Considerations for Using NOAC Reversal Agents

SEPTEMBER 20, 2018


Gary M. Besinque, PharmD, FCSHP; Jaime E. Murillo, MD; Juvairiya Pulicharam, MD; Ralph J. Riello III, PharmD, BCPS; and Peter Salgo, MD, discuss the availability and use of reversal agents for novel oral anticoagulant therapy. 

Peter Salgo, MD: Let’s talk about reversing it. Since we’re talking about bleeding, we’re talking about half-lives. The safety of a drug that has a shorter half-life is probably a rational consideration. Yet, somebody is going to bleed. You give any of these drugs, whether it’s Coumadin [warfarin] or one of these novel agents, and somebody is going to bleed somewhere. What does it mean to have a reversal agent available? 

Gary M. Besinque, PharmD, FCSHP: It’s a nice security blanket to have. But, in reality, it’s not used that often because, No. 1, Praxbind [idarucizumab] is indicated for life-threatening bleeds or emergency surgery. If you don’t know how long ago they took their last dose, you’ll probably be more likely to use the antidote. If they took it yesterday, you might have time to wait.

Peter Salgo, MD: OK. Does the fact that a reversal agent is available increase the acceptance of these NOACs [novel oral anticoagulants] among practitioners across the board, and patients?

Ralph J. Riello III, PharmD, BCPS: By all means, yes.

Gary M. Besinque, PharmD, FCSHP: Yes.

Juvairiya Pulicharam, MD: Like he said, it’s a security blanket. I think it’s important to know that there is a reversal agent because anything can happen at any time, right? If you are having a surgery, or have an emergency situation, I think it’s important to have a reversal agent.

Ralph J. Riello III, PharmD, BCPS: We monitor DOAC [direct oral anticoagulant] prescribing across our health system. Very clearly, we saw that the day that Pradaxa [dabigatran etexilate] had this reversal agent approved by the FDA [US Food and Drug Administration], dabigatran prescribing went up. The same thing happened when it was announced that andexanet alfa was approved. We saw prescribing increase, after that day, for both apixaban and rivaroxaban.

Jaime E. Murillo, MD: That’s interesting. I would argue that because the half-life is not as long as with Coumadin, for instance, and the likelihood of that emergent surgery or life-threatening event is low, you may use fresh frozen plasma, for instance. Can we do something like that? I would not prescribe a medication just because we have a reversal agent. I don’t think it should be the determining factor. 

Gary M. Besinque, PharmD, FCSHP: We determined the criteria for whether we pull the trigger or not for Praxbind. We can find out if we can determine when the last dose was taken. We want to know how well the patient is going to clear the anticoagulant. Then, we can figure out how much time we have before we have to, for instance, repair that femur fracture.

Peter Salgo, MD: It would occur to me, having seen more trauma than I care to have seen, that the problem is renal function. These guys bleed. They get angiograms. Suddenly, their creatinine goes to 5, and now you’re in cloud cuckoo land, with regard to these drugs. So, maybe it’s not unreasonable?

Jaime E. Murillo, MD: Good point.

Peter Salgo, MD: When you look at a reversal agent, what are you looking at? Is it accessibility? Is it ease of use? What are the factors that come to mind?

Ralph J. Riello III, PharmD, BCPS: A lot of things go into considering adding a reversal agent to formulary. It’s far more than complex than anyone ever imagined. 

Peter Salgo, MD: Why is that?

Ralph J. Riello III, PharmD, BCPS: It’s going to be part of our protocol. There needs to be a policy and procedure and a whole response team, basically, for when a life-threatening bleed with 1 of these 2 agents that it’s approved for comes to the hospital. We have to have the resources to compound that drug and bring it to the patient’s bedside in under 15 minutes.

Peter Salgo, MD: Tell me about the ease of use. There’s reconstitution here, I’m told. I’ve never used it. You’ve got to consider the number of vials that you’ve got to mix up. What do these different drugs look like?

Ralph J. Riello III, PharmD, BCPS: The compounding can be cumbersome. You need to have a sterile USP 797-compliant room, and you need to be able to turn that around quickly. The rationale is that you’re using it for a fatal bleed, and you need to reverse that drug now. It can be a little bit cumbersome compounding it. Of course, that’s going to add time to delivery and turnaround. But, it’s a continuous infusion. Usually, a high-dose bolus is given upfront, followed by the continuous infusion for about 6 to 12 hours after. How that’s going to handle the patient definitely determines what bleed is going on and what other supportive care we can provide at the same time.

Peter Salgo, MD: I want to ask a bit more about cost, but I want to go back to something that you mentioned—fresh frozen plasma. I would assume cryoprecipitate, factor VII? I don’t know if factor VII really works. Couldn’t you just use the old-fashioned stuff? 

Gary M. Besinque, PharmD, FCSHP: What if they have heart failure?

