effectiveness of High-Dose Quadrivalent Influenza Vaccine vs. Standard-Dose Quadrivalent Influenza Vaccine in Older Adults; N/A, not applicable.
Event rates in persons with and without atherosclerotic cardiovascular disease
The incidence of all primary, secondary, and exploratory outcomes reported here was higher in participants with pre-existing atherosclerotic cardiovascular disease as compared with those without (Table 2). For example, the primary outcome, i.e. hospitalization for influenza or pneumonia, occurred in 642/46 825 (1.37%) individuals with atherosclerotic cardiovascular disease and in 1706/285 613 (0.60%) without. Hospitalization for any cardiorespiratory disease was reported in 2235/46 825 (4.77%) and 5462/285 613 (1.91%), respectively. Hospitalization for influenza was observed in 98/46 825 (0.21%) with and 182/285 613 (0.06%) without atherosclerotic cardiovascular disease. The composite of death from any cause, hospitalization for myocardial infarction, or hospitalization for stroke occurred in 987/46 825 (2.11%) participants with atherosclerotic cardiovascular disease and 2591/285 613 (0.91%) without.
Table 2.
Number of events in DANFLU-2 participants with and without a history of atherosclerotic cardiovascular disease
| Outcome | No history of ASCVD n = 285 613 |
History of ASCVD n = 46 825 |
|---|---|---|
| Primary outcome, n (%) | ||
| Hospitalization for pneumonia or influenza | 1706 (0.60%) | 642 (1.37%) |
| Secondary outcomes, n (%) | ||
| Hospitalization for any cardiorespiratory disease | 5462 (1.91%) | 2235 (4.77%) |
| All-cause hospitalization | 24 251 (8.49%) | 7255 (15.49%) |
| All-cause mortality | 1595 (0.56%) | 610 (1.30%) |
| Hospitalization for influenza | 182 (0.06%) | 98 (0.21%) |
| Hospitalization for pneumonia | 1541 (0.54%) | 554 (1.18%) |
| Exploratory outcomes, n (%) | ||
| Hospitalization for laboratory-confirmed influenza | 323 (0.11%) | 130 (0.28%) |
| Hospitalization for any respiratory disease | 2496 (0.87%) | 923 (1.97%) |
| Hospitalization for any cardiovascular disease | 3099 (1.09%) | 1380 (2.95%) |
| Death from cardiovascular causes, hospitalization for myocardial infarction, or hospitalization for stroke | 1383 (0.48%) | 590 (1.26%) |
| Death from cardiovascular causes, hospitalization for myocardial infarction, hospitalization for stroke, or hospitalization for heart failure | 1630 (0.57%) | 752 (1.61%) |
| Death from any cause, hospitalization for myocardial infarction, or hospitalization for stroke | 2591 (0.91%) | 987 (2.11%) |
| Death from cardiovascular causes | 364 (0.13%) | 206 (0.44%) |
| Hospitalization for myocardial infarction | 384 (0.13%) | 146 (0.31%) |
| Hospitalization for stroke | 677 (0.24%) | 266 (0.57%) |
| Hospitalization for heart failure | 283 (0.10%) | 197 (0.42%) |
| Hospitalization for atrial fibrillation | 1173 (0.41%) | 374 (0.80%) |
ASCVD, atherosclerotic cardiovascular disease; DANFLU-2, A Pragmatic Randomized Trial to Evaluate the Effectiveness of High-Dose Quadrivalent Influenza Vaccine vs. Standard-Dose Quadrivalent Influenza Vaccine in Older Adults.
