Diuretics or Ultrafiltration?
Michael Felker, MD, MHS, FACC
Associate Professor of Medicine
Director of Heart Failure Research
Disclosures
n
I take no diuretics
n
I own no diuretic stock
n
I have no patents related to diuretics
n
I am not a consultant for the furosemide
medical-industrial complex
Congestion is the Main Cause of HF Hospitalizations
6%
2%
N=3580
9%
53%
30%
Decomp. HF
Pulm. Edema
HTN HF
Cardiogenic shock
RHF
Nieminen, M et al Eur Heart J 2006
Congestion is both Cause and Effect
Worsening
HF
Spherical LV
geometry
Sub-endocardial
Ischemia
Functional MR
Elevated
LVEDP
How Successful Are We at Addressing
Congestion?
33%
35
Patients (%)
30
24%
25
20
13%
15
10
7%
15%
6%
5
3%
2%
(5 to 10)
(>10)
0
(<-20)
(-20 to -15) (-15 to -10) (-10 to -5)
(-5 to 0)
(0 to 5)
Change in Weight (lbs)
Fonarow GC. Rev Cardiovasc Med. 2003
Traditional Approaches to Congestion in HF?
Current Guidelines on Diuretics in ADHF
Class I. Patients admitted with ADHF and significant volume
overload should be treated with IV loop diuretics. Therapy
should begin in ED or outpt clinic without delay. If patients are
already receiving loop diuretic therapy, the IV dose should
equal or exceed their chronic oral daily dose. Diuretic dose
should be titrated to relieve symptoms and reduce extracellular
fluid excess (Level of Evidence C).
Jessup M et al, Circulation 2009
Diuretics in ADHF
n
IV loop diuretics are the mainstay of therapy for ADHF
(given to ≈90% of patients)
n
Relieve symptoms of dyspnea and edema in most
patients
n
Associated with a variety of potential problems
l Electrolyte abnormalities
l Activation of RAAS and SNS
l Diuretic resistance
l Structural changes in distal tubule
l Worsening renal function
l Increased mortality?
Diuretic Resistance in HF
n
n
Heart failure and CKD
are both associated with
relative diuretic
resistance
“Braking Phenomenon”
l
n
A decrease in response to
a diuretic after the first dose
has been administered
Long-term Tolerance
l
Tubular hypertrophy to
compensate for salt loss
Brater DC. N Engl J Med. 1998;339:387, Ellison, Cardiology 2001
Mortality by Diuretic Dose:
Data From ESCAPE
0.50
0.45
0.40
Mortality
Mortality
0.35
0.30
0.25
0.20
0.15
0.10
0.05
0.00
0
100
200
300
400
500
600
700
Maximum in-hospital
In-hospital Diuretic
Maximum
diureticDose
dose
Predicted
Observed
Hasselblad et al. Eur J Heart Fail. 2007;9:1064.
Felker GM et al, NEJM 2011
Study Design
Acute Heart Failure (1 symptom AND 1 sign)
<24 hours after admission
2x2 factorial randomization
Low Dose (1 x oral)
Q12 IV bolus
Low Dose (1 x oral)
Continuous infusion
High Dose (2.5 x oral)
Q12 IV bolus
48 hours
1) Change to oral diuretics
2) continue current strategy
3) 50% increase in dose
72 hours
Co-primary endpoints
60 days
Clinical endpoints
High Dose (2.5 x oral)
Continuous infusion
Patient Global Assessment VAS AUC:
Q12 vs. Continuous
Pt Global Assessment by VAS
100
Q12
Continuous
90
Q12 VAS AUC, mean (SD) = 4236 (1440)
80
Continuous VAS AUC, mean (SD) = 4373 (1404)
70
P = 0.47
60
50
40
30
20
10
0
0
10
Felker GM et al, NEJM 2011
20
30
40
Hours
50
60
70
Patient Global Assessment VAS AUC:
Low vs. High Intensification
Low
Pt Global Assessment by VAS
100
High
90
Low VAS AUC, mean (SD) = 4171 (1436)
80
High VAS AUC, mean (SD) = 4430 (1401)
70
P = 0.06
60
50
40
30
20
10
0
0
10
Felker GM et al, NEJM 2011
20
30
40
Hours
50
60
70
Change in Creatinine at 72 hours
Change in Creatinine (mg/dL)
0.15
p = 0.45
p = 0.21
0.1
0.08
0.07
0.05
0.05
0.04
0
Felker GM et al, NEJM 2011
Q12 Continuous
Low
High
Secondary Endpoints:
Low vs. High Intensification
Low
High
P value
Dyspnea VAS AUC at 72 hours
4478
4668
0.041
% free from congestion at 72 hrs
11%
18%
0.091
