No conflict of interest on this topic Severe decrease in LV - PowerPoint PPT Presentation

No conflict of interest on this topic

Severe decrease in LV function causes Clin J Am Soc Nephrol 8: 1800–1807, October, 2013

Pharmacologic Therapies for Type 1 CRS Treatment goals, same goals as ADHF Removal of Volume ü Diuretics (Loop diuretics) ü Brain Natriuretic Peptide (Nesiritide) ü Vasopressin Antagonists ü Adenosine Antagonists ü Ultrafiltration (SCUF, CVVHF, CVVHDF, SLED…) Optimizing Hemodynamics ü Vasodilatators ü Inotropes

Loop diuretics Travels bound to albumin --> Delivered to Glomerulus --> Filtered --> Acts luminal side of thick ascending loop (Blockage of the thick ascending loop Na/ K/ 2 Cl pump) ---> Are potent natriuretic agents and venodilators

Loop diuretics are “threshold drugs,” so an adequate dose is needed to achieve therapeutic effect. Schematic of Dose–Response Curve of Loop Diuretics in Heart Failure Patients Compared With Normal Controls JACC Vol. 59, No. 24, 2012

Loop diuretics are “threshold drugs,” so an adequate dose is needed to achieve therapeutic effect. Schematic of Dose–Response Curve of Loop Diuretics in Heart Failure Patients Compared With Normal Controls JACC Vol. 59, No. 24, 2012

Diuretics resistance ü Low serum albumin ü Decreased delivery of diuretic to renal tubules ü Reduced delivery of solute to the proximal tubule (Contraction ECFV) ü Enhanced distal nephron solute reabsorption via adaptive epithelial hypertrophy and hyperfunction ü Post-diuretic sodium retention or “rebound” (diuretic concentration below therapeutic level)

How to overcome diuretics resistance Increasing IV doses to achieve therapeutic effect Using continuous infusion or multiple boluses Adding thiazide or aldosterone receptor antagonists

DOSE-AHF study 0.15 creatinine study- Change in Creatinine (mg/dl) that s P=0.45 P=0.21 0.10 a 0.08 that 0.07 ic oral 0.05 0.05 that 0.04 the values liter, 0.00 Bolus Continuous Low Dose High Dose Change in the serum creatinine level over the course of the 72-hour study- treatment period N Engl J Med 2011;364:797-805.

DOSE-AHF study Table 2. Secondary End Points for Each Treatment Comparison.* Bolus Every 12 Hr Continuous Infusion End Point (N = 156) (N = 152) P Value AUC for dyspnea at 72 hr 4456±1468 4699±1573 0.36 Freedom from congestion at 72 hr — 22/153 (14) 22/144 (15) 0.78 no./total no. (%) Change in weight at 72 hr — lb –6.8±7.8 –8.1±10.3 0.20 Net fluid loss at 72 hr — ml 4237±3208 4249±3104 0.89 Change in NT-proBNP at 72 hr — –1316±4364 –1773±3828 0.44 pg/ml Worsening or persistent heart failure 38/154 (25) 34/145 (23) 0.78 — no./total no. (%) Treatment failure — no./total no. (%)† 59/155 (38) 57/147 (39) 0.88 Increase in creatinine of >0.3 mg/dl 27/155 (17) 28/146 (19) 0.64 within 72 hr — no./total no. (%) Length of stay in hospital — days 0.97 Median 5 5 Interquartile range 3–9 3–8 Alive and out of hospital — days 0.36 Median 51 51 Interquartile range 42–55 38–55 The bolus group was twice as likely to require a dose increase as the infusion group (21% versus 11%; P=0.01). N Engl J Med 2011;364:797-805.

