Diuretics or Ultrafiltration? Michael Felker, MD, MHS, FACC Associate 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 Nieminen, M et al Eur Heart J 2006

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

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

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 Braking- this can be restored once restoring volume. Teologically prevents loss of volume- howit occur is not clear- some feel it is due to AG@ 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

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

Felker GM et al, NEJM 2011

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

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

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

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

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

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

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

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

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 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

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) 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

UNLOAD: Dyspnea Score at 48 Hours (co-primary) 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

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 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 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

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)

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)