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.

Speaker 1  00:31
Welcome to HelixTalk, Episode 62 I'm your co host, Dr. Kane. I'm Dr. Sherman and I'm Dr. Patel. Today's title is called devices, not drugs. Stroke risk reduction in atrial fibrillation. So we'll be talking about using devices, as opposed to anticoagulants, to prevent strokes in patients with afib. And I think the best way to kind of kick off this episode is to introduce you to a patient. Case patient that we're talking about today is Frank. So Frank is a fictional 75 year old male who presented to his primary care office, we'll say at Dr. Patel's office, with palpitations and anxiety. He's been feeling it for weeks. So this is not an acute onset afib. It's either unknown duration or kind of a chronic afib. His wife finally convinced him to come to his primary care office visit, and he has a past medical history that's relevant for active alcohol abuse, cirrhosis, thrombocytopenia from his cirrhosis, frequent falls from his alcohol abuse, diabetes and hypertension. After a thorough workup of a lot of different things, it's discovered that he does, in fact, have afib, and that is what's causing his palpitations and anxiety problems.

Speaker 2  01:36
So essentially, there's two problems here to worry about with atrial fibrillation. The first one is going to be about heart rate or rhythm management. So the ventricular heart rate can be fast, and what that happens. When that happens, patients can feel these palpitations in their chest, that kind of pounding out of my chest. It can really make them feel uncomfortable. Usual strategies for that include rate control — slowing the ventricular rate with a beta blocker or a non‑dihydropyridine calcium channel blocker — or rhythm control with a different class of antiarrhythmic medications, or elective cardioversion. Now this isn't necessarily something that's gonna be the focus of today's podcast. That's a whole other topic on its own, but something we need to consider,

Speaker 3  02:16
what we're focusing on today, however, is the stroke risk, and how we mitigate that stroke risk associated with the atrial fibrillation. So we know that with the residual blood, there could be a clot that can form in the left atria, which can then travel up to the brain, causing an ischemic stroke. And so the risk assessment for the development of stroke when somebody has a fib is based on the CHA2DS2‑VASc score that determines whether we need to place patient on just an antiplatelet therapy versus an anticoagulant therapy, or we need to do nothing.

Speaker 1  02:48
And so if we go back to our patient, Frank, he does have a high risk of stroke, and you can see that in his CHA2DS2‑VASc score. So he gets a point for being hypertensive. He actually gets two points for his age being at or above 75 years old. And he also gets a point for being a diabetic. So he gets four total points; if you plug that into the publications for the CHA2DS2‑VASc, every year he has about a 5% risk of stroke because of those risk factors. Normally, with a CHA2DS2‑VASc score of ≥2 you would be indicated for full anticoagulation with either warfarin or a DOAC, or in rare cases, something like low‑molecular‑weight heparin.

Speaker 2  03:28
But at the same time, though, we also have to look at the benefits and the negatives — there's also the risk of adverse outcomes. So we can look at bleeding risk using the HAS‑BLED score, which takes a number of different factors into play. Depending on his comorbidities he has, at the very least, a HAS‑BLED of 3 points (ETOH use, age ≥65, cirrhosis). That corresponds to an approximate major bleeding risk of ~5% per year.

Speaker 3  04:03
so what do we do? And you know, not to dilute the importance of this case, Mr. Frank over here, however, you know we do see these kind of patients in the clinic too. I have a patient currently that we are managing her anticoagulation. And every other week she's in the ER because she has epistaxis episodes occurring; she manages somehow at home, but then they go out of control and she has to come to the hospital. It got to a point where she actually stopped taking warfarin because of the frequent visits, and she ended up having a stroke. So we had to restart her anticoagulation, and this time, we had to really educate the family and say, We need to have her on some sort of anticoagulation. So if we're really trying to manage such patient, you know, their bleeding risk is high, or they're every other week in the ER with a nosebleed, a device might be a better option, and that's what we're going to talk about today.

