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Hyponatremia and Long-term Mortality
in Survivors of Acute ST-Elevation
Myocardial Infarction

Alexander Goldberg, MD; Haim Hammerman, MD; Sirouch Petcherski, MD; Mithal Nassar, MD;Alexander Zdorovyak, MD; Sergey Yalonetsky, MD; Michael Kapeliovich, MD, PhD;Yoram Agmon, MD; Rafael Beyar, MD, DSc; Walter Markiewicz, MD; Doron Aronson, MD Background: Hyponatremia, a marker of neurohor-
tricular ejection fraction, hyponatremia during admis- monal activation, is a common electrolyte disorder among sion remained an independent predictor of postdis- patients with acute ST-elevation myocardial infarction.
charge death (hazard ratio [HR], 2.0; 95% confidence The long-term prognostic value of hyponatremia dur- interval [CI], 1.3-3.2; P = .002). Hyponatremia during ing the acute phase of infarction is not known.
admission was also independently associated with post-discharge readmission for heart failure (HR, 1.6; 95% CI, Methods: We studied 978 patients with acute ST-
1.1-2.6; P=.04). When serum sodium level was used as a elevation myocardial infarction and without a history of continuous variable, the adjusted HR for death or heart heart failure who survived the index event. During the failure was 1.12 for every 1-mEq/L decrease (95% CI, hospital stay, sodium levels were obtained on admis- sion and at 24, 48, and 72 hours. The median durationof follow-up after hospital discharge was 31 months Conclusion: Hyponatremia in the early phase of ST-
elevation myocardial infarction is a predictor of long-term mortality and admission for heart failure after Results: Hyponatremia, defined as a mean serum
hospital discharge, independent of other clinical predic- sodium level less than 136 mEq/L, was present during tors of adverse outcome and left ventricular ejection admission in 108 patients (11.0%). In a multivariable Cox proportional hazards model adjusting for otherpotential clinical predictors of mortality and for left ven- HYPONATREMIAISTHE Neurohormonalactivationinthe
hyponatremia is a potentially serious and life-threatening disorder, which can lead therefore associated with poor short-term tor of 30-day mortality.6 In acute MI, the that probably incorporates different prog- Author Affiliations:
nostic entities, including the severity of left Rambam Medical Center andRappaport Medical School, (REPRINTED) ARCH INTERN MED/ VOL 166, APR 10, 2006 2006 American Medical Association. All rights reserved.
generate the final model. The following baseline clinicalcharacteristics were considered in the multivariate proce-dure: history of diabetes, history of hypertension, smoking PATIENTS
status, Killip class greater than I on admission, hypotension(systolic blood pressure Ͻ100 mm Hg) and tachycardia We used a prospective database consisting of all admissions of (heart rate Ͼ100 beats/min) on admission, anterior location patients with acute ST-elevation MI to Rambam Medical Cen- of infarction, reperfusion therapy with thrombolytics or pri- ter, Haifa, Israel, during a 52-month period ( January 1, 2000, to April 30, 2004). Myocardial infarction was diagnosed ac- Cox proportional hazards modeling was also used to deter- cording to the criteria of the Joint European Society of Cardi- mine the relationship between hyponatremia and admission for ology and American College of Cardiology.11 For this analysis, the treatment of HF. Known predictors of HF development in patients had to be without a history of HF, have an echocar- survivors of MI14 were considered in the model (ie, age, base- diographic evaluation of LVEF, and be alive at the time of dis- line heart rate, Killip class at admission, history of hyperten- charge. The study was approved by the investigational review committee on human research at our institution.
