VIEWPOINT
Treatment of Heart Failure With Normal Ejection FractionAn Inconvenient Truth!
Walter J. Paulus, MD, PhD* and
Joris J.M. van Ballegoij, BSc
Institute for Cardiovascular Research Vrije Universiteit, VU University Medical Center Amsterdam, Amsterdam, the Netherlands
Manuscript received April 28, 2009;
revised manuscript received June 12, 2009,
accepted June 15, 2009.
* Reprint requests and correspondence: Dr. Walter J. Paulus, Institute for Cardiovascular Research VU, VU University Medical Center Amsterdam, Van der Boechorststraat 7, 1081 BT Amsterdam, the Netherlands (Email: wj.paulus{at}vumc.nl).
Despite use of similar drugs, outcomes of recent heart failure (HF) trials were frequently neutral in heart failure with normal left ventricular ejection fraction (HFNEF) and positive in heart failure with reduced left ventricular ejection fraction (HFREF). The neutral outcomes of HFNEF trials were often attributed to deficient HFNEF patient recruitment with inclusion of many HFREF or noncardiac patients. Patient recruitment criteria of 21 HFNEF trials were therefore reviewed in reference to diagnostic guidelines for HFNEF. In the 4 published sets of guidelines, a definite diagnosis of HFNEF required the simultaneous and obligatory presence of signs and/or symptoms of HF and evidence of normal systolic left ventricular (LV) function and of diastolic LV dysfunction. In 3 of 4 sets of guidelines, normal systolic LV function comprised both a left ventricular ejection fraction (LVEF) >50% and an absence of LV dilation. Among the 21 HFNEF trials, LVEF cutoff values ranged from 35% to 50%, with only 8 trials adhering to an LVEF >50%. Furthermore, only 1 trial specified a normal LV end-diastolic dimension as an enrollment criterion and only 7 trials required evidence of diastolic LV dysfunction. Nonadherence to diagnostic guidelines induced excessive enrollment into HFNEF trials of HF patients with eccentric LV remodeling and ischemic heart disease compared with HF patients with concentric LV remodeling and arterial hypertension. Nonadherence to guidelines also led to underpowered HFNEF trials with a low incidence of outcome events such as death or HF hospitalizations. Future HFNEF trials should therefore adhere to diagnostic guidelines for HFNEF.
Key Words: heart failure • diastole • hemodynamics • ejection fraction
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Abbreviations and Acronyms
| | ACEI = angiotensin-converting enzyme inhibitor | | AGE = advanced glycation end product | | ARB = angiotensin II receptor blocker | | cGMP = guanosine 3',5'-cyclic monophosphate | | HF = heart failure | | HFNEF = heart failure with normal left ventricular ejection fraction | | HFREF = heart failure with reduced left ventricular ejection fraction | | LA = left atrial | | LBBB = left bundle branch block | | LV = left ventricle/ventricular | | LVEDP = left ventricular end-diastolic pressure | | LVEDVI = left ventricular end-diastolic volume index | | LVEF = left ventricular ejection fraction | | MMP = matrix metalloproteinase | | NP = natriuretic peptide | | PCWP = pulmonary capillary wedge pressure | | PDE5 = phosphodiesterase-5 | | PFR = peak filling rate | | PKG = protein kinase G | | TDI = tissue Doppler imaging | | TIMP = tissue inhibitors of matrix metalloproteinase |
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