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Digoxin and prognosis of heart failure in older patients with preserved ejection fraction: Importance of heart rate. Results from an observational and multicenter study

Published:October 22, 2018DOI:https://doi.org/10.1016/j.ejim.2018.10.010

      Highlights

      • The role of digoxin in older patients with acute heart failure and preserved ejection fraction remains uncertain.
      • In this type of patients, we found that digoxin was associated with higher risk of 1-year adverse events.
      • However, the prognostic effect of digoxin was dependent of heart rate.
      • Digoxin showed to be related with higher risk at lower heart rates.

      Abstract

      Background

      The value of digoxin in heart failure (HF) remains controversial, particularly in patients with preserved ejection fraction (HFpEF). This study evaluated the 1-year risk of events after digoxin treatment for acute heart failure (AHF) in patients >70 years old with HFpEF.

      Methods

      1833 patients were included in this analysis (mean age, 82 years). The main endpoints were all-cause death and the composite of death and/or HF re-admission within 1 year. Cox regression analysis was used to evaluate the association between digoxin treatment and prognosis.

      Results

      401 patients received digoxin treatment; of these, 86% had atrial fibrillation. The mean baseline heart rate was 86 ± 22 bpm. At the 1-year follow-up, 375 patients (20.5%) died and 684 (37.3%) presented composite endpoints. Patients treated with digoxin showed higher rates of death (3.21 vs. 2.44 per 10 person-years, p = .019) and composite endpoint (6.72 vs. 5.18 per 10 person-years, p = .003). After multivariate adjustment, digoxin treatment remained associated with increased risks of death (HR = 1.46, 95% CI: 1.16–1.85, p = .001) and the composite endpoint (HR = 1.35, 95% CI: 1.13–1.61, p = .001). A distinctive prognostic effect of digoxin was found across the heart rate continuum; the risks for both endpoints were higher at lower heart rates and neutral at higher heart rates (p of the interactions = 0.007 and 0.03, respectively).

      Conclusions

      In older patients with HFpEF discharged after AHF, digoxin treatment was associated with increased mortality and/or re-admission, particularly in patients with lower heart rates.

      Keywords

      Abbreviations:

      Acute heart failure (AHF), Angiotensin converting enzyme (ACE), Angiotensin receptor blockers (ARBs), Beat per minute (bpm), Ejection fraction (EF), Fractional polynomials (FP), The estimated glomerular filtration rate, based on the Modification of Diet in Renal Disease (eGFR-MDRD), Hazard ratios (HR), Heart failure (HF), Heart failure preserved ejection fraction (HFpEF), Heart failure reduced ejection fraction (HFrEF), Hemoglobin (Hb), Sinus rhythm (SR), Standard deviation (SD), Systolic blood pressure (SBP)
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      References

