The Curbsiders (00:00.302)
I got a vaccine the other day and I asked the nurse giving me the vaccine if they moonlight as IT. You know why?

No. Because, Paul, they were excellent at installing antivirus. That's real bad. Yeah, that's real bad. Yet I got very excited about it when I read it. You really did. Yeah, it's an amazing combination of shame and joy that you had there. So I'm looking for a calcium pun, Matt.

And I have to tell you the title is page 100 plus cracking calcium puns, a bonified laugh ride. And I knew I was in the right place. So I just want to let you know, this is at OG puns .com. These, and these are all like chemistry centric, which I like. So Matt, why did the calcium go to therapy? I don't know. It had too many unresolved bonds. All right, Rahul, why was the calcium so brave? I don't know. It had a lot of backbone, not as good as the bonds one, but still.

There's a hundred of these, so our listeners can go and research at their leisure. What was the tagline for the page again? I really like that. A hundred plus cracking calcium puns. A bonified laugh riot. So it has it all.

The Curbsiders (01:18.958)
Termsiders podcast is for entertainment, education and information purposes only and the topics discussed should not be used solely to diagnose, treat, cure or prevent any diseases or conditions. For the more of the views and statements expressed on this podcast are solely those of the host and should not be interpreted to reflect official policy or position of any entity aside from possibly cash like more possible and affiliate outreach programs. If indeed there are any, in fact there are none. Pretty much we are responsible if you screw up, you should always do your own homework and let us know when we're...

The Curbsiders (01:41.902)
Welcome back to the Curbsiders. I'm Dr. Matthew Otto here with America's primary care physician, Dr. Paul Nelson Williams. Hi, Paul. Hi, Matt. How are you? Good. Tonight, this is a hotcakes episode. So we have everybody's favorite whiz kid, epidemiologist slash hospitalist, Dr. Rahul Ganatra with us here to discuss just a mishmash of articles that caught our eye in the recent past.

Paul, before we get to Rahul, can you remind the audience what is it that we do on Curbsiders? I will say that we are the internal medicine podcast and we use expert interviews to bring you clinical curls and practice changing knowledge. I feel more comfortable saying expert interviews because we do have Rahul Ghanachar with us, who I view as a verifiable expert. So even though I would never count us as that, Matt, I think that we have someone who's an expert in critical appraisal. So I think that our tagline still stands. Yeah, absolutely. Hey, Rahul, how are you? Happy New Year.

Hi, I'm great. Happy New Year to you all. How are you? I'm excited for this episode because we have a little bit of critical appraisal. We are piloting or debuting our Corrections and Omissions section because we had some great emails from listeners just pointing things out that, you know, and we want to publicly say, hey, you were right, we were wrong, or we're updating our facts in real time or updating our knowledge in real time. So...

We will get to that. And then of course, we're going to talk a little bit about transfusion. We're going to talk about antivirals for COVID -19 and then whether or not some phenylephrine works as an over -the -counter cough and cold medicine. So great show here. To start us off though, Rahul, tell me about iron deficiency. My sense is that in women, we should probably just screen everyone with a hemoglobin if that's normal.

they're not iron deficient and iron deficient is not that common in women. Rahul, what do you think? Has anyone written about this recently? Gosh, it's almost like you're setting me up to talk about something here. So yeah, Matt, I'm going to start out with my first hot take of the evening. And I do sort of consider this appropriate in the corrections and omissions section, because in my view, we all kind of passed over this paper and this didn't really get much.

The Curbsiders (04:07.766)
airtime. And so I think it's important to kind of talk about this because it's a really important question that affects a lot of people. So I am going to just briefly introduce everyone to a research letter from a June 2023 issue of JAMA. And this was a research letter that was authored by Dr. Angela Wayland, also known as the shematologist on Twitter and colleagues, which included Kribsiders Digest Maven Alex Chaitov.

And the letter was titled, the prevalence of iron deficiency and iron deficiency anemia in US females aged 12 to 21 years, 2003 to 2020. And the study asked the basically the exact question that's in the title. What is the prevalence of iron deficiency with or without anemia among young women in the United States? And it used study, it used data from the National Health and Nutrition Examination Survey or NHANES, which is designed to be nationally representative.

