Errata 1071-9164/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. 37 Journal of Cardiac Failure Vol. 20 No. 5 2014 In the article ‘‘Continuous Ultrafiltration for Congestive Heart Failure: The CUORE Trial’’ by Marenzi et al (J Card Fail 2014;20:9-17), a number of standard deviations were cited incorrectly throughout the article. Because these errors appear throughout the article, the full and corrected version of the article has been posted online along with this erratum. DOI of original article: http://dx.doi.org/10.1016/j.cardfail.2013.11.004 http://dx.doi.org/10.1016/j.cardfail.2014.04.004
Transcript
Errata
1071-9164/$ - see front matter� 2014 Elsevier Inc. All rights reserved.
378
Journal of Cardiac Failure Vol. 20 No. 5 2014
In the article ‘‘Continuous Ultrafiltration for Congestive Heart Failure: The CUORE Trial’’ by Marenzi et al (J Card Fail2014;20:9-17), a number of standard deviations were cited incorrectly throughout the article. Because these errors appearthroughout the article, the full and corrected version of the article has been posted online along with this erratum.
DOI of original article: http://dx.doi.org/10.1016/j.cardfail.2013.11.004http://dx.doi.org/10.1016/j.cardfail.2014.04.004
Background: There are limited data comparing ultrafiltration with standard medical therapy as first-linetreatment in patients with severe congestive heart failure (HF). We compared ultrafiltration and conven-tional therapy in patients hospitalized for HF and overt fluid overload.Methods and Results: Fifty-six patients with congestive HF were randomized to receive standard med-ical therapy (control group; n 5 29) or ultrafiltration (ultrafiltration group; n 5 27). The primary endpoint of the study was rehospitalizations for congestive HF during a 1-year follow-up. Despite similarbody weight reduction at hospital discharge in the 2 groups (7.5 6 4.5 and 7.9 6 5.0 kg, respectively;P 5 .75), a lower incidence of rehospitalizations for HF was observed in the ultrafiltration-treated patientsduring the following year (hazard ratio 0.14, 95% confidence interval 0.04e0.48; P 5 .002).Ultrafiltration-induced benefit was associated with a more stable renal function, unchanged furosemidedose, and lower B-type natriuretic peptide levels. At 1 year, 7 deaths (30%) occurred in the ultrafiltrationgroup and 11 (44%) in the control group (P 5 .33).Conclusions: In HF patients with severe fluid overload, first-line treatment with ultrafiltration is associ-ated with a prolonged clinical stabilization and a greater freedom from rehospitalization for congestive HF.(J Cardiac Fail 2014;20:378.e1e378.e9)Key Words: Congestion, ultrafiltration, diuretics, heart failure.
Fluid overload and congestion are major characteristicsof advanced heart failure (HF) and among the most impor-tant targets of treatment.1,2 In addition to being the cause of
tro Cardiologico Monzino, I.R.C.C.S.; 2Department ofand Community Health, University of Milan, Milan,f Nephrology, Dialysis and Hypertension and 4Depart-edicine Hypertension Centre-Heart Failure Centre, S.ospital, University of Bologna, Bologna, Italy.
