TIPS in the Management of Portal Hypertension Clinician s Opinion

Transcription

1 TIPS in the Management of Portal Hypertension Clinician s Opinion Oliviero Riggio 5 th AISF post meeting course Diagnostic and Therapeutic Procedures in Hepatology 2012

2 Oliviero Riggio Dipartimento di Medicina Clinica Sapienza Università di Roma Il sottoscritto dichiara di non aver avuto negli ultimi 12 mesi conflitto d interesse in relazione a questa presentazione e che la presentazione non contiene discussione di farmaci in studio o ad uso off-label

3 TIPS : well established indications Active variceal bleeding uncontrolled by medical and endoscopic treatment Prevention of variceal rebleeding* Refractory ascites* *RCTs and metanalysis available

4 Variceal bleeding uncontrolled by medical and endoscopic treatment % Efficacy of drugs or endoscopic treatments in the control of variceal bleeding Pool of RCTs 48 No treatment 12 RCTs 319 pts. 74 Drugs 31 RCTs 982 pts 89 Endoscopy 24 RCTs 571 ppts Emergent surgery (PCA or oesophageal transection) has a high mortality rate (about 50%). Patients at greater risk of failing emergent medical and endoscopic treatment are also those least likely to tolerate surgery. Thus, patients who continue to bleed may have a mortality rate as high as 90% (in Child B or C).

5 TIPS in the treatment of uncontrolled variceal bleeding A uthor P atients N C hild C % C ontrol of bleeding % E arly rebleeding N M ortality (40 days) % M cc orm ick Jalan Sanyal G erbes C hou 112 (28 G V ) B anares 56 (19 G V ) B arange K 32G V

6 Acute Bleeding AASLD practice guideline on: TIPS (Hepatology 2005 and 2009) On Prevention and Management of Gastroesophageal Varices and Variceal Hemorrage in Cirrhosis (Hepatology 2007) TIPS is indicated in patients in whom hemorrhage from esophageal varices cannot be controlled or in whom bleeding recurs despite combined pharmacological and endoscopic therapy (Class I, Level C)

7 Prevention of variceal rebleeding (RCTs) Author Control treatment Patients included Cabrera J. EVS 31/32 Rossle M. EVS + Beta-block 61/65 Sanyal AJ. EVS 40/39 Cello JP EVS 21/19 Merli M. EVS 38/43 Sauer P EVS + Beta-block 42/41 Vinel P EVS + Beta-block 32/33* Jalan R. Ligation 31/27 Pomyer-Lelargues G Ligation 41/39 Garcia-Villareal EVS 22/24 Escorsell A P + I 47/44 EVS= Endoscopic Variceal Sclerotherapy; P+I=Propranolol +Isosorbide Mononitrate

8 META-ANALYSIS OF RCTs ON TIPS vs ENDOSCOPIC THERAPY FOR THE PREVENTION OF VARICEAL REBLEEDING TIPS better Endoscopy better RECURRENT BLEEDING MORTALITY ENCEPHALOPATHY Pooled rate difference

9 AASLD practice guideline on: TIPS (Hepatology 2005) On Prevention and Management of Gastroesophageal Varices and Variceal Hemorrage in Cirrhosis (Hepatology 2007) Prevention of rebleeding TIPS should not be used for the prevention of rebleeding in patients who have bled only once from esophageal varices, and its use should be limited to those who fail pharmacological and endoscopic therapy (evidence: grade I)

10 REPORTED REBLEEDING RATES IN RCTs OF DIFFERENT TREATMENTS TO PREVENT VARICEAL REBLEEDING (25 75 percentile) Surgery TIPS B-Bloc+ISMN EVL EVS + B-Bloc EVS B-Blockers Untreated % J Bosch Lancet 2003

11 in patients with a first bleeding from varices TIPS Is considered a rescue therapy for patients with acute bleeding refractory to medical and endoscopic treatment BUT 10 20% of acute bleeders do not respond to first line therapy and rescue-tips mortality rate is still high (14 55% of Pts.) TIPS Is considered a second line treatment for the prevention of rebleeding and should not be used in those who bled only once BUT 20-55% of patients will rebleed within one year after the first line therapy for prevention of rebleeding

12 Poor evolution (n=23) = failure to control bleeding (n=7) or early rebleeding (n=16)

13 Influence of portal hypertension and its early decompression by TIPS placement on the outcome of variceal bleeding Monescillo A. Hepatology, October 2004.