Speaker 1  04:58
Absolutely, you know. And. In thinking about risks and benefits and things like that, I think we have to kind of go back to kind of the pathophysiology of why you're at risk for a stroke in the first place with afib. And it really comes down to this one structure in your left atria called the left atrial appendage. And everyone has one an LAA that we'll call it, and this is implicated in about 90% of clots that form in patients who have afib. So when you have a clot that forms, 90% of the time, that clot is forming in this laa, this appendage off your left atria. So this is really where the problem happens. And of course, if that clot does form and it embolizes, where it travels, it goes from the appendage to your left atrium, to your left ventricle, and then out into your systemic circulation, where it's ripe to form an arterial clot somewhere in your body. Statistically, your brain gets about a quarter of your blood flow. But when you do have these emboli that form, for whatever reason, 90% of the time, those emboli go up to the brain, as opposed to other areas of your body. So if you ever read a package insert for any of the new doacs, for example, for afib, their primary endpoint wasn't stroke, ischemic stroke or CVA, their primary endpoint was a composite of ischemic stroke or CVA, or having what they call the systemic embolization, which just meant that a blood clot formed in your arm or your leg or GI tract, and kind of killed off some tissue. It's a really serious complication, but it also is very rare that this happens.

Speaker 2  06:27
So normally, what we would do is use an anti platelet for low risk or anticoagulant. If somebody was at high risk of clots. We use it to prevent the LAA clot formation and afib. But again, to the cases that our case, for example, Dr. Patel pointed out, not all patients are good candidates. I know in our mental health clinic, for example, we have a number of individuals alcohol abuse can be a concern, which again, leads to fall risk, or just in general, others that are on our fall risk too. So what do we do in these situations where we need to treat you but we're a little bit concerned about the risk of the medications? So a new strategy, again, would be to use one of these laa occlusion devices instead of an anticoagulant. So go the medication free route to reduce the risk of stroke and systemic embolism while avoiding some of these systemic effects of thinning

Speaker 1  07:11
the blood. So you know, there's a bunch of different laa or left atrial appendage occlusion devices that are out there right now, in the US, there's only one that is FDA approved where you only do what's called the endovascular approach. Means that they're not poking any holes in your chest or anything like that. And this particular device is called a watchman device, and what it means is that they're going to take you to the cath lab, just like you would go to the cath lab for a stent if you have a heart attack or something like that, they're going to cannulate your femoral vein. They're going to feed up this cannula all the way to your heart. And they start on the right side of your heart, because that's where the veins dump out, is to the right side of your heart. What they actually do is they literally poke a hole from the right side of your heart to the left side of your heart, and this is called a transeptal puncture. And what happens is they end up on the left side of your heart, which is in the left atria. That's exactly where they want to be, because that's where the left atrial appendage is. So what they do is, once they're in the left atria, they deploy this device, in this case, called the watchman device, and basically it implanted into the left atrial appendage, where blood can't really flow that well, into where the LAA is being occluded. And actually, over a period of about one to two months, the body will form epithelial tissue over where that device is. And it ends up that for the vast majority of patients, they won't get any blood flow, and the heart will kind of form tissue around it where that appendage is essentially gone. You still have the device there, but the tissue has kind of grown over it. And the whole point here is that we're preventing blood from getting to the appendage to form a clot, to potentially increase your risk of embolic stroke.

Speaker 3  08:52
That process just sounds very fascinating. Dr. Kane, so

Speaker 2  08:55
there's another thing, is other other devices that are more invasive do exist for the either aren't FDA approved yet, or again, they're even more problematic because of that more invasive nature.

Speaker 1  09:06
Then if you really want to get crazy, if you're having open heart surgery, they can actually do a surgical ligation or a surgical amputation, where, if they already have you opened up, because they're going to do an open heart surgery for a cabbage, which is coronary artery bypass graft, or if they're going to do a valve repair or valve replacement because they're already there. It's actually very common practice if you already have AFib that they'll just snip off or ligate your left atrial appendage because it's just right there. And not a big deal. Interestingly enough, there's actually almost no data to support this practice. It probably isn't harmful, but you'd expect it would have some data to support, you know, doing this thing while you're already in the chest. But as it turns out, we have very weak retrospective data suggesting that it does reduce your risk of stroke, but we just don't have a lot of prospective data to really support the practice.

Speaker 3  09:58
So now that we know that. That the only device that is FDA approved and currently in use is watchman device. Let's take a look at some of the data pertaining to the watchman device. Currently, we do know that there are about two studies out there, protect AF and the prevail study, and both of these studies were conducted using the watchman device versus the standard of care, which we know is warfarin, maintaining the INR level between two and three, which is usually the INR level for the treatment of atrial fibrillation. So in both the watchman device was implanted, and then Warfarin plus aspirin was used for the first 45 days. Then it was aspirin plus Plavix for six months, and that was aspirin alone. And definitely thereafter, one thing to make sure that both of the studies use patients who had chance to score of one or more. And then also, in both studies, the primary efficacy endpoint was embolic stroke, systemic embolism. So not only a stroke, but embolism elsewhere in body, or cardiovascular death.