And basically what they found was that using a sort of conservative ferritin cutoff of 25, 40 % of young women in the United States were iron deficient. And using a slightly less conservative cutoff of a ferritin of 50, 75 % of the women in this sample were iron deficient. And despite that, only 6 % of women in the sample were anemic. And then the sort of, you could.

talk a lot about what is normal, what are the normal ranges, where do they come from, and Dr. Whalen has a tutorial on this paper sort of summarizing all that. But one of the features of this study that stuck out the most to me was that among iron -deficient young women, almost 85 % of them had a normal hemoglobin. And that was defined at 13, 13 and a half, 14, do you remember what they used?

They use the WHO definitions of anemia, which were different cutoffs for men and women. I don't remember the exact number for the lower limit of normal for women. But you can find that. We'll link that in the show notes. Yeah. Paul, as America's primary care physician, have you seen different numbers based on different places you've worked? Or just, you Yeah, it feels like there's some variability. I'm not going to be able to get the hard numbers, but yeah, I feel like the reference range changes depending on where you're at. Yeah. I'll say anywhere. I've seen them set.

The Curbsiders (06:19.918)
hemoglobin of 12 or more is normal for a woman. It just—so I'm not sure if they're doing that by age or—or just gender or whatever but— Dr. Justin just vibes. Dr. Yeah. I've just—I've seen different—different cutoffs. But yeah, so—so basically, this dovetails with the other correction in omission that I wanted to talk about because it's iron supplementation which, you know, we've talked about many times on the show. And Rahul, anything else you wanted to say about this paper before I get into the—

into the iron supplementation? Yes, just to answer your question, the hemoglobin cutoff was 12 grams per deciliter. It raises the question, is a hemoglobin really an adequate screening tool for iron deficiency? That's something that affects a huge proportion of the population we should be thinking more about. This first appeared on the show back in, I think, 2017 when we first started talking about iron and iron deficiency. We've done...

many episodes and we've sort of talked about this every other day dosing of iron for at least going on like five or six years now. And Dr. Tony Brew, friend of the show, Rahul's real life friend, because they live in the same city, work at the same place. So he has a Substack now, among many other things that he does. And he did this great like post on Substack where he put together,

just all this information about oral iron supplementation and just talking about how, for whatever reason, this very small trial that happened in 2017 with like 60 patients that were iron deficient women who were only mildly anemic, like hemoglobin 12 or 13 or so, that speculated about why every other day dosing was better.

got everybody to start just doing every other day iron dosing. And since that time, I hadn't really given it too too much thought, but there's been a couple more randomized trials in the 2020s, or a couple randomized trials in the 2020s, all showing sort of no clear benefit for treating anemia with daily versus every other day dosing, even on side effects and even on Hepsodin levels, Paul.

The Curbsiders (08:43.758)
It's like, you know, that was the whole thing. It was first in 2015, there was this study by Meredy et al. where they looked at, you know, the fractional absorption of iron if they gave every day versus alternate day dosing iron. And it looked like alternate day was this like sweet spot where it would work better and presumably give the patients less side effects. So everyone has just sort of gone on that.

And Tony actually coined, because this was on the show and he does a little bit of math about how many listeners we have and how many residents and physicians there are in the US, that this could have changed practice and we could have, Paul, potentially been responsible for this every other day iron, which I think is somewhat flattering and also, because it's not necessarily correct, not the best thing.

But Paul, so far, any comments, questions, concerns? Oh, yeah, no, so many. I think it's a nice thought. So certainly, I think we broadened awareness of the study. And I think probably we did have some impact on practice, if we're being honest and giving a hard appraisal. I will say a couple of things. In terms of the every other day dosing, I was not like, oh, this is exciting because it works even better. I think my excitement was more about the idea of being able to minimize side effects and having something that is more tolerable to patients that work just as well. And I know that's not what the study was kind of going for. But on the other hand,

Anecdotally, my patients are like, oh, God, I hate taking iron. It backs me up so much. I hear that over and over again. So I know that there are these meta -analyses and some trials that suggest maybe it's not all that different. But I can tell you, it seems different to me. And I know we're not practicing bias -based medicine. But I was sort of less, I don't care about hepsedin. I mean, I care, but I don't care. It's great for people who are excited about mechanistic stuff. Wonderful. But I want to know, is their anemia better? Do they feel better? And can they take the medication? And this seemed like a way to get them to take it. It still achieved the same effects as daily dosing.