14 Influence of portal hypertension and its early decompression by TIPS placement on the outcome of variceal bleeding. Monescillo A. Hepatology, October NS p<.0001

15 Methods: Retrospective cohort from 4 centers including 117/221 patients with AVB in whom HVPG was measured within 48 h of admission ( ). The main endpoint was 5-day failure, a composite of uncontrolled bleeding, early rebleeding or death within 5 days Relationship between HVPG and Child-Pugh class and outcome according to HVPG 20 mmhg Abraldes J, J Hepatol 2008;48: ; Editorial

16 Multivariable analysis of prognostic indicators for 5-day failure and ROC curves Variable OR 95% CI Model with all variables HVPG P20 mmhg Systolic blood pressure < Non-alcoholic etiology Model excluding HVPG Child B vs A Child C vs A Systolic blood pressure < Non-alcoholic etiology

17 Background: cirrhotic patients in Child-Pugh class B-C with acute varicel bleeding (AVB) have a poor prognosis despite the use of rescue TIPS Aim: to evaluate if an early decision for PTFE-TIPS in such high risk bleeders could decrease treatment failure and mortality Methods: 63 B-C cirrhotic patients with AVB treated with vasoactive drugs plus band ligation (BL), randomized within 72 hrs of admission,to PTEF-TIPS or continue vasoactive drugs+bl followed by β- Blockers+IMN+BL. Follow-up 16 months Endpoints: failure to control AVB, 1-yr failure, 1-yr survival, safety and complications

18 Results and conclusions (Garcia-Pagan et al) Failure to control AVB Medical (n=31) TIPS (n=32) yr failure (cum %) 97% 50% < yr mortality yr ascites (cum%) 33% 13% yr PSE (cum%) 40% 28% NS Conclusions In high risk cirrhotic patients with AVB, early treatment with PTFE-TIPS is associated with significant marked reductions in rebleeding and mortality. P

19 In any patients with variceal bleeding Evaluate if the risk the of treatment failure and of early rebleeding is high Child-Pugh C (score<14) or Child-Pugh B with active bleeding at endoscopy

20 Baveno V Treatment of Acute Bleeding New statement An early TIPS (ideally < 24 hours) should be considered in patients at high-risk of treatment failure ( e.g. Child-Pugh class C but <14 points or Child class B with active bleeding) after initial pharmacological and endoscopic therapy. (1b;A)

21 TIPS has been used in the following clinical settings Active variceal bleeding uncontrolled by medical and endoscopic treatment Prevention of variceal rebleeding* Refractory ascites* Budd-Chiari syndrome Refractory hepatic hydrotorax Severe venoocclusive disease following bone marrow transplantation Hepato-renal Hepato-pulmonary syndrome *RCTs available

22 Revised Diagnostic Criteria for Refractory Ascites

23 Actuarial Probability of Refractory Ascites Planas R Clin Gastroenterl Hepatol 2006 Probability of survival among patients with Ascites, Refractory Ascites or Hepato-Renal Syndrome Gines P N Engl J Med 2004 Ascites

24 TERAPIA DELLA ASCITE REFRATTARIA: 1. TRAPIANTO 2. PARACENTESI EVACUATIVE RIPETUTE CON INFUSIONE Escludere refrattarietà DI ALBUMINA apparente o transitoria 3. SHUNT INTRAEPATICO PORTO-SISTEMICO TRANSGIUGULARE (TIPS) 4. SHUNT PERITONEO-GIUGULARE DI LEVINE Ascites Club 2010, AASLD 2009