Speaker 1  10:56
And you know, the first study protect AF, this was the first one that came out in 2009 This is what really put watchmen on the on the map. So they had 463, patients that got the watchman device, and then 244, got Warfarin as a control. So it was a two to one ratio. And really the goal here was to prove non inferiority in terms of efficacy. That efficacy endpoint indicating that the stroke risk and the embolism risk and the cardiovascular death risk was equivalent between getting Warfarin or getting this device for longer term. You don't have to be on warfarin at all. And what they found was non inferiority confirmed to warfarin, and it was three events per 100 patient years for watchmen versus 4.9 per 100 patient year events with warfarin. And the relative risk was 0.62 in favor of Watchmen, but it did cross the confidence interval of one, meaning that it wasn't better, but it did meet the non inferiority margin that they set out.

Speaker 2  11:49
So what's interesting is, we talked initially that the goal of doing something like this was to potentially avoid some of the negative side effects of the medications. Well, the problem was, here is the watchman device actually was found to be worse in terms of some other safety outcomes that they may be worth considering. So composite safety and endpoint was Major, bleeding, pericardial effusion, procedure related cerebral vascular accidents and device embolization. So what they found were 7.4 events per 100 patient‑years in the WATCHMAN group versus 4.4 events per 100 patient‑years in the warfarin group, which resulted in a relative risk of 1.69 (confidence interval crossed 1 narrowly in other comparisons).

Speaker 1  12:30
And you know, the main driver in terms of the adverse effect profile with the watchman device was pericardial effusion. What that means is that blood collected around the heart, in the pericardial space, probably because of that transeptal puncture and other procedure related events that happened, in my opinion, at least, it's kind of hard to really compare apples to oranges, because what you're doing is you're saying the acute safety profile is worse with Watchmen, which is what you'd expect that you're going to have some procedure related complications. But what it doesn't really adequately capture is things like hemorrhagic stroke or other major bleeding events that happen six months afterwards, if the watchman was successful. So it's a great safety endpoint, but we have to remember that the procedure itself does have risks, and that's really what that safety endpoint captures.

Speaker 2  13:15
And to that end, Dr. Kane, it actually looks like watchmen actually did have fewer hemorrhagic strokes point 2% versus 2.5% so again, potentially, you know, there may be some early complications, but once you get out past that, there may be some long term benefit.

Speaker 3  13:28
And this study was done in 2009 — that was early experience. In later studies that used the WATCHMAN device, the rate of pericardial effusion has decreased, which likely reflects improved procedural technique and operator experience.

Speaker 1  13:46
absolutely, and this is very common that we'll see as cardiologists or interventional radiologists or even surgeons become more familiar with something that familiarity helps them have better outcomes for their patients. So certainly, if you're going to get a watchman device. You want someone who's put in a bunch of Watchmen devices for you to have optimal outcomes.

Speaker 3  14:06
The second study, as we mentioned, was the prevail study. There was a little bit more recent study published in 2014 and again, there was a non inferiority marker, and watchman device was actually unable to show that non inferiority for the efficacy here, the relative risk was 1.07 and it did cross the confidence interval.

Speaker 1  14:27
One in that margin, the confidence interval was point five, seven to 1.89 and for it to show non inferiority, that top number, the 1.89 had to be below 1.75 so they didn't meet their criteria. It's unclear, if they had more people in the study, would they have been more adequately powered to narrow that confidence margin down a little bit to show non inferiority, but this is the second best study that we have, and in this case, it did not demonstrate non inferiority, but the confidence interval was quite wide,

Speaker 3  14:57
and the rates of the events we talked about for the prime. Primary efficacy outcome were almost identical over the 18 month study period.

