Diuretics or Ultrafiltration?
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Transcript of Diuretics or Ultrafiltration?
Diuretics or Ultrafiltration?
Michael Felker, MD, MHS, FACCAssociate Professor of Medicine
Director of Heart Failure Research
Disclosures
I take no diuretics I own no diuretic stock I have no patents related to diuretics I am not a consultant for the furosemide
medical-industrial complex
Congestion is the Main Cause of HF Hospitalizations
53%
30%
9%
6% 2%
Decomp. HFPulm. EdemaHTN HFCardiogenic shockRHF
Nieminen, M et al Eur Heart J 2006
N=3580
Worsening HF
Elevated LVEDP
Spherical LV geometry
Sub-endocardial Ischemia
Functional MR
Congestion is both Cause and Effect
7% 6%
13%
24%
33%
15%
3% 2%
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35
Patie
nts
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(<-20) (-20 to -15) (-15 to -10) (-10 to -5) (-5 to 0) (0 to 5) (5 to 10) (>10)
Change in Weight (lbs)
How Successful Are We at Addressing Congestion?
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
IV loop diuretics are the mainstay of therapy for ADHF(given to ≈90% of patients)
Relieve symptoms of dyspnea and edema in most patients
Associated with a variety of potential problems Electrolyte abnormalities Activation of RAAS and SNS Diuretic resistance Structural changes in distal tubule Worsening renal function Increased mortality?
Diuretic Resistance in HF
Heart failure and CKD are both associated with relative diuretic resistance
“Braking Phenomenon” A decrease in response to
a diuretic after the first dose has been administered
Long-term Tolerance 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
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Maximum In-hospital Diuretic Dose
Mor
talit
y
Predicted Observed
Hasselblad et al. Eur J Heart Fail. 2007;9:1064.
Maximum in-hospital diuretic dose
Mor
talit
y
Felker GM et al, NEJM 2011
Acute Heart Failure (1 symptom AND 1 sign)<24 hours after admission
2x2 factorial randomization
Low Dose (1 x oral)Q12 IV bolus
48 hours
1) Change to oral diuretics2) continue current strategy3) 50% increase in dose
Co-primary endpoints
High Dose (2.5 x oral)Q12 IV bolus
Low Dose (1 x oral)Continuous infusion
High Dose (2.5 x oral)Continuous infusion
72 hours
Study Design
Clinical endpoints
60 days
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Patient Global Assessment VAS AUC:Q12 vs. Continuous
Pt G
loba
l Ass
essm
ent b
y VA
S Q12 VAS AUC, mean (SD) = 4236 (1440)Continuous VAS AUC, mean (SD) = 4373 (1404)
P = 0.47
Q12 Continuous
HoursFelker GM et al, NEJM 2011
Patient Global Assessment VAS AUC:Low vs. High Intensification
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Low HighLow VAS AUC, mean (SD) = 4171 (1436)High VAS AUC, mean (SD) = 4430 (1401)
P = 0.06
Felker GM et al, NEJM 2011
Change in Creatinine at 72 hours
Q12 Continuous
p = 0.45 p = 0.21
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nge
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g/dL
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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
Change in weight at 72 hrs -6.1 lbs -8.7 lbs 0.011
Net volume loss at 72 hrs 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/dLwithin 72 hrs
14% 23% 0.041
Length of stay, days (median) 6 5 0.55
Felker GM et al, NEJM 2011
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Changes in Renal Function over Time:Low vs. High
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nge
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Cystatin CCreatinine
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P > 0.05 for all timepoints
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tin C
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eath
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osp,
or E
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isit Continuous Q12
Death, Rehospitalization, or ED Visit
HR for Continuous vs. Q12 = 1.15 95% CI 0.83, 1.60, p = 0.41
HR for High vs. Low = 0.83 95% CI 0.60, 1.16, p = 0.28
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Felker GM et al, NEJM 2011
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?
Removes both sodium and free water Allows for titration of rate of fluid
removal to match plasma refill rate Allows for reduction in diuretic use
Access
Return
Effluent
Simplified Veno-Venous Ultrafiltration
0.12 m2 polysulphone filter
Blood flow adjustable (10-40 ml/minute)
Total extracorporeal blood volume 33 ml
Peripheral, midline, or central venous access
Anticoagulation with heparin recommended
Costanzo MR et al. J Am Coll Cardiol 2007
Primary End Points
Efficacy • Weight loss at 48 hours after randomization• Dyspnea score at 48 hours after randomization
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)
Wei
ght l
oss
(kg)
m=5.0, CI ± 0.68 kg(N=83)
m=3.1, CI ± 0.75 kg(N=84)
P=0.001
Costanzo MR et al. J Am Coll Cardiol 2007
Dys
pnea
sco
re
m=6.4, CI ± 0.11(N=80) m=6.1, CI ± 0.15
(N=83)
P=0.35
UNLOAD: Dyspnea Score at 48 Hours (co-primary)
Costanzo MR et al. J Am Coll Cardiol 2007
UNLOAD: Heart Failure RehospitalizationPe
rcen
tage
of p
atie
nts
free
from
reho
spita
lizat
ion
P=0.037
Ultrafiltration arm (16 events)
Standard care arm (28 events)
No. of Patients at RiskUltrafiltration arm 88 85 80 77 75 72 70 66 64 45Standard care arm 86 83 77 74 66 63 59 58 52 41
Days
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
Decongestion is important by whatever means Transient worsening of renal function may be less
important than previously thought? Who are the right patients for UF?
Patients with rising CRS? (CARRESS) Patients with high likelihood of diuretic resistance?
Role of other adjunctive therapies? Sequential nephron blockade with thiazides? “renal dose” dopamine or nesiritide (ROSE) Short term tolvaptan (TACTICS)