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Medium Term Effects of Different Dosage of Diuretic, Sodium, andFluid Administration on Neurohormonal and Clinical Outcome in

Patients With Recently Compensated Heart Failure

Salvatore Paterna, MDa, Gaspare Parrinello, MDb, Sergio Cannizzaro, MDc, Sergio Fasullo, MDc,Daniele Torres, MDb, Filippo M. Sarullo, MDd, and Pietro Di Pasquale, MDc,*

Studies have shown that patients with compensated heart failure (HF) receiving highdiuretic doses associated with normal sodium diet and fluid intake restrictions demon-strated significant reductions in readmissions and mortality compared with those whoreceived low-sodium diets, and over a 6-month observation period, a reduction in neuro-hormonal activation was also observed. The aim of this study was to evaluate the effects ofdifferent sodium diets associated with different diuretic doses and different levels of fluidintake on hospital readmissions and neurohormonal changes after 6-month follow-up inpatients with compensated HF. Four hundred ten consecutive patients with compensatedHF (New York Heart Association class II to IV) aged 53 to 86 years, with ejection fractions<35% and serum creatinine <2 mg/dl, were randomized into 8 groups: group A (n � 52):1,000 ml/day of fluid intake, 120 mmol/day, and 250 mg furosemide twice daily; group B(n � 51): 1,000 ml/day of fluid intake, 120 mmol/day, and 125 mg furosemide twice daily;group C (n � 51): 1,000 ml/day fluid intake, 80 mmol/day, and 250 mg furosemide twicedaily; group D (n � 51): 1,000 ml/day fluid intake, 80 mmol/day, and 125 mg furosemidetwice daily; group E (n � 52): 2,000 ml/day fluid intake, 120 mmol/day, and 250 mgfurosemide twice daily; group F (n � 50): 2,000 ml/day fluid intake, 120 mmol/day, and 125mg furosemide twice daily; group G (n � 52): 2,000 ml/day fluid intake, 80 mmol/day, and250 mg furosemide twice daily; and group H (n � 51): 2,000 ml/day fluid intake, 80mmol/day, and 125 mg furosemide twice daily. All patients received the treatments >30days after discharge and for 180 days afterward. Signs of HF, body weight, blood pressure,heart rate, laboratory parameters, electrocardiograms, echocardiograms, brain natriureticpeptide, aldosterone, and plasma renin activity were examined at baseline and 180 dayslater. Group A showed the best results, with a significant reduction (p <0.001) in read-missions, brain natriuretic peptide, aldosterone, and plasma renin activity compared withthe other groups during follow-up (p <0.001). In conclusion, these data suggest that thecombination of a normal-sodium diet with high diuretic doses and fluid intake restriction,compared with different combinations of sodium diets with more modest fluid intakerestrictions and conventional diuretic doses, leads to reductions in readmissions, neuro-hormonal activation, and renal dysfunction. © 2009 Elsevier Inc. All rights reserved. (Am

J Cardiol 2009;103:93–102)

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Diuretics have long been accepted as first-line treatment foratients with severe heart failure (HF) and fluid retention, inddition to dietary sodium restriction and moderate physicalctivity.1–3 Studies have shown that patients with HF treatedith hypertonic saline solution and high-dose intravenous

urosemide combined with a normal-sodium diet duringospitalization achieved significantly faster reductions inrain natriuretic peptide (BNP) levels and dry weight andad shorter hospitalization stays and readmissions.4–10 Inddition, patients receiving after discharge a combination of

Departments of aEmergency Medicine and bInternal Medicine, Univer-ity of Palermo; cDivision of Cardiology “Paolo Borsellino,” G.F. Ingrassiaospital; and dDivision of Cardiology, Buccheri la Ferla Hospital, Pal-

rmo, Italy. Manuscript received June 26, 2008; revised manuscript re-eived and accepted August 10, 2008.

*Corresponding author: Tel: 39-091-524181; fax: 39-091-7033742.

[E-mail address: lehdi@tin.it (P. Di Pasquale).

002-9149/09/$ – see front matter © 2009 Elsevier Inc. All rights reserved.oi:10.1016/j.amjcard.2008.08.043

igh-dose diuretic, normal-sodium diet (120 mmol), andater intake restriction (1,000 ml/day) were less likely to

equiree further hospitalizations and more likely to be alivehan patients receiving a low-sodium diet (80 mmol/day).9

his combination was also effective in reducing neurohor-onal activation (BNP, plasma renin activity [PRA], and

ldosterone).11

To verify if this combined treatment is effective withore conventional doses of diuretics or more modest fluid

estrictions, we performed a study to investigate the effectsf different sodium diets (120 or 80 mmol/day) associatedith different diuretic doses (more conventional or highoses) and different water intake restrictions (1,000 ml/dayr a more modest restriction of 2,000 ml/day) on hospitaleadmissions for worsening HF and on BNP, plasma aldo-terone levels, and PRA after 6-month follow-up in patientsith HF well compensated (New York Heart Association

NYHA] class II) at hospital discharge.

