- Email: [email protected]
Diuretics or Ultrafiltration for Acute Decompensated Heart Failure and Cardiorenal Syndrome?
In the Literature Diuretics or Ultrafiltration for Acute Decompensated Heart Failure and Cardiorenal Syndrome? Commentary on Bart BA, Goldsmith SR, Lee KL, et al. Ultrafiltration in decompensated heart failure with cardiorenal syndrome. N Engl J Med. 2012;367(24):2296-2304.
I
n the United States, more than 1 million patients are admitted annually for acute decompensated heart failure (ADHF). Moreover, many patients with ADHF are discharged without clinical evidence of adequate decongestion.1 Approximately 25% of patients with ADHF are readmitted during the next 30 days,2 and up to 20% die within 6 months.3 During the last 10-20 years, several therapies have been shown to have a beneficial impact on the clinical course of patients with chronic congestive heart failure4; however, similar advances have not occurred for the treatment of ADHF.5 Although there are multiple facets to achieving the compensated state in ADHF, the main focus ultimately is on therapies directly responsible for removing excess sodium and water. Declining kidney function during treatment of the congested state (ie, cardiorenal syndrome type I) is one of the strongest predictors of short- and long-term adverse events, including readmission and mortality.1 The mechanisms behind this relationship are complex and likely are patient specific. Diuretics and blood-based extracorporeal ultrafiltration are the main decongestive therapies. Peritonealbased ultrafiltration has been used as well. Recent studies have shown that ultrafiltration is a very effective method for removing excessive fluid from selected patient populations with ADHF.1 The UNLOAD (Ultrafiltration Versus Intravenous Diuretics for Patients Hospitalized for Acute Decompensated Heart Failure) Study reported that ultrafiltration removed a greater volume of fluid than did a diuretic-based regimen.6 Patients in the ultrafiltration arm of the UNLOAD Study also had a statistically significant decrease in readmissions without an increase in adverse events. Thus, it appeared that ultrafiltration might affect ADHF favorably. However, there were concerns about whether diuretics were used optimally in the control group in this study. Additionally, although the change in serum creatinine (SCr) levels was not increased significantly in the ultrafiltration arm at any point in follow-up, twice as many patients in the ultrafiltration arm experienced an increase in SCr level ⬎0.3 mg/dL during the first 24 hours of therapy. Finally, questions remained after this trial about which patients with ADHF should receive ultrafiltration (eg, early vs later in the course of cardiorenal syndrome type I), how ultrafiltration should be performed (eg, duration of Am J Kidney Dis. 2013;62(3):453-456
treatment and titration to clinical targets), and how ultrafiltration and diuretic treatments differ in terms of safety, especially regarding the development of kidney failure. Against this background, the CARRESSHF (Cardiorenal Rescue Study in Acute Decompensated Heart Failure), which compared ultrafiltration versus stepped pharmacologic (loop diuretic–based) decongestion, was published.7
WHAT DOES THIS IMPORTANT STUDY SHOW? CARRESS-HF was a prospective randomized controlled trial sponsored by the National Heart, Lung, and Blood Institute and conducted at 22 centers. Patients with ADHF were eligible if there was evidence of persistent congestion with an increase in SCr level ⱖ0.3 mg/dL. Participants were randomly assigned to either ultrafiltration (Aquadex System 100; CHF Solutions) or stepped pharmacologic therapy involving increasing doses of loop diuretics (with or without metolazone), vasodilators, and/or inotropes based on a treatment algorithm. The primary end point was a bivariate response, including changes in SCr level and body weight 96 hours after randomization. Power calculations suggested the inclusion of 100 patients in each arm; however, enrollment was terminated early (94 patients in each arm) by the Data Safety Monitoring Board because of a lack of benefit on primary and secondary end points and an increase in adverse events in the ultrafiltration group. Ultrafiltration was inferior to stepped pharmacologic therapy with respect to the bivariate primary end point (P ⫽ 0.003) primarily because of a significant increase in SCr level in the ultrafiltration group compared to stepped pharmacologic therapy (an increase of 0.23 ⫾ 0.70 mg/dL for the ultrafiltration group vs a decrease of 0.04 ⫾ 0.53 mg/dL for the pharmacology group; P ⫽ 0.002). There was no significant difference in weight loss at 96 hours between the 2 groups (5.7 ⫾ 3.9 vs 5.5 ⫾ 5.1 kg in the ultrafiltration and Originally published online April 1, 2013. Address correspondence to Benjamin J. Freda, DO, Tufts University School of Medicine, Baystate Medical Center, Renal Division, Western New England Renal and Transplant Associates, 100 Wason Ave, Ste 200, Springfield, MA 01107. E-mail: [email protected] © 2013 by the National Kidney Foundation, Inc. 0272-6386/$36.00 http://dx.doi.org/10.1053/j.ajkd.2013.03.001 453
