Hi, I'm Scott Biggins. I'm the chair of the ASLD Portal Hypertension SIG, and I'd like to welcome you to our educational session today titled, Controversies in Screening and Prevention of Clinically Significant Portal Hypertension. I'd like to credit the developers of this session, who are the program chairs, Dr. Betsy Verna and Don Rocky. You'll hear four exciting presentations by leaders in the field of portal hypertension. First, you'll hear an update on the non-invasive diagnosis and monitoring of portal hypertension. Then you'll hear an update on the use of statins for prevention of decompensated cirrhosis. You'll hear an exciting debate, pro and con, for the use of non-selective beta blockers for preventing decompensated cirrhosis. Lastly, an update on novel therapies and future treatments for portal hypertension. Thank you very much for joining our session, and we'll get underway here shortly. I'd like to start by thanking Drs. Rocky and Biggins for inviting me to give this lecture on non-invasive diagnosis and monitoring of portal hypertension. My name is Tamar Taddei, and I'm from Yale University and the VA Connecticut in West Haven. I have nothing to disclose, and the objectives I have for you today are to understand the tools and approach to non-invasive diagnosis and monitoring of portal hypertension, review ASLD guidelines for non-invasive assessment of clinically significant portal hypertension, consider the application of these guidelines in a clinical context, and that I think is most important. So let's consider a case. A 51-year-old male comes to clinic with persistently elevated liver enzymes. He has a history of alcohol use disorder, hyperlipidemia, and he has no clinical stigmata of chronic liver disease and no available imaging. His liver enzymes, his AST is 51, ALT is 63, and alcohol and phosphatase is 103. And his relevant labs are a total bilirubin of 1.96, albumin of 4, platelets of 172,000, and his INR is 1. So the question is, is this patient at risk of compensated cirrhosis or compensated advanced chronic liver disease? Compensated advanced chronic liver disease is the term used to describe the spectrum of advanced fibrosis and cirrhosis in asymptomatic patients who are at risk of developing clinically significant portal hypertension. And this term was introduced at the VIVINO 6 conference in 2015, where key new guidance emerged that transient elastography was sufficient to suspect compensated cirrhosis. So let's consider the impact. Why is it critical to identify clinically significant portal hypertension? Well, it's because it's in these patients that you want to intervene and you want to help prognosticate, and you really want to risk stratify them for development of consequences of portal hypertension, like variceal bleeding, hepatic encephalopathy, and ascites. And also, there's a very strong correlation between portal hypertension and hepatocellular carcinoma. So we're all familiar with this spectrum, and I want to focus here on the sort of darker orange and red parts. And we know that the five-year mortality along the spectrum is very different, and it advances with advancing fibrosis. But the populations in each panel are very different, and that should caution the interpretation of noninvasive tests, as many studies have not adequately distinguished between populations. And this entire talk pertains to patients with compensated cirrhosis, where diagnosis and monitoring of clinically significant portal hypertension is imperative to patient management. Patients with decompensated cirrhosis have portal hypertension by definition and do not require screening for clinically significant portal hypertension. So let's talk about HBPG, which is the gold standard for measuring portal hypertension. So hepatic venous pressure gradient, as we know, is the gold standard, and HBPG above 5 millimeters of mercury is consistent with portal hypertension, and HBPG above 10 millimeters of mercury or equal to is equal to clinically significant portal hypertension. But the measurement of HBPG itself is invasive. There's limited availability, so it's not available at every center. There are technical limitations and operator dependency, and it's costly. So what's in our tool chest for noninvasive markers? So here we think about blood-based markers, and these are nonproprietary markers, and we have a lot of them. And we also have imaging-based markers, and here we have transient elastography. We have RFE and 2D shear-wave elastography and MR elastography. It's very important to note that blood-based tests are far more available and less costly than imaging techniques for noninvasive assessment of portal hypertension, but the evidence is not currently strong enough to recommend their use for detection of clinically significant portal hypertension in clinical practice. That's not to say they can't be added to some of the imaging-based modalities, and I'll get to that. So how do we approach our patient? In the soon-to-be-published ASLD guidelines on noninvasive assessment of liver disease, we framed our recommendations around PICO questions, considering the patient, the intervention, comparison group, and outcome, and the published evidence. So I'll be talking about this case in the context of these recommendations. So our first recommendation is that we do not use currently available blood-based markers for thrombocytopenia for the detection of clinically significant portal hypertension because they have poor diagnostic performance. And we know in this study that…by Kumar and colleagues, that a receiver-operator curve could not identify a platelet count that could accurately predict the development of gastroesophageal varices. We also know that FIBR test correlates with HPPG when there's severe portal hypertension, but AUCs for the diagnosis of severe portal hypertension are similar for platelets and child Q score. Other studies have shown that ELF score doesn't correlate with HPPG, and unfortunately, APRI and FIB4 had poor AUCs of 0.64 and 0.65 for CSPH, respectively, much lower than a liver stiffness measurement, which has an AUC of about 0.85. And in our patient, you can see his APRI score and his FIB4 score were incredibly dynamic because two months before he presented, he had a platelet count of 102,000. So, the role of liver stiffness measurement in the diagnosis of CSPH is important, and actually, the ASLD suggests that liver stiffness measurement can be used to exclude CSPH due to its high sensitivity. And we know that liver stiffness measurements should be looked at as continuous variables on a continuum, and so it's important to look at probability where positive predictive value is able to rule in and negative predictive value, you know, goes down the probability scale to rule out. And so, essentially, kilopascals of less than 5 are normal, you know, 10 kilopascals or less would rule out compensated cirrhosis, and then you get to rule in above 15 kilopascals, and above 20 is when you're really starting to rule in clinically significant portal hypertension. So, again, this is a continuous variable, and probability increases with increasing positive predictive value. So, let's think about our patient's liver stiffness measurement. It's important to know that we had an expert review this liver stiffness measurement, and his liver stiffness was 28.9 kilopascals, and the reader noted that it's very elevated and should rule in cirrhosis with CSPH, and that shear waves were outstanding, variability was low, making it reliable. But the patient is consuming alcohol, which is an important caveat, and her recommendation was to repeat liver stiffness after maintaining sobriety. So, it's important to know that she clearly notes the quality of the study, including the shear waves and the variability, and this type of expert reading and chart review is not the norm. So, I'm lucky. So, liver stiffness measurement is a reliable non-invasive tool to accurately identify patients with clinically significant portal hypertension, showing AUCs ranging between 0.74 to 0.94, but a challenge with this literature is that a wide variety of liver stiffness measurement cutoffs have been used as correlates of CSPH, ranging from 8.7 kilopascals to 34.9. So, in studies in patients with cirrhosis, shown in aggregate here, liver stiffness measurement levels in the 20 kilopascal range have a relatively high sensitivity and specificity for detection of CSPH, but an important issue is whether liver stiffness measurement is equivalent across different etiologies, and there have been a number of studies not shown here that also demonstrate the equivalence between transient elastography and 2D shear wave elastography, but MRE liver stiffness requires further investigation. So, can we confirm CSPH in our patient? And this meta-analysis by you looking at transient elastography in over 1,000 patients confirmed the diagnostic capability of this method. For use as a sensitive screening tool, they suggested lower cutoff values of 13.6 to 18 kilopascals, significantly lower than the 21 to 25 kilopascals suggested by Bavino 6, but remember that these studies are conducted in expert centers among heterogeneous populations, usually with a small sample size and high prevalence of CSPH, and that liver stiffness measurement does represent a potentially viable approach to noninvasively assess CSPH, but standardized liver stiffness thresholds still require work, especially across liver diseases, and not all etiologies are the same, as pointed out by recent work by Pons and colleagues, suggesting that while liver stiffness measurement performed well in alcoholic liver disease, chronic hepatitis B and chronic hepatitis C, and in non-obese patients with NASH, with the positive predictive value being greater than 90% for CSPH detection, it