Episode 64- What happens when we give Kcentra to patients with liver failure?

Hello and welcome to Episode 64 of ER-Rx. Last week, we talked about how we shouldn’t use the INR as the sole measure of a patient’s bleeding risk in the setting of acute and chronic liver failure. We also mentioned that we shouldn’t routinely “correct” values like the PT or INR to try to control or prevent bleeding in these patients. This week, we’re gonna look at two studies that laid out their experiences with what happens when you give four-factor prothrombin complex concentrate (4F-PCC) in the setting of liver failure.

4F-PCCs, in our case I’ll use Kcentra, contain nonactivated vitamin K-dependent clotting factors along with anticoagulant proteins C and S. In the United States, Kcentra was approved in 2013 for the urgent reversal of bleeding in patients taking vitamin K antagonists such as warfarin. Kcentra together with vitamin K is recommended as a substitute for fresh frozen plasma (FFP) for warfarin-associated major bleeding given its lower risk of allergic reactions and infection, shorter preparation and infusion times, and lower infusion volumes.

As we discussed in Episode 63, patients with liver failure also have decreased vitamin K-dependent clotting factors, and they often present with elevated INRs- making them an attractive, although misguided, target for getting Kcentra. We now know that in these patients, coagulation is a very intricate process and that the INR does little to tell us exactly what’s going on with their hemostasis. But what if you didn’t know this or just didn’t care? What if you saw an elevated INR in a bleeding patient with liver failure, assumed they had a higher risk of new or continued bleeding, and gave them Kcentra?

Before we get to the more recent study and the topic of this week’s Fresh Fruit series, let’s look at an older retrospective study from 2017, where they wanted to compare patients with liver failure who got Kcentra to those without liver failure who got Kcentra. The patients got Kcentra based on the package insert dosing of 25-50 units/kg if it was given to reverse bleeding and only 500 units if it was given to nonbleeding patients as reversal prior to surgical procedures. The primary outcome was coagulopathy reversal, defined as a post-Kcentra INR of This study included 31 patients with acute or chronic liver failure and 54 patients without liver failure. Both groups of patients were similar at baseline, except those that had liver failure were younger (58 vs 70 years, P < 0.01). The baseline INR was similar between groups, with a median of 2.8 in patients with liver failure and 2.6 in patients without (P =0.65). Also, about 15% of patients with liver failure were actually taking warfarin or a DOAC, but the rest of them weren’t on any anticoagulation.

So, what happened? Only 6 patients (19%) with liver failure achieved the primary outcome of an INR Clinically, significantly less patients with liver failure achieved protocol-defined hemostasis as compared to those without liver failure (19% vs 43%, P= 0.03). Patients with liver failure had significantly longer ICU (8 days vs 3 days, P <0.01) and hospital lengths of stay (20 days vs 7 days, P <0.01). And the worst part; they had significantly higher in-hospital mortality rates at 52 % vs 18 % (P < 0.01). The good news was that safety events were rare, with only 1 patient with liver failure and 8 without developing a clot. All of this stayed basically the same when they did a subgroup analysis excluding patients who received the low fixed dose of Kcentra prior to surgical procedures.

More recently in 2021, a group of authors led by Dr. Small wanted to compare the effects of giving Kcentra to patients with intracranial hemorrhage (ICH) in the setting of cirrhosis in patients who were not on anticoagulation. This was another single-center, retrospective study in an academic, level I trauma center. Unlike the previous study, this study excluded patients who received Kcentra prior to surgical procedures. The primary outcome here was rate of ICH expansion within 24 hours as determined by CT scan.

This study included 21 cirrhotic patients who received Kcentra and 37 cirrhotic patients who did not receive Kcentra (the “standard of care group”). Baseline characteristics were similar with respect to APACHE II and MELD scores. Patients who received Kcentra had significantly higher median INR values at baseline (1.7 vs 1.4, P =0.001) and they were more likely to require surgical intervention (38% vs 11%, P =0.02).

They found that the primary outcome of ICH expansion within 24 hours was still similar between groups, with stable head CTs achieved in 68% of those who received Kcentra versus 73% of those who didn’t (P =0.11). The good news was that patients who got Kcentra had a greater change in their INR within 24 hours (but it was a very small reduction of -0.2 vs no change in INR the standard of care group, P =0.02). The bad news was that the patients that received Kcentra again had significantly higher mortality rates (62% vs 19%, P =0.001). And like the first study, only 1 patient that received Kcentra had a clotting event (vs 0% in the standard of care group, P=0.36).

Of course, there are some confounders here. Patients who got Kcentra may have been sicker, given more of them had Child-Pugh Class C liver disease, had higher baseline INRs, and more often needed surgical intervention. But again, this is a largely negative trial showing minimal benefit of giving Kcentra to these patients.

In conclusion, although there is no consensus for how to correct coagulopathy in the setting of liver failure in patients not on anticoagulation, it seems that just throwing Kcentra at them as a knee-jerk reaction probably isn’t the best way to go. It looks like most patients don’t reach a goal INR reduction or hemostasis as defined by clinical measures or CT scans. INR reductions are minimal and they definitely aren’t reduced by the magnitude we’re used to seeing when simply reversing someone on warfarin. In this setting, it appears that we can expect only a 0.2 – 0.5 absolute reduction in the INR. And worst of all, studies like the two discussed today show higher mortality rates and LOS- which we have to consider despite some confounders.

But to be fair, there is a lot of gray in medicine, and we do have to say that there may be a select group of cirrhotic patients with life-threatening bleeds that it would be reasonable to give Kcentra to, as long as we weigh the risks, benefits, and costs. It’s important to note that there are studies, mostly case reports and case series, that have shown Kcentra to be useful in this setting. And another positive; it seems that clotting events in these two studies were rare.

Personally, I’m leaning towards not recommending the routine use of Kcentra to reverse bleeding in patients who have elevated INRs simply because they have liver failure. To me, the evidence just isn’t there- and most of the evidence we do have tells us that Kcentra does little to the numerical value of the INR, leads to almost no clinical improvements, and comes with numerous risks and heavy costs in this patient population.

As always, thank you so much for your time. Don’t forget to check out the website, errxpodcast.com- where you can listen to all of the episodes, read the key points, and review my references.