Management of Overt HE Transcript

Management of Overt HE

Host: Christina J. Hanson, FNP, South Denver Gastroenterology
Featuring Sharon Magalona, FNP-BC, Reddy GI Associates

Welcome to Clinical Conversations: Management of Overt Hepatic Encephalopathy.

Christina Hanson and Sharon Magalona received payment from Salix Pharmaceuticals for their testimonies.

Christina: Hello, and thanks for tuning in to Clinical Conversations. I’m Christina Hanson, and today we’re going to be talking about an important topic—the management of overt hepatic encephalopathy in adults. Before we get into the discussion of management, I want to start by providing an overview of this disease.

Patients with cirrhosis can develop many complications due to impaired liver function. These can include portal hypertension, gastrointestinal bleeding, ascites, and hepatic encephalopathy, or HE. HE is a brain dysfunction that’s caused by liver insufficiency or portosystemic shunting and is one of the most common and debilitating complications of cirrhosis. Cognitive impairment in HE can range anywhere from seemingly normal cognitive performance, with no observable symptoms, to states of confusion, stupor, and even coma.

HE is classified based on the severity of symptoms. Patients with what we call covert HE may exhibit more subtle neurologic changes, like euphoria or anxiety, a trivial lack of awareness, short attention span, or altered sleep rhythms. Patients with what we call overt HE have more noticeable manifestations, such as pronounced personality and behavioral changes, confusion, gross disorientation, and in the most severe cases, coma.

It’s also important to mention how patients living with hepatic encephalopathy may need assistance from family members and caregivers. In this episode, we’ll be focusing on the management of overt HE. Sharon Magalona, a Nurse Practitioner with Reddy GI Associates in Arizona, is with me today, and she has a lot of experience in HE. Welcome, Sharon!

Sharon: I’m happy to join you, Christina.

Christina: Sharon, what else should we know about HE?

Sharon: I think it’s important to mention that overt HE can have significant consequences for patients compared with covert HE. Cognitive deficits can continue even after an episode of overt HE has resolved, and overt HE—we can call it OHE—is associated with high risk of recurrence. In fact, there’s a 40% cumulative risk that OHE will recur within 1 year of an initial episode. Hospital readmission rates are already high in patients with cirrhosis, and overt HE is a leading cause for repeated readmissions, which can be detrimental to patients, in addition to putting strain on their caregivers and on healthcare institutions.

Christina: Sharon, what’s your approach to care in patients with HE when you see them, either in the office or in a virtual setting? Because early detection is important, and patients may not present with the most obvious symptoms of OHE and may not even have a diagnosis. I should point out that up to 80% of patients with cirrhosis will develop HE—ranging from covert to overt—sometime during their clinical course. So, again, what’s your approach—what do you look for?

Sharon: First, I want to say that, when caring for patients with liver cirrhosis, assessing for HE needs to be a consideration in every visit.

When I have a patient with cirrhosis—whether or not they have an HE diagnosis—I always start by asking questions around awareness and orientation. Is this patient lethargic or responsive to me? If they have cirrhosis, I am on the lookout for HE.

I also think that it is beneficial to have the patient accompanied by their caregiver, who may be better able to recognize signs of HE. As you mentioned earlier, HE can affect memory and awareness. So, these patients might not have insight into their own condition and may not recognize that anything is wrong. They may be forgetting things. Their sleep pattern could have changed. Their personality could have changed, or their reactivity may have changed. In the mind of someone with HE, they may be the same person, but the caregiver may be able to pick up on these changes.

Sometimes, a patient will fall asleep during the visit. But I’ve also had times when the care provider was the one to say, “You know he’s really not himself. He’s irritable. He’s disoriented.” And the care provider or the caregiver can bring these things to our attention.

Christina: That’s a great point. I’ve asked patients, “Are you having any issues with memory? Have you noticed any changes in your personality? Has there been any forgetfulness? Have you been more sleepy?” And they answer “No.” But when you look at the spouse, they’re rolling their eyes and saying, “No, no, no. Not true.” They’re pulling you aside and saying, "Actually, this has really been an issue,” or “I’ve been noticing these other symptoms.” So, I think it does help to have a family member in the room to relay any symptom changes that the patient may not recognize.

Of course, it’s not always possible to have a caregiver present. If the caregiver is not there, I find that putting the questions into real-world context can help create a more accurate picture. For example, instead of asking “Are you confused?” I’ll ask them about attention and working memory during specific activities, like “What happens when you read a book? What happens when you’re having a conversation? Do you notice that you struggle to find your keys?”

Sharon: That’s a great idea. GastroHubAPP.com actually has a helpful tool that’s a symptom checklist. It includes several mental and physical symptoms of HE, like forgetfulness, inappropriate behavior, and changes in sleep patterns. Having the list helps patients and caregivers to look for and recognize these symptoms.

Christina: Right. That can be really useful, especially for those who have less experience with identifying these types of cognitive deficits.