failed to perform in obese NASH patients, in which the positive predictive value was 63%, suggesting liver stiffness measurement greater than or equal to 25 is not sufficient to rule in CSPH in obese patients with NASH. Do additional data improve CSPH detection, and earlier studies showed that adding spleen diameter on ultrasound and platelet count did, the so-called LSPS, liver stiffness spleen diameter to platelet ratio score, and this was then validated with the portal hypertension score, and these additions improved diagnostic accuracy and decreased misclassification. More recent studies have refined these models, and so the study by Ebraldas looked at liver stiffness, then liver stiffness with platelets, and then liver stiffness, the LSPS, and CSPH, so this was the anticipated study with 518 patients with compensated cirrhosis from five centers in Europe, and their models show that the AUCs increased with the addition of these added clinical data, both the platelets and the spleen diameter on ultrasound, and the paper also presented these models for prediction of varices and varices needing treatment, and so the nomograms presented in the paper allow ready calculation of risk. Clearly, our patient has a very high probability to have CSPH. As we can see, he has a liver stiffness of 28 kilopascals, which gives him about 64 points, and then he has a platelet count of around 102 if we look at the earlier platelet count, which gives us 20 points or no points if we discard that platelet count, but if we add 64 and 20, that gives us a score of 84, and so he has very high probability of having clinically significant portal hypertension, and, you know, that's, of course, taking into account the earlier platelet count, so the next question is can we determine the severity of portal hypertension, and so the ASLD suggests that liver stiffness measurement is relatively insensitive for detecting higher levels of portal hypertension above 12 millimeters of mercury, so the correlation between HPPG and liver stiffness measurement is excellent at less than 10 millimeters of mercury, but it decreases when HPPG is above the threshold for CSPH, and this is due to changes in flow not reflected in liver stiffness measurement, so in our patient, you might ask would you perform endoscopy, and this is important to underscore the BIBINO 6 recommendations, which have become even more important during the COVID pandemic in which patients with a liver stiffness less than 20 kilopascals and with a platelet count of greater than 150,000 have very low risk of having varices and can avoid screening endoscopy, and this spares unnecessary invasive tests. It's widely adopted during COVID-19, and it's now validated in numerous retrospective studies and meta-analysis, and I point you to this excellent review, so are there more sensitive ways to detect clinically significant portal hypertension, and the ASLD suggests that spleen stiffness measurement can be used to predict CSPH in patients with suspected advanced fibrosis due to its high sensitivity for detection of CSPH, so spleen stiffness more directly reflects portal hypertension, and in this review by Berzagotti, she beautifully shows that essentially irrespective of the underlying etiology, spleen stiffness reflects congestion rather than inflammation. Now, it is important to note that the range of spleen stiffness is much higher in terms of kilopascals, so we know that from this recent meta-analysis of nine studies that spleen stiffness strongly correlates with HPPG and has good accuracy for predicting CSPH comparable with liver stiffness measurement, although the heterogeneity of studies affects the interpretation of results, but this is promising for spleen stiffness, so do we use liver stiffness or spleen stiffness measurements to follow changes after intervention, and the ASLD suggests that liver or spleen stiffness measurements cannot accurately detect changes in HPPG and are not currently acceptable tools to follow decreases in HPPG after therapeutic intervention. It's well-known that liver stiffness measurement changes in patients with portal hypertension undergoing therapy with non-selective beta blockers do not correlate with changes in HPPG, and changes in liver stiffness measurement after DA therapy also do not correlate with HPPG, so the jury's out on this, but there's much research going on in this domain, so let's come back to our patient, what happened to him. He came to clinic three months later. He didn't have an EGD because he had wanted to abstain from alcohol when counseled, and he did have sustained sobriety. His liver enzymes normalized. His platelet count was 225,000 on recheck. Clearly, there was bone marrow suppression from the alcohol, and his repeat liver stiffness measurement was 16 kilopascals, so we will watch. So, in summary, non-invasive methods to determine clinically significant portal hypertension have an evidence-based place in clinical practice. Addition of platelet count and ultrasound to liver stiffness measurements adds diagnostic accuracy. Nomograms can help determine risk and inform clinical decision-making and study endpoints. Non-invasive tests cannot be used to reliably follow response to therapy in patients with CSPH. Spleen stiffness is an exciting area of research in portal hypertension, specifically when added to liver stiffness measurements, and there's a lot being published on this, and ASLD guidelines are soon to be published, and I've given you a preview, and stay tuned to the VINO 7 consensus conference recommendations. Thank you for your time. Hello, everybody. I first want to thank the organizers for inviting me to participate in the portal hypertension SIG meeting, and I will talk today about the status of cirrhosis, what might be the benefits, but also the potential harms. So, this is the agenda for today. I will talk about the rationale for using statins in cirrhosis, about the initial hemodynamic studies that showed that statins decreased portal pressure, then the scarce information on the effects of statins of clinical endpoints in cirrhosis, and there's only one randomized trial. So, I will talk about the promises on why statins are associated with improved outcomes and the potential perils regarding the safety, and then I will talk about future directions. So, statins might be beneficial in cirrhosis for several reasons. They might improve endothelial dysfunction, and in the cirrhotic liver, there is sinusoidal endothelial dysfunction, and this was probably what triggered testing statins for cirrhosis, but it also has a myriad of other effects, antioxidant, anti-fibrotic, anti-inflammatory looks very relevant, and antithrombotic effects that might improve the natural history of cirrhosis. These pleiotropic effects have triggered a lot of attention, and probably there is no other drug class that has had more attempts at repurposing, and there is studies in cancer, severe sepsis, COPD, multiple sclerosis, a number of conditions, and there are observational studies in each of these conditions that show that statins have a beneficial effect. However, the information from randomized trials has been extremely disappointing. None of these indications, in these indications, statins have shown a benefit in randomized trials, and in fact, the current indication is limited to lowering cholesterol and cardiovascular risk. So, could this be different in cirrhosis? And the initial trigger for assessing statins in cirrhosis was that Roberto Grossman and Don Roque demonstrated in the 90s that the cirrhotic has a decreased production of nitric oxide. This increases hepatic resistance and contributes to portal hypertension, and shortly after, there was this study that showed that statins could increase nitric oxide production in dendrothelium by regulating the AKT pathway, and this is what led our group to initially test this hypothesis, and these are the steps of drug development in portal hypertension. First, you have a therapeutic concept, and you demonstrate that that therapeutic concept is valid in animal models, and this was done both by our group in Barcelona with Jaime Bosch, and by the group in Bonn with Jean-Altruic and Tilman Sauerbruch. Then, you do the proof-of-concept studies in humans to demonstrate target engagement, toxicity, and the physiological effects, in this case, the decrease in portal pressure, and then you have to demonstrate an effect of clinical endpoints that in cirrhosis will be peritoneal bleeding or the complications of cirrhosis and eventually death. So, this was the first study that we did. It was a very simple study. It was taking patients, measuring their portal pressure, giving them a pill of simvastatin-14, and observed what happened with the splenic and systemic hemodynamics, and as you can see here, the administration of 40 millions of simvastatin increased hepatic blood flow by 20% in 30 minutes, and this was a little bit less, but more or less sustained at 60 minutes. The portal pressure did not relevantly change, which means that there was a decrease in hepatic vascular resistance. So, this was the first evidence that it could have a hemodynamic effect in cirrhosis, and this was associated with an increase of the hepatosplenic production of nitric oxide. We measured that by checking nitric oxide degradation products in the hepatic vein. So, demonstrating in some way that the study hit its target. Then, this was the second study. It was a multicenter Spanish trial in which we assessed whether the administration of one month simvastatin could decrease portal pressures. Simvastatin was started at 20 milligrams for 15 days, and then increased to 40 milligrams for another 15 days if there were no side effects, and in fact, all patients achieved the 40-milligram dose, and as you can see here, there