Nationwide Utilization of Danish Government Electronic Letter System for Confirming the Effectiveness of Behavioral Nudges in Increasing InFLUenza Vaccine Uptake Among Adults With Chronic Disease

The study is a prospective, randomized, open-label implementation trial. The study population will consist of persons aged 18-64 years identified as eligible for free-of-charge influenza vaccination due to a chronic condition. Subjects will be identified through Danish nationwide health registries using codes from the International Classification of Diseases, 10th revision (ICD-10). Individuals will be randomized to 1 of 7 arms (1 usual care arm and 6 intervention arms) with each testing different nudging strategies employing various behavioural economic principles. The interventions will be delivered through the official, mandatory Danish electronic letter system. All subject data will be retrieved from the Danish nationwide registries with the exception of information on intervention allocation. Endpoints will be retrieved at prespecified dates using prespecified search algorithms.

• Behavioral Economic Principles (Behavioral): The control arm will receive no letter to reflect the background vaccination uptake. Intervention arms will test the effects of different letters developed using behavioral economic principles.

Primary outcomes

• Number of participants who received an influenza vaccine [Up to 3 months]

Secondary outcomes

• Time from intervention delivery to influenza vaccination [Up to 3 months]

Other outcomes

• Number of participants with laboratory-confirmed influenza [Up to 8 months]
• Number of participants with a hospitalization for influenza or pneumonia [Up to 8 months]
• Number of participants with a hospitalization for any respiratory disease [Up to 8 months]
• Number of participants with a hospitalization for any cardio-respiratory disease [Up to 8 months]
• Number of participants with a hospitalization for any cardiovascular disease [Up to 8 months]
• Number of participants with any hospitalization [Up to 8 months]
• Total number of hospitalizations (first and recurrent) [Up to 8 months]
• All-cause mortality [Up to 8 months]
• Composite of incident heart failure, heart failure hospitalization, or cardiovascular death [Up to 8 months]
• Composite of myocardial infarction, stroke, or cardiovascular death [Up to 8 months]
• Composite of myocardial infarction, coronary revascularization, stroke, or cardiovascular death [Up to 8 months]
• Number of participants with incident heart failure or heart failure hospitalization [Up to 8 months]
• Total number of heart failure events (incident heart failure and first and recurrent heart failure hospitalizations) [Up to 8 months]
• Cardiovascular death [Up to 8 months]
• Number of participants with myocardial infarction [Up to 8 months]
• Number of participants with coronary revascularization [Up to 3 months]
• Number of participants with stroke [Up to 8 months]
• Number of participants with incident atrial fibrillation or atrial fibrillation hospitalization [Up to 8 months]
• Number of contacts to general practitioner (excluding vaccination visit) [Up to 8 months]
• Number of participants with laboratory-confirmed COVID-19 [Up to 8 months]
• Number of participants with a hospitalization for COVID-19 [Up to 8 months]
• Number of participants who received a COVID-19 vaccine [Up to 3 months]
• Number of participants who filled a prescription for any guideline-directed medical therapy for heart failure [Up to 8 months]
• Total number of filled prescriptions for guideline-directed medical therapy for heart failure [Up to 8 months]
• Number of participants who filled a prescription for a sodium-glucose cotransporter 2 inhibitor or glucagon-like peptide 1 receptor agonist [Up to 8 months]

Sex: All, ages: 18 Years to 64 Years

Inclusion Criteria:

1. Age 18-64 years
2. Must be registered in the Danish nationwide registries as meeting at least one of the following eligibility criteria for free-of-charge influenza vaccination in the Danish public health system:

   1. Chronic lung disease
   2. Chronic cardiovascular disease other than hypertension
   3. Type 1 or type 2 diabetes mellitus
   4. Congenital or acquired immunodeficiency
   5. Impaired breathing due to muscular weakness
   6. Chronic renal or hepatic insufficiency
   7. Other chronic conditions with an increased risk of severe influenza as determined by the treating physician
3. Access to the official, mandatory Danish electronic mailbox system

Exclusion Criteria:

None

• Results publication: Johansen ND, Vaduganathan M, Bhatt AS, Modin D, Claggett BL, Janstrup KH, Larsen CS, Larsen L, Wiese L, Dalager-Pedersen M, Kober L, Solomon SD, Sivapalan P, Jensen JUS, Martel CJ, Krause TG, Biering-Sorensen T. Digital Nudges to Increase Influenza Vaccination in Patients with Chronic Diseases. NEJM Evid. 2026 Jan;5(1):EVIDoa2500265. doi: 10.1056/EVIDoa2500265. Epub 2025 Nov 10. PMID 41213006

• Tor Biering-Sørensen, MD, MSc, MPH, PhD, Principal investigator, Center for Translational Cardiology and Pragmatic Randomized Trials, Department of Cardiology, Copenhagen University Hospital - Herlev and Gentofte