Freda, Mallidi, and Braden
stepped pharmacologic therapy groups, respectively; P ⫽ 0.58). At the 60-day follow-up, there were no significant differences in weight loss, mortality, or rate of hospitalization for heart failure between the 2 groups. Also, during the 60-day follow-up period, patients in the ultrafiltration group had significantly higher rates of investigator-reported serious adverse events (72% vs 57%; P ⫽ 0.03), including kidney failure, bleeding complications, and intravenous catheter–related complications.
HOW DOES THIS STUDY COMPARE WITH PRIOR STUDIES? There are 5 randomized controlled trials comparing ultrafiltration to diuretics in patients with ADHF (Table 1). Three of the studies used the Aquadex System 100 machine, whereas the study by Hanna et al8 used System One (NxStage), and the ULTRADISCO (Diuretics on Clinical, Biohumoral and Haemodynamic Variables in Patients With Decompensated Heart Failure) Study9 used the Prisma System (Hospal-Gambro Dasco). In the RAPID-CHF (Relief for Acutely FluidOverloaded Patients With Decompensated Congestive Heart Failure),10 UNLOAD, ULTRADISCO, and CARRESS-HF studies, patients were included if they met the clinical criteria for congestion and excluded if they required vasoactive medicines. In the study by Hanna et al,8 patients were included if they had congestion, defined as elevated pulmonary artery capillary wedge pressure ⱖ20 mm Hg, and vasoactive medicines were permitted.8 Although baseline kidney function was similar among the studies (SCr of 1.5-1.9 mg/dL), CARRESSHF was the only study to specifically target worsening kidney function (increase in SCr ⱖ0.3 mg/dL) as an inclusion criterion. All studies aimed to achieve clinically defined targets of decongestion except for the study by Hanna et al,8 which also targeted an improvement in pulmonary artery capillary wedge pressure to ⱕ18 mm Hg, and the ULTRADISCO Study,9 which used a minimally invasive device to monitor hemodynamic parameters, including blood pressure, cardiac index, and stroke volume index. All studies applied ultrafiltration relatively early in the course of hospitalization. The treating physician managed diuretic dosing according to clinical judgment and baseline diuretic doses, except in CARRESS-HF, in which a steppedcare algorithm aimed at achieving daily urine output of 3-5 L was used. In patients who failed to meet this goal with escalating diuretic doses, clinicians also could consider dopamine, dobutamine, nesiritide, nitroglycerin, or escalation to hemodynamic-guided therapy, left ventricular assist device, dialysis, or crossover to ultrafiltration. Compared with other recent trials, the stepped-care algorithm in CARRESS-HF used more 454
distal-acting diuretics (ie, metolazone was used in ⬃50%) and continuous infusion of loop diuretics. In all the previous studies, either fluid removal or weight loss was significantly greater in the ultrafiltration group. However, in CARRESS-HF, there was no significant difference in mean weight loss at 96 hours between groups. CARRESS-HF is the only randomized controlled trial to report a significantly increased incidence of worsening kidney function in the ultrafiltration group compared to the diuretic group, although there was a trend of increased kidney injury in the UNLOAD Study. Although SCr levels returned to baseline values in the ultrafiltration group during follow-up in CARRESS-HF, there was a significantly greater reduction in SCr levels in the diuretic group at 60 days despite a similar decrease in weight in both groups. In contrast to UNLOAD, there was not a significant reduction in heart failure readmission in the ultrafiltration group in CARRESS-HF. In addition, in CARRESSHF, there was a nonsignificant trend toward a higher all-cause readmission rate in the ultrafiltration group (51% vs 40%; P ⫽ 0.14). A similar trend was noted in the ultrafiltration group in the study by Hanna et al.8 CARRESS-HF highlights the poor prognosis of patients with ADHF. Even in the setting of a closely monitored clinical trial, rates of clinical decongestion were low at 4 days (9%-10%) and more than one-third of patients died or were readmitted to the hospital within 60 days.
