From Sodium Retention to Therapy for Refractory Ascites The Role for New Drugs Florence Wong University of Toronto Falk Symposium October 14, 2007
Sodium Retention in Cirrhosis Occurs as a result of hemodynamic changes that leads to underfilling of the effective arterial circulation Compensatory activation of various neurohumoral mechanisms that act on various parts of the nephron to retain sodium and water
Stages of Sodium Retention in Cirrhosis Subtle sodium retention Obvious sodium retention Avid sodium retention Functional Renal failure Pre-Ascites Responsive ascites Refractory ascites Hepatorenal syndrome Hepatorenal interaction Portal hypertension Systemic arterial vasodilatation Renal vasoconstriction
Refractory Ascites Weight loss 1.5kg/week while on 400mg of spironolactone or 30mg of amiloride plus 160mg of furosemide daily two weeks Dietary sodium restriction 50mmol per day
Management of Refractory Ascites Sodium Restriction Mandatory at all stages of ascites in order to reduce the rate of accumulation of ascites
Management of Refractory Ascites OR Large volume paracentesis TIPS
But. Large volume paracentesis is inconvenient for some patients with refractory ascites TIPS insertion is not appropriate for many patients
Albumin Most abundant plasma protein Physiological function is to maintain colloid osmotic pressure Can improve effective arterial blood volume in cirrhosis Has other ligand binding, antioxidant, anti-inflammatory and transport functions Old drug with new indications for use
(Gentilini et al, J Hepatology 1999) Albumin for Management of Ascites 141 patients Bed rest & sodium-restricted diet 15 Responders 126 Non-responders Potassium Canrenoate 200mg Furosemide 25mg Potassium Canrenoate 200mg Furosemide 25mg Albumin 25g/wk for 1 year, then 25g/2 wks for 2nd & 3rd years 47 Responders 16 Non-responders (74.7%) ( 25.3%) 57 Responders* 6 Non-responders (90.5%) ( 9.5%)
Albumin for Management of Ascites Ascites re-accumulation Hospital re-admission for Ascites Diuretics P<0.03 Diuretics P<0.03 Albumin + diuretics Albumin + diuretics (Gentilini et al, J Hepatology 1999)
Albumin for Management of Ascites Survival P=0.0079 Albumin + diuretics Diuretics (Romanelli et al, World J Gastroenterol 2007)
Albumin for Refractory Ascites 19 patients with refractory ascites Mean age: 54.5 years 50gm of albumin infused per week Assessment made before and after 8 weeks of infusion Serum Serum INR MELD [Na] creatinine Before 133 1.08 1.6 15.1 After 135 1.06 1.6 16.3 (Trotter et al, Dig Dis Sci 2005)
Albumin for Refractory Ascites P=0.005 P=0.002 gm/l 40 35 30 25 20 15 10 5 0 Serum albumin Before After (Trotter et al, Dig Dis Sci 2005) lb 190 180 170 160 150 Before After Weight
Albumin for Management of Ascites Makes physiological sense Improves survival in patients with diuretic responsive ascites Impact on survival in patients with refractory ascites is unknown Cost (albumin & medical manpower) is enormous Await definitive studies to establish albumin as treatment for refractory ascites
Vasoconstrictors for Management of Ascites Aim at reducing the extent of arterial vasodilatation Improves effective arterial circulation Dampens the activated vasoconstrictor systems Should improve renal hemodynamics Increase in renal sodium retention should follow
Vasoconstrictors for Management of Ascites Terlipressin Single intravenous dose of 2mg Improvement in systemic hemodynamics No measurement of renal hemodynmics No improvement in renal sodium excretion in ascitic patients (Kalambokis et al, J Gastroenterol Hepatol 2005)
Vasoconstrictors for Management of Ascites Terlipressin I mg/4hr intravenous administration in patients with refractory ascites and type 2 HRS for 7days Improvement in systemic hemodynamics Improvement in renal hemodynmics No improvement of renal sodium excretion (Alessandria et al, Euro J Gastroenterol Hepatol 2002)
