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 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.

Coding
Please see the Codes table for details.

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, two 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
Clinical Context and Therapy Purpose
The purpose of ultrafiltration in patients with volume overload and heart failure is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does ultrafiltration improve the net health outcome in patients with volume overload and heart failure?

The following PICO was used to select literature to inform this review.

Patients
The relevant population of interest is individuals with volume overload and heart failure.

Interventions
The therapy being considered is ultrafiltration. During ultrafiltration, a small catheter is placed in a vein, and the catheter transports blood to the ultrafiltration machine then back to the patient. After ultrafiltration is complete, the patient restarts on diuretics to keep fluid in balance.

Comparators
The following therapies are currently being used to manage patients with volume overload and heart failure: Diuretics.

Outcomes
The general outcomes of interest are overall survival, quality of life, hospitalizations and treatment-related morbidity.

Follow-up of at least 10 years would be preferable to determine outcomes.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:  

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence
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.^2,3,4,5 Moreover, all but one⁶ of the meta-analyses that reported re-hospitalizations found no evidence that ultrafiltration was significantly associated with a decrease in rates.^2,3,4,5 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.^{2,3,4,5,6,7,8}

Kwok et al. (2017) published a systematic review and meta-analysis of 10 RCTs (N = 857 participants) evaluating ultrafiltration in patients with acute decompensated heart failure.⁵ 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 = .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 = .92). However, in a pooled analysis of 9 RCTs, there was significantly greater weight change in the ultrafiltration group than in the control group (mean difference = -1.86 kg; 95% CI, -4.68 to 0.97 kg; p < .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 = .05).

Randomized Controlled Trials
Transcatheter Aortic Valve Replacement to UNload the Left Ventricle in Patients with ADvanced Heart Failure (TAVRUNLOAD) was a non-blinded 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).⁹ The trial was conducted at 28 U.S. centers. Primary efficacy endpoints were 48-hour weight loss and dyspnea score (1- to 7-point Likert scale). Primary safety endpoints 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 endpoints, including length of index hospitalization, quality of life assessments throughout follow-up, and resource utilization (re-hospitalization 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 = .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 re-hospitalized for heart failure at 90 days than the diuretics group (32%; p = .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 = .018).Costanzo et al. (2010), in an additional subgroup analysis, compared outcomes between ultrafiltration and standard intravenous diuretics by continuous infusion or bolus injection.¹⁰ Similar fluid loss was observed for ultrafiltration and continuous diuretic infusion, with outcomes similar to the original TAVR UNLOAD trial (i.e., fewer re-hospitalizations for heart failure at 90 days only in patients who underwent ultrafiltration).

Detailed analysis of TAVR 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.

Bart et al. (2012) reported on the CAdriorenal REScue Study in Acute Decompensated Heart Failure (CARRESS) trial, comparing fixed-rate ultrafiltration with diuretic-based stepped pharmacologic therapy in 188 patients hospitalized with acute decompensated heart failure and decreased renal function.¹¹ Unlike the TAVR 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 = .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 = .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 = .03). Those events included kidney failure, bleeding complications, and complications related to intravenous catheters.

Marenzi et al. (2014) published findings of the CUORE trial.¹² 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 endpoint was the incidence of heart failure-related re-hospitalizations during the year after treatment. Four re-hospitalizations occurred in the ultrafiltration group, which was significantly fewer instances than the 30 re-hospitalizations in the control group (hazard ratio, 0.14; 95% CI, 0.04 to 0.48; p = .002). At the 1-year follow-up, 7 (26%) deaths were reported in the ultrafiltration group versus 11 (38%) in the control group (p = .33). Weight loss at discharge was similar in both groups (p = .75).

Constanzo et al. (2016) published results of the Aquapheresis versus Intravenous Diuretics and Hospitalization for Heart Failure (Avoid-HF) trial.¹³ This un-blinded 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 re-hospitalization 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 = .106). By 90 days, death occurred in 17 (15%) ultrafiltration patients and 14 (13%) diuretic patients (p = .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 = .026).

Summary of Evidence
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. 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 re-hospitalization 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 randomized controlled trials did not find significant differences in adverse events in groups receiving ultrafiltration or diuretics, some RCTs (e.g., 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 (e.g., un-blinded outcome assessment, incomplete information on patient status). Moreover, long-term outcomes (i.e., > 1 year) have not been reported. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Practice Guidelines and Position Statements
Guidelines or position statements will be considered for inclusion in Supplemental Information if they were issued by, or jointly by, a U.S. professional society, an international society with U.S. representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

American College of Cardiology Foundation and American Heart Association
In 2013, the American College of Cardiology Foundation and American Heart Association published joint guidelines 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).¹⁴ 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.¹⁵

European Society of Cardiology and Heart Failure Association
In 2012, the European Society of Cardiology and Heart Failure Association released joint guidelines 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."¹⁶ In 2016, an updated noted that "ultrafiltration is not recommended and should be confined to patients who fail to respond to diuretic-based strategies" was added.¹⁷

Heart Failure Society of America
In 2010, the Heart Failure Society of America's comprehensive heart failure practice guidelines 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).¹⁸ 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: National clinical trial.

References:

1. U.S. Food and Drug Administration. Aquadex FlexFlow System 2.0 510(k) Summary. 2020. https://www.accessdata.fda.gov/cdrh_docs/pdf19/K192756.pdf. Accessed April 25, 2021.
2. 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): 319-23. PMID 25902884
3. 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
4. Zhi Q, Liang JC. Diuretics and ultrafiltration in acute heart failure syndrome. Int Heart J. 2013; 54(6): 390-4. PMID 24309449
5. 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
6. 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): 611-9. PMID 27154520
7. 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): 131-46. PMID 24686993
8. 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): 365-73. PMID 23801482
9. 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): 675-83. PMID 17291932
10. 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): 277-84. PMID 20350693
11. 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): 2296-304. PMID 23131078
12. 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
13. 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
14. 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
15. 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. Aug 08 2017; 136(6): e137-e161. PMID 28455343
16. 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): 1787-847. PMID 22611136
17. 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. Jul 14 2016; 37(27): 2129-2200. PMID 27206819
18. Lindenfeld J, Albert NM, Boehmer JP, et al. HFSA 2010 Comprehensive Heart Failure Practice Guideline. J Card Fail. Jun 2010; 16(6): e1-194. PMID 20610207

Coding Section

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 Blue Shield Association technology assessment program (TEC) and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

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