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94 The American Journal of Cardiology (www.AJConline.org)

ethods

From June 2005 to September 2007, 410 consecutive pa-ients with compensated HF who were hospitalized previ-usly (within 30 days) for recently decompensated HF withhe following characteristics were included in the study:hey had to have, according to the definition of refractoryF1 and according to Framingham criteria and NYHA func-

ional classification,12 uncompensated HF (dyspnea, weak-ess, lower-limb edema, or anasarca) or NYHA class IV HFhat was unresponsive to treatment with high doses of oralurosemide up to 250 to 500 mg/day and/or combinations ofiuretics (thiazide, loop diuretics, and spironolactone), an-iotensin-converting enzyme (ACE) inhibitors (captopril 75o 150 mg/day), digitalis, � blockers, and nitrates, and to beeceiving this therapy for �2 weeks before hospitalization.atients were judged unresponsive when they had, during

his treatment, decreases in urine volume, constant increasesn body weight, and impairments of clinical symptoms ofF, despite increases in furosemide and combinations of

Figure 1. Flow chart of st

ther diuretics (including thiazide). Additionally, patients c

ad to have left ventricular ejection fractions �35%, serumreatinine �2 mg/dl, blood urea nitrogen (BUN) �60 mg/l, decreased urinary volume (�500 ml/day), and low na-riuresis (�60 mEq/day), despite receiving establishedreatments. None of the patients were taking nonsteroidalnti-inflammatory drugs. All patients received high-doseurosemide (250 mg twice daily), hypertonic saline solution,normal-sodium diet (120 mmol/day), and decreased fluid

ntake (1,000 ml/day) during hospitalization. When theompensated state was achieved (NYHA class II), patientseceived oral furosemide (250 mg twice daily), a normal-odium diet (120 mmol/day), and fluid intake of 1,000l/day, according to previous studies,9,10 and treatment was

ontinued after discharge. The tailored therapy (ACE inhib-tors, digitalis, antialdosterone, � blockers, and nitrates)dministered during hospitalization was also continued afterischarge.

Patients were considered clinically compensated whenhey achieved a change in NYHA functional class to at least

ign and patient selection.

lass II and the accomplishment of an ideal body weight,

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95Heart Failure/Combination of Sodium Diets and Diuretic Doses in HF

alculated by the Lorenz formula and bioelectrical imped-nce measurements.10,13 Diuretic doses were 250 mg twiceaily, because this dose allowed the maintenance of bodyeight and water balance during hospitalization and afterischarge. Only patients in NYHA class II at 30 days afterischarge were included in the study and randomized. Pa-ients with cerebral vascular disease, dementia, cancer, un-ompensated diabetes, and severe hepatic disease were ex-luded, as were patients requiring pacemaker implantationnd those with alcohol habits. Patients were also excluded ifhey declined to take part in the study protocol (but contin-ed the prescribed treatment), were unable to follow thessigned treatment, did not follow the treatment protocol orttend the scheduled clinical visits, did not adhere to theuid intake restriction of 1,000 ml/day, or had reductions oriscontinuations of prescribed treatments. In addition, pa-ients with side effects of ACE inhibitor treatment (cough),ven if these patients were given angiotensin II receptorlockers, were also excluded to obtain as homogenous areatment schedule as possible.

After discharge, all the patients suitable for the studythose in NYHA class II) were controlled with clinical andaboratory evaluations as outpatients every week for the first0 days, and those who at 30 days after discharge met theligibility criteria (NYHA class II) were included in thetudy. During the 30-day period after discharge, treatments

able 1aseline clinical characteristics, treatments, and congestive heart failure ciet

ariable 120 mmol Na/d �250 mg Furosemide Bid

120 mm125 mg Fu

luid intake 1,000 ml/dayPatients 52Age (yrs) 75.6 � 8 76.Men/women 18/34 19Spironolactone (25 mg/day) 47 (90.3%) 48 (9Captopril (37.5–75 mg/day) 52Digitalis (0.125–0.25 mg/day) 17 (32.6%) 18 (3Carvedilol (12.5–25 mg/day) 16 (30.7%) 17 (3DM 16 (30.7%) 15 (2CAD 30 (57.6%) 28 (5HHD 20 (38.4%) 21 (4DC 2 (3%) 2 (3AF 16 (30.7%) 17 (3luid intake 2,000 ml/dayPatients 52Age (yrs) 75.4 � 8 76.Men/women 20/32 18Spironolactone (25 mg/day) 47 (90.3%) 44 (8Captopril (37.5–75 mg/day) 52Digitalis (0.125–0.25 mg/day) 19 (36.5%) 21 (4Carvedilol (12.5–25 mg/day) 21 (40.3%) 19 (3DM 16 (30.7%) 14 (2CAD 31 (59.6%) 26 (5HHD 20 (38.4%) 22 (4DC 1 (1.9%) 2 (4AF 21 (40.3%) 19 (3

Data are expressed as mean � SD or as number (percentage).AF � atrial fibrillation; bid � twice daily; CAD � coronary artery disea

ardiomyopathy.

as necessary) were corrected according to clinical status (

nd laboratory measurements (decreases and/or increases inCE inhibitors, digitalis, antialdosterone, � blockers, anditrates), and therefore, it was not necessary to correct thessigned treatments during follow-up. In fact, all of thenrolled patients were stable in NYHA class II and receivedhe best treatments, which were able to maintain the com-ensated state obtained during hospitalization, after dis-harge and before randomization. During the follow-uperiod, other treatments were not added to those adminis-ered. The correction of therapy was carried out only ineadmitted patients.

