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Intensification of pharmacological decongestion but not the actual daily loop diuretic dose predicts worse chronic heart failure outcome: insights from TIME-CHF

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Abstract

Background

Both loop diuretics (LDs) and congestion have been related to worse heart failure (HF) outcome. The relationship between the cause and effect is unknown. The aim of this study was to investigate the interaction between congestion, diuretic use and HF outcome.

Methods

Six hundred and twenty-two chronic HF patients from TIME-CHF were studied. Congestion was measured by means of a clinical congestion index (CCI). Loop diuretic dose was considered at baseline and month 6. Treatment intensification was defined as the increase in LD dose over 6 months or loop diuretic and thiazide or thiazide-like diuretic co-administration. The end-points were survival and HF hospitalisation-free survival.

Results

High-LD dose at baseline and month 6 (≥ 80 mg of furosemide per day) was not identified as an independent predictor of outcome. CCI at baseline remained independently associated with impaired survival [hazard ratio (HR) 1.34, (95% confidence interval) (95% CI) (1.20–1.50), p < 0.001] and HF hospitalisation-free survival [HR 1.09, 95% CI (1.02–1.17), p = 0.015]. CCI at month 6 was independently associated with HF hospitalisation-free survival [HR 1.24, 95% CI (1.11–1.38), p < 0.001]. Treatment intensification was independently associated with survival [HR 1.75, 95% CI (1.19–1.38), p = 0.004] and HF hospitalisation-free survival [HR 1.69, 95% CI (1.22–2.35), p = 0.002]. Patients undergoing treatment intensification resulting in decongestion had better outcome than patients with persistent (worsening) congestion despite LD dose up-titration (p < 0.001).

Conclusion

Intensification of pharmacological decongestion but not the actual LD dose was related to poor outcome in chronic HF. If treatment intensification translated into clinical decongestion, outcome was better than in case of persistent or worsening congestion.

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Data availability

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References

  1. Simonavičius J, Knackstedt C, Brunner-La Rocca H-P (2019) Loop diuretics in chronic heart failure: how to manage congestion? Heart Fail Rev 24:17–30. https://doi.org/10.1007/s10741-018-9735-7

    Article  CAS  PubMed  Google Scholar 

  2. Ponikowski P, Voors AA, Anker SD et al (2016) 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failureThe 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 Heart J 37:2129–2200. https://doi.org/10.1093/eurheartj/ehw128

    Article  PubMed  Google Scholar 

  3. Simonavičius J, Sanders van-Wijk S, Rickenbacher P et al (2019) Prognostic significance of longitudinal clinical congestion pattern in chronic heart failure: insights from TIME-CHF trial. Am J Med 132:e679–e692. https://doi.org/10.1016/j.amjmed.2019.04.010

    Article  PubMed  Google Scholar 

  4. Zile MR, Bennett TD, St John Sutton M et al (2008) Transition from chronic compensated to acute decompensated heart failure: pathophysiological insights obtained from continuous monitoring of intracardiac pressures. Circulation 118:1433–1441. https://doi.org/10.1161/CIRCULATIONAHA.108.783910

    Article  PubMed  Google Scholar 

  5. Testani JM, Chen J, McCauley BD et al (2010) Potential effects of aggressive decongestion during the treatment of decompensated heart failure on renal function and survival. Circulation 122:265–272. https://doi.org/10.1161/CIRCULATIONAHA.109.933275

    Article  PubMed  PubMed Central  Google Scholar 

  6. Palazzuoli A, Ruocco G, Franci B et al (2020) Ultrasound indices of congestion in patients with acute heart failure according to body mass index. Clin Res Cardiol. https://doi.org/10.1007/s00392-020-01642-9

    Article  PubMed  Google Scholar 

  7. Kobayashi M, Girerd N, Duarte K et al (2020) Prognostic impact of plasma volume estimated from hemoglobin and hematocrit in heart failure with preserved ejection fraction. Clin Res Cardiol. https://doi.org/10.1007/s00392-020-01639-4

    Article  PubMed  Google Scholar 

  8. Kobayashi M, Rossignol P, Ferreira JP et al (2019) Prognostic value of estimated plasma volume in acute heart failure in three cohort studies. Clin Res Cardiol 108:549–561. https://doi.org/10.1007/s00392-018-1385-1

    Article  CAS  PubMed  Google Scholar 

  9. Abraham WT, Adamson PB, Bourge RC et al (2011) Wireless pulmonary artery haemodynamic monitoring in chronic heart failure: a randomised controlled trial. Lancet 377:658–666. https://doi.org/10.1016/S0140-6736(11)60101-3