eived September 10, 2013; revised manuscript receivedrevised manuscript accepted November 12, 2013.s: Giancarlo Marenzi, MD, FESC, Centro Cardiologicorea 4, 20138 Milan, Italy. Tel: þ39-02-580021; Fax:. E-mail: [email protected] device and all accessory kits necessary fordly supplied by Bellco.egistration. ClinicalTrial.gov number: NCT00360958
8 for disclosure information.ee front matterr Inc. All rights reserved./10.1016/j.cardfail.2013.11.004
378.e
several patients’ symptoms, congestion is also closely asso-ciated with short- and long-term outcomes.3,4 The linkbetween congestion and increased mortality can possiblybe explained by the increase in central venous pressurethat negatively affects renal function and, in turn, neurohu-moral activity.5e7 Thus, the negative prognostic role ofedema in HF is likely due to the combined adverse effectsof renal insufficiency and neurohumoral overactivation.7e9
The best treatment for severe fluid overload in HFremains a matter of debate. International cardiologic guide-lines recommend that HF patients admitted with evidenceof significant fluid overload be initially treated with loopdiuretics; when the patient fails to respond to loop diuretics,several options, including combined diuretic therapy, maybe considered. Only when all diuretic strategies are unsuc-cessful, ultrafiltration or other renal replacement strategiesare considered as reasonable alternatives.10 At present,the use of ultrafiltration is recommended only for patients
who become refractory to diuretics.10,11 Growing evidence,however, indicates that treatment with ultrafiltration mayrepresent a more rapid and physiologic method of fluidremoval than diuretic therapy, and that it is associatedwith a longer clinical stabilization and a lower rehospitali-zation rate.12e16 The first randomized study that evaluated asingle 8-hour course of ultrafiltration in addition to usualcare versus usual care alone was the Relief for AcutelyFluid-Overloaded Patients With Decompensated Conges-tive Heart Failure (RAPID-CHF) trial.12 In that trial, earlyultrafiltration treatment caused greater weight and fluid lossat 24 hours in patients hospitalized with congestive HF thanin usual-care patients.Another randomized study, the Ultrafiltration Versus
Intravenous Diuretics for Patients Hospitalized for AcuteDecompensated Heart Failure (UNLOAD) trial, comparedultrafiltration with standard intravenous diuretic therapy asa first-line treatment for acutely decompensated congestiveHF.13 In that study, patients treated with ultrafiltration hada greater acute fluid loss and fewer 3-month rehospitaliza-tions for HF. Several further clinical data support theconcept that a more effective approach to congestion canbe achieved through isotonic (ultrafiltrate) rather thanwith hypotonic (urine) fluid removal in congestive HF.This is possibly due to the different hemodynamic, neuro-humoral, and renal responses elicited by the diversetonicity of the fluid removed.14e18 Thus, the question iswhen patients with congestion may benefit the most fromultrafiltration, and when they should be treated with suchan approach as a first-line therapy. Moreover, recentstudies have raised concerns about the safety of ultrafiltra-tion,19 and procedural-associated serious adverse eventscould potentially offset clinical benefit and hinder its wide-spread use.In the present study, we analyzed the efficacy of ultrafil-
tration versus conventional pharmacologic therapy inpatients with severe systolic HF who were hospitalizedfor HF worsening and significant weight gain due to overtfluid overload.
Methods
Study Population
The Continuous Ultrafiltration for Congestive Heart Failure(CUORE) trial is a prospective, randomized, unblinded studycomparing ultrafiltration and standard medical treatment inpatients with large fluid overload due to congestive HF. Consecu-tive patients were enrolled from August 1, 2006, to May 31, 2010,at 2 Italian Heart Failure units. Inclusion criteria were age O18years, New York Heart Association (NYHA) functional class IIIor IV, left ventricular ejection fraction (LVEF) #40%, estimatedweight gain due to peripheral fluid overload $4 kg in the preced-ing 2 months (estimation of reference body weight was based onbody weight referred by the patient as his or her normal weight).Exclusion criteria were contraindications to anticoagulation, se-vere renal insufficiency (serum creatinine O3.0 mg/dL), acutepulmonary edema, cardiogenic shock, expected impossibility ofcompleting follow-up for reasons other than patients’ health, and
presence of acute or chronic clinical conditions considered byclinicians to be potential contraindication to ultrafiltration. More-over, patients with planned heart transplantation, left ventricularassist device, or other major cardiac surgery procedures werealso excluded.The investigation conforms with the principles outlined in the
Declaration of Helsinki. The Ethical Committees of both institu-tions approved the protocol. All patients provided writteninformed consents to the study. The study has been registered(ClinicalTrial.gov number: NCT00360958).
