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%

0

5

10

15

20

25

30

35

Patie

nts

(%)

(<-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

0.00

0.05

0.10

0.15

0.20

0.25

0.30

0.35

0.40

0.45

0.50

0 100 200 300 400 500 600 700

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

0

10

20

30

40

50

60

70

80

90

100

0 10 20 30 40 50 60 70

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

0

10

20

30

40

50

60

70

80

90

100

0 10 20 30 40 50 60 70Hours

Pt G

loba

l Ass

essm

ent b

y VA

S

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

0.05

0.07

0.04

0.08

0

0.05

0.1

0.15

Cha

nge

in C

reat

inin

e (m

g/dL

)

Low HighFelker GM et al, NEJM 2011

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

0

0.05

0.1

0.15

0.2

0.25

0 10 20 30 40 50 60

0

0.02

0.04

0.06

0.08

0.1

0 10 20 30 40 50 60

Changes in Renal Function over Time:Low vs. High

Days

Cha

nge

in C

reat

inin

e (m

g/dL

)

Cystatin CCreatinine

Days

HighLow

P > 0.05 for all timepoints

Cha

nge

in C

ysta

tin C

(pg/

dL)

0

0.1

0.2

0.3

0.4

0.5

0.6

0 10 20 30 40 50 60

Days

Prop

ortio

n w

ith D

eath

, Reh

osp,

or E

D V

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

0

0.1

0.2

0.3

0.4

0.5

0.6

0 10 20 30 40 50 60

Days

Prop

ortio

n w

ith D

eath

, Reh

osp,

or E

D v

isit

High Low

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)