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Semaglutide for CVD in Diabetes, PAD, and MASH, Semaglutide vs Tirzepatide, Normal Saline vs Lactated Ringer's, Oxygen Targets for Intubated Patients, Platelet Transfusion Guidelines, Apixaban vs Rivaroxaban
In this episode of 'Last Week in Medicine,' Stephen Jenkins and Dr. Brian Locke discuss recent studies on semaglutide, focusing on its cardiovascular benefits in high-risk diabetes patients,...
Semaglutide for CVD in Diabetes, PAD, and MASH, Semaglutide vs Tirzepatide, Normal Saline vs Lactated Ringer's, Oxygen Targets for Intubated Patients, Platelet Transfusion Guidelines, Apixaban vs Rivaroxaban
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Welcome back to last week in medicine. It's Tuesday, June 17th, 2025. I'm Stephen Jenkins and today I'm joined by Dr. Brian Locke. Welcome back Dr. Locke.
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Thanks for having me back. Yeah man always a pleasure. Dr. Rupp is taking the week off due to I don't know childcare and 16 days. I'm just finished 16 days and needed a break which I respect. So yeah I don't man I haven't done a stretch that long since like ever. Yeah. Oh my gosh. That would destroy me. Yeah. So they just do a different thing.
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I guess. But yeah it's good to see it's been a couple months so there's been a lot of interesting papers that have come out in the last couple months so we're going to kind of do some rapid fire review I think of some of these these papers but didn't want to leave out any of the good stuff so.
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I'm going to start us off with just a little round up of some some agglutide papers because I feel like some agglutide is like the sun stoppable force now where every time they study it in something it works and so it's just nice to kind of quickly review some of the some of the winds for some agglutide.
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And then and then we'll look at another one where there was a head to head of some agglutide versus Terzepatide so we always love the head to head competitions so.
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But the first one I wanted to talk about was the the sole trial which was oral semi-glutide and cardiovascular outcomes and high risk type two diabetes.
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This was actually published online back in March but in print May 29th into the New England Journal and the first author was Dr. Daryn McGuire at UT Southwestern and all of these semi-glutide trials were funded by NOVO Nordisk but this was a pretty big trial this was almost 10,000 patients so 9650 with diabetes and known cardiovascular disease or chronic kidney disease or both so kind of these higher risk patients with type two diabetes.
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They had to be 50 years or older and the excluded patients that already had end stage kidney disease and the question they were asking the semi-glutide reduce or reduce risk of cardiovascular disease and death from cardiovascular disease.
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And so they the patients that they got you know average age was like 66 72% males 69% white majority of them were enrolled because of pre existing cardiovascular disease with 13% had chronic kidney disease.
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And they were randomized either oral semi-glutide or placebo so most of the semi-glutide studies have been in injectable semi-glutide which has been really effective I think because you know it's easy to take something once a week it probably has better bio availability but this was looking at oral semi-glutide so just another daily pill.
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And the primary outcome was a composite of death from cardiovascular disease non fatal MI or non fatal stroke and it was a positive study so the folks in the semi-glutide arm they the primary outcome happened in 12% of them versus 13.8% in the placebo arm which was statistically significant and so looking at the hazard ratio of 0.86.
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So basically there's a 14% relative risk reduction and it was interesting to me to just go back and look at like other you know big drugs that reduce your cardiovascular disease risk like the number one is statins right and in looking at kind of a meta analysis of statins that one was associated with a 28% relative risk reduction compared to placebo.
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So about 14% is pretty good and I you know I imagine most of these patients were taking a statin I would guess if they have pre-existing cardiovascular disease so it's pretty impressive that you can get that additional risk reduction with this oral semi-glutide.
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If you looked at the individual components of that composite outcome the strongest signal was really with non fatal MI which had a hazard ratio of 0.7426% relative risk reduction and it wasn't statistically significant for cardiovascular death.
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Interestingly if you're looking at secondary outcomes they did look at major kidney disease events that was also not statistically significant.
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And there was a previous study earlier I remember if it was last year or earlier this year the flow trial that did show a reduction in kidney failure and GFR decline in people that was using subcutaneous semi-glutide so maybe there is a difference there with the world versus the subcutaneous.
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Anyway I thought this was like a pretty interesting study because it's you know it's maybe not every patient wants to use injected injectable semi-glutide they could take a pill and still get a pretty significant risk reduction for their cardiovascular disease.
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What do you think Dr. Luck?
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Yeah I agree I mean I think if I was looking at the flow trial and I think they enrolled folks with quite a bit worse kidney function at baseline so I also wonder if rather than being a difference in how the medication works if that trial was just sort of more enriched for folks where you could detect an outcome because it certainly would look like the point estimate favored you know beneficial kidney effects.
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That's not like it was a inconsistent finding with the prior data.
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Yeah it's a good point.
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Did you catch I didn't see in there how did they define coronary artery disease for trial enrollment you know because I always wonder you know there's sort of radiographic coronary artery disease or like you know which everybody I mean not everybody but you know you get a lot of
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folks that have like had an MI that enrolled them or was that there somewhere that I don't know that's like you know that in the definition yeah.
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Yeah the event rates pretty low you know in the however many months have followed up it was only you know minority of folks having clinical events you know which could reflect that it was a pretty healthy population or perhaps they were a little more lenient with their inclusion criteria.
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Yeah I mean oral stomach blue tide everybody's going to be honest right I imagine that's what no you I really do say I feel which one's no vote.
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This is this one's no vote yeah yeah no vote you know I imagine that's what they're going for is just that injections probably dissuade a lot of folks that really would benefit from these medications and so if they start to get indications or at least you know data supporting the oral
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formulations then boy that's really appealing. Yeah compete with tears appetite as we'll talk about at some point here.
