Heart failure is a serious condition in which the heart is unable to pump blood effectively, and it remains a leading cause of hospitalization and death worldwide despite advances in treatment.

Selenium is an essential micronutrient that plays an important role in cellular energy production, antioxidant defense, and overall cardiovascular function. Low selenium levels are common among patients with heart failure in Northern Europe, and observational studies have shown that selenium deficiency is associated with an increased risk of hospitalization and death. In cases of severe deficiency, such as in Keshan disease, heart dysfunction can be reversed with selenium supplementation, suggesting a potential causal relationship.

However, it is not yet known whether selenium supplementation can improve clinical outcomes in patients with heart failure when added to standard medical therapy.

The SIRI-HF trial is a randomized, placebo-controlled study designed to evaluate whether daily supplementation with 200 micrograms of selenium, in addition to guideline-directed medical therapy, improves outcomes in patients with heart failure.

The primary endpoint is a composite of recurrent heart failure hospitalizations and cardiovascular death. Secondary endpoints include all-cause mortality, changes in symptoms and functional status, and safety outcomes.

This study will include patients from Sweden and Norway and aims to determine whether correcting selenium deficiency can improve prognosis in heart failure.

Heart failure (HF) is a complex, systemic syndrome characterized not only by impaired cardiac function but also by metabolic, inflammatory, and neurohormonal disturbances. Despite advances in guideline-directed medical therapy, patients with HF continue to experience high rates of hospitalization and mortality, highlighting the need for additional therapeutic strategies.

Selenium is an essential trace element incorporated into selenoproteins that play key roles in redox regulation, mitochondrial function, immune modulation, and thyroid hormone metabolism. Observational data from European populations, where dietary selenium intake is relatively low, have demonstrated associations between low selenium status and increased risk of incident HF, impaired functional capacity, reduced quality of life, and higher mortality. Mechanistically, selenium deficiency may contribute to impaired mitochondrial oxidative phosphorylation, increased oxidative stress, and cardiomyocyte dysfunction.

While prior randomized studies of selenium supplementation have yielded mixed results, these have largely been conducted in populations with adequate baseline selenium levels or have not specifically targeted patients with HF. Smaller studies and subgroup analyses suggest potential benefits on cardiac function and clinical outcomes, but definitive evidence is lacking.

The SIRI-HF trial is designed to address this evidence gap using a pragmatic, registry-based randomized clinical trial (RRCT) design. The study is embedded within established national heart failure registries in Sweden (SwedeHF) and Norway (NHFR), enabling large-scale recruitment and efficient long-term follow-up through linkage with national healthcare and administrative registries. This approach allows for comprehensive capture of clinical events, including hospitalizations and mortality, in a real-world setting.

A total of 4,326 adult patients with a diagnosis of heart failure will be randomized in a 1:1 ratio to receive either oral selenium supplementation (200 µg daily) or matching placebo, in addition to standard care. The trial is double-blind, with participants, investigators, and outcome assessors masked to treatment allocation. Recruitment is planned over approximately four years, with follow-up extending up to five years depending on enrollment timing.

The study is conducted using a largely remote design. Eligible patients are identified through registry data and invited to participate via digital or postal consent procedures. Study treatment is distributed directly to participants, and follow-up includes periodic electronic questionnaires assessing symptoms, adherence, and quality of life. Clinical outcomes are ascertained through linkage with national registries, minimizing the need for in-person visits and reducing loss to follow-up.

The primary endpoint is the total number of heart failure hospitalizations and cardiovascular deaths, analyzed as recurrent events over the follow-up period. Secondary endpoints include time-to-event outcomes such as first heart failure hospitalization or cardiovascular death, as well as individual components including cardiovascular mortality and all-cause mortality. Additional exploratory outcomes include broader cardiovascular events, unscheduled hospitalizations, incident dementia, and changes in patient-reported health status measured by the Kansas City Cardiomyopathy Questionnaire.

A predefined mechanistic sub-study will be conducted in a subset of participants to evaluate the effects of selenium supplementation on cardiac structure and function, biomarkers, functional capacity, and biochemical measures of selenium status.

The registry-based design, large sample size, and integration with national health data systems are expected to provide robust and generalizable evidence regarding the effect of selenium supplementation on clinically relevant outcomes in patients with heart failure.

Inclusion Criteria:

To be considered for inclusion in this study, patients must meet all of the following eligibility requirements:

• 18 years of age
• primary discharge diagnosis of HF coded as ICD-10: I50, as recorded in The SwedeHF registry
• be able to provide documented informed consent by signing and dating the designated consent form.

Exclusion Criteria:

• Not suitable in the opinion of the Investigator (for example due to severe or terminal comorbidity with poor prognosis, or characteristics, pregnancy etc.) that may interfere with adherence to trial protocol