So what we're going to do is we're going to shift gears here and go to a lecture we've got Dr. Alan Barkin, who's going to give us a lecture on new tools for non variceal upper GI bleeding. Okay, you can come up. Thank you. Post COVID, I'd still mention I've had this sore throat for two weeks I've been tested it's due to too much lecturing and too much parting in Jamaica, but I will spare you that part. Okay. I'm okay here. I don't mind. Yeah. So, these are my disclosures. So what we're going to do over the next 15 minutes or so is to give you important background information on GI bleeding and look at newer modalities. I'm going to focus on two. I'm going to focus on the endoscopically applied hemostatic topical products, principally hemo spray. And we'll go over a brief video of the guidelines recommendations and I'll bring you latest evidence on this, including data that is not published yet. We'll do the same thing for the cap mounted clips, mainly over the scope clips and try and conclude in a rational fashion. So overall non variceal upper GI bleeding mortality, it has gone down. It's gone down to about 2% in the large population registries we've found. Management is based, as we know, on endoscopic hemostasis, followed by PPI as an adjuvant when that is done successfully for the high risk lesions. Conventional endoscopic therapy can fail in 15% with free bleeding in 25%. And this is why the newer modalities have emerged, at least in part, which I was asked to do is to put this in context for you today. So which ones do we have that work? We have a bunch of them. Bipolar electrocoagulation, heater probe and injection of absolute ethanol, particularly done in Asia, has the best certainty of evidence and with the strongest guideline recommendations. Through the scope clips, APC and a soft monopolar electrocoagulation for GRASPR have lower level evidence but still are recommended. And finally, I remind you that epinephrine alone is fine if that's all you know how to do. But you should know how to do more because epinephrine plus something else is superior to epinephrine alone. That's old story. So what are the refractory lesions? We talked a little bit about some of them here. Hemodynamic instability, even if it's transient at the start. Active bleeding is defined by spurting and or oozing. Ulcers size over two centimeters. And the location of the ulcers, typically what James Lau says, ulcers that have names in anatomy textbooks. So you're looking at the left gastric, which is high in the lesser curvature, and the pancreatic oedudenal and the posterior oedunals. For these patients who do have recurrent bleeding, we recommend repeat endoscopy with the same endoscopic modalities. I'll try and position the more modern two in a second. And in refractory patients, transarterial embolization and rarely surgery, depending on the local expertise. So let's start with the hemostatic powders or gels. I'll focus mainly on the powders. This is for TC325. It adheres, it's important, only to active bleeding sites. But when it does, it absorbs the water, it sticks to the bleeding area, and provides mechanical tamponade. Problem is, within 24 hours, it's gone. So you have to keep that in mind when you're going through your thought process of how you're going to manage this patient, depending on the lesion. So this is from a recent systematic review and meta-analysis that was just published. And you can see we have TC325, which is hemo spray. I'll talk about endoclod briefly. Pyrostat, which is a gel, which is only approved or mainly approved for intra-procedural or periprocedural use and prophylaxis of bleeding, I will not talk about. It's a different kettle of fish. Nexpowder is coming on with some data. And I will not talk about the CGP003, because there are very few data on it. So they are either mineral-based, or they're polysaccharides, or a biocompatible natural polymer. And the mechanism is actually roughly the same as what I showed you on the diagram. They absorb H2O, they form a mechanical tamponade. The big difference is that TC325 remains a powder, sometimes very granular, hard to see if you want to do more at the same setting. And it has to be an actively bleeding lesion. Endoclod is a finer powder. And the Nexpowder actually becomes more clear, and it's a little bit easier to see if you want to do more at the same setting. So what are the data? I'm kind of a data guy, so I'll go over that with you. The guidelines. We suggest endoscopic hemostatic therapy with the hemo spray for patients with actively bleeding ulcers. Delivery of the catheter is one to two centimeters. I'll show you an example of that with some bursts until the bleeding set is covered, and bleeding stops. There are issues with delivery of the catheter. It can get clogged. Andy's published on bone wax tip catheter. We can discuss it if need be. We have one good non-inferior randomized trial, although there are other randomized trials done with 130 ulcers and other lesions as well that satisfy the criteria of non-inferiority compared to standard therapy, suggesting that this is an acceptable first-line approach, including for ulcers. The problem is that there were some methodological issues. I don't want to go into details for this, but there were more malignant bleeds in the hemo spray group, and we know that probably malignancy is not a bad indication for this, and I'll show you randomized trial data for that. Of course, there's also the cost of the procedure. Depending where you are in the world, it's even more so in the U.S. So what are the data? Topical hemostatic agents. Again, mainly hemo spray. The largest meta-analysis, almost 60 studies, almost 3,500 patients. Very good immediate hemostasis rate. Re-bleeding is all over the place because it's observational. If we specifically look at the comparative studies, this includes a recent randomized trial meta-analysis that was done as well. You can see, and this is one main take-home message from me to you, probably these topical products are the ones that provide the most reliable immediate hemostasis. If the powder reaches the