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Right right so I think you know the just looking at the paper again they don't really specify maybe they do in the supplement somewhere but basically they're just saying you know you have CAD you have a history of cerebral
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cardiovascular disease symptomatic peripheral artery disease or kind of how they define cardiovascular diseases so so you have pretty pretty broad definition but not surprising in these folks that have type 2 diabetes in your 50 years
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and older like they're going to have some basket disease is kind of expected as part of that so yeah so so that was a win for some agglutide.
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I just wanted to mention a couple other trials that came out in the last few months for some agglutide that were interesting one of them was looking at symptomatic peripheral artery disease that was the stride trial that one was
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published also back in March 29 in the Lancet and that one was looking at patients with type 2 diabetes with peripheral arterial disease with intermittent
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cladication they had to have an ABI less than or equal to 0.9 and the end point they looked at in those folks was maximum walking distance which they did on like a standard kind of treadmill
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at a fixed speed on a fixed incline of 12% and normal folks should be able to walk about 6 to 800 meters on a treadmill with those settings these folks with peripheral arterial disease could only walk about 185 meters
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in the study group and they randomized them to either semi-glutide injection or placebo for a year and then they so they did baseline treadmill and then at a year they did repeat and both groups actually improved compared to their baseline which I thought was interesting but the semi-glutide did have a higher ratio of improvement 1.21 compared to the placebo of 1.08
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so they did improve their maximum walking distance which I'm sure is an important metric if you have PAD and that does seem to be like a disease where not much actually improves their disease trajectory
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and so it's nice to have another medication that might be useful for those patients.
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Yeah, I mean that's an interesting question of like how why that's working so effectively you know it's like if you lose weight that's certainly less muscular effort that has to you know propel you along walking or you know maybe it is actually sort of regression of some of the plaques or who knows but yeah I mean
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yeah I have another win in the column for the LP ones we will keep it all here another win for novo Nordisk yeah and then there's this other one they came out June 5th in the New England Journal this was the essence study it was a phase 3 trial of semi-glutide and metabolic dysfunction associated stiato hepatitis which is you know we call mash or massal deagas but this was stiato hepatitis variant
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and this one they they were looking at adults who'd already had a liver biopsy with proven mash with stage 2 or 3 fibrosis they randomized 1197 patients to again injection weekly semi-glutide or placebo and this was for 72 weeks they did an interminalysis of the first 800 patients at 72 weeks and they found that semi-glutide led to resolution of stiato hepatitis without worsening of fibrosis
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in 63% of patients versus 34% in the placebo group with improvement in their fibrosis stage in 36.8 versus 22.4%. So another kind of disease where there's not a lot of drugs that actually help right so it's kind of exciting that these GLP1 agonists might be effective in folks with metabolic liver disease which we all know is extremely prevalent I think we used to say it was the most common cause of liver disease I feel like in my experience
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it's probably still alcoholic liver disease that I'm seeing but I think the two together if you know if this if this drug can help those folks and that's that's a huge win.
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Yeah yeah pretty incredible and I guess they're really it sounds like swinging for the fence on this one with the you know that the main trial result is cirrhosis free survival at 240 weeks you know which is a pretty ambitious end point to you know show basically
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mortality benefit you know several years down the line so right yeah I'll be pretty interesting I mean I got to imagine you know that both the you know the co primary end points for resolution of the hepatitis portion on the repeat biopsy and you know regression or improvement of the cirrhosis portion or the fibrosis I guess since they weren't necessarily
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all serotic but you know pretty pretty compelling that if those improve it would be sort of odd if that doesn't translate to clinical improvements down the line.
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Yeah yeah and I think it's interesting that yeah like you said it's like you say 240 weeks that's like a pretty pretty long trial this one at 72 weeks you know they had six patients in the placebo arm died in three patients in the stomach lute type arm so obviously this this study isn't probably powered to the dead end point
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and I don't think it's going to be a good idea to detect any mortality benefit but maybe out at 224 weeks they'll be able to see a separation there.
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Yeah yeah although I wonder I wonder how much they're sort of stacking the population with requiring folks to have biopsies you know just today I don't see a ton of biopsies and folks with kind of run of the mill mash you know
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yeah yeah you know have sort of an odd suspicion for maybe the Zato immune or something else is going on.
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Yeah that's a fair point I wonder how much of that could be like regional differences in the way that we manage serosis because yeah for sure here in Utah like I feel like you know we do the shotgun work up and if we don't you know find the smoking gun that explains the serosis
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and they have like the right phenotype then we'll typically just blame it on metabolic dysfunction without getting the liver biopsy but I do wonder if you know across the country if other centers are more likely to do biopsies it's a good point.
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Yeah I mean it seems like even I mean say these results pan out and it turns out the GLP ones are super effective I mean it probably wouldn't be that contingent for all the you know like all these folks that you are considering
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whether they have mash or not like I don't know so you did the biopsy and they didn't they still probably have like three other indications for GLP ones.
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You know if you're going to put them on some of the data is appetite anyway.
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Right.
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What's the point of necessarily doing that unless you're trying to rule out autoimmune or something.
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Yeah.
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Truth management.
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Higherly different way.
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And I think it's funny we always send off the autoimmune liver labs and a lot of times they come back positive and the hepatologists are still like nah it's probably a false positive.
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They still don't get the biopsy.
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It was test.
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Two sensitive I guess.
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So that was that one and then we'll end this semi-glute tide round up with maybe maybe it's not a win for semi-glute tide but it's still an interesting trial.
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This was to zip it tied as compared with semi-glute tide for the treatment of obesity the surmount five trial.
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So you know semi-glute tides have been hot for a few years now but there's there's this other drug that's been on the market for a bit by Eli Lilly to zip it tied sold as moon jarro and zett bound now for weight loss.
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And I think you know in the initial trials for zett bound like they showed a pretty significant reduction in weight loss that seemed to be more impressive even then what you got with semi-glute tide.
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So then Eli Lilly magnetimously you know funded this trial to prove that it did cause more weight loss even than semi-glute tide did.
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So the difference is between the drugs.
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So the average age was 45, 65% women and 76% white and they looked at them over 72 weeks and Terzepa Tide was associated with the 20.2% mean percent body weight reduction versus 13.7% percent percent percent of glute tide which was a statistically significant difference.
