The WRAP-IT trial looked at the use of an antibacterial envelope to prevent CIED infection in patients undergoing device implant. Dr. Bruce Wilkoff and Dr. Thomas Callahan discuss special populations who are at specific risk for hematoma, who may benefit the most from the envelope during implant.
Podcast: Episode 2 – WRAP-IT Transcript
Callahan, M.D., Thomas
Hello and welcome to the LEADconnection podcast where we talk about all topics related to lead management. I’m Tom Callahan.
Wilkoff, M.D., Bruce
And I’m Bruce Wilkoff and we’re both from the Cleveland Clinic and we are both working with the LEADConnection.org website and hope that you listen to us on a regular basis.
Callahan, M.D., Thomas
So – I’m excited to for our topic today. We are going to be talking about the WRAP-IT trial, the absorbable antibiotic envelope for devices and specifically we are going to get a little bit more granular and talk about some special populations today.
But, for background, you were the senior author on the WRAP-IT trial. That was really a landmark trial looking at about 6800 patients and demonstrating this 40% relative risk reduction in major infection at 12 months for patients that were considered high risk for CIED infection. In the trial, high risk was defined as patients that were undergoing replacement, patients that were getting an upgrade either a pocket or a lead revision, or patients that were undergoing initial CRT D implant.
So, I wonder can you talk a little bit about how the decision was made to focus on that population in the trial.
Wilkoff, M.D., Bruce
So, when you’re doing a clinical trial, there are a lot of aspects to what you’re trying to do. You want to make sure that the population is clean, that what we are going to find out is going to be attributable to the intervention. And so, sometimes some bizarre decisions have to be made in order to keep it clean, and we were mostly concerned about reinterventions of various sorts. So replacements, upgrades, extractions. But there was also evidence that defibrillators were a bigger problem, and there was also some evidence that CRT might have a higher rate of pocket contamination. This is in part because defibrillators are larger, but also because there’s just more time with the pocket open.
On the other hand. There are other high risk populations, but they also can have problems with other mechanisms of infection, other than bacterial contamination at the time of surgery. So for instance, you have the dialysis population and the dialysis patient population is always at risk for having transvenous contaminations, hematogenous spread. And the question would be was it the surgical intervention or was it from the from the dialysis? Immunosuppressed patients, they also have problems of various sorts. How do you define immunosuppressed status? We allowed some Prednisone and minor immunosuppression. But we didn’t want to include people that were really not typical of what we were trying to test.
We were testing for pocket contamination and knocking down the bacterial load and being having an intervention, absorbable antibiotic envelope, that does that. So that’s how we chose this population. And we thought that the infection rate was going be about 2% and it just shows you how we really are poor at estimating the endpoint rates. Because two large studies, both the WRAP-IT and the PAD-IT studies, showed that if you’re really careful with aseptic surgical technique, the infection rates are more in the 1.2% range, at least they can be that way when you’re really careful. The problem is that people are not really careful all the time. So when you’re studying it, it’s 1.2% just as it was in both in PADIT and in WRAP-IT.
But when you’re not quite that careful, consider the Danish study and it’s much higher, 2-4%. There are parts of the world – and the parts of the world, could be anywhere in the United States too or anywhere in Asia or whatever, and the infection rates are really not low at all. And it really it’s very important that we pay attention to our outcomes.
Callahan, M.D., Thomas
Yes, I mean we both work with trainees and early in in working with each trainee I reinforce that really infection is the thing that we fear the most and one of the most important things that we can do is just being really diligent about our technique – sterile technique and the rest. It was interesting; well, not interesting, maybe, maybe not even surprising, but the bulk of this benefit from the antibiotic envelope was really in reducing pocket infection. So, if you looked at the sort of bacteremia, endocarditis, the rates were pretty similar between the control and the intervention group. If you look at pocket infection, that was really what drove the bulk of this benefit from the device. With that in mind, you know other subsequent analyses have looked at other populations that that might be at risk for pocket infection and one thing that leaps to mind is patients who develop hematomas.
Wilkoff, M.D., Bruce
Yeah, you’re absolutely right. We knew that hematomas were a problem for infections. I mean, it was logical. I don’t think that surprised anybody, but the magnitude of it and also the magnitude of the benefit of the using an envelope in that situation was surprising. And we learned a great deal. So while we said all replacements and similar procedures, it’s really the replacements, upgrades and extractions that that are complicated with hematomas. Because although the overall hematoma rate was 2.2%, the risk of infection in those patients who had hematomas was much higher. It was eleven times higher and up to 13% without an envelope and then came back down to almost control levels even with the hematoma if you had the envelope.
So two things. One is hematomas were a big deal and second of all the value of the antibiotic envelope was much greater in those patients with hematomas and the really interesting thing here is that everybody knew that large hematomas, the ones that you know you’re thinking should you open up or not are a problem. But actually, small hematomas were the same, and if we’re honest, small hematomas happen a lot, a lot more than we’re willing to really think about it. So that is really, really a thing of concern.
Callahan, M.D., Thomas
Yeah, and it wasn’t just that study, I mean this has been found in a couple of studies, you know, BRUISE CONTROL, I think found similar rates of hematoma, you know, significant hematoma development. And then the rate of infection was, I think sevenfold in that study as well. So I mean, this is consistent. It’s not just one study showing us this.