In supporting analyses, the multivariate models were repeated after correcting sodium levels for the presence of DEFINITION OF HYPONATREMIA
hyperglycemia, based on the assumption that plasma sodiumconcentration should fall by 1.6 mEq/L for every 100-mg/dL Venous blood samples were obtained on admission and at 24, (5.6-mmol/L) rise in plasma concentration of glucose.6,15 We 48, and 72 hours thereafter.6 Based on these measurements, hy- also performed supplementary analyses for the combined ponatremia was defined as a mean serum sodium level less than end point of death and HF after dividing the study partici- 136 mEq/L during the first 72 hours of the hospital stay.
pants into 6 groups on the basis of the presence or absenceof hyponatremia and 3 categories incorporating clinical evi- ASSESSMENT OF RENAL FUNCTION
dence of HF during admission or reduced left ventricularsystolic function, including (1) Killip class I on admissionand preserved (Ն45%) predischarge LVEF; (2) Killip classes Glomerular filtration rate (GFR) (measured as milliliters per II to IV on admission or reduced (Ͻ45%) predischarge minute per 1.73 m2) was calculated using the following
LVEF; and (3) Killip classes II to IV on admission and abbreviated Modification of Diet in Renal Disease Study Differences were considered statistically significant at the GFR = 186 ϫ(Serum Creatinine Level)−1.154 2-sided PϽ.05 level. All statistical analyses were performed us- ϫ(Age)−0.203ϫ0.742 (If Female)ϫ1.210 (If Black).
ing SPSS statistical software, version 12.0 (SPSS Inc, Chicago, Ill).
This equation accurately predicts GFR from the serum cre- atinine concentration, in contrast to the Cockcroft-Gault equa- tion, which estimates creatinine clearance and systematicallyoverestimates GFR.12,13 SUBJECTS
STUDY END POINTS
During the study period, 1109 patients without a history The primary end points of the study were (1) all-cause mor- of HF were admitted with ST-elevation MI and survived tality and (2) readmission for HF, defined as readmission to the index event. Of those, LVEF was missing in 131 (11.8%).
the hospital for management of HF (defined by the presence However, LVEF data were missing at random, because the of new symptoms of dyspnea or edema with Ն1 concurrent sign, survival of the 131 nonstudy patients with missing LVEF including ventricular gallop rhythm, bilateral posttussive rales data was similar to that of the 978 study patients with com- in at least the lower third of the lung fields, elevated venous plete data (log-rank P=.59). The incidence of hyponatre- pressure, or pulmonary venous congestion on radiograph with mia was similar in patients with missing LVEF data and interstitial or alveolar edema). The diagnosis of HF was con- those with complete data (8.4% vs 11.0%; P=.36).
firmed by reviewing hospital records and discharge summa- Hyponatremia during hospitalization (defined as a ries. The secondary end point was the combined end point ofdeath and HF. After hospital discharge, clinical endpoint in- plasma mean sodium level Ͻ136 mEq/L) was present in formation was acquired by reviewing the national death reg- 108 patients (11.0%). Demographic and clinical charac- istry, contacting each patient individually, and independently teristics of the study patients according to the presence reviewing the hospital course for major clinical events if the and severity of hyponatremia are shown in Table 1. Pa-
tients with hyponatremia were older, had higher creati-nine levels, and were more likely to have diabetes and a STATISTICAL ANALYSIS
history of smoking. They presented more often with ananterior infarction, a higher heart rate, and a higher Killip Continuous data are expressed as mean±SD. The baseline char- class. Use of diuretics was greater in patients with hy- acteristics of the groups were compared by use of the un- ponatremia. However, most patients with hyponatre- paired t test for continuous variables and the ␹2 statistic for cat- mia (61%) were not treated with diuretics.
Event-free survival was estimated by the Kaplan-Meier RELATION OF HYPONATREMIA TO LONG-TERM
method, and curves were compared with the log-rank test.
Multivariate Cox proportional hazards analyses were per- MORTALITY AFTER HOSPITAL DISCHARGE
formed to determine the relation between hyponatremia andmortality. After forcing age, sex, and baseline GFR into each The median duration of follow-up after hospital dis- model, backward stepwise variable selection was used to charge was 31 months (range, 9-61 months). During (REPRINTED) ARCH INTERN MED/ VOL 166, APR 10, 2006 2006 American Medical Association. All rights reserved.