Only patients judged to be compensated according toYHA class II by an independent external team of �2 ofhysicians blinded to the study protocol were included inhe study and randomized by a preliminary computer algo-ithm, and the assignment of all patients was decided ataseline (30 days after discharge) before performing clinicalnd laboratory measurements. In this way, we obtained 8roups of patients (Figure 1): group A (n � 52): 1,000l/day fluid intake, 120 mmol sodium/day, and furosemide

50 mg twice daily; group B (n � 51): 1,000 ml/day fluidntake, 120 mmol sodium/day, and furosemide 125 mgwice daily; group C (n � 51): 1,000 ml/day fluid intake, 80mol sodium/day, and furosemide 250 mg twice daily;

roup D (n � 51): 1,000 ml/day fluid intake, 80 mmolodium/day, and furosemide 125 mg twice daily; group E

f the enrolled patients according diuretic dose, fluid intake, and sodium

�e Bid

80 mmol Na/d �250 mg Furosemide Bid

120 mmol Na/d �125 mg Furosemide Bid

p Value

51 51 NS74.3 � 8 75.6 � 10 NS

19/32 18/33 NS45 (88.2%) 48 (94.1%) NS

51 51 NS20 (39.2%) 19 (37.2%) NS19 (36.5%) 20 (39.2%) NS14 (27.4%) 15 (29.4%) NS27 (52.9%) 29 (56.8%) NS23 (45%) 20 (39.2%) NS1 (1.9%) 2 (3%) NS

19 (36.5%) 20 (39.2%) NS

52 51 NS75.7 � 8 75.6 � 7 NS

20/32 20/31 NS48 (92.3%) 46 (90.1%) NS

52 51 NS19 (36.5%) 20 (39.2%) NS20 (38.4%) 19 (37.2%) NS14 (26.9%) 13 (25.4%) NS28 (53.8%) 26 (50.9%) NS22 (42.3%) 24 (47%) NS2 (3.8%) 1 (1.9%) NS

20 (38.4%) 19 (37.2%) NS

� dilated cardiomyopathy; DM � diabetes mellitus; HHD � hypertensive

auses o

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515 � 9/324.1%)

515.2%)3.3%)9.4%)4.9%)1.1%)%)3.3%)

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n � 52): 2,000 ml/day fluid intake, 120 mmol sodium/day,

Table 2Clinical and laboratory parameters at baseline in all groups

Group SBP(mm Hg)

DBP(mm Hg)

HR(beats/min)

BW(kg)

Diuresis(ml/day)

Serum Na(mEq/L)

Serum K(mEq/L)

BUN(mg/dl)

Creatinine(mg/dl)

Natriuresis(mEq/day)

Fluid intake 1,000 ml/dayGroup A (120 mmol Na/d �

250 mg furosemide bid)113 � 11 71 � 6 70 � 5 76 � 8 2,050 � 500 139.7 � 0.6 3.8 � 0.4 53 � 4.4 1.45 � 0.05 103 � 12

Group B (120 mmol Na/d �125 mg furosemide bid)

111 � 9 70 � 8 69 � 6 77 � 7 1,975 � 550 140.1 � 0.8 3.8 � 0.3 52 � 4.1 1.46 � 0.08 106 � 11

p value NS NS NS NS NS NS NS NS NSFluid intake 1,000 ml/day

Group C (80 mmol Na/d �250 mg furosemide bid)

114 � 11 71 � 5 73 � 12 75 � 10 2,060 � 350 140.4 � 0.4 3.9 � 0.5 53 � 3.5 1.47 � 0.09 105 � 14

Group D (120 mmol Na/d �125 mg furosemide bid)

115 � 10 69 � 7 72 � 8 74 � 12 2,025 � 450 140.8 � 0.5 3.8 � 0.4 52 � 4.5 1.49 � 0.06 103 � 13

p value NS NS NS NS NS NS NS NS NSFluid intake 2,000 ml/day

Group E (120 mmol Na/d �250 mg furosemide bid)

115 � 11 72 � 6 71 � 6 73 � 13 1,950 � 400 140.1 � 0.6 3.8 � 0.3 50 � 5.1 1.46 � 0.07 106 � 11

Group F (120 mmol Na/d �125 mg furosemide bid)

