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Diuretic Resistance and Toxicity in the setting of ADHF

Diuretic Resistance and Toxicity in the setting of ADHF. John Wigneswaran MD Chief Medical Officer CHF Solutions Inc. June 2009. Frequency of Kidney Disease in 118,465 Admissions 1. eCrCl >90 60 – 89 30 – 59 15–29 <15 mL/min.

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Diuretic Resistance and Toxicity in the setting of ADHF

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  1. Diuretic Resistance and Toxicity in the setting of ADHF John Wigneswaran MD Chief Medical Officer CHF Solutions Inc. June 2009

  2. Frequency of Kidney Disease in 118,465 Admissions1 eCrCl >90 60–89 30–59 15–29 <15 mL/min Heywood et al. J Am Coll Cardiol. 2005;173A:843-848.

  3. The Cardiorenal Syndrome of HF Diuretic Therapy Increased Morbidity and Mortality Neurohormonal Activation Development of Diuretic and Natriuretic Resistance Diminished Blood Flow Impaired Renal Function Decreased Renal Perfusion??

  4. Mechanisms of Renal Failure: 1. Increased Renal Vein Pressures, diminished sodium excretion, decreased GFR 2. Increased Interstitial edema- leading to hypoxia 3. Disruption of renal autoregulation by stimulation of vascular reflexes Mc

  5. Mechanisms of Sodium and Water Retention in ADHF Heart Failure Catecholamines↑ Vasopressin ↑ Atrial Natriuretic Peptide ↑ Renin↑ Aldo ↑ ANP Resistance AII ↑ Passive Na and H2O Reabsorption Proximal Tubule ↑ Via Efferent Constriction (indirect effect ) Na Reabsorption Collecting Duct↓ Excretion of Free Water Collecting Tubule ↓ Thirst Na Reabsorption Proximal & Distal Tubule↑ Na Reabsorption Proximal Tubule↑ (Direct Effect) Inhibition of Renin and AldosteroneSecretion Na Reabsorption Collecting Duct↑ Courtesy of Robert Schrier, MD, University of Colorado School of Medicine.

  6. Most Common Intravenous Medications All Enrolled Discharges (n=105,388) October 2001–January 2004 100 88% 90 80 70 60 Patients (%) 50 40 30 10% 10% 20 6% 6% 3% 1% 10 0 IV Diuretic Dobutamine Dopamine Milrinone Nesiritide Nitroglycerin Nitroprusside IV Vasoactive Meds ADHERE® Registry. Benchmark Report. 2004.

  7. Diuretics and ADHF • No long-term studies of diuretics for the treatment of ADHF1 • Despite widespread use in ADHF, their effect on morbidity and mortality is not known2 1. Ravnan et al. Congest Heart Fail. 2002;8:80. 2. Kramer et al. Nephrol Dial Transplant. 1999:14(suppl 4):39-42.

  8. Diuretic Resistance • Can be described as a clinical state in which the diuretic response is diminished or lost before the therapeutic goal of relief from edema has been reached1 • Affects 20%–30% of patients with HF2 1. Kramer et al. Nephrol Dial Transplant. 1999;14(suppl 4):39-42. 2. Ellison. Cardiology. 2001;96:132-143.

  9. Diuretic Resistance: Two Types • “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. N Engl J Med. 1998;339:387.

  10. Diuretics Activate Neurohormonal Systems in HF 50 1000 Mean, 95% Confidence Interval 600 10 Plasma Renin Activity (ng/mL/h) Plasma Aldosterone (pmol/L) 2.5 200 0.5 P =.0007 100 P =.0002 After Diuretic (n=11) After Diuretic (n=11) Before (n=12) Before (n=12) Bayliss et al. Br Heart J. 1987;57:17

  11. Furosemide Monotherapy Causes Significant Decline in Renal Function (GFR) Change in GFR after IV furosemide 80 mg in CHF 15 Placebo 10 5 0 -5 GFR (% Change) IV furosemide -10 -15 -20 -25 0 500 1000 1500 2000 2500 Urine Output (mL) 0–8 h Gottlieb et al. Circulation. 2002;105:1348.

  12. Reaccumulation of Na+ Despite Ongoing Furosemide Treatment1 300 250 200 150 100 50 0 Na+ Excretion Net Diuresis After 4 Days of Rx = 0 mL UNaV, mEq/6 h Na+ Intake Before F F1 F2 F3 F4 Time, Days F = Furosemide Na+ Reaccumulation Between Furosemide Doses 1. Wilcox et al. Kidney Int. 1987;31:135.

  13. Dose Response Curves for Loop Diuretics in ADHF Are Altered Fractional Na Excretion 20 18 16 14 12 10 8 6 4 2 0 Normal CRF CHF Decreased Maximal Response Secretory Defect FENa ,% 0.01 0.1 1 10 100 [Furosemide], µg/mL Ellison. Cardiology. 2001;96:132-143.

