Prognostic Significance of Hyponatremia Among Ambulatory Patients With Heart Failure and Preserved and Reduced Ejection Fractions

      Hyponatremia in heart failure (HF) is an established predictor of adverse outcomes in hospitalized patients with reduced ejection fraction (EF). However, there is a paucity of data in ambulatory patients with HF with preserved ejection fraction (HFpEF). We examined the prevalence, risk factors, and long-term outcomes of hyponatremia (serum sodium ≤135 mEq/L) in ambulatory HFpEF and HF with reduced EF (HFrEF) in a national cohort of 8,862 veterans treated in Veterans Affairs clinics. Multivariable logistic regression models were used to identify factors associated with hyponatremia, and multivariable Cox proportional hazard models were used for analysis of outcomes. The cohort consisted of 6,185 patients with HFrEF and 2,704 patients with HFpEF with a 2-year follow-up. Hyponatremia was present in 13.8% and 12.9% patients in HFrEF and HFpEF, respectively. Hyponatremia was independently associated with younger age, diabetes, lower systolic blood pressure, anemia, body mass index <30 kg/m2, and spironolactone use, whereas African-American race and statins were inversely associated. In multivariate analysis, hyponatremia remained a significant predictor of all-cause mortality in both HFrEF (hazards ratio [HR] 1.26, 95% confidence interval [CI] 1.11 to 1.44, p <0.001) and HFpEF (HR 1.40, 95% CI 1.12 to 1.75, p = 0.004) and a significant predictor of all-cause hospitalization in patients with HFrEF (HR 1.18, 95% CI 1.07 to 1.31, p = 0.001) but not in HFpEF (HR 1.08, 95% CI 0.92 to 1.27, p = 0.33). In conclusion, hyponatremia is prevalent at a similar frequency of over 10% in ambulatory patients with HFpEF and HFrEF. Hyponatremia is an independent prognostic marker of mortality across the spectrum of patients with HFpEF and HFrEF. In contrast, it is an independent predictor for hospitalization in patients with HFrEF but not in patients with HFpEF.
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        • Adrogue H.J.
        • Madias N.E.
        N Engl J Med. 2000; 342: 1581-1589
        • De Luca L.
        • Klein L.
        • Udelson J.E.
        • Orlandi C.
        • Sardella G.
        • Fedele F.
        • Gheorghiade M.
        Hyponatremia in patients with heart failure.
        Am J Cardiol. 2005; 96: 19L-23L
        • Bettari L.
        • Fiuzat M.
        • Felker G.M.
        • O'Connor C.M.
        Significance of hyponatremia in heart failure.
        Heart Fail Rev. 2012; 17: 17-26
        • Rusinaru D.
        • Tribouilloy C.
        • Berry C.
        • Richards A.M.
        • Whalley G.A.
        • Earle N.
        • Poppe K.K.
        • Guazzi M.
        • Macin S.M.
        • Komajda M.
        • Doughty R.N.
        • Investigators M
        Relationship of serum sodium concentration to mortality in a wide spectrum of heart failure patients with preserved and with reduced ejection fraction: an individual patient data meta-analysis (dagger): meta-analysis global group in chronic heart failure (MAGGIC).
        Eur J Heart Fail. 2012; 14: 1139-1146
        • Deswal A.
        • Petersen N.J.
        • Urbauer D.L.
        • Wright S.M.
        • Beyth R.
        Racial variations in quality of care and outcomes in an ambulatory heart failure cohort.
        Am Heart J. 2006; 152: 348-354
        • Ather S.
        • Chan W.
        • Bozkurt B.
        • Aguilar D.
        • Ramasubbu K.
        • Zachariah A.A.
        • Wehrens X.H.
        • Deswal A.
        Impact of noncardiac comorbidities on morbidity and mortality in a predominantly male population with heart failure and preserved versus reduced ejection fraction.
        J Am Coll Cardiol. 2012; 59: 998-1005
        • Levey A.S.
        • Coresh J.
        • Greene T.
        • Stevens L.A.
        • Zhang Y.L.
        • Hendriksen S.
        • Kusek J.W.
        • Van Lente F.
        • Chronic Kidney Disease Epidemiology C
        Using standardized serum creatinine values in the modification of diet in renal disease study equation for estimating glomerular filtration rate.
        Ann Intern Med. 2006; 145: 247-254
        • Bettari L.
        • Fiuzat M.
        • Shaw L.K.
        • Wojdyla D.M.
        • Metra M.
        • Felker G.M.
        • O'Connor C.M.
        Hyponatremia and long-term outcomes in chronic heart failure – an observational study from the Duke Databank for cardiovascular diseases.
        J Card Fail. 2012; 18: 74-81
        • DeWolfe A.
        • Lopez B.
        • Arcement L.M.
        • Hebert K.
        Low serum sodium as a poor prognostic indicator for mortality in congestive heart failure patients.
        Clin Cardiol. 2010; 33: E13-E17
        • Balling L.
        • Schou M.
        • Videbaek L.
        • Hildebrandt P.
        • Wiggers H.
        • Gustafsson F.
        • Danish Heart Failure Clinics N
        Prevalence and prognostic significance of hyponatraemia in outpatients with chronic heart failure.
        Eur J Heart Fail. 2011; 13: 968-973
        • Rusinaru D.
        • Buiciuc O.
        • Leborgne L.
        • Slama M.
        • Massy Z.
        • Tribouilloy C.
        Relation of serum sodium level to long-term outcome after a first hospitalization for heart failure with preserved ejection fraction.
        Am J Cardiol. 2009; 103: 405-410
        • Klein L.
        • O'Connor C.M.
        • Leimberger J.D.
        • Gattis-Stough W.
        • Pina I.L.
        • Felker G.M.
        • Adams Jr., K.F.
        • Califf R.M.
        • Gheorghiade M.
        • Investigators O-C
        Lower serum sodium is associated with increased short-term mortality in hospitalized patients with worsening heart failure: results from the Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure (OPTIME-CHF) study.
        Circulation. 2005; 111: 2454-2460
        • Gheorghiade M.
        • Gattis W.A.
        • O'Connor C.M.
        • Adams Jr., K.F.
        • Elkayam U.
        • Barbagelata A.
        • Ghali J.K.
        • Benza R.L.
        • McGrew F.A.
        • Klapholz M.
        • Ouyang J.
        • Orlandi C.
        • Acute, Chronic Therapeutic Impact of a Vasopressin Antagonist in Congestive Heart Failure I
        Effects of tolvaptan, a vasopressin antagonist, in patients hospitalized with worsening heart failure: a randomized controlled trial.
        JAMA. 2004; 291: 1963-1971
        • Deubner N.
        • Berliner D.
        • Frey A.
        • Guder G.
        • Brenner S.
        • Fenske W.
        • Allolio B.
        • Ertl G.
        • Angermann C.E.
        • Stork S.
        Dysnatraemia in heart failure.
        Eur J Heart Fail. 2012; 14: 1147-1154
        • Konstam M.A.
        • Gheorghiade M.
        • Burnett Jr., J.C.
        • Grinfeld L.
        • Maggioni A.P.
        • Swedberg K.
        • Udelson J.E.
        • Zannad F.
        • Cook T.
        • Ouyang J.
        • Zimmer C.
        • Orlandi C.
        • Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan I
        Effects of oral tolvaptan in patients hospitalized for worsening heart failure: the EVEREST outcome trial.
        JAMA. 2007; 297: 1319-1331