Table 1. Baseline Clinical Characteristics
According to Sodium Level*
Sodium Level, mEq/L
P
Characteristic
Figure 1. Kaplan-Meier plot showing the crude cumulative incidence of death
dence of HF during admission or reduced left ventricu- lar systolic function. As shown in Figure 2, after ad-
justment for other clinical risk factors, the presence of hyponatremia during admission was associated with a higher risk of death, even among patients with no evi- dence of HF during admission and with preserved pre- discharge LVEF, as well as in patients with clinical evi-dence of HF during admission or with left ventricular Abbreviations: ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; BP, blood pressure.
SI conversion factor: To convert creatinine to micromoles per liter, POSTDISCHARGE HF
*Unless otherwise indicated, data are expressed as number (percentage) During follow-up, 114 (11.7%) of 978 study patients withcomplete data were admitted for the treatment of HF. Me- the follow-up period, 104 patients (10.6%) died, with dian sodium levels were significantly lower among pa- 26 deaths (24.1%) and 78 deaths (9.0%) occurring in tients who developed HF during follow-up than among patients with and without hyponatremia, respectively.
those patients who did not (137 mEq/L [interquartile Median sodium levels were significantly lower among range, 136-139 mEq/L] vs 139 mEq/L [interquartile range, patients who died during follow-up than among 137-140 mEq/L]; Mann-Whitney PϽ.001). Recurrent MI patients who survived (137 mEq/L [interquartile before the episode of HF occurred equally among pa- range, 135-139 mEq/L] vs 139 mEq/L [interquartile tients with and without hyponatremia (9.8% vs 13.0%; range, 137-140 mEq/L]; Mann-Whitney PϽ.001).
P = .66). However, Kaplan-Meier analysis showed an in- Kaplan-Meier analysis showed an increased probabil- creased probability of HF during follow-up among pa- ity of death during follow-up in patients with hypona- tients with hyponatremia during admission (Figure 3).
tremia during admission (Figure 1). In a multivari-
After adjustments for known predictors of postinfarc- able Cox proportional hazards model adjusting for tion HF, hyponatremia during admission remained an in- other potential clinical predictors of mortality and for dependent risk factor for admission for HF during fol- LVEF, hyponatremia during admission remained an low-up (Table 3).
independent predictor of postdischarge death Hyponatremia during readmission for HF was more (Table 2).
common among patients who were hyponatremic dur- After correcting sodium levels for hyperglycemia, 28 ing the index admission (47.8% vs 23.1%; P = .02). In ad- patients with sodium levels initially classified as hypo- dition, compared with patients without hyponatremia dur- natremic were reclassified as nonhyponatremic. The ad- ing the index hospitalization, patients who had justed hazard ratio for long-term mortality in patients with hyponatremia during the acute MI had lower median so- hyponatremia after this correction was 2.3 (95% confi- dium levels when they were readmitted for HF (136 mEq/L dence interval, 1.4-3.8; PϽ.001). Additional adjust- [interquartile range, 134-138 mEq/L] vs 138 mEq/L [in- ments for concomitant cardiovascular medications at dis- terquartile range, 136-141 mEq/L]; Mann-Whitney charge had no discernible effect on these estimates. We found no significant interaction between hyponatremiaand LVEF (P = .18) or renal function (P = .95).
COMBINED END POINT
We further estimated the hazard ratios for long-term mortality after dividing the study participants into 6 Mortality and HF increased linearly throughout the groups on the basis of sodium levels and clinical evi- entire spectrum of serum sodium levels. Death or HF (REPRINTED) ARCH INTERN MED/ VOL 166, APR 10, 2006 2006 American Medical Association. All rights reserved.
Table 2. Unadjusted and Adjusted Cox Proportional Hazards Model for Postdischarge All-Cause Mortality*
Characteristics
Unadjusted OR (95% CI)
P Value
Adjusted OR (95% CI)
P Value
Abbreviations: CI, confidence interval; GFR, glomerular filtration rate; LVEF, left ventricular ejection fraction; OR, odds ratio.
*Adjusted for age, sex, baseline GFR, history of hypertension and diabetes, smoking status, presence of anterior infarction, Killip class at admission, heart rate and blood pressure on admission, use of reperfusion therapy, and LVEF.