DOSE-AHF study Table 2. Secondary End Points for Each Treatment Comparison.* Bolus Every 12 Hr Continuous Infusion Low Dose High Dose End Point (N = 156) (N = 152) P Value (N = 151) (N = 157) P Value AUC for dyspnea at 72 hr 4456±1468 4699±1573 0.36 4478±1550 4668±1496 0.04 Freedom from congestion at 72 hr — 22/153 (14) 22/144 (15) 0.78 16/143 (11) 28/154 (18) 0.09 no./total no. (%) Change in weight at 72 hr — lb –6.8±7.8 –8.1±10.3 0.20 –6.1±9.5 –8.7±8.5 0.01 Net fluid loss at 72 hr — ml 4237±3208 4249±3104 0.89 3575±2635 4899±3479 0.001 Change in NT-proBNP at 72 hr — –1316±4364 –1773±3828 0.44 –1194±4094 –1882±4105 0.06 pg/ml Worsening or persistent heart failure 38/154 (25) 34/145 (23) 0.78 38/145 (26) 34/154 (22) 0.40 — no./total no. (%) Treatment failure — no./total no. (%)† 59/155 (38) 57/147 (39) 0.88 54/147 (37) 62/155 (40) 0.56 Increase in creatinine of >0.3 mg/dl 27/155 (17) 28/146 (19) 0.64 20/147 (14) 35/154 (23) 0.04 within 72 hr — no./total no. (%) Length of stay in hospital — days 0.97 0.55 Median 5 5 6 5 Interquartile range 3–9 3–8 4–9 3–8 Alive and out of hospital — days 0.36 0.42 Median 51 51 50 52 Interquartile range 42–55 38–55 39–54 42–56 The high-dose strategy was associated with greater diuresis and more favorable outcomes in some secondary measures but also with transient worsening of renal function. N Engl J Med 2011;364:797-805.

Analysis from DOSE-AHF study Shah RV, Am Heart J 2012

Dopamine in Acute Decompensated Heart Failure (DAD-HF) Trial 40 mg initial IV furosemide bolus, HDF (20 mg/h) continuous infusion for 8 hours vs. LDFD (5 mg/h plus dopamine 5 µg kg/min) continuous infusion for 8 hours Table 3. Short-Term (60-Day) Outcomes in the Two Study Groups, n (%) HDF Group LDFD Group End Point (n 5 30) (n 5 30) P Value Mortality All cause 3 (10%) 3 (10%) 1.000 Cardiovascular 3 (10%) 2 (6.7%) 1.000 Non e HF-related 0 (0%) 0 (0%) 1.000 Due to worsening HF 3 (10%) 2 (6.7%) 1.000 Rehospitalization All cause 2 (6.7%) 6 (20%) .254 Cardiovascular 2 (6.7%) 4 (13.3%) .671 Non e HF-related 0 (0%) 1 (3.3%) 1.000 Due to worsening HF 2 (6.7%) 3 (10%) 1.000 The higher incidence of WRF in the non-dopamine arm could have been attributed to the high-dose diuretic regimen rather than a benefit from dopamine in the low-dose diuretic arm. Journal of Cardiac Failure Vol. 16 No. 12 2010

CARRESS-HF study Metolazone was added to augment diuresis. Vasodilators or inotropes could be added on the basis of failure to achieve clinical targets and depend- ing on BP and ejection fraction. Journal of Cardiac Failure Vol. 18 No. 3 March 2012

CARRESS-HF study Creatinine Increase (mg/dl) 1.0 0.8 Ultrafiltration 0.6 (N=92) 0.4 0.2 Weight Weight Loss 0.0 Gain (lb) − 20 − 18 − 16 − 14 − 12 − 10 − 8 − 6 − 4 − 2 0 (lb) − 0.2 Pharmacologic therapy (N=94) − 0.4 P=0.003 − 0.6 − 0.8 Creatinine Decrease (mg/dl) N Engl J Med 2012;367:2296-304