116 � 9 71 � 7 70 � 5 74 � 12 2,050 � 350 140.5 � 0.7 3.7 � .0.2 51 � 4.7 1.48 � 0.06 104 � 15

p value NS NS NS NS NS NS NS NS NSFluid intake 2,000 ml/day

Group G (80 mmol Na/d �250 mg furosemide bid)

112 � 8 72 � 8 70 � 11 70 � 10 1,975 � 550 139.4 � 0.6 4.0 � 0.4 53 � 3.7 1.49 � 0.05 103 � 14

Group H (80 mmol Na/d �125 mg furosemide bid)

113 � 12 71 � 5 70 � 8 74 � 11 2,010 � 450 139.7 � 0.7 3.9 � 0.5 52 � 4.2 1.47 � 0.07 105 � 12

p value NS NS NS NS NS NS NS NS NS

Data are expressed as mean � SD.BW� body weight; DBP � diastolic blood pressure; HR � heart rate; SBP � systolic blood pressure. Other abbreviations as in Table 1.

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Table 3Clinical and laboratory parameters after 180 days in all groups

Group n SBP (mm Hg) DBP (mm Hg) HR (beats/min) BW(kg)

Diuresis(ml/day)

Serum Na(mEq/L)

Serum K(mEq/L)

BUN(mg/dl)

Creatinine(mg/dl)

Natriuresis(mEq/day)

Fluid intake 1,000 ml/dayGroup A (120 mmol Na/d �

250 mg furosemide bid)51 110 � 8 68 � 9 69 � 7 77 � 7 1,900 � 550† 139.6 � 0.5† 3.9 � 0.5* 52 � 4.5† 1.48 � 0.06† 107 � 11

Group B (120 mmol Na/d �125 mg furosemide bid)

49 111 � 9 70 � 12 76 � 10 80 � 6 1,600 � 500† 140.4 � 0.5*,† 4.1 � 0.6* 51 � 6.5† 1.49 � 0.06† 104 � 12

p value NS NS 0.0001 0.024 0.005 0.005 NS NS NS 0.005Fluid intake 1,000 ml/day

Group C (80 mmol Na/d �250 mg furosemide bid)

46 112 � 11 77 � 11 81 � 9 79 � 5 1,400 � 600† 132.2 � 0.4*,† 3.6 � 0.2* 102 � 5.5† 2.0 � 0.09† 77 � 9

Group D (120 mmol Na/d �125 mg furosemide bid)

44 111 � 10 83 � 12 84 � 12 81 � 9 1,350 � 400† 134.8 � 0.5*,† 3.9 � 0.3 93 � 3.5† 1.97 � 0.08† 76 � 7

p value NS 0.015 NS 0.025 NS NS 0.0001 0.0001 NS NSFluid intake 2,000 ml/day

Group E (120 mmol Na/d �250 mg furosemide bid)

47 109 � 11 79 � 9 86 � 12 80 � 11 1,550 � 650† 134.3 � 0.4† 3.6 � 0.2* 71 � 3.4† 1.75 � 0.07† 98 � 16

Group F (120 mmol Na/d �125 mg furosemide bid)

44 112 � 12 88 � 12 90 � 9 83 � 10 1,450 � 550† 135.1 � 0.5† 3.7 � 0.2* 68 � 4.3† 1.74 � 0.06† 101 � 15

p value NS 0.0001 NS NS 0.02 0.0001 0.019 0.0001 NS NSFluid intake 2,000 ml/day

Group G (80 mmol Na/d �250 mg furosemide bid)

46 107 � 8 80 � 8 88 � 13 83 � 12 1,250 � 650† 131.4 � 0.5† 3.6 � 0.3* 115 � 7.1† 2.3 � 0.06† 77 � 8

Group H (80 mmol Na/d �125 mg furosemide bid)

43 108 � 7 78 � 9 90 � 10 85 � 11 1,150 � 450† 133.1 � 0.3† 3.8 � 0.3 101 � 5.3† 2.2 � 0.07† 76 � 9

p value NS NS NS NS NS 0.0001 0.002 0.0001 0.0001 NS

Data are expressed as mean � SD. The analysis among all 8 groups studied showed significant differences for all results (p �0.0001) except SBP.* p �0.05; † p �0.0001 (comparisons between group A and groups B to H).Abbreviations as in Tables 1 and 2.

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nd furosemide 250 mg twice daily; group F (n � 50): 2,000l/day fluid intake, 120 mmol sodium/day, and furosemide

25 mg twice daily; group G (n � 52): 2,000 ml/day fluidntake, 80 mmol sodium/day, and furosemide 250 mg twiceaily; and group H (n � 51): 2,000 ml/day fluid intake, 80mol sodium/day, and furosemide 125 mg twice daily.Written informed consent was obtained from each pa-

ient before starting the study. The protocol was approvedy the local ethics committee. Baseline characteristics of thetudy subjects are listed in Tables 1 and 2.