Figure 2. Adjusted hazard ratios for long-term mortality after hospital
discharge according to sodium level, clinical evidence of heart failure on
admission, and left ventricular systolic function. The percentage of events in
Figure 3. Kaplan-Meier plot showing the crude cumulative incidence of
each group is given above each bar. LVEF indicates left ventricular ejection admission for the treatment of heart failure (HF) according to sodium level.
tivation. Readmission for late HF in patients after MI is occurred in 36.2% of patients in the lowest sodium particularly ominous because these patients have a sev- decile (Ͻ135 mEq/L) and 9.7% of patients in the high- eralfold increase in the risk of death when compared with est sodium decile (Ն143 mEq/L) (Figure 4). When
other MI survivors.14,16 In a recent study, MI survivors serum sodium level was used as a continuous variable who were readmitted for HF had a 10-fold risk of death in a Cox proportional hazards model, the adjusted compared with patients who did not develop HF.14 hazards ratio for every 1-mEq/L decrease in sodium Several clinical predictors for the development of HF level was 1.12 (95% confidence interval, 1.07-1.18; after MI have been identified, with advanced age, diabe- tes, and reduced LVEF being the most consistent.14,16 Oneof the most important mechanisms that leads to late de- velopment of HF in MI survivors is progressive remod-eling, which is closely linked to the degree of neurohor- The present study demonstrates a strong association be- monal activation.10,17 Our data indicate that hyponatremia tween hyponatremia in the early phase of MI and long- early in the course of MI, a marker of excessive neuro- term mortality in survivors of acute MI. Hyponatremia hormonal activation,18-21 may identify patients at high risk remained a strong and independent predictor of mortal- for HF even after hospital discharge.
ity after adjustment for established clinical predictors of In cardiovascular diseases, hyponatremia is fre- adverse outcome, including LVEF. Furthermore, the re- quently encountered in patients with advanced HF. In lationship between hyponatremia and adverse outcome this setting, hyponatremia is an established indicator of remained robust when assessed in low-risk patients (pre- HF progression and death.5,18,22-24 Hyponatremic pa- served LVEF and Killip class I during admission), as well tients with HF have greater activation of the renin- as in high-risk patients (reduced LVEF and clinical evi- angiotensin-aldosterone system,18,21 higher norepineph- rine and epinephrine levels,20 and more severe impairment Our results also show that hyponatremia in the acute of renal and hepatic blood flow.19 The relationship be- phase of MI predicts future admissions for the treatment tween hyponatremia and poor outcome in HF is there- of HF, supporting the underlying pathophysiological re- fore explained, in part, by the marked neurohormonal lationship between hyponatremia and neurohormonal ac- activation that characterizes hyponatremia.
(REPRINTED) ARCH INTERN MED/ VOL 166, APR 10, 2006 2006 American Medical Association. All rights reserved.
Table 3. Unadjusted and Adjusted Cox Proportional Hazards Model for Postdischarge Admission for the Treatment of Heart Failure*
Characteristics
Unadjusted OR (95% CI)
P Value
Adjusted OR (95% CI)
P Value
Abbreviations: CI, confidence interval; LVEF, left ventricular ejection fraction; OR, odds ratio.
*The final model adjusted for age, sex, baseline glomerular filtration rate, history of hypertension and diabetes, presence of anterior infarction, Killip class at admission, heart rate on admission, and LVEF.