was no significant effects of the placebo, but simvastatin decreased portal pressure by 8%. That is not a big effect, but is we thought it was relevant to move the concept forward to a clinical trial. Another relevant effect of Zimbastatin was that it was an increase in the endocyanin green cledens, which is a fine test of liver function that did not occur in placebo, and that we thought that it was a promising effect in terms of liver protection or improving liver function. So regarding statins and clinical endpoints, there are a huge number of observational studies that is very difficult to keep track of everything that is published that have shown that patients that take statins as compared to patients that do not take statins have lower risk of liver cancer, lower risk of cirrhosis progression, decompensation, mortality, and infections, and this has been demonstrated in patients with hepatitis C, hepatitis B alcohol, and NAFLD, so almost the whole spectrum of chronic liver diseases. These studies have shown unrealistic effect sizes because in most of these studies, the effect of statins is a decrease of more than 50 percent in the incidence rates of the events, which will position that as the most effective drugs in history because, in fact, the effect of statins for cardiovascular risk, it never exceeds 30 to 35 percent decrease in the relative risk of the incidence rate of events. And in terms of liver cancer, giving a statin and achieving a decrease in 50 percent of the risk of cancer will mean that they will be almost the perfect chemopreventive drugs. In terms of randomized control trials, we only have three trials in advanced liver cancer with bravastatin that show no effect, that were negative, and then only one trial in cirrhosis, which is the BLEPS trial. So, this is the BLEPS trial that was the natural continuation of that program for developing statins as a treatment for cirrhosis. It was a multi-center Spanish trial in 14 centers, 158 patients, and the aim of the trial was that it was assessing patients after a varicial bleeding episode, whether adding simvastatin to the standard therapy, which was varicial ligation and beta blockers, could improve the rates of rebleeding and survival. We thought that would be both an effect of rebleeding because it decreased portal pressure and survival because we showed some effect in liver function. The primary endpoint was a composite of rebleeding and death, and the key secondary endpoints were the two components of the composite, rebleeding and death, separately. These were the baseline characteristics of the study. Most of the patients, 70 percent, were of alcoholic etiology. Fifteen percent in each group were CHALC patients, and these were relatively advanced patients because half in the simvastatin group and one-third in the placebo group had ascites. All of them had a previous episode of varicial bleeding, so they were all decompensated patients. These were the results on the main endpoint, and as you can see, it was a negative trial because simvastatin did not decrease the rate of the primary endpoint. There was no difference in the rate of rebleeding or death. When we look at each of the components of the composite, we showed that there was no effect on rebleeding, so given simvastatin on top of beta blockers and EVL, which is already quite effective in preventing varicial rebleeding, did not add anything in preventing rebleeding. However, when we look at the rate of death, simvastatin was more effective than placebo in preventing death. In fact, I talk about unrealistic effect size, and this was decreasing in more than 60 percent on the rate of death with simvastatin, which I think is probably a winner's curse because the study was not power to detect difference in death, and it's very important to understand, and we emphasize that very much in the paper, that this was a secondary outcome, and these results should be taken with caution. When we look at a preplanned subgroup analysis, there was a major effect in the rate of death. It was a 16 percent reduction, absolute reduction in the rate of death in child A or B patients, and there was no effect in child C patients. Again, they were only 15 percent of the patients that were child C, so these results should be taken with caution. So, what were the causes of death in placebo and in simvastatin? Simvastatin was mainly effective in decreasing the liver-related deaths. There were five deaths related to bleeding in placebo and only one in simvastatin, and four related to infections and only one in simvastatin. So, it looks like that even if simvastatin was not preventing the complications of cirrhosis, and in fact there were no effect on any of the other complications apart from bleeding, it was preventing the death from those complications, and we did a large amount of working experimental models to try to understand this finding. In fact, it's very clear that simvastatin, at least in those experimental models, has a strong anti-inflammatory effect, for example, after a hypovolemic shock or upon infections or experimental infections or LPS challenge. So, what might be the perils of using statins in patients with cirrhosis? And these were the adverse events in the blood study that, in fact, were not different between placebo and simvastatin, but there was one particular adverse effect that we were monitoring very carefully, which was rhabdomyolysis, and there were two instances of rhabdomyolysis in patients to do with simvastatin. Both patients got very advanced liver disease with a bilirubin over 5 milligrams per deciliter, and they recovered uneventfully after stopping the drugs, and only there was one discontinuation because of an increase in transaminases, and there were no instances of clear or relevant drug-induced liver disease. When we look at these, we did a systematic review to assess the potential adverse effects of statins in cirrhosis, and we could only pull the results of simvastatin because there were very scarce data on other statins, but when we pulled the rates of rhabdomyolysis with simvastatin 40 in patients with cirrhosis, the pool frequency was 2 percent of the patients developed rhabdomyolysis, which, in fact, is a 40-fold increase as compared to the rate of rhabdomyolysis in patients without cirrhosis. And in this study by Posse from the Liverhub Consortium, in which all patients were child B and C, they were also receiving refaximing, the rate of rhabdomyolysis was 19 percent, which is a huge rate of rhabdomyolysis. In the same study, there were patients treated with simvastatin 20, and there were no rhabdomyolysis, but, in fact, the amount of patients reported in the literature after simvastatin 20 that showed no rhabdomyolysis is very limited, only 52 patients. So, it's still a little bit uncertain whether simvastatin 20 will be safe in patients with decompensated cirrhosis. All the studies that showed zero percent rhabdomyolysis were in much earlier cirrhosis stages. So, there is clearly danger in patients that have decompensated cirrhosis. Another call of attention is this observational study based on the Naxal cohort led by Guadalupe Garcia-Sau and presented in this meeting last year, and it assessed what would be the effect of starting use in patients hospitalized with advanced cirrhosis. And after matching for several potential confounders, what the authors observed was that patients on statins had worse in-hospital mortality and worse even when this was considered mortality of discharge to a hospice. So, this was a selected cohort of patients because the inclusion criteria was a bilirubin of more than 3 milligrams per deciliter, but these patients that were on statins had poor outcomes, including great in-hospital mortality. So, the conclusion was that until results of randomized control trials are available, these results will raise caution regarding the use of statins in advanced cirrhosis. And it's very impressive because I think this is the first observational study showing worse outcomes with statins in patients with cirrhosis, and it's probably the study that includes more advanced patients. Another relevant study was this study from Germany. It was a cross-sectional study, so the causal inference is limited, but they assessed whether having the SLCO1B1 variant, which is associated with the uptake of the hepatocytes of the statins, whether having a polymorphism that is associated with a loss-of-function variant could be associated with a lower efficacy of statins. This polymorphism is also associated with the risk of rathomiolosis because there is less uptake to the hepatocytes, so there is more systemic exposure to the statins. What they found is that patients that had the loss-of-function polymorphisms had potentially less benefits of the statin on the trajectory of cirrhosis. As I said, this was a cross-sectional study, so the inference is limited. But, you know, we had…there is only…with the progression of cirrhosis, there is also a phenotypic decrease in the expression of a SLCO1B1 gene. As you can see here, this is a study that we did in the Barcelona unit when I was there. It's still not published, but what we found is that in Chelsea patients, there was a major decrease in the expression of the transporter, and this could explain why in patients in Chelsea there is more susceptibility for statin toxicity and there is more risk…and there is less potential beneficial effects. So, this is something that should be taken into account in the future trials. So, there's a number of trials going on with statins. From the earlier phases of cirrhosis, patients without clinically significant polyhypertension, with suspected clinically significant polyhypertension, with clinically significant polyhypertension, and in much more advanced stages of cirrhosis