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)

心力衰竭是一种全球性流行病，1年死亡率约为36%。在德国、意大利和瑞典，这一比例约为2%，随着人口老龄化，这一比例还在上升。对心力衰竭病理生理学的更好理解为改善预后的医疗药物铺平了道路，如β受体阻滞剂、肾素血管紧张素系统抑制剂、矿皮质激素受体拮抗剂、SGLT2抑制剂，以及Vericiguat在选定患者中的应用，未来可能会有Omecamtiv mecabil。随机对照试验是当今评估此类治疗干预措施的黄金标准。它们能够描述干预措施和确定结果之间的因果关系，因此是循证医学的基础。试验质量主要有两个质量指标：内部效度和外部效度。内部效度是指试验排除干预因素以外的因素对结果的影响的能力。它受到系统和随机误差的损害。例如，适当的样本量可能会遇到这些挑战。另一方面，增加样本量会导致试验支出的大幅增加，研究参与者招募的时间延长，以及更多参与者暴露于潜在的安全问题。因此，浓缩战略已由研究发起人制定并得到管理当局机构的认可。然而，这些策略可能会以外部有效性为代价。外部效度描述了试验结果可以应用于目标人群的程度，从而可以在临床实践中推广。外部效度方面直到最近才进入临床研究的范围。因此，目前只对目前的试验进行了调查，重点是研究其结果对目标人群的普遍性。因此，有兴趣（重新）评估旧的试验，这些试验仍然与现在的心力衰竭药物指南建议有关，它们对现实世界心力衰竭人群的普遍性。申请人计划采用独特的瑞典心力衰竭登记处（SwedeHF）： SwedeHF被设计为全国性的连续健康质量和研究登记处；它成立于2000年，直到2003年在整个瑞典实施。超过10万名注册患者和6万名患者被纳入其中，每年约有1万名已知患者和新患者注册。在这个项目中，申请人的目标是：(1)深入了解基于注册表的心力衰竭研究，(2)分析过去HFrEF试验的通用性，(3)在内部效度和外部效度之间提出心力衰竭研究的实用试验设计，(4)学习基于注册表的随机试验的基础知识，并评估其在未来心力衰竭循证医学中的潜力。

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.