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So you also had bigger change in waist circumference with Terzepa Tide. Interestingly there was more GI side effects with semi-glute tide. There were more injection side reactions with Terzepa Tide.
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So I guess the question I have from this is great we have two pretty effective weight loss drugs now.
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Are we going to assume that all of these amazing benefits that have been shown with semi-glute tide and all these other diseases are going to translate to Terzepa Tide as well or is Eli Lilly going to go out and have to do all the same trials that Nava Nordisk has been doing.
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I think they are doing most of them. I guess some of the indications we didn't talk about half-path. There's also Terzepa Tide and semi-glute tide trials either ongoing or finished.
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Terzepa Tide has sleep apnea now as an indication. I think both are doing PCOS trials. So I think the profit motive of trying to get FDA indications and coverage for all of this is really a carrot that's pushing the pharmaceutical companies to invest in run the trials.
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I think the ethical justification for running them is that most patients can't get these medications covered anyway. So you can say there's some equipoids to cover folks.
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I mean that window is going to close eventually is these indications come out and then it's not going to be appropriate to randomize to placebo.
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If you know that semi-glute tide improves cirrhosis free mortality and mash then it's no longer acceptable to do a Terzepa Tide versus placebo study.
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So I think they're really sort of raising along. But I don't know if Terzepa Tide I haven't seen peripheral artery disease or CKD as the ones that they're there. I think everything else they're either in the process or have sort of replicated findings because I think they really want those big broad indications.
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And then there's reddit true tide the triple GLP1 GIP and then insulotropic glucose peptide. I forget what the last one stands for.
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But you know yet yet another hormone in that same sort of cascade that appears to you know preliminarily probably and do you see even more weight loss.
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So you know maybe we're going to have to do it all a third time.
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Yeah well I guess it's probably not you know the totally bad news for Denmark that Terzepa Tide was better because semi-glute tide has plenty of indications and you know it's already being saturated everyone's using it.
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So I've been wondering as a hospitalist like what our role is going to be because you know for a lot of patients that's like one of their main contacts with the health care system is when they get admitted to the hospital.
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And we generally do not worry about trying to get people started on these types of medications since it's not an acute need.
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But you know with it's like with heart failure you know someone comes in with decomstated heart failure we do make an effort to get them on the guideline directed medical therapy.
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So if like these drugs become kind of standard guideline directed medical therapy then we probably will have more of a role getting patients started on while they're in the hospital.
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Yeah I mean certainly the folks that are like having admissions related to these metabolic diseases are like a high risk subgroup that really should you know benefit.
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Substantially so I do think that you know I think there's a health care delivery problem and that like as the inpatient teams were not the ones managing it and following things and so the approvals and management soltough but you know from what's right for the patients it does certainly seem like these pipelines need to start at the first place that patients get touched.
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So yeah it's interesting I mean I'm actually running into this issue right now in my pulmonary clinic just because I think the I see a lot of patients who have sort of respiratory indications you know that are generally softer but like should probably be on a GLP1 you know of hef pep is contributing their dysnia they absolutely path you can't do a CPAP but like I don't know pulmonary clinic prescribing metabolic medications is like you know not the paradigm but like cardiology got into the game easy.
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Yeah you know and so I think you know in the future hospital based providers and you know other specialties that are related going to be prescribing these I mean probably should.
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Yeah yeah I mean really it's all about do you have a good pharmacy and infrastructure to get all those prior off going.
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Yeah exactly.
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Yeah I didn't realize you mentioned that tersepartheid has an indication for sleep apnea like it has an FDA approval for that.
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Yeah yeah it's a recent thing so surmount OSA was the trial it came out within the last year you know it should both HI and symptom benefits for folks you know it's not as effective as CPAP and the folks that will tolerate it at least in resolving symptoms but you know probably as all these other off target effects that the sleep community we've been trying to prove that CPAP would improve but like clearly tersepartheid you know prevents cardiovascular events and all those things.
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By a bunch of different mechanisms so yeah you know I think the sleep apnea management pipelines are in and flux to try to figure out like hey what do we do with this since yeah you know all of the patients that we see probably have multiple indications for being on these medications but it's a much different workflow than the usual sleep treatment so right right a lot of change there.
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As a hospitalist I'm trying to think of like which would be easier for me to get from my patient CPAP or tersepartheid.
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Yeah right I mean with that the delays in sleep testing certainly yeah it's easier sometimes to just get them on tersepartheid.
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Yeah yeah I just had like a really tough inpatient admission for patient with like severe sleep apnea it was so frustrating that we're like just discharging them home on oxygen because he needs a sleep study needs to get into the sleep clinic and
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and I hope it happens right you never know. Yeah I actually this is deviating from our normal belly lick but I actually presented some research that we're doing at ATS to say how many folks who come in with
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Piper Capnic respiratory failure actually get sleep testing in the year after hospitalization and it's low very yeah yeah that's a cross you talk so lots of room for improvement there.
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Interesting all right well let's switch gears then get away from some agglutide and let's talk about one of our perennial favorites about which fluids should we use in the hospital.
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Yeah yeah well switch it from huge trials with huge effects huge trials looking for tiny effects.
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Yeah yeah so I was going to start reviewing a trial that just got presented at a conference called critical care reviews which just happened and they presented a lot of trials in the critical care space and so you know there's a dozen trials that were just released in the last week or so and you know I'll say the conference is actually pretty cool because they
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do these presentations and discussions they're pretty in depth they spend like a couple hours on each study and actually post the live streams of those conversations and so I haven't actually listened to him yet this year but last year sort of went through all those and you know the trialist sort of say hey this is what we're you know why we made the decisions we made or what we were looking for.