    Article  PubMed  Google Scholar 

  10. Mullens W, Damman K, Testani JM et al (2020) Evaluation of kidney function throughout the heart failure trajectory: a position statement from the heart failure association of the European society of cardiology. Eur J Heart Fail 22:584–603. https://doi.org/10.1002/ejhf.1697

    Article  PubMed  Google Scholar 

  11. Brunner-La Rocca H-P, Linssen GC, Smeele FJ et al (2019) Contemporary drug treatment of chronic heart failure with reduced ejection fraction: the CHECK-HF registry. JACC Heart Fail 7:13–21. https://doi.org/10.1016/j.jchf.2018.10.010

    Article  PubMed  Google Scholar 

  12. Eshaghian S, Horwich TB, Fonarow GC (2006) Relation of loop diuretic dose to mortality in advanced heart failure. Am J Cardiol 97:1759–1764. https://doi.org/10.1016/j.amjcard.2005.12.072

    Article  CAS  PubMed  Google Scholar 

  13. Damman K, Kjekshus J, Wikstrand J et al (2016) Loop diuretics, renal function and clinical outcome in patients with heart failure and reduced ejection fraction. Eur J Heart Fail 18:328–336. https://doi.org/10.1002/ejhf.462

    Article  PubMed  Google Scholar 

  14. Lawson CA, Testani JM, Mamas M et al (2018) Chronic kidney disease, worsening renal function and outcomes in a heart failure community setting: a UK national study. Int J Cardiol 267:120–127. https://doi.org/10.1016/j.ijcard.2018.04.090

    Article  PubMed  PubMed Central  Google Scholar 

  15. Vardeny O, Claggett B, Kachadourian J et al (2019) Reduced loop diuretic use in patients taking sacubitril/valsartan compared with enalapril: the PARADIGM-HF trial. Eur J Heart Fail 21:337–341. https://doi.org/10.1002/ejhf.1402

    Article  CAS  PubMed  Google Scholar 

  16. Pfisterer M, Buser P, Rickli H et al (2009) BNP-guided vs symptom-guided heart failure therapy: the trial of intensified vs standard medical therapy in elderly patients with congestive heart failure (TIME-CHF) randomized trial. JAMA 301:383–392. https://doi.org/10.1001/jama.2009.2

    Article  CAS  PubMed  Google Scholar 

  17. Brunner-La Rocca HP, Buser PT, Schindler R et al (2006) Management of elderly patients with congestive heart failure–design of the trial of intensified versus standard medical therapy in elderly patients with congestive heart failure (TIME-CHF). Am Heart J 151:949–955. https://doi.org/10.1016/j.ahj.2005.10.022

    Article  PubMed  Google Scholar 

  18. Simonavicius J, Puronaite R, Brunner-La Rocca H-P (2020) The reply. Am J Med 133:e330–e332. https://doi.org/10.1016/j.amjmed.2019.12.011

    Article  PubMed  Google Scholar 

  19. Maeder MT, Rickli H, Pfisterer ME et al (2012) Incidence, clinical predictors, and prognostic impact of worsening renal function in elderly patients with chronic heart failure on intensive medical therapy. Am Heart J 163(407–414):414.e1. https://doi.org/10.1016/j.ahj.2011.12.003

    Article  Google Scholar 

  20. Mullens W, Verbrugge FH, Nijst P, Tang WHW (2017) Renal sodium avidity in heart failure: from pathophysiology to treatment strategies. Eur Heart J 38:1872–1882. https://doi.org/10.1093/eurheartj/ehx035

    Article  CAS  PubMed  Google Scholar 

  21. Anuradha L, McNulty SE, Mentz RJ et al (2015) Relief and recurrence of congestion during and after hospitalization for acute heart failure. Circ Heart Failure 8:741–748. https://doi.org/10.1161/CIRCHEARTFAILURE.114.001957

    Article  Google Scholar 

  22. Selvaraj S, Claggett B, Pozzi A et al (2019) prognostic implications of congestion on physical examination among contemporary patients with heart failure and reduced ejection fraction: PARADIGM-HF. Circulation 140:1369–1379. https://doi.org/10.1161/CIRCULATIONAHA.119.039920

    Article  CAS  PubMed  Google Scholar 

  23. Yancy CW, Jessup M, Bozkurt B et al (2013) 2013 ACCF/AHA guideline for the management of heart failure: a report of the American college of cardiology foundation/American heart association task force on practice guidelines. Circulation 128:e240–e327. https://doi.org/10.1161/CIR.0b013e31829e8776