After randomization (at 30 days after discharge) andaseline clinical and laboratory assessments, patients werevaluated every week for the first month, every 2 weeks forhe next 2 months, and then every month for the remainderf the study period. A complete physical examination, withcareful assessment of signs and symptoms of HF, includ-

ng measurement of body weight (in the morning beforereakfast), supine and standing arterial blood pressuremean of 3 measurements), and heart rate, was performed atvery follow-up assessment. At baseline (before receivinghe scheduled treatments), fasting blood samples wererawn to determine serum sodium, potassium, chlorine,icarbonate, albumin, uric acid, creatinine, urea, and glyce-ia. Plasma aldosterone and BNP levels and PRA were also

etermined by radioimmunoassay in core laboratories Ahest x-ray, electrocardiogram, and echocardiogram (to ob-ain the ejection fraction according to the modified Simp-on’s rule, which uses 2 cross-sectional views [4- and-chamber apical views]) were also evaluated. All thesearameters were also obtained at 180 days of follow-up inll groups. In addition, all of the patients with diabeteseceived insulin therapy; however, oral antidiabetic drugsere discouraged after discharge and during follow-up.After randomization, all patients received multiple writ-

en standard diets containing 80 mmol sodium prepared byur dieticians and also received diaries in which they re-orted their amounts of daily fluid intake and diet variations.n case of diet variation, patients reported the amount of thehanged or added food. At every programmed control,linded physicians received the diaries, and new diariesere given to patients. The group receiving the normal-

odium diet (120 mmol/day) received the same diets butith the addition of 40 mmol sodium/day. In this way, allatients received the same amount of saturated fat, fruits,egetables, and so on. In addition, patients were also con-acted every week during follow-up by physicians and die-icians for telephone interviews to determine their adher-nce to the reduced fluid intake as well as the prescribediet. Other information was also obtained by regular contactith family doctors, who were informed about the endoints of the study. Any of the patients experiencing wors-ning HF according to their family doctors were invited tottend the hospital for evaluation and were hospitalizedgain if indicated. The readmitted patients again receivedhe hypertonic saline solution plus high-dose diuretics, wa-er restriction, and 120 mmol/day sodium diet, and labora-ory parameters were collected before treatment onset andncluded in the follow-up analysis (Table 3). Two physi-ians blinded to the study protocol performed the evalua-ions to verify the clinical status and whether worsening HF

as present. o

We performed a multiple regression sample size calcu-ation on the basis of an � value of 0.5 (95% power) and an

value of 0.05. The sample size obtained was 24 for eachroup, and this number was considered the minimum forhis study. We estimated a 50% of reduction in readmissionsor worsening HF (the study end point) on the basis of ourrevious reports.9,11 We calculated event distributions usinghe Kaplan-Meier method and compared them using log-ank analysis. Data were analyzed using 2-tailed Student’s test to identify differences between groups and analysis ofariance for repeated measures with Bonferroni’s post hocest correction for intragroup data. Univariate and multivar-ate analyses were performed to determine the independentredictors of readmission rate. Nominal data were analyzedsing the chi-square test, and p values �0.05 were consid-red statistically significant. All calculations were done us-ng SPSS version 13.0 (SPSS, Inc., Chicago, Illinois), andhe results are expressed as mean � SD.

esults

Of the 849 patients admitted to the hospital for worseningF, 36 did not show reduced urinary volume (�500 ml/day)r low natriuresis (�60 mEq/day), 102 had severe co-orbidities, 15 had side effects of ACE inhibitors, 16 had

lcohol habits, 93 had creatinine levels �2.0 mg/dl and/orUN �60 mg (on hospital admission), 97 were classified inYHA class III on hospital admission, 24 refused consent,1 required pacemaker implantation, and 26 did not followhe treatment protocol (programmed clinical visits, fluidntake of 1,000 ml/day, and reduction or discontinuation ofrescribed treatments) during the run-in period. In addition,9 patients classified in NYHA class III after hospital dis-harge were also excluded from the study.

The remaining 410 eligible patients were randomized toeceive different sodium diets (120 or 80 mmol/day) andifferent fluid intakes (1,000 or 2,000 ml/day) combinedith different loop diuretic doses (250 or 125 mg twiceaily). In this way, we obtained 8 groups of patients aseported previously (Figure 1). All groups were homoge-ous and well matched for general characteristics, clinicalnd laboratory parameters, and cause of HF at randomiza-ion visit (Tables 1 and 2). All patients maintained therescribed treatments, the sodium diets, and the daily fluidntakes assigned during follow-up. No corrections in treat-ents were required after randomization or at the assigned

isits. During the run-in period, no patient required admis-ion for worsening HF. The analysis (performed at the endf the study) of the diaries given to patients showed goodompliance with assigned diets and fluid intakes. Ranges of15 to 125 and 75 to 85 mmol sodium/day were observed inhe groups assigned to normal-sodium and low-sodium di-ts, respectively. Ranges of 1,000 to 1,100 and 1,900 to,100 ml/day were observed in the groups assigned to fluidestriction and more modest fluid restriction, respectively.

