==== Front ESC Heart FailESC Heart Fail10.1002/(ISSN)2055-5822EHF2ESC Heart Failure2055-5822John Wiley and Sons Inc. Hoboken 10.1002/ehf2.12229EHF212229ESCHF-17-00134Letter to the EditorLetters to the EditorDiuretic dosing in heart failure: more data are needed Letter to the EditorR. De Vecchis et al.De Vecchis Renato devecchis.erre@virgilio.it 1 Rigopoulos Angelos 2 Bigalke Boris 3 Manginas Athanassios 4 Tschöpe Carsten 5 6 7 Noutsias Michel 2 1 Cardiology Unit Presidio Sanitario Intermedio “Elena d'Aosta” via Cagnazzi 29, c.a.p 80137 Napoli Italy 2 Department of Internal Medicine III, Division of Cardiology, Angiology and Intensive Medical Care University Hospital Halle, Martin‐Luther‐University Halle Ernst‐Grube‐Straße 40 D‐06120 Halle (Saale) Germany 3 Department of Cardiology Charité ‐ Universitätsmedizin Berlin, Campus Benjamin Franklin (CBF) Berlin Germany 4 Interventional Cardiology and Cardiology Department Mediterraneo Hospital Ilias Street 8‐12 16675 Glyfada Greece 5 Department of Cardiology Charité ‐ Universitätsmedizin Berlin, Campus Virchow Klinikum (CVK) Berlin Germany 6 Deutsches Zentrum für Herz Kreislaufforschung (DZHK) – Standort Berlin Charité ‐ Universitätsmedizin Berlin, Campus Virchow Klinikum (CVK) Berlin Germany 7 Berlin Center for Regenerative Therapies (BCRT), Campus Virchow Klinikum (CVK) Berlin Germany 25 3 2018 8 2018 5 4 10.1002/ehf2.v5.4649 650 10 8 2017 25 9 2017 © 2017 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. source-schema-version-number2.0component-idehf212229cover-dateAugust 2018details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:version=5.4.4 mode:remove_FC converted:03.08.2018 De Vecchis , R. , Rigopoulos , A. , Bigalke , B. , Manginas , A. , Tschöpe , C. , and Noutsias , M. (2018 ) Diuretic dosing in heart failure: more data are needed . ESC Heart Failure , 5 : 649 –650 . 10.1002/ehf2.12229 . ==== Body In the study by Okabe et al.1 the oral dose of 40 mg of furosemide proved being a cut‐off beyond which both all‐cause and cardiovascular mortality were significantly higher. The above‐mentioned value has been obtained using C‐statistics from a total of 215 chronic heart failure (CHF) patients investigated through a median follow‐up of 641 days. This interesting inference has been derived from a relatively small sample of CHF patients and may be therefore deemed as hypothesis generating. However, the study is confined to finding an association without affirming any causal value of it. In other words, in this observational study, it is not excluded that adverse prognosis profiles of higher doses (>40 mg/d) might depend on a greater severity of the baseline clinical picture (so‐called confounding by indication). Indeed, furosemide at doses of >40 mg/d is effective in reducing congestion, relieving cardiac workload, and decreasing ventricular wall stress, thereby preventing the progression of cardiac chambers' dilatation. However, these favorable effects might fail in improving survival for the simultaneous occurrence of unfavorable repercussions on other organs and apparatuses. For example, a greater electrolyte loss (consisting of increased urinary excretion of Na+, K+, Ca++, and Mg++) related to doses of >40 mg furosemide/d might worsen ruinous vertebral osteoporosis,2 a disease relatively common in the elderly patients with cardiac decompensation, which results in fragility fractures or subluxations at the level of the spine with related neurological lesions (e.g. aching pain, paraplegia, and tetraplegia) with significant adverse impact on the patient's life expectancy. In addition, relatively high oral doses may excessively stimulate the macula densa receptors in the kidneys with tubule‐glomerular feedback, resulting in diuretic resistance.3 Subsequent adoption of sequential blockade of the nephron by means of thiazide addition might favor the occurrence of hyponatremia,4 resulting in neurological disturbances, such as postural instability and falls with the potential for fatal outcomes such as traumatic lesions (especially endocranial hematomas). Vasopressin antagonists prevent hyponatremia without increasing adverse events.5 Interferences between the dosage of diuretics and further factors of conditions such as the combination of diuretics with low‐dose dopamine infusion and its significant biological effects such as improved renal function profile and potassium homeostasis have been described in the DAD‐HF trial.6 We conclude that we need more solid data deciphering these intricate interactions in heart failure, which might ultimately translate to improved prognosis of this disease being associated with high mortality and morbidity.7 Conflict of interest M.N. has received grants from the Deutsche Forschungsgemeinschaft (DFG) through the Sonderforschungsbereich Transregio 19 “Inflammatory Cardiomyopathy” (SFB TR19) (TP B2), and from the University Hospital Giessen and Marburg Foundation Grant “T cell functionality” (UKGM 10/2009). C.T. has received a grant from the DFG (SFB TR19 TP B5 and Z3). M.N. has been consultant to the IKDT (Institute for Cardiac Diagnosis and Therapy GmbH, Berlin) June 2004–June 2008 and has received honoraria for presentations and/or participated in advisory boards from AstraZeneca, Bayer, Fresenius, Miltenyi Biotech, Novartis, Pfizer, and Zoll. M.N. is among others the local p.i. of the RELAX‐AHF‐2 and TRANSITION trials at the site University Hospital Jena. The remaining authors, i.e. R.D.V., A.R., B.B., and A.M., declare that they have no conflict of interest. ==== Refs References 1 Okabe T , Yakushiji T , Kido T , Oyama Y , Igawa W , Ono M , Ebara S , Yamashita K , Yamamoto MH , Saito S , Amemiya K , Isomura N , Ochiai M . Association between high‐dose loop diuretic use at discharge and cardiovascular mortality in patients with heart failure . ESC Heart Fail 2017 10.1002/ehf2.12221 . 2 Paik JM , Rosen HN , Gordon CM , Curhan GC . Diuretic use and risk of vertebral fracture in women . Am J Med 2016 ; 129 : 1299 –1306 .27542612 3 Kazory A , Ross EA . Contemporary trends in the pharmacological and extracorporeal management of heart failure: a nephrologic perspective . Circulation 2008 ; 117 : 975 –983 .18285578 4 De Vecchis R , Ariano C , Esposito C , Giasi A , Cioppa C , Cantatrione S . In right or biventricular chronic heart failure addition of thiazides to loop diuretics to achieve a sequential blockade of the nephron is associated with increased risk of dilutional hyponatremia: results of a case‐control study . Minerva Cardioangiol 2012 ; 60 : 517 –529 .23018431 5 Li B , Fang D , Qian C , Feng H , Wang Y . The efficacy and safety of tolvaptan in patients with hyponatremia: a meta‐analysis of randomized controlled trials . Clin Drug Investig 2017 ; 37 : 327 –342 . 6 Giamouzis G , Butler J , Starling RC , Karayannis G , Nastas J , Parisis C , Rovithis D , Economou D , Savvatis K , Kirlidis T , Tsaknakis T , Skoularigis J , Westermann D , Tschöpe C , Triposkiadis F . Impact of dopamine infusion on renal function in hospitalized heart failure patients: results of the Dopamine in Acute Decompensated Heart Failure (DAD‐HF) Trial . J Card Fail 2010 ; 16 : 922 –930 .21111980 7 Hamo CE , Butler J , Gheorghiade M , Chioncel O . The bumpy road to drug development for acute heart failure . Eur Heart J Suppl 2016 ; (Suppl G ): G19 –G32 .