    Article  PubMed  Google Scholar 

  24. Ellison DH, Felker GM (2017) Diuretic treatment in heart failure. N Engl J Med 377:1964–1975. https://doi.org/10.1056/NEJMra1703100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Felker GM, Lee KL, Bull DA et al (2011) Diuretic strategies in patients with acute decompensated heart failure. N Engl J Med 364:797–805. https://doi.org/10.1056/NEJMoa1005419

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Rohde LE, Rover MM, Figueiredo Neto JA et al (2019) Short-term diuretic withdrawal in stable outpatients with mild heart failure and no fluid retention receiving optimal therapy: a double-blind, multicentre, randomized trial. Eur Heart J 40:3605–3612. https://doi.org/10.1093/eurheartj/ehz554

    Article  PubMed  Google Scholar 

  27. Simonavicius J, Brunner-La Rocca H-P (2020) Do chronic heart failure patients receive optimal decongestive interventions in a real-life setting? Eur J Heart Fail. https://doi.org/10.1002/ejhf.1839

    Article  PubMed  Google Scholar 

  28. Ahmed A, Husain A, Love TE et al (2006) Heart failure, chronic diuretic use, and increase in mortality and hospitalization: an observational study using propensity score methods. Eur Heart J 27:1431–1439. https://doi.org/10.1093/eurheartj/ehi890

    Article  PubMed  Google Scholar 

  29. Hamaguchi S, Kinugawa S, Tsuchihashi-Makaya M et al (2012) Loop diuretic use at discharge is associated with adverse outcomes in hospitalized patients with heart failure: a report from the Japanese cardiac registry of heart failure in cardiology (JCARE-CARD). Circ J 76:1920–1927

    Article  Google Scholar 

  30. Jm TM, M P, D K et al (2020) Higher doses of loop diuretics limit uptitration of angiotensin-converting enzyme inhibitors in patients with heart failure and reduced ejection fraction. Clin Res Cardiol 109:1048–1059. https://doi.org/10.1007/s00392-020-01598-w

    Article  CAS  Google Scholar 

  31. Neuberg GW, Miller AB, O’Connor CM et al (2002) Diuretic resistance predicts mortality in patients with advanced heart failure. Am Heart J 144:31–38

    Article  Google Scholar 

  32. Abdel-Qadir HM, Tu JV, Yun L et al (2010) Diuretic dose and long-term outcomes in elderly patients with heart failure after hospitalization. Am Heart J 160:264-271.e1. https://doi.org/10.1016/j.ahj.2010.05.032

    Article  CAS  PubMed  Google Scholar 

  33. Dini FL, Guglin M, Simioniuc A et al (2012) Association of furosemide dose with clinical status, left ventricular dysfunction, natriuretic peptides, and outcome in clinically stable patients with chronic systolic heart failure. Congest Heart Fail 18:98–106. https://doi.org/10.1111/j.1751-7133.2011.00252.x

    Article  CAS  PubMed  Google Scholar 

  34. Trullàs J-C, Casado J, Morales-Rull J-L et al (2019) Prevalence and outcome of diuretic resistance in heart failure. Intern Emerg Med 14:529–537. https://doi.org/10.1007/s11739-018-02019-7

    Article  PubMed  Google Scholar 

  35. Jardim SI, Ramos Dos Santos L, Araújo I et al (2018) A 2018 overview of diuretic resistance in heart failure. Rev Port Cardiol 37:935–945. https://doi.org/10.1016/j.repc.2018.03.014

    Article  PubMed  Google Scholar 

  36. Galluzzo A, Frea S, Boretto P et al (2020) Spot urinary sodium in acute decompensation of advanced heart failure and dilutional hyponatremia: insights from DRAIN trial. Clin Res Cardiol. https://doi.org/10.1007/s00392-020-01617-w

    Article  PubMed  PubMed Central  Google Scholar 

  37. Shah N, Madanieh R, Alkan M et al (2017) A perspective on diuretic resistance in chronic congestive heart failure. Ther Adv Cardiovasc Dis 11:271–278. https://doi.org/10.1177/1753944717718717

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Kaissling B, Bachmann S, Kriz W (1985) Structural adaptation of the distal convoluted tubule to prolonged furosemide treatment. Am J Physiol 248:F374-381. https://doi.org/10.1152/ajprenal.1985.248.3.F374

    Article  CAS  PubMed  Google Scholar 

  39. Rao VS, Planavsky N, Hanberg JS et al (2017) Compensatory distal reabsorption drives diuretic resistance in human heart failure. J Am Soc Nephrol 28:3414–3424. https://doi.org/10.1681/ASN.2016111178

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Brunner-La Rocca H-P, Knackstedt C, Eurlings L et al (2015) Impact of worsening renal function related to medication in heart failure. Eur J Heart Fail 17:159–168. https://doi.org/10.1002/ejhf.210

