The Curbsiders (00:00.918)
Paul, why did the ghosts go into the bar?

I feel like I should be able to figure this one out, but I don't have any energy. Why, Matt, why did the ghost go into the bar? For the booze. That's a great joke. Maybe I should stop there, just- Straight up, that is- You have one, Paul? A bit of fat on that, that is perfect. Matt, would you like to hear some skeleton puns? Oh, well, of course. This is spooky kids. They're very humorous. And-

The Curbsiders (00:35.01)
To follow up, it's gonna be a great Halloween. I can feel it in my bones. So these are both courtesy of good housekeeping, by the way. So that's just to give you a sense of where I'm judging my puns from. It seems like it, Paul. I'm not surprised. Not your edgiest humor I've heard from you. Women's Wear Daily was not very helpful. So I had to dig a little bit deeper.

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The Curbsiders (01:19.554)
All right, welcome back to The Curbsiders. I'm Dr. Matthew Watto here with my great friend and America's primary care physician, America's spookiest primary care physician. Probably true. Dr. Paul Nelson Williams. Paul, how are you doing? I am overall well, Matt. Thanks for asking. How are you? I'm doing well. And we have a ton of things to get to tonight, really wide ranging. We're gonna talk about blood pressure, vaccines. We're gonna talk about anticoagulation.

Cotton Fever, you'll explain what that is. A bunch more stuff. So this is gonna be a lot of fun. And we have a great co-host. If you're watching the video, you can already see him. But Paul, remind people what we do on the show and then introduce our wonderful co-hosts. Well, sure, Matt. Typically with the Curbsiders, we are the, well, we're always the internal medicine podcast, but usually we use expert interviews to bring you clinical pros and practice changing knowledge. We have an expert with us, but Matt and I are also gonna serve as like fake experts. Matt more than me.

And just to recap, some articles that have tickled our fancy or perhaps that have irritated us and sort of talk about whether they'll change our practice, any potential biases or flaws. And to help us figure this out is our resident epidemiologist, my low-grade one of my heroes, friend, dare I say, Dr. Rahul Ganatra. Rahul, great to see you. How are you doing? Well, shucks, guys. I'm gonna tear up. I'm doing great. Yeah, Rahul and-

Just to warn you, in the spring, I know there's some conferences in your home city. So Paul and I are probably going to have to like sleep on your couch or something like that. Or if you have two couches, I'd prefer not to share a couch with Paul. We'll share a couch. I'm very excited for that. Yes. We'll move kids around and make it work for you to each have an adult sized bed. Yeah, that will be delightful. We have a lot to get to. And maybe at the end, we'll even get into some picks of the week. But first, Paul.

I would love it if you would tell me about, what is miscuffing? And can we talk about blood pressure here? Is it cuffing season? I can't remember when that's supposed to correlate with. I guess that came and went probably. But I'm here to tell you about an article from Ishigami et al that was in JAMA Internal Medicine that looked at the effective cup size on the accuracy of blood pressure readings. And this is from the delightfully named Cuff parentheses SZ randomized crossover trial.

The Curbsiders (03:40.634)
I didn't actually investigate what that stands for, but it's fine. It's at least kind of appropriate. The cuff part is relatively self-explanatory. But Matt, we as internists treat a lot of blood pressure stuff, hypertension usually. And it's a really, it's like obviously a very prevalent diagnosis. It's a huge cardiovascular risk factor. And the medications that we treat it with are not necessarily benign. Like they are necessary, but they do have potential side effects. So it's really important that we diagnose it correctly and that we have accurate readings to then therefore manage it correctly. So we know.

both anecdotally and from some studies that we don't do a great job of measuring blood pressure appropriately in outpatient clinics. And this has been looked at in prior studies in terms of the effect of blood pressure cuff size on the accuracy of these measurements. It's been looked at in manual cuffs previously, so things that require a sculptor methods, but there's not a whole lot of data about the automated blood pressure cuffs that tend to be used in clinical practice now. And so what the authors were hoping to figure out is, does it matter if we use...

an incorrectly sized blood pressure cuff in measuring a patient's blood pressure with these automated blood pressure cuffs, which is, I think, really clinically relevant. It impacts how we might actually manage these patients. So this was a study that sort of hit my heartstrings, which is not, I think, the right saying, but I'm tired, so you're just gonna have to deal with it. So that was the question. So the bottom line is, what was the impact of using a regular sized blood pressure cuff versus an appropriately sized blood pressure cuff on automated blood pressure readings? So regular being sort of the standard size, and then.

The appropriate size being if you actually measure the patient's arm and then chose whether it would be a small, large, or extra large cuff, or indeed the regular size cuff. Remember in med school, they used to tell us everyone was 75 kilograms, but now everyone's more like 100 kilograms, at least a lot of the patients that I'm seeing. So if you're using a cuff meant for a 75 kilogram person, the arm circumference is probably gonna be different than your 100 kilogram person. It probably doesn't matter. I think it's all just.

It was probably just a manual cuff phenomenon. It doesn't matter if you're using an automated cuff. Just classic Watto pedagogical method. I love it. This was in fact a positive study, meaning it did in fact matter. And the measurements done with the blood pressure cuff that was too large or too small, either way were inaccurate readings. If the cuff was too big for the patient, it actually read slightly low compared to the actual true blood pressure for the patients. Not much, like three millimeters of mercury, I think was the...

The Curbsiders (06:01.942)
the number that sticks in my head. So it could be clinically significant, but not huge. But conversely, if you required a larger blood pressure cuff and you used one that was either a size too small or worse, two sizes too small, then those actually measured significantly higher blood pressure readings, like close to like 20 millimeters of style. Like, so like not nothing, like things that really the difference between hypertension and not hypertension. So this is a diagnosis that would change insurance rates and change the way that you manage these patients versus a healthy patient.