in patients with decompensated cirrhosis. And these trials are going to use imbastatin 40-40, which is an appropriate decompensated cirrhosis, atorvastatin, which has major abnormalities in the metabolism in patients with cirrhosis, and in decompensated cirrhosis, the combination of imbastatin 20 of rifaximin preventing the progression to ACLF. And I think until we have these studies, it's prudent to put a break on the use of statin in cirrhosis. What will be the ideal statin? I have commented upon a little bit in the previous slide. There is extensive information for simvastatin in cirrhosis, but there are really no pharmacokinetic studies in this field. Atorvastatin has major abnormalities in metabolism. The only pharmacokinetic study with repeated doses was done with rosuvastatin. However, there is some observational data suggesting that the benefit of studies will be limited to lipophilic studies. Rosuvastatin is a hydrophilic study, so there is some uncertainty on this. There is no clear, I think, biological rationale to think that's the case that the observational data suggests. So this is my last slide. This is the take-home messages that studies induced a mild decrease in portal pressure, and this is not enough to improve the results of beta-blockers or EVL. It could have some effect, for example, in patients with contraindications to beta-blockers, but we don't know. There is only one randomized trial with clinical endpoints with simvastatin giving aftereffects of bleeding episode that improved survival, but survival was a secondary outcome, and the trial was overall negative. There are ongoing randomized trials from early phases to late phases of cirrhosis. Myopathy is a major concern, especially in decompensated cirrhosis, and currently the use of statins should be limited to early cirrhosis and for cardiovascular indication and not for the treatment of cirrhosis itself, and it is my view that in CHALC patients, statins should be deprescribed, and I thank you very much for your attention. Good evening. I'm Christina Rappoll. I would first like to thank the organizers for inviting me to participate in this interesting debate, and I would especially like to thank the organizers for giving me the easiest part of the task. So as you all know, when you have a chronic liver disease, eventually you may develop compensated cirrhosis, and then one can develop these complications, ascites, hepatic encephalopathy, or variceal bleeding, and then you go into the decompensated phase of the disease, and these are the patients who are at risk of dying from their liver disease. Distinguishing between compensated and decompensated cirrhosis is clinically relevant because we know that patients who remain compensated have a good prognosis in the long run, over 50% at 10 years, while patients who develop decompensation, these are the ones who have a marked reduction in their prognosis. So the thing is that in the compensated patients, what we really want to avoid is that the patients decompensate, while in the decompensated patients, what we really want to avoid is that our patients die. So the first approach to trying to prevent decompensation in compensated patients was done in this clinical trial that you all know, this is the Tymolol study published by the late Dr. Grossman in 2005, and in this study, only patients with compensated cirrhosis with clinically significant portal hypertension were included. The main endpoint of the study was prevention of the development of varices and variceal bleeding, and it was a negative trial in this sense, but the secondary endpoints of this study were to prevent the development of complications of cirrhosis, as you can see here on the slide, and again, the study had no differences in the development of decompensation during follow-up. But we did obtain significant information, relevant information from this study, and what we saw in a secondary analysis of this study is that those patients who were at risk of decompensation were the patients who had a clinically significant portal hypertension. That is that they had an HVPG above 10 millimeters of mercury. These patients had a six-fold increase in the incidence of decompensation compared to patients who had an HVPG under this threshold at baseline. So, the first important information was this subgroup of patients who are at increased risk of decompensating we could identify by means of HVPG. The second important background that was necessary for the development of the trial to prevent decompensation was this study by Candide Villanueva and his group, in which he evaluated or they evaluated the incidence of ascites in a large group of compensated patients, all with viruses, and they stratified the incidence of ascites according to the presence of a hemodynamic response to the beta blocker or not. And as you can see here, those patients who were hemodynamic responders, they had a higher likelihood of being free of ascites during follow-up than those who were hemodynamic non-responders. So, the information of how we could identify this at-risk subgroup with clinically significant portal hypertension and this second study that showed us that actually with beta blockers we can prevent the development of ascites was the rationale that was used to design this study, that you all know. This is a study by, again, Candide Villanueva published in Lancet 2019, and in this study what they evaluated was a completely new concept, and that is prevention of decompensation. So, what they did is they had compensated patients who were at risk, that is, with clinically significant portal hypertension, and these patients were randomized to placebo or to beta blockers. Their endpoint was a combined endpoint with decompensation and death, and here you can see the curves of these two groups. In red, the beta blocker group, and in blue, the placebo group, and you can see that those who were under beta blockers had a much lower incidence of this endpoint than the patients who were on placebo. The main sub-analysis showed that the main difference was due actually to a different incidence of ascites. So, in this study, the number needed to treat was nine, so you had to treat nine patients to prevent one decompensation with a medium follow-up of 37 months. There are some setbacks of the trial, of course, and I'm sure that my colleague will mention them extensively. The first one is that many had HCV-associated cirrhosis. That is obviously something that nowadays is not so present with the development of effective treatment and easy treatment against hepatitis C. They had actually an invasive determination of clinically significant portal hypertension, and then it's clear that this cannot be used on large scale in the population to identify which patients should have this prevention of decompensation, but was very necessary for the study because this is a study in which a new concept was being tested. It was important to have the risk group, the high risk group, clearly defined, which was the presence of clinically significant portal hypertension. We do have ways, though, to identify clinically significant portal hypertension non-invasively. On one hand, in compensated cirrhosis, we can check collaterals on imaging, and if the patient has had no treatment or the cause of the liver disease has not been suppressed and the patient has collaterals, then we can consider that the patient has clinically significant portal hypertension. We can also do a liver stiffness measurement and platelet count, and if the patient has a liver stiffness measurement above 25, no matter what the platelet count is, we're relatively sure that the patient's going to have clinically significant portal hypertension. If the patient is between 20 and 25, has low platelet count, we are also relatively sure that the patient has clinically significant portal hypertension. If the patient has liver stiffness under 20 or in this range here with platelet count above 150,000, well, these patients do not have clinically significant portal hypertension and should just be controlled during routine follow-up. Another setback of the trial was the use of propanolol and carvedilol. And this was done despite the fact that we knew that carvedilol is a much more effective drug. My mentor from Madrid, Rafael Bañad, has already shown in 2002 that the mean decrease in HVPG with carvedilol was much greater than with propanolol, and therefore the proportion of responders under carvedilol is much greater than with propanolol. In the Villanueva study, there were, and at the time it was designed, there were still concerns about the safety of carvedilol in our patients, and therefore they only use carvedilol for those patients who did not have a hemodynamic response to an intravenous bolus of propanolol. This is the acute response to propanolol. And therefore, if the patient had no response, they would be stratified to carvetilol, they would be randomized to carvetilol or placebo. And if they did have a response, this was the stratus of propanolol versus placebo. What would have happened if all patients would have had carvetilol as the much more effective drug? This has been recently evaluated in this meta-analysis, which was presented by Candide in the ILC last spring. And they included randomized controlled trials with adult patients with roses, obviously, which were designed to prevent first bleeding, development or growth of varices or decompensation. In the study, they had to have an arm with carvetilol and another arm, which was a control arm. This could be no active therapy, placebo, or endoscopic band ligation. And they looked at the individual data and only patients without any previous decompensating event were included to pool the individual data. So actually, these were only the compensated patients. The primary outcome measures were development of decompensation, that is, ascites, portal hypertensive bleeding, or overt hepatic encephalopathy, or death from any cause. From over 2,500 records that were evaluated, they identified 12 eligible trials, of which seven were excluded because five included classical beta-blockers, propanolol, nadolol, or so on. One combined carvetilol and band ligation, and one was a randomized controlled trial. So there were left five. They contacted all the PIs. Only four answered. So the final analysis is done with these four trials, two were randomized controlled trials comparing carvetilol versus placebo, two were randomized controlled trials comparing carvetilol versus band ligation. 