Relative vaccine effectiveness in persons with and without atherosclerotic cardiovascular disease
Results were consistent among participants with and without atherosclerotic cardiovascular disease, i.e. no significant effect modifications were detected (Figure 1). The rVE for the primary outcome was 6.87% (95% CI, −2.52 to 15.42) among individuals without atherosclerotic cardiovascular disease and 4.71% (95% CI, −11.58 to 18.63) in those with (Pinteraction = .80). For hospitalization for any cardiorespiratory disease, the estimates were 6.64% (95% CI, 1.51–11.50) and 4.81% (95% CI, −3.51 to 12.47), respectively (Pinteraction = .69). For hospitalization for influenza, the rVE was 42.88% (95% CI, 22.07–58.44) in those without a history of atherosclerotic cardiovascular disease and 45.73% (95% CI, 16.68–65.16) for those with a history of atherosclerotic cardiovascular disease (Pinteraction = .84). For major adverse cardiovascular events, the rVE was 4.29% (95% CI, −6.50 to 14.00) in participants without, and 0.30% (95% CI, −17.56 to 15.44) in participants with, pre-existing atherosclerotic cardiovascular disease (Pinteraction = .68). Inclusion of participants with pre-existing heart failure or atrial fibrillation in the atherosclerotic cardiovascular disease group did not meaningfully alter the results (see Supplementary data online, Figure S1).
Figure 1.
Number of events and relative vaccine effectiveness in DANFLU-2 participants with and without a history of atherosclerotic cardiovascular disease. ASCVD, atherosclerotic cardiovascular disease; CI, confidence interval; DANFLU-2, A Pragmatic Randomized Trial to Evaluate the Effectiveness of High-Dose Quadrivalent Influenza Vaccine vs. Standard-Dose Quadrivalent Influenza Vaccine in Older Adults; HD-IIV, high-dose inactivated influenza vaccine; HF, heart failure; MI, myocardial infarction; rVE, relative vaccine effectiveness; SD-IIV, standard-dose inactivated influenza vaccine
Discussion
In this prespecified, exploratory analysis of the DANFLU-2 trial, the incidence of both respiratory and cardiovascular events was higher among participants with pre-existing atherosclerotic cardiovascular disease than among those without. The rVE of the high-dose vs. standard-dose inactivated influenza vaccine was consistent across these two subgroups (Structured Graphical Abstract).
Influenza as a pathogen is associated with increased cardiovascular risk, and persons with atherosclerotic cardiovascular disease, e.g. coronary artery disease, are considered particularly susceptible to its hazards.25 The role of influenza vaccination for cardiovascular event reduction among individuals with atherosclerotic cardiovascular disease is also well-established.10 Despite premature termination of enrolment, the IAMI trial (Influenza Vaccination After Myocardial Infarction) found a significant reduction in the composite outcome of death, myocardial infarction, or stent thrombosis in 2571 patients with recent myocardial infarction or high-risk stable coronary artery disease, with standard-dose influenza vaccination vs. placebo.9 Accordingly, there is a Class I recommendation for annual influenza vaccination after an acute coronary syndrome in contemporary European and North American guidelines.26,27
Because the humoral immune response after standard-dose influenza vaccination is less robust among high-risk persons, it has been postulated that these individuals may derive particular benefit from high-dose vaccination.15,18 The VIP-ACS trial (Vaccination against Influenza to Prevent cardiovascular events after Acute Coronary Syndromes) randomized 1801 patients with a recent acute coronary syndrome to double-dose or standard-dose quadrivalent inactivated influenza vaccination and found no significant difference in the primary, hierarchical composite outcome of all-cause death, myocardial infarction, stroke, unstable angina, hospitalization for heart failure, urgent coronary revascularization, or hospitalization for respiratory causes.28 In the larger INVESTED trial (Influenza Vaccine to Effectively Stop Cardio Thoracic Events and Decompensated Heart Failure), 5260 individuals with either a recent myocardial infarction or decompensated heart failure were randomly allocated to either a high-dose (quadruple dose) trivalent inactivated influenza vaccine vs. a standard-dose quadrivalent inactivated influenza vaccine.29 The trial was terminated prematurely due to futility. Despite more pronounced antibody response and seroconversion status among high-dose vaccine recipients, there was no significant between-group difference in the primary outcome of time to first occurrence of all-cause death or cardiopulmonary hospitalization, or in any of the secondary outcomes; however, the population recruited were critically ill at baseline, so the exceptionally high risk of death or hospitalization at baseline may explain the inability of high-dose inactivated influenza vaccine to meaningfully alter their clinical trajectory.19,29