So it was really significant and seems like the larger the cuff that was required for the arm to be appropriately fitted the more important this was so it's Really, I think a very practical state that actually has a lot of real-world implications And I wonder having read through it we can talk about sort of the methods and stuff It's sort of just hearing this initially like what questions you had or what you thought about the initial read-through Rahul you I want to hear what you had to say about this any chinks in the armor of this study

Yeah, I mean, from a pedagogical and learning standpoint, I really couldn't find a lot to take issue with about the conduct of this study. They did a randomized crossover design where every patient kind of got their blood pressure measured by a cuff that was either appropriate, too small, or too big, so effectively serving as their own control. So that's a very strong type of study design.

And the authors detailed how they measured the blood pressure and they kind of did it exactly according to the 2017 AHA recommendations. They even included a washout period of two minutes of walking between each blood pressure measurement to kind of undo the effect of the sort of sitting quietly. So they really went to great pains to do this very well. So it seems very well conducted from that standpoint. So the only things I could really think to do

talk about with this paper are in how we apply these results to, you know, the rest of the world and the rest of the sort of target population of people in whom we care about their blood pressure. And, you know, I was struck that the mean BMI in this study was 28. And as Paul kind of laid out very well, the relationship between cuff size and arm size, if you're using a cuff that's too small, that's really likely to overestimate blood pressure.

The Curbsiders (08:25.858)
So I would expect that this degree of mismatch might be even worse in the real world for patients who are larger than a BMI of 28. So something to keep in mind, this degree of mismatch might be underestimated in the real world. And Paul, I think the authors made this point that if you buy a blood pressure cuff from your local pharmacy, a lot of the times it only comes with one size cuff. So if that cuff is way too big or way too small, you're gonna get really inaccurate readings.

It's tough. I think you have to just tell the patients trying to get a cuff that is appropriately sized to their arm. And the authors went into a lot of detail, Paul, about how they measured the arm. Like measuring from the acromion to the olecranon and then the midway point. And you measure the circumference of the arm at that point. And then they actually list the size. So I'm not sure, Paul. Do you think we should be measuring the...

circumference of someone's arm and then tell them like you should have a cuff that's like small regular large or Extra large based on how many centimeters? I'm not sure how crazy you're gonna go with this or just Based on the size of the cuff you use in your clinic. I don't know what's the right way I think Realistic where this is gonna be being cognizant that it makes a difference if you know that you have a patient that's gonna require A larger cuff size just by didn't the familiarity making sure that you advise that when they actually buy their blood pressure cuff Like it the measurement is obviously ideal But I think you know again the practicality versus the aspirational

There's going to be a little bit of a difference. Anything else you wanted to point out with this study? I think it has obviously really strong implications, but any other implications of this? The question, it's not even really much of a question, but I guess the consideration that I would think about is because this is a good experimental study, they controlled for all the variables. And then I think in the clinic, there's the variabilities that are not just blood pressure, or cuff size, where I have patients with their legs crossed and being talked to with a full bladder and a recent tobacco use and all that kind of stuff.

most of which probably will cause an increase in measured blood pressure as well. So I just wonder to what degree this actually compounds what is already sort of potentially elevated blood pressure reading in clinics. I think there's just, for this study itself, it's a great study. It answers a really important question. I think it should be practice changing and policy changing for a lot of practices. So I love this study. And I know it does make a whole lot of great teaching points from a sort of an analysis standpoint, but in terms of what it has to say, I think it's really important. So for me, this is.

The Curbsiders (10:47.126)
Beware Williams, like five hotcakes, I think. Like this is top tier, should be like clinic changing practice. Paul, can we get, can we change them to spooky cakes or are you totally boycotting the fact that this is a Halloween episode? I've already humiliated myself. So like it's, if we can make it spooky cakes, we can call them whatever you want to, Matt. I thought your joke was good, your joke was good, Paul. Oh no, I meant by endorsing the whole hotcake rating system. My joke was great. All right. Next up.

Paul, this is something that I really wanted to cover. This is the study by Walsh et al. This is the Renoir Trial Group, Paul, and they were looking at the efficacy and safety of a bivalent RSV pre-fusion F-vaccine in older adults. This came out in New England Journal, April of 2023. It is now approved for two purposes.

This vaccine is approved for pregnant individuals at 32 through 36 weeks gestational age to protect infants from birth to six months of age as well. So we're going to be getting a lot of questions about that. And I have already started to get a lot of questions about it. Um, so I wanted to go through this and RSV in older adults, like we, I mostly thought of it as something in kids, but RSV does affect older adults, something like up to a hundred thousand RSV associated hospitalizations per year.

and up to 10,000 deaths per year in older adults, and that's according to the CDC. And there's been attempts in the past at vaccines that didn't go so well, but now we have this PreFusion F vaccine, and the top line results are that this prevents RSV-associated respiratory illness and caused only mild side effects for the most part. There were some serious adverse events, but they were rare, and the efficacy was about 67%.

for preventing infection with two or more symptoms and 86% at preventing infection with three or more symptoms. Any questions so far, Paul or Rahul? Questions or comments? I'm just curious, are you already getting questions in your, you know, from patients about should they be getting the RSV vaccine? Yeah, literally yesterday, multiple patients and most days in my inbox, there's like, I have like,