Although hyponatremia has been traditionally inves- tigated in the context of chronic HF, it may be as impor- tant during acute cardiac injury. In patients with acute MI, hyponatremia develops primarily owing to exces- sive or inappropriate vasopressin secretion that occurs in response to nonosmotic stimuli.9 These include theacute development of left ventricular dysfunction, pain, and nausea and administration of analgesics and diuret- ics.3,4 Elevated vasopressin concentrations lead to the in- sertion of aquaporin-2 water channels into cell mem- branes of the collecting duct of the kidney and result in Acute MI also results in marked activation of the renin- angiotensin system and increased catecholamine pro- duction.8,25 These factors promote renal vasoconstric- tion, leading to diminished GFR and subsequent deliveryof tubular fluid to the diluting segment of the nephron, Figure 4. Long-term mortality or admission for the treatment of heart failure
further contributing to the reduction of renal water ex- (HF) among strata of patients, according to deciles of sodium levels.
cretion.4 Thus, neurohormonal activation in the acutephase of MI bears a striking resemblance to that seen in similar approach for our main analyses, with a chronic HF. Consequently, patients with acute MI are pre- recently recommended cutoff for hyponatremia.3 How- disposed to hyponatremia, especially if marked neuro- ever, when sodium level was used as a continuous variable, we found no clear cutoff value for the asso- Despite the potential pathophysiological link be- ciation between sodium level and adverse outcome.
tween hyponatremia and neurohormonal activation,19,26 Indeed, the inverse association between sodium level our previous study6 addressed the short-term prognos- and mortality or admission for HF was present across tic implication of hyponatremia. Therefore, most of the prognostic information was contributed by early events Our study has several important limitations. The study occurring in the intensive care setting. Such events are was prospective in patient enrollment but observational often associated with prolonged hemodynamic deterio- in nature. Information on neurohormonal activation was ration and shock and with complications such as acute not available in the study patients. Thus, we have no sup- renal failure and infection, all potentially contributing porting evidence that hyponatremia in the setting of acute MI reflects profound neurohormonal activation. In ad- The results of the present analysis demonstrate that dition, we collected no information on sodium levels af- the prognostic implications of hyponatremia extend be- ter hospital discharge. Thus, the prognostic implica- yond the early phase of MI and are not related to the as- tions of transient vs persistent hyponatremia could not sociated in-hospital complications. Hyponatremia in the early phase of MI provided prognostic information with We conclude that hyponatremia in the early phase of regard to long-term mortality and subsequent develop- ST-elevation MI is a predictor of long-term mortality and ment of HF in patients who survived the acute event. The admission for HF after hospital discharge, independent effect of hyponatremia was also independent of renal func- of other clinical predictors of adverse outcome and LVEF.
tion and left ventricular systolic function.
Serum sodium level appears to be a simple marker of ex- Previous studies5,18,22-24,27 of patients with chronic HF have evaluated the relationship between sodiumlevel and prognosis using dichotomous groupings (eg, Accepted for Publication: September 22, 2005.
those above and below an arbitrary cut point for hypo- Correspondence: Doron Aronson, MD, Department of
natremia). In those studies, cutoff values for the defi- Cardiology, Rambam Medical Center, Bat Galim, POB nition of hyponatremia varied greatly, from less than 9602, Haifa 31096, Israel (daronson@netvision.net.il).
125 to 140 mEq/L. In the present study we used a Author Contributions: Dr Aronson had full access to all
(REPRINTED) ARCH INTERN MED/ VOL 166, APR 10, 2006 2006 American Medical Association. All rights reserved.
the data in the study and takes responsibility for the in- filtration rate from serum creatinine: a new prediction equation. Ann Intern Med.
tegrity of the data and the accuracy of the data analysis.
14. Lewis EF, Moye LA, Rouleau JL, et al. Predictors of late development of heart Financial Disclosure: None.
failure in stable survivors of myocardial infarction: the CARE Study. J Am CollCardiol. 2003;42:1446-1453.
15. Katz MA. Hyperglycemia-induced hyponatremia: calculation of expected serum sodium depression. N Engl J Med. 1973;289:843-844.
16. Pfeffer M. Myocardial infarction and heart failure: a dangerous intersection. Am 1. Anderson RJ, Chung HM, Kluge R, Schrier RW. Hyponatremia: a prospective analy- sis of its epidemiology and the pathogenetic role of vasopressin. Ann Intern Med.
17. Pfeffer MA, Braunwald E. Ventricular remodeling after myocardial infarction: 2. Chung HM, Kluge R, Schrier RW, Anderson RJ. Postoperative hyponatremia: a experimental observations and clinical implications. Circulation. 1990;81: prospective study. Arch Intern Med. 1986;146:333-336.
