2024-2025 COVID-19 Vaccine and Major Adverse Cardiovascular Events Among US Veterans.

Importance: COVID-19 vaccines were previously shown to reduce risk of major adverse cardiovascular events (MACEs). Whether the 2024-2025 COVID-19 vaccine continues to reduce COVID-19-associated MACEs in the context of evolving variants and widespread population immunity is unknown. Objective: To determine whether the 2024-2025 COVID-19 vaccine is associated with reduced risk of COVID-19-associated MACE. Design, Setting, and Participants: This cohort study was a target-trial emulation using US Department of Veterans Affairs (VA) electronic health records. Participants were veterans with vaccination encounters between September 3, 2024, and December 31, 2024. Exposures: Same-day coadministration of the 2024-2025 COVID-19 and influenza vaccines vs influenza vaccine alone. Main Outcomes and Measures: Composite end point of COVID-19-associated MACE, defined as COVID-19-associated cardiovascular death, myocardial infarction, stroke, or hospitalization for heart failure. Secondary outcomes included all-cause MACE, hospitalization, and death. Vaccine effectiveness (VE), calculated as 1 minus the risk ratio, and risk difference were estimated at 8 months using inverse probability weighting. Results: Among 1 039 659 participants who received influenza vaccine (mean [SD] age, 70.1 [12.4] years; 954 341 [91.8%] men), 349 085 received COVID-19 vaccine and 690 574 did not. At 8 months, the COVID-19 vaccine was associated with lower risk of COVID-19-associated MACE (VE, 37.7% [95% CI, 18.2%-54.9%]; risk difference per 10 000 persons, 2.0 [95% CI, 0.9-3.7]). VE for COVID-19-associated MACE was statistically significant only in individuals older than 75 years (VE, 50.7% [95% CI, 31.8%-65.6%]), a group that also experienced the largest absolute risk reduction (5.5 fewer events per 10 000 individuals). No statistically significant vaccine effectiveness was observed among those younger than 65 years or aged 65 to 75 years. While VE for COVID-19-associated MACE on the relative scale was statistically significant across subgroups of participants with and without comorbid health conditions, the absolute benefit was consistently and substantially greater for individuals with the comorbid health condition. Secondary analyses of all-cause MACE, all-cause hospitalization, and all-cause death suggested substantially larger absolute risk reductions (risk difference for all-cause MACE, 23.7 [95% CI, 14.1 to 34.7]). Conclusions and Relevance: In this cohort study, receipt of the 2024-2025 COVID-19 vaccine was associated with reduced risk of COVID-19-associated MACE, with reductions most prominent in those 75 years or older and those with comorbidities. While the reduction in COVID-19-associated MACE was modest, the substantially larger reduction in all-cause MACE suggests that the vaccine's protective association extends to the hidden burden of undetected SARS-CoV-2 and its sequelae.