Episode 78- “If it ain’t broke…”: Fixed versus variable Kcentra dosing

Hello and welcome to Episode 78 of ER-Rx- a podcast tailored to your clinical needs. I’m your host, Adis Keric, and I feel great about this week’s episode because we’ll be reviewing a study published out of my site by a few of my colleagues. This study isn’t as “fresh” as most of the other study reviews I usually bring on the show, but I wanted to do a couple of episodes about Kcentra and I figured this would be a great place to start. This article was published in the American Journal of Emergency Medicine back in May of 2021 and is entitled; “Evaluation of fixed versus variable dosing of 4-factor prothrombin complex concentrate for emergent warfarin reversal.” The lead authors include Dr. Zach Stoecker who was my preceptor in the ED when I was a first- and second-year resident and Dr. Brandon Van Amber- who was my co-resident during PGY1 year, and this was actually his residency research project at the time. It’s been really fun following the progress of this study through things like the Midwest Pharmacy Residents Conference to publication in a major medical journal – so congrats to these guys on getting it done.

Despite the wide use of Kcentra since its approval in 2013, we’re still trying to figure out its optimal dosing strategy. We’re all familiar with the FDA-approved variable-dose scheme which is based on pretreatment INR and body weight (INR 2 – <4: 25 IU/kg, INR 4-6: 35 IU/kg, INR >6: 50 IU/kg), but there’s been a good number of studies looking to use lower, fixed doses that differ from the approved dosing scheme. Besides attempting to maximize efficacy and minimize adverse events, using a fixed-dose strategy could also help cut the out-of-control healthcare costs we have and reduce time to administration. For example, previous trials showed that using a fixed-dose strategy could reduce time from order to administration by 13 minutes (51 min vs 38 min) and save almost $1,000 per patient.

The study I’m discussing today is a single-center, prospective, open-label, randomized, controlled trial that compared a fixed 1,500 IU dose of Kcentra with the FDA-approved variable dosing scheme in patients on warfarin. The primary outcome, “reversal success,” was defined as a laboratory-confirmed INR of 1.5 to receive that extra dose. They also looked at costs ($1.57/ unit at the time) of each dosing strategy and clotting events within 7 days.

They enrolled adults 18 years and older who had an INR >/= 2 who were eligible to receive Kcentra based on our institution’s protocol. They ran the study over a period of 25 months and ended it earlier than their planned 100 patients given slow enrollment. They finally ended up with 71 patients; 34 in the fixed-dose group and 37 in the variable-dose group- with no differences in patient characteristics including age, weight, initial INR, or indication for reversal between the groups. There were 21 cases of “reversal success” in the fixed-dose group versus 33 cases of success in the variable-dose group- with a significantly greater rate of reversal in the variable-dose group (62% vs 89% p = 0.011). A sensitivity analysis found that the difference in the rate of successful reversal decreased as the initial INR increased for those in the fixed-dose group compared to the variable-dose group. There were no clotting events noted within 7 days in either group, but cost of medication was significantly higher in the variable-dose group compared to the fixed-dose group (median $3,372 vs $2,524, p < 0.0001).

This study did have a few limitations—one of which was that they chose the primary outcome of achieving a specific and pretty conservative goal INR 100 kg, lowering external validity to countries with lower obesity rates and likely affecting efficacy of reversal, since reversing INRs has been shown to be harder in obese patients. They also had to stop the study early and before reaching their goal of 100 patients, which affected their final analysis.

In conclusion, this study found that a 1,500 unit, fixed-dose strategy for reversing warfarin-induced bleeding was not as effective in reaching an INR target of As always, thank you so much for your time, and thank you for wanting to learn more about pharmacotherapy. What do you guys think? Does your site have a fixed-dosing Kcentra protocol for warfarin or DOAC reversal? I’d love to hear your thoughts- please leave a comment on the @errxpodcast Instagram page or on errxpodcast.com. Stay tuned for next week’s episode where I discuss my site’s Kcentra protocol and how the implementation of that protocol into the EPIC system led to a lot less inappropriate and contraindicated use and less waste.