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

No conflict of interest on this topic

Clin J Am Soc Nephrol 8: 1800–1807, October, 2013

Severe decrease in LV function causes

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.

JACC Vol. 59, No. 24, 2012

Schematic of Dose–Response Curve

• f Loop Diuretics in Heart Failure Patients

Compared With Normal Controls

Loop diuretics are “threshold drugs,” so an adequate dose is needed to achieve therapeutic effect.

JACC Vol. 59, No. 24, 2012

Schematic of Dose–Response Curve

• f Loop Diuretics in Heart Failure Patients

Compared With Normal Controls

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)

Diuretics resistance

How to overcome diuretics resistance

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

N Engl J Med 2011;364:797-805.

Change in Creatinine (mg/dl)

0.15 0.05 0.10 0.00

Bolus Continuous Low Dose High Dose

P=0.45 P=0.21 0.05 0.07 0.04 0.08

creatinine study- that s a that ic

• ral

that the values liter,

Change in the serum creatinine level over the course of the 72-hour study- treatment period

DOSE-AHF study

N Engl J Med 2011;364:797-805. Table 2. Secondary End Points for Each Treatment Comparison.* End Point Bolus Every 12 Hr (N = 156) Continuous Infusion (N = 152) P Value AUC for dyspnea at 72 hr 4456±1468 4699±1573 0.36 Freedom from congestion at 72 hr — no./total no. (%) 22/153 (14) 22/144 (15) 0.78 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 — pg/ml –1316±4364 –1773±3828 0.44 Worsening or persistent heart failure — no./total no. (%) 38/154 (25) 34/145 (23) 0.78 Treatment failure — no./total no. (%)† 59/155 (38) 57/147 (39) 0.88 Increase in creatinine of >0.3 mg/dl within 72 hr — no./total no. (%) 27/155 (17) 28/146 (19) 0.64 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

DOSE-AHF study

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. Table 2. Secondary End Points for Each Treatment Comparison.* End Point Bolus Every 12 Hr (N = 156) Continuous Infusion (N = 152) P Value Low Dose (N = 151) High Dose (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 — no./total no. (%) 22/153 (14) 22/144 (15) 0.78 16/143 (11) 28/154 (18) 0.09 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 — pg/ml –1316±4364 –1773±3828 0.44 –1194±4094 –1882±4105 0.06 Worsening or persistent heart failure — no./total no. (%) 38/154 (25) 34/145 (23) 0.78 38/145 (26) 34/154 (22) 0.40 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 within 72 hr — no./total no. (%) 27/155 (17) 28/146 (19) 0.64 20/147 (14) 35/154 (23) 0.04 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

• utcomes in some secondary measures but also with transient worsening of renal

function.

DOSE-AHF study

Shah RV, Am Heart J 2012

Analysis from DOSE-AHF study

Journal of Cardiac Failure Vol. 16 No. 12 2010

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 (%) End Point HDF Group (n 5 30) LDFD Group (n 5 30) P Value

Mortality All cause 3 (10%) 3 (10%) 1.000 Cardiovascular 3 (10%) 2 (6.7%) 1.000 NoneHF-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 NoneHF-related 0 (0%) 1 (3.3%) 1.000 Due to worsening HF 2 (6.7%) 3 (10%) 1.000

Dopamine in Acute Decompensated Heart Failure (DAD-HF) Trial

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.

CARRESS-HF study

Journal of Cardiac Failure Vol. 18 No. 3 March 2012

Metolazone was added to augment diuresis. Vasodilators or inotropes could be added on the basis of failure to achieve clinical targets and depend- ing

• n BP and ejection fraction.

CARRESS-HF study

Creatinine Increase (mg/dl) Creatinine Decrease (mg/dl)

1.0 0.6 0.8 0.4 0.2 0.0 −0.2 −0.4 −0.6 −0.8 −20 −18 −16 −14 −12 −10 −8 −6 −4 −2

Weight Loss (lb) Weight Gain (lb)

P=0.003 Ultrafiltration (N=92) Pharmacologic therapy (N=94)

N Engl J Med 2012;367:2296-304

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

Take home message I

• JAMA. 2007;297:1319-1331

V2-Recepteur antagonist, Tolvaptan: EVEREST trial

N Engl J Med 2011;365:32-43.

Nesiritide (rhBNP) ASCEND-HF study

Table 2. Primary and Secondary Clinical End Points and Safety End Points through Day 30.* End Point Nesiritide (N = 3496) Placebo (N = 3511) Percentage-Point Difference or Odds Ratio (95% CI)† P Value Primary clinical end points Death from any cause or rehospitalization for heart failure — no./total no. (%) 321/3423 (9.4) 345/3413 (10.1) −0.7 (−2.1 to 0.7) 0.31 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 Persistent or worsening heart failure or death from any cause through hospital discharge — no./total no. (%) 147/3459 (4.2) 165/3462 (4.8) −0.6 (−1.5 to 0.5) 0.30 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 Rehospitalization or death from cardiovascular causes — no./total no. (%) 372/3423 (10.9) 402/3415 (11.8) −0.9 (−2.4 to 0.6) 0.24 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 — no./total no. (%) 1032/3289 (31.4) 968/3278 (29.5) 1.09 (0.98 to 1.21) 0.11 Baseline estimated GFR <60 ml/min/1.73 m2 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 m2 548/1575 (34.8) 519/1561 (33.2) 1.07 (0.92 to 1.24) 0.38