bleeding lesion, the lesion will stop bleeding in the great, great majority of cases, probably better than what else we have right now. No difference in subsequent re-bleeding for all the methodological issues related to it. A low adverse event, but low certainty of evidence because of the number of trials and patients. So I thought if we can play the video, just to give you an example, and it'll transition to the issue of malignant bleeding. So using these powders has advantages to it. There's no touch method. You can see here a very large GE cancer, and this highlights a number of issues with malignant bleeding. Reduce area, multiple bleeding points, tissue that's just asking to fall apart in front of your eyes. As soon as you touch it with any of the endoscopic hemostatic modalities, it's going to cause more bleeding. So this at least is an advantage for using a spray. In addition, the spray has the advantage of being able to be passed along a large surface area, and you can see it here. It gradually is covering the area. How much you use is really dependent on a number of issues. Don't forget, however, as well, because as you're doing this, it's CO2 pressure driven. The patient may complain of discomfort if they're not intubated, and you need to suction regularly. This is when I took it over and wanted to show that you can apply it very quickly if you need to. And again, on contact, it works very well to stop bleeding in most cases. So a lot of theoretical reasons why this may be helpful, particularly in malignant bleeding, something to keep in mind when I'm going to show you the data. So what are the data? So malignant bleeding, we have few approaches that have been found to be helpful in malignant bleeding. There were some baseline recommendations on this, because there were few data, and very few high quality studies. We now have two randomized trials. The first one included both cohort and randomized trials. Primary hemostasis, again, amazing primary hemostasis rate, particularly in malignant bleeding, probably better than what else we have. These are not all just, these are not all comparative. Early and delayed bleeding is high, but these patients are a problem group. And when you look at all cause mortality and GI bleeding related mortality, there's no reason why putting spray powder up front will help the mortality of someone who's got cancer down the road. So you wouldn't really expect it. And indeed, that's not a major take home message. This is where there's new data. There's actually the largest randomized trial looking at hemo spray malignant bleeding has not been published yet. It has been submitted and will be published probably within the next six months or so. I'm not at liberty to discuss with you the results of it, but I am at liberty to discuss a subsequent patient level meta-analysis, RCT, that includes the large trial. And what you can see here, the take home message, and this is randomized trial data, immediate hemostasis much greater than the conventional approaches. So clearly I think we'll be able to push the recommendations from guidelines in saying that we finally have something we can recommend. Many of us have been doing it, but now we'll have data. There's no significant improvement in re-bleeding, but interestingly, when you remove one of the studies, then stuck with only two studies and not many patients, they actually show significant improvement down the road. Why applying a powder at point A improves re-bleeding 20 days, 30 days later when the tumor is still there, despite co-intervention with radiation and so on, is not clear cut, but there is a signal there. Another reason maybe to use that, even though the data aren't very clear cut. So that's for the powders. If we move on to over the scope clip. So I thank Amrita Sethi for this, because I think it highlights a number of issues. So this is the over the scope clip that probably most of you are familiar with, maybe not for bleeding. This is a patient who present had bleeding, had re-bleeding, had initial endoscopic therapy, had a second endoscopic therapy, re-bled after that, and needed, as you can see there, coils. The patient also had radiation, radiological embolization with coil insertion. Sure enough, this is the bulb. This is the pancreatic adrenal artery, and we know this is a very high risk for re-bleeding, as is the case here. So you can see the operator is there. It looks amazing. It looks clean. Why would something like that ever cause so much bleeding? Well, the pancreatic adrenal artery is a problem. So when you go ahead and you approach it with the cap mounted clip, you can try here. They tried to bring the tissue into the cap. It did not work. Luckily, the base is not too fibrotic, and they're going to try and go ahead and suction up a little bit like was discussed for varices, and it's the same principle. You want to be able to suction as much of the tissue, especially in this case, because you're going to get a transmural bite. This is the big advantage of using these over the scope clips. When you say to yourself, it's cool, I've got this, you've got this, but thank goodness, by the time it really starts bleeding and you're not going to see nothing, the lesion is in the cap. And now you can understand why there's been so much re-bleeding. This is after multiple maneuvers attempts. And the reason I showed you this is because it highlights the transmural thickness bite that these over the scope clips provide, because if you actually look carefully, you can see that the coils are even closer than they were before, because you've gotten a transmural bite there. So this is very helpful in highlighting a number of issues, but it's not a complete solution, the over the scope clips, and we'll come to the data. So what about these cap mounted clips? I'm going to refer to over the scope clips, which as you know, is one of the manufacturers, because almost all the data is from them. So we did recommend it as a hemostatic therapy for patients who develop recurrent bleeding due to ulcers. There's actually a small randomized trial, but well done and was