The Curbsiders (13:09.59)
this triple-demic of RSV, COVID, and influenza, I'm getting questions like, which vaccine should I get? When should I get them? The timing of it. And it is, yeah, we don't, I would say, Paul, do we have clear guidance and great answers for all of this? Except for flu. Sharing decision-making, Matt. We should just be sharing decisions left and right. Just a lot of sharing. Yeah, so that's the point. Paul's bringing up the fact that this was...

approved for through shared decision making. You know, so the CDC, ACIP, they said, you may consider giving this to adults over 60 and through a process of shared decision making. And, you know, what does shared decision making mean? So if they're recommending a vaccine outright, then the default decision for most patients that fall into that group would be to get the vaccine. But for shared decision making, you kind of take individual characteristics into account.

and how much the patient is likely to benefit from it. And so this is one of those shared decision-making vaccines. So they're like, talk to your health care provider about it. I beg your pardon. But Matt, I guess I wanted to ask you, in terms of the outcomes looked at. So reading through the paper, the whole setup is that RSV actually has significant impact on adult patients. There's hospitalizations. There's mortality. It's probably underreported because we don't always test for it. In terms of the outcomes that were actually studied in this trial, like what

what did they do with these sort of hard endpoints in terms of like death and hospitalizations? Cause I was like, oh no, like now I'm excited about this. And then I had a hard time kind of parsing out whether that was looked at, or you know, how that was sort of accounted for when they actually did the trial. At this time, that is one of the limitations. They are looking at that, but this was a pre-specified interim analysis. And basically they said like, if we have enough patients that have RSV with two or more symptoms, then we'll look at that.

And then if we have enough patients with three or more symptoms, we'll look at that. They needed at least 12 hospitalizations or, you know, severe cases of RSV, which was like hospitalization or need for mechanical ventilation, that sort of thing. And they did not reach that with the interim analysis. And part of what they're still looking at, they gave one shot. This is a one shot vaccine. They're not yet sure if it's going to last for one season or two RSV seasons. And if you'll need to be re-vaccinated.

The Curbsiders (15:30.162)
And so this, they're still collecting data on this. And what was also kind of odd about this is that they were studying it during, you know, the lockdowns for COVID-19 and during COVID-19. So I imagine that affected a little bit the RSV season. So it, I think that all makes it a little bit hard to interpret. We can really just say with confidence that it does seem to prevent RSV infection in adults.

there were a small number of, but there were only a small number, like less than 50 patients had RSV with two or more symptoms. So Rahul, any other comments about this? I know you looked through the paper as well. Yeah, you're absolutely correct. This was a planned interim analysis of the phase three trial for this pre-fusion vaccine. And you're right, there was a small number of events, only 44 cases.

across the 17,000 or so people who got the vaccine. And the primary outcome in this study was symptomatic RSV, lower respiratory tract illness that was diagnosed by confirmed PCR or an antigen test within seven days of symptom onset with at least two or at least three symptoms.

And that's kind of a lot for a primary outcome. As Paul pointed out, that's not hospitalizations, that's not deaths, that's really just symptomatic lower respiratory tract disease. And then as Matt pointed out, the vaccine effectiveness, or excuse me, the vaccine efficacy was 67% for infection with two or more symptoms, and then 86% for infection with three or more symptoms. And for any positive study like this, I always like to go back to the clinicaltrials.gov registry.

to look at the original primary outcome and just see if there were any changes made. And in this study, there was a change made. The protocol is kind of difficult to sift through because it's long, but the original primary outcome was moderate or severe RSV, lower respiratory tract infection. And what we see in the paper is this two primary outcomes of RSV, lower respiratory tract infection with at least two or at least three symptoms.

The Curbsiders (17:45.43)
So anytime you see that, it's worthwhile to sort of look for a justification for, you know, why was the primary outcome changed? Because the situation you want to avoid is, you know, significant results being created by changing to a different primary outcome than what the initial plan was. And the authors say clearly in the manuscript that, you know, severe RSV-associated lower respiratory tract infection was not included in the analysis because the number of cases of severe disease that had accrued by the data caught off date...

did not meet the pre-specified minimum number for the internal analysis. So they justified that. It makes the learning point that any time you do see a positive outcome, especially one that seems a little strange, maybe not what you were expecting, it's always worth it to go to the protocol and verify that that's what the original intent was. And you know, this study had a lot of patients, like over 34,000 patients, but they did exclude patients who were immunocompromised. And

The consort diagram, Rahul, which you always talk to us about, was interesting because they didn't show exactly how many patients they screened. They just sort of, you know, did you notice that as well? I did. I couldn't find the total, like, what did they funnel it down from? Yes, I just love it. There's a missing box here, the how many patients screened. You are correct. If you're watching the YouTube feed, he was holding up where he drew the box in that was missing. Yes, you are correct. And you know, it's part of the...

template of the concert diagram. So if you are making a concert diagram, you have to very deliberately not include that. For a big trial like this, I'm sort of less concerned about funny business. But I do want to just get a sense of how highly selected is the study population. Because you also sort of care how representative of the target population is a study population. Because when you're thinking about

you know, making a recommendation for a population, you want to know how closely does the study population resemble the population you're going to apply it to? Yeah, and that brings me to one of the big limitations that a lot of the editorialists pointed out, is that this was really, most of the patients were between 60 and 69 years old, and almost close to half of the patients didn't have any serious comorbidities. So...

