Assessing the generalisability of heart failure medication trials in a real-world population – a large-scale registry-based analysis in the Swedish heart failure registry (SwedeHF)

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Heart failure is a global pandemic with a 1-year mortality of approximately 36%. The prevalence in Germany, Italy and Sweden is roughly 2% - and rising in an ageing population. A better understanding of heart failure’s pathophysiology has paved the way for prognosis improving medical drugs like beta blockers, renin-angiotensin system inhibitors, mineralocorticoid receptor antagonists, SGLT2 inhibitors as well as by Vericiguat in selected patients and potentially Omecamtiv mecabil in the future. Randomised controlled trials are today’s gold standard for the assessment of such therapeutical interventions. They are able to describe causal relationships between an intervention and a defined outcome and are therefore the foundation of evidence-based medicine. There are two main quality indicators of trial quality: internal and external validity. Internal validity captures the trial’s capability to rule out other than the intervention’s influence on the outcome. It is impaired by both systematic and random errors. These challenges can be encountered by, e.g., a proper sample size. Increasing the sample size, on the other hand, results in considerable increase of the trial’s expenditure, longer duration of study participant recruitment and exposure of more participants to potential safety issues. Thus, enrichment strategies have been developed by study sponsors and endorsed by regulative authority bodies. However, these strategies may come at the cost of external validity. External validity describes the extent to which a trial’s results can be applied to the target population and can thus be generalised in clinical practice. The aspect of external validity has not been in the scope of clinical research until recently. As a consequence, only current trials have been investigated with a focus on the generalisability of their results to the target population, yet. Therefore, it is of interest to (re-) assess older trials which are still relevant for nowadays guideline recommendations on heart failure medication about their generalisability to a real-world heart failure population. The applicant plans to do so employing the unique Swedish Heart Failure Registry (SwedeHF): SwedeHF is designed as a nationwide continuous health quality and research registry; it was founded in 2000 and until 2003 implemented in the whole of Sweden. Vastly more than 100,000 registrations and 60,000 patients have been included added by approximately 10,000 further registrations of both known and new patients each year. In this project, the applicant aims to: (1) gain insight into registry-based heart failure research, (2) analyse the generalisability of past HFrEF trials, (3) propose a pragmatic trial design in heart failure research between the poles of internal and external validity and (4) learn fundamentals in registry-based randomised trials and assessing their potential for future evidence-based medicine in heart failure.