Abstract Body (Do not enter title and authors here): Background: Influenza infection increases the risk of serious cardiovascular (CV) events, including myocardial infarction (MI) and stroke. Tailored messaging that emphasizes the CV benefits of influenza vaccination may not only improve vaccine uptake but also encourage better management of other cardiovascular, kidney and metabolic (CKM) risk factors. However, it remains unknown whether this targeted approach, compared to usual care messaging, can effectively improve CKM health and reduce clinical events.

Methods: The KP VACCINATE study was a multicenter, individually randomized trial across Kaiser Permanente Northern California and Mid-Atlantic States during the 2024–2025 influenza season, testing CV benefit–focused messaging vs. usual care communications to promote influenza vaccination. We will assess the effects of randomization on changes from baseline in blood pressure, lipid markers, and HbA1c and CKM-related medication use. We will also assess the effects of CV-focused messaging on prespecified clinical outcomes of all-cause and cause-specific hospitalization, major adverse CV events (new or worsening HF, MI, atrial fibrillation, venous thromboembolism and stroke), and all-cause death. All outcomes will be assessed from randomization through August 31, 2025.

Results: A total of 3,668,428 members were randomized across a multiregional health system in 3 U.S. states and the District of Columbia. Participants had mean (SD) age of 48.3 (18.2) years, 52.9% (N=1,939,380) were women, 10.5% (N=386,330) were Black, 21.6% (N=791,658) were Asian/Native Hawaiian/Pacific Islander. Overall, at baseline, 13.6% had diabetes (n=497,295), 5.1% had CKD (n=187,456), 5.0% had ASCVD (n=183,352), and 2.7% had HF (n=97,244). Mean LDL-C at baseline was 104 mg/dL, mean SBP 127mmHg, and mean HBA1c 5.9% and similar across randomization arms; 668,068 (18%) were prescribed statins. Clinical CKM endpoints will be collected through August 2025, with results available in time for presentation at the AHA 2025 Scientific Sessions.

Conclusions: KP-VACCINATE is the largest individually randomized trial ever conducted—enrolling >3.6 million adults—and uniquely embedded within existing health system operational workflows. The effects of messaging highlighting CV benefits of vaccination on CKM prevention patterns and clinical outcomes will directly inform scalable, real-world public health strategies.