Narrator - Dr. Abel 00:00 Welcome to HelixTalk, an educational podcast for healthcare students and providers, covering real life clinical pearls, professional pharmacy topics and drug therapy discussions. This podcast Narrator - ? 00:11 is provided by pharmacists and faculty members at Rosalind Franklin University, College of Pharmacy. Narrator - Dr. Abel 00:17 This podcast contains general information for educational purposes only. This is not professional advice and should not be used in lieu of obtaining advice from a qualified health care provider. Narrator - ? 00:27 And now on to the show. Dr. Sean Kane 00:31 Welcome to HelixTalk. Episode 42 I'm your co host, Dr. Kane. I'm Dr. Schuman, and I'm Dr. Patel. And today we're talking about bridging, and specifically the bridge trial, which came out New England Journal of Medicine back in August of 2015 but it's one of those landmark, Pivotal trials that is really going to impact clinical practice. We wanted to cover that today. Speaker 1 00:50 Yeah, and let's just start out by definition of bridging. So basically, we call that bridging occurs when an anticoagulation coverage is provided by either a low molecular weight heparin, such as enoxaparin or dalteparin or heparin during warfarin therapy interruption when the INR is subtherapeutic. So there is that vulnerable window when we want to cover it with a shorter-acting anticoagulant. Speaker 2 01:12 And these interruptions are usually for what we define as major procedures. So we're not talking about thing, you know, if you're the minor dental procedures, minor skin surgeries, or if they're doing, you know, I think even like a punch biopsy on the skin or cataract removal and anticoagulation is generally not interrupted, with some exceptions. But we're going to focus on more than generalities. Dr. Sean Kane 01:31 There's kind of two ways that you can do bridging. One is more of a prophylactic regimen where you're kind of doing low doses or even intermediate doses of, let's say, Lovenox, or any low molecular weight heparin, but more commonly, you're actually therapeutically bridging the patient, which means that you give them a full dose of heparin, or low molecular weight heparin, that would get them to the point where they're equally as anticoagulated as if they were on warfarin with an INR of two to three. Speaker 1 01:57 And they're having more trials studying the complete therapeutic bridging, which is the therapeutic dose bridging. But there weren't any trial until the bridge trial, that actually looked at whether there is need for bridging or not, and what are the risk of bridging involved. So that's why we were focusing on the bridge trial. Dr. Sean Kane 02:15 So the bridge trial, as we said, came out back in August of 2015 it was a double blind, randomized, placebo controlled trial of patients with chronic afib. And all of these patients were undergoing an elective procedure where they knew the timeline of when they'd go to the or have an invasive procedure done, and they actually stopped their Warfarin five days before that period happened. Speaker 1 02:36 And it was aimed for a non inferiority to bridging when they looked at the prevention of thromboembolism, and when we look at the end points, we'll define what they meant by that arterial thromboembolism. And they also aim for superiority to bridging when they're looking at the risk associated for bleeding, and Speaker 2 02:54 whether you divide it up into treatment groups using dalteparin (Fragmin) at a dose of 100 international units per kilogram twice daily, and they compared that to a matching placebo that was also given twice daily. And then that's also the same dalteparin dose used for DVT or PE as the treatment dose. But again, we're talking in this study about a population with AFib. Dr. Sean Kane 03:14 So in terms of the timeline, warfarin was stopped five days before the procedure, and then they resumed it 24 hours after the procedure, and then three days prior to the procedure, all the way up to a day before the procedure, they initiated treatment with either dalteparin or placebo. And then after the procedure, they resumed dalteparin or the low molecular weight heparin, in addition to warfarin, and waited for the INR to come back to normal. Speaker 1 03:38 And this dalteparin was started 24 hours after the procedure if it was a low-bleeding-risk procedure, but they waited until 48 to 72 hours to start if the procedure involved higher bleeding risks. And this is Speaker 2 03:50 pretty common in clinical practice when we think about, you know, after a procedure, when do you initiate even DVT prophylaxis, or, you know, a full dose of anticoagulant? So in terms of the timeline here, this, to me, really reflects what clinical practice normally would be in terms of initiating Warfarin pretty early, knowing that it takes a while to kick