Study Protocol
Patients were randomized within 24 hours from hospital admis-sion, in a 1:1 ratio, to receive standard medical therapy (controlgroup) or ultrafiltration (ultrafiltration group), based oncomputer-generated random numbers. Randomization assignmentwas kept in a sealed envelope. A physician not involved in thestudy opened the envelope and assigned the patients. The controlgroup was treated with intravenous loop diuretics by experiencedHF cardiologists according to guideline recommendations.10,11
Patients of the ultrafiltration group were treated with a single ordouble session of ultrafiltration (according to local organizationand availability of nursing surveillance during the night) up to acumulative fluid removal of O2 liters. Fluid withdrawal wasrecommended not to exceed 75% of the estimated initial weightincrease to reduce the risk of hypovolemia-induced acute kidneyinjury associated with excessive dehydration. In both groups, addi-tional medical therapy was left to the discretion of the cardiologistresponsible for the patient. The intravenous dosage of diureticsstarted before randomization was left unchanged in both groups,unless required by the clinical condition. Specifically, pharmaco-logic therapy withdrawal, including diuretics, was not requiredand actually not advised during ultrafiltration sessions. Duringthe follow-up period, physicians modified mainly loop diureticsdose, if needed, because patients were already on optimized andup-titrated treatment at study entry.A complete clinical examination, with particular attention to
body weight and fluid balance, was performed at baseline (beforerandomization), daily during hospitalization, at discharge, and at a1-year follow-up (with study clinical evaluations performed at the6th and 12th months). Renal function (serum creatinine concentra-tion, estimated glomerular filtration rate [eGFR]), plasma electro-lytes, and B-type natriuretic peptide (BNP) levels were evaluatedat baseline, hospital discharge, and at the 6th and 12th months offollow-up. Glomerular filtration rate was estimated with the use ofthe abbreviated Modification of Diet in Renal Disease (MDRD)equation.20 LVEF was measured by echocardiography at baselineand at the 6th and 12th months of follow-up. During the follow-up,all adverse events, unscheduled office visits, emergency depart-ment admissions, and rehospitalizations for congestive HF wererecorded. In case of body weight increase O2 kg after discharge,associated with worsening of the NYHA functional class and needfor diuretic dose increase, patients were re-treated for fluid over-load according to the initial randomization arm. The emergencydepartment physicians, who were not involved in the study andwho were blinded to the treatment arm, made decisions onrehospitalizations.
Ultrafiltration Protocol
Ultrafiltration treatment was performed with the use of a simpli-fied device (Dedyca; Bellco, Mirandola, Italy) specific for patients
Fig. 1. Diagram showing the flow of participants through eachstage of the trial.
378.e3 Journal of Cardiac Failure Vol. 20 No. 5 May 2014
with HF, consisting of a peristaltic pump, a polysulphone filterwith a 50,000-Da membrane cutoff, a blood flow adjustablefrom 40 to 100 mL/min, and a total extracorporeal blood volumeof 100 mL. The vascular access was obtained by a double-lumencatheter ($8 Fr) placed in a major venous vessel. The followinganticoagulation protocol was used: a loading bolus of3,000e5,000 IU heparin (2,000 UI for patients with an interna-tional normalized ratio value of 2e4) was administered insidethe circuit before allowing blood to pass into the filter; and thena continuous heparin infusion rate of 500 IU/h was maintainedduring the ultrafiltration session. The session duration and theultrafiltration rate (100e500 mL/h) were left to the discretion ofthe treating physician; the ultrafiltration rate could be changedduring the procedure according to the clinical situation. Notably,the hematocrit was automatically and continuously monitoredinside the extracorporeal circuit by a dedicated integrated sensorto guide ultrafiltration rate adjustments and thus prevent hypovo-lemia during ultrafiltration.14
Study End Points
The primary end point of the CUORE trial was the incidence ofrehospitalizations for congestive HF in patients treated with ultra-filtration versus standard therapy. Secondary end points included:1) all cause mortality; 2) a combined end point of death and reho-spitalizations for congestive HF; 3) changes in diuretic dose, renalfunction, and BNP values during the follow-up.
Statistical Analysis
For the calculation of the sample size, we assumed a 3-monthrehospitalization rate of 40% in control subjects.21 Moreover,we assumed an incidence of rehospitalizations in the ultrafiltrationgroup of 8% (32% absolute and 80% relative reduction). Using a2-sided c2 test with a significance level of 0.05 and 80% power, 27subjects in each group and a total sample size of 54 were requiredto demonstrate the expected difference between groups.Continuous variables are presented as mean 6 standard devia-
tion and were compared using the t test for independent samples.Variables not normally distributed are presented as median andinterquartile range (IQR) and compared with the Wilcoxon ranksum test. Categoric data are presented as percentages and werecompared with the use of the chi-square test or the Fisher exacttest as appropriate. The primary analyses were analyzed accordingto the intention-to-treat principle. Change over time within treat-ment groups was tested by means of repeated analysis ofcovariance.Cox regression analysis was used to estimate univariate hazard
ratios and their 95% confidence intervals (CIs). Kaplan-Meieranalysis was used to generate time-to-event curves for the clinicalend points (rehospitalizations for congestive HF and combinedend point of death and rehospitalizations for HF). All tests were2 tailed, and a P value of !.05 was required for statistical signif-icance. All calculations were computed with the aid of the SASsoftware package (version 9.13; SAS Institute, Cary, NorthCarolina).
