Division of Nephrology, Hypertension, and Renal ......Congestion The main reason for hospitalization...

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Ultrafiltration for Congestive Heart Failure

Amir Kazory, MD, FASNDivision of Nephrology, Hypertension, and Renal Transplantation

University of Florida

Disclosures

CHF Solutions, Inc. - Scientific Advisory Board

Otsuka America Pharmaceutical, Inc. - ADPKD Expert Advisory Board

W.L. Gore Inc. - Consultant

Disclosures

Congestion The main reason for hospitalization of patients with Acute Heart Failure (93% )

ADHERE Registry

Diuretic Resistance Observed in up to 35% of patients with Acute Heart Failure

Ultrafiltration Several RCT’s on the role of UF in Acute Heart Failure

Acute Decompensated Heart Failure

(ADHF)- Lifetime prevalence: 20–33 %

- Currently, over 5 million Americans with HF (more than 8 million by 2030)

- ADHF : the leading cause of hospitalization in patients over 65

- ADHF: the highest rate of 30-day re-hospitalization among all medical conditions

- ADHF: the 3-month re-hospitalization rate of 40%

- ADHF: the 1-year mortality rate of over 30%

- Total costs for HF: $31 billion in 2012, estimated at $70 billion in 2030

(80% due to hospitalization) – Major Financial Burden on Healthcare

How well are we managing congestion in

ADHF now?

(-) > 20 (-) 15-20 (-) 10-15 (-) 5-10 (-) 0-5 (+) 0-5 (+) 5-10 (+) > 10

Change in weight (lbs)

Change in Body Weight at Discharge ADHERE Database (n= 51,013)

[Gheorghiade M and Filippatos G. Eur Heart J 2005; 7: B13-B19]-Adapted

(-) > 20 (-) 15-20 (-) 10-15 (-) 5-10 (-) 0-5 (+) 0-5 (+) 5-10 (+) > 10

Congestion and Outcomes in ADHF(n=27,724)

[Cooper LB. Am J Cardiol 2019; Online May 25 2019]

Mortality

HF Re-Hospitalization

Optimize-HF Registry

P<0.001

Post-discharge mortality and HF-Rehospitalization were consistently higher among those with more severe congestion scores, at 90-day, 180-day, and 1-year time points

What other options can be used for decongestion?

↑ SodiumRe-absorption

↑ Renal VenousPressure

↓ CardiacOutput

↓ TissuePerfusion

↑ NeurohormonalActivity

SystemicVasoconstriction

Secondary Hyperaldosteronism

↓ WaterClearance

↓ Distal SodiumDelivery

DiureticResistance

↑ LVEDP ↑ InflammatoryCytokines

↑ OxidativeStress

↑ Right Atrial Pressure

↑ InflammatoryCytokines

↑ EndothelialActivation

Figure-1

↑ ImmuneSystem Activity

↑ VenousCircumferential

Stretch

Decompensated Heart Failure

Congestion Renal Dysfunction

↑intra-abdominalpressure

[Kazory A. – Clin J Am Soc Nephrol.2016; 11:1463]

↑ SodiumRe-absorption

↑ Renal VenousPressure

↓ CardiacOutput

↓ TissuePerfusion

↑ NeurohormonalActivity

SystemicVasoconstriction

Secondary Hyperaldosteronism

↓ WaterClearance

↓ Distal SodiumDelivery

DiureticResistance

↑ LVEDP ↑ InflammatoryCytokines

↑ OxidativeStress

↑ Right Atrial Pressure

↑ InflammatoryCytokines

↑ EndothelialActivation

Figure-1

↑ ImmuneSystem Activity

↑ VenousCircumferential

Stretch

Decompensated Heart Failure

Congestion Renal Dysfunction

↑intra-abdominalpressure

[Kazory A. – Clin J Am Soc Nephrol.2016; 11:1463]

Ultrafiltration

Landmark Clinical Trials

The UNLOAD Trial

[Costanzo MR. J Am Coll Cardiol 2007; 49: 675]

MulticenterRCT

Diuretic(n=100)

UF(n=100)

The primary efficacy end points: weight loss and patients’ dyspnea assessment 48 h after randomizationThe primary safety end points: 1- changes in serum blood urea nitrogen, creatinine, and electrolytes at 8, 24, 48, and 72 h after randomization, discharge, 10, 30, and 90 days 2- episodes of hypotension (a decrease in systolic blood pressure requiring therapeutic intervention) at 48 h after randomization.

The secondary efficacy end points: 1) net fluid loss 48 h after randomization; 2) length of index hospitalization; 3) change in B-type natriuretic peptide levels at 48 h after randomization, 30, and 90 days; 4) changes in New York Heart Association functional class, Minnesota Living with Heart Failure Questionnaire scores, Global Assessment scores, 6-min walk distance and loop diuretic doses at discharge, 30, and 90 days; and 5) rehospitalizations for HF, percentage of patients rehospitalized for HF, days of rehospitalization, and unscheduled office and emergency department visits within 90 days. Cause of death was adjudicated by 2 independent observers.

