CAM 20222

Ultrafiltration in Decompensated Heart Failure

Category:Medicine   Last Reviewed:February 2020
Department(s):Medical Affairs   Next Review:February 2021
Original Date:February 2007    

Description:
Ultrafiltration is a technique used to remove excess fluid from patients with volume overload and heart failure. It removes fluid from the blood by using pressure differentials with dialysis equipment or similar filtration devices.

For individuals who have decompensated heart failure who receive ultrafiltration, the evidence includes randomized controlled trials (RCTs) and systematic reviews. Relevant outcomes are overall survival, quality of life, hospitalizations and treatment-related morbidity. Some, but not all, published RCTs reported beneficial effects of ultrafiltration on physiologic measures and intermediate outcomes such as weight loss, and/or reductions in intensive care unit stay or readmissions for heart failure; however, RCTs have not demonstrated improvement in clinical outcomes, such as survival. Additionally, significant worsening of renal function and serious adverse events have been reported following ultrafiltration in patients with acute heart failure. Finally, available trials have several methodologic limitations and long-term outcomes have not been reported. The evidence is insufficient to determine the effects of the technology on health outcomes.

Background 
Heart Failure 
Heart failure is a relatively common condition that frequently results in hospitalizations and readmissions. 

Treatment 
Various treatment approaches are being explored, especially when the condition is refractory to conventional therapy. Ultrafiltration, also referred to as aquapheresis, is a technique being investigated for a possible role in hospitalized patients with marked volume overload from heart failure. It is used to remove fluid from the blood via pressure differentials during treatment with a dialysis machine or similar filtration device. 

It has been suggested that ultrafiltration may offer greater and more expeditious volume and sodium removal than conventional therapies, particularly in patients with decompensated heart failure whose fluid overload is unresponsive to medical management. 

Newer devices that allow continuous ultrafiltration in ambulatory patients are under investigation to reduce volume overload. 

Outcome Measures 
Heart failure is a condition with a variable natural history and multiple confounders of outcome. Clinical outcomes of interest in the treatment of heart failure include survival, hospitalization, complications, and quality of life; although removal of fluid and sodium, and weight loss, are important, they are surrogate outcomes that do not necessarily translate into clinical outcomes. Because ultrafiltration does not directly affect ventricular function, its effect on clinical outcomes is difficult to evaluate.

Regulatory Status
In June 2002, the Aquadex FlexFlow System (Baxter, Deerfield, IL) was cleared for marketing by FDA through the 510(k) process. An amended 510(k) approval (classified as a high permeability dialysis system) was given in September 2007 following modifications. FDA determined that this device was substantially equivalent to existing devices for use in temporary (8 hours) ultrafiltration treatment of patients with fluid overload who have failed diuretic therapy and for extended (>8 hours) ultrafiltration treatment of patients with fluid overload who have failed diuretic therapy and require hospitalization. FDA product code: KDI.

Policy:
The use of ultrafiltration is investigational and/ or unproven and is therefore considered NOT MEDICALLY NECESSARY in patients with heart failure.

Policy Guidelines
This policy does not apply to patients with renal failure being treated using dialysis.

There are no specific CPT codes for this procedure. There is an ICD-9-CM procedure code specific to the procedure:

99.78 Aquapheresis

Benefit Application
BlueCard®/National Account Issues
State or federal mandates (e.g., FEP) may dictate that all FDA-approved devices may not be considered investigational and, thus, these devices may be assessed only on the basis of their medical necessity.

