Global heart failure epidemiology versus enrolment in pivotal trials: A formidable mismatch

Randomized clinical trials (RCTs) that inform international clinical practice guidelines should adequately represent regions burdened with disease. We aimed to assess the geographic representativeness of pivotal heart failure (HF) RCTs using two methodological approaches.

We assessed the global geographic distribution of HF cases using the Global Burden of Disease 2021 dataset. We then assessed the geographic representativeness of pivotal phase 3 RCTs that have shaped international guidelines using two metrics: the representation index (RI), a ratio of regional trial sites to disease distribution, and the participant-to-prevalence ratio (PPR), a ratio of regional trial participants to disease distribution. In 2021, there were 55.4 million people with HF worldwide, with the greatest population in Asia (50%), followed by Europe (18%), Africa (14%), North America (10%), and Central & South America (8%). PPR estimates were limited by the variation in how trials classified regions when reporting participant enrolment. Yet, RI and PPR estimates revealed similar estimates of geographic representation. Europe (RI: 2.41, PPR: 2.69) and North America (RI: 3.25, PPR: 2.58) were over-represented in trials, while Asia (RI: 0.26, PPR: 0.22) and Africa (RI: 0.14, PPR: 0.05) were grossly under-represented. In contrast, Central & South America (RI: 1.29, PPR: 1.59) were adequately represented.

Pivotal HF RCTs generate evidence primarily from Europe and North America, and grossly under-represent Africa and Asia. RI and PPR are correlated measures of regional representativeness, highlighting that regional participant enrolment is related to the number of trial sites in a region. Unlike PPR, RI can be estimated during trial planning and guide trial design for better regional representativeness.