ByMohamed Essam

Nephrology specialist at KUC

UF versus Diuretics in management of ADHF

Agenda:

1.Heart failure.2.Cardiorenal syndrome.3.Current practice and its

limitations4.UF : Could it help?5.Plasma refill rate and its

implications6.Clinical trials.7.Pros and Cons.8.Questions and answers.9.Questions with no answers.10.Conclusion.

Heart Failure & Cardiorenal Syndrome

Heart Failure (HF) is a major public health problem with

increasing prevalence owing to the substantial rise in

population aged over 65 years of age.

Fluid overload and congestion are major characteristics

of HF and among the most important targets of

treatment.

Acute Cardiorenal syndrome (type 1) is worsening of

renal function in acute decompensated heart failure

(ADHF).

Current Practice:

IV Diuretics Diuretic resistance

Stepped

Pharmacological approachIn caseOf renalImpairment

Ultrafiltration

Guidelines:

Should we start treatment of CRS type 1 by UF ?

Limitations of diuretic therapy:

1. Efficacy: In the ADHERE registry with over than 100000 patients enrolled, around half of the patients admitted for ADHF were discharged with symptoms of congestion after receiving conventional diuretic based therapy

2. Diuretic resistance: common in Heart failure (HF).

3. New onset AKI during hospital admission or worsening of renal function.

4. Uncertainties about optimal dose, mode of administration and stepped approach in resistant cases. “Diuretic secretion is impaired in CKD”

5. Electrolyte abnormalities: (hypokalemia, etc.,,,)

6. Hypersensitivity and ototoxicity.

UF : Could it help at the early start?Theoretical advantages of ultrafiltrationUF (Pros)

1. Higher mass clearance of sodium for similar volumes of fluid removal.

2. Rapid controlled fluid removal.3. Decreased renal venous congestion.4. Lack of neurohormonal activation.5. No resistance to its action.6. Low risk of electrolyte abnormalities.7. Sustained clinical benefits.8. Decreased hospital length of stay and

rehospitalization for HF.9. Ability to restore diuretic sensitivity.

Enhanced Sodium Extraction with Ultrafiltration Compared to Intravenous Diuretics

15 hospitalized ADHF patients with presumed diuretic resistance and clinical evidence of volume overload.

Urine electrolyte concentrations measured after a dose of IVD.

UF was then begun and ultrafiltrate electrolyte concentrations were measured 8 hours later and compared to the initial urine values.

Ali SS et al. Congest Heart Fail. 2009; 15: 1-4

0

20

40

60

80

100

120

140

mg

/dL

URINE ELECTROLYTES AFTER INTRAVENOUS DIURETICS OR ULTRAFILTRATION

IVD

UF

0

20

40

60

80

100

120

140

mg

/dL

URINE ELECTROLYTES AFTER INTRAVENOUS DIURETICS OR ULTRAFILTRATION

IVD

UF

Sodium

Potassium Magnesium

P= 0.000025

P= 0.000017

P= 0.017

Prevalence of Worsening Renal Function During Hospitalization

According to Categories of Admission CVP, CI, SBP, and PCWPMullens, W. et al. J Am Coll Cardiol 2009;53:589-596

Should we start treatment of CRS type 1 by UF ?

Theoretical advantages should be proved in RCT

2 large RCTs UNLOAD

CARRESS-HF

PRR (Plasma Refill Rate)

UF

VascularSpace

InterstitialSpace (Edema)

Na

Na

Na

Na

K

P

H2O

K

P

PR

Ultrafiltration can remove fluid from the blood at the same rate that fluid can be naturally recruited from the tissue

The transient removal of blood elicits a compensatory mechanism, called plasma or intravascular refill (PR), aimed at minimizing this reduction

The rate of plasma refill is important, for if the ultrafiltration rate is too aggressive intravascular volume may decrease because the rate of refill from the interstitial to the intravascular space is exceeded. This in turn may lead to hemodynamic instability and renal dysfunction.

Marenzi GC et al. JACC 2001; 38: 963-968

Changes in Plasma Volume and Refilling Rate During

UF

2 implications:

How to monitor PRR during UF?

How to minimize extracorporeal blood volume to minimize circulatory instability during UF?

Hematocrit monitoring:

Ionometer

Veno-Venous Ultrafiltration devices:

Small sized portable devices.

Adjustable blood flow rates (10-40 ml/min).

Small polysulphone filters (0.12 m2).

Small extracorporeal blood volume of less than 50 ml.

The ability to use peripheral veins.

Aquadex FlexFlowGambro

Clinical Trials

Ultrafiltration versus IV Diuretics for Patients Hospitalized for

Acute Decompensated Congestive Heart Failure:

A Prospective Randomized Clinical Trial

UNLOAD Trial

UNLOAD (Method)

randomized 200 patients with ADHF to receive either UF therapy or

standard intravenous (IV) diuretic therapy. UF was done at a rate up to 500 cc / hour, while IV diuretics

were given at least 2 times the daily oral dose for the first 48 hours as bolus or continuous

infusion.