3. Adrogue HJ, Madias NE. Hyponatremia. N Engl J Med. 2000;342:1581-1589.
18. Lee WH, Packer M. Prognostic importance of serum sodium concentration and 4. Kumar S, Berl T. Sodium. Lancet. 1998;352:220-228.
its modification by converting-enzyme inhibition in patients with severe chronic 5. Klein L, O’Connor CM, Leimberger JD, et al. Lower serum sodium is associated heart failure. Circulation. 1986;73:257-267.
with increased short-term mortality in hospitalized patients with worsening heart 19. Lilly LS, Dzau VJ, Williams GH, Rydstedt L, Hollenberg NK. Hyponatremia in con- failure: results from the Outcomes of a Prospective Trial of Intravenous Milri- gestive heart failure: implications for neurohumoral activation and responses to none for Exacerbations of Chronic Heart Failure (OPTIME-CHF) Study. Circulation.
orthostasis. J Clin Endocrinol Metab. 1984;59:924-930.
20. Mettauer B, Rouleau JL, Bichet D, et al. Sodium and water excretion abnormali- 6. Goldberg A, Hammerman H, Petcherski S, et al. Prognostic importance of hy- ties in congestive heart failure: determinant factors and clinical implications. Ann ponatremia in acute ST-elevation myocardial infarction. Am J Med. 2004;117: Intern Med. 1986;105:161-167.
21. Schaer GL, Covit AB, Laragh JH, Cody RJ. Association of hyponatremia with in- 7. Sigurdsson A, Held P, Swedberg K. Short- and long-term neurohormonal acti- creased renin activity in chronic congestive heart failure: impact of diuretic therapy.
vation following acute myocardial infarction. Am Heart J. 1993;126: Am J Cardiol. 1983;51:1635-1638.
22. Kearney MT, Fox KA, Lee AJ, et al. Predicting death due to progressive heart fail- 8. Foy SG, Crozier IG, Richards AM, et al. Neurohormonal changes after acute myo- ure in patients with mild-to-moderate chronic heart failure. J Am Coll Cardiol.
cardial infarction: relationships with haemodynamic indices and effects of ACE inhibition. Eur Heart J. 1995;16:770-778.
23. Chin MH, Goldman L. Correlates of major complications or death in patients ad- 9. Schaller MD, Nussberger J, Feihl F, et al. Clinical and hemodynamic correlates mitted to the hospital with congestive heart failure. Arch Intern Med. 1996; of elevated plasma arginine vasopressin after acute myocardial infarction. Am J 24. Saxon LA, Stevenson WG, Middlekauff HR, et al. Predicting death from progres- 10. Cohn JN, Ferrari R, Sharpe N. Cardiac remodeling—concepts and clinical impli- sive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy.
cations: a consensus paper from an international forum on cardiac remodeling.
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11. Alpert JS, Thygesen K, Antman E, Bassand JP. Myocardial infarction redefined: 25. Rouleau JL, Packer M, Moye L, et al. Prognostic value of neurohumoral activa- a consensus document of the Joint European Society of Cardiology/American tion in patients with an acute myocardial infarction: effect of captopril. J Am Coll College of Cardiology Committee for the redefinition of myocardial infarction.
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26. Dzau VJ, Hollenberg NK. Renal response to captopril in severe heart failure: role 12. Levey A, Greene T, Kusek J, et al. A simplified equation to predict glomerular of furosemide in natriuresis and reversal of hyponatremia. Ann Intern Med. 1984; filtration rate from serum creatinine [abstract]. J Am Soc Nephrol. 2000; 27. Elisaf M, Theodorou J, Pappas C, Siamopoulos K. Successful treatment of hy- 13. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D; Modification of Diet ponatremia with angiotensin-converting enzyme inhibitors in patients with con- in Renal Disease Study Group. A more accurate method to estimate glomerular gestive heart failure. Cardiology. 1995;86:477-480.
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