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Incidence of hospital-acquired hyponatremia by the dose and type of diuretics among patients with acute heart failure and its association with long-term outcomes
Corresponding author at: Division of Cardiology, Department of Medicine, Keio University School of Medicine, 35 Shinanomachi Shinjuku-ku, Tokyo 160-8582, Japan.
Thiazide diuretics were independently associated with hospital-acquired hyponatremia.
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Mortality rate was higher in the thiazide users even after statistical matching.
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Thiazide diuretic use in acute decompensation of heart failure may be a modifiable risk factor for adverse outcomes.
Abstract
Background
Diuretics are the cornerstone therapy for acute heart failure (AHF) but can lead to various electrolyte disturbances and inversely affect the patients’ outcome. We aimed to evaluate whether (1) the dose of loop diuretics could predict hospital-acquired hyponatremia (HAH) during AHF treatment, (2) addition of thiazide diuretics could affect development of HAH, and (3) assess their impact on long-term outcomes.
Methods
We analyzed the subjects enrolled in the multicenter AHF registry (WET-HF). Risk of HAH, defined as hyponatremia at discharge with normonatremia upon admission, was evaluated based on oral non-potassium-sparing diuretics via multivariate logistic regression analysis. Additionally, we performed one-to-one matched analysis based on propensity scores for thiazide diuretics use and compared long-term mortality.
Results
Of total 1163 patients (mean age 72.6 ± 13.6 years, male 62.6%), 92 (7.9%) had HAH. Compared with low-dose loop diuretics users (<40 mg; without thiazide diuretics), risks for developing HAH were significantly higher in patients with thiazide diuretics, regardless of the dose of loop diuretics (OR 2.67, 95% CI 1.13–6.34 and OR 2.31, 95% CI 1.50–5.13 for low- and high-dose loop diuretics, respectively). The association was less apparent in patients without thiazide diuretics (OR 1.29, 95% CI 0.73–2.27 for high-dose loop diuretics alone). Among 206 matched patients, all-cause and cardiac mortality rate was 27% and 14% in non thiazide diuretics users and 50% and 30% in thiazide diuretics users, respectively (HR 2.46, 95% CI 1.29–4.69, p = 0.006 and HR 2.50, 95% CI 1.10–5.67, p = 0.028, respectively) during a mean 19.3 months of follow-up.
Conclusions
Thiazide diuretics use, rather than loop diuretics dose, was independently associated with HAH; and mortality was higher in thiazide diuretics users even after statistical matching.
Characteristics and outcomes of patients hospitalized for heart failure in the United States: rationale, design, and preliminary observations from the first 100,000 cases in the Acute Decompensated Heart Failure National Registry (ADHERE).
] have been particularly noted to be at higher risk for adverse clinical events such as death or rehospitalization. Whether this relationship is causal or, using high-dose and multiple types of diuretics just represents a marker of more advanced disease, remains unclear.
Further, diuretics, at higher doses and simultaneous use of loop diuretics and thiazide and thiazide-type diuretics (TZ) are known to induce iatrogenic hyponatremia [
]. Hyponatremia defined as serum sodium (Na) concentration < 135 mEq/L is common in AHF, and has been documented to not only reflect AHF severity, but also be a strong predictor of adverse short- and long-term outcomes [
Relationship between admission serum sodium concentration and clinical outcomes in patients hospitalized for heart failure: an analysis from the OPTIMIZE-HF registry.
The beneficial prognostic value of hemoconcentration is negatively affected by hyponatremia in acute decompensated heart failure: data from the Korean Heart Failure (KorHF) Registry.
]. Reports have shown that hospital-acquired (progressive) hyponatremia, rather than hyponatremia based on single measurement at admission, was associated more strongly with an increased risk for adverse events, including prolonged hospital stay [
]. However, the impact of diuretic management in the acute phase of AHF on hospital-acquired hyponatremia remains to be elucidated. Unfortunately, conducting sufficiently powered, prospective, randomized clinical trials to investigate the effect of diuretics types and dose on adverse outcomes in patients with AHF are challenging.
