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Fussing Over the Middle Child

2017; Lippincott Williams & Wilkins; Volume: 135; Issue: 14 Linguagem: Inglês

10.1161/circulationaha.117.027324

1524-4539

Carolyn S.P. Lam, Scott D. Solomon,

Child Nutrition and Feeding Issues

HomeCirculationVol. 135, No. 14Fussing Over the Middle Child Free AccessArticle CommentaryPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessArticle CommentaryPDF/EPUBFussing Over the Middle ChildHeart Failure With Mid-Range Ejection Fraction Carolyn S.P. Lam, MBBS, PhD and Scott D. Solomon, MD Carolyn S.P. LamCarolyn S.P. Lam From National Heart Centre, Singapore and Duke-National University of Singapore. and Scott D. SolomonScott D. Solomon From National Heart Centre, Singapore and Duke-National University of Singapore. Originally published4 Apr 2017https://doi.org/10.1161/CIRCULATIONAHA.117.027324Circulation. 2017;135:1279–1280In 2014, we dubbed heart failure (HF) with mid-range ejection fraction (EF) of 40% to 50% (HFmrEF) as the "middle child" in HF—unloved and neglected in contrast to the well-behaved older sibling (HF with reduced EF [HFrEF]) and the somewhat more turbulent youngest child (HF with preserved EF [HFpEF]).1 In 2016, HFmrEF achieved recognition in the European Society of Cardiology's HF Guidelines. The specified aim for adopting the nomenclature was to "stimulate research into the underlying characteristics, pathophysiology and treatment of this group of patients." This recognition was certainly an improvement from dismissing the EF 40% to 50% range as a grey zone, as done previously, and has indeed led to greater attention being paid to this group of patients. Because HFmrEF represents almost one fifth of the HF population, this fussing appears warranted. But have we gone too far?Historically, most HF clinical trials published after 1990 selected patients based on EF and showed survival benefit only in patients with EF 40% in the CHARM program (Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity), in whom no specific therapy had been identified, and the component trial consisting of this group was CHARM-Preserved. At the same time, purists in the field were arguing that the EF cutoff for HFpEF should be defined as ≥45% or even 50%, acknowledging that EFs in the 40% to 50% range are clearly not normal and that these patients, in many ways, resembled their lower EF siblings. This growing chasm inevitably left an EF gap between the accepted HFrEF and HFpEF cutoffs.The term, "HFmrEF" did not arise from the discovery of a new phenotype that mysteriously appeared in 2016 or the recognition that patients in this range were biologically distinct from those with lower or higher EFs. Our intention was simply to acknowledge the EF gap, rather than leave it undefined, and to highlight the lack of knowledge about this group of patients as well as encourage investigation of their phenotypic and biological characteristics. The growing appreciation that there can be prognostic differences and different responses to therapeutic interventions throughout the EF spectrum2,3 reinforced the need to understand this middle range.The perils of being overly pedantic with HFmrEF lie in the imprecise methods by which we measure left ventricular EF and the fact that EF measurements are not static over time in a single patient. A systematic analysis of the reliability of echocardiographic determination of left ventricular EF—the technique most commonly used clinically—by Simpson's rule showed an interobserver variability of 8% to 21% and an intraobserver variability of 6% to 13%.4 Compared with radionuclide or contrast ventriculography, the Bland-Altman limits of agreement ranged from LVEF ±7% to ±25% (median ±18%). The authors remarked that this level of accuracy may be adequate for establishing whether EF is in the clearly abnormal range of 50%; however, in the range of 30% to 50%, the evidence indicated that echocardiography was imprecise.4 This imprecision is further illustrated in the TOPCAT trial (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist),2 which enrolled patients with HF and EF ≥45% as determined by EF measurements at sites. Comparing site measurements with core laboratory measurements, we found that at the EF cutoff of 50% (upper cutoff of HFmrEF), 19% of patients would have been reclassified from HFpEF to HFmrEF or vice versa (S. D. Solomon, unpublished data, 2017). Moreover, most echocardiography laboratories report EF semiquantitatively for both clinical work and in clinical trials, with the majority of EF measures in multiples of 5. Indeed, an EF of 50% may really mean anything between 45% and 55%, making cutoffs at 40% and 50% more likely to increase the risk of misclassification. Collectively, these problems may unnecessarily complicate our future clinical trials and, worse, may impede clinical care if guideline groups in the future apply these cutoffs to therapies.Beyond misclassification, it is increasingly recognized that HFmrEF may represent a group in transition between HFrEF and HFpEF. Indeed, the change in EF over time among patients with HF was quantified in the Olmsted County, Minnesota, cohort, where EF decreased by ≈6% over 5 years in HFpEF and increased by ≈7% over 5 years in HFrEF, representing a crossing of the 50% threshold in 38.5% of patients transitioning from HFpEF to HFrEF and 38.8% from HFrEF to HFpEF.5 Moreover, recent data from TOPCAT2 and CHARM-Preserved3 have shown that patients with HFmrEF behave similarly to those with HFrEF, in terms of both prognosis and response to therapy. This finding may be attributable to the similarly high burden of coronary artery disease in HFmrEF and HFrEF, in contrast to the lower burden in HFpEF, suggesting that it is the underlying etiology that matters, rather than the EF per se.We are delighted that the middle child in heart failure has finally received some attention. By doing so, we can better understand a substantial proportion of patients with HF who have been neglected and yet have substantial morbidity and mortality. Nevertheless, we should resist the temptation to fuss over names or become overly rigid in our partitioning. After all, all of the heart failure children are part of the same family.DISCLOSURESDr Lam is supported by a Clinician Scientist Award from the National Medical Research Council of Singapore; has received research support from Boston Scientific, Bayer, Thermofisher, Medtronic, and Vifor Pharma; and has consulted for Bayer, Novartis, Takeda, Merck, Astra Zeneca, Janssen Research & Development, LLC, Menarini, Boehringer Ingelheim, and Abbott Diagnostics. Dr Solomon reports no conflicts of interest.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Circulation is available at http://circ.ahajournals.org.Correspondence to: Carolyn S.P. Lam, MBBS, PhD, National Heart Centre Singapore, 5 Hospital Dr, Singapore 169609. E-mail [email protected]References1. Lam CS, Solomon SD. The middle child in heart failure: heart failure with mid-range ejection fraction (40-50%).Eur J Heart Fail. 2014; 16:1049–1055. doi: 10.1002/ejhf.159.CrossrefMedlineGoogle Scholar2. Solomon SD, Claggett B, Lewis EF, Desai A, Anand I, Sweitzer NK, O'Meara E, Shah SJ, McKinlay S, Fleg JL, Sopko G, Pitt B, Pfeffer MA; TOPCAT Investigators. Influence of ejection fraction on outcomes and efficacy of spironolactone in patients with heart failure with preserved ejection fraction.Eur Heart J. 2016; 37:455–462. doi: 10.1093/eurheartj/ehv464.CrossrefMedlineGoogle Scholar3. Shah AM, Shah SJ, Anand IS, Sweitzer NK, O'Meara E, Heitner JF, Sopko G, Li G, Assmann SF, McKinlay SM, Pitt B, Pfeffer MA, Solomon SD; TOPCAT Investigators. 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April 4, 2017Vol 135, Issue 14 Advertisement Article InformationMetrics © 2017 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.117.027324PMID: 28373521 Originally publishedApril 4, 2017 Keywordsejection fractionheart failurePDF download Advertisement SubjectsHeart Failure