Diuretics or Ultrafiltration? Michael Felker, MD, MHS, FACC
Associate Professor of Medicine Director of Heart Failure Research
Slide 2 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 Slide 3 Congestion is
the Main Cause of HF Hospitalizations Nieminen, M et al Eur Heart J
2006 N=3580 Slide 4 Worsening HF Elevated LVEDP Spherical LV
geometry Sub-endocardial Ischemia Functional MR Congestion is both
Cause and Effect Slide 5 How Successful Are We at Addressing
Congestion? Fonarow GC. Rev Cardiovasc Med. 2003 Slide 6
Traditional Approaches to Congestion in HF? Slide 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 Slide 8 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? Slide 9 Diuretic Resistance in HF n Heart failure and
CKD are both associated with relative diuretic resistance Braking
Phenomenon Braking Phenomenon l A decrease in response to a
diuretic after the first dose has been administered n Long-term
Tolerance l Tubular hypertrophy to compensate for salt loss Brater
DC. N Engl J Med. 1998;339:387, Ellison, Cardiology 2001 Slide 10
Mortality by Diuretic Dose: Data From ESCAPE Hasselblad et al. Eur
J Heart Fail. 2007;9:1064. Maximum in-hospital diuretic dose
Mortality Slide 11 Slide 12 Felker GM et al, NEJM 2011 Slide 13
Acute Heart Failure (1 symptom AND 1 sign) Secondary Endpoints: Low
vs. High Intensification LowHighP value Dyspnea VAS AUC at 72
hours447846680.041 % free from congestion at 72 hrs11%18%0.091
Change in weight at 72 hrs-6.1 lbs-8.7 lbs0.011 Net volume loss at
72 hrs3575 mL4899 mL0.001 Change in NTproBNP at 72 hrs
(pg/mL)-1194-18820.06 % Treatment failure37%40%0.56 % with Cr
increase > 0.3 mg/dL within 72 hrs 14%23%0.041 Length of stay,
days (median)650.55 Felker GM et al, NEJM 2011 Slide 18 Changes in
Renal Function over Time: Low vs. High Days Change in Creatinine
(mg/dL) Cystatin CCreatinine Days HighLow P > 0.05 for all
timepoints Change in Cystatin C (pg/dL) Slide 19 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 Felker GM et al, NEJM 2011 Slide 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 Slide 21
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
Slide 22 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 Slide 23 Costanzo MR et al. J Am Coll Cardiol
2007 Slide 24 Primary End Points n n Efficacy Weight loss at 48
hours after randomization Dyspnea score at 48 hours after
randomization n 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 Slide 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) P=0.001 Costanzo
MR et al. J Am Coll Cardiol 2007 Slide 26 Dyspnea score 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
Slide 27 UNLOAD: Heart Failure Rehospitalization Percentage of
patients free from rehospitalization P=0.037 Ultrafiltration arm
(16 events) Standard care arm (28 events) 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 Days Costanzo MR et al. J Am Coll
Cardiol 2007 Slide 28 Current Guidelines on Ultrafiltration Class
IIa: Ultrafiltration is reasonable for patients with refractory
congestion not responding to medical therapy (Level of Evidence B)
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 Slide 29 Comparing
DOSE and UNLOAD DOSEUNLOAD Mean age6662 Mean Creatinine1.5 Taking
loop diuretics at entry 100%75% Mean baseline dose in furosemide
equivalents 132 mg123mg (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 days42% (included death,
rehosp,ED visit) ~15% (HF rehosp only) Slide 30 Persistent vs.
Transient Worsening Renal Function Aronson et al. J Card Failure
2010 Slide 31 Successful Decongestion Critical To Success Testani,
J. M. et al. Circulation 2010;122:265-272 Slide 32 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)