The Curbsiders (20:06.258)
And then maybe that's why they didn't see that many severe cases, because they were just not looking at the right population. But they didn't have a lot of patients over 80. They didn't have immunocompromised patients. So my question is like, if we give it to those patients, are patients over 80 or immunocompromised patients going to actually respond to the vaccine and will they actually benefit from it? The people who need it most. And so this trial, I think, wasn't powered to answer that question. We can say that it prevents

RSV, you know, symptomatic RSV in relatively healthy adults over 60. But it kind of lacked that question, that older sicker group, um, is it going to work for them? I guess to round it out here, I would just say that the, some other things that we don't know practically about this is like, is it safe to be given with our, uh, with the influenza vaccine and the COVID-19 vaccine? You know, can you get them all three at once or should you space them out? And

how long is it going to last when you get protection? I just mentioned about older sicker patients. Those are the ones that I'm more likely to recommend it to just because like if I'm making shared decision-making, I'm like, you're the one that seems like they should need this if it works, but we don't yet know. So this is an interim analysis. So I'm telling a lot of my patients, like I'll probably know more in a year or two when like we have the rest of the information from this, but right now it seems to protect patients from getting a symptomatic infection.

whether or not it protects you from being hospitalized, we don't know. And then the cost of this is it could be, if they're on Medicare Part D for now, it's somehow covered, but this is the Medicare Part D, the drug benefit part of Medicare Part D. So it seems like it's covered right now, but they have to get it at their local pharmacy, not in a doctor's office, usually for things covered under Part D. And then if they...

have private insurance, they would have to pay out of pocket for this. And it's probably going to be around, let's say, $200 to $300 just to use round numbers. So it could be pretty expensive right now. So I would give this, I guess, 3.5 hotcakes. I mean, I'm cautiously optimistic. Spooky cakes. Yeah, come on. Spooky cakes with some candy corn. I'm optimistic that maybe when we get more data that this could be a vaccine that's going to prevent...

The Curbsiders (22:30.854)
hospitalization, death, some of those big hard endpoints we care about, but we just don't know yet. So I'm not rushing all my patients out to get this. It's just a bit tricky. But patients that are older with underlying cardiopulmonary disease that I don't think would do well if they got RSV, I'm telling them it's okay to get it. Sure. Why not? Can I ask Rahul just a quick trial type question? No, go ahead. I know we're running short on time for this particular topic, but in terms of...

how they actually assess whether someone got infection or not. I'm just wondering how reliable that is. Like the patients, I guess, had a diarrhea or they sort of self-reported symptoms that sort of what triggered for the actual self-swabbing and that kind of stuff. And I could see it going either way where either someone who's enrolled in the vaccine trial is hyper-vigilant about their symptoms. Like the number of times I wake up with like a scratchy throat, I'm like, no, I'm fine. Maybe by the end of the day, like is fairly common as opposed to the person who, you know, maybe is like me. And it's like, no, it's going to be okay. And then maybe they even had sort of like some clinical RSV and just never actually swabbed themselves. Like, I guess I wonder.

From a design standpoint, I don't know how you do it any differently, but do we have a sense of how effective this is in terms of actually capturing diagnoses? Yeah, it's a very germane question. If you were enrolled in a vaccine trial, I'd say it's the reason you would be kind of thinking about symptoms that could be related to the disease you might be vaccinated against. So my thought there is that as long as there was not a reason to worry,

that the detection of the outcome was different between the placebo and the vaccine group. Even if the sort of vigilance that people have in the trial is heightened compared to what the general population would have, as long as there's not a source of sort of differential ascertainment between the placebo group and the vaccine group, I wouldn't be worried that would introduce a source of bias as far as vaccine efficacy. But if you're doing a bunch of swabs in...

you know, one group but not the other group, that would be something that would be knowable, that's probably in the supplement. And that would be how I would investigate, you know, whether that was a source of bias, is if there were dramatically more swabs in one group than the other, which I have no reason to expect. You know, it's not like we saw more cases than they expected, you know, that's, so probably, I think there probably wasn't that much more, I doubt there was that much more undetected.

The Curbsiders (24:46.27)
I think it was probably a hard time to study this, to give the authors their due. I mean, it must have been hard to study it when people are like trying to avoid respiratory illnesses. That's like a hard time to study something that prevents respiratory. No one's going outside, everyone's wearing masks. Yeah, good luck. Yeah. All right, so Rahul, let's talk about a trial. And does this have a clever name? Tell me it does. This has...

perhaps the cleverest of names. And I will tell you the name, and then I would just like to pause to hear Paul's reflections on the name. So this is the frail AF study, Paul. Yeah, I mean, cardiologists have no shame. There's nothing else to say at this point. They should be ashamed of themselves clearly or not with the number of AF trials they've had. Paul, I think for the first one they didn't know, but I think by now they know, and now they're just trying to be cool.

At some point, one of their millennial medical students who's just kind of hanging around, had to have said something. But yeah, I agree with you 100%. They know what they're doing now. Can we pause for one second, Paul? Renoir? So for the one that I just presented, that was Renoir. And then the arm for the pregnancy, vaccination and pregnancy was Matisse. What do you think? Classy. Classy, like ID docs are. That's nice. Okay, thank you, Paul. All right, Rahul, now let's proceed with the frail AF. Moving right along.

