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The Inescapable Heterogeneity of Heart Failure
Accepted Manuscript Title: The Inescapable Heterogeneity of Heart Failure Author: Lars H. Lund PII: DOI: Reference:
S1071-9164(17)30067-2 http://dx.doi.org/doi: 10.1016/j.cardfail.2017.03.007 YJCAF 3934
To appear in:
Journal of Cardiac Failure
Please cite this article as: Lars H. Lund, The Inescapable Heterogeneity of Heart Failure, Journal of Cardiac Failure (2017), http://dx.doi.org/doi: 10.1016/j.cardfail.2017.03.007. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Lund, HF heterogeneity
The inescapable heterogeneity of heart failure Lars H. Lund, MD PhD1,2 (1) Karolinska Institutet, Department of Medicine, 17177 Stockholm, Sweden (2) Karolinska University Hospital, Heart and Vascular Theme, 17176 Stockholm, Sweden Correspondence Lars H. Lund MD, PhD, Karolinska Institutet, Solna 171 76 Stockholm
Fax: +46-8- 311044 Phone: +46-8-51770000 email: [email protected]
No conflicts of interest to declare
Page 1 of 3
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Lund, HF heterogeneity
In oncology, cancers and tumors are typed, sub-typed and phenotyped using staging and grading, with tools such as imaging, tissue histology and tumor markers, circulating biomarkers, and genetics, to refine screening and diagnosis, assess prognosis and treatment targets, and select for and monitor response to therapy. To consider “cancer” as one disease would be unthinkable.
Yet that is how we regard heart failure (HF), or in recent years perhaps as 2 arbitrary syndromes (HF with reduced and preserved ejection fraction, HFrEF and HFpEF) or more recently adding a third category, HF with mid-range EF (HFmrEF)1. We got away with this and were perhaps blinded by the remarkable success of neurohormonal antagonist drugs in HFrEF trials conducted over the last generation. But trials in HFpEF and in acute HF have repeatedly failed and it is becoming increasingly clear that to successfully move into the next era in HF, we must acknowledge, study, and address the inescapable heterogeneity of HF, where few if any future interventions will fit all patients with HF.
In this issue of the Journal, numerous aspects of heterogeneity are addressed. Women constitute a minority of patients in HF trials but more than half of patients with HF overall, particularly with an ageing population and increasing dominance of HFpEF2. Women with HF differ distinctly from men and often from one another, with risk factors and etiologies that differ by age and comorbidity. If, as several papers in this issue point out (should we reference all 3 and Lam’s editorial here?), the roles of hypertension, vascular stiffness and obesity differ between men and women, should prevention, diagnostics and treatment differ between men and women?
While useful for diagnosis and prognosis, natriuretic peptides have repeatedly disappointed as a tool to guide therapy, and it remains unclear if they are useful as surrogate endpoints in early phase trials3, 4. In a post-hoc study from TIME-CHF, NT-proBNP guided therapy reduced the risk of recurrent HF hospitalization in patients younger than age 75 (ref). Instead of repeated post-hoc subgroup analyses, how can trial designers account for heterogeneity in the initial determination of eligibility criteria and outcomes?
As these and other contemporary studies suggest, we may need to be more targeted in future HF trials, using eligibility criteria not only by EF and biomarkers, but by specific targets such as e.g. microvascular endothelial dysfunction in HFpEF5 or by cluster analysis or phenomapping to identify specific phenotypes most likely to respond to therapy. HF trials are already too selective, limiting generalizability and external validity of the findings. Further reducing heterogeneity and Page 2 of 3
Page 2 of 3
Lund, HF heterogeneity
restricting eligibility in trials will hopefully not lead to even fewer patients participating in trials and benefitting from evidence based treatment, but different patients participating in different trials and benefitting from different targeted treatments. References 1. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, Falk V, GonzalezJuanatey JR, Harjola VP, Jankowska EA, Jessup M, Linde C, Nihoyannopoulos P, Parissis JT, Pieske B, Riley JP, Rosano GM, Ruilope LM, Ruschitzka F, Rutten FH, van der Meer P, Authors/Task Force M, Document R. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail 2016;18(8):891-975. 2. Lund LH, Mancini D. Heart failure in women. Med Clin North Am 2004;88(5):1321-45, xii. 3. Savarese G, Hage C, Orsini N, Dahlstrom U, Perrone-Filardi P, Rosano GM, Lund LH. Reductions in N-Terminal Pro-Brain Natriuretic Peptide Levels Are Associated With Lower Mortality and Heart Failure Hospitalization Rates in Patients With Heart Failure With Mid-Range and Preserved Ejection Fraction. Circ Heart Fail 2016;9(11). 4. Savarese G, Donal E, Hage C, Oger E, Persson H, Daubert JC, Linde C, Lund LH, KaRen i. Changes in natriuretic peptides after acute hospital presentation for heart failure with preserved ejection fraction: A feasible surrogate trial endpoint? A report from the prospective Karen study. Int J Cardiol 2017;226:65-70. 5. Lam CS, Lund LH. Microvascular endothelial dysfunction in heart failure with preserved ejection fraction. Heart 2016;102(4):257-9.