    Article  CAS  PubMed  Google Scholar 

  41. Hillege Hans L, Girbes Armand RJ, de Kam Pieter et al (2000) Renal function, neurohormonal activation, and survival in patients with chronic heart failure. Circulation 102:203–210. https://doi.org/10.1161/01.CIR.102.2.203

    Article  Google Scholar 

  42. Rangaswami J, Bhalla V, Blair JEA et al (2019) Cardiorenal syndrome: classification, pathophysiology, diagnosis, and treatment strategies: a scientific statement from the American Heart Association. Circulation 139:e840–e878. https://doi.org/10.1161/CIR.0000000000000664

    Article  PubMed  Google Scholar 

  43. Boulos J, Darawsha W, Abassi ZA et al (2019) Treatment patterns of patients with acute heart failure who develop acute kidney injury. ESC Heart Fail 6:45–52. https://doi.org/10.1002/ehf2.12364

    Article  PubMed  Google Scholar 

  44. Metra M, Davison B, Bettari L et al (2012) Is worsening renal function an ominous prognostic sign in patients with acute heart failure? The role of congestion and its interaction with renal function. Circ Heart Fail 5:54–62. https://doi.org/10.1161/CIRCHEARTFAILURE.111.963413

    Article  PubMed  Google Scholar 

  45. Damman K, Testani JM (2015) The kidney in heart failure: an update. Eur Heart J 36:1437–1444. https://doi.org/10.1093/eurheartj/ehv010

    Article  PubMed  PubMed Central  Google Scholar 

  46. Stevenson LW, Perloff JK (1989) The limited reliability of physical signs for estimating hemodynamics in chronic heart failure. JAMA 261:884–888

    Article  CAS  Google Scholar 

  47. McMurray JJV, Solomon SD, Inzucchi SE et al (2019) Dapagliflozin in patients with heart failure and reduced ejection fraction. New Engl J Med. https://doi.org/10.1056/NEJMoa1911303 (0:null)

    Article  PubMed  Google Scholar 

  48. Packer M, Anker SD, Butler J et al (2020) Cardiovascular and renal outcomes with empagliflozin in heart failure. New Engl J Med. https://doi.org/10.1056/NEJMoa2022190 (0:null)

    Article  PubMed  Google Scholar 

  49. Mordi NA, Mordi IR, Singh JS et al (2020) Renal and cardiovascular effects of SGLT2 inhibition in combination with loop diuretics in patients with Type 2 diabetes and chronic heart failure: the RECEDE-CHF trial. Circulation. https://doi.org/10.1161/CIRCULATIONAHA.120.048739

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors would like to thank the participants and investigators of the TIME-CHF.

Funding

This substudy has no specific funding. The TIME-CHF study was sponsored by the Helmut Horten Foundation (Lugano, Switzerland), and by smaller unrestricted grants from Roche Diagnostics, AstraZeneca, Novartis, Menarini, Pfizer, Servier, Roche Pharma, and Merck.

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Authors and Affiliations

  1. Department of Cardiology, Maastricht University Medical Centre, Maastricht, The Netherlands

    Justas Simonavičius, Casper G. M. J. Eurlings, Arantxa Barandiarán Aizpurua & Hans-Peter Brunner-La Rocca

  2. Centre of Cardiology and Angiology, Vilnius University Hospital Santaros Klinikos, Santariskiu str. 2, 08406, Vilnius, Lithuania

    Justas Simonavičius

  3. The Faculty of Medicine of Vilnius University, Vilnius, Lithuania

    Justas Simonavičius

  4. Cardiology Department, Kantonsspital St. Gallen, St. Gallen, Switzerland

    Micha T. Maeder

  5. Institute of Clinical Medicine, Medical Faculty of Vilnius University, Vilnius, Lithuania

    Jelena Čelutkienė & Jūratė Barysienė

  6. Division of Cardiology, Heart Centre Lucerne, Luzerner Kantonsspital, Lucerne, Switzerland

    Stefan Toggweiler

  7. Department of Cardiology, University Hospital Basel, Basel, Switzerland

    Beat A. Kaufmann

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  1. Justas Simonavičius
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Correspondence to Justas Simonavičius.

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Simonavičius, J., Maeder, M.T., Eurlings, C.G.M.J. et al. Intensification of pharmacological decongestion but not the actual daily loop diuretic dose predicts worse chronic heart failure outcome: insights from TIME-CHF. Clin Res Cardiol 110, 1221–1233 (2021). https://doi.org/10.1007/s00392-020-01779-7

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