Results
Sixty-four consecutive patients with overt congestive HFwere initially screened and 56 (mean age 75 6 8 years, 46men) were included in the study. Twenty-seven patients
were randomized to the ultrafiltration group and 29 to thecontrol group (Fig. 1). In the overall population, the averageestimated body weight increase due to fluid overload was8 6 4 kg.
Baseline characteristics of the 2 groups were similar(Table 1). In particular, the 2 groups had similar NYHAfunctional class, LVEF, and renal insufficiency severity.The frequency of additional comorbidities was also similarin the 2 groups.
In most (n 5 20; 74%) ultrafiltration-treated patients, asingle session was performed; in the remaining 7 cases,a double daily session was needed, accounting for a totalof 34 procedures. The double session was planned, owingto reduced nurse surveillance during the night, in 4 cases;it was due to technical problems (circuit or filter clotting)in 2 cases and to a clinical reason (transient hypovolemiareflected by hematocrit O10% increase) in 1 case. Nosignificant ultrafiltration-associated complications, inparticular, symptomatic hypotension, acute kidney injury,local infections, or major bleeding, were observed. In 2patients, minor bleeding occurred at the site of vascular ac-cess. In both cases, bleeding was managed by compressivemeasures and heparin dose reduction without interruptionof treatment.
In 6 patients, the filter was changed during treatment forpremature clotting. The mean time of the ultrafiltrationtreatment was 19 6 10 hours, and the ultrafiltrate volumeremoved at the end of the procedure was 4,254 6 1,842mL (range 2,000e8,100 mL). Procedural characteristicsof each ultrafiltration session are presented in Table 2.
In both groups, the stage of congestive HF (NYHA func-tional classification) improved, pulmonary edema wasrelieved, and peripheral edema was significantly reduced
Table 1. Baseline (at Randomization) Characteristics of the Study Patients
Control (n 5 29) Ultrafiltration (n 5 27) P Value
Clinical characteristicsAge, y 73 6 9 75 6 8 .38Men, n (%) 24 (83%) 22 (81%) .91Weight, kg 89 6 17 83 6 12 .13Height, cm 171 6 8 169 6 7 .32Diabetes mellitus, n (%) 13 (45%) 16 (59%) .28Systemic hypertension, n (%) 19 (66%) 13 (48%) .18COPD, n (%) 10 (34%) 14 (52%) .18NYHA III, n (%) 19 (66%) 15 (56%) .44NYHA IV, n (%) 10 (34%) 12 (44%) .44Chronic atrial fibrillation, n (%) 11 (38%) 15 (56%) .18PM/ICD, n (%) 11 (38%) 14 (52%) .29PM/ICD with CRT, n (%) 1 (3%) 2 (7%) .60LVEF, % 32 6 8 32 6 8 1.00EDV, mL 182 6 69 179 6 72 .87ESV, mL 126 6 57 124 6 62 .90Mitral valve insufficiency severity, 0e4 2.2 6 1.0 2.3 6 0.9 .69Heart rate, beats/min 77 6 16 82 6 15 .23Systolic blood pressure, mm Hg 127 6 20 120 6 17 .16Hospitalizations for HF in the past year 1.9 6 1.1 2.2 6 1.8 .45
in response to the assigned treatment. The average dailyintravenous furosemide dose during hospitalization alsowas similar in the 2 groups (Table 1). Recorded hospitaliza-tion time was not significantly shorter in the ultrafiltrationgroup than in the control group (7.4 6 5.6 vs 9.1 6 4.9days, respectively; P 5 .23).At hospital discharge, a similar absolute body weight
reduction was attained in the 2 groups (7.56 4.6 kg in ultra-filtration group vs 7.9 6 5.0 kg in control group; P 5 .75).Clinical and laboratory parameters changes at hospital
discharge and the 1-year follow-up in the 2 study groupsare presented in Table 3. At the 6-month evaluation, pa-tients of the ultrafiltration group had a more stable clinicalcondition than those of the control group. Indeed, onaverage, body weight, renal function, and furosemidedose remained almost unchanged compared with hospitaldischarge in the former group, whereas body weight and
furosemide dose increased and renal function worsened inthe latter group. Finally, BNP values remained unchangedin the control group at the 6-month evaluation, whereasthey were reduced in the ultrafiltration group.
