Niklas Dyrby Johansen, Daniel Modin, Jacobo Pardo‐Seco, Carmen Rodrı́guez-Tenreiro, Matthew M. Loiacono, Rebecca C. Harris, Marine Dufournet, Robertus van Aalst, Ayman Chit, Carsten Schade Larsen, Lykke Larsen, Lothar Wiese, Michael Dalager‐Pedersen, Brian Claggett, Kira Hyldekær Janstrup, Carmen Durán‐Parrondo, Marta Piñeiro-Sotelo, Martín Cribeiro-González, Mónica Conde-Pájaro, Susana Mirás‐Carballal, Juan‐Manuel González‐Pérez, Scott D. Solomon, Pradeesh Sivapalan, Cyril Jean‐Marie Martel, Jens‐Ulrik Stæhr Jensen, Federico Martinón‐Torres, Tor Biering‐Sørensen, Katja Vu Bartholdy, Katrine Feldballe Bernholm, Julie Inge-Marie Helene Borchsenius, Filip Soeskov Davidovski, Lise Witten Davodian, Maria Dons, Lisa Steen Duus, Caroline Espersen, Frederik Holme Fussing, Anne Marie Reimer Jensen, Nino Emanuel Landler, Adam Cadovius Femerling Langhoff, Mats Christian Højbjerg Lassen, Anne Bjerg Nielsen, Camilla Ikast Ottosen, Morten Sengeløv, Kristoffer Grundtvig Skaarup, Ana Maria Abal Senin, Pilar Alonso Vence, Rosa María Álvarez Gil, Talia Alvarez Suarez, Lidia Alvarez Dapia, Jose Manuel Alvarez Pena, Silvia Amoedo Casqueiro, Patricia Aran Abelenda, Josefa Araujo Rodriguez, Ana Ares Martinez, Maria Asensio Nieto, Noelia Belen Ayllon Morcillo, Mónica Barral Carregal, Maria Begoña Baquero Sabajanes, Alejandro Baña Tomé, Lorena Bayon Diz, Damian Bernardez Sende, Beatriz Blanco Salgado, Lucia Bruquet Costa, Faustino Caballero Muinelo, Noelia Cabeiras Alvarez, Maria Guadalupe Cainzos Fernandez, Alba Campero Ojea, Isabel Campos Pardo, Diego Canedo Cotelo, Lidia Carreira Diaz, Miguel Angel Carreiro Alonso, Almudena Carro Orgeira, Adriana Maria Castelo Triñanes, Ana Belen Castelo Vazquez, César Castro Pita, Andrea Castro Sande, Manuel Castro Guizan, Mercedes Castro Bacariza, Maria Jose Castro Castro, Maria Jose Castroman Souto, Sabela Ceide Fernandez, Olga María Ces Ozores, Rebeca Chouza Alonso, Verónica Civeira Pérez, Carla Alexandra Correia Parauta, Ana Isabel Corbal Obelleiro, Angela Coutado Belon, Xurxo Couto Catoira, Ana Isabel Couto Tobío, Evaristo Cuerdo Coton, Angeles Cuiña Caneda, Sonia De Miguel Cañas, Paola De Castro Garcia, Maria Eugenia De Jesús Torrealba Valente, Carmen Del Ojo Paez, María Begoña Del Oro Saez, Romina Deus Suarez, Paula Diaz Lopez, Lucia Diaz Gonzalez, Alejandro Docal Pombo
BACKGROUND: The high-dose inactivated influenza vaccine (HD-IIV) has demonstrated superior protection against a range of hospitalization end points versus standard-dose inactivated influenza vaccine (SD-IIV), but its effectiveness against specific cardiovascular outcomes and in those with pre-existing cardiovascular disease (CVD) is not well elucidated. METHODS: In a prespecified secondary analysis of the FLUNITY-HD (Pooled Analysis of Methodologically Harmonized Pragmatic Randomized Trials of High-Dose vs. Standard-Dose Influenza Vaccine Against Severe Clinical Outcomes) individual-level pooled data set integrating 2 methodologically harmonized pragmatic, individually randomized trials conducted in Denmark and Spain, we investigated the relative vaccine effectiveness of HD-IIV versus SD-IIV against severe cardiovascular outcomes and according to pre-existing CVD among adults ≥65 years of age. Data were primarily obtained from routine health care databases, with follow-up from 14 days after vaccination to May 31 the following year. RESULTS: The pooled data set encompassed 466 320 individually randomized participants, of whom 107 700 (23.1%) had a history of CVD. HD-IIV reduced the incidence of hospitalization for influenza or pneumonia, cardiorespiratory disease, laboratory-confirmed influenza, and any cause compared with SD-IIV, irrespective of the presence or absence of pre-existing CVD ( P interaction >0.66 for all outcomes). Compared with the SD-IIV group, the HD-IIV group had a significantly lower incidence of hospitalization for any CVD (HD-IIV, 1.15%, versus SD-IIV, 1.24%; relative vaccine effectiveness, 6.6% [95% CI, 1.6–11.4]; P =0.010), hospitalization for any respiratory disease (HD-IIV, 0.92%, versus SD-IIV, 0.98%; relative vaccine effectiveness, 6.5% [95% CI, 0.7–11.9]; P =0.027), and hospitalization for heart failure (HD-IIV, 0.11%, versus SD-IIV, 0.15%; relative vaccine effectiveness, 21.3% [95% CI, 7.6–33.0]; P =0.003). CONCLUSIONS: In a prespecified pooled analysis of 466 320 individually randomized older adults, HD-IIV reduced the incidence of a wide range of severe cardiovascular and respiratory outcomes compared with SD-IIV, with consistent findings regardless of previous history of CVD. Among cardiovascular outcomes, the protective effect of HD-IIV versus SD-IIV was particularly pronounced against hospitalization for heart failure. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT06506812.