The purpose of this study was to assess the hypothesis that diuretic use, in its higher dose or additional use of TZ, is an independent predictor for hospital-acquired hyponatremia, and possibly for long-term adverse outcomes in patients with AHF. Quantification of their effects on sodium imbalance could aid physicians in the appropriate choice of the medications and dosing.
Methods
Study population
We retrospectively analyzed the data from 1844 consecutive AHF cases registered in the West Tokyo Heart Failure (WET-HF) registry from January 2006 to November 2015. This database is an ongoing, prospective, multicenter registry designed to collect the clinical background and outcome data of patients with AHF; patients presenting with AHF complicated with acute coronary syndrome were not included. The WET-HF registry recruited patients from four teaching hospitals within the metropolitan Tokyo area in Japan. Diagnosis of AHF was based on Framingham criteria [
]. Approximately 100 variables were collected from each patient. Participating hospitals were instructed to record and register data from consecutive hospital visits for AHF using an internet-based data collection system. The data entered were checked for completeness and internal consistency. Quality assurance was achieved through automatic system validation and reporting of data completeness and through education and training of dedicated clinical research coordinators specifically trained for this percutaneous coronary intervention registry. Extensive on-site auditing by the investigator (S.K.) ensured proper registration of each patient. The present study was approved by each center's ethics review committee.
For the present analysis, we excluded the patients who died during hospitalization (n = 82), those without the data for oral non-potassium-sparing diuretic use (n = 491), those without data of serum sodium level at admission and discharge (n = 42), and those without follow-up (n = 66).
Outcomes and definition
The change in serum sodium level during hospitalization (Na at admission–Na at discharge) was evaluated based on oral non-potassium-sparing diuretic use on discharge. The formula used to convert other loop diuretics to furosemide equivalents was as follows: furosemide 40 mg = azosemide 60 mg = torasemide 8 mg [
Beneficial effects of torasemide on systolic wall stress and sympathetic nervous activity in asymptomatic or mildly symptomatic patients with heart failure: comparison with azosemide.
]. Within the registered patients, median of oral loop diuretics dose was 40 mg. Consequently, diuretic groups were stratified into four groups: A (n = 827), low-dose loop diuretics (<40 mg) without TZ; B (n = 231), high-dose loop diuretics (≥40 mg) without TZ; C (n = 51), low-dose loop diuretics with TZ; and D (n = 54), high-dose loop diuretics with TZ (Fig. 1). Hospital-acquired hyponatremia was defined as the development of hyponatremia (Na < 135 mEq/L) at discharge with normonatremia (135 mEq/L ≤ Na ≤ 145 mEq/L) on admission. In addition to the degree of prospective hyponatremia, we compared the long-term outcome that consisted of all-cause and cardiovascular deaths between groups with and without TZ. The estimated glomerular filtration rate (eGFR) was calculated with the following formula: eGFR = 194 × serum creatinine−1.094 (mg/dl) × age−0.287 (years) [×0.739 (for women only)] [
Fig. 1Study flow chart. TZ, thiazide and thiazide-type diuretics. *, Dose of loop diuretics <40 mg, †, dose of loop diuretics ≥40 mg, ‡, number of patients with normonatremia at admission.
Continuous data were expressed as mean ± standard deviation, non-parametric data as median [interquartile range], and categorical data as number and ratio. An unpaired t-test, Mann–Whitney test was performed for continuous data; the Chi-square test was performed for categorical data appropriately. Skewed distributed variables were log transformed for analysis.
The difference in serum sodium change during hospitalization was adjusted for potential confounding factors among four diuretic groups. The “adjusted means” are the least square means from the multivariable linear regression models. The association of diuretic use with hospital-acquired hyponatremia was evaluated using multivariable logistic regression to calculate the adjusted odds ratio (OR) and 95% confidence intervals (95% CI). These models were adjusted for age, gender, brain natriuretic peptide (BNP), systolic blood pressure, eGFR, left ventricular ejection fraction, hemoglobin, and baseline serum sodium level at admission. In addition, missing data for these covariates were imputed (missing information is shown in Supplemental Table 1). Imputation was performed with 10 data sets using chained equations.