And then to that point, you know BRUISE CONTROL looked at bridging versus continuation of warfarin and actually found that bridging with heparin really significantly increased the risk of bleeding and hematoma formation.
Wilkoff, M.D., Bruce
It really did and particularly with heparin. So, heparin is, I don’t know an evil substance in this regard. We worry about clots, we worry about strokes, but it’s virtually universal that patients get into trouble either with IV heparin infusions or with low molecular weight preparations. And, the contributions of BRUISE CONTROL were that it was far better to keep somebody on Coumadin or warfarin than it was to interrupt it and then allow the INR to go down and back up again with heparin bridging.
BRUISE CONTROL 2, looked more at more at the direct anticoagulants, but the point being is that staying away from heparin or heparin by products is important and it’s important to understand that those studies were designed to comparing the use of how you managed the anticoagulation, not how any anticoagulation impacted hematomas.
With stopping and restarting or continuing the products, but we don’t know. There was not a control group that said, well, what if you weren’t on anticoagulation? What do you do for that situation and what are the other ways we could be handling this? And I think the WRAP-IT data brought out some very interesting aspects to this dynamic.
First of all, that anticoagulation and antiplatelet therapy is extremely common, so it was only 15% of the population, and we’re talking worldwide that did not have either antiplatelets – or anticoagulation – or both, 15% had both. And it was evenly divided, half on anticoagulant, half on antiplatelets. Our patients have coronary disease, cerebral vascular disease, indications for these medications.
They’re on antiplatelets. And when we look at it, there’s a there’s a complex interaction that we saw in WRAP-IT that you know the rate of hematomas was 2.2% overall. But, if you were not on anticoagulation, not on antiplatelets, it was much lower. It was less than 1%. So that’s a big deal. And then, it varies a little bit between warfarin, and the novel agents, and how you handled it is important, but the point is it’s higher. So staying on Coumadin is OK, but it’s still better to be off of Coumadin.
Callahan, M.D., Thomas
Right, right.
Wilkoff, M.D., Bruce
And being on a NOAC is OK, but it’s better to be off of the NOAC as to go with it and then the other point is that antiplatelets about doubled the rate of hematomas if you’re on anticoagulation and antiplatelet at the same time.
Callahan, M.D., Thomas
I was going to ask where antiplatelets agents fall on your scale of evil.
Wilkoff, M.D., Bruce
Yeah, well, they’re not necessarily as bad. The heparin stuff is really worrisome because those hematomas can happen even late. I mean you can be going a week, two weeks out and put somebody on heparin even without bolusing them and they develop hematomas. So I would much rather if I have, let’s say, interrupted my Coumadin, which I do sometimes, yes, – then I will just restart the Coumadin and work on it that way. It overweighs the potential risk of clots and strokes. I mean it is a problem. I’m not saying that there’s no risk on the other side, but you got to balance it both out.
Callahan, M.D., Thomas
You know, so with some of this newer data suggesting this increased risk of hematoma formation in patients that are on anticoagulation, especially if they’re on antiplatelet agents as well. So maybe that’s reshaping how we think about high risk populations and who might benefit from an antibiotic envelope.
Wilkoff, M.D., Bruce
I think so. So if I were to step back, we talked about how we chose the population initially. Well I think we should be doing an assessment of what we think their hematoma risk is and certainly – patients on dialysis that are getting intermittent heparin, patients who are immunosuppressed have poor tissue characteristics – are patients that we should seriously consider and, you know, we probably didn’t think about it much before. But I think we need to talk about is it possible to stop antiplatelets agents for enough time to get you through this procedure? I mean, I know there are good reasons for antiplatelets and there’s a time not to do it. The surgeons seemed to get this. Well, I don’t think we’ve done as good a job of figuring this out. I think we have to recreate our priorities and introduce the alternative thought. If it’s possible to stop the antiplatelets, I think we should. And if it is possible to let the INR to float down or to stop the novel agents, I think it’s appropriate to do so on a patient by patient basis to risk hematomas, infections and ultimately deaths. But if it’s not we we need to say, can I get rid of one of them? How can I manage this risk?
Callahan, M.D., Thomas
Right. Yeah. And because just sort of circling back to that increase risk of infection, when you do see hematoma development, it’s just it’s so powerful, such an incredible risk factor.
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Wilkoff, M.D., Bruce
That’s really good. So I think you know this is just the beginning of this story. I think we’re just starting to become creative about this. But I really think that we have to strategize, think about every single patient as they come into the lab, see what we can do to reduce their risk. I know people have done lead extractions even on Coumadin, and that can be done. I’m not sure that that’s necessary. I certainly think I’d rather do it off of Coumadin than consider restarting heparin afterwards, but I think that’s open for some more discussion.
Wilkoff, M.D., Bruce
Well, this has been great Tom. I really like talking with you about these trials and the dynamics of how do we actually treat our patients and improve the outcomes and I look forward to doing this more on the LEADconnection podcast and I hope everybody joins us again soon for another discussion.
Callahan, M.D., Thomas
Thanks. That was a great discussion.
Read more about the World-wide Randomized Antibiotic Envelope Infection Prevention Trial (WRAP-IT) with links to important studies.