in, and then waiting, based on the bleeding risk of the procedure to initiate your parenteral anticoagulant, right? So again and this, so one of the things they also did moving forward was they did monitoring for 30 days, and even up to 37 days, in some cases, following that procedure again, to look for some of those adverse outcomes. Again, bleed clots, whatever may have happened. And then the inclusion criteria here, where they're looking at the population specific, had to be greater than 18 years old, have either permanent or paroxysmal atrial fibrillation, including valvular afib, had to be on Warfarin for at least three months, had to have an INR between two to three and again, it was an elective operation, not something that was spontaneous. And then they had to have at least one CHADS2 risk Dr. Sean Kane 04:50 factor, and hopefully they all had at least one CHADS2 risk factor if they're put on Warfarin for their afib, right? So it's one of those things that it's a box to. Check. But you know, many of these patients had at least two which has two risk Speaker 1 05:04 factors right? And then patients who had either stroke or TIA or a thromboembolism in the past 12 weeks, or within three months, a major bleed within past six months, if their creatinine clearance was less than 30 mL/min, if their platelet was less than 100, if they were going under planned intracranial or intraspinal surgeries, or if they had a mechanical heart valve, these patients were excluded. And kind of have to focus on, you know, some of these higher risk patients who can get either thrombosis or are at a higher risk of bleeding are excluded from the study. Speaker 2 05:36 And then, to be clear, the issue with renal function has nothing to do with warfarin; dalteparin is renally eliminated, and there really aren't dosing adjustments available if you have a creatinine clearance less than 30 mL/min. As we mentioned, the primary endpoints here were thromboembolism, including TIA (transient ischemic attack), strokes, and systemic embolism (such as an arterial clot), and then safety endpoints such as major bleeding. Other secondary endpoints included MI, DVT, PE, death, and minor bleeds. Speaker 1 06:12 And when they looked at the study and put all the statistics together, they figured that, you know, they actually revised power calculation a couple of times because the study had a little hard time recruiting patients, but at the end, they figured out that they needed 1882 patients to get about 90% power, assuming that the rate of thromboembolism was about 1% and that apparently is a significant reduction in VTE risk. Something to note is that they did not use data from 71 patients who discontinued the trial, and the study was designed as a non-inferiority trial that showed that bridging was not worse in preventing stroke or embolism versus no bridging. So they ended Dr. Sean Kane 06:58 up randomizing about 1800 patients, which is close to what they had planned. And as we said, a portion of those weren't included in the final analysis for a variety of reasons. And on top of that, a number of patients actually didn't go through surgery, so only about 1700 total patients kind of did the whole thing in terms of being randomized, getting study drug, not being withdrawn from the study, and then actually getting the surgical procedure. The patients who were included were around 70 years of age. About three quarters of them were men. So women were definitely underrepresented. Most of them were Caucasian. So you know, other ethnic groups were underrepresented. As we said, the CHADS2 score was a mean of 2.3 so you could argue that maybe we're not looking at a very, very high risk patient population in terms of risk of stroke. Good on them, the INR was 2.4 as a mean baseline. So these patients, on average, had a good INR, which would be in the therapeutic range. They basically had good renal function, and about a third of them were on aspirin. That's relevant, because, again, we're thinking about bleeding risk, and we're adding a parenteral anticoagulant on top of, let's say, aspirin, it's something that we need to know about. Speaker 2 08:02 An important thing to note is that 90% of them underwent what was defined as a minor procedure, which inherently had a low bleeding risk versus higher risk procedures, Most common procedures were minor gi procedures, minor cardiothoracic procedures, as well as some major orthopedic procedures. Speaker 1 08:19 So when we look at the primary outcome again, we were looking at the risk or rate of thromboembolism that occurred with 0.4% in the non-bridging group versus 0.3% in the bridging group. So we're really looking at four events in the non bridging group versus three events in the bridging group. And that P value was 0.01 for non-inferiority and 0.73 for superiority. Again, we can't really test for