WHAT SHOULD CLINICIANS AND RESEARCHERS DO? Ultrafiltration is a very effective method to remove fluid from congested patients with ADHF. However, it appears that ultrafiltration joins the ranks of other strategies, such as nesiritide11and Swan-Ganz catheter– guided treatment,12 that cannot be applied broadly across most patients with ADHF or cardiorenal syndrome. As shown in CARRESS-HF, when diuretic dosages are titrated effectively and in a timely manner that uses a continuous infusion of loop diuretics and adds distal-acting diuretics, it is possible in many patients to remove an amount of fluid similar to ultrafiltration. The use of continuous diuretic infusion and distal diuretics may be particularly important in patients with kidney disease and cardiorenal syndrome, in which diuretic resistance is more likely. Although the meaning of transient increases in SCr levels in individual patients is difficult to interpret, it is clear from CARRESS-HF and other studies that ultrafiltration has no “kidney-sparing” benefit. Ultrafiltration clearly is more expensive than diuretics, a difference that is particularly striking if it is unable to reduce readmissions.1 Am J Kidney Dis. 2013;62(3):453-456
Study
Diuretic Dosing
UFR and Duration
CARRESS-HF7 (n ⫽ 188)
Stepped algorithm of furosemide and metolazone titrated to daily urine output of 3-5 L; many received continuous infusion of loop diuretic and 46% received metolazone Dosing at discretion of physician; average daily dose of furosemide, 181 mg; 32% received continuous infusion of diuretic
Prescribed UFR, 200 mL/h; median duration of UF, 40 (IQR, 28-67) h
Weight loss at 96 h of 5.7 (UF) vs 5.5 kg (diuretic), P ⫽ 0.87
Change in SCr at 96 h of ⫹0.23 (UF) vs ⫺0.04 mg/dL (diuretic), P ⫽ 0.003
Prescribed UF duration and UFR (max, 500 mL/h) at discretion of physician; average UFR, 241 mL/h; average UF duration, 12.3 h
Weight loss at 48 h of 5.0 (UF) vs 3.1 kg (diuretic), P ⫽ 0.001
⬎0.3 mg/dL increase in SCr at 24 h in 14.4% (UF) vs 7.7% (diuretic), P ⫽ 0.53; at 48 h: 26.5% (UF) vs 20.3% (diuretic), P ⫽ 0.43
RAPID-CHF10 (N ⫽ 40)
Dosing at discretion of physician; median daily dose of furosemide, 160 mg
Single 8-h session, with most sessions removing 3-4 L
No significant difference in change in SCr
NR
Hanna et al8 (N ⫽ 36)
Dosing at discretion of physician (dose NR)
No significant difference in change in SCr or serum CysC
Readmission at 90 d in 42% (UF) vs 35% (diuretic), P ⫽ 0.087
ULTRADISCO9 (N ⫽ 30)
Continuous infusion of furosemide, 250-500 mg/d, titrated to urine output ⬎2 L/d, signs and symptoms of congestion, hemodynamic targets and change in SCr; dose NR