Can you also talk about how liver insufficiency can lead to these cognitive deficits that are associated with HE?

Sharon: Well, the pathophysiology of HE is complex. It is thought to involve the accumulation of gut-derived toxins—like ammonia—in the body, as well as other factors like inflammation and oxidative stress. For people with cirrhosis or portosystemic shunting, the liver isn’t able to remove toxins from the blood like it does in healthy individuals. As a result, these toxins can then travel through the systemic circulation to the brain. These gut-derived toxins can cross the blood-brain barrier, and high blood levels of ammonia can result in altered brain function. Studies suggest that gut dysbiosis—or disruptions to the balance of bacteria that typically reside in the gut—is associated with HE. This suggests that gut microbiota may play a role in the pathophysiology of HE.

Christina: This is really interesting. In addition to correcting any precipitating factors, the goal for many therapies is to remove or reduce the level of toxins from systemic circulation.

Sharon: Exactly, and practice guidelines from the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver recommend that lactulose be used to help treat the acute episode of overt HE. These guidelines also recommend that lactulose be prescribed to help reduce the risk of recurrence following an episode of overt HE. Lactulose is thought to work by preventing absorption of ammonia into the blood, and it also helps facilitate excretion of ammonia byproducts from the colon.

However, the practice guidelines also raise points to keep in mind regarding lactulose monotherapy to reduce the risk of overt HE recurrence. Patients with recurrent overt HE have a 40% cumulative risk for another recurrence within 6 months of the previous episode—despite the lactulose treatments.

Christina: I’ve also found that there may be a lack of education among some patients that were prescribed lactulose after an episode of overt HE. They think it was prescribed for constipation and may not understand that they should be taking it long term to help reduce the risk of another overt HE episode. So, education is really important around that, and I think the same is true for XIFAXAN, which is also recommended in the guidelines as an add-on therapy to lactulose to reduce the risk of overt HE recurrence after a patient has a recurrence while on lactulose alone…and I want to talk more about why that is and why it’s important.

XIFAXAN 550 mg tablets are indicated for the reduction in risk of overt HE recurrence in adults. XIFAXAN is contraindicated in patients with a hypersensitivity to rifaximin, rifamycin antimicrobial agents, or any of the components in XIFAXAN. Hypersensitivity reactions have included exfoliative dermatitis, angioneurotic edema, and anaphylaxis.

So, for those who may not be familiar with XIFAXAN for patients with overt HE, I’ll briefly review how it is thought to work in these patients. XIFAXAN is an oral, nonsystemic antibiotic, and less than 1% is normally absorbed from the gut. This means that most of XIFAXAN doesn’t get into the bloodstream. It inhibits the growth of bacteria in the gut by blocking bacterial protein synthesis. XIFAXAN is thought to alter the microbiome, which may be associated with the production of the nitrogen-containing compounds implicated in the pathogenesis of HE.

Although XIFAXAN is minimally absorbed from the gastrointestinal tract, it is important to note that there is an increased systemic exposure in patients with severe hepatic impairment and caution should be exercised when administering XIFAXAN to these patients.

I mentioned that XIFAXAN is recommended in the guidelines—in addition to lactulose—to help reduce the risk of overt HE recurrence after a patient has a recurrence while on lactulose alone. In fact, the guidelines taskforce gave XIFAXAN their highest possible recommendation (which is a GRADE I,A,1 recommendation) based on high-quality evidence.

Understanding and being aware of guideline recommendations, and adhering to their recommendations, is important. Some providers may get “stuck in a rut” or only do what they have prior experience doing. But it’s so important to stay current and have access to the most up-to-date information. Sharon, I know you are a huge proponent of consulting guideline recommendations…maybe you can share some of the evidence behind these recommendations.

Sharon: In my opinion, it’s of extreme importance. Some days I’ll look at my caseload and think “I need to brush up on my guidelines!” I would say at least every couple of months I check to see if there’s anything new in the guidelines that I need to do or things that I’m doing currently that I need to correct.

As you mentioned, the guideline recommendations are based on high-quality evidence, which I think is important to cover, so I’ll walk you through this study. The efficacy and safety of XIFAXAN for the reduction in risk of overt HE recurrence in adults with a recent history of recurrent overt HE was assessed in a randomized, placebo-controlled, double-blind, multicenter, multinational, 6-month study. In this study, 299 adult patients* were randomized to receive XIFAXAN 550 mg twice daily (n=140) or placebo twice daily (n=159) for 6 months or until they had a breakthrough episode of HE or another reason.

91% of patients in each treatment group were taking concomitant lactulose therapy.

The primary endpoint for this study was the time to first breakthrough overt HE episode, which was defined as a marked deterioration in neurological function. This was defined as an increase in Conn score to grade 2 or more or, if the patient entered the study at grade 0, an increase in Conn score and asterixis grade of 1. HE-related hospitalization was a key secondary endpoint.

