Why do we use non-selective beta-blockers in cirrhosis? - Part 1

A 54 year-old with compensated alcohol-associated cirrhosis (last alcoholic drink was 5 years ago) presented to the clinic for routine evaluation. Liver Stiffness was 26 kPa and the platelet count was 145. Patient is scheduled for EGD as based on the Baveno VI criteria, patient needs variceal screening (Baveno VI: patients with LSM <20 AND platelet count >150 are unlikely to have varices needing treatment, therefore can safely avoid screening endoscopy, but everyone else needs screening endoscopy). Endoscopy shows 2 columns of large varices with red wale markings, what is the next step?

Based on current AASLD guidelines, you can either band or start the patient on NSBBs (Nonselective Beta Blockers). My goal is to explain how NSBBs work, and hopefully be able to convince you to choose NSBB over banding. You are not wrong if you band the varices, however I’m going to advocate for NSBBs. Here is why:

Where do NSBBs came from and what do they actually do?

Beta blockers were first developed by Sir James Black after the sudden death of his father from a heart attack when he was in medical school. His goal was to stop the effects of adrenaline on the heart and improve chest pain. The first beta blocker was propranolol, which is nonselective.

Nonselective means that it has a similar affinity for both B1 and B2 receptors and some affinity for B3 as well. With the development of new “cardioselective” beta blockers such as metoprolol, propranolol went out of favor. However, the nonselective nature of these beta blockers is what makes them perfect for management of poral HTN. B1 receptors are located in the cardiac muscle, and blocking it will result in a decrease in cardiac output. B2 is located in the splanchnic vessels and blocking it will leave a1 receptors unopposed, resulting in splanchnic vasoconstriction. The latter is actually much more important for decreasing portal pressure compared to the B1 effect.

The first study showing the effect of NSBBs on portal HTN in patients with cirrhosis dates back to 1980, in a study by Lebrec et al. which showed propranolol is able to decrease the portal pressure in patients with variceal hemorrhage. It was a small trial published in Lancet with only 16 patients after variceal hemorrhage; 8 patients received propranolol and 8 received placebo, and the study showed a significant reduction in HVPG (Hepatic venous pressure gradient) in patients receiving propranolol.

Following this study, multiple trials showed benefits of NSBBs in primary and secondary prevention. NSBBs include propranolol, nadolol and timolol. A newer NSBB is carvedilol, which has the additional benefit of inhibiting a1 receptors by which it can result in intrahepatic vasodilation, thus decreasing intrahepatic vascular resistance and bringing down the portal pressure even further. However, due to its vasodilatory properties, carvedilol is associated with a greater decrease in blood pressure, which can limit its use in some patients. It also has a longer half-life and is more bioavailable in patients with cirrhosis.

This is a graph from a randomized trial by Banares et al, comparing hemodynamic effects of propranolol vs carvedilol. The study used carvedilol at mean dose of 31 mg per day, and propranolol at 73 mg per day. Carvedilol caused a greater decrease in HVPG compared to propranolol (19 vs 12, p<0.001).

However it also resulted in a more pronounced decrease in mean arterial pressure (-11 vs -5, p=0.05) compared to propranolol. Although more patients in the carvedilol group developed orthostatic hypotension (35% vs 20%), the difference was not statistically significant.

It is important to note that the mean dose of carvedilol used in this study is almost 3 times what is used in clinical practice (12.5 daily).

Who benefits from NSBBs?

1. Compensated patients with medium/large varices for prophylaxis of variceal bleed: or so called “primary prophylaxis for VB"
   
   Based on the AASLD guidelines:
   
   “Either traditional NSBBs (propranolol, nadolol), carvedilol, or EVL is recommended for the prevention of first VH (primary prophylaxis) in patients with medium or large varices. Choice of treatment should be based on patient preference and characteristics."
   
   “NSBB is the recommended therapy for patients with high-risk small EV (red wale marks, and/or in patients with CTP C). The recommended treatment is NSBBs, because performing EVL in these varices and defining eradication may be challenging.” ² What about small varices without high risk stigmata? More to come on that later!
   
   

   Although based on the guidelines, patients can be started on NSBBs or banded, there is significant evidence that NSBBs do much more than just preventing variceal bleeding.  In patients with varices, prevention of decompensation should be the ultimate goal, and the most common decompensation is actually development of ascites (not variceal bleed). NSBBs work by decreasing portal pressure and thus preventing decompensation (both development of ascites and/or VB), whereas ligation is only a local treatment and does not alter the progression of the disease.