UF started at 400 mL/h ⫻ 6 h, then decreased to 200 mL/h guided by hemodynamic and clinical assessment and blood volume monitor; mean UFR, 272 mL/h UFR, 100-300 mL/h, titrated according to SBP (87% had UFR of 100 mL/h); duration according to signs and symptoms of congestion and hemodynamic targets; median duration, 46 (IQR, 39-71) h
Weight loss at 24 h of 2.5 (UF) vs 1.86 kg (diuretic), P ⫽ 0.240; fluid removal at 24 h of 4.65 (UF) vs 2.84 L (diuretic), P ⫽ 0.001 Time to achieve PCWP ⱕ18 is 22 (UF) vs 34.8 h (diuretic), P ⫽ 0.081; total volume removed of 5.2 (UF) vs 2.2 L (diuretic), P ⫽ 0.041 Cumulative fluid loss at 36 h of 9.7 (UF) vs 7.8 kg (diuretic), P ⫽ 0.047
No significant difference in change in SCr at end of treatment
NR
UNLOAD6 (n ⫽ 200)
Fluid Loss
Change in Kidney Function
Hospital Readmission
HF hospitalization at 60 d in 26% (UF) vs 26% (diuretic), P ⫽ 0.97; anycause hospitalization at 60 d in 51% (UF) vs 40% (diuretic), P ⫽ 0.12 HF rehospitalization at 90 d in 18% (UF) vs 32% (diuretic), P ⫽ 0.037; unscheduled office and ER visits in 21% (UF) vs 44% (diuretic), P ⫽ 0.009
Abbreviations: CysC, cystatin C; ER, emergency room; HF, heart failure; IQR, interquartile range; NR, not reported; PCWP, pulmonary capillary wedge pressure (in mm Hg); SBP, systolic blood pressure; SCr, serum creatinine (mg/dL); UF, ultrafiltration; UFR, ultrafiltration rate (mL/h).
In the Literature
Am J Kidney Dis. 2013;62(3):453-456
Table 1. Randomized Controlled Trials of UF Versus Diuretics
455
Freda, Mallidi, and Braden
At the present time, we can recommend ultrafiltration only in patients with ADHF who are unable to achieve decongestion with a rational stepped-up diuretic regimen and usual hemodynamic care. Although ultrafiltration has been effective at removing fluid in these patients with otherwise refractory disease, some may progress to requiring dialysis and have poor outcomes despite this treatment.1,13 Because readmission and mortality rates remain high for patients with ADHF and cardiorenal syndrome, further studies are needed to guide clinicians in the use of diuretics and ultrafiltration. In order to improve care, we need methods that optimize active monitoring of congestion and the hemodynamic and kidney responses to treatment that go beyond measurement of body weight and SCr.14 Benjamin J. Freda, DO Jaya Mallidi, MD Gregory L. Braden, MD Baystate Medical Center Springfield, Massachusetts
ACKNOWLEDGEMENTS Support: None. Financial Disclosure: The authors declare that they have no relevant financial interests.
REFERENCES 1. Freda BJ, Slawsky M, Mallidi J, Braden GL. Decongestive treatment of acute decompensated heart failure: cardiorenal implications of ultrafiltration and diuretics. Am J Kidney Dis. 2011;58: 1005-1017. 2. Ross JS, Chen J, Lin Z, et al. Recent national trends in readmission rates after heart failure hospitalization. Circ Heart Fail. 2010;3:97-103.