Okay, so this is the Frail AF study by Linda Juustin and colleagues and this was published in an August issue of circulation And the results were also presented at the European Society of Cardiology meeting So what was the question that this paper was asking? Well, this was asking whether frail elderly patients who are already on a vitamin K antagonist for atrial fibrillation should they be switched to a DOAC, okay and

Why is the study important? Well, there's clear evidence that DOACs are superior to warfarin for stroke risk reduction in AFib, and that's in terms of efficacy and safety and also convenience because of the lack of any monitoring that's really needed. However, elderly patients and frail patients in particular were excluded from those trials. The sort of seminal ones were Rocket AF, Aristotle, and RELY. And so there's uncertainty about whether this population is going to

The Curbsiders (27:00.246)
the populations who are studied. And we know that a large proportion of elderly patients with AFib are still on warfarin. Estimates are like 30 to 40%. And so the question of whether they should switch is kind of relevant. So before we get into questions that you have that I should address in my appraisal, I'll just tell you the top line results because I feel like that's how we all kind of read papers, isn't it? Just look at the conclusion and decide if you have to figure it out. So the take home top line of this paper,

was that switching patients who were on a vitamin K antagonist to a DOAC was associated with more bleeding without better stroke risk reduction. And so much so that the trial was stopped early for futility. So this was therefore a positive trial, albeit for a bad outcome. So I'll stop there. Do people have thoughts or questions that I should address? Yeah, I mean, this was an open label trial.

does that concern you for this particular study? Yeah, so that's a great question. We talked a little bit before recording about, when does blinding sort of help and when is blinding kind of necessary? So anytime you're talking about adjudication or ascertainment of outcomes that might depend on knowing your treatment allocation status, blinding could be important. So the situation where blinding is kind of critically important is when the outcome is a symptom.

because your subjective experience of a disease could be modified by your knowledge of whether you were receiving a treatment or not. So outcomes that are symptoms are kind of the case where blinding really matters. And then outcomes where blinding probably matters less are things where there's really no adjudication required. And kind of the best example is mortality. Either a person is alive or they are dead. So knowing the treatment is sort of less relevant there.

So as you mentioned, Matt, this was a pragmatic, multi-center, open label superiority trial. It was done at seven sites in the Netherlands from 2018 to 2022. And the funding for this came from the Dutch government. And what the investigators actually did was they randomized 1300 patients in one to one fashion, all of whom were had to be sort of doing well and stable on a vitamin K antagonist. They randomized one to one to either staying on the VK or switching to a DOAC.

The Curbsiders (29:22.558)
And I'll just say that this was done in the Netherlands. So they weren't using warfarin. The VKAs that were used in this study were two things called Akenocumeral, I apologize if I mispronounced that, or Finprocumon. Not familiar with eyes. I've heard those. I didn't catch one, that's rough. Well, I had to Google these and apparently they're more commonly used in Europe and the thought is that they are sort of less vulnerable to individual differences in drug metabolism. So that's.

sort of the reason for that. But anyway, these are all patients with nonvalvular aphid. They all had to have a grant in clearance above 30 in sort of stable outpatients. And I don't know if I mentioned this already, but the choice of DOAC was left to the discretion of treating clinicians. That's sort of the pragmatic nature. All four DOACs were used. The most common in this study was rivaroxaban, it was 50%, followed by pixaban at 17%, and then adoxaban, another 16% in dibigatran.

was just under 10%. And the primary outcome was a composite of major and clinically relevant non-major bleeding at one year. And thromboembolic events was looked at as a secondary outcome. And the primary outcome of bleeding in this study at one year happened in 9.4% of patients who stayed on a vitamin K antagonist. And this occurred in 15.3% of patients who were switched to a DOAC. That's a hazard ratio of 1.69.

and the confidence interval indicates statistical significance. So questions people have before I tell you a little more? Yeah, Rahul, I wonder if they addressed sort of INR control in this particular trial. Speaking of pragmatically, I can tell in my own practice a lot of the times if I have an older patient who is on warfarin and they're just rock solid stable and their INR has been between two and three for a bazillion years, I would have much less enthusiasm for switching them to a DOAC than I do for the patient who has this wildly labeled INR. And I just.

I wonder if that calculus factored in to the study design or what the INR control looked like in this particular patient population. Because I feel like that's a big consideration in terms of making actually the pragmatic decision to make the switch. Yeah. So excellent question. And this really gets at the sort of external validity of these results and the application of these results to patients like ours. So to answer your question, Paul, they didn't.

The Curbsiders (31:46.934)
They made a decision not to report the time in the therapeutic range or TTR for patients in the study. And in some interviews with the study authors that were published around the time of the European Society of Cardiology, the authors kind of describe how the Netherlands is really a place where vitamin K antagonist management is really quite good. The ability for people to kind of get their INRs monitored.

And to have an integrated health system that kind of is able to coordinate all that is pretty high. In time, the therapeutic range there is very typically up to 60 to 75%. The United States, on the other hand, is lower. 60% is kind of an optimistic estimate from the literature I found. I'll link that in the show notes. But these were all patients who were stable and doing well on a vitamin K antagonist, and they were all patients who were tolerating a vitamin K antagonist.

So the study question is asking about switching, not necessarily starting de novo. So these patients are a little selected in the sense that they have already been doing great on a vitamin K antagonist. Yeah, because practically speaking, Paul was making this point before. He's mostly switching people to a, if they're on a vitamin K antagonist, switching them over if they're not doing well. How would you apply these results in practice if someone was asking you? Yeah.

I mean, so despite the author's conclusion that, you know, there was increased bleeding with DOACs, I think, you know, Matt, your question is about, you know, figuring out how to apply that to our patients. And to me, this all comes down to, you know, are there any sources of chance or bias we can identify that could explain that finding that we see in the results? And there are a couple sources of bias towards DOACs looking worse.

We already talked about how VKA management in the Netherlands is thought to be really good. So this represents kind of a best case scenario for vitamin K antagonists. The fact that rivaroxaban was the most commonly used DOAC also makes me wonder if we would see the same rates of bleeding with like a pixaban, which is thought to be safer from a bleeding standpoint. The authors also described needing to modify the study protocol, because initially they had patients switch when their INR was less than two.