superiority, because the study wasn't designed for that for the primary efficacy outcome. So looking at P value 0.01 for non-inferiority, and all of the events were either a stroke or a TIA. There were no systemic thromboembolism. Speaker 2 09:00 And then important thing to know is that non-inferiority was defined as less than 1%, so they actually found that this did meet the criteria. The 95% confidence interval showed that dalteparin was between an absolute 0.6% worse to 0.8% better than placebo. So again, we have both sides the spectrum. So again, then that, because of that information, you can say, okay, there's there's not a difference between them, or it's not inferior. Dr. Sean Kane 09:23 And just in thinking about the placebo arm, we're basically saying that if you don't get an anticoagulant (no bridging), your risk of having a stroke in the 30-day period around a minor surgical procedure is somewhere between 0.3% and 0.4% — an incredibly low value. Even if a drug reduced that further, safety matters. When they looked at major bleeding, it was far more common with dalteparin versus placebo. Non-bridged patients had 1.3% major bleeding versus 3.2% in the dalteparin group (P = 0.005 for superiority; NNH ≈ 53). So we see essentially no benefit but clear harm associated with routine bridging with a parenteral anticoagulant. Speaker 1 10:20 when they look at the secondary outcomes such as heart attack, DVT PE or total rate of death, they found no difference between the two groups. They also looked at minor bleeding as one of the secondary safety endpoint, and they found similar outcomes. There were 12% bleeding scenarios in non bridging group versus 20.9% in the bridging group. And again, this was significant for superiority, where P < 0.001, so again, looking at the number needed to harm to put it in clinical context, was about 11 patients. Yeah. Speaker 2 10:52 So what we have here is, again, a procedure where doing it bridging, in this case, doesn't really make any better outcomes in terms of thromboembolisms, but it has that increased risk of bleeding. So that being said, though, I believe Dr. hand, there were some issues, though, with the study, yeah. Dr. Sean Kane 11:07 So, you know, they powered the study. They they were really close to meeting the end that they needed in terms of number of patients. But they actually powered it with the assumption that they would have about a 1% primary endpoint rate, and it was closer to 0.4% so they did lose some power with that, with that said, though, in evaluating safety versus efficacy, we can say, based on the power of the study, the 95% confidence interval, if a difference does exist, that difference in terms of absolute benefit, is less than a 1% absolute reduction of stroke, meaning that we can increase your major bleeding risk by about 2% absolute percentage points. But at best, if the drug did work in terms of preventing strokes, that benefit is less than 1% absolute percentage points. So in terms of risks and benefits, for this patient population, which, again, the CHADS2 score was in the twos, so a lower stroke risk patient population, they just don't drive benefit, and despite the low power, we can sufficiently say that the risks do outweigh the benefits, right? Speaker 1 12:07 And we looked at some of the inclusion exclusion criteria of the trial, so it's worthwhile to make a note that some of the patient groups were not included, such as patients who had a CHADS2 score greater than five. These patients are at higher thrombosis risk, such as those who had mechanical valves, or patients who underwent or would be going under very high-risk bleeding procedures such as intracranial or intraspinal procedures. And just looking at baseline patient population too, like majority of these patients were men and they were white. So what about the female patients. What about the patients who are non white? Speaker 2 12:43 And then again, to be clear, this was also looking at it in individuals with atrial fibrillation, and this does not make any comments upon individuals receiving anticoagulants for other indications, such as history of VTE. And then the other thing too with it is, what are the results? How would the results be different if we were talking about our novel oral anticoagulants or direct oral anticoagulants. What would they do differently? Would they be any better or worse? Here we're only talking about individuals who are using warfarin, Dr. Sean Kane 13:09 you know, from my point of view, this would be an argument both in favor and not in favor of using the NOACs. So the NOACs, you could say that you don't have to bridge because, you know, they're just as short acting as dalteparin or any other low molecular weight heparin. But then on the warfarin side, if you're a pro Warfarin advocate, you can say it doesn't matter if you bridge or not, because