Results of the UNLOAD trial:

Weight and fluid loss were greater in the UF group without significant change in blood pressure (BP) or serum creatinine.

The ultrafiltration group showed fewer patient rehospitalizations for HF at 90 days.

Critical Appraisal:

1. Patients with hemodynamic instability were excluded, systolic BP of > 90 mmHg or requiring IV vasopressors were excluded. This might be in favor for the UF group as UF theoretically has more hemodynamic instability.

2. Suboptimal use of diuretics at 48 hours made the fluid loss greater in the UF group which had an UF rate up to 500 cc / hour.

3. Higher serum creatinine in UF group although not significant.

CARdiorenal REScue Study in Acute Decompensated

Heart Failure (CARESS-HF)

Methods

randomized 188 patients with ADHF, worsened renal functions and persistent congestion despite standard therapy to receive stepped pharmacological therapy or UF.

Results1. UF didn’t show greater weight loss than stepped

medical therapy (5.7 kg for UF versus 5.5 kg for medical therapy; P=0.58).

2. Patients in UF group showed significant increase in serum creatinine level (+0.23 mg/dl for UF group versus -0.04 mg/dl for medical therapy group; P=0.003).

3. Higher rate of serious adverse events in UF group was also noted. (72% vs 52%)

4. Significantly higher mortality in the ultrafiltration group at 60 day observation (17% vs 13%)

Results (Cont.)

Critical Appraisal:

1. The addition of IV vasodilators or positive inotropic agents was prohibited in the UF group unless indicated as a rescue therapy, while it was allowed in the diuretic group for patients in whom the target urine output (3-5 liters/day) could not be attained.

2. Although the pharmacological approach was stepped up to target urine output of 3-5 liters/day, UF was delivered in a constant rate of 200 ml/hour. As discussed above the UF rate should be adjusted according to the plasma refill rate, but delivering a constant rate of UF to different patients may contribute to the greater rise in serum creatinine in this group.

Critical Appraisal (cont.):

3. In the ultrafiltration group, most of the fluid removal was achieved with ultrafiltration, which implied that less fluid was eliminated by the kidney through glomerular filtration.

By contrast, in the pharmacologic-therapy group, the excess fluid was eliminated exclusively through the kidney.

Since, according to the manufacturer, creatinine is not removed with the Aquadex System 100 ultrafiltration procedure used in the study, it could be anticipated that a smaller amount of creatinine was excreted through glomerular filtration and tubular secretion.

Hence, besides being clinically irrelevant, the small increase in the serum creatinine level in the ultrafiltration group, as compared with the changes observed in the pharmacologic-therapy group, was nothing other than the expected result given the choice of this primary end point.

Heart Failure Hospitalizations after Aquapheresis Therapy Compared to Intravenous (IV) Diuretic Treatment

(AVOID-HF)

AVOID-HF

Ongoing trial. to determine if patients have fewer

Heart Failure (HF) events after receiving Aquapheresis (AQ) therapy compared to IV diuretics up to 90 days of discharge from the hospital.

Heart Failure events are defined as returning to the hospital, clinic or emergency department (ED) for treatment of HF symptoms.

Questions with answers:

How to compare CARRESS-HF results to UNLOAD results?

How would we manage the patient then?

What are the drawbacks of UF?

UF (Cons.)

1. Hypotension: The incidence of cardiovascular instability in UF & the development of hypotension episodes is a frequent problem during UF and can seriously affect long term outcome.

2. Effect on renal functions: Data are conflicting regarding the effect of UF on renal functions. Studies have failed to show any protective effects of UF.

3. Cost versus standard medical therapy is much higher. Studies to impact that by proving the decrease incidence of rehospitalization.

4. No data regarding long term outcome.5. Problems with vascular access, although peripheral

veins may be used.6. Uncertainties regarding patient choice, UF rate and

monitoring efficacy.

Questions with no answers:

1. Which patient? Is UF better in CKD patients?

2. Rate and Duration of UF?

3. Monitoring?

4. When to stop?

5. Long term outcome? QOL ?

Conclusion:

1. Fluid overload and congestion are major characteristics of HF and among the most important targets of treatment.

2. Diuretics have many limitations including resistance, WRF, electrolyte disturbance and low effecacy.

3. UF could help, theoretically UF has many advantages over diuretics in management of ADHF.

Conclusion: (Cont.)

4. UNLOAD and CARRESS-HF have conflicting results, New trials are needed to :▪ Compare both strategies▪ Compare long term outcome

5. Monitoring PRR during UF is still a point of research, New technology may help in stabilizing UFR with PRR.

6. UF advantage over diuretics is still unproven, Current practice should be followed till new evidence from RCTs show up.

THANK YOU