In total, 18 patients (37%) died during the 1-year follow-up: 7 patients (26%) in the ultrafiltration group and 11(38%) in the control group (P 5 .33). Two patients didnot participate in the follow-up owing to chronic dialysisinitiation (control group) and urgent cardiac transplantation(ultrafiltration group).
Only 3 patients (11%) were readmitted for congestive HF(primary end point) in the ultrafiltration group, and allunderwent a new ultrafiltration session, as scheduled byprotocol. Of them, only 1 patient had a further hospitaliza-tion for congestive HF during the follow-up and this patientwas again treated with ultrafiltration. Therefore, 4 rehospi-talizations for congestive HF during the 1-year follow-up
Table 2. Procedural Characteristics of Ultrafiltration (UF) Sessions
Patient SessionCatheter
Venous SiteCatheterSize (F)
UFTime (h)
UFVolume (mL)
Average UFRate (mL/h)
HeparinBolus (IU)
HeparinInfusion (IU/h)
Reason forStopping UF
ProceduralComplication
1 1 femoral 8 10 2,000 200 3,000 500 end of treatment none2 1 femoral 10.5 18 5,440 302 5,000 1,000 end of treatment none3 1 femoral 12 10 2,350 235 5,000 1,000 O10% Htc increase none4 1 femoral 8 10 2,000 200 5,000 1,000 end of treatment none5 1 femoral 8 17 5,000 294 2,000 500 filter clotting filter clotting5 2 femoral 8 11 2,200 200 2,000 500 end of treatment none6 1 femoral 8 15 3,500 233 5,000 600 end of treatment none7 1 femoral 11.5 21 3,530 168 5,000 1000 end of treatment none8 1 femoral 10.5 10 2,560 256 5,000 500 technical problem venous access9 1 femoral 10.5 19 3,000 158 5,000 800 filter clotting filter clotting9 2 femoral 10.5 20 4,000 200 2,500 800 end of treatment none10 1 femoral 11.5 45 6,300 140 3,000 500 end of session none10 2 femoral 11.5 50 7,000 140 3,000 500 end of treatment none11 1 femoral 11.5 24 5,300 220 5,000 400 end of treatment none12 1 femoral 11.5 24 3,600 150 5,000 500 end of treatment none13 1 femoral 11.5 10 2,800 280 3,000 600 end of treatment none14 1 femoral 11.5 31 8,100 261 3,000 1,000 end of treatment none15 1 femoral 8 25 5,000 200 5,000 1,400 end of treatment none16 1 femoral 10.5 24 2,400 100 5,000 600 end of treatment filter clotting17 1 femoral 11.5 20 2,000 100 5,000 800 end of treatment none18 1 femoral 8 22 3,100 140 5,000 400 end of treatment none19 1 femoral 11 20 5,000 250 5,000 500 end of treatment filter clotting20 1 femoral 11.5 22 7,700 350 2,000 500 end of session none20 2 femoral 11.5 15 4,950 330 2,000 500 end of treatment none21 1 femoral 11.5 22 4,500 205 2,000 500 end of session none21 2 femoral 11.5 17 4,000 235 2,000 500 end of treatment none22 1 femoral 10.5 29 4,500 155 5,000 600 end of treatment filter clotting23 1 femoral 11.5 19 7,300 384 2,000 600 end of treatment none24 1 femoral 8 21 7,600 362 2,000 600 end of treatment none25 1 femoral 11 11 3,500 318 2,000 400 O10% Htc increase none25 2 femoral 11 10 3,600 360 2,000 200 end of treatment none26 1 femoral 11.5 9 2,770 307 1,000 400 end of treatment circuit clotting27 1 femoral 11.5 12 5,820 485 1,000 500 end of session none27 2 femoral 11.5 10 2,450 245 1,000 500 end of treatment none
Htc, hematocrit.