25 PSEUDO-REFRACTORY ASCITES PROBLEM Treatement with loop diuretics only or with insufficient doses of antimineral-corticoids Overdiuresis (negative fluid balance >900 ml/day) leading to prerenal azotemia Renal function impaired by iatrogenic (FANS, ACEinhibitors, nephrotoxic drugs) or cuncurrent complications (vomiting, diarrhoea, bleeding, infection) POSSIBLE RESOLUTION Adjust the dose of diuretics Diuretic withdrawal Withdrawal or treat Uncompliance to sodium restriction Appropriate counselling

26 HVPG modifications after TIPS N of Patients = mmhg Pre Post

27 Effetti del TIPS sulla escrezione urinaria di sodio e sulla funzione renale 45 6 Sodiur ia (microm /min) P<0.04 Creatinina (mg/dl) 4 2 P< Base 24 ore 30 giorni 0 Base 7 giorni 30 giorni Wong F. Ann.Intern Med Guevara M. Hepatology 1998

28 OPPURE 5 studi controllati randomizzati confronto tra TIPS e paracentesi evacuativa + albumina pazienti con ascite refrattaria o ricorrente

29 RCTs TIPS vs PARACENTESIS Characteristics of the patients Trial N Patients TIPS/Para Age Child-Pugh score Alcohol origin Lebrec * /12 50/ /9.2 77%/83% Rossle /31 54/61 9.1/ %/74% Gines /35 59/56 9.3/9.2 51%/60% Sanyal /57 56/52 9.2/9.3 61%/58% Salerno /33 58/60 9.4/9.4 45%/39% *TIPS in 10 pts.

30 RCTs: TIPS vs PARACENTESIS Control of ascites and incidence of HE Trial Definition Control of ascites Encephalopathy Lebrec 1996 No ascites 61 vs 0% p=0.05 Rossle 2000 No ascites 79 vs 24% p= Gines 2002 Sanyal 2002 Salerno 2004 Recurrence of ascites Recurrence of tense ascites >4 para. in un mese 49 vs 83% p= vs 84% p= vs 57% p= pz. vs 0 pz NS 58 vs 48% NS Severe: 60 vs 34% p= 0.03 Severe: 38 vs 12% NS 63 vs 43 % NS Severe p=0.04

31 RCTs: TIPS vs PARACENTESIS Two-years survival rates Trial TIPS PARA p = Transplanted during the study Lebrec % 0% in Child C 60% vs 1 Rossle %^ 32% vs 2 Gines % 26% NS 7 vs 7 Sanyal %* 63%* NS 16 vs 17 Salerno % 29% 0.02* 4 vs 4 ^ TIPS related to better survival at the multivariate analysis *Difference in survival rate manteined in Child C pts (70% of pts.)

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33 EASL Clinical Practice Guidelines: J. Hepatology 2010 Repeated paracentesis plus albumin (8 g/l of ascites removed) is the first line of treatment. TIPS is effective but associated with a high risk of HE and does not convincingly improve survival compared to repeated paracentesis. TIPS cannot be recommended in patients with severe liver failure (serum bilirubin >5 mg/dl, INR >2 or Child-Pugh score >11).

34 AASLD Practice Guidelines: Hepatology 2009 TIPS may be considered in appropriately selected patients who meet criteria similar to those of published randomized trials. Age > yrs. Previous or present Hepatic Encephalopathy Bilirubin > 3 10 mg/dl (CPS> 11 in one RCT) Renal failure (creatinine >1.5 3mg/dl) Cardiac failure (not better defined)

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36 Validation cohort Probability of survival among patients with Refractory Spanish (external) cohort Ascites Gines P N Engl J Med 2004

37 Bilirubin < 3 mg/dl Creatinin < 1.9 mg/dl) Child-Pugh < 11

38 Early TIPS for Ascites Ongoing prospective, multi-center, randomized comparison of TIPS with covered stents to Large Volume Paracentesis (LVP) for the treatment of difficult to treat ascites Lack of response to at least 80 mg of furosemide and 200 mg aldactone leading to a paracentesis of >5 liters Ascites recurrence requiring paracentesis of >5 liters within 45 days after therapeutic paracentesis of >5 liters At least one paracentesis of 5 liters in addition to a complication of diuretic therapy (serum sodium < 130 mmol/l or creatinine > 1.8 mg/dl) within the last 90 days