181 patients had carvetilol, 171 had the controlled treatment. And when we look at the outcomes, the primary outcome, decompensation, and in this meta-analysis, death and liver transplants are competing events. We can see here that the patients who received carvetilol had significantly less decompensation during follow-up than the patients who were receiving the control arm. You can also see this here clearly on these Kaplan-Meier curves. So the hazard ratio was 0,466. But not only were there less decompensation among the patients who were receiving carvetilol, they also died less. So the patients who were receiving carvetilol had less death during follow-up than the patients who were receiving the control arm. So we can see here on the Kaplan-Meier curves how these patients had significantly less death during their follow-up, and the sub-hazard ratio was 0,417. So not only does it prevent decompensation, in this meta-analysis also presented death. So with this, I come to my concluding statement. Do beta-blockers prevent decompensation? I can only say yes. In patients with clinically significant portal hypertension, that is the appropriate risk group, beta-blockers do prevent decompensation. Not only that, treatment with carvetilol can improve survival in this group of compensated cirrhosis. Thank you for your attention. Good evening, everyone. My name is Ruhail Kohli. I'm one of the hepatologists at Johns Hopkins. I'd like to thank the organizers for giving me a chance to give this talk today. So today I would be talking about portal hypertension, specifically beta-blockade for the prevention of decompensation in cirrhosis. I have no disclosures relevant to this talk. So we will be discussing the use of non-selective beta-blockers for the prevention of decompensation in cirrhosis. And I'd be arguing against it, specifically the fact that one size does not fit all. We saw this in the other presentation, but it's important to have a refresher. Cirrhosis is a spectrum, it's a continuum. And cirrhosis goes from being very compensated and as the disease progresses, patients could start developing complications and the disease progresses into decompensated cirrhosis. As time progresses, especially if the underlying etiology continues, patients can develop further decompensations and eventually death. So for today's talk, we are focusing on the prevention of decompensation of cirrhosis. So on the compensated cirrhosis side, and we are focusing on the use of beta-blockade in prevention of decompensated cirrhosis. More specifically, I'd like to make the distinction between two different entities, mild portal hypertension, as well as clinically significant portal hypertension in cirrhosis, and we will discuss the use of these medications for this condition. It is very important to risk stratify patients as they can range anywhere from compensated to decompensated cirrhosis. Most of the time, this depends on clinical as well as biochemical parameters. So certainly clinically, when patients develop complications like ascites, variceal hemorrhage, hepatic encephalopathy, or when these conditions become hard to manage and recurrent, patients are in decompensated cirrhosis or they have decompensated cirrhosis. It is important to stratify patients because it does matter and it affects the survival. Patient with compensated cirrhosis can have a survival more than a decade and a patient with decompensated cirrhosis, the survival could be as low as 1.8 years on average. The stage which lasts the longest and which gives us the most time to intervene is actually the compensated cirrhosis stage. In this stage, it is important to look for the center that you would discuss before called clinically significant portal hypertension. That is when the hepatic venous portal gradient, HVPG, is more than 10 millimeters of mercury. And it is important as we heard in the other presentation because it correlates with complications and complications that cause decompensation. It is important to note that clinically significant portal hypertension can be present in about 50 to 60% of patients with compensated cirrhosis even without gastroesophageal varices. So it is important to recognize it and intervene if that is present or ideally have intervention to prevent decompensations. We're talking about portal hypertension so it is nice to have a refresher on the pathophysiology. So even in portal hypertension, there is a stage called mild portal hypertension when the hepatic venous portal gradient is less than 10 millimeters of mercury. In that case, the mechanism, the primary mechanism with portal hypertension in that stage is actually more architectural and structural. And this is related to fibrosis, nodule formation and increased resistance in the liver. And that causes increased pressure and the pressure gradient at that stage. There is a smaller component of increased intravascular, sorry, increased intrahepatic tone at that stage but the majority is still structural. And the target in patients with mild portal hypertension should be to treat the underlying etiology of cirrhosis to prevent any further decompensation or worsening of portal hypertension. By the time patients develop clinically significant portal hypertension, there are different mechanisms at play including spinach basal dilation, neurohormonal activation and hyperdynamic circulation. And in this case, the target could be reduction of heart rate and cardiac output. Looking at beta blockers, we can see that different beta blockers work on different targets. Usually beta blockers have a beta-1 blockade, a beta-2 blockade, and then carvedilol also has an alpha-1 adrenergic blockade. And looking at the pathophysiology, we can see the beta-1 blockade leads to reduction in cardiac output and heart rate. Beta-2 blockade helps with spinach basal constriction and decrease in portal flow. And then carvedilol, which has the alpha-1 blockade can help with some of the dynamic changes. But as you see for this part with increased intrahepatic resistance, which is the most predominant etiology of portal hypertension and mild portal hypertension, the most of the changes are architectural. So coming back, we discussed that most of the changes are architectural. And at that point, it is important to treat the etiology of cirrhosis. We saw this data before, and I will briefly mention it. Beta blockers for the prevention of varices has been studied in the Timolol study. It is important to note that the patients who were selected had compensated cirrhosis, no varices, and the HVPG was more than five. However, this did include patients with both mild and clinically significant portal hypertension. There was no difference in prevention of varices, but it did show the compensation threshold of 10 milliliters per day. And this is data in visual form, which shows that if your baseline HVPG was less than 10 millimeter, you did better, as opposed to if the baseline HVPG was higher. This is another study, very exciting, looking at beta blockers for the prevention of decompensation. And in this case, the endpoint was not the development of varices, but prevention of decompensated cirrhosis. So any of those things, ascites, hemorrhage, encephalopathy, these only included patients with clinically significant portal hypertension. That means that they had HVPG measured, and the response was based on initial response to IV propranolol. As you can see in select cases in clinically significant portal hypertension, there was a risk reduction with beta blockers for both decompensation and death, which were lower in beta blocker group despite adjusting for risk factors. There was decreased heart rate, cardiac index, HVPG was low, but we saw in the pathophysiology, that is because at this stage, patients have developed those underlying changes as the etiology or primary etiology of their portal hypertension. This is showing that for selected patients, beta blockers did help. However, I wanna point out that this trial had some things that might not be common in our clinical practice. So every patient required HVPG measurement. Not every patient that we seen in our outpatient setting or hospital actually gets an HVPG measurement, and only patients with clinically significant portal hypertension were included. And EGD was also done. Beta blockers were not without risk. We all know from treating patients that if you do start beta blockers, and especially if they're used correctly, which is titration of beta blockers to the highest tolerated dose, patients can develop side effects, including things like weakness, shortness of breath, bradycardia, impotence, hypotension. And in this study, there were patients who had to withdraw beta blockers because of side effects. So while in select patients, there is certainly some benefit, it is not in all patients. And patients who have side effects may need to discontinue them. One of the things that they did in the trial we just discussed was use HVPG measurement. And these days, there's new thinking, and there's certainly non-invasive fibrosis measurement