Welcome to ReachMD. This medical industry feature, titled “Evaluating Strategies for Warfarin Reversal” is sponsored by CSL Behring. This program is intended for physicians.
Here’s your host, Dr. Jennifer Caudle.
Bleeding is the most common complication of anticoagulant use. And to better care for patients either experiencing acute bleeding or urgently needing surgery, it's critical that clinicians thoroughly understand how to assess, treat, and reverse anticoagulation. And with various treatment strategies in consideration, let's take a closer look at the pros and cons of some of the treatment options specific to warfarin.
This is ReachMD, and I'm your host, Dr. Jennifer Caudle. Joining me to explore the various warfarin reversal strategies is Dr. Aryeh Shander, a critical care medicine specialist at Inglewood Hospital and Medical Center in Englewood, New Jersey. He's an adjunct clinical professor of anesthesiology, medicine, and surgery at Icahn School of Medicine at Mount Sinai, New York. And he's also a courtesy clinical professor at the University of Florida College of Medicine and a clinical professor of anesthesiology and critical care at Rutgers Medical School in New Jersey. Dr. Shander, welcome to the program.
Thank you so much, Dr. Caudle. It's a pleasure being here and I’m looking forward to your questions.
Before we begin, let's review some important safety information.
Kcentra®, Prothrombin Complex Concentrate (Human), is a blood coagulation factor replacement product indicated for the urgent reversal of acquired coagulation factor deficiency induced by Vitamin K antagonist (VKA–eg, warfarin) therapy in adult patients with acute major bleeding or the need for urgent surgery or other invasive procedure. Kcentra is for intravenous use only.
Stay tuned for the complete Important Safety Information for Kcentra throughout this podcast.
Now that we have that understanding, let's get into our discussion for today. Dr. Shander, with so many anticoagulation treatments available, can you talk us through some of the different anticoagulation reversal strategies?
Thank you, Dr. Caudle. This is a good question. But before we start answering it, we need to understand the difference between reversal and actual replacement of clotting factors. Keeping in mind that these are a little different. When we talk about vitamin K antagonist, what we're doing is actually replacing clotting factors, whether it be plasma, or PCC and expecting that to reverse the effect of this particular anticoagulant. The categories include vitamin K antagonist, factor Xa inhibitors, and direct thrombin inhibitors. And last, we cannot forget heparin and the heparinoids, again, can be reversed with protamine, which binds them.
Now, getting more specific here with warfarin, Dr. Shander. Can you give us a brief overview of warfarin’s mechanism of action?
Yes. And I think it's very important to understand warfarin action. So, warfarin essentially inhibits the synthesis of vitamin K dependent clotting factors, which include II, VII, IX and X. In addition, though, it also inhibits the anticoagulants which are called protein C and protein S, which again, they're fleeting but very potent anticoagulants. In fact, when we start patients on warfarin, the first thing that happens is they become procoagulant because the effect of the anticoagulants of protein S and protein C are again inhibited. So, we need to bridge these patients, usually with a heparinoid, until the anticoagulant effect of vitamin K antagonist takes its effect.
Thanks for sharing that overview with us. Well, under which circumstances should we consider urgently reversing warfarin?
So, we need to understand that the number one adverse event of any anticoagulation is bleeding, and the bleeding can be severe. The acute bleeding in patients clearly becomes an issue, especially if they're bleeding into a closed space, such as an intracranial hemorrhage. The other, of course is in acute GI bleed. And when these two bleeds occur, it adds to the mortality of patients, especially if they're on anticoagulants whether it be vitamin K or others. So, we're seeing a prevalence of somewhere between 30 to 60% of patients who are on vitamin K antagonist with GI bleeds. And we also see those individuals who have an intracranial hemorrhage, who bleed have the mortality increases by twice the mortality that we see with patients who are not on anticoagulants. So, the two urgent areas include acute bleeding, as I just mentioned. But the other is, if we need to do an intervention, which is an invasive one, such as urgent surgery or a procedure that could be invasive with a risk of bleeding.
