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

J Card Fail. 2017 Jul;23(7):517-524. doi: 10.1016/j.cardfail.2017.04.006. Epub 2017 Apr 18.


Aims: To 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 results: We applied the key eligibility criteria of 7 phase III HFpEF studies (Digitalis Investigation Group Ancillary, Candesartan in Patients With Chronic Heart Failure and Preserved Left-Ventricular Ejection Fraction, Perindopril in Elderly People With Chronic Heart Failure, Irbesartan in Heart Failure With Preserved Systolic Function, Japanese Diastolic Heart Failure, Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist, and Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction [PARAGON-HF; ongoing]) to a typical and well-characterized HFpEF population (n = 557) seen in modern European cardiological practice. Follow-up was available for a minimum of 24 months in each patient. 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.

Conclusions: Trial 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 used in more recent randomized trials in HFpEF have identified patients at higher risk of all-cause mortality.

Keywords: Heart failure with preserved ejection fraction; diagnosis; phase III clinical trials; trial selection criteria.

MeSH terms

  • Aged
  • Aged, 80 and over
  • Angiotensin II Type 1 Receptor Blockers / pharmacology
  • Angiotensin II Type 1 Receptor Blockers / therapeutic use
  • Angiotensin-Converting Enzyme Inhibitors / pharmacology
  • Angiotensin-Converting Enzyme Inhibitors / therapeutic use
  • Clinical Trials, Phase III as Topic / standards*
  • Female
  • Follow-Up Studies
  • Heart Failure / diagnostic imaging
  • Heart Failure / drug therapy*
  • Heart Failure / mortality
  • Humans
  • Male
  • Middle Aged
  • Mortality / trends
  • Patient Selection*
  • Phenotype*
  • Randomized Controlled Trials as Topic / standards*
  • Retrospective Studies
  • Stroke Volume / drug effects
  • Stroke Volume / physiology*


  • Angiotensin II Type 1 Receptor Blockers
  • Angiotensin-Converting Enzyme Inhibitors