  14. Brater. N Engl J Med. 1998;339:387-395.

  15. Diuretic Toxicity • Peacock et. al. studies 82,540 patients from the ADHERE Registry • Eshaghian et. al. studied 1,354 patients with HF • Patients were divided into groups by diuretic dose • The ≥80 mg groups… • Had significantly higher mortality • Were 3x times more likely to receive dialysis (≥160 mg) • There is an independent, dose-dependent association between loop diuretic use and impaired survival HF patients on doses ≥ 80 mg would benefit from Aquapheresis Eshaghian S. et al. Am J Cardiol 2006;97:1759 –1764. Peacock WF Cardiology 2009;113:12-19.

  16. Outcomes with Standard Care Change in Weight During HospitalizationJanuary 2001 to April 2006 (n=96,094) Evidence of Incomplete Relief From Congestion Nearly 50% of ADHF patients discharged with weight gain or losing less than 5 lbs 27% 30 26% 25 20 Enrolled Discharges (%) 13% 15 16% 7% 6% 10 3% 2% 5 0 (<-20) (–20 to –15) (-15 to –10) (–10 to –5) (–5 to 0) (0 to 5) (5 to 10) (>10) Change in Weight (lbs) Adhere National Benchmark Report Data, January 2001 to April 2006. Note: n represents the number of patients who have both baseline and discharge weight, and the percentage is calculated based on the total patients in the corresponding population. Patients without baseline or discharge weight are omitted from the histogram calculations.

  17. ULTRAFILTRATION allows for the production of plasma water from whole blood across a semipermeable membrane in response to a transmembrane pressure gradient • The ensuing fluid or ultrafiltrateis isotonic to plasma Ronco et al. Cardiology. 2001;96:155-168.

  18. 1940 1950 1960 1970 1980 A History of Ultrafiltration 1979: Paganiniand others reported the practical application of ultrafiltration in a volume-overloaded patient4 1974: Silverstein described solitary ultrafiltration on 5 ESRD patients via a modified dialysis circuit3 1949: Schneierson proposed intermittent peritoneal dialysis for refractive ADHF1 1954: Kolff noted that ultrafiltration could be used for a “reduction of intractable edema”2 1. Schneierson SJ. Am J Med Soc. 1949;298. 2. Kolff et al. Cleve Clin Q. 1954;21. 3. Silverstein et al. N Engl J Med. 1974;291:747-751. 4. Paganini et al. Adv Ren Replace Ther. 1996;3:166-173.

  19. Hemodynamic Effects of UF in CHF CO (L/m) SV (mL) 5.0 – 4.0 – 3.0 – 2.0 – 70 – 60 – 50 – 40 – 30 – Before UF 1 liter 2 liter 3 liter 4 liter After UF 24h after UF Before UF 1 liter 2 liter 3 liter 4 liter After UF 24h after UF RAP (mmHg) PWP (mmHg) 30 – 25 – 20 – 15 – 10 - 25 – 20 – 15 – 10 – 5 – 0 - Before UF 1 liter 2 liter 3 liter 4 liter After UF 24h after UF Before UF 1 liter 2 liter 3 liter 4 liter After UF 24h after UF Marenzi et al. J Am Coll Cardiol. 2001;38:963-968.

  20. + 170 – + 80 – + 40 – % 0 – - 40 - Effects of Ultrafiltration vs IV Furosemide Neurohormones NE PRA ALD • + 80 – • + 40 – • % 0 – • 140 – • + 80 – • + 40 – • % 0 – • 140 – d 0 1d 2d 3d 4d 3m d 0 1d 2d 3d 4d 3m d 0 1d 2d 3d 4d 3m Triangles = Ultrafiltration Squares = Furosemide Agostoni et al. Am J Med. 1994;96:191-199.

  21. Ultrafiltration and Severe Chronic Kidney Disease • High rates of ultrafiltration may be associated with worsening renal function in certain patient subsets • 4/11 patients with ADHF, late Stage 4/Stage 5 CKD (CrCl <30 mL/min), experienced ARF* with high rates and volumes of UF (up to 485 mL/h for 8 h, multiple treatments)1 • High ultrafiltration rates and coexistent severe chronic kidney disease are important factors to consider when prescribing ultrafiltration *>0.3 mg/dL creatinine increase Liang et al. J Card Fail. 2006;12:707-714.

  22. Fluid Removal by Ultrafiltration Interstitial Space (edema) • Ultrafiltration can remove fluid from the blood at the same rate that fluid can be naturally recruited from the tissue • The transient removal of blood illicits compensatory mechanisms, termed plasma or intravascular refill (PR), aimed at minimizing this reduction1,2 Na P H2O Na K UF K PR P Vascular Space Na Vascular Space Na 1. Lauer et al. Arch Intern Med. 1983;99:455-460. 2. Marenzi et al. J Am Coll Cardiol. 2001;38:4.

  23. Conclusions • Diuretic Resistance may be seen in 1/3 of admissions for ADHF • Loop Diuretic PK/PD properties may play a role in deciding treatment protocols • High Doses of diuretics may be associated with poor outcomes

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