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3. O’Connor CM, Hasselblad V, Mehta RH, et al. Triage after hospitalization with advanced heart failure: the ESCAPE (Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness) risk model and discharge score. J Am Coll Cardiol. 2010;55:872-878. 4. McMurray JJ. Clinical practice. Systolic heart failure. N Engl J Med. 2010;362:228-238. 5. Kociol RD, Konstam MA. Nesiritide ASCENDs the ranks of unproven treatments for acute heart failure. Am J Kidney Dis. 2012;60:8-11. 6. Costanzo MR, Guglin ME, Saltzberg MT, et al. Ultrafiltration versus intravenous diuretics for patients hospitalized for acute decompensated heart failure. J Am Coll Cardiol. 2007;49:675-683. 7. Bart BA, Goldsmith SR, Lee KL, et al. Ultrafiltration in decompensated heart failure with cardiorenal syndrome. N Engl J Med. 2012;367:2296-2304. 8. Hanna MA, Tang WH, Teo BW, et al. Extracorporeal ultrafiltration vs. conventional diuretic therapy in advanced decompensated heart failure. Congest Heart Fail. 2012;18:54-63. 9. Giglioli C, Landi D, Cecchi E, et al. Effects of ULTRAfiltration vs. DIureticS on clinical, biohumoral and haemodynamic variables in patients with deCOmpensated heart failure: the ULTRADISCO study. Eur J Heart Fail. 2011;13:337-346. 10. Bart BA, Boyle A, Bank AJ, et al. Ultrafiltration versus usual care for hospitalized patients with heart failure: the Relief for Acutely Fluid-Overloaded Patients With Decompensated Congestive Heart Failure (RAPID-CHF) trial. J Am Coll Cardiol. 2005;46: 2043-2046. 11. O’Connor CM, Starling RC, Hernandez AF, et al. Effect of nesiritide in patients with acute decompensated heart failure. N Engl J Med. 2011;365:32-43. 12. Binanay C, Califf RM, Hasselblad V, et al. Evaluation study of congestive heart failure and pulmonary artery catheterization effectiveness: the ESCAPE trial. JAMA. 2005;294:1625-1633. 13. Patarroyo M, Wehbe E, Hanna M, et al. Cardiorenal outcomes after slow continuous ultrafiltration therapy in refractory patients with advanced decompensated heart failure. J Am Coll Cardiol. 2012;60:1906-1912. 14. Ronco C, Kaushik M, Valle R, Aspromonte N, Peacock WF. Diagnosis and management of fluid overload in heart failure and cardio-renal syndrome: the “5B” approach. Semin Nephrol. 2012;32:129-141.
Am J Kidney Dis. 2013;62(3):453-456
I
n the United States, more than 1 million patients are admitted annually for acute decompensated heart failure (ADHF). Moreover, many patients with ADHF are discharged without clinical evidence of adequate decongestion.1 Approximately 25% of patients with ADHF are readmitted during the next 30 days,2 and up to 20% die within 6 months.3 During the last 10-20 years, several therapies have been shown to have a beneficial impact on the clinical course of patients with chronic congestive heart failure4; however, similar advances have not occurred for the treatment of ADHF.5 Although there are multiple facets to achieving the compensated state in ADHF, the main focus ultimately is on therapies directly responsible for removing excess sodium and water. Declining kidney function during treatment of the congested state (ie, cardiorenal syndrome type I) is one of the strongest predictors of short- and long-term adverse events, including readmission and mortality.1 The mechanisms behind this relationship are complex and likely are patient specific. Diuretics and blood-based extracorporeal ultrafiltration are the main decongestive therapies. Peritonealbased ultrafiltration has been used as well. Recent studies have shown that ultrafiltration is a very effective method for removing excessive fluid from selected patient populations with ADHF.1 The UNLOAD (Ultrafiltration Versus Intravenous Diuretics for Patients Hospitalized for Acute Decompensated Heart Failure) Study reported that ultrafiltration removed a greater volume of fluid than did a diuretic-based regimen.6 Patients in the ultrafiltration arm of the UNLOAD Study also had a statistically significant decrease in readmissions without an increase in adverse events. Thus, it appeared that ultrafiltration might affect ADHF favorably. However, there