In the overall DANFLU-2 trial, the primary outcome of hospitalization for influenza or pneumonia was not significantly reduced by the high-dose as compared with the standard-dose inactivated influenza vaccine.23 Nevertheless, the rates of both hospitalization for influenza and laboratory-confirmed influenza were lower than in the standard-dose inactivated influenza vaccine group, and the high relative effectiveness for these two secondary and exploratory endpoints was consistent when stratified by atherosclerotic cardiovascular disease status in the current analysis. The incidences of hospitalization for any cardiorespiratory disease, hospitalization for any cardiovascular disease, and hospitalization for heart failure were also significantly lower in the high-dose vaccine group and showed apparent consistency of effect in this sub-analysis, although the event rates and absolute risk reductions were generally low.24 In the main analysis, the reductions in these specific cardiovascular events seemed to be more pronounced during periods with high levels of influenza circulation. This fits the notion that decreasing the influenza burden leads to fewer respiratory and cardiovascular hospitalizations and deaths. Most of the exploratory cardiovascular outcomes, including major adverse cardiovascular events, were not statistically significantly affected by high-dose inactivated influenza vaccination, irrespectively of atherosclerotic cardiovascular disease status. However, systematic influenza testing was not conducted as part of DANFLU-2, and most individuals with laboratory-confirmed influenza are not admitted to the hospital. Patients with atherosclerotic cardiovascular disease likely also have other, more important, determinants of adverse risk. While the present results are not sufficient to drive immediate policy changes, the consistent positive direction of effectiveness in most cardiac endpoints warrants further research with respect to a potential added benefit of high-dose inactivated influenza vaccination in the atherosclerotic cardiovascular disease population. Nevertheless, influenza vaccination per se remains strongly recommended among those with atherosclerotic cardiovascular disease.
The study is notable for its large, well-characterized population and complete follow-up. Data were derived from the largest high-dose inactivated influenza vaccine trial ever conducted, including the largest study population with atherosclerotic cardiovascular disease. Indeed, the number of patients with atherosclerotic cardiovascular disease, even those with prior myocardial infarction alone, far exceeded the study population of both the VIP-ACS and INVESTED trials. The nationwide registries and the governmental digital mail system enabled recruitment of virtually all who were willing to participate. Nevertheless, the study also had several important limitations. DANFLU-2 was conducted as an open-label trial; however, the investigators were not involved in vaccine administration, daily clinical management of the participants, or data collection. Hard outcomes like myocardial infarction, stroke, and death are also less likely to be affected by knowledge of the treatment to which a participant is allocated.30 Another potential limitation relates to the use of administrative registries. The Danish registries are known for very high-quality data,31 but the reliance on administrative, routinely collected data may introduce misclassification bias. This may potentially dilute between-treatment group differences, but not exaggerate them, in a randomized setting. The findings from this exploratory analysis should be interpreted in light of the overall neutral result with respect to the primary outcome.23 Comparisons between persons with and without atherosclerotic cardiovascular disease were observational in nature and could have been subject to confounding. Atherosclerotic cardiovascular disease may comprise a heterogeneous group of persons, but stratified analyses were not conducted because of the low event rates. Therefore, these exploratory analyses should be seen as adding important literature to this underserved population and should be interpreted as hypothesis-generating. Finally, as the Danish population is predominantly white, generalizability to other ethnicities may be questioned. Similarly, the generalizability to younger individuals may be limited.
Conclusions
This prespecified analysis of the DANFLU-2 trial found that the rVE of high-dose vs. standard-dose inactivated influenza vaccination was similar among individuals ≥65 years of age with pre-existing atherosclerotic cardiovascular disease as compared with those without.
