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?
76
13
24
33
11
32
0
5
10
15
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25
30
35
(-) > 20 (-) 15-20 (-) 10-15 (-) 5-10 (-) 0-5 (+) 0-5 (+) 5-10 (+) > 10
Change in weight (lbs)
Per
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f p
atie
nts
Change in Body Weight at Discharge ADHERE Database (n= 51,013)
[Gheorghiade M and Filippatos G. Eur Heart J 2005; 7: B13-B19]-Adapted
76
13
24
33
11
32
0
5
10
15
20
25
30
35
(-) > 20 (-) 15-20 (-) 10-15 (-) 5-10 (-) 0-5 (+) 0-5 (+) 5-10 (+) > 10
Change in weight (lbs)
Per
cen
t o
f p
atie
nts
Change in Body Weight at Discharge ADHERE Database (n= 51,013)
[Gheorghiade M and Filippatos G. Eur Heart J 2005; 7: B13-B19]-Adapted
76
13
24
33
11
32
0
5
10
15
20
25
30
35
(-) > 20 (-) 15-20 (-) 10-15 (-) 5-10 (-) 0-5 (+) 0-5 (+) 5-10 (+) > 10
49%
Change in weight (lbs)
Per
cen
t o
f p
atie
nts
Change in Body Weight at Discharge ADHERE Database (n= 51,013)
[Gheorghiade M and Filippatos G. Eur Heart J 2005; 7: B13-B19]-Adapted
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
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.
ADHF
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
[Costanzo MR. J Am Coll Cardiol 2007; 49: 675]
Ultrafiltration: trend for WRF
[Costanzo MR. J Am Coll Cardiol 2007; 49: 675]
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
[Costanzo MR. J Am Coll Cardiol 2007; 49: 675]
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.
CRS
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]
The CARRESS-HF Trial
UF and SPT: comparable outcomes[Bart BA. New Engl J Med 2012; 367: 2296]
The CARRESS-HF Trial
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
[Costanzo MR, JACC Heart Fail 2016; 4: 95-105]
Algorithm for Medical
Therapy
[Costanzo MR, JACC Heart Fail 2016; 4: 95-105]
Algorithm for UF
Therapy
[Costanzo MR, JACC Heart Fail 2016; 4: 95-105]
[Costanzo MR, JACC Heart Fail 2016; 4: 95-105]
[Costanzo MR, JACC Heart Fail 2016; 4: 95-105]
[Costanzo MR, JACC Heart Fail 2016; 4: 95-105]
The CARRESS-HF Trial (per-protocol analysis)
[Grodin JL, Europ J Heart Fail 2018doi:10.1002/ejhf.1158]
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
The CARRESS-HF Trial (per-protocol analysis)
[Grodin JL, Europ J Heart Fail 2018doi:10.1002/ejhf.1158]
?
The CARRESS-HF Trial (per-protocol analysis)
[Grodin JL, Europ J Heart Fail 2018doi:10.1002/ejhf.1158]
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]
The CARRESS-HF Trial (post-hoc analysis)
[Kitai T, Circ Heart Fail 2017Circ Heart Fail. 2017 Feb;10(2):e003603]
The CARRESS-HF Trial (post-hoc analysis)
[Kitai T, Circ Heart Fail 2017Circ Heart Fail. 2017 Feb;10(2):e003603]
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