Proefschrift

2.2 Eligibility for HFrEF trials 55 INTRODUCTION Eligibility criteria of phase III randomized controlled trials in heart failure (HF) defines a target population in which an intervention is most likely to be efficacious.1,2 However, restrictive eligibility criteria has been a long-standing concern as it can jeopardize trial accrual and lead to overly narrow trial populations.3 In the latter, generalizability of study results to real-world patients becomes compromised, causing uncertainties in treatment decisions for under-represented subgroups of women, older persons and multi-comorbid patients. Potentially, it is patients with more complex disease that would benefit most from treatment. HF trials have become larger and take longer to complete as a series of successful drug therapies translated to an initial decline in mortality.4 Although this decline in mortality have since plateaued5,6, proving incremental benefit of new therapy amid existing background treatment becomes more challenging. In efforts to enrich for outcome event rates, inclusion and/or exclusion criteria can become more complex and restrictive.7 Overly complex criteria increase the risk for low enrolment, protocol amendments or in worst cases, non-completion. Of 644 HF trials in ClinicalTrials.gov from 2005 to 2015, more than half of study terminations were due to poor accrual.8 Similarly, A gradual decline in completed HF trials was observed as industry and researchers divert resources to other clinical domains.9 Decisions on inclusion and exclusion criteria of a trial clearly affects its length and cost.3 It is thus time to move from carry-forward criteria selection to one that is data-guided.10 This approach decreases reliance on assumed recruitment rates, thereby minimising opportunity costs lost from protocol amendment or study extension. Another key change in trials for HF is the rise in globalization for reasons such as growing trial sizes, lower research costs in developing nations and market expansion.11 With larger geographical differences also comes greater heterogeneity in patient characteristics and outcomes of these ‘megatrials’.4 In the EVEREST trial for hospitalized heart failure, regional differences were evident for patient comorbidities, biomarkers, treatment and outcomes.12 Disparities in patient characteristics directly impact enrolment at international sites. In this respect, characterization of regional variation, for instance between Western Europeans and Asians with HF and understanding how these differences impact patient eligibility enables early anticipation of differential accrual across international sites.

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