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S1071-9164(17)30067-2 http://dx.doi.org/doi: 10.1016/j.cardfail.2017.03.007 YJCAF 3934
To appear in:
Journal of Cardiac Failure
Please cite this article as: Lars H. Lund, The Inescapable Heterogeneity of Heart Failure, Journal of Cardiac Failure (2017), http://dx.doi.org/doi: 10.1016/j.cardfail.2017.03.007. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Lund, HF heterogeneity
The inescapable heterogeneity of heart failure Lars H. Lund, MD PhD1,2 (1) Karolinska Institutet, Department of Medicine, 17177 Stockholm, Sweden (2) Karolinska University Hospital, Heart and Vascular Theme, 17176 Stockholm, Sweden Correspondence Lars H. Lund MD, PhD, Karolinska Institutet, Solna 171 76 Stockholm
Fax: +46-8- 311044 Phone: +46-8-51770000 email: [email protected]
No conflicts of interest to declare
Page 1 of 3
Page 1 of 3
Lund, HF heterogeneity
In oncology, cancers and tumors are typed, sub-typed and phenotyped using staging and grading, with tools such as imaging, tissue histology and tumor markers, circulating biomarkers, and genetics, to refine screening and diagnosis, assess prognosis and treatment targets, and select for and monitor response to therapy. To consider “cancer” as one disease would be unthinkable.
Yet that is how we regard heart failure (HF), or in recent years perhaps as 2 arbitrary syndromes (HF with reduced and preserved ejection fraction, HFrEF and HFpEF) or more recently adding a third category, HF with mid-range EF (HFmrEF)1. We got away with this and were perhaps blinded by the remarkable success of neurohormonal antagonist drugs in HFrEF trials conducted over the last generation. But trials in HFpEF and in acute HF have repeatedly failed and it is becoming increasingly clear that to successfully move into the next era in HF, we must acknowledge, study, and address the inescapable heterogeneity of HF, where few if any future interventions will fit all patients with HF.
In this issue of the Journal, numerous aspects of heterogeneity are addressed. Women constitute a minority of patients in HF trials but more than half of patients with HF overall, particularly with an ageing population and increasing dominance of HFpEF2. Women with HF differ distinctly from men and often from one another, with risk factors and etiologies that differ by age and comorbidity. If, as several papers in this issue point out (should we reference all 3 and Lam’s editorial here?), the roles of hypertension, vascular stiffness and obesity differ between men and women, should prevention, diagnostics and treatment differ between men and women?
While useful for diagnosis and prognosis, natriuretic peptides have repeatedly disappointed as a tool to guide therapy, and it remains unclear if they are useful as surrogate endpoints in early phase trials3, 4. In a post-hoc study from TIME-CHF, NT-proBNP guided therapy reduced the risk of recurrent HF hospitalization in patients younger than age 75 (ref). Instead of repeated post-hoc subgroup analyses, how can trial designers account for heterogeneity in the initial determination of eligibility criteria and outcomes?
As these and other contemporary studies suggest, we may need to be more targeted in future HF trials, using eligibility criteria not only by EF and biomarkers, but by specific targets such as e.g. microvascular endothelial dysfunction in HFpEF5 or by cluster analysis or phenomapping to identify specific phenotypes most likely to respond to therapy. HF trials are already too selective, limiting generalizability and external validity of the findings. Further reducing heterogeneity and Page 2 of 3
Page 2 of 3
Lund, HF heterogeneity
restricting eligibility in trials will hopefully not lead to even fewer patients participating in trials and benefitting from evidence based treatment, but different patients participating in different trials and benefitting from different targeted treatments. References 1. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, Falk V, GonzalezJuanatey JR, Harjola VP, Jankowska EA, Jessup M, Linde C, Nihoyannopoulos P, Parissis JT, Pieske B, Riley JP, Rosano GM, Ruilope LM, Ruschitzka F, Rutten FH, van der Meer P, Authors/Task Force M, Document R. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail 2016;18(8):891-975. 2. Lund LH, Mancini D. Heart failure in women. Med Clin North Am 2004;88(5):1321-45, xii. 3. Savarese G, Hage C, Orsini N, Dahlstrom U, Perrone-Filardi P, Rosano GM, Lund LH. Reductions in N-Terminal Pro-Brain Natriuretic Peptide Levels Are Associated With Lower Mortality and Heart Failure Hospitalization Rates in Patients With Heart Failure With Mid-Range and Preserved Ejection Fraction. Circ Heart Fail 2016;9(11). 4. Savarese G, Donal E, Hage C, Oger E, Persson H, Daubert JC, Linde C, Lund LH, KaRen i. Changes in natriuretic peptides after acute hospital presentation for heart failure with preserved ejection fraction: A feasible surrogate trial endpoint? A report from the prospective Karen study. Int J Cardiol 2017;226:65-70. 5. Lam CS, Lund LH. Microvascular endothelial dysfunction in heart failure with preserved ejection fraction. Heart 2016;102(4):257-9.
Page 3 of 3
Page 3 of 3