No patients received � blockers at the time of admission (ondmission, the patients were in NYHA class IV, stage D). Betalockers were also started when patients were compensateduring hospitalization and after discharge, but only 151 patientsfrom all groups) tolerated the � blocker (carvedilol), whereas the

ther patients had signs of worsening HF, and � blockers were

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iscontinued. In addition, only the 153 patients with atrial fibril-ation received digitalis. This suboptimal medical managementith � blockers and digitalis did not cause a bias in results,ecause it was similar in all the groups.

All patients continued the tailored treatments adminis-ered during hospitalization and the run-in period, as indi-ated in Table 1. No patient in any group was excludeduring follow-up from the study for renal deteriorationcreatinine �2.0 mg/dl), but only the readmitted patientsad increases in plasma creatinine levels �2.0 mg/dl.

Table 3 lists the clinical and laboratory values after 180ays of follow-up. The group receiving 1,000 ml/day of fluidntake combined with high doses of furosemide and 120 mmolodium/day showed greater daily diuresis comparison with thether groups (p �0.05). Interestingly, serum sodium valuesere maintained in the normal range in groups A and B, receiv-

ng 120 mmol sodium/day and restricted fluid intake during fol-ow-up (p � NS). The other six groups showed significant reduc-ions in serum sodium 180 days afterward (p �0.0001; Tables 2nd 3). In addition, the same groups, A and B, showed a modestlyignificant difference in the renal function parameters controlledt baseline and after 6 months of follow-up (creatinine: group A.45 � 0.05 vs 1.48 � 0.06 mg/dl, p �0.05; group B: 1.46 � 0.08s 1.49 � 0.06 mg/dl, p � 0.037) and a nonsignificant differencen BUN in the 2 groups 180 days afterward (p � NS). In contrast,ll the other groups showed significant increases in creatinine andUN values after 6 months of follow-up compared with baselinealues (p �0.0001; Tables 2 and 3).

In all groups, systolic and diastolic blood pressure valuesere decreased without clinical orthostatic events. Group A

able 4esults of the study (180 days): readmissions and mortality

roup n Readmissions

luid intake 1,000 ml/day 103Group A (120 mmol Na/d �

250 mg furosemide bid)52 4 (7.69%)†

Group B (120 mmol Na/d �125 mg furosemide bid)

51 15 (29.4%)*

p value 0.034luid intake 1,000 ml/day 102Group C (80 mmol Na/d �

250 mg furosemide bid)51 25 (49%)†

Group D (120 mmol Na/d �125 mg furosemide bid)

51 28 (54.9%)†

p value NSluid intake 2,000 ml/day 102Group E (120 mmol Na/d �

250 mg furosemide bid)52 27 (51.9%)†

Group F (120 mmol Na/d �125 mg furosemide bid)

50 29 (58%)†

p value NSluid intake 2,000 ml/day 103Group G (80 mmol Na/d �

250 mg furosemide bid)52 37 (71.1%)*,†

Group H (80 mmol Na/d �125 mg furosemide bid)

51 40 (78.4%)*,†

p value NS

The analysis among all 8 groups studied showed significant differences* p �0.05; † p �0.001 (comparisons between group A and groups B toAbbreviations as in Table 1.

normal sodium diet, fluid intake restriction, and high di- d

retic dose) showed a significantly reduced incidence ineadmissions (p �0.001) compared with all the other groupsnd a favorable trend in mortality compared with the groupseceiving low- or normal-sodium diets and higher fluidntake (2,000 ml/day) and with all groups receiving a low-odium diet combined with high or more conventional dosesf diuretics and restriction or more moderate fluid intakeTable 4). Similar results were observed for BUN and cre-tinine plasma levels (Table 3).

The reduction in readmissions in group A showed an inter-sting association with neurohormonal changes. In fact, BNP,ldosterone plasma levels, and PRA were significantly lower inhe group receiving 120 mmol sodium/day combined with highiuretic doses and restricted fluid intake compared with the allhe other groups at the final visit (after 180 days of follow-up).n addition, this group did not show increases in BNP, PRA,nd aldosterone values compared with baseline plasma levels,hereas the other groups showed significant increases (Table 5).ecause of the complexity of the results and the many groupsbtained and analyzed, we list the data in the tables, in which theesults are analyzed and compared by intra- and intergroup anal-sis. The univariate analysis showed that the best independentredictors for readmissions were daily water, sodium intake, andigh diuretic doses during follow-up, and these results were alsoonfirmed in the multivariate analysis (Table 6).

Figure 2 shows the Kaplan-Meier cumulative eventurves for the primary end point (readmissions) in allroups during 180 days of follow-up. This analysis showedn evident early (first 30 days) beneficial effect of theormal-sodium diet, water restriction, and high diuretic

lity Sudden Death Irreversible HF Other Causes

) 1 (1.9%) 0 0

) 0 2 (3.9%) 0

NS NS NS

) 1 (1.96%) 4 (7.8%) 0

%) 2 (3.9%) 4 (7.8%) 1 (1.96%)

NS NS NS

) 1 (1.9%) 3 (5.8%) 1 (1.9%)

) 0 5 (10%) 1 (2%)

NS NS NS

%) 1 (1.9%) 5 (9.6%) 0

%) 2 (3.9%) 5 (9.8%) 1 (1.96%)

NS NS NS

dmissions (p �0.0001).