technology, which can help us stratify patients in compensated versus decompensated, but also in compensated cirrhosis in patients who may have a high likelihood of clinically significant portal hypertension or not. This includes things like liver stiffness and a platelet count. In this new paradigm, which is proposed, we still wanna look for clinically significant portal hypertension and start beta blockade. So it is important to have the right patient and the right patient selection in case we were to start beta blockers. So in conclusion, I'd like to say there's increasing benefits. However, in initially mild portal hypertension, the changes are mostly structural, and these are not affected by beta blockade. And I would like to say that patient selection is key. It is important to know if patients have HVPG, a clinically significant portal hypertension or not. This is my little poll. I asked the liver Twitter to see if people agree, and you can see the results. And I'd like to thank you, the organizers, for letting me speak on this very important topic. Thank you. Good evening, everyone. My name is Elizabeth Verna, and I'm honored to be here today on behalf of the Portal Hypertension SIG to have a discussion with our excellent speakers here who I'd like to thank for their valiant debate about the role of beta blockers in the prevention of decompensation among patients with cirrhosis. So I just want to thank both of you for excellent talks. And I'd like to just start by asking both of you whether you're using this in practice these days in patients with cirrhosis, and whether you are advocating for invasive measurements or largely non-invasive measurements in order to sort of risk stratify patients for this treatment strategy. And maybe we can start with Dr. Ripple. Thanks. Well, the first question, whether I am using this now in clinical practice, I mean, this has just been recommended by the Boveno-Consensus Conference a few weeks ago. So I cannot say that I have implemented this in a mass, you know, massively in the patients that I treat in my outpatient clinic. It is clear, though, that I do not, since a bit longer since this study is published, I do not recommend to remove any beta blocker that has already been given to a patient with cirrhosis who has a beta blocker for other reasons. I always recommend, for example, when he has a beta blocker because of arterial hypertension or some other cardiological disease, I always recommend that this beta blocker gets switched over to Carvedilol, which is a very easy drug to dose. You know, you start off with 625, put it up to 12,5, and then it's done. There's no more dose titration to do in these cases, and that's what I recommend. And your second question was about- About your mechanism for risk stratifying patients to identify the clinically significant portal hypertension. So the risk stratification, well, you know, if I know if the patient has varices, doesn't matter, big, small, or whatever, if the patient's had varices, then the patient has clinically significant portal hypertension, as long as the cause of the liver disease has not been treated. In the context, when the liver disease, the etiology of the liver disease has been treated, then it's more difficult to know where the- if the patient has clinically significant portal hypertension or not. And obviously, these patients get ultrasound or get other imaging, and if in the ultrasound, he has a recanalization of the umbilical vein or I see any other collaterals, then- and the patient has, again, not been treated for the cause of the liver disease, then you can take- you can assume that the patient has clinically significant portal hypertension, and then you can start the treatment. I think with these indicators, it's easy to know which patients have clinically significant portal hypertension. The use of liver stiffness and platelets, this has just been recommended in Baveno. This I have not yet implemented widely in my clinical practice, but I'm looking forward to do so. Okay. Thank you very much for letting me speak on this topic. I think it's a very important intervention, but we are, at least here in the United States or at least in Baltimore, we're not using beta blockers at this time for prevention of decompensation, for established criteria for variceal hemorrhage or secondary bleed. Even then, there's a little bit of a hesitancy in actually using beta blockers because there is this pervasive thought that they cause hypotension and make things worse. So in practice, a lot of times, people end up using endoscopic variceal ligation more than beta blockade. As far as determining and risk stratifying patients, obviously, we are using a lot more non-invasive studies, including liver stiffness through a fibroscan, or at least here at Hopkins, we use a lot of MRI elastography, which can help, but also imaging, if that shows, like Dr. Ripple was saying, varices, recanalized umbilical veins, splenomegaly, that can help risk stratify some of these patients. The simplified criteria, I think, would be very helpful. And with the new data coming out, hopefully that can change some practice patterns. But at this point, I think we could do better. Okay, great. So Dr. Ripple, I'm also very interested because there's another intervention that I think is being studied in multiple different ways. I think both the United States and Europe, and we just heard a great talk summarizing the data for statins, is how do you feel about the role of combining these agents? If we have data that look promising for both of them, should they both be used? How do you think about these combinations? Yeah, thanks for the question. Well, statins are fascinating in the context of cirrhosis and portal hypertension. They reduce the intra-hepatic vascular resistance. So it has been demonstrated in patients in secondary prophylaxis that the use of statins on top of beta blockers, not only is it safe, but has a greater effect on HVPG and better clinical outcomes. Now, whether or not statins could be used in the context of compensated cirrhosis to prevent decompensation, this is an unanswered question. There is now a study, I think it's VA in the US, a study ongoing, I think it is VA-based, called the SACRED study, in which they are using, with this idea to prevent clinically decompensation, they're using a non-invasive measurement to select the high-risk patients, which is important in this context. Then this non-invasive tool, I think it's liver stiffness, actually, and platelets, they're using this to select the high-risk patients, and these patients are randomized to simbacitin or not, and whatever standard of care the patients have with beta blockers and so on. So this is obviously a question that needs to be answered. It's quite interesting. What I'm not so sure about is if the patient is taking Carvedilol, which has an alpha antagonism, that's the special thing about Carvedilol, this is why it works more, because it also reduces the intrahepatic vascular resistance. So if you have two drugs that are reducing intrahepatic vascular resistance, is this effect additive, or is just doing the same thing? There is one study that has evaluated this from Dr. Sarin, and they did not see further effect of adding simbacitin on top of Carvedilol. This question remains to be clarified. Did I answer your question? Yes, yes, thank you. Difficult topic. So I have one last question for Dr. Coley, which is, you know, the data overall, I think, sound promising, and certainly can be used to help and certainly can understand why selecting the highest risk group was essential for these clinical trials, but why wouldn't there be a role for these types of preventative agents in those that have not yet achieved clinically significant portal hypertension? Perhaps treating people earlier is something that should also be looked at or considered. I wondered what your thoughts were on that. I mean, I think we should definitely optimize whatever we can to prevent development of clinically significant portal hypertension. You know, as we saw patients with mild portal hypertension with, you know, the pressures that are not above 10 millimeter mercury, the pathophysiology of portal hypertension is a little bit different, mostly related to the structural changes, but also the intrahepatic tone. So there might be actually a role for more beta blockers like Carvedilol, as opposed to the traditional ones we've used, the non-selective beta blockers, which are Propranolol or Natalol, which have just the beta blockade as opposed to Carvedilol, which is a little unique. At that stage of portal hypertension, if we could use that to prevent development of clinically significant portal hypertension and actually target that, that might be the only one that actually has a role. So I think we should absolutely strive to do anything we can to prevent decompensation and treat any modifiable risk factors. So as more data comes out, there might be a role for select beta blockers, just not indiscriminate all the beta blockers. Great. Okay, I think that concludes our session. Thank you very much to our excellent speakers and to the audience for participating. Many thanks to the ASLD and to the SIG program organizers for inviting me to speak. I'm a physician scientist and a practicing hepatologist in Edinburgh, and this is where I'm based, and my research spans basic science through to clinical trials in portal hypertension and in liver fibrosis. These are my disclosures. In my talk, I'll briefly cover the mechanistic basis of portal hypertension pathogenesis and regression and the rationale for novel disease-modifying treatments. I'll discuss the current therapeutic landscape, highlighting some selected important studies of emerging agents, and then share some thoughts for