Take home message I Strategy for loop diuretics in ADHF patients ü High doses over low doses (definition?) ü Continuous infusion over boluses (number?) ü Initial bolus in patients on a high outpatient diuretic dose (definitions?) ü Thiazide or aldosterone antagonists in combination to augment diuresis if necessary

V2-Recepteur antagonist, Tolvaptan: EVEREST trial JAMA. 2007;297:1319-1331

Nesiritide (rhBNP) ASCEND-HF study Table 2. Primary and Secondary Clinical End Points and Safety End Points through Day 30.* Percentage-Point Nesiritide Placebo Difference or Odds End Point (N = 3496) (N = 3511) Ratio (95% CI)† P Value Primary clinical end points Death from any cause or rehospitalization for heart failure — 321/3423 (9.4) 345/3413 (10.1) − 0.7 ( − 2.1 to 0.7) 0.31 no./total no. (%) Death from any cause 126/3490 (3.6) 141/3499 (4.0) − 0.4 ( − 1.3 to 0.5) Rehospitalization for heart failure 204/3422 (6.0) 208/3411 (6.1) − 0.1 ( − 1.2 to 1.0) Secondary clinical end points 7141 Patients with ADHF received either nesiritide or Persistent or worsening heart failure or death from any cause 147/3459 (4.2) 165/3462 (4.8) − 0.6 ( − 1.5 to 0.5) 0.30 through hospital discharge — no./total no. (%) placebo for 24 to 168 hours in addition to standard Days alive and out of hospital through day 30 20.9±6.9 20.7±7.1 0.2 ( − 0.13 to 0.53) 0.16 care Rehospitalization or death from cardiovascular causes — 372/3423 (10.9) 402/3415 (11.8) − 0.9 ( − 2.4 to 0.6) 0.24 no./total no. (%) Safety end points Death from cardiovascular causes — no./total no. (%) 112/3498 (3.2) 124/3509 (3.5) − 0.3 ( − 1.2 to 0.5) 0.44 Sudden death from cardiac causes — no./total no. (%) 19/3324 (0.6) 16/3327 (0.5) 0.1 ( − 0.3 to 0.4) 0.61 Hypotension — no./total no. (%) 930/3498 (26.6) 538/3509 (15.3) 11.3 (9.4 to 13.1) <0.001 Asymptomatic 748/3498 (21.4) 436/3509 (12.4) 9.0 (7.2 to 10.7) <0.001 Symptomatic 250/3496 (7.2) 141/3509 (4.0) 3.2 (2.1 to 4.2) <0.001 >25% decrease in estimated GFR from study-drug initiation — 1032/3289 (31.4) 968/3278 (29.5) 1.09 (0.98 to 1.21) 0.11 no./total no. (%) Baseline estimated GFR <60 ml/min/1.73 m 2 484/1714 (28.2) 449/1717 (26.2) 1.11 (0.96 to 1.3) 0.16 Baseline estimated GFR � ≥ 60 ml/min/1.73 m 2 548/1575 (34.8) 519/1561 (33.2) 1.07 (0.92 to 1.24) 0.38 N Engl J Med 2011;365:32-43.

Nesiritide (rhBNP) ASCEND-HF study 5,864 subjects with urine output measurements Predictors of UO with treatment added Pr > j t j Parameter Estimate Standard Error t-value Baseline BMI 0.0073 0.0011 6.33 < 0.0001 Baseline diastolic BP 0.0035 0.0006 5.74 < 0.0001 Male sex 0.1134 0.0174 6.51 < 0.0001 Previous weight 0.0999 0.0182 5.48 < 0.0001 gain? Jugular venous 0.0927 0.0169 5.47 < 0.0001 distension? Log BUN � 0.0885 0.0145 � 6.09 < 0.0001 Log diuretic dose 0.0902 0.0111 8.14 < 0.0001 Treatment 0.0199 0.0163 1.22 0.222 Nesiritide did not lead to increased UO in patients with ADHF J Am Coll Cardiol 2013;62:1177–83