And as a follow up to that, given the need for urgent reversal of warfarin, Dr. Shander, what are some factors we should consider when selecting an agent for warfarin reversal?
So, I think things that we need to consider each time we look at the patient who is on an anticoagulant and is bleeding, is the type and the extent of bleeding. Clearly, there may be some minor bleeding, which may not require either the reversal or the replacement of the anticoagulant factors. Again, we have guidelines and recommendations that have to be considered in terms of severe bleeding, whether it be intracranial or GI bleeding. And one of the things that we need to do is to also test to see whether there is an endpoint that we want to achieve, including one which is an INR. And if we can normalize the INR or get it close to normal again, we may achieve a laboratory indicator in terms of considering the reversal of an anticoagulant. And lastly, of course, is the cost. The cost has to include all of the blood components that we usually support patients while they're having a significant bleed, including other things such as medications as well, as the cost of a prothrombin complex concentrate.
For those of you who are just tuning in, you're listening to ReachMD. I'm your host, Dr. Jennifer Caudle, and today I'm speaking with Dr. Aryeh Shander about some of the different considerations we should take into account when selecting a warfarin reversal option.
Before we continue our conversation, let's review some additional important safety information for Kcentra.
WARNING: ARTERIAL AND VENOUS THROMBOEMBOLIC COMPLICATIONS
Patients being treated with Vitamin K antagonist therapy have underlying disease states that predispose them to thromboembolic events. Potential benefits of reversing VKA should be weighed against the risk of thromboembolic events, especially in patients with history of such events. Resumption of anticoagulation therapy should be carefully considered once the risk of thromboembolic events outweighs the risk of acute bleeding. Both fatal and nonfatal arterial and venous thromboembolic complications have been reported in clinical trials and postmarketing surveillance. Monitor patients receiving Kcentra and inform them of signs and symptoms of thromboembolic events. Kcentra was not studied in subjects who had a thromboembolic event, myocardial infarction, disseminated intravascular coagulation, cerebral vascular accident, transient ischemic attack, unstable angina pectoris, or severe peripheral vascular disease within the prior 3 months. Kcentra might not be suitable for patients with thromboembolic events in the prior 3 months.
So, Dr. Shander, let's focus on the current warfarin reversal treatment options and the pros and cons of each. As we know, one of the options for warfarin reversal is plasma, and while plasma is generally safe to administer, it's often associated with risks and challenges. Can you share a few with us?
Absolutely, Dr. Caudle. I think that first and foremost, we need to know that the U.S. is the number one user of plasma across the globe. In addition to that, there is a considerable variability from one unit to the next in terms of the amount of clotting factors which are contained in that unit. In addition to that, as we all know, plasma is kept frozen and needs to be thawed before its use which takes time as well as managing that. Plasma also needs to be ABO compatible, so the blood group must be specific, and again, that may delay administration. What is unknown to many clinicians is that plasma actually has a dose per kilo, that is mL per kilo, anywhere from 10 to 15 to as high as 30 mL per kilo. And as such, when you do your calculations to get plasma into the patient, you're dealing with a considerable amount of volume that gets infused. And in addition to the volume, which may have some cardiovascular impact, there are also clearly risks associated with plasma. The main ones, of course, are pulmonary complications, which include TRALI, which is a transfusion related acute lung injury, as well as transfusion associated circulatory overload. Both are not easy to treat and have a significant morbidity and mortality with that. And again all of these sum up to have a substantial healthcare burden.
Another warfarin reversal option is prothrombin complex concentrate or PCC. How does this option compare to plasma?
So, when we look at comparison of PCC or prothrombin complex concentrate, such as Kcentra versus plasma, we know that PCC is highly concentrated and therefore the volume is significantly reduced. Again, as mentioned, we replenish all the factors that are inhibited, such as II, VII, IX and X, as well as protein S and proteins C without delivering large intravascular volume loads as compared to plasma. So that is no longer a concern, especially in the patients who are in anticoagulated and have complications, they’re usually of advanced age and cannot tolerate large volume. And in the meta-analysis, that was published we saw that PCC was favored over fresh frozen plasma both in terms of volume associated as well as in terms of its reversal of laboratory values such as INR. And this is done again with a lower volume.