Morta

1 (1.9%

2 (3.9%

NS

5 (9.8%

7 (13.7

NS

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6 (12%

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for reaH).

oses, which was more consistent during the subsequent

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100 The American Journal of Cardiology (www.AJConline.org)

onths. Kaplan-Meier curves were compared according toiuretic doses, sodium diet, and water intake. In this anal-sis, the groups were associated to perform a comparisonccording to the diuretic dose, fluid intake, and sodium diet.

iscussion

To our knowledge, this was the first investigation to assess theutcomes of different levels of sodium intake combined withifferent fluid intakes and loop diuretic doses in medically treatedatients with NYHA class IV HF recently discharged in NYHAlass II. In the present study, all patients received the same treat-

able 6rude and adjusted analysis of factors associated with hospital

eadmission in patients with heart failure

ariable Crude OR(95% CI)

Adjusted OR(95% CI)

p Value

odiumNormal 1Low 3.07 (2.05–4.58) 2.46 (1.84–3.29) �0.0001ater (ml/d)

1,000 12,000 3.34 (2.22–5.01) 3.82 (2.84–5.14 �0.0001urosemideHigh dose 1Low dose 1.54 (1.04–2.27) 1.84 (1.38–2.44) �0.0001

CI � confidence interval; OR � odds ratio.

able 5omparison between baseline and 180 days of follow-up for plasma renin

roup Aldosterone (pg/ml)

Baseline 180 Days p Value

luid intake 1,000 ml/dayGroup A (120 mmol Na/d �

250 mg furosemide bid)181 � 133 183 � 156*,† NS

Group B (120 mmol Na/d �125 mg furosemide bid)

179 � 137 235 � 174*,† NS

p value NS NSluid intake 1,000 ml/dayGroup C (80 mmol Na/d �

250 mg furosemide bid)177 � 141 295 � 184† 0.0001

Group D (120 mmol Na/d �125 mg furosemide bid)

178 � 136 335 � 238*,† 0.0001

p value NS NSluid intake 2,000 ml/dayGroup E (120 mmol Na/d �

250 mg furosemide bid)180 � 138 325 � 137*,† 0.0001

Group F (120 mmol Na/d �125 mg furosemide bid)

176 � 149 402 � 252*,† 0.0001

p value NS NSluid intake 2,000 ml/dayGroup G (80 mmol Na/d �

250 mg furosemide bid)179 � 151 425 � 316* 0.0001

Group H (80 mmol Na/d �125 mg furosemide bid)

184 � 142 475 � 384* 0.0001

p value NS NS

Data are expressed as mean � SD. The analysis among all 8 groups st* p �0.0001; † p �0.05 (comparisons between groups A and B and groAbbreviations as in Table 1.

ent during hospitalization and 30 days after discharge. This s

riterion allowed us to evaluate the effects of different therapeutictrategies (diuretic doses, sodium diets, and fluid intakes) in theollow-up period in well-matched patients for clinical character-stics and treatments.

We choose 120 mmol sodium/day because epidemio-ogic studies have estimated that in Europe and Italy, theean sodium consumption is 3.5 g (150 mmol) per day.14,15

ur data suggest that a normal-sodium diet with limiteduid intake (1,000 ml/day) associated with high doses of

oop diuretics could be the best treatment, compared withhe other combinations. This combination resulted in a sig-ificant reduction in hospital readmissions for worseningF (the primary end point) and in neurohormonal activation

BNP and aldosterone plasma levels and PRA) after 6onths of follow-up, compared with the other combined

trategies for sodium diet, loop diuretic dose, and fluidntake. We think that the combination of normal sodiumntake associated with high diuretic dose and water restric-ion is probably able to maintain a suitable plasma volumehat per se inhibits the neurohormonal activation observeduring a low-sodium diet, and in the same way induces anmprovement in renal function.16–19

Our results can also appear surprising, because one wouldxpect an increase in creatinine and BUN as observed in aeneral HF population treated with high doses of diuretics andater intake restrictions and spironolactone. In fact, the main-

enance of plasma volume expansion caused increased diuresisnd natriuresis associated with reduced levels of arginine va-

y, aldosterone, and brain natriuretic peptide

PRA (ng/ml/h) BNP (pg/ml)

line 180 Days p Value Baseline 180 Days p Value

2.7 3.42 � 2.8*,† NS 375 � 145 415 � 155* NS

2.8 4.22 � 3.8† NS 365 � 135 555 � 175*,† 0.0001

NS NS 0.0001

3.2 5.73 � 4.1† 0.0001 365 � 155 675 � 225*,† 0.0001

3.1 5.92 � 5.1† 0.0001 370 � 125 745 � 305* 0.0001

NS NS NS

3.3 5.68 � 4.7† 0.024 360 � 165 705 � 245* 0.0001

3.4 6.05 � 5.4† 0.014 355 � 165 795 � 355* 0.0001

NS NS NS

3.2 6.61 � 6.2*,† 0.005 375 � 165 835 � 545* 0.0001

3.7 6.85 � 5.7*,† 0.005 365 � 135 975 � 565* 0.0001

NS NS NS

howed significant differences for all results (p �0.0001).to H).

