Diuretics or Ultrafiltration?

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 N=3580 Nieminen, M et al Eur Heart J 2006

4. 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 • 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 Brater DC. N Engl J Med. 1998;339:387, Ellison, Cardiology 2001

10. Mortality by Diuretic Dose: Data From ESCAPE Mortality 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 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 High 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 0 Q12 Continuous Low High Felker GM et al, NEJM 2011

17. Secondary Endpoints:Low vs. High Intensification Felker GM et al, NEJM 2011

18. Low High 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 = 1.1595% 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. 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 Ultrafiltration as a Therapy for Congestion?

22. Simplified Veno-Venous Ultrafiltration A c c e s s • 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 R e t u r n E f f l u e n t

23. Costanzo MR et al. J Am CollCardiol 2007

24. 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 Primary End Points

25. UNLOAD: Weight Loss at 48 Hours (Co-Primary) P=0.001 m=5.0, CI ± 0.68 kg(N=83) Weight loss (kg) 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) P=0.35 m=6.4, CI ± 0.11(N=80) m=6.1, CI ± 0.15(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 patientsfree from rehospitalization P=0.037 Days 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 Costanzo MR et al. J Am CollCardiol 2007

28. Class IIa: Ultrafiltration is reasonable for patients with refractory congestion not responding to medical therapy (Level of Evidence B) Current Guidelines on Ultrafiltration Jessup M et al, Circulation 2009

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

30. Successful Decongestion Critical To Success Testani, J. M. et al. Circulation 2010;122:265-272

31. Conclusions and Next Steps • Decongestion is important by whatever means • Transientworsening 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)