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So there's hours of content on these trials if this treatment isn't enough but to jump into the actual trial so like I mentioned it was it's called the fluid trial it's in the June 12th New England Journal McKin tire is the first author and you know this is a trial looking at lactated ringers versus normal saline which you know there's already been a handful of
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trials that have looked at both all cosm mortality silacoms and then kidney events with the idea that like probably the main difference here is normal salines got 150 mill equivalents of both sodium and chloride and the idea being that the excess chloride load is presumably a little bit or suspected to be a bit nephrotoxic and so that may impact downstream outcomes and so there's a lot of
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there's a meta analysis out there are 13 trials and sort of 35,000 patients that summarizes all the all the literature on this and if you just look at the six low risk trials the more all cosm mortality estimated sort of 0.96 for lactated ringers going from 0.91 to 1.01 so like I don't know kind of a borderline finding but maybe this does impact all cosm mortality and so this Canadian
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trials group endeavored to sort of more definitively settle the question and what they did is open label two period two sequence cross sectional cluster
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randomized crossover trial which is kind of a mouthful to explain but you know the idea here is that so open label refers to they didn't try to hide
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whether patients were getting normal saline or lactated ringers the two period two sequence means that they would randomize hospitals to either have so they're going to have two periods and it was either going to be a lactated ringers period followed by a normal saline period or a normal saline period followed by a lactated ringers period and you know as as that sort of implies the unit of randomization here is at the hospital level
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and so the way that they did it is you know all these hospitals in Ottawa would you know get sort of randomized and then they would just give everybody normal saline if it was the normal saline period or at least that's the idea or give everybody lactated ringers during lactated ringers period and then they would swap
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and so that's the cluster part the cross sectional part just means that they it's not that they were following the patients like the cross different hospitalizations other than to see if they got readmitted but it was just looking at the one hospitalization that occurred during a period and then the crossover meaning that at the hospital level each hospital has one period and one one the other and so the way they did that is that you'd get 12 weeks of one type of fluid
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there'd be a wash out period of two weeks to make sure that folks weren't getting sort of half and half and then there'd be another 12 week period of whatever the other fluid type that you got didn't get randomized to
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so it's sort of a complicated design but I feel like these are becoming much more common particularly in critical care because you know as long as you're testing two interventions that you know you might just encounter
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depending on who you had as an ICU doc or what hospital you showed up you know that either way there's variation in this care and so like there's no excess harm to randomizing it because we don't know which one's better and you might receive either one in the usual care of things and so they actually don't do individual consent for these trials which makes it a little interesting you know because they were shooting to say you know we want 140,000 patients that are in the hospital
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they're cumulatively going to be in this trial but at the same time actually in some ways it's like less of a big lift than like certainly these GLP1 trials where they're like individually consenting randomizing tracking doing outcome stuff for 10,000 patients like this is super low
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you know overhead and so that you know an embedded pragmatic trial is sort of how they refer to these
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and that so as I mentioned you know the I should say the outcome that they chose is also influenced because of this so they they chose either so 90 day death or read mission was the outcome just as a as a binary of whether that happened or not you know and the reason to do this is because Ottawa has you know nice integrated health systems where they can capture all these events electronically and so it means like
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the study team isn't out there tracking down in each individual patient trying to figure out what's going on there's a query on these databases to see you know like what happened
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the downside of that though is like I don't know is it really that plausible that like getting a little bit extra salt is going to make a break the difference on whether you die or come back into the hospital
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like I would be much much much more interested in the kidney outcomes but you know you can't like the if you try to assess creatinine well some patients don't get a creatinine check because the kidney function seems fine they don't have any problems so this embedded pragmatic nature of the trial really limits the types of things that you're
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looking able to look for and so you're sort of stuck just saying like all right well I guess we got to just see whether people died or not which is a little bit dubious and I think what will probably circle back to that point on whether this is really the right
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outcome to look for for this intervention but that you know so they they knew they were looking for a small effect like I mentioned they you know power calculations are a little bit tougher for this sort of trial because you have to estimate like how much variation there's going to be any
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hospital how correlated the outcomes are going to be they did a cool method where they sort of looked back for the preceding years before the trial to get estimates of all these things may actually sort of nail the
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rates for their power calculation but you know they said hey we're going to we're going to design this trial so that we have 80% power to find a 1% absolute difference in
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death or readmission in 90 days and that they estimated that was going to take 14 hospitals and that that would lead to about 144,000 patients total getting enrolled and so they fired that all
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up and then COVID happened and like blew it all apart and so they basically just said like we can't continue the trial with COVID and I think actually they didn't say this in the
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brand newizing 14 units now all of a sudden this big thing happens where temporarily the after behavior and the before behavior way different and how many people are dying away different you've got this bad confounder and that even with
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randomization you're going to really have troubles and so they kind of just had to acts the trial which is too bad and so they only enrolled seven sites and roughly 45,000 patients instead of the 144 that they were targeting
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you know which is a big problem because you know they said hey we're going to make this so we have 80% power to detect a 1% difference but if you drop that down to a third the
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Sam the size of the trial you are initially going to do your power to affect to detect a small sample a small effect like that just really plummet so I think truthfully you can't really do power
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calculations after the fact that are valid but they probably only had like a one in three chance of detecting an effect of that really is a real one at that 1% threshold but you got to do what you got to do and the New England general makes you do your
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frequentist hypothesis test like you said you are even if the enrollment totally goes off the wheels and so they did and they said they didn't detect a difference which is true so they the
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composite occurred in 20.3% of the folks that got cared during one of the Lacta Gringer's periods and there's 21.4 in the normal saline periods and so
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that relative risk reduction for Lacta Gringer's the point estimate is 0.97 with a 95% confidence interval that goes from 0.9 to 1.05 so not a significant result but I think that actually sort of doesn't really represent the finding because it's
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a relative risk of a 15% period like nobody thought that Lacta Gringer is going to have a bigger effect than like 10% relative risk reduction or whatever and so I think the actual you know the headline interpretation here is like we did not detect a difference but they also didn't do an
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experiment that was going to detect a reliable difference and so I think the more truthful interpretation which is actually what the author is putting their discussion after that you get past the sort of bullet plate that the journal editors expect is that this is you know another data point in a growing body of evidence that sort of supports a small beneficial
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effect of Lacta Gringer's but you can't really say on the basis of this trial and it's certainly not definitive so I don't know there's a there's a lot of interesting ways we could go with the discussion but you know I think this trial is worth thinking about just because I think this is sort of a near term future for critical care and probably
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hospital medicine trials is more of these embedded pragmatic trials due because it turns out it's actually in a lot of ways easier to just run a giant trial and randomize everybody than it is to individually consent folks in the current research environment you know so long as it's
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defensible to do that.
