CHAPTER 4 196 Therefore, re-examining eligibility criteria of HFrEF trials in these times of rising trends of HF comorbidities has its merits.49 Non-cardiovascular comorbidities most often excluded from HFrEF trials were chronic kidney disease (CKD) (55% of trials), COPD or asthma (28%), cancer (25%), liver disease (21%), anaemia or iron deficiency (17%), neurological disorder including dementia, thyroid disorder, depression and so on. Majority of these conditions are clustered with HFrEF.50,51 Excluding major comorbidities such as anemia and COPD or asthma would mean that more than one-third and one-fifth of HFrEF registry patients are ineligible. Rather than solely presenting with competing risks, existing literature indicate that concomitant CKD and anaemia or iron deficiency in HF do contribute independent risks to cardiovascular progression.52–54 Therefore, phase III HFrEF trials should generally be inclusive of patients with CKD, anaemia or iron deficiency and COPD unless justified by unacceptable safety risks such as advanced disease stages, contraindication or involvement with drug metabolism or excretion. Further research on the relative competing risks from each prevalent comorbid conditions in HF will enable data-driven eligibility criteria decisions, balancing between impact on primary endpoint detection and gains in trial accrual rates. To identify patients with higher event rates for cardiovascular outcomes, contemporary trials in HFrEF utilize prognostic enrichment markers or characteristics. A quarter of RCTs for HFrEF enriched for higher CV risk from a recent HF hospitalization and a-fifth applied minimum threshold criterion N-terminal pro btype natriuretic peptide (NT-proBNP) or brain natriuretic peptide (BNP). It is FDAaccepted clinical trial practice to establish efficacy in narrower subsets of high-risk patients follow with larger studies in lower risk patients.45 However, follow-up trials of patients with the same HF phenotype but without the prognostic marker or pragmatic trials are rarely conducted.55 Moreover, the absence of a standardized way for practicing clinicians to prospectively identify patients with greater likelihood to respond to treatment only adds to hesitation in adopting newer treatments. To navigate the issue of restrictive prognostically enriched trial populations, adaptive designs that include a subset of patients who do not meet the enrichment criterion is useful, particularly when sensitivity of a prognostic marker is not fully understood.56 Results for the full spectrum of patients, whether marker positive and negative, can then be reported as secondary efficacy outcomes.56
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