the future. This pathogenic model of portal hypertension is well-established and will be familiar to all, but it's important to emphasize that increased intrahepatic vascular resistance is the primary factor in the development of portal hypertension, and this precedes the maladaptive splanchnic vasodilatation and homeostatic mechanisms, including activation of neurohormonal reflexes that progressively impair extrahepatic organ perfusion, not least in the kidneys. Once decompensation has occurred, of course, cirrhosis becomes a systemic disease with multi-organ involvement associated with a dysregulated inflammatory state. It's fair to say that this complex interplay of intra- and extrahepatic systems poses a substantial challenge for the development of safe and effective therapies. About two-thirds of increased intrahepatic vascular resistance in cirrhosis is caused by structural factors, including regenerative nodules, fibrotic scepter, microvascular thrombosis, and angiogenesis, whereas around a third is due to a functional dynamic component mediated by contraction of perisinusoidal myofibroblasts and sinusoidal endothelial dysfunction associated with an imbalance of vasoactive factors, particularly a reduction in nitric oxide and an increase in endothelin-1. Interestingly, in compensated NASH cirrhosis patients in the CYM2ZOMAB trial, hepatic alpha-smooth muscle actin staining was an independent predictor of clinically significant portal hypertension. Data from rodent and human cirrhosis has shown both morphologically and mechanistically how fibrous regions in the hepatic parenchyma can be returned towards a normal appearance following successful etiological therapy. But these studies have also elucidated the factors that are recalcitrant to spontaneous resolution, such as microvascular thrombosis, extrahepatic angiogenesis, and hepatic arterialization. Etiological therapy is the best, in fact the only, available antifibrotic therapy and is also associated with improvements in portal hypertension. For example, following alcohol abstinence, lifestyle modification, and treatment of chronic hepatitis C, where here in this study patients who resolved clinically significant portal hypertension were protected from hepatic decompensation. However, importantly, clinically significant portal hypertension may persist in up to 53-65% of patients 96 weeks after SVR, indicating a persistent risk of decompensation. The goal of treatment in advanced chronic liver disease and the therapeutic strategy depends very much on the stage of disease and the clinical phenotype, because portal hypertension pathophysiology changes along the natural history of cirrhosis. Therefore, in pre-cirrhosis and early compensated cirrhosis, etiological therapy or drugs to reduce the fixed or modulable components of increased hepatic vascular resistance are key. Whereas in patients with clinically significant portal hypertension or decompensated disease, the focus shifts somewhat to portal hypotensive or pro-regenerative therapies in addition to treatment of specific cirrhosis complications. This modified schematic from one of several excellent recent review articles that are all listed here provides an overview of the treatments that have been investigated for their potential to ameliorate portal hypertension and liver fibrosis in chronic liver disease. These include agents that either promote intrapathic vasodilatation by augmenting nitric oxide activity or inhibiting key vasoconstrictor axes, such as endothelin-1, urotensin-2, or the renin-angiotensin system. It also includes approaches to modulate the gut microbiota, anti-apoptotic agents, anti-inflammatories, anticoagulants, anti-diabetic drugs, and anti-fibrotic agents. Although these therapies have shown promise in preclinical models, many are failing in clinical trials. In terms of drug development for portal hypertension, the ideal therapy should reduce intrapathic vascular resistance, decrease portal pressure, whilst maintaining or even enhancing hepatic blood flow. The vasodilatation effect, if there is one, should be limited to the liver to prevent further splanchnic or systemic vasodilatation. Rodent models, summarised here, are commonly employed to recapitulate human portal hypertension phenotypes, but there are issues such as variability and inadequate human translatability. Using older animals may reflect the clinical demographic picture more accurately in this study here referred to, and also introducing the wild mouse gut microbiota may increase the reproducibility and the bench-to-bedside success of interventional studies. Additionally, novel technologies can be harnessed, such as this microfluidic device developed by Jordi Gracia's group that models the human liver sinusoid, or even ex situ normothermic human liver perfusion that we are adapting in Edinburgh for therapy evaluation. This table summarises information mostly gleaned from clinicaltrials.gov on the current and recent clinical studies of investigational portal hypertension drugs. You'll immediately see that there are only a few registered trials that are active, that they're all pretty large and many involve statins, with a focus not specifically on portal pressure, but on preventing decompensation, ACLF, hospitalisations, deaths, and so on. A notable exception is the galactin-3 inhibitor belopectin that I'll discuss in a bit more detail later. The unsuccessful trials of the pan-CASPase inhibitor emricosan and loxal-2 inhibitor simtuzumab will be familiar to most, but there are some other recent positive studies, including metformin and taurine, that have published data. Other studies have been terminated, some torpedoed by the COVID pandemic. Although the trial of the endothelium A antagonist, ambrosentan, was stopped prematurely, promising data has recently been published from a proof of concept study that investigated local intra-hepatic administration of the endothelium A antagonist, BQ123, and systemic oral administration of ambrosentan. Now I know you'll all have just been vigorously debating the role of non-selective beta blockers, so I won't dwell on this slide too much. The data are very well known. Other than underscoring the fact that carfetolol is very much the drug of choice now, and this was recently reinforced by a study showing that conversion of propranolol to carfetolol improved renal perfusion and was associated with a significantly lower two-year risk of further decompensation or death. Because the recent long-term follow-up studies have shown that compared to variceal band ligation for either secondary prophylaxis or primary prophylaxis, carfetolol is associated with a significant survival benefit. It's important, I think, to consider how carfetolol might mediate beneficial effects beyond its direct hemodynamic activity. Potential mechanisms include amelioration of fibrosis, bacterial translocation, and systemic inflammation, and additionally carfetolol has been shown to activate antioxidant and cytoprotective pathways, including ENOS, HO1, and NRF2 in multiple tissues. With this in mind, it's not surprising that some are asking whether it's time to reconsider when we start non-selective beta blockers in cirrhosis patients. You'll have heard about statins and how they work from Dr. Abraldes, but although the landmark randomized controlled trial showing portal hypotensive effects of statins was over 12 years ago now, they've not yet been widely adopted into routine clinical practice, in part due to the potential for side effects such as muscle toxicity. However, modified statins such as NCX6560 have been shown to have a better toxicity profile. I think there was much interest in the more recent study that showed a survival benefit with the addition of simvastatin to standard care that was independent of bleeding, and may be relevant to this, the combination of statins and non-selective beta blockers was shown to activate pro-survival mechanisms in a rat myocardial infarction model. Of note, the large randomized controlled trials of statins that are currently underway, sacred, stat liver, and liver hope efficacy, are not focused specifically on portal hypertension, but they may provide further support for the use of these drugs in patients with cirrhosis. Belapectin is an IV-administered galactin-3 inhibitor, and galactin-3 is the most important galactin protein secreted in the disease state, mainly by macrophages, and it binds to the cell surface and to extracellular matrix glycans to regulate a variety of physiological and pathological processes, including cell apoptosis, adhesion, migration, antigenesis, and inflammatory processes. Belapectin ameliorated NASH and fibrosis in preclinical models, but in a phase 2 trial in patients with compensated NASH cirrhosis and portal hypertension, the NASH-CX trial, belapectin failed to achieve the primary endpoint of a reduction in HVPG in the total population. Nevertheless, in a post hoc analysis, patients without varices at baseline had a significantly reduced HVPG and a lower incidence of varices development in the drug-treated group compared to placebo, although interestingly, there was no dose response effect. These results should probably be viewed cautiously and are now being validated in a further phase 2b, phase 3 seamless adaptive trial in 1010 patients with NASH cirrhosis without esophageal varices at baseline to assess the effect of belapectin on the incidence of new varices. And during the first 18 months, two belapectin dose levels will be compared to placebo and at the interim analysis, one dose will then be selected based on efficacy and safety for continued evaluation in phase 3. Now, metformin is also an adenosine monophosphate activated protein kinase inhibitor amongst other things, and one week gavage of metformin in cirrhotic