7141 Patients with ADHF received either nesiritide or placebo for 24 to 168 hours in addition to standard care

J Am Coll Cardiol 2013;62:1177–83

Nesiritide did not lead to increased UO in patients with ADHF

Parameter Estimate Standard Error t-value Pr > jtj 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 gain? 0.0999 0.0182 5.48 <0.0001 Jugular venous distension? 0.0927 0.0169 5.47 <0.0001 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

5,864 subjects with urine output measurements Predictors of UO with treatment added

Nesiritide (rhBNP) ASCEND-HF study

J Am Coll Cardiol 2011;57:1899–907

Risk of Morbidity and Mortality in Relation to Baseline Renal Function

PROTECT study,

Adenosine A1 receptor antagonist, Rolofylline

PROTECT study,

Adenosine A1 receptor antagonist, Rolofylline

2,033 patients with AHF, volume overload, eGFR 20 - 80 ml/min were randomized between rolofylline 30 mg/day or IV placebo for up to 3 days

J Am Coll Cardiol 2011;57:1899–907

Rolofylline exerted modest diuretic effects, but had no protective effect on renal function in AHF patients with mild to moderate renal dysfunction

PROTECT study

J Am Coll Cardiol 2011;57:1899–907

Individual Components of Secondary Efficacy Endpoint of Persistent WRF Table 2 Individual Components of Secondary Efficacy Endpoint of Persistent WRF

Placebo Rolofylline Subjects in ITT population 677 1,356 Subjects with available data for secondary endpoint 644 1,297 Subjects with persistent WRF* 88 (13.7) 195 (15.0) SCr increase 0.3 mg/dl (days 7 and 14) 72 (81.8) 167 (85.6) Initiation of hemofiltration or dialysis to day 7 6 (6.8) 6 (3.1) Death by day 7 14 (15.9) 23 (11.8)

www.cjasn.org Vol 8 October, 2013

www.cjasn.org Vol 8 October, 2013

Levosimendan may ü Augment renal perfusion via vasodilatation arising from its KATP channel agonism ü Reverse angiotensin-2- mediated mesangial cell contraction increasing glomerular capillary surface area

Cardiovasc Drugs Ther. 2013 Dec;27(6):581-90

Levosimendan, myofilament calcium sensitizer and K+ channel opener

Cardiovasc Drugs Ther. 2013 Dec;27(6):581-90

Effects of Levosimendan on GFR, RBF, and renal

• xygenation after CBP

Crit Care Med 2013; 41:2328–2335

Levosimendan, LD of 12 µg/kg and 0.1 µg/kg/min (n = 15), or placebo (n = 15).

฀

฀฀฀

฀

฀฀฀

Differential effect on RBF of Levosimendan (0.1 µg/kg/min)

• vs. dopamine (2 µg/kg/min) in

postcardiac surgery patients.

Dopamine data were from Acta Anaesthesiol Scand 2010

*p < 0.05 ***p < 0.001

Serelaxin

Recombinant human relaxin-2 Relaxin is a endogenous heterodimer peptide that belongs in the insulin/IGF/Relaxin superfamily It mediates the hemodynamic changes that occur during pregnancy, ü Increased cardiac output, ü Increased renal blood flow ü Increased arterial compliance

Kaplan-Meier analysis of death in the ITT population

Lancet 2013; 381: 29–39

1161 patients with ADHF received standard care plus 48-hour IV placebo or serelaxin (30 mg/kg per day)

J Am Coll Cardiol 2013;61:196–206

Effect of Serelaxin on renal biomarkers in (RELAX-AHF) Development Program

20 0.20 0.10 0.05

• 0.05

0.15 15 10 5

• 5

Creatinine μmol/L mg/dL mmol/L mg/dL

1

*** *** *** *** ***

2 3 4 Day 5 14 3.5 3.0 2.5 1.0 1.5 2.0 0.5 10 8 6 2 4

BUN

1

** *** * * *

2 3 4 Day 5 14

A B

J Am Coll Cardiol 2013;61:196–206

Effect of Serelaxin on renal biomarkers in (RELAX-AHF) Development Program

Number at risk: ≥22 nmol/L increase <22 nmol/L increase 869 212 851 202 841 199 834 194 826 187 819 184 815 181 804 179 798 179 687 160

Cumulative Risk

≥22 nmol/L increase (0.3 mg/L) <22 nmol/L increase (0.3 mg/L)

B Cystatin C C

0.05 0.10 0.15 0.20 20 40 60 80 Study Day 2.10 (1.38, 3.20) p=0.0004

Number at risk:

100120140160180

Cystatin C 1.00 1.05 1.10 1.15 1.20 2 14 5 Days *** ** * Ratio of follow-up to baseline

B

Placebo Serelaxin

Serelaxin reduced cardiac and renal damage, and persistent congestion during the first few days after admission, and these beneficial effects may be associated with increased survival

Journal of Cardiac Failure Vol. 19 No. 6 2013

Journal of Cardiac Failure Vol. 19 No. 6 2013

Strategy for loop diuretics in ADHF patients ü High doses to reach the target effect ü Continuous infusion over boluses ü Initial bolus in patients on a high outpatient diuretic dose ü Thiazide or aldosterone antagonists in combination to augment diuresis if necessary

Take home messages

Renal dose dopamine should not be used routinely in CRS management Pharmacologic doses of nesiritide in ADHF fails to provide significant clinical benefits and to prevent acute CRS and Inotropic support should be guided by the underlying pathology with or without hemodynamic guidance Pharmacologic doses of nesiritide and agents that target receptors for adenosine), vasopressin in ADHF patients fails to provide significant clinical benefits and to prevent acute CRS The development of novel therapies hold significant promise

Take home messages

CARRESS