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

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Presentation on theme: "Diuretics or Ultrafiltration? Michael Felker, MD, MHS, FACC Associate Professor of Medicine Director of Heart Failure Research."— Presentation transcript:

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

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

3 Congestion is the Main Cause of HF Hospitalizations Nieminen, M et al Eur Heart J 2006 N=3580

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

5 How Successful Are We at Addressing Congestion? 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 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?

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

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

11

12 Felker GM et al, NEJM 2011

13 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 diuretics 2) continue current strategy 3) 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

14 Patient Global Assessment VAS AUC: Q12 vs. Continuous Pt Global Assessment by VAS Q12 VAS AUC, mean (SD) = 4236 (1440) Continuous VAS AUC, mean (SD) = 4373 (1404) P = 0.47 Q12Continuous Hours Felker GM et al, NEJM 2011

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

16 Change in Creatinine at 72 hours Q12Continuous p = 0.45 p = 0.21 0.05 0.07 0.04 0.08 0 0.05 0.1 0.15 Change in Creatinine (mg/dL) Low High Felker GM et al, NEJM 2011

17 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

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)

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

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? 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

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

23 Costanzo MR et al. J Am Coll Cardiol 2007

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

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

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

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

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

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)

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;122:265-272

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)


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