Peter Salgo, MD: Yes. What if they have heart failure? Add Lasix [furosemide] and keep going.

Ralph J. Riello III, PharmD, BCPS: I think we alluded to this earlier. Tincture of time is a pretty effective reversal agent for a lot of the direct anticoagulants because of their short half-life. It’s really only in times of acute kidney injury and the drugs—maybe they weren’t held during that time—where we do begin to worry about accumulation.

Jaime E. Murillo, MD: It’s amazing how fast they work. Within 5 minutes, 92% of the activity is already...

Peter Salgo, MD: When you say they, you mean the reversal?

Jaime E. Murillo, MD: Yes, the reversal.

Peter Salgo, MD: We’ve got 2 out there, right? There’s idarucizumab. How much does that cost? Compare that with coagulation factor Xa. What are we talking about here?

Ralph J. Riello III, PharmD, BCPS: It’s about $3500 per treatment of Praxbind. We actually have a unique kind of payment program where we have a vial sitting in our intravenous room and it’s on consignment. We only pay for it once we use it. The thought is that patients on DOACs tend to bleed a lot less. So, it’s less attractive for pharmacy departments to keep an expensive vial hanging around just for it to expire. Rather, you pay on administration, which is a pretty unique pathway to take.

Peter Salgo, MD: And the other one—the coagulation factor Xa [recombinant], inactivated-zhzo? That’s a lot more.

Ralph J. Riello III, PharmD, BCPS: It is. Depending on the intensity of the treatment needed, it could be anywhere between about $25,000 to $50,000...
Peter Salgo, MD:I’m sorry, my hearing is gone. I thought you said $25,000 to $50,000. That couldn’t be right.

Ralph J. Riello III, PharmD, BCPS: I did, and it is right. When you look at the data, andexanet alfa has nearly the best mortality data for intracranial hemorrhage. So, they felt that this product really brought something new to the market. Because it’s kind of a promiscuous antidote, it can reverse edoxaban. It can reverse apixaban and rivaroxaban. It’s a whole host of Xa-inhibiting medications that you don’t get the benefit of by just using Pradaxa, which is only reversed by Praxbind.

Gary M. Besinque, PharmD, FCSHP: Right. I want to clarify, though, that the on-label dose, the on-label andexanet alfa, is only FDA approved for Eliquis [apixaban] and Xarelto [rivaroxaban].

Ralph J. Riello III, PharmD, BCPS: And I’m sure that’s all we’ll ever use it for.

 


Gary M. Besinque, PharmD, FCSHP; Jaime E. Murillo, MD; Juvairiya Pulicharam, MD; Ralph J. Riello III, PharmD, BCPS; and Peter Salgo, MD, discuss the availability and use of reversal agents for novel oral anticoagulant therapy. 

Peter Salgo, MD: Let’s talk about reversing it. Since we’re talking about bleeding, we’re talking about half-lives. The safety of a drug that has a shorter half-life is probably a rational consideration. Yet, somebody is going to bleed. You give any of these drugs, whether it’s Coumadin [warfarin] or one of these novel agents, and somebody is going to bleed somewhere. What does it mean to have a reversal agent available? 

Gary M. Besinque, PharmD, FCSHP: It’s a nice security blanket to have. But, in reality, it’s not used that often because, No. 1, Praxbind [idarucizumab] is indicated for life-threatening bleeds or emergency surgery. If you don’t know how long ago they took their last dose, you’ll probably be more likely to use the antidote. If they took it yesterday, you might have time to wait.

Peter Salgo, MD: OK. Does the fact that a reversal agent is available increase the acceptance of these NOACs [novel oral anticoagulants] among practitioners across the board, and patients?

Ralph J. Riello III, PharmD, BCPS: By all means, yes.

Gary M. Besinque, PharmD, FCSHP: Yes.

Juvairiya Pulicharam, MD: Like he said, it’s a security blanket. I think it’s important to know that there is a reversal agent because anything can happen at any time, right? If you are having a surgery, or have an emergency situation, I think it’s important to have a reversal agent.

Ralph J. Riello III, PharmD, BCPS: We monitor DOAC [direct oral anticoagulant] prescribing across our health system. Very clearly, we saw that the day that Pradaxa [dabigatran etexilate] had this reversal agent approved by the FDA [US Food and Drug Administration], dabigatran prescribing went up. The same thing happened when it was announced that andexanet alfa was approved. We saw prescribing increase, after that day, for both apixaban and rivaroxaban.

Jaime E. Murillo, MD: That’s interesting. I would argue that because the half-life is not as long as with Coumadin, for instance, and the likelihood of that emergent surgery or life-threatening event is low, you may use fresh frozen plasma, for instance. Can we do something like that? I would not prescribe a medication just because we have a reversal agent. I don’t think it should be the determining factor. 