We used multivariable Cox proportional hazard regression to estimate the association between TZ use and mortality in all patients. In addition, we developed a propensity score for TZ use and controlled for potential confounding and selection bias, because TZ use was not randomly assigned in the patient population. The propensity score for TZ use was determined by multivariable logistic regression analysis, without taking patient outcome into account. Specifically, the logistic regression model was fit with TZ use as a dependent variable, which included clinically relevant variables shown in Table 1 as independent variables. A propensity score for TZ use was calculated from this logistic regression equation for each patient. This propensity score represented the probability that a patient would be given TZ during hospitalization. The C-statistic for this model was 0.78. Patients administered TZ (treated) and controls were matched on the logit of the propensity score without replacement, using calipers of width equal to 0.25 times the standard deviation of the logit of the propensity score. We used the nearest neighbor matching attempting a 1:1 ratio, with no interactions included. The balance between the treatment and control groups was assessed by standardized mean differences. In the matching cohorts, Kaplan–Meier method with log-rank tests was used to compare event curve for all-cause mortality. The risk of outcomes in the group with TZ use vs. without TZ use was estimated using Cox proportional hazard regression model stratified on the matched pairs [
]. All p-values were two-sided, and a p-value of 0.05 was pre-specified as indicative of statistical significance. Statistical analyses were performed using SAS, version 9.4 (SAS Institute Inc., Cary, NC, USA), or R software packages, version 3.2.2 (R Development Core Team, Vienna, Austria).
Table 1Baseline characteristics according to use of thiazide diuretics before and after propensity score matching.
Variables
All patients
Propensity-matched patients
No TZ n = 1058
TZ n = 105
p-Value
Standardized difference, %
No TZ n = 103
TZ n = 103
p-Value
Standardized difference, %
Age (years)
72.3 (13.7)
74.8 (12.3)
0.076
19.20
75.6 (11.3)
75.0 (12.4)
0.814
5.89
Male (%)
659 (62.3)
70 (66.7)
0.399
9.20
72 (69.9)
69 (67.0)
0.653
6.46
BMI (kg/m2)
23.5 (4.0)
23.3 (3.8)
0.675
−3.80
23.1 (3.2)
23.3 (3.8)
0.963
5.69
Prior heart failure (%)
377 (36.0)
65 (61.9)
<0.001
53.60
62 (60.2)
63 (61.2)
0.887
2.05
Hypertension (%)
673 (64.8)
59 (56.2)
0.088
−17.60
56 (54.4)
57 (55.3)
0.988
1.95
Diabetes mellitus (%)
368 (35.0)
37 (35.6)
0.914
1.25
33 (32.0)
35 (34.0)
0.729
4.25
NYHA class, III or IV (%)
651 (68.7)
68 (66.0)
0.170
−5.76
70 (67.9)
67 (65.0)
0.818
6.14
Systolic BP (mmHg)
138.6 (32.5)
128.1 (29.9)
0.002
33.62
131.2 (30.5)
128.3 (30.1)
0.438
9.57
Diastolic BP (mmHg)
80.3 (21.5)
76.1 (19.5)
0.058
−20.46
76.9 (19.2)
76.5 (19.5)
0.791
2.06
Heart rate (beat/min)
92.9 (29.1)
88.6 (23.7)
0.139
16.20
88.4 (28.8)
88.5 (24.0)
0.594
0.37
Hemoglobin (g/dL)
12.3 (2.4)
11.6 (2.8)
0.006
−26.84
11.8 (2.4)
11.7 (2.8)
0.555
3.83
eGFR (mL/min/1.73 m2)
52.1 (24.8)
43.2 (22.4)
<0.001
−37.66
45.3 (23.0)
43.8 (22.1)
0.444
6.65
BUN (mg/dL)
25.1 (14.6)
33.0 (17.9)
<0.001
48.36
32.6 (20.4)
31.8 (15.6)
0.903
4.40
Sodium (mEq/L)
139.3 (4.2)
138.3 (4.4)
0.016
−23.25
138.5 (5.7)
138.3 (4.4)
0.338
3.92
Potassium (mEq/L)
4.38 (0.70)
4.36 (0.67)
0.731
−2.92
4.36 (0.80)
4.39 (0.63)
0.597
2.32
BNP (pg/mL)
536 [273, 1015]
614 [334, 1420]
0.073
17.44
696 [360, 1191]
607 [333, 1401]
0.955
8.23
Total bilirubin (mg/dL)
1.02 (0.69)
1.13 (0.57)
0.140
17.38
1.16 (0.80)
1.14 (0.56)
0.453
−2.61
LVEF (%)
43.2 (15.6)
40.9 (16.8)
0.175
14.18
40.9 (14.9)
40.7 (16.9)
0.888
1.25
Leg edema (%)