        • Gheorghiade M.
        • Adams Jr., K.F.
        • Colucci W.S.
        Digoxin in the management of cardiovascular disorders.
        Circulation. 2004; 109: 2959-2964
        • Ahmed A.
        • Rich M.W.
        • Fleg J.L.
        • Zile M.R.
        • Young J.B.
        • Kitzman D.W.
        • et al.
        Effects of digoxin on morbidity and mortality in diastolic heart failure: the ancillary digitalis investigation group trial.
        Circulation. 2006; 114: 397-403
        • Gheorghiade M.
        • Patel K.
        • Filippatos G.
        • Anker S.D.
        • van Veldhuisen D.J.
        • Cleland J.G.
        • et al.
        Effect of oral digoxin in high-risk heart failure patients: a pre-specified subgroup analysis of the DIG trial.
        Eur J Heart Fail. 2013; 15: 551-559
        • Uretsky B.
        • Young J.B.
        • Shahidi F.E.
        • Yellen L.G.
        • Harrison M.C.
        • Jolly M.K.
        Randomized study assessing the effect of digoxin withdrawal in patients with mild to moderate chronic congestive heart failure: results of the PROVED trial.
        J Am Coll Cardiol. 1993; 22: 955-962
        • Hallberg P.
        • Lindbäck J.
        • Lindahl B.
        • Stenestrand U.
        • Melhus H.
        • RIKS-HIA group
        Digoxin and mortality in atrial fibrillation: a prospective cohort study.
        Eur J Clin Pharmacol. 2007; 63: 959-971
        • Packer M.
        • Gheorghiade M.
        • Young J.B.
        • Costantini P.J.
        • Adams K.F.
        • Cody R.J.
        • et al.
        RADIANCE Study investigators. Withdrawal of digoxin from patients with chronic heart failure treated with angiotensin-converting-enzyme inhibitors.
        N Engl J Med. 1993; 329: 1-7
        • Ahmed A.
        • Rich M.W.
        • Love T.E.
        • Lloyd-Jones D.M.
        • Aban I.B.
        • Colucci W.S.
        • et al.
        Digoxin and reduction in mortality and hospitalization in heart failure: a comprehensive post hoc analysis of the DIG trial.
        Eur Heart J. 2006; 27: 178-186
        • Ponikowski P.
        • Voors A.A.
        • Anker S.D.
        • Bueno H.
        • Cleland J.G.
        • Coats A.J.
        • et al.
        Authors/Task Force members; Document Reviewers. 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: 891-975
        • Kirchhof P.
        • Benussi S.
        • Kotecha D.
        • Ahlsson A.
        • Atar D.
        • Casadei B.
        • et al.
        Authors/Task Force M, Document R. 2016 ESC guidelines for the management of atrial fibrillation developed in collaboration with EACTS: the task force for the management of atrial fibrillation of the European Society of Cardiology (ESC) developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC Endorsed by the European Stroke.
        Eur J Cardiothorac Surg. 2016; : 50
        • The Digitalis Investigation Group
        The effect of digoxin on mortality and morbidity in patients with heart failure.
        N Engl J Med. 1997; 336: 525-533
        • Whitbeck M.G.
        • Charnigo R.J.
        • Khairy P.
        • Ziada K.
        • Bailey A.L.
        • Zegarra M.M.
        • et al.
        Increased mortality among patients taking digoxin--analysis from the AFFIRM study.
        Eur Heart J. 2013; 34: 1481-1488
        • Turakhia M.P.
        • Santangeli P.
        • Winkelmayer W.C.
        • Xu X.
        • Ullal A.J.
        • Than C.T.
        • et al.
        Increased mortality associated with digoxin in contemporary patients with atrial fib- rillation: findings from the TREAT-AF study.
        J Am Coll Cardiol. 2014; 64: 660-668
        • Shah M.
        • Avgil Tsadok M.
        • Jackevicius C.A.
        • Essebag V.
        • Behlouli H.
        • Pilote L.
        Relation of digoxin use in atrial fibrillation and the risk of all-cause mortality in patients ≥ 65 years of age with versus without heart failure.
        Am J Cardiol. 2014; 114: 401-406
        • Gjesdal K.
        • Feyzi J.
        • Olsson S.B.
        Digitalis: a dangerous drug in atrial fibrillation? An analysis of the SPORTIF III and V data.
        Heart. 2008; 94: 191-196
        • Phan T.T.
        • Shivu G.N.
        • Abozguia K.
        • Davies C.
        • Nassimizadeh M.
        • Jimenez D.
        • et al.
        Impaired heart rate recovery and chronotropic incompetence in patients with heart failure with preserved ejection fraction.