At 48 hours, significantly greater amount of weight loss seen with ultrafiltration as compared to diuretics (5 kg vs. 3.1 kg)

The UNLOAD TrialPrimary Efficacy Endpoint: Weight Loss

Ultrafiltration: trend for WRF

The UNLOAD TrialPrimary Safety Endpoint: Change in Serum Creatinine

Ultrafiltration Standard Care P Value

Patients rehospitalized for HF, % 18 32 .037

HF re-hospitalizations, # 0.22 0.46 .022

Rehospitalization days per patient 1.4 3.8 .022

Unscheduled office + ED visits, % 21 44 .009

Ultrafiltration: better outcomes

The UNLOAD Trial

MulticenterRCT

SPT(n=94)

UF(n=92)

The primary end point: the change in the serum creatinine level and the change in weight, considered as a bivariate response, between the time of randomization and 96 hours after randomization

Secondary End Points: a) Primary endpoint (change in serum creatinine AND weight together as a “bivariate” endpoint) assessed after randomization on hospital days 1 - 3 and at one week. b) Significant weight loss and renal improvement assessed at 96 hours and one week. c) Treatment failure during the first seven days after randomization. d) Changes in renal function from randomization to days 7, 30 and 60. Peak creatinine during hospitalization. e) Changes in electrolytes from randomization to 96 hours and one week. f) Changes in weight measured daily from randomization to one week, 30 and 60 days. g) Percent of patients achieving clinical decongestion at 96 hours, one week, 30 and 60 days. h) Total net fluid loss from randomization to 96 hours and 1 week. i) Changes in biomarkers from randomization to 96 hours, at one week and at 60 days. j) Changes in global assessment and visual analogue scores from enrollment to 96 hours and one week.

The CARRESS-HF Trial

[Bart BA. New Engl J Med 2012; 367: 2296]

Primary Endpoint: changes in weight and serum creatinineUF and SPT: comparable decongestion, WRF only with UF

[Bart BA. New Engl J Med 2012; 367: 2296]

UF and SPT: comparable outcomes[Bart BA. New Engl J Med 2012; 367: 2296]

CARRESS-HFUNLOAD

Customized Flexible UF (up to 500 ml/hr)vs.

Suboptimal Unprotocolized Medical Therapy

Suboptimal UF with Fixed UFR (200 ml/hr)vs.

Customized Stepped Pharmacologic Therapy

UFMedicalTherapy

Need for a “Fair” Comparison…

MulticenterRCT

ALD(n=114)

AUF(n=110)

The primary end point: Time to first HF event within 90 days after discharge . HF event: HF re-hospitalization or ED visit needing IV diuretic or UF therapy.

Secondary End Points: 1) Efficacy: Total fluid removed during the index hospitalization, Net fluid removed during the index hospitalization, Weight loss at 72 hours after randomization, Total weight loss during the index hospitalization, Time to freedom from congestion, freedom from congestion…

2) Clinical: Length of stay (LOS) during the index hospitalization, Total number of days re-hospitalized for HF at 30 and 90 days after discharge, Total number of Emergency Department (ED) or unscheduled office visits requiring IV therapy for HF, Total number of HF re-hospitalizations at 30 and 90 days after discharge, Mortality rates up to 90 days after randomization

3) Safety: Changes in renal function variables after treatment up to 90 days after randomization, serum creatinine (sCr), blood urea nitrogen (BUN), BUN/sCr, glomerular filtration rate (eGFR) estimated with the Modification of Diet in Renal Disease(MDRD) formula

ADHF(224)

The AVOID-HF Trial

[Costanzo MR, JACC Heart Fail 2016; 4: 95-105]

Planned to include 810 patients. Halted due to slow recruitment (0.4/site/month)

Algorithm for Medical

Therapy

Algorithm for Medical

Therapy

Algorithm for UF

Therapy

The CARRESS-HF Trial (per-protocol analysis)

[Grodin JL, Europ J Heart Fail 2018doi:10.1002/ejhf.1158]

In contrast to the original trial (intention-to-treat), UF was associatedwith significantly more fluid loss and weight reduction

Death, HF hospitalization, or any ED or outpatient visit

Death, any hospitalization, or any ED or outpatient visit

The CARRESS-HF Trial (post-hoc analysis)

[Kitai T, Circ Heart Fail 2017Circ Heart Fail. 2017 Feb;10(2):e003603]

More Efficient Decongestion at a

Higher Cost?

Hospital Cost Analysis

[Costanzo et al. J Med Econ 2019:1-7]

Hospital Cost AnalysisBased on UNLOAD trial

[Costanzo et al. J Med Econ 2019:1-7]

Post-discharge 90-day cost (excluding index admission)

Cumulative 90-day cost (including index admission)

Less than 50%

More Efficient Decongestion(with no negative impact on renal function, mortality, or adverse events)

Ultrafiltration vs. Medical Therapy

?Lower HF Re-Hospitalization Rate?Lower HF-Related Cost

Greater Weight Loss Greater Fluid Removal

1) Early (vs. Late)

2) Customized Prescription (vs. Fixed Protocol)

3) Objective Monitoring of Decongestion

Optimal Ultrafiltration Protocol for ADHF and Fluid Overload

Multicenter, prospective, randomized, parallel-group, controlled

Fresenius Medical Care Deutschland GmbH – 11 centers in Germany and Sweden

Actual Study Start Date: November 3, 2017 Actual Study Completion : April 30, 2019Estimated Study Completion Date: October 31, 2019 (as of May 2019)

Estimated Enrollment: 864 participants (48 participants)

Primary Outcome Measures:1)Heart Failure Event [within 90 days after discharge ]Heart failure hospitalization or unscheduled outpatient or emergency department treatment with IV loop diuretics or ultrafiltration. 2.Cardiovascular death up to 90 days after randomization

Peripheral Ultrafiltration for the Relief From Congestion in Heart Failure

(PURE-HF)

1) Congestion should be a key target in management of ADHF

2) UF is an efficient therapeutic option for decongestion in ADHF

3) UF prescription needs to be customized, and preferably helped with objective monitoring

Take Home Message

Amir.Kazory@medicine.ufl.edu

Division of Nephrology, Hypertension, and Renal ......Congestion The main reason for hospitalization...

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