378.e5 Journal of Cardiac Failure Vol. 20 No. 5 May 2014
were observed in the ultrafiltration group. Conversely, 14patients (48%) in the control group had at least 1 rehospi-talization for congestive HF; during the 1-year follow-up,a cumulative number of 30 rehospitalizations occurred inthe control group.
The number of rehospitalizations for causes other thancongestive HF was not significantly different in the 2groups (4 patients in the ultrafiltration group and 3 in thecontrol group). During follow-up, 2 patients were admit-ted for symptomatic atrial fibrillation, 2 for implantablecardioverter-defibrillator infection, 1 for gastrointestinalbleeding, 1 for pneumonia, and 1 for transient acute kidneyinjury due to severe decongestion. Therefore, the numbersof 1-year all-cause rehospitalizations were 8 in the ultrafil-tration group and 33 in the control group.
Figure 2 shows the Kaplan-Meier curves for the primaryend point of the study; a significantly greater freedom fromrehospitalization for congestive HF was observed for pa-tients treated with ultrafiltration (hazard ratio 0.14, 95%confidence interval 0.04e0.48; P5 .002). A parallel signif-icant lower rate of events was observed in ultrafiltration-treated patients when the combined end point of deathand re-hospitalization for HF was considered (hazard ratio0.35, 95% confidence interval 0.15e0.69; P 5 .0035;Fig. 3).
Discussion
Ultrafiltration, a mechanical strategy to remove fluidoverload in HF patients, has been a matter of intense inves-tigative interest in recent years and is clearly emerging as auseful therapeutic strategy.12e18 Indeed, several studieshave consistently shown that ultrafiltration is able toimprove signs and symptoms of congestion, to amelioratehemodynamics and neurohumoral status, to increasediuresis, and to lower diuretic requirements in patientswith advanced HF.12e16,22e26 Nevertheless, no officialguidelines for the use of ultrafiltration in patients with HFhave been defined, nor has ultrafiltration been consideredto be a frontline treatment option for HF patients with se-vere fluid overload. It should be recognized that informa-tion about clinical indications, therapeutic protocols, andimpacts of this adjunctive treatment on hard clinical endpoints is still uncertain. At present, cardiologic guidelinesrecommend the use of ultrafiltration only in patients whohave not responded to diuretic therapy.10,11 However,when ultrafiltration was used late during hospitalization,particularly in patients who had already developed acutekidney injury, as in the recently published CardiorenalRescue Study in Acute Decompensated Heart Failure(CARRESS-HF), no advantage from ultrafiltration over a
Table 3. Laboratory Parameters at Baseline, Hospital Discharge, and Follow-Up in the 2 Study Groups
ANCOVA, analysis of covariance; BNP, B-type natriuretic peptide; eGFR, estimated glomerular filtration rate; LVEF, left ventricular ejection fraction.*P values refer to 6-month follow-up.yFurosemide dose at baseline refers to intravenous administration.
Ultrafiltration in CHF � Marenzi et al 378.e6
pharmacology strategy was demonstrated.19 On the otherhand, the UNLOAD trial has shown that early treatmentwith ultrafiltration in hospitalized HF patients with hyper-volemia produces greater weight and fluid loss than intrave-nous diuretics and is associated with a 44% reduction ofrehospitalizations for HF over the subsequent 3 months.13
Fig. 2. Freedom from rehospitalization for congestive heart failureat 1 year in patients treated with ultrafiltration or standard therapy.
For logistical, technical, and economic reasons, ultrafiltra-tion can not be applied to all congestive HF patients, butfurther investigative effort is required to identify the idealcandidates for the therapy.
At first glance, our observations are inconsistent withthose of the CARRESS-HF.19 However, several differencesfrom the CARRESS-HF should be noted. First, clinicalindications for ultrafiltration and HF population studiedwere different, with ultrafiltration being an elective first-line treatment in our study and a rescue therapy in HFcomplicated by acute kidney injury in the CARRESS-HF.Second, the decongestion protocol used in ultrafiltration-treated patients in the CARRESS-HF was likely too aggres-sive in terms of speed and total amount of fluid removal, asclearly highlighted in the editorial comment of the CARR-ESS-HF,27 particularly when the clinical context (precari-ous hemodynamic stability of patients with acute kidneyinjury) and the lack of a well defined prudential volumetarget are considered. Third, the fluid removal rate wasnot customized (in the CARRESS-HF, ultrafiltration wasperformed at a fixed rate of 200 mL/h). Fourth, the use ofa stepped pharmacologic therapy in the control group ofthe CARRESS-HF, including intravenous vasodilators andinotropic agents, aimed to maintain a predefined urineoutput target. Fifth, in the CARRESS-HF, as well as in
Fig. 3. Freedom from the combined end point of rehospitalizationfor congestive heart failure and death at 1 year in patients treatedwith ultrafiltration or standard therapy.