625 (63.9)
80 (80.0)
<0.001
36.42
76 (73.8)
80 (77.7)
0.673
4.46
Carperitide (%)
524 (51.4)
69 (67.0)
0.003
32.15
67 (65.0)
67 (65.0)
1.000
0.00
Intravenous furosemide (%)
585 (56.6)
61 (58.7)
0.756
4.25
59 (57.3)
60 (58.2)
0.951
2.02
Oral furosemide (%)
690 (65.2)
92 (87.6)
<0.001
54.69
89 (86.4)
90 (87.4)
0.836
2.96
ACE inhibitors (%)
294 (27.9)
32 (30.5)
0.570
5.72
28 (27.2)
32 (31.1)
0.540
8.60
Angiotensin receptor blockers (%)
419 (39.6)
42 (40.0)
1.000
0.82
44 (42.7)
42 (40.8)
0.778
−3.93
β blockers (%)
819 (77.7)
81 (77.1)
0.902
−1.43
81 (78.6)
81 (78.6)
1.000
0.00
Aldosterone blockers (%)
389 (37.7)
44 (42.3)
0.397
9.40
41 (39.8)
44 (42.7)
0.951
5.89
Data are shown as numbers (%), mean (standard deviation), and median [1st, 3rd quartiles].
ACE, angiotensin-converting enzyme; BMI, body mass index; BNP, brain natriuretic peptide; BP, blood pressure; BUN, blood urea nitrogen; eGFR, estimated glomerular filtration rate; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association; TZ, thiazide and thiazide-type diuretics.
A total of 1163 patients were included in the present study; mean age of the study group was 72.6 ± 13.6 years old, and 62.6% were males (n = 729). Table 1 compares baseline patient characteristics by TZ use before the propensity score matching. Before matching, the patients with TZ (n = 105, 9.0%) had statistically lower level of systolic blood pressure level, eGFR, hemoglobin, baseline serum sodium, and higher blood urea nitrogen than those without TZ. They were also more likely to have a history of HF admission. Although the groups with TZ tended to be older, and have higher BNP, these differences did not show statistical significance.
Diuretics and hospital-acquired hyponatremia
Among the study patients, we found a statistically significant difference in the adjusted means of sodium change among diuretic groups (low-dose loop diuretics without TZ, −0.52 ± 0.11 mEq/L; high-dose loop diuretics without TZ, −0.90 ± 0.22 mEq/L; low-dose loop diuretics with TZ, −1.37 ± 0.45 mEq/L; and high-dose loop diuretics with TZ, −2.46 ± 0.45 mEq/L, p for trend <0.001) (Fig. 2). Compared between the group with low-dose loop diuretics and high-dose loop diuretics in post hoc Tukey analysis, we did not observe a dose relationship of loop diuretics on the degree of sodium change not only in patients without TZ (p-value = 0.316), but also in those with TZ (p-value = 0.393).
Fig. 2Adjusted means value for change in serum sodium level during hospitalization. Adjusted mean values with 95% confidence intervals as estimated with multivariable analysis, adjusted for age, gender, brain natriuretic peptide, systolic blood pressure, estimated glomerular filtration rate, left ventricular ejection fraction, hemoglobin, and baseline serum sodium level at admission.
Hospital-acquired hyponatremia was observed in 92 patients (9.2%) in the patients with normonatremia at admission (n = 1001). Diuretic use was independently associated with hospital-acquired hyponatremia after adjusting for covariates (Table 2). Compared with low-dose loop diuretics without TZ as a reference, adjusted odds ratios of hospital-acquired hyponatremia were 1.29 (95% CI, 0.73–2.27) in high-dose loop diuretics without TZ, 2.67 (95% CI, 1.13–6.34) in low-dose loop diuretics with TZ, and 2.31 (95% CI, 1.50–5.13) in high- dose loop diuretics with TZ, respectively. When the diuretics groups were divided into two groups based on only loop diuretics dose (high-dose and low-dose loop diuretics group), similarly dose of loop diuretics was not associated with hospital-acquired hyponatremia (Supplemental Tables 2 and 3). In addition, higher BNP and lower hemoglobin were associated with hospital-acquired hyponatremia.