were concerns about whether diuretics were used optimally in the control group in this study. Additionally, although the change in serum creatinine (SCr) levels was not increased significantly in the ultrafiltration arm at any point in follow-up, twice as many patients in the ultrafiltration arm experienced an increase in SCr level ⬎0.3 mg/dL during the first 24 hours of therapy. Finally, questions remained after this trial about which patients with ADHF should receive ultrafiltration (eg, early vs later in the course of cardiorenal syndrome type I), how ultrafiltration should be performed (eg, duration of Am J Kidney Dis. 2013;62(3):453-456
treatment and titration to clinical targets), and how ultrafiltration and diuretic treatments differ in terms of safety, especially regarding the development of kidney failure. Against this background, the CARRESSHF (Cardiorenal Rescue Study in Acute Decompensated Heart Failure), which compared ultrafiltration versus stepped pharmacologic (loop diuretic–based) decongestion, was published.7
WHAT DOES THIS IMPORTANT STUDY SHOW? CARRESS-HF was a prospective randomized controlled trial sponsored by the National Heart, Lung, and Blood Institute and conducted at 22 centers. Patients with ADHF were eligible if there was evidence of persistent congestion with an increase in SCr level ⱖ0.3 mg/dL. Participants were randomly assigned to either ultrafiltration (Aquadex System 100; CHF Solutions) or stepped pharmacologic therapy involving increasing doses of loop diuretics (with or without metolazone), vasodilators, and/or inotropes based on a treatment algorithm. The primary end point was a bivariate response, including changes in SCr level and body weight 96 hours after randomization. Power calculations suggested the inclusion of 100 patients in each arm; however, enrollment was terminated early (94 patients in each arm) by the Data Safety Monitoring Board because of a lack of benefit on primary and secondary end points and an increase in adverse events in the ultrafiltration group. Ultrafiltration was inferior to stepped pharmacologic therapy with respect to the bivariate primary end point (P ⫽ 0.003) primarily because of a significant increase in SCr level in the ultrafiltration group compared to stepped pharmacologic therapy (an increase of 0.23 ⫾ 0.70 mg/dL for the ultrafiltration group vs a decrease of 0.04 ⫾ 0.53 mg/dL for the pharmacology group; P ⫽ 0.002). There was no significant difference in weight loss at 96 hours between the 2 groups (5.7 ⫾ 3.9 vs 5.5 ⫾ 5.1 kg in the ultrafiltration and Originally published online April 1, 2013. Address correspondence to Benjamin J. Freda, DO, Tufts University School of Medicine, Baystate Medical Center, Renal Division, Western New England Renal and Transplant Associates, 100 Wason Ave, Ste 200, Springfield, MA 01107. E-mail: [email protected] © 2013 by the National Kidney Foundation, Inc. 0272-6386/$36.00 http://dx.doi.org/10.1053/j.ajkd.2013.03.001 453
Freda, Mallidi, and Braden
stepped pharmacologic therapy groups, respectively; P ⫽ 0.58). At the 60-day follow-up, there were no significant differences in weight loss, mortality, or rate of hospitalization for heart failure between the 2 groups. Also, during the 60-day follow-up period, patients in the ultrafiltration group had significantly higher rates of investigator-reported serious adverse events (72% vs 57%; P ⫽ 0.03), including kidney failure, bleeding complications, and intravenous catheter–related complications.
HOW DOES THIS STUDY COMPARE WITH PRIOR STUDIES? There are 5 randomized controlled trials comparing ultrafiltration to diuretics in patients with ADHF (Table 1). Three of the studies used the Aquadex System 100 machine, whereas the study by Hanna et al8 used System One (NxStage), and the ULTRADISCO (Diuretics on Clinical, Biohumoral and Haemodynamic Variables in Patients With Decompensated Heart Failure) Study9 used the Prisma System (Hospal-Gambro Dasco). In the RAPID-CHF (Relief for Acutely FluidOverloaded Patients With Decompensated Congestive Heart Failure),10 UNLOAD, ULTRADISCO, and CARRESS-HF studies, patients were included