The Curbsiders (34:12.566)
but found that led to an increased frequency of bleeding events. I wasn't able to figure out how much, but I think it was a maximum of 15% of bleeds probably occurred before the protocol switch, because that was when 100 some of the 662 patients in that arm had been enrolled. So then they changed the protocol to have people wait until the iron R was less than 1.3. And there was also a built-in bias towards the DOAC's looking worse, which is there was a delay between

randomization and when people would actually switch to the DOAC and that was a median of about 50 days So any bleeds that happened during that time were attributed to DOACs But actually patients were taking more vitamin K antagonists during that time Oh, wow, that seems like a really long time to it feels like a flaw It does feel like a long time and the nice thing about this type of observation is you should be able to verify if that Was a big deal or not and they do report in the supplement how many patients had bleeds after being

randomized and what drug they were still on. And it was only seven cases of bleeding where people were in the switch to DOAC group that were still taking their VK at that point. So probably not a big deal, even though it's a potential source of bias. So to bring it back around, how do you apply these results? You know, I think in the absence of the exact RCT data that you want, you have to be a little careful about extrapolating these results to new populations. I think if you've got a frail elderly patient who's doing well on warfarin,

their time in the therapeutic range is acceptable, they don't mind the monitoring. To me, this suggests that you don't need to change things up, you don't need to mess with success. But I think individual decision-making for patients who are newly starting on treatment, patients who might not do so well with warfarin, it could still be totally appropriate to start that patient on a DOAC, and it still could be totally appropriate to switch patients from warfarin to a DOAC if, for example, they have had variable INARs. So...

I feel like shared decision making is kind of the theme of the night, but that's how I would use these results. Now how many spooky cakes would you give this one? I thought this was a great study and a great opportunity to kind of dig into this and learn, so I'm going to give this four out of five spooky cakes. All right. That's not bad. That's how I would score. Yeah. And speaking of spooky, Paul's recording with a black cat.

The Curbsiders (36:32.554)
which is pretty much every episode, but still, you know. It feels like it's- It's really standard stuff at this point. It feels like it's for spooky cakes. So Paul, tell me about cotton fever, because this is something that I hadn't heard of and I'm interested to learn more. Yeah, so I barely remember how this came up. I think I was talking to one of my patients with a history of opioid use disorder who mentioned a history of cotton fever. And I was like, I don't know what that is. And so I did some-

some digging and found a couple of case reports. And one of them that I found was actually this lovely 2014 case report from actually J. Jim by Z. Edel. I hope I pronounced that OK. Cotton Fever does this does the patient know best. So I also really like the framing of this article. So, Matt, to answer your question, cotton fever is the is a diagnosis of exclusion. It looks for all the world like sepsis, basically. So these patients with a history of injection drug use, usually heroin, will come in with.

usually acute symptoms like six to 12 hours after injection, they'll be febrile, they'll feel awful. They will have a leukocytosis. They often have like chills, headache, myelodysabdominal pain, like the type of patient that would scare me if I was still doing inpatient stuff. And then it's self-limited. It gets better anywhere between six hours and two days later, you know, no matter what you do, their symptoms kind of go away. And the thinking is that this is, they're still not entirely sure, but it could be.

a pyrogenic response to something in the cotton swab itself that the patients are using to draw the drug suspension up through. It could be some sort of weird immunologic response to cotton, though I don't think that one has a whole lot of adherence. Or it could be a response to an endotoxin and types of bacteria that actually colonize cotton, which also sounds kind of like a stretch because I don't know how they would survive the cotton swab making process, but what do I know?

Did you already say this, but how is the cotton being used exactly? Like, I don't, where are they putting the cotton? So it's used as a filter, is my understanding. So you're actually sort of dissolving whatever in a liquid, and then you're drawing it up through the cotton to kind of get rid of any particulate matter so that you're not injecting particulates, if I understand how works work correctly. Okay, interesting. But the idea is that it's coming from the cotton and not whatever it is that you're injecting and certainly not like the introduction of like skin flora, that kind of stuff.

The Curbsiders (38:49.27)
the patients get better. And what I love about this article, what the authors talk about is on the day of discharge, the patient's like, I think I had cotton fever. And the author's like, I don't know what that is. So they looked it up and they're like, oh, I think I have cotton fever. And then I was asking patients about this, some of my patients who inject or have injected drugs. And I'm like, have you heard of cotton fever? Which it feels like a weird random question to me, ask my patients, but they're used to me at this point. And like almost to a person like, oh yeah, I've heard of that. And if you talk to clinicians, they're like, I've never heard of that. So I just think.

The article acknowledges, and I think this really nicely underscores the importance of lived experience and appreciating that our patients actually know things. And now they're assuming that we always know best. So I just, I love that the authors copped the patient diagnosing themselves and made that the teaching point of the case in addition to this sort of this entity of cotton fever. So it's a great little paper and the authors should be proud of themselves. It's about a decade old at this point, but I was just tickled when I read it. Yeah, probably, I bet you it's that people.

they're not seeking care for it because they sort of know what it is and they've observed it. They're like, oh yeah, sometimes I got a fever for a day and then it goes away and someone figured out somewhere along the line that it was due to the cotton, I guess. It's also a point the authors make. There is a lot of information in that community where they're sort of sharing educational resources that again, that the physicians do not know about, we're not privy to. So there's a lot of sort of self-education about these things that we should again, really value it and talk to our patients,

I know, Matt, we try to avoid that when we can, but unfortunately, it seems like talking to patients again is the answer. Yeah, I suppose. Well, I have a talking to patients type thing to talk about next, which is bloating and belching. Paul, did you know there's a bloating and belching clinical practice update from the AGA? Did you know about that? By Google alert, yeah. Okay. I've been waiting for it. This was by Moshery.