Gary M. Besinque, PharmD, FCSHP: We determined the criteria for whether we pull the trigger or not for Praxbind. We can find out if we can determine when the last dose was taken. We want to know how well the patient is going to clear the anticoagulant. Then, we can figure out how much time we have before we have to, for instance, repair that femur fracture.

Peter Salgo, MD: It would occur to me, having seen more trauma than I care to have seen, that the problem is renal function. These guys bleed. They get angiograms. Suddenly, their creatinine goes to 5, and now you’re in cloud cuckoo land, with regard to these drugs. So, maybe it’s not unreasonable?

Jaime E. Murillo, MD: Good point.

Peter Salgo, MD: When you look at a reversal agent, what are you looking at? Is it accessibility? Is it ease of use? What are the factors that come to mind?

Ralph J. Riello III, PharmD, BCPS: A lot of things go into considering adding a reversal agent to formulary. It’s far more than complex than anyone ever imagined. 

Peter Salgo, MD: Why is that?

Ralph J. Riello III, PharmD, BCPS: It’s going to be part of our protocol. There needs to be a policy and procedure and a whole response team, basically, for when a life-threatening bleed with 1 of these 2 agents that it’s approved for comes to the hospital. We have to have the resources to compound that drug and bring it to the patient’s bedside in under 15 minutes.

Peter Salgo, MD: Tell me about the ease of use. There’s reconstitution here, I’m told. I’ve never used it. You’ve got to consider the number of vials that you’ve got to mix up. What do these different drugs look like?

Ralph J. Riello III, PharmD, BCPS: The compounding can be cumbersome. You need to have a sterile USP 797-compliant room, and you need to be able to turn that around quickly. The rationale is that you’re using it for a fatal bleed, and you need to reverse that drug now. It can be a little bit cumbersome compounding it. Of course, that’s going to add time to delivery and turnaround. But, it’s a continuous infusion. Usually, a high-dose bolus is given upfront, followed by the continuous infusion for about 6 to 12 hours after. How that’s going to handle the patient definitely determines what bleed is going on and what other supportive care we can provide at the same time.

Peter Salgo, MD: I want to ask a bit more about cost, but I want to go back to something that you mentioned—fresh frozen plasma. I would assume cryoprecipitate, factor VII? I don’t know if factor VII really works. Couldn’t you just use the old-fashioned stuff? 

Gary M. Besinque, PharmD, FCSHP: What if they have heart failure?

Peter Salgo, MD: Yes. What if they have heart failure? Add Lasix [furosemide] and keep going.

Ralph J. Riello III, PharmD, BCPS: I think we alluded to this earlier. Tincture of time is a pretty effective reversal agent for a lot of the direct anticoagulants because of their short half-life. It’s really only in times of acute kidney injury and the drugs—maybe they weren’t held during that time—where we do begin to worry about accumulation.

Jaime E. Murillo, MD: It’s amazing how fast they work. Within 5 minutes, 92% of the activity is already...

Peter Salgo, MD: When you say they, you mean the reversal?

Jaime E. Murillo, MD: Yes, the reversal.

Peter Salgo, MD: We’ve got 2 out there, right? There’s idarucizumab. How much does that cost? Compare that with coagulation factor Xa. What are we talking about here?

Ralph J. Riello III, PharmD, BCPS: It’s about $3500 per treatment of Praxbind. We actually have a unique kind of payment program where we have a vial sitting in our intravenous room and it’s on consignment. We only pay for it once we use it. The thought is that patients on DOACs tend to bleed a lot less. So, it’s less attractive for pharmacy departments to keep an expensive vial hanging around just for it to expire. Rather, you pay on administration, which is a pretty unique pathway to take.

Peter Salgo, MD: And the other one—the coagulation factor Xa [recombinant], inactivated-zhzo? That’s a lot more.

Ralph J. Riello III, PharmD, BCPS: It is. Depending on the intensity of the treatment needed, it could be anywhere between about $25,000 to $50,000...
Peter Salgo, MD:I’m sorry, my hearing is gone. I thought you said $25,000 to $50,000. That couldn’t be right.

Ralph J. Riello III, PharmD, BCPS: I did, and it is right. When you look at the data, andexanet alfa has nearly the best mortality data for intracranial hemorrhage. So, they felt that this product really brought something new to the market. Because it’s kind of a promiscuous antidote, it can reverse edoxaban. It can reverse apixaban and rivaroxaban. It’s a whole host of Xa-inhibiting medications that you don’t get the benefit of by just using Pradaxa, which is only reversed by Praxbind.

Gary M. Besinque, PharmD, FCSHP: Right. I want to clarify, though, that the on-label dose, the on-label andexanet alfa, is only FDA approved for Eliquis [apixaban] and Xarelto [rivaroxaban].

Ralph J. Riello III, PharmD, BCPS: And I’m sure that’s all we’ll ever use it for.

 
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