JOURNAL PRESENTATION. Dr Tina Fan Tseung Kwan O Hospital 17 th Jan 2013

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1 JOURNAL PRESENTATION Dr Tina Fan Tseung Kwan O Hospital 17 th Jan 2013

2 THE COMBINATION OF OCTREOTIDE AND MIDODRINE IS NOT SUPERIOR TO ALBUMIN IN PREVENTING RECURRENCE OF ASCITES AFTER LARGE-VOLUME PARACENTESIS CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2012 OCT Khurram Bari et al

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4 Refractory ascites Ascites that has failed to respond to standard treatment of dietary salt restriction and diuretics: spironolactone 400 mg and furosemide 160 mg/day), or appearance of diuretic-induced complications International Ascites Club definition

5 Current Mx of refractory ascites

6 Current Mx of refractory ascites First-line recommended therapy: large-volume paracentesis (LVP) + IV albumin (recommended by AASLD and EASL) IV albumin can prevent the development of postparacentesis circulatory dysfunction (PCD) PCD is defined as a significant increase (50%) in plasma renin activity (PRA) 6 days after LVP PCD is associated with faster recurrence of ascites, development of hepatorenal syndrome, dilutional hyponatremia and reduced survival

7 Postparacentesis circulatory dysfunction

8 Summary of studies exploring plasma volume expansion and development of PCD

9 Use of vasoconstrictors Vasoconstrictors

10 Terlipressin Use in HRS Meta-analysis of all randomized, controlled trials assessing the effects of terlipressin on renal function Forest plot of random effects meta-analysis of randomized trials on vasconstrictors alone or with albumin Vs no intervention or albumin for HRS. The outcome measure is all-cause mortality Hepatology 2010;51:576 84

11 Midodrine hydrochloride an α1-agonist, orally available Increases effective circulating blood volume and renal perfusion by increasing systemic and splanchnic blood pressure Midodrine is a prodrug that is absorbed from the gastrointestinal tract and metabolized by the liver into an active metabolite, desglymidodrine, eliminated in urine Approved by the US Food and Drug Administration to treat symptomatic orthostatic hypotension. Investigations of midodrine alone or in combination have shown conflicting results for systemic and renal hemodynamics and renal function in patients with cirrhosis-related complications

12 Octreotide Octreotide is known to inhibit the secretion of glucagon (a vasodilator that may play a role in cirrhosis-associated vasodilation) In patients with HRS, octreotide administration alone does not elicit any vasoconstrictor/vasopressor effect and does not improve renal function Midodrine plus octreotide, which has the advantage of subcutaneous administration, appears to have some efficacy. However, there are no randomized clinical trials and the study numbers are small

13 5-10mg tds for 3days 12.5 mg tds for 2days LAR 20mg IM

14 THE COMBINATION OF OCTREOTIDE AND MIDODRINE IS NOT SUPERIOR TO ALBUMIN IN PREVENTING RECURRENCE OF ASCITES AFTER LARGE-VOLUME PARACENTESIS CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2012 OCT Khurram Bari et al

15 Aims of the study compare the effect of long-term administration of the combination of vasoconstrictors, octreotide/midodrine Vs standard single-dose albumin after LVP in the recurrence of ascites and the development of PCD in patients with cirrhosis and refractory ascites

16 Study design prospective, randomized, double-blind, double-placebo, controlled trial comparing intravenous albumin Vs vasoconstrictors (combination of octreotide long acting release and midodrine) after LVP in patients with cirrhosis and refractory ascites.

17 Study patients Inclusion criteria: Age between 18 and 80 years old cirrhosis of any etiology diagnosed by liver biopsy or based on firm clinical grounds, refractory ascites Exclusion criteria: hepatic hydrothorax Small amount of ascites recent (within 1 mo) gastrointestinal hemorrhage active bacterial infection cardiac failure findings suggestive of organic renal disease hepatocellular carcinoma baseline serum creatinine level greater than 3.0 mg/dl