the bleeding risk is higher if you do bridge. So maybe there's some benefit to not having, you know, a NOAC on board. You know, the study wasn't designed to investigate that question, but it definitely is in favor of using Warfarin in the sense that bridging is not necessary, and that was one of the downsides, if you will, to using warfarin. Speaker 1 13:45 So when we look at bridging altogether, you know, based on the bridge trial, you're going to select your patients whether they qualify for bridging or not. But what goes behind the decision making of the bridging is we evaluate what the thrombosis risk are and what the bleeding risk are. So there are certain patients are at higher risk of thrombosis, and when we say higher, it's defined as greater than 10% annual risk of developing a clot without anticoagulation. So some example of these patients are patients who had VTE in the last three months, patients who got severe thrombophilia, such as protein C, protein s or anti thrombin deficiency, mechanical heart valve patients who had mitral valve replacement or had a stroke or TI in the past six months, or AFib patients, like we mentioned, CHADS2 score of greater than five they had a stroke or TIA in the last three Months, or patients had a thrombus while being on anticoagulation or while doing the anticoagulation interruption. Speaker 2 14:46 And their moderate risk, we look at individuals who do have a history of recurrent vte, those who have mechanical aortic valves, those who have cancer treatment within the last six months, heterozygous factor V Leiden or a protein C or prothrombin gene mutation as well. Dr. Sean Kane 15:02 And then kind of our low risk patients, which, again, I would classify this group as in the bridge trial, as those lower risk patients less than 5% chance of having a clot within a year. These would be patients who had a VTE more than three months ago, that don't have any existing risk factors for VT recurrence, those with a bileaflet aortic valve, and then also those who have AFib without any of the high risk features that we talked about that would be present in a CHADS2 score. And then Speaker 2 15:30 you've got to compare this, again, to the bleed risk. So we're looking at high risk procedure. So you know, if somebody is at a high risk of bleed, we you may also want to factor that into your decision whether or not to use bridging. And one nice thing that we do at our facility, again, is you calculate a HAS-BLED score, which can be a number that can give you an idea about, does a patient meet certain risk factors that would make them at higher risk of bleed. And you can use that. You also want to use patient preference, other factors related to the surgery, the nature of, again, how long the rehabilitation may be. And then lastly, you can, you can't forget about clinical judgment as well. You have to, you know, this is going to be something that, again, when I'm talking bridge, this is, this is generally not something we do in isolation, but we're doing when I'm discussing it with the patient, I'm discussing with their primary care provider, we may even be discussing with the surgeon as well. And so there's a lot of people there, and you have to use that clinical judgment as part of the team. And you're not, you're not gonna be replacing that clinical judgment, really, with any of this. Dr. Sean Kane 16:24 So Dr. Patel, you know, there's a lot, obviously, as Dr. Schuman mentioned, that goes into the process of decision making with bridging. If you could break it down into just a couple points, what would be the main take home points of the decision making process? Speaker 1 16:37 So basically, you want to continue through the anti coagulation without any interruption. When you're looking at high thrombosis risk, low bleeding risk or low thrombosis risk with low bleeding risk, you do want to hold anticoagulation and bridge the warfarin. Even consider maybe prophylactic bridging when you're looking at patients who have high risk of thrombosis, but they're also at high risk of bleeding. And when it comes to patients with low risk of thrombosis but high risk of bleeding, they say, go ahead and hold the anticoagulation, and there is no need to bridge the warfarin, because they're already at a higher risk of bleeding. Dr. Sean Kane 17:16 So you know, we've talked a lot about in the bridge trial, how did they decide to bridge but again, is this typical to what you guys see in clinical practice for bridging, especially in the outpatient side, and then, if not, what other things or what other considerations do to see? Speaker 1 17:30 Yeah, pretty much. It was a really nice chart on the very first figure in the trial. That's pretty much what the clinical definition of bridging is. And that's as far as Aurora is concerned. That's what we use, Speaker 2 17:40 yeah, and again, the