Drosmin and Schockett, and this came out in 2023. This was an expert review that appeared in the journal Gastroenterology. Basically talking about this bloating, bloating or abdominal bloating or abdominal distension, and then belching as sort of two separate things, and that these are disorders of gut brain interaction. We talked about some of this with Dr. the great Dr. Iris Wang.

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We talked about IBS and functional dyspepsia. This is, these are some more conditions that fall under that category. And belching, I just didn't know too much about this. I did have maybe a week or two ago, someone was asking me about belching a lot. And I had like no framework for approaching it. So if you look at this article, it does have.

an algorithm to approach both belching and bloating, abdominal bloating and abdominal distension are grouped together in the same separate algorithm. So a quick recap of this is that belching can be super gastric, which tends to be more frequent and goes away with distraction or when patients are sleeping. And the idea is that super gastric is sort of a voluntary, almost like learned behavior versus gastric belching.

tends to be less frequent, Paul, but more forceful and can be associated with GERD. So that can be treated with proton pump inhibitor, but both types of belching can be treated with diaphragmatic breathing. And we can link to a YouTube video that tells patients how to do that. And really just reassurance and a little bit of education. If it's really bothersome, and this will be a theme also when we talk about abdominal

bloating and distension, but central neuromodulators can also help. So those would be things like TCAs or SNRIs. And really, they think this is like decreasing any kind of visceral hypersensitivity that is bothering the patient from this condition. And of course, if you want to, there's fancy testing like...

high resmonometry and impedance monitor, impedance and pH testing, but you don't really need to do that. You can try some of these practical things. If you think it's gastric, give them a PPI. If you think it's super gastric, tell them to do some diaphragmatic breathing and maybe try a neuromodulator if it's really bothersome. Abdominal bloating and abdominal distension. These, you know, you can go through a little bit of an algorithm. Some of the conditions you might think about would be constipation.

The Curbsiders (43:18.538)
Uh, you want to rule that out. Could they have a food allergy or intolerance celiac, uh, non-celiac gluten sensitivity, which is really, uh, sensitivity of fructans, SIBO, and you know, some motility disorders, things like that. So. Abdominal bloating and distension also, Paul respond to diaphragmatic breathing and central neuromodulators. Um, if you didn't find something like a dietary thing or constipation.

bacterial overgrowth, then you can again resort to these things. So I would encourage people to check out these guidelines, especially if you have patients struggling with this. Paul or Rahul, any comments about this? Are they like 124 pages, like most guidelines? Because I may not take it up. No, I think this was like eight pages, Paul. Oh, what a dream. It's a quick read. Yeah, it's a quick read. Like I said, this is an expert review. As you might imagine, there's not a lot of evidence for this.

Hypnotherapy is another thing. Dr. Iris Wang also said she actually does this for her patients. So that which reminds me that a lot of these behavioral therapies are hard to come by. And more and more now there's be there's like smartphone apps that are trying to address this. There's a lot of them for IBS out there and hopefully there will be for some of these other conditions in the future. But this is something that I think

hopefully can augment what we do as clinicians in the office. Some self-directed therapy that patients can do at home with these apps seems promising to me. So we're running towards the end of the show here, Rahul. We have one last hot take, and this one, definitely important. First, is there a trial name? And then tell the audience what this is about. All right, so packing a big punch at the end of the show here. This is the ACORN trial.

This was just published in an October issue of JAMA. Paul, any thoughts on the trial name? I know I called IDFoaks classy. This is a little bit of a, that's what I'm gonna miss, I think. I don't know where you get acorn from this subject matter. Yeah, there's some creative capitalization that's involved, but in any case, this is actually kind of a big deal. I have a feeling that this is gonna.

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become a practice changing paper. And so, you know, we're just gonna introduce this now. I'm sure there'll be lots more discussion on Twitter and we may do a walkthrough video of this paper down the road. But anyway, this is the Acorn trial. This is a study that fills a gap in the literature because the comparative safety of pipercilentazobactam and cepapim with respect to...

some important clinical outcomes, namely acute kidney injury and neurologic dysfunction, was really not known before this paper was done. These authors conducted a randomized open-label pragmatic superiority trial among adults with suspected infections who presented to the emergency department or the ICU at Vanderbilt. This is a single center study. It was done from 2021 to 2022.

The included patients were about 2,500 people, a mean age of 58. And three quarters of them were also receiving vancomycin at the time of enrollment. Half of patients had sepsis. It was mostly intra-abdominal and pulmonary sources. So these 2,500 patients were randomized in a one-to-one fashion to either cephipeme or piptazo. And that was done using an automated alert embedded in the EHR. So the physicians just had to decide.

whether anticeudamonal antibiotics were indicated and then patients were randomized using EHR. So pretty cool design. The bottom line was that at 14 days, after a median of three days of getting each of those antibiotics, there were no differences in severe AKI, in death or in major adverse kidney outcomes. However, patients who were randomized to cepapeme did have slightly fewer days alive without coma or delirium.

So the bottom line, you know, piptasa alone or in combination with vancomycin was really not associated with acute kidney injury, but it did seem to be associated with increased or, excuse me, piptasa was associated with less or decreased delirium and coma than cepapine. Yeah, I just wonder because there were so many articles. I think some of them were observational. You know, I'm not an expert on this literature, of course, but...

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between vancomycin and Piptazo, just worrying that they caused acute kidney injury. And that was probably five, six years ago. So everyone switched to vancomycin and cepapeme. And now I guess we're giving everyone delirium and maybe not preventing kidney injury after all. So I'm not sure if this totally puts that all to rest, but I will definitely be looking for comments on this because this could be very practice-changing for a lot of people.

