Populations	Interventions	Comparators	Outcomes
Individuals: With decompensated heart failure	Interventions of interest are: Ultrafiltration	Comparators of interest are: Diuretics	Relevant outcomes include: Overall survival Quality of life Hospitalizations Treatment-related morbidity

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 2002, the Aquadex FlexFlow™ System (Baxter; acquired by CHF Solutions in 2016) was cleared for marketing by the U.S. Food and Drug Administration (FDA) through the 510(k) process. An amended 510(k) approval (classified as a high permeability dialysis system) was given in 2007 following system modifications. The 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.

Related Policies

• None

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 use 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 policy 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 policy.

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.

Ultrafiltration is managed by cardiologists and performed in a hospital setting.

Comparators

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

Patients with heart failure are managed by cardiologists in an outpatient clinical setting.

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.

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 one^5, 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,}

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.^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=.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 (TAVR 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 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 (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=.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=.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.^9, Similar fluid loss was observed for ultrafiltration and continuous diuretic infusion, with outcomes similar to the original TAVR UNLOAD trial (ie, fewer rehospitalizations 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.^10, 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.^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 endpoint 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=.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.^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=.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 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 randomized controlled trials 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.

SUPPLEMENTAL INFORMATION
Practice Guidelines and Position Statements
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).^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

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."^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" was added.^16,

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).^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 policy are listed in Table 1.

Table 1. Summary of Key Trials

NCT No.	Trial Name	Planned Enrollment	Completion Date
Ongoing
NCT02829450	Home-based Ultrafiltration for Congestive Heart Failure: Impact on Survival, Hospitalizations Rate, Quality of Life, Peritoneal Membrane Characteristics and Residual Renal Function With Different Treatment Modes	40	Oct 2020
NCT02846337	Ultrafiltration Versus Medical Therapies in the Management of the Cardio Renal Syndrome (UF-CARE)	154	Sep 2021

NCT: national clinical trial.]
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Horizon BCBSNJ Medical Policy Development Process:

This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.

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Index:
Ultrafiltration in Decompensated Heart Failure
Aquadex Flex Flow System
Aquapheresis

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): 319-23. 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. 2013; 54(6): 390-4. 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): 611-9. 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): 131-46. 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): 365-73. 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): 675-83. 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): 277-84. 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): 2296-304. 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. Aug 08 2017; 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): 1787-847. 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. Jul 14 2016; 37(27): 2129-2200. PMID 27206819

17. 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

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