rats was shown to reduce hepatic resistance and portal pressure via amelioration of both liver fibrosis and inflammation and increased hepatic nitric oxide bioavailability. It also had an additive effect when co-administered with propranolol. And interestingly, in a recent small randomized controlled trial, a single dose of oral metformin acutely lowered HVPG in patients with cirrhosis and portal hypertension, with a clinically relevant 16% reduction in HVPG observed in nearly half of patients, although it's worth noting that some placebo-treated patients also had a significant decrease in HVPG. The acute mechanism was not clear from this study as there was no change in ICG clearance or pro-inflammatory cytokines. Validations clearly needed in a larger randomized trial and the longer term effects of metformin on HVPG and outcomes, possibly in combination with non-selective beta blockers should definitely be evaluated. The amino sulfonic acid taurine has been shown to reduce oxidative ER stress and inhibit hepatic stellate cell activation, and in a small randomized controlled trial in patients with cirrhosis and clinically significant portal hypertension, the HVPG decreased by more than 10% in 7 out of 12 participants who received four weeks of oral taurine supplementation, compared to none in the placebo group. And although taurine was safe, more studies on the underlying mechanism of action and the longer term effects are required. FXR agonists are being intensively investigated for the treatment of NASH, but abetacolic acid has also been shown to reduce portal pressure in cirrhotic rats, potentially via a number of mechanisms, and it also decreased HVPG in a proportion of patients in an unpublished proof of concept study from 2014. More recently, the non-steroidal FXR agonist silifexor decreased portal pressure, deactivated hepatic stellate cells, and resolved liver scarring in a rat model of NASH cirrhosis. And although the mode of action appeared to be primarily through reducing hepatic resistance, the combination with propranolol did not translate into a synergistic effect on portal pressure reduction. The pan-PPAR agonist lanifibrinol exerted positive effects on hepatic fibrosis and microvascular function in preclinical studies by improving the phenotype of hepatic stellate cells and liver sinusoidal endothelial cells, evidenced here by a reduction in alpha smooth muscle actin and von Willeban factor expression, respectively, and a decrease in hepatic resistance. Lanifibrinol has not yet been studied in human portal hypertension, but it was recently shown to have antifibrotic effects in patients with NASH. Recombinant human relaxin has been an investigational agent of interest and was previously shown to be antifibrotic and portal hypotensive in rat cirrhosis models, including an increase in hepatic nitric oxide bioavailability. However, we didn't obviously see a translation into a beneficial acute effect on HVPG in patients with clinically significant portal hypertension. Although this study was stopped early due to a global drug supply issue, it's possible also that relaxin might be most effective in early portal hypertension when an increase in hepatic vascular resistance is a predominant pathogenic factor. The extra hepatic effects of relaxin are potentially relevant too, given its ability to substantially increase renal perfusion in cirrhosis, and so I think it's fair to say that relaxin and the RXFP1 axis will continue to be pursued as a therapeutic target in the future. Targeted delivery of portal hypertension therapies would also theoretically mitigate against off-target effects while also potentially increasing efficacy, and there are several interesting examples shown here, such as at the top right, a rho kinase inhibitor attached to an albumin carrier modified with PDGFR receptor beta-recognizing peptides to target the agent to activated hepatic stellate cells, which decreased fibrogenesis and portal hypertension without systemic off-target effects, and also an improvement in renal function was observed. Simvastatin-loaded polymeric micelles allowed targeted delivery to liver sinusoidal endothelial cells. This improved the cell phenotype and reduced portal pressure in barred-up ligated rats with greater efficacy and less toxicity than free simvastatin, and then nanoparticles decorated with vitamin A allowed delivery of nitric oxide donor molecules into hepatic stellate cells, seen here bottom right, and this reduced portal pressure by about 20%, with no effect on mean arterial blood pressure, again in barred-up ligated rats. Cell therapies that have been investigated in cirrhosis patients have largely focused on augmenting liver synthetic function rather than specifically treating portal hypertension. Prominent examples are autologous macrophage infusion, which we've shown to be safe in a recent phase one study, and are currently evaluating for efficacy across a range of outcomes in a randomized controlled trial in compensated cirrhosis. Mesenchymal stromal cells are also being investigated in decompensated cirrhosis patients. Open questions remain regarding the most suitable cell type, the best patient population, and the optimal route and dosing schedule. Interestingly, in rat cirrhosis models, MSCs derived from either adipose tissue or from amniotic tissue have both been shown to reduce portal pressure. What about precision medicine in portal hypertension? Well, portal hypertension treatment trials are challenging, and responses to therapies are generally rather heterogeneous. Potentially, treatment could be tailored based upon disease stage and the predominant pathophysical drivers in an individual patient, and this could be done through leveraging biomarkers in serum or imaging or in clinical trials, and this could also be done in clinical trials. This could be done by leveraging biomarkers in serum or imaging or through multiomics, supplemented with data from wearables or the electronic health record, and this is, you know, potentially reliant on artificial intelligence and machine learning modalities, but I think there's great potential. It would also require a palette of safe and effective treatments with very well-defined mechanisms of action. Currently, although pharmacogenomics is not routinely used in hypertension treatment, loss of function variants in the SCLO1B1 gene that encodes the hepatic statin transporter have been linked to decreased uptake, reduced efficacy, and high risk from rhabdomyolysis. I think the question is, what is feasible in a real-world setting? This conceptual diagram here was adapted by me from respiratory disease, and I think it encapsulates quite nicely the complexity of portal hypertension and acknowledges the fact that phenotypes can coexist in the same patient, such that an approach based on treatable traits is proposed. I want to just finish with a final key consideration, which is assessment of treatment response, which still relies on repeated measurements of invasive HVPG at different time points. This important recent paper highlighted the inherent test-retest variability in HVPG, especially in patients with decompensated cirrhosis, also its implications for trial design and the meaning of HVB change in an individual patient. Unsurprisingly, the search for a non-invasive method for portal hypertension monitoring goes on, and changes in liver stiffness, either by transient elastography or MR elastography, don't appear to predict HVPG response to beta blockers, but a spleen stiffness reduction more than 10% might identify hemodynamic responders. One thing that most diagnostic modalities do not capture is the effects of therapies on the microcirculation in cirrhosis, which could be an important determinant of organ function, outcomes, and also treatment response. We've got a particular interest in studying the retinal microvasculature as a proxy for the systemic microcirculatory changes in cirrhosis. I think other recommended reading for you is this provocative paper from Stephen Sen, who's an eminent Edinburgh statistician, that calls into question the dichotomization of responders versus non-responders, and encourages testing of new interventions in a patient on more than one occasion. And finally, the emerging concept of using ordinal outcomes in clinical trials in compensated cirrhosis patients appears to be extremely important with respect to rationalizing sample sizes. So just to summarize, there are multiple reasons that underlie the lack of translation of new treatments of portal hypertension. Reducing portal pressure continues to be important, even after etiological cure in patients with clinically significant portal hypertension, because the risk of decompensation remains. As predicted by the late, great Andy Burroughs, non-selective beta blockers are becoming the aspirin of hepatology, and depending on the efficacy and safety of signals from ongoing large-scale clinical trials, statins could increasingly become part of standard care in cirrhosis in the future. There are a paucity of active clinical trials evaluating novel interventions, partly due to COVID, but new and repurposed agents will continue to emerge, and beneficial treatments could be tailored to individual patients as monotherapies or as part of combination regimens in the future if precision medicine in portal hypertension becomes a reality. And the optimal way to measure drug response will continue to be debated and refined. I'd just like to acknowledge funders, collaborators, local research infrastructure, and with that I thank you for your attention.

meta-analysis

Dr. Villanueva

carvetilol

cirrhosis

decompensation

variceal bleeding

mortality

portal hypertension

non-selective beta blockers

precision medicine

biomarkers

omics data

microcirculation effects