Supplementary Material
Acknowledgements
The authors wish to thank all personnel at European LifeCare Group for collaborating and assisting with study procedures. The authors would also like to thank personnel at Sanofi for their contributions: Sandrine Samson, Ayman Chit, Robertus van Aalst, Martin Ryser, Marion Fournier, and Tamala Moore (scientific advice), Camille Salamand (biostatistics advice), and Pierre Bourron and Marie-Caroline Guichard (administrative and dose provision logistical support).
Contributor Information
Manan Pareek, Department of Cardiology, Copenhagen University Hospital – Herlev and Gentofte, Gentofte Hospitalsvej 8, 3.th., Hellerup 2900, Denmark; Center for Translational Cardiology and Pragmatic Randomized Trials, Faculty of Health and Medical Sciences, Department of Biomedical Sciences, University of Copenhagen, Gentofte Hospitalsvej 8, 3.th., Hellerup 2900, Denmark.
Niklas Dyrby Johansen, Department of Cardiology, Copenhagen University Hospital – Herlev and Gentofte, Gentofte Hospitalsvej 8, 3.th., Hellerup 2900, Denmark; Center for Translational Cardiology and Pragmatic Randomized Trials, Faculty of Health and Medical Sciences, Department of Biomedical Sciences, University of Copenhagen, Gentofte Hospitalsvej 8, 3.th., Hellerup 2900, Denmark.
Daniel Modin, Department of Cardiology, Copenhagen University Hospital – Herlev and Gentofte, Gentofte Hospitalsvej 8, 3.th., Hellerup 2900, Denmark; Center for Translational Cardiology and Pragmatic Randomized Trials, Faculty of Health and Medical Sciences, Department of Biomedical Sciences, University of Copenhagen, Gentofte Hospitalsvej 8, 3.th., Hellerup 2900, Denmark.
Matthew M Loiacono, Sanofi, Swiftwater, PA, USA.
Rebecca C Harris, Sanofi, Singapore.
Marine Dufournet, Sanofi, Lyon, France.
Carsten Schade Larsen, Department of Clinical Medicine and Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark; Danske Lægers Vaccinations Service, European LifeCare Group, Søborg, Denmark.
Lykke Larsen, Department of Infectious Diseases, Odense University Hospital, Odense, Denmark.
Lothar Wiese, Department of Infectious Diseases, Zealand University Hospital, Roskilde, Denmark.
Michael Dalager-Pedersen, Department of Infectious Diseases, Aalborg University Hospital, Aalborg, Denmark; Department of Clinical Medicine, Aalborg University, Aalborg, Denmark.
Brian L Claggett, Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA.
Kira Hyldekær Janstrup, Department of Cardiology, Copenhagen University Hospital – Herlev and Gentofte, Gentofte Hospitalsvej 8, 3.th., Hellerup 2900, Denmark; Center for Translational Cardiology and Pragmatic Randomized Trials, Faculty of Health and Medical Sciences, Department of Biomedical Sciences, University of Copenhagen, Gentofte Hospitalsvej 8, 3.th., Hellerup 2900, Denmark.
Katja Vu Bartholdy, Department of Cardiology, Copenhagen University Hospital – Herlev and Gentofte, Gentofte Hospitalsvej 8, 3.th., Hellerup 2900, Denmark; Center for Translational Cardiology and Pragmatic Randomized Trials, Faculty of Health and Medical Sciences, Department of Biomedical Sciences, University of Copenhagen, Gentofte Hospitalsvej 8, 3.th., Hellerup 2900, Denmark.
Katrine Feldballe Bernholm, Department of Cardiology, Copenhagen University Hospital – Herlev and Gentofte, Gentofte Hospitalsvej 8, 3.th., Hellerup 2900, Denmark; Center for Translational Cardiology and Pragmatic Randomized Trials, Faculty of Health and Medical Sciences, Department of Biomedical Sciences, University of Copenhagen, Gentofte Hospitalsvej 8, 3.th., Hellerup 2900, Denmark.