Table 2Association of diuretic use and other factors with hospital-acquired hyponatremia in the patients with normonatremia at admission.
Variables
OR (95% CI)
p-Value
Age, per 10 years old
0.94 (0.78–1.14)
0.525
Gender, male
1.22 (0.75–2.00)
0.417
BNP (log), per 1SD
1.40 (1.05–1.80)
0.020
Systolic BP, per 10 mmHg
0.95 (0.88–1.03)
0.199
eGFR, 10 ml/min/1.73 m2
1.01 (0.91–1.11)
0.926
LVEF, per 10%
1.06 (0.89–1.26)
0.518
Hemoglobin, per 1 g/dL
0.84 (0.75–0.93)
0.002
Low-dose loop diuretics without TZ
Reference
High-dose loop diuretics without TZ
1.29 (0.73–2.27)
0.377
Low-dose loop diuretics with TZ
2.67 (1.13–6.34)
0.025
High-dose loop diuretics with TZ
2.31 (1.50–5.13)
0.039
Model was adjusted for age, gender, brain natriuretic peptide, systolic blood pressure, estimated glomerular filtration rate, hemoglobin, left ventricular ejection fraction, baseline sodium level, and use of diuretics.
Among all patients, 51 (48.6%) and 31 patients (29.5%) in the group with TZ use died from all causes and cardiovascular cause respectively, compared with 177 (16.7%) and 81 (7.7%) patients in the group without TZ use during a mean 19.3 month follow-up. TZ use was independently associated with all-cause and cardiovascular mortality after adjustment for selected covariates (HR, 2.52; 95% CI, 1.81–3.50; and HR, 3.08; 95% CI, 1.99–4.76, respectively; Table 3).
Table 3Cox proportional hazard analysis for thiazide diuretic use among total and matched patients.
Model 2: adjusted for covariates in model 1 plus brain natriuretic peptide, systolic blood pressure, estimated glomerular filtration rate, left ventricular ejection fraction, and hemoglobin.
Cox proportional hazard regression model stratified on the matched pairs. CI, confidence interval; HR, hazard ratio.
(n = 206)
2.46 (1.29–4.69)
0.006
2.50 (1.10–5.67)
0.028
a Model 1: adjusted for age and gender.
b Model 2: adjusted for covariates in model 1 plus brain natriuretic peptide, systolic blood pressure, estimated glomerular filtration rate, left ventricular ejection fraction, and hemoglobin.
c Cox proportional hazard regression model stratified on the matched pairs.CI, confidence interval; HR, hazard ratio.
Propensity matching was performed for TZ-treated patients, given the significance of TZ use and its association with long-term outcomes. We were able to match 103 TZ patients using TZ to 103 unique patients not using TZ (two patients using TZ could not be matched). The absolute standardized differences for all covariates were ≤10% after the score matching, demonstrating substantial improvement in covariate balance across the treatment groups (Table 1). Within this cohort of 206 patients, 79 patients (38.3%) and 45 patients (21.8%) died from all causes, and from cardiovascular cause, respectively. Compared with 28 (27%) deaths in the patients in the group without TZ, 51 (50%) of those in the group with TZ died from all causes (HR, 2.46; 95% CI, 1.29–4.69; p-value = 0.006; Table 3). Kaplan–Meier survival curve for all-cause mortality is shown in Fig. 3. Mortality due to cardiovascular cause occurred in 14 (14%) patients in the group without TZ and 31 (30%) of those in the group with TZ (HR, 2.50; 95% CI, 1.10–5.67; p-value = 0.028).
Fig. 3Kaplan–Meier curve for all-cause mortality relating to thiazide diuretic use among propensity-matched patients.