378.e7 Journal of Cardiac Failure Vol. 20 No. 5 May 2014
the UNLOAD study, loop diuretics were discontinued orprohibited during ultrafiltration.
In the CUORE study, we randomized highly selectedpatients with severe systolic congestive HF, defined byLVEF #40%, and fluid overload, defined by $4 kg ofrecent weight gain, to ultrafiltration or standard therapy.Notably, although patients with severe renal insufficiencywere excluded, our ultrafiltration-treated patients hadmore severe HF than those enrolled in the UNLOAD trial,as reflected by older mean age (75 vs 62 y), higher rate ofleft ventricular systolic dysfunction (100% vs 70% of pa-tients with LVEF #40%), worse baseline renal function(serum creatinine 1.9 mg/dL vs 1.5 mg/dL), and higherfurosemide daily dose requirement (153 mg vs 129 mg).Similar characteristics to those in our study were observedin patients enrolled in the Effects of Ultrafiltration VersusDiuretics on Clinical, Biohumoral, and Hemodynamic Vari-ables in Patients With Decompensated Heart Failure (UL-TRADISCO) study, in which ultrafiltration treatment wasdemonstrated to facilitate a greater clinical improvementand to ameliorate hemodynamics compared with diureticinfusion.16 Altogether, the differences in HF patients popu-lation and ultrafiltration methodology make the studiesdifficult to compare though they allow clarification of theclinical scenario where ultrafiltration appears to be indi-cated or not useful, if not deleterious.
The presence of overt peripheral edema characterizespatients with higher neurohumoral activation, particularlyof the renin-angiotensin-aldosterone system.28 In thesepatients, glomerular filtration rate is usually decreased,sodium reabsorption in the proximal tubule is increased,and urinary sodium excretion is reduced, despite apparentlyoptimized diuretic therapy.7,28 Thus, although they can notstrictly be classified as having refractory HF, they areunderresponsive to, and can not take full advantage of,diuretics, with the result of long time for achievement ofclinical stabilization, further neurohumoral activation, andworsening renal function.5e7 This results in dischargewith unresolved congestion in most cases,29 a high rateof hospital readmissions for congestive HF, and poor
prognosis.4,30 Conversely, ultrafiltration, by providing amore ‘‘physiologic’’ (isotonic) decongestion, is able toincrease the amount of sodium eliminated for a given fluidvolume, resulting in a resetting of neurohumoral activityand achievement of a more favorable and long-lasting waterand salt balance.15,31 Ultrafiltration may contribute to theclinical improvement of congestive HF patients via severalpathways: first, by a direct mechanical action achieved viathe correction of fluid overload, which reduces ventricularfilling pressures and extracardiac constraint and improveslung-heart interaction and cardiac performance32; and sec-ond, by tending to correct the neurohumoral imbalanceand underfilling the arterial component, which is inducedby HF and diuretic therapy.
Reduction in venous congestion and enhancement incardiac performance and intravascular volume improvesystemic and renal hemodynamics and promote urineoutput and sodium excretion.28 Importantly, the favorableeffects of ultrafiltration are not reproduced by the removalof an equivalent fluid volume by high-dose intravenousdiuretic infusion.15,16 Indeed, in the CUORE trial, patientsrandomized to ultrafiltration had a significantly lowerfrequency of rehospitalization for congestive HF than didcontrol subjects. This beneficial effect was maintained forup to 1 year. The reduction in rehospitalizations was asso-ciated with maintenance of a more stable body weight,renal function and lower diuretic dose in the first 6 monthsafter discharge compared with control subjects.