if they met the clinical criteria for congestion and excluded if they required vasoactive medicines. In the study by Hanna et al,8 patients were included if they had congestion, defined as elevated pulmonary artery capillary wedge pressure ⱖ20 mm Hg, and vasoactive medicines were permitted.8 Although baseline kidney function was similar among the studies (SCr of 1.5-1.9 mg/dL), CARRESSHF was the only study to specifically target worsening kidney function (increase in SCr ⱖ0.3 mg/dL) as an inclusion criterion. All studies aimed to achieve clinically defined targets of decongestion except for the study by Hanna et al,8 which also targeted an improvement in pulmonary artery capillary wedge pressure to ⱕ18 mm Hg, and the ULTRADISCO Study,9 which used a minimally invasive device to monitor hemodynamic parameters, including blood pressure, cardiac index, and stroke volume index. All studies applied ultrafiltration relatively early in the course of hospitalization. The treating physician managed diuretic dosing according to clinical judgment and baseline diuretic doses, except in CARRESS-HF, in which a steppedcare algorithm aimed at achieving daily urine output of 3-5 L was used. In patients who failed to meet this goal with escalating diuretic doses, clinicians also could consider dopamine, dobutamine, nesiritide, nitroglycerin, or escalation to hemodynamic-guided therapy, left ventricular assist device, dialysis, or crossover to ultrafiltration. Compared with other recent trials, the stepped-care algorithm in CARRESS-HF used more 454
distal-acting diuretics (ie, metolazone was used in ⬃50%) and continuous infusion of loop diuretics. In all the previous studies, either fluid removal or weight loss was significantly greater in the ultrafiltration group. However, in CARRESS-HF, there was no significant difference in mean weight loss at 96 hours between groups. CARRESS-HF is the only randomized controlled trial to report a significantly increased incidence of worsening kidney function in the ultrafiltration group compared to the diuretic group, although there was a trend of increased kidney injury in the UNLOAD Study. Although SCr levels returned to baseline values in the ultrafiltration group during follow-up in CARRESS-HF, there was a significantly greater reduction in SCr levels in the diuretic group at 60 days despite a similar decrease in weight in both groups. In contrast to UNLOAD, there was not a significant reduction in heart failure readmission in the ultrafiltration group in CARRESS-HF. In addition, in CARRESSHF, there was a nonsignificant trend toward a higher all-cause readmission rate in the ultrafiltration group (51% vs 40%; P ⫽ 0.14). A similar trend was noted in the ultrafiltration group in the study by Hanna et al.8 CARRESS-HF highlights the poor prognosis of patients with ADHF. Even in the setting of a closely monitored clinical trial, rates of clinical decongestion were low at 4 days (9%-10%) and more than one-third of patients died or were readmitted to the hospital within 60 days.
WHAT SHOULD CLINICIANS AND RESEARCHERS DO? Ultrafiltration is a very effective method to remove fluid from congested patients with ADHF. However, it appears that ultrafiltration joins the ranks of other strategies, such as nesiritide11and Swan-Ganz catheter– guided treatment,12 that cannot be applied broadly across most patients with ADHF or cardiorenal syndrome. As shown in CARRESS-HF, when diuretic dosages are titrated effectively and in a timely manner that uses a continuous infusion of loop diuretics and adds distal-acting diuretics, it is possible in many patients to remove an amount of fluid similar to ultrafiltration. The use of continuous diuretic infusion and distal diuretics may be particularly important in patients with kidney disease and cardiorenal syndrome, in which diuretic resistance is more likely. Although the meaning of transient increases in SCr levels in individual patients is difficult to interpret, it is clear from CARRESS-HF and other studies that ultrafiltration has no “kidney-sparing” benefit. Ultrafiltration clearly is more expensive than diuretics, a difference that is particularly striking if it is unable to reduce readmissions.1 Am J Kidney Dis. 2013;62(3):453-456