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Yeah yeah I mean especially if there's equa poise right then then yeah it seems like ethically that's okay to do it that way and it definitely helps you scale things up in a bigger way so so I guess yeah you mentioned that you so I went back and look the last time we talked about this topic of balance
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crystalid versus normal saline was 2022 and that's when the plus trial with came out and that new England journal evidence meta analysis that you mentioned and that one had like you know 35,000 you know patients
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including the meta analysis this this one that just got published at like 44,000 patients is it possible to do a meta analysis a new meta analysis including this one or or do you think that would even like show any difference.
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Yeah it is possible you know the key thing to know is that the like effective sample size of the cluster randomized trial is smaller you know meaning even though it's 44,000 patients
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the amount of information like the precision of estimates a little bit smaller and so the meta analysis has to sort of use the waiting according to the width of the confidence interval and so you know I think this would be a major contributor to the new meta analysis and I'm sure it's being done if it hasn't
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already been done by somebody you know that I don't think this will dominate the weights of the meta analysis or you know certainly won't be half of the information contribution but I suspect it's just going to you know slightly smaller narrow the width of the confidence intervals just because it is broadly a consistent finding.
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You know so my personal practice is still like I don't know if I don't have a reason to choose to still go with lactated ringers not because I like definitively know it really matters for this but you know the cumulative evidence you know is more favorable toward lactated ringers than it is toward normal say lean and like you got to choose one so you know it doesn't have to be definitive to know but I'll say like it's interesting because the adherence in the arms in the lactated ringer.
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I think that's partly just because like I mean I don't know exactly how many sort of order sets and like backers from medications they switched over to lactated rings but lactated ringers has some calcium in it and so you can't give it with like blood products because the citrate is going to.
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Keylet it on you can't give it with septra axone because it you know in the same IV I should say because there's a precipitation risk
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You know, so I think there's like even though it's not exactly that there's no downsides to lactated ringers
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You know, it may be a little bit more complex and you probably have to think a little bit more about your IV access and timing of things
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Because it was actually like a 15% advance difference. It was like 95% or 93% I think in the
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Normal saline periods and only like 78% adherence in the lactated ringer. So I think cost wise it's kind of a wash now. Neither is very expensive
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Mm-hmm. Mm-hmm. We did have a serious IV fluid shortage, you know in the last year after Hurricane
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I don't remember which hurricane it was Helen. I don't know there was a you know and so and we were on major
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Kind of shortage and then every time you went to order fluids you get a pop-up that's like, you know
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Do you really need fluids for this patient and and so we were you know able to reduce our fluid usage pretty dramatically
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Just by like kind of evaluating like how necessary is this fluid?
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You know and like like you mentioned, there's like all these order sets that use IV fluids
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You know and we you know going through all of those order sets
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It was clear that not all of them were really necessary and so our biggest reductions were actually probably like in some of like the surgical
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Services who were just putting everyone on fluids, you know maintenance fluids that maybe didn't always need it
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And so now that we've we've switched and we I think I don't know if we're using a different
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Vendor for our fluids, but you know, we're not on shortage anymore, but everyone still kind of acts like they're on shortage a little bit
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for a little while and you know
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Patient this is funny, right? Because patients will be like hey, can I have some fluids doc and you're like, I don't know
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Couldn't you just drink that water right there on your table?
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Like do you really need me to give you IV fluids? Yeah, yeah, no, it's interesting and I don't know
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I sort of see a segue here to the next article that we're gonna talk about but you know
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There's all these decisions that we like spend a lot of time thinking about just because we have to do something
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But the evidence that it really matters is like not all that strong
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You know like if you think about like the cumulative amount of time that we spend like debating like oh do we give 500 to CCs of fluids or
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You know do we do lactated ringers and normal saline?