In this study, XIFAXAN cut the risk of overt HE recurrence and HE-related hospitalizations in half over the 6-month treatment period versus placebo. To be specific, the risk of overt HE recurrence was reduced by 58% versus placebo and the risk of HE-related hospitalizations by 50% versus placebo.

[XIFAXAN 550 mg twice daily significantly reduced the risk of overt HE recurrence in adults by 58% compared to placebo over the 6-month period (HR=0.42; 95% CI, 0.28-0.64; P<0.0001).

Breakthrough episodes of overt HE were reported in 22% of patients (31/140) who received XIFAXAN 550 mg twice daily and 46% of patients (73/159) who received placebo at 6 months.

XIFAXAN 550 mg twice daily significantly reduced the risk of HE-related hospitalizations in adults by 50% compared to placebo over the 6-month period (HR=0.50; 95% CI, 0.29-0.87; P=0.0129).

HE-related hospitalizations were reported in 14% of patients (19/140) who received XIFAXAN 550 mg and 23% of patients (36/159) who received placebo at 6 months.]

In this study, the most common adverse reactions occurring in greater than or equal to 10% of HE patients receiving XIFAXAN and at a higher rate than placebo included peripheral edema, nausea, dizziness, fatigue, and ascites. (91% of patients in each arm of the trial concomitantly used lactulose.)

*Inclusion criteria: Currently in remission (Conn score of 0 or 1) from HE and ≥2 episodes of HE associated with chronic liver disease in the previous 6 months.

Christina: It’s so important that we do our best to educate ourselves – and this includes making ourselves aware of what you just discussed: guideline recommendations, understanding the efficacy and safety of the medications we should consider prescribing for these patients. I have seen patients come out of the hospital after another overt HE recurrence while on lactulose alone, without a XIFAXAN prescription—despite the guideline recommendations. Or maybe they were started on XIFAXAN in the hospital to help reduce the risk of another OHE recurrence, but they see it’s an antibiotic and think “Oh, it’s an antibiotic. I was only supposed to take it for a little while,” or “It was the prescription they gave me in the hospital,” and once they run out, they don’t continue to take it even though their healthcare provider may have intended it for them to stay on therapy. So when you have a patient who’s been prescribed XIFAXAN from the hospital—or maybe the hospital didn’t prescribe it and you realize you need to get your patient started on it, what’s your approach? What do you discuss with the patient…or maybe their caregiver?

Sharon: Some patients have been told by their primary care doctor that, oh, XIFAXAN? It’s an antibiotic. Why are they giving it to you? That still comes up sometimes in my conversations with patients.

So, I like to talk to them and strongly recommend the addition of XIFAXAN to the lactulose regimen that they already have. And the guidelines also state that educating patients and caregivers should include a conversation around the effects of medication and potential side effects, the importance of adherence, as well as early signs of recurring OHE and what actions should patients take if this occurs. Another thing we talk about is that HE is a chronic condition, it is not going to go away. We talk about how there are good days and there are bad days for patients with chronic disease. However, clinical trial data showed that XIFAXAN can play an important role in helping to reduce the risk of recurring episodes of overt HE that may eventually put them in the hospital.

Christina: I think—especially after a patient has a history of overt HE—if you can educate them that these medications are prescribed to help reduce the risk of an episode happening again, that’s really important to help them piece things together. I would like to point out that Clostridium difficile-associated diarrhea has been reported with use of nearly all antibacterial agents, including XIFAXAN, and may range in severity from mild diarrhea to fatal colitis. If C. diff–associated diarrhea is suspected or confirmed, ongoing antibiotic use not directed against C. diff may need to be discontinued.

Sharon: This makes me think of a patient I have. She’s a 59-year-old woman with cirrhosis and overt HE and she takes lactulose and XIFAXAN. Prior to being prescribed XIFAXAN, however, she had been hospitalized a couple times for overt HE, which was becoming a big burden, especially for her husband, who was her caretaker. We started her on XIFAXAN 6 months ago, and I explained that XIFAXAN was shown in a clinical trial to help reduce the risk of overt HE recurrence and HE-related hospitalizations. I just saw her and her husband the other day and she hasn’t had a recurrence of overt HE. (Based on clinical trials in patients with overt HE, individual response to treatment with XIFAXAN may vary. The safety and efficacy of XIFAXAN in HE have not been studied beyond 6 months in randomized, placebo-controlled clinical trials.)

Christina: Wow. It really does show that, even though this is a chronic disease, if we can help reduce the risk of recurrent episodes of overt HE, it can really help these patients.

We should remember, though, that response to treatment with XIFAXAN may vary. Sharon, thank you so much for sharing some of your insights around managing overt HE and your experience with XIFAXAN. It’s been so great speaking with you today.

Sharon: It’s been my pleasure, Christina.

Christina: Now we’re going to review the indication and full important safety information for XIFAXAN.