Rationale
Evidence reviews assess the clinical evidence to determine whether the use of a technology improves the net health outcome. Broadly defined, health outcomes are length of life, quality of life, and ability to function -- including benefits and harms. Every clinical condition has specific outcomes that are important to patients and to managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of a technology, 2 domains are examined: the relevance and the quality and credibility. To be relevant, studies must represent one or more intended clinical uses of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. RCTs are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Heart failure
Systematic Reviews
A number of systematic reviews of RCTs have been published. None of the meta-analyses reporting all-cause mortality found significant differences in mortality between ultrafiltration and diuresis.1,2,3,4, Moreover, all but one5, of the meta-analyses that reported rehospitalizations found no evidence that ultrafiltration was significantly associated with a decrease in rates.1,2,3,4, All meta-analyses found that ultrafiltration resulted in significantly greater weight loss and fluid removal than diuretic therapy and none of the pooled analyses found significant differences between treatments in adverse events.1,2,3,4,5,6,7,

Most recently, Kwok et al (2017) published a systematic review and meta-analysis of 10 RCTs (total N=857 participants) evaluating ultrafiltration in patients with acute decompensated heart failure.4, A pooled analysis of 7 RCTs did not find a significant difference between groups in all-cause mortality (relative risk (RR), 1.08; 95% confidence interval (CI), 0.77 to 1.52; p=0.65). A pooled analysis of 7 RCTs did not find a significant difference in absolute change in creatinine levels (mean difference (MD), 0.01 mg/dL, 95% CI, -0.17 to 0.19 mg/dL; p=0.92). However, in a pooled analysis of 9 RCTs, there was significantly greater weight change in the ultrafiltration group than in the control group (MD = -1.86 kg; 95% CI, -4.68 to 0.97 kg; p<0.001). Pooled analyses of hospitalization rates did not find a statistically significant benefit of ultrafiltration. In a pooled analysis of 3 RCTs, the RR for all-cause hospitalization was 0.89 (95% CI, 0.43 to 1.86) and, in a pooled analysis of 5 RCTs, the RR was 0.71 (95% CI, 0.51 to 1.00; p=0.05).

Randomized Controlled Trials
UNLOAD was a nonblinded trial that randomized 200 patients hospitalized for heart failure and hypervolemia during the first 24 hours of hospitalization to ultrafiltration or to usual care (diuretics).8, The trial was conducted at 28 U.S. centers. Primary efficacy end points were 48-hour weight loss and dyspnea score (1- to 7-point Likert scale). Primary safety end points were changes in blood urea nitrogen, creatinine, and electrolyte levels throughout hospitalization and 90-day follow-up, and episodes of hypotension requiring therapeutic intervention at 48 hours. The trial had at least 13 secondary efficacy end points, including length of index hospitalization, quality of life assessments throughout follow-up, and resource utilization (rehospitalization for heart failure, unscheduled office and emergency department visits) during follow-up. Results showed more weight loss in the ultrafiltration group (5.0 kg) than in the usual care group (3.1 kg) from baseline to 48 hours (p=0.001), with no difference between groups in dyspnea scores. There was no significant difference in the length of stay of the index hospitalization between groups, but the ultrafiltration group (18%) had a smaller percentage of patients rehospitalized for heart failure at 90 days than the diuretics group (32%; p=0.037). There were no significant differences between treatment groups for quality of life assessments or renal function, except for a greater likelihood of hypokalemia in the diuretics group (p=0.018). Additional subgroup analysis by Costanzo et al (2010) compared outcomes between ultrafiltration and standard intravenous diuretics by continuous infusion or bolus injection.9, Similar fluid loss was observed for ultrafiltration and continuous diuretic infusion, with outcomes similar to the original UNLOAD trial (ie, fewer rehospitalizations for heart failure at 90 days only in patients who underwent ultrafiltration).

Detailed analysis of UNLOAD identified methodologic concerns that could have influenced trial results. The publication provided insufficient detail on patient status during the trial. The investigators reported that 20 patients died during the trial (9 in the ultrafiltration group, 11 in the usual care group), but the timing of deaths was not reported. The trial results, as reported, also raised concerns about dropout rates and patient follow-up for various outcome measures. For example, although 100 patients were randomized to each group, at 48 hours, only 83, 80, and 69 patients in the ultrafiltration group and 84, 83, and 75 patients in the standard care group, respectively, were reported for the 3 primary outcomes (weight loss, dyspnea score, change in serum creatinine level, respectively). For readmission at 90 days, while the denominators were reported as 89 for the treatment group and 87 for the usual care group, information from the report lists 45 and 41 patients at risk, respectively, at 90 days. In addition, it is not clear from the methods that intention-to-treat analyses were performed; and, despite the number of outcomes assessed, there appears to have been no statistical correction for multiple comparisons. Finally, neither participants nor investigators were blinded to treatment, which is a potential source of bias for outcomes such as rehospitalizations, which are clinically based decisions.