Study
Diuretic Dosing
UFR and Duration
CARRESS-HF7 (n ⫽ 188)
Stepped algorithm of furosemide and metolazone titrated to daily urine output of 3-5 L; many received continuous infusion of loop diuretic and 46% received metolazone Dosing at discretion of physician; average daily dose of furosemide, 181 mg; 32% received continuous infusion of diuretic
Prescribed UFR, 200 mL/h; median duration of UF, 40 (IQR, 28-67) h
Weight loss at 96 h of 5.7 (UF) vs 5.5 kg (diuretic), P ⫽ 0.87
Change in SCr at 96 h of ⫹0.23 (UF) vs ⫺0.04 mg/dL (diuretic), P ⫽ 0.003
Prescribed UF duration and UFR (max, 500 mL/h) at discretion of physician; average UFR, 241 mL/h; average UF duration, 12.3 h
Weight loss at 48 h of 5.0 (UF) vs 3.1 kg (diuretic), P ⫽ 0.001
⬎0.3 mg/dL increase in SCr at 24 h in 14.4% (UF) vs 7.7% (diuretic), P ⫽ 0.53; at 48 h: 26.5% (UF) vs 20.3% (diuretic), P ⫽ 0.43
RAPID-CHF10 (N ⫽ 40)
Dosing at discretion of physician; median daily dose of furosemide, 160 mg
Single 8-h session, with most sessions removing 3-4 L
No significant difference in change in SCr
NR
Hanna et al8 (N ⫽ 36)
Dosing at discretion of physician (dose NR)
No significant difference in change in SCr or serum CysC
Readmission at 90 d in 42% (UF) vs 35% (diuretic), P ⫽ 0.087
ULTRADISCO9 (N ⫽ 30)
Continuous infusion of furosemide, 250-500 mg/d, titrated to urine output ⬎2 L/d, signs and symptoms of congestion, hemodynamic targets and change in SCr; dose NR
UF started at 400 mL/h ⫻ 6 h, then decreased to 200 mL/h guided by hemodynamic and clinical assessment and blood volume monitor; mean UFR, 272 mL/h UFR, 100-300 mL/h, titrated according to SBP (87% had UFR of 100 mL/h); duration according to signs and symptoms of congestion and hemodynamic targets; median duration, 46 (IQR, 39-71) h
Weight loss at 24 h of 2.5 (UF) vs 1.86 kg (diuretic), P ⫽ 0.240; fluid removal at 24 h of 4.65 (UF) vs 2.84 L (diuretic), P ⫽ 0.001 Time to achieve PCWP ⱕ18 is 22 (UF) vs 34.8 h (diuretic), P ⫽ 0.081; total volume removed of 5.2 (UF) vs 2.2 L (diuretic), P ⫽ 0.041 Cumulative fluid loss at 36 h of 9.7 (UF) vs 7.8 kg (diuretic), P ⫽ 0.047
No significant difference in change in SCr at end of treatment
NR
UNLOAD6 (n ⫽ 200)
Fluid Loss
Change in Kidney Function
Hospital Readmission
HF hospitalization at 60 d in 26% (UF) vs 26% (diuretic), P ⫽ 0.97; anycause hospitalization at 60 d in 51% (UF) vs 40% (diuretic), P ⫽ 0.12 HF rehospitalization at 90 d in 18% (UF) vs 32% (diuretic), P ⫽ 0.037; unscheduled office and ER visits in 21% (UF) vs 44% (diuretic), P ⫽ 0.009
Abbreviations: CysC, cystatin C; ER, emergency room; HF, heart failure; IQR, interquartile range; NR, not reported; PCWP, pulmonary capillary wedge pressure (in mm Hg); SBP, systolic blood pressure; SCr, serum creatinine (mg/dL); UF, ultrafiltration; UFR, ultrafiltration rate (mL/h).
In the Literature
Am J Kidney Dis. 2013;62(3):453-456
Table 1. Randomized Controlled Trials of UF Versus Diuretics
455
Freda, Mallidi, and Braden
At the present time, we can recommend ultrafiltration only in patients with ADHF who are unable to achieve decongestion with a rational stepped-up diuretic regimen and usual hemodynamic care. Although ultrafiltration has been effective at removing fluid in these patients with otherwise refractory disease, some may progress to requiring dialysis and have poor outcomes despite this treatment.1,13 Because readmission and mortality rates remain high for patients with ADHF and cardiorenal syndrome, further studies are needed to guide clinicians in the use of diuretics and ultrafiltration. In order to improve care, we need methods that optimize active monitoring of congestion and the hemodynamic and kidney responses to treatment that go beyond measurement of body weight and SCr.14 Benjamin J. Freda, DO Jaya Mallidi, MD Gregory L. Braden, MD Baystate Medical Center Springfield, Massachusetts
ACKNOWLEDGEMENTS Support: None. Financial Disclosure: The authors declare that they have no relevant financial interests.
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