Invasive Evaluation of Portal Hypertension. Vincenzo La Mura, MD PhD Department of Biomedical Sciences for Health University of Milan

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1 Invasive Evaluation of Portal Hypertension Vincenzo La Mura, MD PhD Department of Biomedical Sciences for Health University of Milan

2 Vincenzo La Mura, MD, PhD Dipartimento di scienze Biomediche per la Salute, Università degli studi di Milano Il sottoscritto dichiara di non aver negli ultimi 12 mesi conflitto d interesse in relazione a questa presentazione e che la presentazione non contiene/contiene discussione di farmaci in studio o ad uso off-label

3 What we are talking about? TIPS: direct measurement IVC pressure PPG portal pressure PPG>5mmHg Portal pressure gradient PPG and HVPG: 100% agreement in non- cholestatic cirrhosis Hemodynamic study: indirect measurement Wedged pressure Free pressure 1. Extra-hepatic post-sinusoidal 2. Intra-hepatic post-sinusoidal 3. Sinusoidal 4. Intrahepatic pre-sinusoidal 5. Extra-hepatic pre-sinusoidal HVPG Hepatic Venous Pressure Gradient

4 Wedged Hepatic Venous Pressure Portal Pressure (mmhg) Agreement Overall series HCV Alcohol HCV + alcohol Ri: Intraclass correlation coefficient Ri WHVP (mmhg) Perelló, Hepatology 1999 Wedged WHVP accurately reflects portal pressure in CIRRHOSIS

5 Groszmann RJ, Hepatology 2004 The need of an internal zero reference HVPG=WHVP-FHVP P1 = Intraluminal Wedged + Free intra abdominal P2 = Intraluminal Free + intra abdominal HVPG=P1-P2=Wedged-Free Wedged Free HVPG is not affected by intra-abdominal pressure standardization

6 Factors determining portal pressure in cirrhosis PP = Flow X Resistance Functional Hepatic Resistance Structural PORTAL PRESSURE (PP) Porto-Systemic Collaterals Splanchnic Flow Splanchnic arterial vasodilation Hyperdynamic circulation Na and water retention HVPG/PPG resumes all intra- ed extrahepatic changes!!! C O M P E N S A T E D D E C O M P E N S A T E D

7 Excellent tool to study pathophysiology

8 Cirrhosis evolution Compensated Decompensated We need: Correctly diagnosing Classifying patients for the risk of decompensation and HCC Monitoring disease progression Testing therapeutic efficacy HCC DEATH Modified from Abraldes EASL monothematic

9 May HVPG help physicians?

10 CASO CLINICO Donna 44 anni, normopeso Piastrinopenia Splenomegalia IPERTENSIONE PORTALE Varici F1, ricanalizzazione v. ombelicale CIRROSI EPATICA (???) Fegato bozzuto, v. porta ingrandita (Tc addome) No cause comuni di epatopatia IP pre-sinusoidale INCPH/(I)NCPH Fibroscan 5.7 KPa (IQR 2,1 SR 100%) v. media Presenza di comunicanti veno-venose Dx HVPG: 6 mmhg SOFFERENZA VASCOLARE CD34+

11 Cirrhosis evolution Compensated Decompensated We need: Correctly diagnosing Classifying patients for the risk of decompensation and HCC Monitoring disease progression Testing therapeutic efficacy HCC DEATH Modified from Abraldes EASL monothematic

12 Threshold of risk: 10mmHg Clinically significant portal Hypertension (CSPH) PATIENTS WITH COMPENSATED CIRRHOSIS W/O VARICES Development of Varices First decompensation HCC 1.0 P<0.001 Baseline HVPG 10mmHg Baseline HVPG<10mmHg Probability of developing hepatocellular carcinoma (HCC) P=0.001 HVPG 10mmHg HVPG <10mmHg months Groszmann et al NEJM 2005 Ripoll et al Gastroenterology 2007 Ripoll et al J Hepatol 2009 Patients with CSPH (37% of 213 patients w/o varices) are different!!!

13 Bleeders HVPG p<0.001 Non-bleeders Threshold of risk: 12mmHg variceal rupture 12 mmhg PPG García-Tsao et al, Hepatolgy 1985 Casado M et al, Gastroenterology 1998

14 MORTALITY Threshold of risk: 16mmHg stable cirrhosis Threshold of risk: 20mmHg unstable cirrhosis During Acute Variceal Bleeding HVPG<16mmHg HVPG 16mmHg <20 mmhg >20 mmhg <20 mmhg >20 mmhg 5-day failure 1-yr mortality Stanley QJM 1998; Merkel Hepatology 2000; Berzigotti, J Gastroenterol 2011; Silva-Junior Hepatology 2015 Moitinho 1999, Monescillo 2004

15 Single HVPG measurements may discriminate low- vs high risk cirrhosis Does HVPG reduction predict good-clinical response?

16 HVPG-reduction under NSBBs: surrogate end-point Variceal bleeding Pre-primary prophylaxis Primary prophylaxis Secondary prophylaxis 1,0 Cumulative probability,8,6,4,2 nonresponders responders p= , months Groszmann et al. NEJM 2005 Turnes et al Am J Gastro 2006 Abraldes et al. Hepatology 2003

17 HVPG-reduction under NSBBs: surrogate end-point ascites patients with large varices and HVPG>12mmHg Hernandez-Gea et al Am J Gastro 2012

18 HVPG-reduction under NSBBs: surrogate end-point Survival * Only secondary prophylaxis * * D Amico et al. Gastroenterology 2006

19 HVPG predicts prognosis and good-clinical response What to do with non-responders? EBL in prophylaxsis of bleeding (add-on strategy) it makes sense DRUGs other portal-hypotensive drugs (Simva-) statin LMWH/anticoagulants Rifaximin NON-PHARMACOLOGICAL STRATEGIES TIPS OLT

20 RCT: HVPG-guided group (up to 3 measurements!) vs standard of treatment Prophylaxis of Rebleeding Villanueva et al Hepatology 2017 An add-on strategy to further reduce portal pressure (prazosin+ismn) may ameliorate survival in HVPG-non-responders

21 Cirrhosis: a multistage disease Baveno VI: Stratifying Risk and Individualizing Care COMPENSATED DECOMPENSATED SECOND DECOMPENSATING EVENT FIRST NON BLEEDING DECOMPENSATION BLEEDING VARICES NO VARICES * STAGE 4 STAGE 3 STAGE 2 STAGE 1 One-year mortality STAGE 5 88% 30% 20% 10% 1% * 20 mmhg: high bleeding related mortality (42 days) HVPG/PPG thresholds of risk > 16 mmhg 12 mmhg 10 mmhg Few options Non-invasive and/or EGDS Clinical variables The highest potential of HVPG may be optimizing selection of patients for alternative strategies of treatment (TIPS/simvastatin) in decompensated cirrhosis

22 Is it necessary to test new algorithms of treatment allocation in the era of good/excellent etiologic therapy?

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24 SVR to DAA and HCV-induced portal hypertension Baseline HVPG<10mmHg Baseline HVPG<16mmHg Baseline HVPG 16mmHg All patients remained below 10mmHg Half of patients below 10mmHg Only one patients below 10mmHg HVPG 16mmHg: the point of no-return? Mandorfer M,et al. J Hepatol 2016

25 CONCLUSION Accurate selection is mandatory to planning new RCTs for treatment allocation in low-/high-risk cirrhosis DAA/etiologic therapies NSBBs+/-EBL Carvedilol (prazosin/ismn) Simvastatin LMWH/anticoagulants Rifaximin TIPS OLT HVPG? It s up to you!