This study demonstrated that diuretic use particularly TZ, rather than loop diuretic dose, was independently related to hospital-acquired hyponatremia in the patients admitted with AHF. Moreover, TZ use was associated with increased risk of long-term all-cause and cardiovascular mortality. These findings provide insights into management of oral diuretic therapy, suggesting that TZ use maybe a modifiable risk factor for adverse outcomes.
We found higher long-term mortality among TZ users in our propensity-matched cohort. Although leading professional society guidelines recommend the use of combined loop diuretics and TZ therapy as one of the approaches to fluid status, particularly in patients who are refractory to loop diuretic monotherapy, the level of evidence is classified as C (expert opinion only) [
ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC.
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.
]. The aggregate body of previous literature examining efficacy or adverse events of TZ is limited by the small size of studies (less than 40), study design with lack of control groups, and focus on physiologic details such as weight loss or clearance of edema rather than clinical outcomes [
]. Neuberg et al. previously reported that TZ use was an independent predictor for total mortality in an observational study; however, it may be a marker of increased disease severity as they quoted in their limitations [
]. Adequate balancing of the clinical characteristics and baseline covariates between the groups with and without TZ could distinguish our study from theirs. Our result implies that the association between diuretics and adverse clinical events is not entirely caused by selection bias, that is, confounding by diuretic indication.
One plausible explanation why TZ use is associated with increased risk of mortality is the unfavorable diuretic effects, particularly hyponatremia. Our result adds to the current knowledge by showing that TZ use was an independent strong predictor of hospital-acquired hyponatremia after adjusting for potential confounding factors related to HF. Previous studies have documented that hospital-acquired hyponatremia as well as hyponatremia at admission was associated with poor outcomes in patients with HF [
]. Notably, the dose relationship of loop diuretics to change in serum sodium level was not obvious in our study, neither qualitatively nor quantitatively [
]. These findings are best explained by a pharmacological mechanism: TZ acting solely in the distal tubules do not interfere with urinary concentration and the ability of arginine vasopressin (AVP) to promote water retention, which is the critical point for the development of hyponatremia [
Another mechanistically possible explanation is the activation of the neuroendocrine system, in particular the renin–angiotensin–aldosterone system, mediated by diuretics [
Comparison of neuroendocrine activation in patients with left ventricular dysfunction with and without congestive heart failure. A substudy of the Studies of Left Ventricular Dysfunction (SOLVD).
]. Activation of angiotensin II and aldosterone is associated with the stimulation of pro-inflammatory cytokines, myocardial fibrosis, and disease progression with consequently poor outcomes in HF [
]. This neurohormonal activation leads to the development of hyponatremia through AVP stimulation in the patients with AHF, and interestingly, post hoc analysis of the DOSE-AHF study has demonstrated the group with “treatment-induced” hyponatremia had higher level of serum renin-activity level at discharge compared with those without hyponatremia, despite similar baseline neurohormonal levels [
]. Prescription rates of angiotensin-converting enzyme inhibitor and mineral corticoid receptor antagonists were similar between groups with and without TZ in our propensity-matched cohort. However, further study is needed to determine how neurohormonal activation due to active diuresis treatment affects adverse events, including hyponatremia and mortality.
Our findings may suggest that chronic TZ use is a potentially modifiable risk factor for hospital-acquired hyponatremia, and consequently long-term mortality. Specifically, in light of hyponatremia, physicians probably should titrate the loop diuretic dose appropriately before adding TZ, particularly in low-dose loop diuretic (<40 mg) prescription status. Certainly, the most anticipated benefits of adding TZ to loop diuretic therapy include fluid removal with resolution of volume overload and congestion, even in patients who are refractory to loop diuretics alone [
Combination therapy with metolazone and loop diuretics in outpatients with refractory heart failure: an observational study and review of the literature.
]. The current result and several previous reports may imply that adding TZ should be selected for patients with AHF with excessive volume overload, and after careful consideration the possibility of titrating loop diuretic dose. Moreover, physicians should discontinue TZ immediately after clinical signs of volume overload disappear.
A newly added class of diuretics, the AVP antagonists (e.g. vaptams) has been reported to have the efficacy of alleviating signs and symptoms of congestion without inducing hyponatremia [
]. In the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) trial, albeit no benefit of AVP antagonist was found on long-term mortality over a mean 9.9 month follow-up period [
Short-term clinical effects of tolvaptan, an oral vasopressin antagonist, in patients hospitalized for heart failure: the EVEREST Clinical Status Trials.