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udied sups C

opressin (AVP), PRA or angiotensin II, and aldoste-

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101Heart Failure/Combination of Sodium Diets and Diuretic Doses in HF

one.11,20,21 We think that the reduction in diuretic dose inroup B with a normal-sodium diet and water intake restrictionas not able to maintain the achieved balance in plasmaticolume (as obtained during hospitalization and the run-in pe-iod). In fact, group B showed a reduction in diuresis comparedith group A, receiving a high diuretic dose, and also increases

n BNP, PRA, and aldosterone levels. Groups C and D, withuid restriction, high and modest diuretic doses, and a low-odium diet, showed a greater reduction in diuresis, withigher nueurohormonal activation, confirming the role of so-ium diet.10,11,16 In fact, these patients also showed significanteductions in sodium plasma levels as well as higher values ofreatinine compared with the previous groups. These resultsndicate that a low-sodium diet caused worsening renal func-ion associated with a subsequent increase in readmissions.

200,0150,00100,0050,000,00

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nt Furosemide 250 mg/Bid

Furosemide 125 mg/Bid

Log Rank p = 0.002

A

C

igure 2. Kaplan-Meier curves according to different sodium diets (A),eadmission). The analysis showed an evident early beneficial effect of theonsistent during the subsequent months. Cum � cumulative.

The groups receiving a more modest fluid restriction and s

ither a normal-sodium diet or a low-sodium diet and high orore conventional diuretic doses (groups E to H) also showed

egative findings in either clinical or neurohormonal values. Its possible that the increase in fluid intake caused dilutionalyponatremia, causing similar results to those in the groupseceiving a low-sodium diet (groups C and D). In agreement,roups D and H, receiving more conventional diuretic doses,howed reductions in diuresis associated with higher neuro-ormonal values and a higher incidence of readmissions.roups G and H, receiving a low-sodium diet combined withore modest fluid intake and high or conventional diuretic

oses, showed the worst results.The observation of diuresis of almost 2,000 ml/day at

nrollment (when patients were restricted to 1,000 ml/dayater intake) and of 1,200 to 1,900 ml/day at 180 days may

200,00150,00100,0050,000,00

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2000 ml/day

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take (B), and furosemide dose (C) for the primary end point (hospitall-sodium diet, water restriction, and high diuretic doses, which was more

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102 The American Journal of Cardiology (www.AJConline.org)

ruits, vegetables, and so on. The apparent gain in daily fluidn groups E to H must be evaluated with caution, becausehese groups showed a higher incidence of readmissionsfrom 27 to 40 patients for group).

In addition, all the readmitted patients received hyper-onic saline solution and a high dose of loop diuretics andater restriction, which resulted in rapid compensation (�6ays), especially in patients receiving the low-sodium diet.n addition, the difference in natriuresis observed betweenhe groups receiving a normal-sodium diet and those receiv-ng a low-sodium diet confirmed that all patients followedhe assigned diets.

The small variation in aldosterone and PRA plasma levelsn group A suggest that a normal-sodium diet, water restriction,nd a high oral dose of furosemide (enough to maintain a stableody weight) did not allow a further stimulation of the renin-ngiotensin-aldosterone system, which maintained similar val-es to those observed at baseline.11,21–26

The univariate analysis showed that daily water andodium intake were the most important predictors of read-issions. The multivariate analysis confirmed these results

nd showed that water intake was the most important pre-ictor of readmissions.

The most important limitations of the study were the limitedample of patients and the brief follow-up period, but thenterim analysis (as stipulated by the ethics committee) after80 days of follow-up showed a significant decrease in theeadmission rate and recommended the discontinuation of thetudy. Another important limitation was its unblinded design.lthough we attempted to perform a double-blind study, thisas not possible because the patients receiving the prescribediets perceived the difference in the amounts of salt betweenhe 2 diets. However, to reduce bias, randomization was per-ormed by an external team of physicians blinded to the studyrotocol, and another set of different physicians, also blindedo the study protocol, performed the evaluation of the pro-rammed controls and evaluated the readmitted patients withF during follow-up. The laboratory and neurohormonal con-

rols were also performed by physicians blinded to the studyrotocol. Adherence to diet, fluid intake, and doses of furo-emide were also controlled by 2 physicians blinded to thetudy protocol. All of these physicians communicated the re-ults after the conclusion of the study. Another limitation washe low rate of �-blocker therapy, but the enrolled patientsere unresponsive before hospitalization to conventional treat-ent (high doses of furosemide and a combination of diuretics,blockers, ACE inhibitors, etc.), and, during previous hospi-

alizations, �-blocker treatment was discontinued for repeatedpisodes of pulmonary edema.

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