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You know we've looked at it
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You know there's been conservative versus liberal fluid amounts
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Trials that haven't shown a difference and so you know it seems like at least in all comers is certainly there's not big effects
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All the small effects could be important if they were real, but you know the
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Two theories are like maybe it just doesn't matter that much which you know
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I actually think it's pretty credible
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Yeah, we should actually really just focus on the other things that's like is your patient on a GLP one or not
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Or there's some folks were really matters in one direction and it's and it is the opposite in another direction
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You know, which is possible
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You know, we've had a little trouble teasing that out for a lot of these things, but you know
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I think that's the the thing that people wonder about is like is there actually some folks where it's really important to do a one way and other
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Folks is really important to do it the other way and we just don't know that yet
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Which I guess time will tell
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And so you know the segue is we've been looking at oxygen targets for ever
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I can't actually remember if we've talked about oxygen targets on the
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Podcasts, but the I think we have
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Yeah, I think we did, but I don't know one of our it was a while ago
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I know yeah, if we had Austin he would remember but
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The the other trial that was released at critical care reviews which I'll do a little bit quicker is called UK rocks
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And that was published in JAMA this last week and you know, it's another one where they're looking at the question saying hey
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When we get somebody in the ICU that's intubated
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We have to choose essentially like how much oxygen are we going to give them do we want to just shoot for
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Like a pulse oximetry rating of 88 to 92 percent which is sort of that conservative oxygen meaning you know
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Just enough to get by or so we think or should we be more
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Liberal with our oxygen use and shoot for a higher target which is kind of the routine care, you know that most folks are
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You know having 94 95 percent or higher saturation. I should say that's an altitude and sole lake here
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4,000 or 1300 meters or so that you know people have higher saturations
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Lower altitudes. So there's this question of like, you know, it doesn't matter and there's some thought that you know
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Maybe excess oxygen is
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Toxic that there's been sort of retrospective studies of folks that have way high oxygen levels seem to do worse
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But whether that's really a physiologic thing or is that just a marker for like hey your
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Intensivist isn't actually paying very close attention to your care and they're probably missing other things is not certain
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So there's been a number of trials and sort of similar to this lactated ringers versus normal saline approach
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They haven't been definitive one way or another or I should say you know the cumulative evidence supports
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There's probably not a huge difference on average between those two strategies
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But you know if there was say a 1% difference in
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90-day mortality from choosing one of those
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Settings that would actually be pretty important just because
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Everybody gets an oxygen target and so if you can actually prevent death and you know
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Even a small fraction of something that everybody gets
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That would be important and so that's sort of the justification for this UK rocks trial
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And so what this was was
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They had they have in
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England and
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To I gotta remind myself actually it's 97 NHS hospitals
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They haven't registry of sort of all ICU care and so they actually embedded this trial into that registry
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With the idea being that they they did sort of a
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Waiver of informed consent initially and then when folks
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Woke up they'd ask him hey is it okay if we use your data which everybody for the most parts said yes
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And that anybody that was intubated during an unplanned ICU admission
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They potentially be eligible for this trial that would randomize you toward the lower target versus the higher target of oxygen
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They ran this trial in all of these NHS hospitals and you know 50,000 potentially eligible patients
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Uh
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Would have possibly been included you know their enrollment diagrams interesting because the
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You know 10,000 of the 50,000 Scott
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Excluded because the clinicians thought that one arm was like clearly contraindicated, which I have to just be like
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I don't know what you guys are talking about. There's not there are not clear-cut populations where this is contraindicated
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But I think that tells you more about sort of how physicians view knowledge than it does about the patients
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20,000 couldn't be enrolled
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And that's because you know they had a window after
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Intubation of you know when they would say hey you're soon enough in your course that we can randomize thing and 20,000 people didn't hit that
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Which that just speaks to like it's really hard to enroll people in critical care trials because things change fast
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And that's part of the reason why the approaches like the fluid trial or so appealing is just because you lose like half of the eligible patients
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Just because even for a low
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Uh
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effort or low
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required
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Tasks to enroll study like this it's still a lot of logistics to try to get people enrolled up front um
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And then about 6k had things happen like they were gonna get excavated soon so they didn't count and so that left about
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16,000 patients to be enrolled so again
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This is still a huge trial especially by critical care standards and that they were gonna look at 90-day
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Mortality sort of like the last study they weren't gonna necessarily reach out to patients and do assessments
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But then they took a subset of those patients about two and a half thousand and did sort of in-depth data collection to try to get
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Like what actually happened in this study and um
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You know they randomized them the more liberal oxygen group had a median FI to 0.35 the more
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Restricted group had 0.31 and that did
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Translate to a difference of like 95 percent saturation versus 93 percent saturation
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So there was a difference between the groups
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you know in the
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More restrictive lower target group about 10% of the time was not adhered with the protocol
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Which was basically to down-try trade things to shoot for that target until you got down to room air
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F02 of 21 percent and then leave it there
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Um, but you know, so it is kind of hard to get people to do it. They recommended setting alarms on both
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sides
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And they found that you know 35.4% in the
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low target group died by 90 days whereas
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34.9% in the higher target or usual care one did for a relative risk of 1.02
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With the conference center of a vulgar from sort of 0.98 to 1.06
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You know again being sort of similar to what the prior literature has shown which is that a you know
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No significant difference between the groups and sort of yeah, there's not a huge effect here
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But again, uh, you know people were hypothesizing a small effect to begin with um
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You know there is
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At ongoing so this was UK rocks there's an ongoing one called mega rocks that is worldwide that is targeting 40,000 people to look at the same question same deal, you know low
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Uh, it's an embedded trial. They're not collecting super detailed outcome stuff, but just looking at a mortality endpoint
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You know, and it's it's interesting because I think at the end of the day, you know with the cumulative evidence
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I can say you know with pretty good confidence
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There are not huge difference here, but there's this question of like are there certain people that benefit from one strategy and other folks that don't
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I mean clearly
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Some clinicians really believe that because you know
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A quarter of the people that were eligible for this trial their clinicians wouldn't even randomize them because they thought they knew
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But none of the subgroups in this study or the other ones have been all that convincing and I'll say like it's tough
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Because the usual way to do this would be like I don't know come up with a scientific theory about who would benefit and then randomize
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Those folks but honestly our theories just like aren't very helpful here, right? Because like I don't know
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I can make a story for why any particular subgroup would fit and you could come up with an equally compelling story
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Why I wouldn't like at the end of the day you just got to randomize and see if it makes a difference um
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And so I think actually like the the way this is going to be useful probably is that folks are you know doing essentially
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uh machine learning style analyses to improve on subgroups to say like hey
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Maybe if you have this profile of comorbidities or issues, you know
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Can we predict who is going to respond favorably to this which takes a whole boat loaded data
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And so I think you know what we'll be seeing in the future is that people are going to train the model on this
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16,000 patient
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trial and then apply it to mega rocks because you got to you got to do it in a new population that you didn't train your model in
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And see if it works and I think it's an open question, you know
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I think everybody really likes this idea of personalized medicine
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And sort of trials to predict who individually is going to respond
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But like it honestly hasn't worked that great yet. So yeah, this is probably the most likely
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Clinical question where that's going to come to bear and see if it really works soon. Yeah
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So what is your prediction for mega rocks is there going to be a difference?