Julie Inge-Marie Helene Borchsenius, Department of Cardiology, Copenhagen University Hospital – Herlev and Gentofte, Gentofte Hospitalsvej 8, 3.th., Hellerup 2900, Denmark; Center for Translational Cardiology and Pragmatic Randomized Trials, Faculty of Health and Medical Sciences, Department of Biomedical Sciences, University of Copenhagen, Gentofte Hospitalsvej 8, 3.th., Hellerup 2900, Denmark.
Filip Søskov Davidovski, Department of Cardiology, Copenhagen University Hospital – Herlev and Gentofte, Gentofte Hospitalsvej 8, 3.th., Hellerup 2900, Denmark; Center for Translational Cardiology and Pragmatic Randomized Trials, Faculty of Health and Medical Sciences, Department of Biomedical Sciences, University of Copenhagen, Gentofte Hospitalsvej 8, 3.th., Hellerup 2900, Denmark.
Lise Witten Davodian, Department of Cardiology, Copenhagen University Hospital – Herlev and Gentofte, Gentofte Hospitalsvej 8, 3.th., Hellerup 2900, Denmark; Center for Translational Cardiology and Pragmatic Randomized Trials, Faculty of Health and Medical Sciences, Department of Biomedical Sciences, University of Copenhagen, Gentofte Hospitalsvej 8, 3.th., Hellerup 2900, Denmark.
Maria Dons, Department of Cardiology, Copenhagen University Hospital – Herlev and Gentofte, Gentofte Hospitalsvej 8, 3.th., Hellerup 2900, Denmark; Center for Translational Cardiology and Pragmatic Randomized Trials, Faculty of Health and Medical Sciences, Department of Biomedical Sciences, University of Copenhagen, Gentofte Hospitalsvej 8, 3.th., Hellerup 2900, Denmark.
Lisa Steen Duus, Department of Cardiology, Copenhagen University Hospital – Herlev and Gentofte, Gentofte Hospitalsvej 8, 3.th., Hellerup 2900, Denmark; Center for Translational Cardiology and Pragmatic Randomized Trials, Faculty of Health and Medical Sciences, Department of Biomedical Sciences, University of Copenhagen, Gentofte Hospitalsvej 8, 3.th., Hellerup 2900, Denmark.
Caroline Espersen, Department of Cardiology, Copenhagen University Hospital – Herlev and Gentofte, Gentofte Hospitalsvej 8, 3.th., Hellerup 2900, Denmark; Center for Translational Cardiology and Pragmatic Randomized Trials, Faculty of Health and Medical Sciences, Department of Biomedical Sciences, University of Copenhagen, Gentofte Hospitalsvej 8, 3.th., Hellerup 2900, Denmark.
Frederik Holme Fussing, Department of Cardiology, Copenhagen University Hospital – Herlev and Gentofte, Gentofte Hospitalsvej 8, 3.th., Hellerup 2900, Denmark; Center for Translational Cardiology and Pragmatic Randomized Trials, Faculty of Health and Medical Sciences, Department of Biomedical Sciences, University of Copenhagen, Gentofte Hospitalsvej 8, 3.th., Hellerup 2900, Denmark.
Anne Marie Reimer Jensen, Department of Cardiology, Copenhagen University Hospital – Herlev and Gentofte, Gentofte Hospitalsvej 8, 3.th., Hellerup 2900, Denmark; Center for Translational Cardiology and Pragmatic Randomized Trials, Faculty of Health and Medical Sciences, Department of Biomedical Sciences, University of Copenhagen, Gentofte Hospitalsvej 8, 3.th., Hellerup 2900, Denmark.
Nino Emanuel Landler, Department of Cardiology, Copenhagen University Hospital – Herlev and Gentofte, Gentofte Hospitalsvej 8, 3.th., Hellerup 2900, Denmark; Center for Translational Cardiology and Pragmatic Randomized Trials, Faculty of Health and Medical Sciences, Department of Biomedical Sciences, University of Copenhagen, Gentofte Hospitalsvej 8, 3.th., Hellerup 2900, Denmark.