        Circ Heart Fail. 2010; 3: 29-34
        • Borlaug B.A.
        • Melenovsky V.
        • Russell S.D.
        • Kessler K.
        • Pacak K.
        • Becker L.C.
        • et al.
        Impaired chronotropic and vasodilator reserves limit exercise capacity in patients with heart failure and a preserved ejection fraction.
        Circulation. 2006; 114: 2138-2147
        • Montero-Pérez-Barquero M.
        • Manzano L.
        • Formiga F.
        • Roughton M.
        • Coats A.
        • Rodríguez-Artalejo F.
        • et al.
        RICA investigators. Utility of the SENIORS elderly heart failure risk model applied to the RICA registry of acute heart failure.
        Int J Cardiol. 2015; 182: 449-453
        • Royston P.
        • Sauerbrei W.
        Multivariable Model-building: A Pragmatic Approach to Regression Analysis Based on Fractional Polynomials for Modelling Continuous Variables.
        Wiley Series in Probability and Statistics, Chichester, UK2008
        • Hashim T.
        • Elbaz S.
        • Patel K.
        • Morgan C.J.
        • Fonarow G.C.
        • Fleg J.L.
        • et al.
        Digoxin and 30-day all-cause hospital admission in older patients with chronic diastolic heart failure.
        Am J Med. 2014; 127: 132-139
        • Sartipy U.
        • Dahlström U.
        • Fu M.
        • Lund L.H.
        Atrial fibrillation in heart failure with preserved, mid-range, and reduced ejection fraction.
        JACC Heart Fail. 2017; 5: 565-574
        • Bertomeu-González V.
        • Núñez J.
        • Núñez E.
        • Cordero A.
        • Fácila L.
        • Ruiz-Granell R.
        • et al.
        Heart rate in acute heart failure, lower is not always better.
        Int J Cardiol. 2010; 145: 592-593
        • Simpson J.
        • Castagno D.
        • Doughty R.N.
        • Poppe K.K.
        • Earle N.
        • Squire I.
        • et al.
        Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC). Is heart rate a risk marker in patients with chronic heart failure and concomitant atrial fibrillation? Results from the MAGGIC meta-analysis.
        Eur J Heart Fail. 2015; 17: 1182-1191
        • Böhm M.
        • Perez A.C.
        • Jhund P.S.
        • Reil J.C.
        • Komajda M.
        • Zile M.R.
        • et al.
        Relationship between heart rate and mortality and morbidity in the irbesartan patients with heart failure and preserved systolic function trial (I-Preserve).
        Eur J Heart Fail. 2014; 16: 778-787
        • Bristow M.R.
        • Hershberger R.E.
        • Port J.D.
        Beta-adrenergic pathways in non-failing and failing human ventricular myocardium.
        Circulation. 1990; 82: 12-25
        • Colucci W.S.
        • Ribeiro J.P.
        • Rocco M.B.
        • Quigg R.J.
        • Creager M.A.
        • Marsh J.D.
        • et al.
        Impaired chronotropic response to exercise in patients with congestive heart failure.
        Circulation. 1989; 80: 314-323
        • Sanders P.
        • Kistler P.M.
        • Morton J.B.
        • Spence S.J.
        • Kalman J.M.
        Remodeling of sinus node function in patients with congestive heart failure.
        Circulation. 2004; 110: 897-903
        • Komajda M.
        • Isnard R.
        • Cohen-Solal A.
        • Metra M.
        • Pieske B.
        • Ponikowski P.
        • et al.
        prEserveD left ventricular ejectIon fraction chronic heart failure with ivabradine studY (EDIFY) investigators. Effect of ivabradine in patients with heart failure with preserved ejection fraction: the EDIFY randomized placebo-controlled trial.
        Eur J Heart Fail. 2017; 19: 1495-1503
        • Bristow M.R.
        • Altman N.L.
        Heart Rate in Preserved Ejection Fraction Heart failure.
        JACC Heart Fail. 2017; 5: 792-794
        • Messerli F.H.
        • Rimoldi S.F.
        • Bangalore S.
        • Bavishi C.
        • Laurent S.
        When an increase in Central Systolic pressure Overrides the Benefits of Heart Rate Lowering.
        J Am Coll Cardiol. 2016; 68: 754-762
        • Lupón J.
        • Domingo M.
        • de Antonio M.
        • Zamora E.
        • Santesmases J.
        • Díez-Quevedo C.
        • et al.
        Aging and Heart Rate in Heart failure: Clinical Implications for long-term Mortality.
        Mayo Clin Proc. 2015; 90: 765-772