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No, I think mega rocks is going to be negative. Yeah, and I actually I mean this is getting way nerdy
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But if anybody wants to take a bet, you know that I think you know
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You can you can put your confidence in terms of betting odds and I would give like pretty strong odds against
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You know like I'd say one to five odds, which is actually like pretty
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You know, I really think it's going to be a little study
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But you know if anybody wants to earn some money and thinks they know something else we can we can bet on it
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So one to five odds for anyone else to take it. I was looking at mega rocks and one of their hypotheses is that patients with
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Substance might actually benefit from a higher oxygen target
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um
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But
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Yeah, like again like you say like that's just a theory and and I don't know you know
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The I think that's based on prior studies maybe a signal there, but I don't know like yeah like
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Here at the University of Utah. We're at altitude right like 4500 feet or something
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And and we definitely aim for just 90% like we yeah at least on the hospitalist side right like when I'm weaning people off oxygen
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You know that's the goal 90% we're happy 88% we're happy when I'm sending someone home so
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So to me it's it I guess when I look at this
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Study and I see a no-result
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I'm like great that means that the the lower target's probably just as safe as the higher target
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It's like yeah, I don't need it to be better. I just need it to be as safe
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Yeah, no, I think that's true, you know, and I mean like a concentrated oxygen takes a lot of resources to make like in terms of environmental impacts and
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Costs to the whole system and so yeah, you know other parts of the world where there's less well resource healthcare settings
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You know actually just delivering enough oxygen to like have somebody on high flow for weeks or whatever is like a
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A big burden on the system and so if they really are equivalent that they yes, certainly like to go with the
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The lower
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Resource use option, you know, they did look at things like
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duration of icy use day in in UK rocks and didn't see a big difference, but you know
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That's a little tricky just because a lot of these folks weren't necessarily
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Intivated for hypoxemic respiratory failure like that average F02 or median F02 is pretty low pretty low
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You know, and so it like in and there have been ones that are smaller trials, but specifically look like
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COVID, you know that where the course really is something that might be amenable to more aggressive
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Down titration of the oxygen leading to improvements and duration and such, but you know, they didn't see
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differences mainly I think probably because they aren't big enough to detect those you know, but which goes back to that thing is that like
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You know, if you're really interested in studying say ards
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Exclusively, you know, you can go through the labor some
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Process of identifying those with ards and trying to enroll them really quick or you can just
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Randomize 40,000 patients and like I don't probably two thousand of them we're gonna have ards
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And it'll be like, you know, one of the biggest ards trials ever
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You know, so that's really the direction. I think the both of these trials that we talked about are going is to say
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You know, let's just randomize everybody and then you know, if we have a particular hypothesis
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We'll look at it on the back end, which you know presents some problems about pre-specification and right
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Already of tests and all but you know, I think logistic rate certainly and easier way to go. Yeah
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Yeah, and if you're looking at hard outcomes like mortality, hopefully
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You know, it's not gonna be as biased, but yeah, that's really interesting
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I just had a couple more that I wanted to plug
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Uh
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With with the little time we have so one of them was some some new guidelines that came out on platelet transfusion published May 29th in jama
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first author on that was dr. Ryan met calf and
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dr. Metcalf is actually the head of transfusion here at the University of Utah
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Um, and in one of these big advocates for patient blood management and stewardship and and so it was it was interesting to see these guidelines come out with him and
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And he's been involved with the hemoglobin or you know with red blood cell transfusion
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targets as well
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But these guidelines come from the a a b b which is association for the advanced in blood and biotherapies and the ictmg
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Which is the international collaboration for transfusion medicine guidelines
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Uh, and they came out with 11 recommendations based on 21 randomize trials and 13 observational studies
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Um, and so there were four strong recommendations. I'm only gonna
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Comment on two of those um, and then and then I think like seven conditional recommendations that they made they were based on kind of lower quality evidence
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Um, but the ones that thought were interesting from the strong recommendations were for non bleeding patients
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Um, with hypo proliferative thrombocytopenia who were receiving chemotherapy or undergoing allergenic stem cell transplant
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They recommended transfusing platelets only if the count dropped below
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10,000
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Um, and I think people have frequently used higher thresholds for that population
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I actually have a buddy who's going through chemotherapy right now and uh and usually on you know about a week after he gets out of the hospital for his chemo
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He's getting his labs checked and if his you know platelets are under like 20
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They want him to come up to the infusion center and get a transfusion and so uh, you know and in last time he went up there
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To get his lab checked and they told him he had to stay and get this transfusion. He said no
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I'm leaving uh
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And uh he's like I this is you know
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My time is too precious. I'd rather be with my family than be at this infusion center getting blood products
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So I thought that was that was interesting
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The other one that I think is is going to be interesting going forward is patients undergoing lumbar puncture
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They recommended a platelet transfusion threshold of 20,000
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Which I think is probably quite a bit lower than what people use around the country in the world
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So a few years ago, I you know
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I went through and and kind of reviewed all of the guidelines and trials that I could find on this for our institution
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Because we were trying to come up with a cutoff that everyone felt good about and it's all over the map
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You know what whatever you you know what places are doing
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Um, and and so we kind of had to settle on what our interventional radiologists were comfortable with because
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They end up doing a lot of the lumbar punctures if if the you know bedside LP is unsuccessful
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And uh they've always used a hard cutoff of 50,000
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Um, and it's interesting because if you if you look at the guidelines from the society of interventional radiology that came out and like
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I think 2019
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They classify lumbar puncture as a low
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Low risk procedure and in their own guidelines they say 20,000 is actually acceptable
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But we've never been able to get our folks over here to use that number
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Uh, and even our own hospitalists will use the 50,000 to guide lumbar puncture
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So I am very interested in implementing this number at our institution to to avoid unnecessary