good enough to drive the evidence for us to recommend it. You can see here, compared to the conventional standard approach, it decreased recurrent bleeding for patients without any differences in the other outcome measures, because it was a small study. Cost effectiveness data are here or there, they vary tremendously depending on where you practice and so on, and I won't go into that unless you have specific questions about it. Now, what about, however, the over the scope clips, not as rescue as I just showed you where the data are good, as initial treatment for non-variant CLIP for GI bleeding? So we actually have meta-analyses. Meta-analyses of both cohort and randomized trials published last year in GIE by Bapai and colleagues, 10 studies, lower 730 day re-bleeding, clinical success rate is higher, we're off to the races, everybody thinks it's terrific. Hold on. It is, but you need to understand the data. As yet unpublished, meta-analysis of four RCTs specifically looked at this. The composite outcome measure, which included immediate hemostasis and then subsequent recurrent bleeding did fine, but there's no difference in the persistent bleeding, the immediate bleeding rate, and I'm going to come to why that is. However, the 30 day re-bleeding was lower. So my take home message to you about the over the scope CLIP is that if you can put the CLIP on, it's the best thing we have available, yes, but the problem is you can't always put it on, and is it worthwhile from a cost effect issues and so on, those are different issues. So there are issues, and these are the issues I want to bring up with you. I wrote actually an editorial in the annals to the most recent largest randomized trial in this area that was published, until it wasn't published a couple of weeks ago. Methodological issues, imbalances between groups, one RCT focused only on large peptic ulcer, bleeds over 15 millimeters, by the way, it was a negative trial, so it's not a complete answer for this problem group. No operator blinding, issues with standardized criteria for crossing over, which is a problem when you're using intention to treat conclusions. Sometimes varying definition and points, no improvements in immediate hemostasis, but robust benefits in preventing re-bleeding, as I mentioned to you, and varying use of routine second look, which is an issue because it confounds the outcome to a certain extent. But the main issue comes to the success rate of the over the scope CLIP application, which is variable. In the studies that reported it is between 2 and 8%. This is significantly higher than what's reported with all the other methods, granted the 8% was in large ulcer bleeds. Related to patient anatomic factors. So they actually looked in and said, we're going to randomize this patient. And then they looked at the ulcer and said, oh crap, no, I'm not randomizing this patient. So this patient wasn't counted, but should have been counted as a failure. And the reason for why these patients, the anatomical factors are areas near the pylorus where you risk to cause obstruction of the pylorus, or in the duodenal bulb where it's very tight fit, and again, it's very difficult to place. So be aware of that. And in addition to this, these were highest group centers. They were trained on using the CLIPS and even they had trouble putting them in. So please understand that there are some issues in putting these CLIPS if we're going to use them as a primary method. Lower salvage rates as well. Once your over the scope CLIP is in place, good luck if the patient rebleeds. It limits what you can do in the scopically thereafter. And the adverse events rates include the pseudopolyp formation, which is basically partial obstruction because you brought in the lumen as well. These are all new entities that you may be familiar with in other indications, but not when we're doing primary indication for bleeding. So that's an issue. So buyer beware. These may affect the so-called generalizability, meaning the types of patients who use or the type of operating expertise that is needed, and unfortunately may have affected as well a little bit of what's called internal validity, the conclusions of the randomized trials. I'm wearing my epidemiologist hat for a second when telling you that. So the conclusion. Endoscopic hemostasis is improving outcomes for patients with refractory bleeding and perhaps malignant bleeding. And that's very exciting. Neuromodalities you need to know how to use include the hemostatic agents, particularly hemostatic, but others are coming, and the cap mounted CLIPS with the data mainly being for over the scope CLIPS. These are ready for prime time. Both modalities are useful in refractory bleeding and in rescue therapy. But there's still uncertainty about what clinical context, whether it's good for first line as well, and which patients with which lesions are good candidates, particularly for the over the scope first line approach. So that includes PUD versus malignant lesion versus others for the hemo spray and the anatomical locations I've mentioned for the over the scope. So guidelines suggest using topical agents and likely will also suggest, as I mentioned, using the over the scope not only for rescue, but for first line and hopefully for malignant in the case of the topical agents. Cost effectiveness issues, however, do remain poorly addressed at this point, unfortunately. And I always end all my talks like this, and I'm sorry if I sound like it too, but I think it's an important take home message you've heard already today. Always perform endoscopic hemostasis in a setting that is optimized from the patient, the endoscopist, the assistant, the technique, the suction as we heard, and always remember that you can and should reach out to colleagues, other endoscopists, radiologists, surgeons in challenging cases. There's no room for an ego when you want to take care of a patient properly. Thank you very much.

non-variceal upper GI bleeding

endoscopically applied hemostatic topical products

cap-mounted clips

conventional endoscopic therapy

refractory and malignant bleeding