VA, we have, you know, coming out with newer guidance. But again, a lot of them are based upon the bridge trial. And we also look at, you know, we want to look at patient history, number of those individuals who go through multiple elective procedures. We have a good history for them as far as how they've done in the past, and we can then use that clinically take to guide them moving forward. Speaker 1 17:58 So in general, when we are using Warfarin and bridging, we are stopping the warfarin five days before the procedure. We start the bridging agent, such as the low molecular weight heparin, or heparin itself two days after stopping the warfarin. So that becomes, you know, three days before the procedure, the day before the procedure, basically they stop. Go ahead and stop the low molecular weight heparin. There are some clinical groups that would use like half the dose of low molecular weight heparin, if they're giving it once a day, when it comes to heparin that stopped at least six hours before the procedure. Remember, heparin is a quick switch on and off. Has a shorter half life the day of the procedure. Though, technically, there is no warfarin, no low molecular weight heparin, depending on the bleeding risk of the procedure that low molecular weight heparin, or heparin could be started within either 24 hours or 48 to 72 hours after the procedure, but we know that Warfarin takes a little while to start getting into action, so we can go ahead and usually start the warfarin the night of the procedure or the day after the procedure. And then, basically, most institutions follow this rule, where they would prefer at least five days of overlap between Warfarin and low molecular weight heparin, check the INR and then maybe continue the low molecular weight heparin for a couple more days after the INR is therapeutic. In my clinic, I go ahead and usually evaluate, let them be stable on warfarin dose for seven days, and then have them recheck their INR. And if the INR is within therapeutic range, I go ahead and discontinue the LMWH or heparin itself. Dr. Sean Kane 19:33 And the NOACs are a little bit simpler, because it's one agent the whole time, and it depends on the agent, depends on the procedure, but generally it also depends on the patient's renal function. But generally what happens is that you're going to stop it anywhere from 24 to up to 48 hours prior to the procedure. The procedure is done, then you initiate it when you would normally initiate your parenteral anticoagulant during bridging. So typically, you know the day after surgery is a typical timeframe. But again, it depends on how the patient's doing the clinical picture and things like that, Speaker 2 20:03 and that's why I always find it important to discuss it with the individual, let them know why we're doing this, to give them that picture about talking about the risks and the benefits of bridging. Because I've had a number of individuals who decide that, you know, I really don't like this idea about giving myself these injections, so I'm just going to go ahead and stop it after a few more days. And so I, and you occasionally run into that, we said, well, actually, I already stopped it four days ago, so we're good now. And so it really is important that I learned to educate on why we're doing this and give them some of it. You know, we're not trying to scare anyone, but give them the facts about the risk and the benefit of it, so the individual is on board, so we at least know whether you know in our agreement with with the picture moving forward. Speaker 1 20:39 And I really hope like this trial was more just for patients who had atrial fibrillation, but I really hope in future, they do trials with patients who had, you know, stroke in the past, or VTE in the past. But you know, why are we so aggressive with the bridging? Can we go a little bit flexible or moderate? Absolutely? Dr. Sean Kane 20:59 And I think that on the basis of this trial, it makes it easier for those other trials to happen, because now there's this clinical question of, are we actually doing harm by having this process of bridging patients, whereas historically, I think the risks and benefits weren't as well described, and it was less clear that's the whole point of the bridge trial in the first place. So with that, I'm Dr. Kane, Unknown Speaker 21:19 I'm Dr. Schuman Unknown Speaker 21:20 and I'm Dr. Patel and study well. Narrator - Dr. Abel 21:23 If you enjoyed the show, please help us climb the iTunes rankings for medical podcasts by giving us a five star review in the iTunes Store. Search for HelixTalk and place your review there Narrator - ? 21:35 to suggest an episode or contact us. We're online at HelixTalk.com thank you for listening to this episode of HelixTalk. This is an educational production copyright Rosalind Franklin University of Medicine and Science.