Adam Cadovius Femerling Langhoff, Department of Cardiology, Copenhagen University Hospital – Herlev and Gentofte, Gentofte Hospitalsvej 8, 3.th., Hellerup 2900, Denmark; Center for Translational Cardiology and Pragmatic Randomized Trials, Faculty of Health and Medical Sciences, Department of Biomedical Sciences, University of Copenhagen, Gentofte Hospitalsvej 8, 3.th., Hellerup 2900, Denmark.
Mats Christian Højbjerg Lassen, Department of Cardiology, Copenhagen University Hospital – Herlev and Gentofte, Gentofte Hospitalsvej 8, 3.th., Hellerup 2900, Denmark; Center for Translational Cardiology and Pragmatic Randomized Trials, Faculty of Health and Medical Sciences, Department of Biomedical Sciences, University of Copenhagen, Gentofte Hospitalsvej 8, 3.th., Hellerup 2900, Denmark.
Anne Bjerg Nielsen, Department of Cardiology, Copenhagen University Hospital – Herlev and Gentofte, Gentofte Hospitalsvej 8, 3.th., Hellerup 2900, Denmark; Center for Translational Cardiology and Pragmatic Randomized Trials, Faculty of Health and Medical Sciences, Department of Biomedical Sciences, University of Copenhagen, Gentofte Hospitalsvej 8, 3.th., Hellerup 2900, Denmark.
Camilla Ikast Ottosen, Department of Cardiology, Copenhagen University Hospital – Herlev and Gentofte, Gentofte Hospitalsvej 8, 3.th., Hellerup 2900, Denmark; Center for Translational Cardiology and Pragmatic Randomized Trials, Faculty of Health and Medical Sciences, Department of Biomedical Sciences, University of Copenhagen, Gentofte Hospitalsvej 8, 3.th., Hellerup 2900, Denmark.
Morten Sengeløv, Department of Cardiology, Copenhagen University Hospital – Herlev and Gentofte, Gentofte Hospitalsvej 8, 3.th., Hellerup 2900, Denmark; Center for Translational Cardiology and Pragmatic Randomized Trials, Faculty of Health and Medical Sciences, Department of Biomedical Sciences, University of Copenhagen, Gentofte Hospitalsvej 8, 3.th., Hellerup 2900, Denmark.
Kristoffer Grundtvig Skaarup, Department of Cardiology, Copenhagen University Hospital – Herlev and Gentofte, Gentofte Hospitalsvej 8, 3.th., Hellerup 2900, Denmark; Center for Translational Cardiology and Pragmatic Randomized Trials, Faculty of Health and Medical Sciences, Department of Biomedical Sciences, University of Copenhagen, Gentofte Hospitalsvej 8, 3.th., Hellerup 2900, Denmark.
Scott D Solomon, Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA.
Martin J Landray, Nuffield Department of Population Health, University of Oxford, Oxford, UK.
Gunnar H Gislason, Department of Cardiology, Copenhagen University Hospital – Herlev and Gentofte, Gentofte Hospitalsvej 8, 3.th., Hellerup 2900, Denmark; Faculty of Health and Medical Sciences, Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark; The Danish Heart Foundation, Copenhagen, Denmark.
Lars Køber, Faculty of Health and Medical Sciences, Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark; Department of Cardiology, Copenhagen University Hospital – Rigshospitalet, Blegdamsvej 9, Copenhagen 2100, Denmark.
Pradeesh Sivapalan, Faculty of Health and Medical Sciences, Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark; Respiratory Medicine Section, Department of Medicine, Copenhagen University Hospital – Herlev and Gentofte, Copenhagen, Denmark.
Cyril Jean-Marie Martel, Epidemiological Infectious Disease Preparedness, Statens Serum Institut, Copenhagen, Denmark.