Clinical course of patients with hyponatremia and decompensated systolic heart failure and the effect of vasopressin receptor antagonism with tolvaptan.
]. Only 16 patients (1.4%) were treated with AVP antagonists in our study, and detailed analysis was not possible. A further randomized control trial is needed to directly compare the adverse events between AVP antagonists and TZ in the patients with volume overload refractory to standard loop diuretic treatment.
Our study has several limitations. First, this is a non-randomized multi-center observational study. When analyzing a single baseline variable, propensity score matching is one of the most robust ways of approaching observational data in order to reduce confounding and assess possible causality. Although acceptable balance between treated and controls was achieved in this study, our study might be potentially limited by biases related to unmeasured or hidden covariates, and incomplete and/or inexact matching. Second, data of types and doses of TZ were not available. Meta-analysis has documented that three common TZs: hydrochlorothiazide, chlorthalidone, and bendroflumethiazide had markedly different potency for blood pressure [
Meta-analysis of dose-response relationships for hydrochlorothiazide, chlorthalidone, and bendroflumethiazide on blood pressure, serum potassium, and urate.
]. In addition, a recent report has shown that chlorthalidone was associated with increased risk of hyponatremia compared with hydrochlorothiazide at an equal milligram-to-milligram dose per day [
]. The class effect and dose relationships of TZ might affect the association between hospital-acquired hyponatremia and mortality in patients with AHF. Third, loop diuretic doses in our cohort were somewhat lower than those in HF cohorts in western countries. This difference probably depends on the differences in physical size; the body mass index of patients with AHF in western countries is higher compared with those in Asian countries. When our findings are generalized, carefully taking into account the differences in loop diuretic dose is important.
Conclusion
In conclusion, rather than loop diuretic dose, TZ use was independently associated with hospital-acquired hyponatremia; and mortality was higher in the patients with TZ after rigorous statistical matching. Our results have implications for appropriate diuretic management, suggesting TZ use may be a modifiable risk factor for adverse outcomes.
Funding
This research was supported by Ministry of Education, Culture, Sports, Science and Technology (MEXT)/Japan Society for the Promotion of Science (JSPS) KAKENHI [Grant Numbers JP23591062, JP26461088, and JP14528506].
Conflict of interest
The authors declare that there is no conflict of interest.
Acknowledgments
The authors are deeply indebted to the staff members of West Tokyo Heart Failure Registry. We also thank Mitsuaki Isobe, Sakakibara Heart Institute, for the helpful comments.
Appendix A. Supplementary data
The following are the supplementary data to this article:
Characteristics and outcomes of patients hospitalized for heart failure in the United States: rationale, design, and preliminary observations from the first 100,000 cases in the Acute Decompensated Heart Failure National Registry (ADHERE).
Relationship between admission serum sodium concentration and clinical outcomes in patients hospitalized for heart failure: an analysis from the OPTIMIZE-HF registry.
The beneficial prognostic value of hemoconcentration is negatively affected by hyponatremia in acute decompensated heart failure: data from the Korean Heart Failure (KorHF) Registry.
Beneficial effects of torasemide on systolic wall stress and sympathetic nervous activity in asymptomatic or mildly symptomatic patients with heart failure: comparison with azosemide.
ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC.
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.
Comparison of neuroendocrine activation in patients with left ventricular dysfunction with and without congestive heart failure. A substudy of the Studies of Left Ventricular Dysfunction (SOLVD).
Combination therapy with metolazone and loop diuretics in outpatients with refractory heart failure: an observational study and review of the literature.
Short-term clinical effects of tolvaptan, an oral vasopressin antagonist, in patients hospitalized for heart failure: the EVEREST Clinical Status Trials.
Clinical course of patients with hyponatremia and decompensated systolic heart failure and the effect of vasopressin receptor antagonism with tolvaptan.
Meta-analysis of dose-response relationships for hydrochlorothiazide, chlorthalidone, and bendroflumethiazide on blood pressure, serum potassium, and urate.
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