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platelet transfusions especially platelets are like one of your you know um
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I guess the lowest like as far as um shortages and things like that platelets are what we are often running short on
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And so you definitely want to be very um judicious with who you're giving platelets to
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Yeah, I think I think they're the harder to store right right they
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Julf life's like seven days or something because they go at room temperature
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Yeah, that's yeah, because yeah, you know, I see in in here
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They also sort of reaffirm that I are you know low risk I are procedures
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Use that lower 20k cutoff, you know 50k if it's a high risk procedure
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Which is sort of also what they recommend for surgery and stuff which
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You know, it's great. I mean likewise. I traditionally have always used the
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50,000 just because you know, I don't know. It's a little bit conservative
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But you know the uh he metoma in the spinal canal such a like fear something where you're just like oh, I don't want to
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Right, so you know, I don't know. I think I'll probably have to
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Give myself to push it down to this more evidence-based threshold
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But it's certainly a bit of a change for me
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Yeah, yeah, and then the other one I wanted to ask you on one of their conditional recommendations was a playl account of 10,000
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Threshold for placing a central line
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Yeah, how do you feel about that number? Well, and it compressible so I mean
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I feel like that guideline probably
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applies more toward the folks that are like getting an onerige in dialysis line or something
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Because I feel like ultimately in the ICU will put it you know, if somebody needs a central line
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We'll put it in even if they have zero playlets, you know, it's just that the risk benefit
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Changes a little bit and so you know, there was a trial. I can't remember if we
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Yeah, we did talk about it. Yeah, the one where they sort of said, uh, you know
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The risk starts to take all up at 30,000
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But you know in the in the ICU setting the
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Horms of not doing a procedure can be so high that I feel like the
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the threshold itself doesn't
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Make too much of a difference, but like I don't know if I'm putting
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ij central line
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I usually don't worry about it
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much and less there
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Below like 20,000 and would still do it even if it was sort of semi-elective down to 10
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I think it's a reasonable guideline, but the more interesting thing is if you're trying to do like a sub clavian line where you really can't compress things
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Right then I'll still I'll steer clear if they're below 30,000 or so just so I don't
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cause a problem that is harder to manage
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But you know I'll say we we end up sitting at the side of the bed and holding pressure to keep a hema toma from
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forming a lot in those folks that have no platelets
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So yeah, you can definitely see like hey if that blood somewhere else or in a related procedure
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I think uh certainly the harms are different
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Yeah
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Uh the last study I wanted to plug and this is just because you know how much I love thrombosis and I love a
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Pixaban I love wins for a pixaban so
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I just had to plug this one and and this was in jama internal medicine
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I think last month
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And in the
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There's no head-to-head trials of a pixaban versus rock river ox band
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Although I learned that there is an ongoing one looking at bleeding risk between the two
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Called the cobra trial
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So uh, I'm very excited for whenever that gets published. But anyhow um
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There's like observational data that maybe a pixaban is safer than river ox band for bleeding
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And so that's that's kind of my practice pattern is mostly a pixaban um, but this study
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Wenton and pulled uh, you know three large health claims databases to try to get like the biggest possible
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You know samples of of patients to look at this question of which orlana quadulence are the safest
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Which ones, you know prevent recurrent VTE the best which ones also have the you know lower risk of bleeding
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So they they pulled these three uh different
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populations from Medicare claims the Meredith market scan and from optum
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And they had 163,593 eligible individuals
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Of those and and they were just looking at who was prescribed an orlana
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Coagulant after a hospitalization for uh, a VTE event
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Uh, and so 58.5% of them are on a pixaban 25.7 around river ox band 15.8% were on warfriend
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And I think that uh, you know, I think that tracks pretty well with like what what I'd expect to see
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I'm definitely into climbing a number of people being prescribed warfriend
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incident rate uh, so the the primary outcomes were incidents rate for hospitalization for recurrent VTE
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And so that was 23.3 per thousand person years for pixaban versus 26.8 for river ox band 38.3 for warfriend
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Um, and so it's interesting because if you go back and look at the rcts
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Um warfriend was about just as good as the doax in preventing VTE where you really saw the the benefit and the doax was the lower risk of bleeding
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But here in the real world and and again, this is based on claims data
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So it's not like an rct or anything
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But um both river ox band and a pixaban had significantly lower bleeding risk than warfriend um, but a pixaban
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Also had a lower bleeding risk compared to river oxaban
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Uh, which which does track with what kind of prior observational data has shown and then oh, sorry that was uh for incidents of recurrent VTE
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Pixaban was better than river oxaban
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Then if you look at major bleeding
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Uh, it was 30.6 per thousand years for pixaban 44.6 for river ox band and 47.2 so as expected a pixaban had a much lower bleeding risk than both warfriend and river ox band
spk_0
There was really no difference between river ox band and warfriend and um, you know, so I think this this is just more
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I guess data to support
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Uh pixaban should probably be your first line agent for direct orlana coagulants for most folks
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Sometimes insurance requires you to do river oxaban
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And I think that's still reasonable because it does prevent VTE pretty dang well
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But if you have a patient with the higher risk of bleeding then then I would go with the pixaban
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Which do you think has a better last week in medicine track record?
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The glp's or pixaban. Oh man. I mean
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Gialp's your horse. Yeah, glp's never lose but a pixaban, you know
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Also seems to never lose
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Or or maybe I just have such a strong confirmation bias. I only pick the the studies where a pixaban wins
spk_0
Yeah, yeah, no, I think uh, if uh if it fact sizes count
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I think glp's got you beat but pixaban doesn't always seem to win
spk_0
Yeah, I don't know it seems like if you just choose a pixaban here usually right
spk_0
Yeah, I mean glp's have a few were downsides if pixaban does still cause a lot
spk_0
Of bleeding so yeah overall
spk_0
But glp's do not prevent blood clots that I'm aware of so maybe maybe that trial is gonna be I was gonna say
spk_0
Oh, be sure to use a risk factor though. Yeah. Yeah. Oh, man
spk_0
Reach out to no more nordesco Eli Lilly and see who wants to pony up and
spk_0
Uh
spk_0
On the drink Jenkins trial. Wow. That sounds great. Yeah. Okay
spk_0
Cool, man. Well, thanks for thanks for uh for for helping out today
spk_0
Oh, it was a pleasure. We'll have to get Austin back for the next one. Yeah. Yeah, we should we should try to do one in a month so that we don't have so many trials pile up
spk_0
Amen
spk_0
You