Speaker 1  15:05
They also looked at safety endpoints, but unlike with the Protect AF study, they didn't do an active comparator for safety, and that was one of the weaknesses of the trial. So instead, they used a historical safety comparator, and in my opinion, that really weakens the ability to look at the safety profile. But what they did show, and Dr. Patel, you alluded to it earlier, so the overall composite safety event rate was 2.2% which was anything from pericardial effusion to major bleeding, things like that. And even if you just look at the pericardial effusions, which was the biggest problem in the Protect AF study. And protect AF, which, again, was five years earlier, they had a rate of about 5% of pericardial effusion, whereas here in prevail, it was, you know, roughly 2% or less in terms of these procedure related complications and other safety endpoints. So again, as clinicians have more familiarity with it, they probably do get better and have fewer complications from the procedure. So it kind of

Speaker 2  16:05
That takes us back to Frank. For Frank to be a candidate for WATCHMAN, a few criteria should be met. One — no current LAA clot. Two — assess need for dual antiplatelet therapy plus anticoagulation (triple therapy where applicable). Other indications include higher bleeding risk (low platelets, recurrent GI bleeding, prior intracerebral hemorrhage), poor anticoagulation adherence, frequent falls, etc.

Speaker 3  16:35
a candidate. And then, as we already established, our patient Frank has a high risk of strokes and also a high bleeding risk; at the same time he is at high risk of having an embolic stroke. So we're kind of balancing those risks.

Speaker 1  16:51
And admittedly, we don't have a great deal of data for the watchman device, but of the data we have, it does appear to offer some benefit in terms of stroke prevention, somewhat comparable to what you would get from Warfarin as an example. So for Frank, potentially, he could have his cake and eat it too, in the sense that he may be able to have stroke risk prevention using watchmen without having long term. We're talking months down the road bleeding risk that clearly he's at a very high risk

Speaker 3  17:18
for, yeah, and the device will be used by itself. So looking at the protector of trial study design, we probably would be giving him the watchman device if he is a good candidate for that. But then he also will be on warfarin plus aspirin for 45 days, and then aspirin plus Plavix for six months, and then aspirin there after alone and not to negate the bleeding risk of the anti platelets over here too. So we're not using warfarin, but at the same time, you're kind of using one sort of anti platelet, which is the aspirin in this case. So the risk of bleeding is still high in patient. Education should still ensue.

Speaker 1  17:56
We should admit that there is a small amount of data where you don't use Warfarin in those extremely high risk patients who do get a watchman device, but that's not how it was studied, and protect AF and prevail. And for that reason, you're really in uncharted waters if you choose to go the watchman route, but they have some absolute contraindication to warfarin. So if they're at let's say they had a head bleed two weeks ago, and you're very worried about their risk of stroke, embolic stroke. Could you do a watchman? Sure, but it's not going to be supported by the literature, because you wouldn't be able to give that patient Warframe because of their recent head bleed, for example, and you would be basically in a gray area in terms of what is their risk of procedure related complication and bleeding risk and stuff like that. So if we kind of summarize where we're at. It sounds like Frank might be a candidate, if we go back to some of the key points we talked about. The first is going to be anyone with afib is going to be at an increased risk of stroke. And we can actually use the Chas two vasc scoring system to figure out how bad their stroke risk is. And the reason that those that they're at a stroke risk is because they have clots that form in the left atrial appendage. Those clots travel to the brain, and that includes blood flow causing an embolic stroke.

Speaker 2  19:07
So for patients who are not deemed to be good candidates for anti coagulation, again, for some of the reasons we've already discussed, high bleed risk, for example, watchman device and other future devices that work similarly, their occlusion devices may reduce the risk of stroke similarly to a full anticoagulation.

Speaker 3  19:24
So again, in patients with a CHA2DS2‑VASc score of 1–2 or more, anticoagulation with warfarin or DOACs is the primary method of reducing the risk of stroke, per the CHEST guidelines.

Speaker 1  19:37
Then finally, the WATCHMAN device does have reasonable data regarding efficacy versus warfarin. There is a risk of procedure‑related complications (notably pericardial effusion), but the long‑term bleeding risk is substantially reduced if the device is successful because patients are not maintained on long‑term warfarin thereafter. And depending on your risk, a typical risk is about two to 3% per year of major hemorrhage for any full anticoagulant. So we always have to consider that as well. So with that, that concludes episode 62 we absolutely love the five star reviews in iTunes. We also love review comments that tell us what kinds of episodes you guys want to hear, what topics you're interested in. We read every single one, and always talk about it when we have our planning meetings. So if you want a specific topic, either email us and our contact information is at HelixTalk.com you can find us on Twitter at HelixTalk, or you can leave those beautiful five star reviews with comments to help us understand what you want to hear more about. With that, I'm Dr. Kane, I'm

Unknown Speaker  20:47
Dr. Sherman, and I'm Dr. Patel, and as always, study hard.

Narrator - Dr. Abel  20:51
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 to

Narrator - ?  21:03
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.