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Different Definitions of HFpEF Have an Impact on Patient Outcomes

Key findings

  • In a study of 461 patients, subgroups of patients who met various definitions of heart failure with preserved ejection fraction (HFpEF) demonstrated marked differences in clinical profile and exercise capacity
  • The differences in clinical profiles were mirrored by differing clinical outcomes, with a nearly four-fold difference in the incidence of future cardiovascular-related hospitalization or death depending on which HFpEF definition was applied
  • Restrictive definitions of HFpEF lacked sensitivity to detect physiologic HFpEF (e.g., abnormal rest or exercise filling pressures), even though that phenotype has functional and prognostic significance
  • Conversely, the American College of Cardiology/American Heart Association's broad definition of HFpEF resulted in inclusion of many patients who lacked evidence of physiologic HFpEF
  • Comprehensive hemodynamic phenotyping of patients suspected of having HFpEF may help identify those who are at greatest risk of poor outcomes

No medication intended to treat heart failure with preserved ejection fraction (HFpEF) has ever demonstrated efficacy in advanced-stage clinical trials, according to the 2013 ACCF/AHA Guidelines. A contributor to these neutral and negative results may be that different medical societies and clinical trial investigators have never agreed on the optimal definition of HFpEF.

Jennifer E. Ho, MD, cardiologist in the Heart Failure and Transplant Program and the Cardiovascular Research CenterGregory Lewis, MD, section head of Heart Failure at Massachusetts General Hospital, and colleagues recently applied various HFpEF definitions to a cohort of patients who underwent uniform, comprehensive evaluation of dyspnea on exertion. In Circulation, they confirmed significant heterogeneity in clinical profiles, exercise capacity and clinical outcomes.

Classification of the Cohort

In this retrospective study, 461 patients with chronic New York Heart Association class II–IV symptoms and left ventricular EF ≥50% who underwent exercise testing with invasive hemodynamic monitoring between 2006 and 2017 were evaluated. The average age was 58 and 62% of the patients were women.

The researchers determined how many of the patients fit each of seven definitions of HFpEF:

  • Met the HFpEF definition of the American College of Cardiology/American Heart Association (ACC/AHA): 90%
  • European Society of Cardiology (ESC): 44%
  • Heart Failure Society of America (HFSA): 12%
  • RELAX-HF trial: 34%
  • PARAGON-HF trial: 12%
  • I-PRESERVE trial: 10%
  • TOPCAT trial: 10%

The more restrictive society definitions, ESC and HFSA, captured a subgroup that was older, was more male and had a greater burden of comorbid illnesses than average.

The greatest evidence of neurohormonal activation and inflammation, assessed via N-terminal pro-B type natriuretic peptide (NT-proBNP) and high-sensitivity C-reactive protein, was found among patients meeting HFSA criteria for HFpEF, and the least among those meeting ACC/AHA criteria.

With regard to clinical trial criteria for HFpEF, the PARAGON-HF group had the highest NT-proBNP and the RELAX group had the lowest. 96% of patients who met TOPCAT criteria versus 46% of those who met RELAX criteria had a previous cardiovascular hospital admission, with PARAGON-HF and I-PRESERVE falling in between.

Exercise Parameters

  • Among patients in all HFpEF classifications, exercise capacity was reduced and ventilation was inefficient
  • Within different HFpEF classifications, 29% to 63% of participants had elevated resting pulmonary capillary wedge pressure (PCWP) detected by invasive hemodynamic testing. An additional 16% to 31% had normal resting PCWP but had abnormal exercise PCWP detected with exercise testing
  • Only 53% of patients who met the ACC/AHA definition of HFpEF had abnormal rest or exercise filling pressures, compared with 78% of those meeting ESC criteria and 75% of those meeting HFSA criteria

Comparison with Physiologically Defined HFpEF

243 participants had abnormal rest or exercise filling pressures and therefore met the classic definition of HF. This proved to be an intermediate group: 91% of these patients met ACC/AHA criteria for HFpEF, whereas only 15% met TOPCAT criteria, with other patients falling in between.

The sensitivity and specificity for detecting physiologically defined HFpEF varied widely among definitions. The ACC/AHA definition had the greatest sensitivity (91%) but a specificity of 11%. The HFSA definition had a sensitivity of only 17% but a specificity of 94%.


Except for the group that met the ACC/AHA definition, patients who met a society definition or trial criteria for HFpEF had significantly poorer outcomes (average follow-up 3.8 years) than those who did not:

  • Patients who met HFSA criteria had a three-fold increased risk of a combined outcome, cardiovascular-related hospitalization or death, compared with those who did not meet HFSA criteria (HR, 2.99; 95% CI 1.96–4.55; P < .001)
  • Patients who met ESC criteria had a two-fold increased risk of the combined outcome (HR, 2.02; 95% CI, 1.38–2.97; P < .001)
  • Patients with physiologically defined HFpEF had 60% increased risk (HR, 1.62; 95% CI, 1.11–2.35; P = .01)

Implications for Clinical Practice and Research

Exercise testing and hemodynamic phenotyping of patients with HFpEF may help identify who is at highest risk of adverse outcomes. For example, some data show the benefits of non-inhaled inorganic nitrates on exercise PCWP or favorable hemodynamic changes with intra-atrial septal shunts. For such interventions, it may be useful to target patients with abnormal exercise PCWP.

Conversely, patients who lack physiologic evidence of HFpEF during a comprehensive evaluation may be less likely to respond to a treatment designed to improve hemodynamic performance.

In addition, segregation of patients based on predominant rest or exercise HFpEF may assist in trial design to identify potential interventions.

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