The CARRESS Trial, reported by Bart et al (2012), compared fixed-rate ultrafiltration with diuretic-based stepped pharmacologic therapy in 188 patients hospitalized with acute decompensated heart failure and decreased renal function.10, Unlike the UNLOAD trial, outcomes in CARRESS were better in the diuretic group. Primary outcomes were changes in serum creatinine and body weight, as measured 96 hours after randomization. The ultrafiltration group experienced a significant increase in serum creatinine levels (0.23 mg/dL) compared with the pharmacologic therapy group (0.04 mg/dL), which had a decrease (p=0.003). Mean weight loss did not differ significantly between groups (5.7 kg in the ultrafiltration group vs 5.5 kg in the pharmacologic therapy group; p=0.58). Serious adverse events occurred more frequently in the ultrafiltration group (72%) during the 60-day follow-up period than in the pharmacologic therapy group (57%; p=0.03). Those events included kidney failure, bleeding complications, and complications related to intravenous catheters.

Marenzi et al (2014) published findings of the CUORE trial.11, This RCT included 56 hospitalized heart failure patients without severe renal insufficiency who were treated with ultrafiltration (n=27) or standard medical therapy (n=29). All patients had a left ventricular ejection fraction of 40% or less, fluid overload of 4 kg or more of recent weight gain, and were partially responsive to diuretic therapy. The primary end point was the incidence of heart failure-related rehospitalizations during the year after treatment. Four rehospitalizations occurred in the ultrafiltration group, which was significantly fewer instances than the 30 rehospitalizations in the control group (hazard ratio, 0.14; 95% CI, 0.04 to 0.48; p=0.002). At the 1-year follow-up, 7 (26%) deaths were reported in the ultrafiltration group vs 11 (38%) in the control group (p=0.33). Weight loss at discharge was similar in both groups (p=0.75).

The most recently published RCT is the AVOID-HF (Aquapheresis versus Intravenous Diuretics and Hospitalization for Heart Failure) trial by Costanzo et al (2016).12, This unblinded multicenter RCT tested a strategy of adjustable ultrafiltration and compared it with adjustable intravenous loop diuretic treatment. Eligibility included hospitalization with a primary diagnosis of acute decompensated heart failure, and participants were randomized within 24 hours of hospital admission. The trial originally aimed to enroll 810 patients and the sample size calculation determined that this number of participants was needed to have sufficient power for the primary end point. However, after enrolling 224 (27.5%) patients, the trial sponsor terminated the study due to slow enrollment. The analysis reports on 221 (110 patients in the ultrafiltration group, 111 in the diuretic group) enrolled at the time of study termination. The primary end point (a composite of heart failure rehospitalization or unscheduled or outpatient or emergency department treatment for heart failure) occurred in 25% of the ultrafiltration group and 35% of the diuretic group (exact numbers not reported). The difference in event rates between groups was not statistically significant (p=0.106). By 90 days, death occurred in 17 (15%) ultrafiltration patients and 14 (13%) diuretic patients (p=0.827). The proportion of patients who experienced any adverse event or serious adverse event did not differ significantly between groups, but the ultrafiltration group (15%) experienced significantly more serious adverse events determined to be related to trial therapy than the diuretic group (5%; p=0.026).