-6.1 lbs
-8.7 lbs
0.011
3575 mL
4899 mL
0.001
Change in NTproBNP at 72 hrs (pg/mL)
-1194
-1882
0.06
% Treatment failure
37%
40%
0.56
% with Cr increase > 0.3 mg/dL
within 72 hrs
14%
23%
0.041
6
5
0.55
Change in weight at 72 hrs
Net volume loss at 72 hrs
Length of stay, days (median)
Felker GM et al, NEJM 2011
Changes in Renal Function over Time:
Low vs. High
Low
High
Cystatin C
0.1
0.08
0.06
0.04
0.02
0
0
10
20
30
40
50
60
Change in Cystatin C (pg/dL)
Change in Creatinine (mg/dL)
Creatinine
0.25
0.2
0.15
0.1
0.05
0
0
Days
10
20
30
Days
P > 0.05 for all timepoints
40
50
60
Death, Rehospitalization, or ED Visit
HR for Continuous vs. Q12 = 1.15
95% CI 0.83, 1.60, p = 0.41
0.5
Continuous
Proportion with Death, Rehosp, or ED visit
Proportion with Death, Rehosp, or ED Visit
0.6
Q12
0.4
0.3
0.2
0.1
0
0
10
20
30
Days
Felker GM et al, NEJM 2011
40
50
60
HR for High vs. Low = 0.83
95% CI 0.60, 1.16, p = 0.28
0.6
High
0.5
Low
0.4
0.3
0.2
0.1
0
0
10
20
30
Days
40
50
60
Take Home from DOSE
• No advantage of infusion over bolus
• Suggestion of greater decongestion in
higher dose at cost of transient changes in
renal function
• No evidence of longer term harm from
higher doses
Ultrafiltration as a Therapy for Congestion?
n
Removes both sodium and free water
n
Allows for titration of rate of fluid
removal to match plasma refill rate
n
Allows for reduction in diuretic use
Simplified Veno-Venous Ultrafiltration
Access
 0.12 m2 polysulphone filter
Return
 Blood flow adjustable (10-40
ml/minute)
 Total extracorporeal blood
volume 33 ml
 Peripheral, midline, or central
venous access
 Anticoagulation with heparin
recommended
Effluent
Costanzo MR et al. J Am Coll Cardiol 2007
Primary End Points
n
Efficacy
• Weight loss at 48 hours after randomization
• Dyspnea score at 48 hours after randomization
n
Safety
• Changes in serum blood urea nitrogen, creatinine,
and electrolytes at 8, 24, 48 and 72 hours after
randomization, discharge, 10, 30 and 90 days
• Episodes of hypotension during the first 48 hours
after randomization
UNLOAD: Weight Loss at 48 Hours (Co-Primary)
6
Weight loss (kg)
P=0.001
5
4
3
m=5.0, CI ± 0.68 kg
(N=83)
2
m=3.1, CI ± 0.75 kg
(N=84)
1
0
Ultrafiltration arm
Standard care arm
Costanzo MR et al. J Am Coll Cardiol 2007
UNLOAD: Dyspnea Score at 48 Hours (co-primary)
7
P=0.35
Dyspnea score
6
5
m=6.4, CI ± 0.11
(N=80)
4
m=6.1, CI ± 0.15
(N=83)
3
2
1
Ultrafiltration arm
Standard care arm
Costanzo MR et al. J Am Coll Cardiol 2007
Percentage of patients
free from rehospitalization
UNLOAD: Heart Failure Rehospitalization
100
Ultrafiltration arm (16 events)
80
60
Standard care arm (28 events)
40
P=0.037
20
0
0
10
20
30
40
50
60
70
80
90
Days
No. of Patients at Risk
Ultrafiltration arm
88
85
80
77
75
72
70
66
64
45
Standard care arm 86
83
77
74
66
63
59
58
52
41
Costanzo MR et al. J Am Coll Cardiol 2007
Current Guidelines on Ultrafiltration
Class IIa: Ultrafiltration is reasonable for patients with
refractory congestion not responding to medical
therapy (Level of Evidence B)
Jessup M et al, Circulation 2009
Persistent vs. Transient Worsening Renal Function
Aronson et al. J Card Failure 2010
Successful Decongestion Critical To Success
Testani, J. M. et al. Circulation 2010;122:265-272
Conclusions and Next Steps
n
Decongestion is important by whatever means
n
Transient worsening of renal function may be less
important than previously thought?
n
Who are the right patients for UF?
l Patients with rising CRS? (CARRESS)
l Patients with high likelihood of diuretic resistance?
n
Role of other adjunctive therapies?
l Sequential nephron blockade with thiazides?
l “renal dose” dopamine or nesiritide (ROSE)
l Short term tolvaptan (TACTICS)