39 Characteristics of post-tips HE: HE is frequent in the first months but generally improves during follow-up Either precipitant induced or spontaneous episodes may occur Sympthoms are generally mild but might also be severe and cause hospitalization The majority of episodes are successfully treated with medical therapy Chronic recurrent HE may occur in 3-10% of patients Cumulative incidence Survivorship: S(t) 1,000 0,750 0,500 0,250 N = 160 0,000 0,0 25,0 50,0 75,0 100,0 Months

40 Prevention of post-tips HE Actuarial rate of patients free of hepatic encephalopathy No treatment Lactitol Rifaximin ,00 Patients free of HE 0,75 0,50 0,25 p = Time (days) Riggio O. J Hepatol. 2005

41 INTRACTABLE HEPATIC ENCEPHALOPATHY AFTER TIPS WITH PTFE-COVERED STENT-GRAFT Incidence rate: 8% 400 TIPS Shunt reduction ,9 Ammonia (µg/dl) Ammonia PSE-index 0,8 0,7 0,6 0,5 0,4 0,3 0,2 0,1 PSE-index Days

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43 Shunt reduction

44 OUTCOME AFTER SHUNT REDUCTION Pts Reason for shunt reduction TIPS indication Time to shunt reduction (months) HE amelioration Relapsed complication Outcome 1 5 HE episodes (III-IV grade) in 2 months + Persistent HE Ascites 2.4 Yes Yes OLT 2 5 HE episodes (III-IV grade) in 2.5 months Variceal bleeding 28.6 Yes Yes Death for variceal bleeding 3 13 HE episodes (with many hospitalizations) in 17 months + Persistent HE Ascites 37.5 Yes No Alive 4 4 HE episodes (III-IV grade) in 3.7 months + Persistent HE Variceal bleeding 33.7 Yes No Alive 5 3 HE episodes (2 of III-IV grade) in 3 months + Persistent HE 6 4 HE episodes in 3 months + Persistent HE Ascites 10.6 Yes No Death (at 18 months) Ascites 3.2 Yes No Death (at 22 months)

45 Studies N with refractory HE/ Treated with TIPS N of Pts. improved Adverse Events after TIPS reduction Cookson DT /NR 5 Bleeding 3 Deaths 2 Fanelli F / Ascites 1 OLT 1 Deaths 4 Riggio O /78 6 Ascites 1 Death for bleeding 1 Chung HH /113 4 Maleux G / Ascites 1 Bleeding 1 OLT 1 Maleux G / Ascites 1 Hydrothorax 1 Kochar N / Bleeding 3 Ascites 3 Deaths 15 Karlan RK /NR 4 Bleeding 1

46 Factors influencing the decision of reducing the diameter of the shunt in patients with refractory HE after TIPS Factors Strict definition of refractory post TIPS hepatic encephalopathy Suggestions - At least three episodes of nonprecipitant-induced severe encephalopathy requiring hospitalization in the last 3 months despite continuous treatment with nonabsorbabledisaccharides; or - Persistent HE, defined as the presence of a continuously detectable altered mental state despite protein restriction to 1 g/kg of body weight and treatment with nonabsorbable disaccharides

47 Factors influencing the decision of reducing the diameter of the shunt in patients with refractory HE after TIPS Factors Causal relationship between the shunt and HE Suggestions Likely if: - short distance between the onset of refractory HE and TIPS implantation - Low portal systemic gradient supporting the importance of blood diversion Unlikely if - Clinical signs of portal hypertension before revision - Deterioration of liver function after TIPS

48 Factors influencing the decision of reducing the diameter of the shunt in patients with refractory HE after TIPS Factors Low risk of variceal bleeding Suggestions - Check the varices before and after the shunt revision - Start preventive treatment after the revision

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