Best Practices for the Treatment of Hemophilia - Episode 7
Practice Pearl 2: Administration Concerns, Costs, and Risks
Panelists review the contraindication with emicizumab and aPCC.
- Practice Pearl 2: Determining the Role of Factor VIII
- Practice Pearl 2: Patient Factors for Other Treatments
Luigi Brunetti, PharmD, MPH: I remember when the HAVEN studies were coming out, some patients developed more severe complications, whether that would be thrombosis or TMA [thrombotic microangiopathy], and that was related to aPCC [activated prothrombin complex concentrate] administration. So that, of course, is something we need to consider. And in fact, if you have someone with inhibitors, they may be on aPCC.
Robert F. Sidonio, Jr, MD: Correct.
Luigi Brunetti, PharmD, MPH: That's something we need to be cognizant of when we're transitioning. When transitioning with someone who's on aPCC, how do you transition them over to Hemlibra [emicizumab] to reduce the risk of that adverse effect?
Giles Slocum, PharmD: The formal recommendation, the package insert, is when you're starting the 3 mg/kg once weekly for 4 weeks, if you're on aPCC right up to it, the day before you would start your injection is the formal recommendation for starting your bolus—or your load, if you will—of emicizumab.
Luigi Brunetti, PharmD, MPH: Yes, and I think that's an important point, and something that we probably need to make sure we do. We should encourage our clinicians that, "Hey, don't rush." And of course, is that recommendation the same if they don't have inhibitors if they're on a factor VIII product concentrate? Do you still have to hold the factor VIII for 24 hours, or is it not essential to do that?
Giles Slocum, PharmD: With this, great question, we do have a little bit more flexibility with this so it does stray from the activated PCC. You'll see anywhere between 1 to 2 weeks. I'm not sure what you do at your HTC [hemophilia treatment center]. Allowing emicizumab to get to steady state, it takes about that full 28 days. But there is a little bit of a lag effect, so I'm watching both of those pharmacokinetic curves taking place.
Luigi Brunetti, PharmD, MPH: I guess it depends on the bleeding risk of the patient as well.
Robert F. Sidonio, Jr, MD: Yes, and you have to remember, on the trial they had to stop factor VIII within a few days of starting the study. I remind people when they get really nervous about starting it, I say, "We had inhibitor patients who had to hold their aPCC for days before they started." We're all holding our breath hoping they're not going to bleed. And so, like you said, it takes a while before it gets to that steady state where you have the full protection that you expect. But there seems to be a little bit of protection early on, even after the first injection within a few days. We saw this, and we didn't see breakthrough bleeding events in the first couple of weeks on the trials.
And for factor VIII, like you said, particularly if the family is really nervous, if they're participating in a bunch of sporting events, you could easily say, "I want to do prophylaxis that first week and then stop doing it the second week." The unique thing for Hemlibra that makes it interesting is that they made it such that it doesn't bind as avidly as factor VIII. So when you infuse factor VIII, Hemlibra has very little effect because it gets displaced, and factor VIII always wins in the battle of trying to get factor IXa and factor X together.
If you look at the studies, there have been almost 300 instances in which factor VIII was given. There were no issues of blood clotting events, even in patients who received 100% correction for multiple days. And that's in contrast obviously to aPCC. Unfortunately, we learned that the hard way in the study, in which a few patients developed thrombotic microangiopathy, which was a little bit surprising to a lot of us and scared us initially. And then there are thrombotic events. But that only happened when they were getting more than 100 U/kg within a 24-hour period. They made a nice box, and you can see all the events happened in the bottom right corner when they got it more than a day, more than 100 U/kg.
We talk to the patients, because a lot of our patients were on aPCC prophylaxis before. And some of them felt very strongly about it. But once they switched to Hemlibra and they stopped having bleeding events, nobody complained about not using aPCC. I've not had one person say, "We want to go back to using that," because they're so infrequently using a bypassing agent to treat bleeds and that worry has just disappeared.
Luigi Brunetti, PharmD, MPH: We've already covered the use of emicizumab, or Hemlibra, in patients with and without inhibitors. And please correct me if I'm wrong, but just to summarize that, it sounds like individuals with inhibitors, especially those who have more frequent bleeding, are probably the patients who would benefit most. But you can use it in individuals without inhibitors as well.
Robert F. Sidonio, Jr, MD: Oh yes, definitely. And the label is clear for that. They got the inhibitor patients label first, and then the noninhibitor patients label. And so it's more of a choice for the families, because certainly there are patients who have done well and they really don't want to switch anything because they feel, "I haven't bled in years; I just don't want to risk it." And so I totally get that.
Luigi Brunetti, PharmD, MPH: If it's not broke...
Robert F. Sidonio, Jr, MD: Yes, don't fix it. So that mentality is still there. And it's interesting, we were talking about this. There are certain centers that have switched almost all of their patients and some that have switched a smaller portion, and some families have said that, "I want to see what's in the next clinical trial. I want to think about things like gene therapy."
And so we want to make sure that they understand all the things that are happening in the next few years so they can make an informed decision. And certainly, starting Hemlibra is not going to limit their ability to receive gene therapy, but it may limit their ability to go on a gene therapy trial. We just have all these discussions about it. And I think it's nice to have that meeting, and I'm sure you meet your patients as well. And having everybody from the team meet the patient so they get a full understanding of what's going on is important.
Luigi Brunetti, PharmD, MPH: Yes. In terms of risk-benefit comparison, factor VIII concentrate versus Hemlibra, what are the risks and benefits of each? And from a cost perspective, we already touched upon how administration cost is likely to be less because of the way it's administered.
Robert F. Sidonio, Jr, MD: The ICER [Institute for Clinical and Economic Review] group did a study and showed that there was clear benefit. It almost didn't even need to be done because there was already improved efficacy and it was cheaper. You don't really have to do any mathematical analysis. I've done cost utility analysis before. Clearly there was a benefit. I don't think it's been done yet for noninhibitor patients.
We conducted a study looking at the cost over a 20-year period, and there appeared to be a benefit if you take it from a societal perspective, because there's less nursing cost; you're not sending nurses out to do this. Certainly, there are fewer visits to the emergency department, less need for a central line. And if you factor all those things in, there definitely seems to be a benefit. It was from our analysis, and it's always hard to calculate this perfectly over a 20-year horizon because we are having to make some guesses about how people are treating.
But clearly, it's really important for those patients who start Hemlibra, they're still going to need factor VIII. They're still going to need a few doses at home. We were at a meeting recently and one of the patients was on Hemlibra, and he didn't even carry any factor VIII with him to this meeting. Patients quickly forget, because he said, "Well, I haven't had any bleeding in a while." And I said, "Well, that can change any minute." And so it's really important that we have our pharmacists and everybody continually educating them and also educating the payers about this because there have been some restrictions as well.
I think it really goes down to patient preference, which is nice. Patients have a lot of options. Particularly if we feel like they're utilizing a lot of factor VIII, there definitely is going to be benefit of doing that. For somebody on once or twice a week prophylaxis, who is not bleeding that much, there may not be a cost benefit for them on emicizumab compared to factor VIII. But we can obviously talk to the insurance companies because we have had rare people who are not satisfied with Hemlibra. There have been very few who felt like they didn't have as good protection.