Summary of Evidence
For individuals who have decompensated heart failure who receive ultrafiltration, the evidence includes randomized controlled trials and systematic reviews. Relevant outcomes are overall survival, quality of life, hospitalizations, and treatment-related morbidity. A number of RCTs and meta-analyses of these controlled trials have been published. Meta-analyses did not find significant differences in all-cause mortality in patients receiving ultrafiltration or diuretics, and nearly all meta-analyses found no significant between-group differences in rehospitalization rates. RCTs and meta-analysis found that patients undergoing ultrafiltration had significantly greater weight loss and more fluid removal than diuretic therapy. Although pooled analyses of RCTs did not find significant differences in adverse events in groups receiving ultrafiltration or diuretics, some RCTs (eg, CARESS, AVOID-HR) have reported higher rates of adverse events after ultrafiltration, including significant worsening of renal function and treatment-related serious adverse events. The available trials have several methodologic limitations (eg, unblinded outcome assessment, incomplete information on patient status). Moreover, long-term outcomes (ie, >1 year) have not been reported The evidence is insufficient to determine the effects of the technology on health outcomes.

Practice Guidelines and Position Statements 
American College of Cardiology Foundation and American Heart Association
The American College of Cardiology Foundation and American Heart Association published joint guidelines (2013) on the diagnosis and management of heart failure in adults (under Recommendations for Hospitalized Patient) that list ultrafiltration as a class IIb recommendation (benefit greater than or equal to risk, additional studies needed).13, The recommendations indicated that ultrafiltration "may be considered for patients with obvious volume overload to alleviate congestive symptoms and fluid weight" (level of evidence B: conflicting evidence) and "for patients with refractory congestion not responding to medical therapy" (level of evidence C: recommendation less well established). A 2017 update from the American College of Cardiology, the American heart Association Task Force on Clinical Practice Guidelines, and the Heart Failure Society of America did not mention ultrafiltration.14,

European Society of Cardiology and Heart Failure Association

The European Society of Cardiology and Heart Failure Association released joint guidelines (2012) on the diagnosis and treatment of acute heart failure, which stated "ultrafiltration is sometimes used to remove fluid in patients with HF [heart failure],although [it] is usually reserved for those unresponsive or resistant to diuretics."15,In 2016, an updated noted that "ultrafiltration is not recommended and should be confined to patients who fail to respond to diuretic-based strategies."16,

Heart Failure Society of America
The Heart Failure Society of America's comprehensive heart failure practice guidelines (2010) indicated that ultrafiltration may be considered for the treatment of acute decompensated heart failure fluid overload in lieu of diuretics (level B evidence: cohort or smaller studies).17, The Society's guidelines also indicated ultrafiltration may be considered when congestion continues despite diuretic therapy (level C evidence: opinion).

U.S. Preventive Services Task Force Recommendations
Not applicable.

Ongoing and Unpublished Clinical Trials 
Some currently unpublished trials that might influence this review are listed in Table 1. 

Table 1. Summary of Key Trials

NCT No. Trial Name Planned Enrollment Completion Date

Ongoing

NCT02846337

Ultrafiltration Versus Medical Therapies in the Management of the Cardio Renal Syndrome (UF-CARE)

154 Sep 2019

NCT: national clinical trial.

References:

