Generalisability of heart failure medication trials in a real-world population – a large-scale registry-based analysis in the Swedish Heart Failure Registry (SwedeHF)

• Applicant: Dr. Benedikt Beer
• Subject Area: Cardiology, Angiology ; Epidemiology and Medical Biometry/Statistics ; Public Health, Healthcare Research, Social and Occupational Medicine
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 535014557

Heart failure affects over 26 million people worldwide and carries an approximate one‑year mortality of 36 %. In Germany, Italy, and Sweden its prevalence is currently around 2 % – and continues to rise as populations age. Improved insight into heart failure pathophysiology has led to therapies that meaningfully improve prognosis, including beta‑blockers, renin‑angiotensin‑system inhibitors, mineralocorticoid receptor antagonists, SGLT2 inhibitors, and, in selected patients, vericiguat – with potential new agents such as omecamtiv mecarbil on the horizon. Randomised controlled trials (RCTs) are the cornerstone of evidence‑based medicine because they alone can demonstrate causal effects of an intervention on specified outcomes. Trial quality is judged by two main criteria: internal validity (how well a study distinguishes true treatment effects from bias or chance) and external validity (the extent to which results can be generalised to the target population and thus routine clinical practice). While large sample sizes bolster internal validity and statistical power, they also escalate costs, prolong recruitment, and expose more participants to potential risks. To reconcile these trade‑offs, sponsors and regulators employ enrichment strategies that focus on patients most likely to benefit or demonstrate events, thereby trimming sample size and costs – but sometimes at the expense of external validity. This project aims to address three interrelated objectives: 1. Assess the effectiveness and safety of key heart failure therapies in real‑world patients who would have been excluded by enrichment criteria in pivotal RCTs. 2. Evaluate the generalisability of landmark and ongoing RCTs to a broader heart failure population. 3. Generate robust evidence for patient subgroups unlikely to be enrolled in future RCTs by conducting pragmatic yet methodologically rigorous observational studies. To achieve these aims, the investigator will employ the Swedish Heart Failure Registry (SwedeHF), a nationwide, continuously updated registry established in 2000 and linked via Sweden’s unique personal identification numbers to multiple complementary national health registries. Using a spectrum of study designs – from cross‑sectional and longitudinal cohorts to target‑trial emulation – and advanced statistical approaches (including overlap weighting based on machine learning-derived propensity scores), the project will rigorously quantify treatment effects and address gaps left by traditional RCTs. Ultimately, this work will broaden the evidence base for underrepresented heart failure patients and inform more inclusive, evidence‑driven clinical decision‑making.

• DFG Programme: WBP Fellowship
• International Connection: Sweden
• Host: Professor Dr. Gianluigi Savarese