Jens Ulrik Stæhr Jensen, Faculty of Health and Medical Sciences, Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark; Respiratory Medicine Section, Department of Medicine, Copenhagen University Hospital – Herlev and Gentofte, Copenhagen, Denmark.
Tor Biering-Sørensen, Department of Cardiology, Copenhagen University Hospital – Herlev and Gentofte, Gentofte Hospitalsvej 8, 3.th., Hellerup 2900, Denmark; Center for Translational Cardiology and Pragmatic Randomized Trials, Faculty of Health and Medical Sciences, Department of Biomedical Sciences, University of Copenhagen, Gentofte Hospitalsvej 8, 3.th., Hellerup 2900, Denmark; Department of Cardiology, Copenhagen University Hospital – Rigshospitalet, Blegdamsvej 9, Copenhagen 2100, Denmark; Steno Diabetes Center Copenhagen, Borgmester Ib Juuls Vej 83, Herlev 2730, Denmark.
Supplementary data
Supplementary data are available at European Heart Journal online.
Declarations
Disclosure of Interest
M.P. discloses the following relationships. Advisory board: AstraZeneca, Janssen-Cilag, Novo Nordisk. Grant support: Danish Cardiovascular Academy funded by the Novo Nordisk Foundation and the Danish Heart Foundation. Speaker honorarium: AstraZeneca, Bayer, Boehringer Ingelheim, Janssen-Cilag, Novo Nordisk. M.M.L., R.C.H., and M.D. are full-time employees of Sanofi and may own shares and/or stock options in the company. C.S.L. has received speaker fees and served on advisory boards for GSK, MSD, Pfizer, Takeda, and Valneva. B.L.C. has received consulting fees from Amgen, Cardurion, Corvia, MyoKardia, and Novartis. K.G.S. has served on an advisory board for Sanofi and received financial support for congress participation from AstraZeneca. S.D.S. has received research grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, BMS, Celladon, Cytokinetics, Eidos, Gilead, GSK, Ionis, Lilly, Mesoblast, MyoKardia, NIH/NHLBI, Neurotronik, Novartis, Novo Nordisk, Respicardia, Sanofi, Theracos, and US2.AI and consulted for Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi Sankyo, GSK, Lilly, Merck, MyoKardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, Sarepta, Lexicon, Anacardio, Akros, and Puretech Health. M.J.L. reports institutional research grants from Novartis, Sanofi, Regeneron, Moderna, GSK, and Boehringer Ingelheim. L.K. has received speaker fees from Novo Nordisk, Novartis, AstraZeneca, Boehringer Ingelheim, and Bayer. T.B.-S. has received research grants from Bayer, Novartis, Pfizer, Sanofi Pasteur, GSK, Novo Nordisk, AstraZeneca, Boston Scientific, and GE Healthcare; consulting fees from Novo Nordisk, IQVIA, Parexel, Amgen, CSL Seqirus, GSK, and Sanofi Pasteur; and lecture fees from AstraZeneca, Bayer, Novartis, Sanofi Pasteur, GE Healthcare, and GSK. All other authors declare no competing interests.
Data Availability
Individual-level participant data stemming from the nationwide Danish health registries cannot be shared according to Danish law. Summarized data can be made available upon reasonable request.
Funding
The DANFLU-2 trial was funded by Sanofi which participated in the study design, protocol development, and manuscript review, but had no responsibilities in trial conduct, data collection, or data analysis.
Ethical Approval
The trial was approved by the Danish Medical Research Ethics Committees and the Danish Medicines Agency and conducted in accordance with the Declaration of Helsinki and the International Council for Harmonization Good Clinical Practice guidelines.
Pre-registered Clinical Trial Number
The pre-registered clinical trial number is NCT05517174 (ClinicalTrials.gov).
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
Individual-level participant data stemming from the nationwide Danish health registries cannot be shared according to Danish law. Summarized data can be made available upon reasonable request.