CHAPTER 2.2 70 DISCUSSION In this study, we characterized all registered phase III HF trials by their subtype and eligibility criteria specifically for HFrEF. There are four key findings. First, the patient characteristics most frequently used for selection in HFrEF trials were indicators of heart failure severity, namely LVEF, NYHA class, prior worsening of HF, natriuretic peptides followed by cardiovascular comorbidities and events/ procedures i.e., history of MI, cardiac devices, revascularization and optimised background HF treatment. Second, eligibility of two distinct HF patient populations for existing HFrEF trials did not significantly differ; they were both low in that only 20% on average were eligible. Accordingly, we identified the most restrictive criteria amongst these trials and these were prior HF hospitalization, MRA background treatment and anemia. When frequency in trials is taken in consideration, prior MI, NYHA functional class, age and prior HF hospitalization had the highest impact on restrictiveness. Fourth, as eligibility criteria work collectively rather than independently in patient selection, we have evaluated available RWD against trial eligibilities and showed we can test assumptions on impact of combinations of eligibility criteria on trial accrual. It is reassuring to note that patients from the Asian registry population have equal, if not slightly higher eligibility for phase III HFrEF trials compared to European patients, although most clinical trials are designed and weighted towards Western Europe and North American populations.27,28 This is especially important as clinical trials increasingly gear towards cross-continent sites including those in Asia for both scientific and ethical reasons. Although large pharmaceutical markets in Asia such as China and Japan no longer require local data for market authorization, foreign clinical trial data will nevertheless be scrutinized for ethnic and other inconsistencies and if present, add-on local bridging studies will incur cost.29 On this note, incorporating global sites for instance in Asia at the planning stage is cost-efficient given its high disease burden.29 With regard to overall eligibility, having only one-fifth of the target population that is eligible reveals a sizeable gap in representation of real-world patients. This average is comparable to eligibility estimates of single contemporary HFrEF drug trials, which ranged between 11- 35%.30–32 Although estimates found for HFrEF trials are higher than the other large scale eligibility criteria analysis of cancer (2-5%) and diabetes trials (5%), there remains much room for improvement.3,21
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