And what do the different guidelines say about the use of PCC over plasma to reverse the effects of warfarin?
What we've seen over time is that many professional organizations have moved PCC to first line therapy in terms of “reversal” of vitamin K antagonists as compared to plasma. We go to the Neurocritical Care Society, which deals with intracranial hemorrhage and other closed space neural bleeding. The Society of Critical Care Medicine, which deals with patients in the intensive care unit and GI bleeding. Those have moved PCC to the front line as compared to plasma.
The American College of CHEST Physician and their CHEST guideline publication again put PCC as front line versus plasma. The American Society of Gastroenterologist Endoscopists has also done the same. And there are few other organizations or professional organizations that have moved PCC to front line as compared to the use of plasma for the treatment or reversal of vitamin K antagonists. In addition to that, the circular of information which accompanies any biologic, any pharmaceutical, and device, this one for plasma, was jointly prepared by the American Associational Blood Bank, the American Red Cross Blood Services, America's Blood Centers, and the Armed Forces blood programs. And the FDA recognizes this as an acceptable extension of their package insert or container label.
What it indicates that it's contraindicated to use plasma for the correction of coagulopathy associated with warfarin, and instead recommends other agents such as PCC for warfarin reversal.
Before we close Dr. Shander. Can you elaborate on the benefits of Kcentra?
Absolutely. I think we can make the case for Kcentra. This is the only FDA approved alternative to plasma for urgent reversal of warfarin in adults with acute major bleeding or those who need either urgent surgery or an invasive procedure who are on anticoagulation with warfarin or vitamin K antagonist, as we call it. We've demonstrated with PCC that it is a faster reduction in INR, which is sustained over the time that the two were compared, plasma and PCC, which is about 24 hours. There's a faster time to the procedure, whether it be surgery or invasive procedure, because the reversal is much quicker demonstrated by a laboratory measure of INR. And there's a faster administration because it takes less time. That has two impacts, again, the less volume it takes less time to infuse, and there's less issues associated with the volume overload that we talked about before. And we can get the effect much quicker because the volume of PCC is so much smaller. And we also know that PCC has a very effective homeostatic effect compared with plasma in terms of stopping the bleeding and reversing the effect of vitamin K antagonists.
Well, with those thoughts in mind, I'd like to thank my guest, Dr. Aryeh Shander, for helping us better understand the importance of urgent warfarin reversal and the current treatment strategies available to help address this issue. Dr. Shander, it was great having you on the program today.
Thank you so much, Dr. Caudle, and thank you for your insightful questions.
I'm Dr. Jennifer Caudle, and before we close, let's take a moment to review additional important safety information.
Kcentra is contraindicated in patients with known anaphylactic or severe systemic reactions to Kcentra or any of its components (including heparin, Factors II, VII, IX, X, Proteins C and S, Antithrombin III and human albumin). Kcentra is also contraindicated in patients with disseminated intravascular coagulation. Because Kcentra contains heparin, it is contraindicated in patients with heparin-induced thrombocytopenia (HIT).
Hypersensitivity reactions to Kcentra may occur. If patient experiences severe allergic or anaphylactic type reactions, discontinue administration and institute appropriate treatment.
In clinical trials, the most frequent (≥2.8%) adverse reactions observed in subjects receiving Kcentra were headache, nausea/vomiting, hypotension, and anemia. The most serious adverse reactions were thromboembolic events, including stroke, pulmonary embolism and deep vein thrombosis.
Kcentra is derived from human plasma. The risk of transmission of infectious agents, including viruses and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent and its variant (vCJD), cannot be completely eliminated.
This program was sponsored by CSL Behring. If you missed any part of this discussion, visit reach-m-d-dot-com-slash-industry-feature. This is ReachMD. Be Part of the Knowledge.
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