1. Diuretics or Ultrafiltration?
Michael Felker, MD, MHS, FACC
Associate Professor of Medicine
Director of Heart Failure Research

2. 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

3. Congestion is the Main Cause of HF Hospitalizations
Nieminen, M et al Eur Heart J 2006

4. Congestion is both Cause and Effect
Worsening HF
Elevated LVEDP
Sub-endocardial Ischemia
Spherical LV geometry
Functional MR

5. How Successful Are We at Addressing Congestion?
Although congestion is the main reason for heart failure hospitalizations, the ADHERE Registry data showed that close to 50% of patients have minimal or no weight loss during their hospital stay.
Fonarow GC. Rev Cardiovasc Med. 2003

6. Traditional Approaches to Congestion in HF?

7. 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

8. 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?

9. 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
Braking- this can be restored once restoring volume. Teologically prevents loss of volume- howit occur is not clear- some feel it is due to or SNS- but when those pathways are blocked this event still occurs either by ACE-inhibitor or adrenergic blockade.
Long term one gets distal tubule hypertrophy which is thought to be due to increased exposure to solute- how this occurs is not quite clear… he use of thiazides obviously I a way of counterating this effect.
Brater DC. N Engl J Med. 1998;339:387, Ellison, Cardiology 2001

10. Mortality by Diuretic Dose: Data From ESCAPE
Maximum in-hospital diuretic dose
Hasselblad et al. Eur J Heart Fail. 2007;9:1064.

12. Felker GM et al, NEJM 2011

13. 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
High Dose (2.5 x oral)
Continuous infusion
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

14. Patient Global Assessment VAS AUC: Q12 vs. Continuous
Q12 VAS AUC, mean (SD) = 4236 (1440)
Continuous VAS AUC, mean (SD) = 4373 (1404)
P = 0.47
Pt Global Assessment by VAS
Hours
Felker GM et al, NEJM 2011

15. Patient Global Assessment VAS AUC: Low vs. High Intensification
Low VAS AUC, mean (SD) = 4171 (1436)
High VAS AUC, mean (SD) = 4430 (1401)
P = 0.06
Pt Global Assessment by VAS
Hours
Felker GM et al, NEJM 2011

16. Change in Creatinine at 72 hours
0.15
p = 0.45
p = 0.21
0.1
0.08
0.07
Change in Creatinine (mg/dL)
0.05
0.05
0.04
Q12 Continuous
Low High
Felker GM et al, NEJM 2011

17. Secondary Endpoints: Low vs. High Intensification
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/dL
within 72 hrs
14%
23%
Length of stay, days (median) 6 5
0.55
Felker GM et al, NEJM 2011

18. Changes in Renal Function over Time: Low vs. High
Creatinine
Cystatin C
Change in Creatinine (mg/dL)
Change in Cystatin C (pg/dL)
Days
Days
P > 0.05 for all timepoints

19. Death, Rehospitalization, or ED Visit
HR for Continuous vs. Q12 = % CI 0.83, 1.60, p = 0.41
HR for High vs. Low = % CI 0.60, 1.16, p = 0.28
Felker GM et al, NEJM 2011

20. 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

21. 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

22. Simplified Veno-Venous Ultrafiltration
0.12 m2 polysulphone filter
Blood flow adjustable ( ml/minute)
Total extracorporeal blood volume 33 ml
Peripheral, midline, or central venous access
Anticoagulation with heparin recommended A c c e s s R e t u r n
SCUF, or Slow Continuous Ultrafiltration, provides patient fluid removal by ultrafiltration only.
No replacement fluid is used.
The maximum Patient Fluid Removal Rate in SCUF is 2000 ml/hr. E f f l u e n t

23. Costanzo MR et al. J Am Coll Cardiol 2007

24. 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

25. UNLOAD: Weight Loss at 48 Hours (Co-Primary)
Weight loss (kg)
m=5.0, CI ± 0.68 kg (N=83)
m=3.1, CI ± 0.75 kg (N=84)
Costanzo MR et al. J Am Coll Cardiol 2007

26. UNLOAD: Dyspnea Score at 48 Hours (co-primary)
m=6.4, CI ± 0.11 (N=80)
m=6.1, CI ± (N=83)
Dyspnea score
Costanzo MR et al. J Am Coll Cardiol 2007

27. UNLOAD: Heart Failure Rehospitalization
Ultrafiltration arm (16 events)
Standard care arm (28 events)
Percentage of patients free from rehospitalization
P=0.037
Days
No. of Patients at Risk
Ultrafiltration arm
Standard care arm
Costanzo MR et al. J Am Coll Cardiol 2007

28. 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

29. Comparing DOSE and UNLOAD
Mean age 66 62
Mean Creatinine
1.5
Taking loop diuretics at entry
100%
75%
Mean baseline dose in furosemide equivalents
132 mg
123mg (only in pts receiving loop diuretics at baseline)
Mean treatment diuretic dose/day
119mg (low dose)
258 mg (high dose)
181 mg
Event rate at 60 days
42% (included death, rehosp,ED visit)
~15% (HF rehosp only)

30. Persistent vs. Transient Worsening Renal Function
Aronson et al. J Card Failure 2010

31. Successful Decongestion Critical To Success
Testani, J. M. et al. Circulation 2010;122:

32. 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)