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19 Low salt diet and held diuretics for minimal 3 days Index LVP Body weight, abdominal girth, heart rate, BP, routine blood test, blood test for aldosterone and PRA Control group IV albumin 8g/L of ascitic fluid removed + IM 5m of saline solution (octreotide placebo) every mon. + one tablet (midodrine placebo) tds Study group IV infusion of saline solution (albumin placebo) + IM 20mg octreotide every month (long acting) + one tablet 10 mg of midodrine tds Follow-up visits at days 6 and 15, and then monthly after randomization detailed history and physical examination: any alcohol use, weight, abdominal girth, mean arterial pressure (MAP), routine laboratory tests, spot urine sodium and creatinine, and blood samples for aldosterone and PRA

20 Primary end point Time to recurrence of ascites Defined as the requirement of a repeat LVP, as indicated by the presence of moderate to severe ascites and weight gain to 90% to 100% of baseline weight and an increase in abdominal girth to 90% to 100% of baseline abdominal girth

21 Secondary end points 1. The development of PCD, defined as an increase in PRA by more than 50% from baseline to a level greater than 4 ng/ml/h at postparacentesis day 6 2. Average changes in mean arterial pressure and heart rate from baseline as surrogates of the hyperdynamic circulatory state 3. Development of hepatorenal syndrome (HRS) defined as the development of de novo HRS or progression from type 2 to type 1 HRS Criteria for diagnosis of hepatorenal syndrome were based on recommendations of the International Ascites Club

22 The study was to be terminated and the study medications discontinued: Development of primary end point (ie, recurrence of ascites requiring LVP) death liver transplant or completion of 6 months of study drugs from randomization

23 Statistical Analysis Time to recurrence of ascites was calculated and event-free survival was estimated in each group using the Kaplan Meier method with 95% confidence intervals. Analysis for secondary outcomes included changes in plasma renin activity, pulse, MAP at day 6 from baseline, and development of HRS type I at the time of repeat paracentesis An independent sample t test was used to compare means of variables with normal distribution and a nonparametric test (Mann Whitney U test) was used to compare medians of variables with non-normal distribution Additional analysis included changes in model for end-stage liver disease (MELD) score, serum creatinine level, and serum sodium level at the time of repeat paracentesis Results were considered significant for a P value less than.05 and a confidence interval of 95% IBM SPSS version 19.0 (Armonk, NY) was used

24 RESULTS

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26 Primary and secondary outcomes

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28 Effect on renal function and MELD score

29 Change of renin activity

30 Long term follow up evaluation 25 patients 9 patients died 9 patients alive and required freq paracentesis 4 patients received liver transplant 2 patients were lost 1 patient in albumin gp has not required repeat paracentesis Albumin gp : 4 Vasoconstrictor gp: 5 Albumin gp: 5 Vasoconstrictor gp : 4 Albumin gp: 2 Vasoconstrictor gp: 2 Albumin gp: 1 Vasoconstrictor gp :1

31 Conclusion of the study Double-blind, placebo-controlled, proof-of concept study, long-term administration of a combination of orally administered midodrine and intramuscular long-acting octreotide was not superior to albumin in delaying the recurrence of ascites after LVP or in preventing PCD

32 Limitations of the study small sample size fixed dose of midodrine/ octreotide, not titrated to increases in mean arterial pressure did not evaluate the adherence to midodrine

33 Vasoconstrictor use in ascites patient? Probably not the combination of midodrine and octerotide Use more potent vasoconstrictor like terlipressin Different combinations of vasoconstrictors Right dosage and duration of vasoconstrictors

34 Albumin infusion seems to be better! Time to recurrence of ascites: 10 days (albumin gp) Vs 8 days ( vasoconstrictor gp) P=0.318 Rate of PCD: 18% ( albumin gp) Vs 25% ( vasoconstrictor gp) P=0.574 At the time of recurrent ascites, serum Creat is higher in vasoconstrictor gp: 1.2mg/dL ( vasoconstrictor gp) Vs 0.9mg/dL (albumin gp) P=0.051 MELD score decreased in Albumin gp ( 2 )and slightly increased in vasoconstrictor gp ( 0.5 ) P=0.033 Albumin gp is sicker at baseline ( higher Child score)

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38 Current Mx of refractory ascites

39 END Thank you!