2.2 Eligibility for HFrEF trials 71 Variation in eligibility between trials could be explained in part by the trial intervention type. Those which evaluated drugs make up a majority of explanatory trials in HFrEF, and are as expected, more representative than device or procedure trials with 25% average eligibility. Trials for cardiac devices and procedures are understandably more restrictive as these target small subsets of patients with arrhythmia or conduction problems, advanced heart failure or require device optimization. Next, it is important to recognize that eligibility for HFrEF trials was declining since the early 2000s with a slight increase in more recent years as a consequence of improved trial registration with time33 and growing lists of eligibility criteria, including those for prognostic enrichment.7 Availability of numerous guideline-directed drug therapy (GDMT) have to an extent decreased mortality in HFrEF, making present day HF trials increasingly difficult, complex and costly to conduct.12,34 While maintaining as broad a population as possible, excluding patients at either end of the disease severity spectrum, LVEF 36- 40% or NYHA class IV did not influence overall proportion of eligible patients. Conversely, adding history of HF hospitalization substantially reduced the proportion of eligible participants suggesting that use of this criterion should be approached with care, particularly for HFrEF, although it is deemed useful to drive event rates in HFpEF trials.32,35 Next, although excluding patients with recent cardiovascular instability can be explained from a safety perspective, it is harder to justify exclusion of patients with comorbidities such as iron-deficiency/ anaemia, COPD and cancer, which are all common in HF.36,37 As these conditions tend to cluster with HF, whether from correlated risks or effects from chemotherapy, broadening of eligibility to include patients with these comorbid conditions would provide efficacy and safety data to a wider spectrum of patients.1,38 Rather than restricting a trial sample to only patients who meet cardiovascular enrichment criteria, newer adaptive trial designs have been proposed to allow for data from both target and non-target subpopulations.39 Considering difficulties in defining a single optimal GDMT, the Heart Failure Collaboratory agrees that a gradient of options for optimal treatment, from (i) no background therapy to (ii) any dose ACEI/ARB/angiotensin receptor-neprilysin inhibitor (ARNI) plus BB therapy and then (iii) add an MRA to finally a strictest requirement of (iv) 100% target doses of all GDMT, with sodium-glucose transporter2 inhibitors could be considered.40 In the present study, we assessed the impact of
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