Assessing the Eligibility Criteria in Phase III Randomized Controlled Trials of Drug Therapy in Heart Failure With Preserved Ejection Fraction: The Critical Play-Off Between a “Pure” Patient Phenotype and the Generalizability of Trial Findings

Abstract

AimsTo investigate the effect of the different eligibility criteria used by phase III clinical studies in heart failure with preserved ejection fraction (HFpEF) on patient selection, phenotype and survival. Methods and ResultsWe applied the key eligibility criteria of seven phase III HFpEF studies (DIG-Ancillary, Increasing the number of study eligibility criteria identifies a progressively smaller group of patients from real life practice suitable for recruitment into clinical trials; using the J-DHF criteria, 81% of our clinic patients would have been eligible, whereas, the PARAGON-HF criteria significantly reduced this proportion to 32%. The patients identified from our clinical population had similar mortality rates using the different criteria, which were consistently higher than those reported in the actual clinic trials. ConclusionsTrial eligibility criteria have become stricter with time which reduces the number of eligible patients, affecting both generalizability of any findings and feasibility of completing an adequately powered trial. We could not find evidence that the additional criteria employed in more recent randomised trials in HFpEF have identified patients at higher risk of all-cause mortality.4

Clinical Trial Generalizability Assessment in the Big Data Era: A Review

“…Generalizability assessments have been conducted on trials of various disease areas, including cancer (N = 35; e.g., Sam et al 37 ), cardiovascular diseases (N = 34; e.g., Patel et al 38 ), mental diseases (N = 33; e.g., Zimmerman et al 13 ), musculoskeletal diseases (N = 8; e.g., Becker et al 39 ), HIV/acquired immunodeficiency syndrome (N = 6; e.g., Saeed et al 31 ), endocrine diseases (N = 6; e.g., Wittbrodt et al 40 ), drug or alcohol abuse (N = 6; e.g., Susukida et al 36 ), respiratory diseases (N = 5; e.g., Agweyu et al 41 ), and smoking (N = 5; Susukida et al 12 ), surgery (N = 3; e.g., Fischer et al 42 ), ear diseases (N = 3; e.g., Rovers et al 43 ), digestive disease (N = 3; Millard et al 44 ), sleep disorders (N = 3; Huls et al 45 ), skin diseases (N = 3; Yiu et al 46 ), pain (N = 2; de C Williams et al 47 ), and other diseases (N = 11; e.g., Laskay et al 48 ). 21 articles did not specifically focus on a particular disease (e.g., Hong et al 49 ).…”

Hospitalisation in Patients With Heart Failure With Preserved Ejection Fraction

“…This is a common observation in HF trials, perhaps explained by the fact that registries often find patients based on previous admissions to hospital, whereas trial patients are often stable patients who are sought via specific screening programmes to enhance recruitment. 32 , 33 …”

“…This is a common observation in HF trials, perhaps explained by the fact that registries often find patients based on previous admissions to hospital, whereas trial patients are often stable patients who are sought via specific screening programmes to enhance recruitment. 32,33 Regardless of the type of HF, treatment of elevated filling pressures to reduce fluid accumulation has been demonstrated to prevent HF decompensation and is recommended in the guidelines. 10 The CardioMEMS Heart Sensor Allows Monitoring of Pressure to Improve Outcomes in NYHA Class III Heart Failure Patients (CHAMPION) trial studied the role of an implantable haemodynamic monitor to measure pulmonary artery pressure in patients with NYHA class III symptoms and recent HF hospitalisation.…”

Use of angiotensin receptor blocker is associated with improved 1 year mortality in heart failure with mid‐range ejection fraction

“…However, the robustness of the result was weakened by multiple comparisons of outcomes and the post hoc nature of the analysis, leading to the increased risk of a chance finding 10 . Additionally, the patients were selected through strict criteria of the trial; whether the results can be generalized to a broader population in clinical practice is unclear 11–14 . Further study regarding the effect of ARB on the outcome of HFmrEF in a real‐world setting is required to provide insights for future recommendations on the management of HFmrEF.…”

“…10 Additionally, the patients were selected through strict criteria of the trial; whether the results can be generalized to a broader population in clinical practice is unclear. [11][12][13][14] Further study regarding the effect of ARB on the outcome of HFmrEF in a real-world setting is required to provide insights for future recommendations on the management of HFmrEF. Accordingly, we aim to explore the association of ARB use with 1 year all-cause mortality among the patients with HFmrEF, using data of a multicentre prospective cohort of patients hospitalized primarily for HF.…”