  1. Cheng Z, Wang L, Gu Y, et al. Efficacy and safety of ultrafiltration in decompensated heart failure patients with renal insufficiency. Int Heart J. May 13 2015;56(3):319-323. PMID 25902884.
  2. Kwong JS, Yu CM. Ultrafiltration for acute decompensated heart failure: a systematic review and meta-analysis of randomized controlled trials. Int J Cardiol. Mar 15 2014;172(2):395-402. PMID 24512880.
  3. Zhi Q, Liang JC. Diuretics and ultrafiltration in acute heart failure syndrome. Int Heart J. Dec 2013;54(6):390-394. PMID 24309449.
  4. Kwok CS, Wong CW, Rushton CA, et al. Ultrafiltration for acute decompensated cardiac failure: A systematic review and meta-analysis. Int J Cardiol. Feb 01 2017;228:122-128. PMID 27863352.
  5. Jain A, Agrawal N, Kazory A. Defining the role of ultrafiltration therapy in acute heart failure: a systematic review and meta-analysis. Heart Fail Rev. Sep 2016;21(5):611-619. PMID 27154520.
  6. De Vecchis R, Esposito C, Ariano C. Efficacy and safety assessment of isolated ultrafiltration compared to intravenous diuretics for acutely decompensated heart failure: a systematic review with meta-analysis. Minerva Cardioangiol. Apr 2014;62(2):131-146. PMID 24686993.
  7. Wen H, Zhang Y, Zhu J, et al. Ultrafiltration versus intravenous diuretic therapy to treat acute heart failure: a systematic review. Am J Cardiovasc Drugs. Oct 2013;13(5):365-373. PMID 23801482.
  8. Costanzo MR, Guglin ME, Saltzberg MT, et al. Ultrafiltration versus intravenous diuretics for patients hospitalized for acute decompensated heart failure. J Am Coll Cardiol. Feb 13 2007;49(6):675-683. PMID 17291932.
  9. Costanzo MR, Saltzberg MT, Jessup M, et al. Ultrafiltration is associated with fewer rehospitalizations than continuous diuretic infusion in patients with decompensated heart failure: results from UNLOAD. J Card Fail. Apr 2010;16(4):277-284. PMID 20350693.
  10. Bart BA, Goldsmith SR, Lee KL, et al. Ultrafiltration in decompensated heart failure with cardiorenal syndrome. N Engl J Med. Dec 13 2012;367(24):2296-2304. PMID 23131078.
  11. Marenzi G, Muratori M, Cosentino ER, et al. Continuous ultrafiltration for congestive heart failure: the CUORE trial. J Card Fail. Jan 2014;20(1):9-17. PMID 24269855.
  12. Costanzo MR, Negoianu D, Jaski BE, et al. Aquapheresis versus intravenous diuretics and hospitalizations for heart failure. JACC Heart Fail. Feb 2016;4(2):95-105. PMID 26519995.
  13. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. Oct 15 2013;62(16):e147-239. PMID 23747642.
  14. Yancy CW, Jessup M, Bozkurt B, et al. 2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. Circulation. 2017 Aug 8;136(6):e137-e161. PMID: 28455343.
  15. McMurray JJ, Adamopoulos S, Anker SD, et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J. Jul 2012;33(14):1787-1847. PMID 22611136.
  16. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2016 Jul 14;37(27):2129-2200. PMID: 27206819.
  17. Heart Failure Society of A, Lindenfeld J, Albert NM, et al. HFSA 2010 Comprehensive Heart Failure Practice Guideline. J Card Fail. Jun 2010;16(6):e1-194. PMID 20610207.

Coding Section

Codes Number Description
CPT No speciific code  
ICD-9 Diagnosis   Investigational for all relevant diagnoses
  428.0-428.9 Heart failure code range
ICD-9 Procedure 99.78 Aquapheresis
HCPCS    
ICD-10-CM (effective 10/01/15)   Investigational for all relevant diagnoses
ICD-10-PCS (effective 10/01/15)   No code specific to ultrafiltration
  5A1D00Z, 5A1D60Z Hemodialysis code list (extracorporeal assistance and performance, urinary filtration)
Type of Service Cardiology  
Place of Service Inpatient  

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross and Blue Shield Association technology assessment program (TEC) and other non-affiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

"Current Procedural Terminology © American Medical Association.  All Rights Reserved" 

History From 2013 Forward     

02/05/2020 

Annual review, no change to policy intent. Updating rationale and references. 

02/13/2019 

Annual review, no change to policy intent. Updating background and rationale. 

02/27/2018 

Annual review, no change to policy intent. Updating rationale and references. 

02/01/2017 

Annual review, no change to policy intent. Updating background, description, rationale and references. 

02/04/2016 

Annual review, no change to policy intent. Updating background, description, rationale and references. Adding regulatory status. 

02/18/2015 

Annual review, no change to policy intent. Updated rationale and references. Added guidelines and coding. 

02/6/2014

Updated rationale and references. No change to policy intent.


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