New strategies for heart failure with preserved ejection fraction: the importance of targeted therapies for heart failure phenotypes

Eur Heart J. 2014 Oct 21;35(40):2797-815. doi: 10.1093/eurheartj/ehu204. Epub 2014 Aug 7.


The management of heart failure with reduced ejection fraction (HF-REF) has improved significantly over the last two decades. In contrast, little or no progress has been made in identifying evidence-based, effective treatments for heart failure with preserved ejection fraction (HF-PEF). Despite the high prevalence, mortality, and cost of HF-PEF, large phase III international clinical trials investigating interventions to improve outcomes in HF-PEF have yielded disappointing results. Therefore, treatment of HF-PEF remains largely empiric, and almost no acknowledged standards exist. There is no single explanation for the negative results of past HF-PEF trials. Potential contributors include an incomplete understanding of HF-PEF pathophysiology, the heterogeneity of the patient population, inadequate diagnostic criteria, recruitment of patients without true heart failure or at early stages of the syndrome, poor matching of therapeutic mechanisms and primary pathophysiological processes, suboptimal study designs, or inadequate statistical power. Many novel agents are in various stages of research and development for potential use in patients with HF-PEF. To maximize the likelihood of identifying effective therapeutics for HF-PEF, lessons learned from the past decade of research should be applied to the design, conduct, and interpretation of future trials. This paper represents a synthesis of a workshop held in Bergamo, Italy, and it examines new and emerging therapies in the context of specific, targeted HF-PEF phenotypes where positive clinical benefit may be detected in clinical trials. Specific considerations related to patient and endpoint selection for future clinical trials design are also discussed.

Keywords: Clinical trial; Diabetes mellitus; Exercise tolerance; Heart failure, Diastolic; Phenotype; Preserved ejection fraction.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Aminobutyrates / therapeutic use
  • Anemia / prevention & control
  • Angiotensin Receptor Antagonists / therapeutic use
  • Angiotensin-Converting Enzyme Inhibitors / therapeutic use
  • Arrhythmias, Cardiac / prevention & control
  • Biphenyl Compounds
  • Cardiotonic Agents / therapeutic use
  • Clinical Trials as Topic
  • Diabetic Angiopathies / prevention & control
  • Diuretics / therapeutic use
  • Drug Combinations
  • Exercise Therapy / methods
  • Heart Failure / physiopathology
  • Heart Failure / therapy*
  • Homeostasis
  • Humans
  • Hypertension, Pulmonary / prevention & control
  • Iron Deficiencies
  • Mineralocorticoid Receptor Antagonists / therapeutic use
  • Molecular Targeted Therapy / methods
  • Obesity / prevention & control
  • Observational Studies as Topic
  • Patient Selection
  • Phenotype
  • Phosphodiesterase 5 Inhibitors / therapeutic use
  • Sodium Channel Blockers / therapeutic use
  • Stroke Volume / physiology
  • Tetrazoles / therapeutic use
  • Valsartan
  • Vascular Stiffness / physiology


  • Aminobutyrates
  • Angiotensin Receptor Antagonists
  • Angiotensin-Converting Enzyme Inhibitors
  • Biphenyl Compounds
  • Cardiotonic Agents
  • Diuretics
  • Drug Combinations
  • Mineralocorticoid Receptor Antagonists
  • Phosphodiesterase 5 Inhibitors
  • Sodium Channel Blockers
  • Tetrazoles
  • Valsartan
  • sacubitril and valsartan sodium hydrate drug combination