Yeah, this rabbit hole goes deep. If you dig back into the Josh Farkas wrote a blog post about this very topic in 2022 that was excellent. And it really persuaded me that the sort of idea that the combo of Venk and Piptazo having you know, more nephrotoxicity than either one alone didn't make a lot of mechanistic sense and that the evidence supporting that possibility was quite weak. So you know, this

Finally, we have RCT level evidence to kind of, you know, answer this question and we'll dig more into this in a future show, I'm sure, but yeah. Let's call for Josh Farkas to do it. I mean, if anyone's gonna go down rabbit holes and summarize like tons and tons of evidence, I mean, he's the guy to do it. So I would love to see that from him because I can't figure it out, but I would love for him to do that. All right, let's get some quick picks of the week. It's Halloween, hang with us if you want to for a few more minutes.

You know, Paul Williams is gonna lead us off with what I imagine will be a stellar pick of the week. Maybe, is it a spooky pick, Paul? It should be spooky if you can. Nope. Not at all. Okay, fair enough. I'm gonna do actually one and a quarter picks of the week. I hope that's okay. You can do it with everyone, Paul. This is your show. I'm just gonna throw it out there. Are you familiar with this songwhip.com? No.

It's really cool. It's a website where if you type in an artist or even just a song, it will generate the Spotify link, the YouTube link, a link to all the streaming services so people can kind of choose their favorite to actually listen to whatever song you want to share with them. And it does it free, you don't have to sign in or anything. It's very, very cool. So I mentioned this only to introduce that I'm gonna choose an album. I'd recommended a Royal Blood album earlier. I can't remember when, I guess back when Typhoons came out, I think was the name of it. Royal Blood is this English duo. It is a bassist named Drummer.

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And the bassist has all kinds of pedal effects and overdubs and looping and stuff to kind of sound like a really full and kind of impressive band. And their most recent album came out September 1st of this year. I was completely unaware that they dropped an album until one of our patrons on the Discord was like, hey, what do you think of the album? I was like, oh, no. I paid for it immediately because I like Real Blood very much. It's their best work. Like it is.

I am so in love with it. I'm just obsessed with it. Like, they started out as kind of straight ahead rock. They're really great straight ahead rock. And they've evolved over time. Like, the last album was kind of dancey. This one has some really straightforward, kind of almost jazzy little pop numbers on it that are just perfect three-minute songs. The singer's voice remains perfectly. He's got perfect pitch. It's wonderful to listen to. Like, the songs are beautifully produced, well-structured, sing along a bolt. The lyrics are great. So the album is back to the water below. The band is royal blood. And they just keep getting better with every record. So.

I can't recommend it enough. Yeah, Paul, I need to check this out. I have not had a chance to listen to the first out. I listened to like a minute of the first song, but I need to get back to it. So that's a good recommendation. Always enjoy your recommendations, Paul. I think that's really why most people listen to the show is for your recommendations. That's why they're so directorate. They're now already changed. All right, Rahul, what is your pick of the week? So I have one that is a little spooky. I'm currently reading a sci-fi book

called The Three Body Problem. It's a book that was originally written by a Chinese author named Liu Sushin. I'm only like five or six chapters in, but it is really spooky. And I haven't sort of figured out what the big arc is yet, but it feels very appropriate for this time of year. It's kind of a thriller, it's kind of gripping. I sort of don't want to put it down. And yeah, it's a little creepy, five or six chapters in.

So check it out, the three body problem. And my pick of the week, I've been watching some older horror movies. This one is actually as old as I am because it came out in 1982. This was the original, The Thing, Paul. Do not watch the 2011 version. After watching The Thing, this is 1982. So it's all practical effects. They are spectacular. They are gross. And it's a lot of fun.

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I don't want to really spoil anything, but I mean, it's been out for what? Paul, 40 years, 40 plus years. So I can just say there's one part, there's one part where a character is, is using a defibrillator and when he goes to put the paddles down, the patient's stomach opens up and bites his arms off almost up to the elbow. It is one of the greatest scenes in movie history. And it is, it is really good.

So check that out, the original movie, The Thing. It's that Morricone score. Kurt Russell has never been better. Just a spectacular hair in that particular movie. Keith David's great. The cast, Wilfred Brimley, you've never seen him before. Just, yeah. What a great recommendation for spooky season. All right, so Paul, let's get to an outro.

The Curbsiders (53:28.078)
This has been another episode of the Curbsiders, bringing you a little knowledge food for your brain hole. Yummy. Okay. That's it. I was hoping there'd be a spooky take, but I like that one better, I think. Get your show notes at thecurbsiders.com and sign up for our mailing list to get our weekly show notes in your inbox. Plus each month you'll get our Curbsiders Digest, which recaps the latest practice changing articles, guidelines, and news and internal medicine. And we're committed to high value, practice changing knowledge, and we want your feedback. So you can email us at askc

And please, if you would subscribe, rate and review the show on YouTube, Spotify, or Apple podcasts really does help other people find the show. A reminder that this and most episodes are available for CME for all health professionals through VCU health at curb And I wanted to give a special thanks to Paul and Rahul for helping to write and produce this episode. The Curbsiders is produced and edited by the team at PodPaste. Elizabeth Proto runs our social media. Chris the Chew Man Chew.

runs our Discord or moderates our Discord, and Stuart Brigham composed our theme music. And with all that, until next Halloween, I've been Dr. Matthew Frankuado. I've been Dr. Rahul Ganatra. I feel like this was a missed opportunity to do spooky nicknames that we should have played out in the past. Maybe next year. We're not very organized for that sort of thing anyway. Like, Poltergeist is as much as I can come up with. As always, I remain Dr. Paul Nelson Williams. Thank you and goodbye.