   The other benefit of NSBBs over EVL is that repeat endoscopy is not needed. In studies that repeated the EGD they showed the varices are still present and there has not been any modifications in size; however once the patient is on NSBBs the risk of bleeding is reduced similarly to eradicating the varices with EVL.

2. After first variceal bleed as secondary prophylaxis to prevent re-bleeding
   
   Based on the AASLD guidelines:

   “Combination of NSBB+EVL is first‐line therapy in the prevention of rebleeding”
   
   

   This requires another Why Series by itself, and in this series, I want to mainly focus on compensated patients. But there are multiple systematic reviews showing significant benefit of combination therapy over either alone.

How do we use NSBBs?

Here is a table from the guidelines discussing the dose and titration of NSBBs.

Key take aways from this table in my view are:

Propranolol is started at 20-40mg BID, nadolol is 20-40mg daily; we increase the dose every 2-3 days until HR goal is achieved (55-60) as long as the systolic blood pressure (SBP) remains above 90 mmHg. The maximum dose is different in patients with or without ascites.

Carvedilol is started at 6.25mg and can be increased to 12.5 mg daily (as long as SBP>90). Although carvedilol is sometimes used BID in clinical practice, 12.5 mg daily is the dose that was studied in the initial randomized trial (Tripathi et al) and is being further studied in 2 major ongoing trials (CALIBRE, BOPPP).

Now, NSBBs seem amazing, they decrease portal pressure! Can we use NSBBs to prevent formation of varices?

We saw that NSBBs decrease portal pressure, so in theory, by using this early on in patients with compensated cirrhosis, we might be able to prevent development of varices. This hypothesis led to a landmark study by Groszmann et al, published in NEJM in 2005. What were the results?

Interestingly it did not prevent formation of varices! To understand the reason why, when thinking about patients with compensated cirrhosis, it is important to know the different stages, as each stage has a different prognosis and goals of treatment.

What is CSPH? Clinically Significant Portal Hypertension (CSPH) is defined as HVPG ≥10 mm Hg via direct measurement. However, it can also be identified by noninvasive tests LS > 20‐25 kPa, alone or combined with platelet count and spleen size. Also, patients with portosystemic collaterals on imaging or varices (of any size) on endoscopy have CSPH.

Let’s think about the pathophysiology of portal HTN and the cascade of events that lead to an increase in portal pressure:

In early stages, the portal HTN is due to an increase in hepatic vascular resistance to blood flow through the liver, which happens both from changes in the liver architecture from fibrosis (structural component) and an increase in hepatic vascular tone (functional component). This is the main contributor to portal HTN in patients with mild portal HTN (stage 1).

As the disease progresses, there is a progressive splanchnic vasodilatation in response to increased hepatic vascular resistance, which results in increased portal inflow further worsening the portal HTN. The splanchnic vasodilation also leads to a decrease in effective arterial volume, activation of compensatory neurohormonal mechanisms, causing Na and water retention and plasma volume expansion, with a subsequent increase in cardiac output and a further increase in portal flow

The progressive splanchnic vasodilation and the hyperdynamic circulatory state (systemic vasodilation and increased CO), is a feature of compensated cirrhosis with CSPH, and that is where NSBBs can play a major role and attenuate the portal inflow by causing splanchnic vasocontraction and decreasing CO. In patients with only mild portal HTN who usually do not have the hyperdynamic circulation, NSBBs are not as effective. A study by Villanueva et al, nicely shows that propranolol resulted in much greater reduction in portal HTN in patients with CSPH compared to ones with only mild portal HTN (reduction of 16% vs 8%), and resulted in 20% reduction in baseline HVPG in 40% vs 13% of the patients. 

Now you can understand why the timolol trial was a negative study, as it included many patients with very early stages of cirrhosis and only mild portal hypertension (6<HVPG<10). These patients have not yet developed a hyperdynamic circulation and have normal cardiac index and thus the NSBBs are not as effective. 

So what about using NSBBs to prevent decompensation in patients with CSPH?

• Maybe the focus should be on patients who have CSPH and have developed the hyperdynamic circulation, as we know those are the ones that would benefit the most.
• And maybe in the future we should focus on preventing decompensation as an outcome, rather than formation of varices or variceal bleed.

If you are thinking about a trial that combined these 2 important points, you are on the right track! Tune in for more on this in part 2! We’ll discuss the PREDESCI trial.