Vasoconstrictors for Management of Ascites Midodrine Orally active alpha agonist Single oral dose of 15mg in ascitic patients Improvement in systemic and renal hemodynmics ml/min 100 90 80 70 60 50 40 30 20 10 0 µmol/min Before GFR P<0.025 UNaV 3 hours after Increase in renal sodium excretion Reduction in vasoconstrictor levels Effects maintained for at least 3 hours (Angeli et al, Hepatology 1998) 100 90 80 70 60 50 40 30 20 10 0 Before P<0.025 3 hours after
Vasoconstrictors for Management of Ascites Midodrine 7.5mg t.i.d. for 7 days Delayed improvement in systemic and renal hemodynmics Delayed improvement in renal sodium excretion Reduction in vasoconstrictor levels Significant correlation between change in systemic hemodynamics & increase in GFR and increase in UNaV (Kalambokis et al, J Hepatol 2007) ml/min 100 95 90 85 80 75 70 65 60 mmol/day 60 50 40 30 20 10 0 GFR P<0.01 Before Day 7 UNaV P<0.05 Before Day 7
Vaspressin Receptor Antagonists Urinary space Collecting Principal Duct Cell Basolateral space H 2 O H 2 O H 2 O AP2 PKA camp V 2 receptor S G protein AVP AVP AVP Adenyl cyclase ATP H 2 O H 2 O H2 O H 2 O H2 O S = V 2 receptor antagonist
Vaspressin Receptor Antagonists Aquaretic agents Initially developed for the treatment of hyponatremia from whatever cause promote aquaresis in conditions of water excess: - congestive heart failure - decompensated cirrhosis - syndrome of inappropriate ADH
Aquaretic Agents- Vaptans Aquaretic agents are collectively known as Vaptans - Mozavaptan (OPC-31260) - Lixivaptan (VPA-985) - Tolvaptan (OPC-41061) - RWJ 351647 - Satavaptan - Conivaptan (V 1 & V 2 receptor antagonist)
Lixivaptan Corrects Hyponatremia Lixivaptan - VPA 985 140 Serum [Na] 135 ** * * Serum [Na] in mmol/l ± SEM 130 125 120 Baseline Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Day -1 (Wong F et al, Hepatology 2004)
Satavaptan Corrects Hyponatremia Mean serum sodium (mmol/l) (±SE) 140 138 136 134 132 130 128 126 124 HypoCAT Satavaptan Placebo 2 7 4 8 12 24 40 52 Day Week
Vaptans for Ascites Management Vasopressin receptor antagonists act on a different site of the nephron compared to standard diuretics to induce a water diuresis They may help to improve the control of ascites and reduce recurrence after large volume paracentesis Mannitol Metolazone Spironolactone Amiloride furosemide H20 V 2 receptor antagonist
Satavaptan for Ascites Management (14 days) Kg 1.0 0.0 Change in body weight at day 14 compared to baseline Worsening ascites -0.5-1.0-1.5-2.0-2.5-0.36-2.46* -2.08* -2.28* placebo 5mg 12.5mg 25mg Satavaptan *p<0.05 compared to placebo Patients (%) 60 50 40 30 20 10 0 29 17 10** 10** placebo 5mg 12.5mg 25mg Satavaptan ** p<0.1 vs. placebo
Satavaptan for Ascites Management (12 weeks)
Satavaptan for Ascites Management (12 weeks) Reduction in number of paracenteses versus placebo Relative risk of paracentesis was 0.69, 0.66, 0.63 for the 5 mg, 12.5 mg and 25 mg groups respectively Corresponding adjusted p-values are 0.026, 0.018, 0.017 for the three treated groups n=36 n=39 n=36 n=40
Take Home Messages From Sodium Retention to Therapy for Refractory Ascites The Role for New Drugs Sodium restriction is still an important and necessary part of the management of refractory ascites Albumin may be useful as an adjunct treatment for refractory ascites Vasoconstrictor therapy shows promise in improving natriuresis, but long-term studies are lacking. V 2 receptor antagonists correct hyponatremia, and therefore may allow re-introduction of diuretics in patients with diuretic resistant ascites V 2 receptor antagonists, independent of serum [Na], have the potential to reduce recurrence of ascites for up to 12 weeks of treatment