The reduction of rehospitalizations for HF, observed inour trial as well as in the UNLOAD trial, confirms thatcongestion represents one of the major prognostic determi-nants, but it also indicates that decongestion alone is notsufficient, because we achieved similar decongestion inboth groups but the ultrafiltration-treated patients had agreater freedom from rehospitalization. Basically, our studypatients were not refractory to diuretics; indeed, during theindex hospitalization, both groups had a similar bodyweight reduction, and both clinical stability and congestionresolution were achieved in a fairly similar time. This waspossibly due to our prudential recommendation of incom-plete (!75% of estimated body weight gain) and slowlyobtained fluid removal to avoid untoward acute hemody-namic or renal effects which may offset the positive actionof ultrafiltration. To do so, hematocrit was continuouslymonitored during ultrafiltration and only minor hematocritincreases were allowed. Notably, even if hypervolemiawas not completely resolved at the end of ultrafiltration,long-term clinical benefit was greater than that obtainedwith standard therapy. This emphasizes the fact that the‘‘quality’’ of the fluid withdrawn, more than its amount,was the major causative factor for the different outcomeobserved in the 2 groups.
The mechanisms underlying the long-term positive effectof ultrafiltration remain unclear, and they can not be fullyelucidated by our data. However, based on earlier studies,it is likely that differences in neurohumoral response tofluid withdrawal might play a role, despite a similar
Ultrafiltration in CHF � Marenzi et al 378.e8
capacity of ultrafiltration and diuretic therapy to improvesymptoms and promote short-term clinical stabilization inpatients without refractory HF.15 Indeed, the decongestionobtained with ultrafiltration, compared with diuretictherapy, does not elicit, or even turns off, neurohumoralcompensatory mechanisms, resulting in long-term mainte-nance of the clinical benefit and, consequently, in a reduc-tion of further hospitalizations.15,18 When ultrafiltration isrepeated, as in our study, to treat rehospitalized patients,these differences in neurohumoral response are expectedto increase in parallel with the length of the consideredfollow-up and the number of rehospitalizations.Despite the fact that the short-term effects of ultrafiltra-
tion in congestive HF have been extensively studied, fewstudies have evaluated the impact of ultrafiltration on mor-tality in long-term follow-up. To our knowledge, this is thefirst prospective randomized study evaluating 1-year clin-ical outcomes; although the study was largely underpow-ered to allow for any conclusive inference on the effect ofultrafiltration on mortality, the data strongly suggest apossible positive effect on patients’ survival.
Study Limitations
First, the size of the population was small and, moreover,enrolled in a longer than planned period of time. This wasdue to the strict inclusion and exclusion criteria of the pre-sent study. Second, although patients’ allocation to ultrafil-tration versus conventional treatment was randomized,treatment was not, and could not be, blinded. Therefore,the presence of an investigator bias can not be excluded.However, it is unlikely that a placebo effect influencedobjective parameters such as body weight, renal function,and long-term outcomes. The Study of Heart Failure Hospi-talizations After Aquapheresis Therapy Compared WithIntravenous Diuretic Treatment (AVOID-HF) is an ongoingrandomized controlled trial recruiting 800 patients(NCT01474200). The trial is intended to determine whetherpatients will have fewer HF events after receiving ultrafil-tration therapy compared with intravenous diuretics. Theresults of that study are expected to provide much moredefinitive information on the effect of ultrafiltration onHF events. Third, the short- and long-term economicimpact of ultrafiltration was not evaluated in our trial andshould be a matter of dedicated investigation, particularlyconsidering the potential use of upcoming less invasive(single-lumen cannula inserted in a peripheral vein) andless expensive devices. Fourth, differently from recentstudies,19 in our study we did not use elaborate drug algo-rithms involving continuous infusion of diuretics, vasoac-tive therapy, or both; we left the patients treatment to theuncharged physician. The lack of a standardized protocol-based diuretic use and/or titration in the control arm mayhave influenced, at least in part, our results. Fifth, the olderage of our population may limit generalizability to youngerpopulations. Finally, physicians having a long experiencewith ultrafiltration treated all of the patients, and this aspect
may have significantly affected the results of our study.Therefore, the overall applicability of our findings remainsuncertain.
Conclusion
The CUORE trial shows that early (first-line) treatmentwith ultrafiltration in fluid-overloaded HF patients, selectedon the basis of only partial responsiveness to diuretics, isassociated with a significant long-term reduction in rehospi-talizations for HF, without any impact on mortality.
Acknowledgment
The authors acknowledge Ilaria Vicini, PhD, for herimportant contribution to this work.
Disclosures
None.
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