And my suspicion is a lot of people felt that same way. And it wasn't just our hearty endorsement of it, but also the fact that it seemed like a more humane way to treat patients who didn't like the daily iron. And I'll stop there for this last point. Because I also, I don't see people waving isopropyl alcohol swabs underneath everybody else's nose. Like Zofran around Dynastron is not out of business because of us. So like there are, this caught on for more than just the fact that we kind of gave a raving endorsement. There are other features that also made it attractive, I think, to the broader public.

The Curbsiders (11:03.79)
Yeah, it was, he didn't lay it all on our shoulders. He did say it's just, you know, it's a neat piece of physiology. It has a mechanism that's, you know, just say, Hepsisthenin goes up. So you give it less frequently. The paper from 2023, this by Sibinthal et al was this placebo controlled where they did daily versus alternate day. And the daily was given for 90 days. And then the alternate day was given for, you know, over 180 days. And at the end of that,

either 90 -day period or 180–if you got it every day or 180 -day period, the numbers looked pretty similar. So basically, I think it's really up to you as a primary care physician, you know, if your patient has no problem taking it, they wanna take iron every day, more power to them, they can do that. If they wanna take it every other day, uhm–I think it–it may get–be a little bit slower to get them, uh–their iron levels up. But, uhm–I don't think you're gonna harm them with either strategy and that's sort of my–

my take home from this. And the other thing I just wanted to say, this Hepcidin hypothesis, to me, based on all the data that Tony presents, seems like it was either too simplistic or just frankly wrong. And that it's a little, I think it's probably more complicated than that just you take a bunch of iron, your Hepcidin goes up, and then that means if you're taking it chronically, you know, every other day dosing is better. It just doesn't seem to pan out when you look at the hard end points. So just wanted to put that together. So.

As Rahul said, there's a lot of iron deficiency out there. So prescribe oral iron, but up to you if you want to give it every day or every other day. The other correction I want to make is up until this very moment, I've been saying Hepcidin. Is that just way out in left field? I think Hepcidin, I probably say it wrong. I would say I think Hepcidin is probably right. You both sound so sophisticated though. You're making me. It's like the Winnie the Pooh meme. We're the ones wearing the tuxedo and Rahul.

Yeah. You're the one with your head in the honey jar. Just a shirt. Okay. And then in this corrections and omissions section, this is another one that this one, we got this through an email from a listener named Andrew. Andrew works at MUSC, which is the Medical University of South Carolina. I'm going to withhold his last name because we didn't get permission to mention his name on air, but he sent us like three citations and a Things We Do For No Reason article on...

The Curbsiders (13:27.16)
corrected calcium, which was something that from medical school, you know, I was so proud of myself. I learned how to correct calcium and, you know, have been teaching it ever since. I don't know that I think about it as much these days, mostly because I'm working in the outpatient setting. It just, you know, maybe it comes up a little bit, but maybe it seemed to come up more when I was on the inpatient side. But Paul, had you been aware of this? This corrected calcium is no longer the thing to do? I was not aware. I...

No, no, I'll do that. I tend to chase down ionized calcium if I'm truly concerned, but not because I thought corrected calcium was rather favor. Rahul, what about you? Do you think this is like just a blind spot for me and Paul, or is this something that you've known this is kind of up there where you're practicing? No, I think this is another one of those areas where everyone, at least in my world, kind of learned about corrected calcium and then didn't think to question it.

going forward and the first time this popped into my head was recently Joel Toff had tweeted something about how poorly correlated ionized calcium values are with corrected calcium levels. And it can even be the difference between hyper and hypocalcemia. It can be really quite wide. So that kind of clued me in that this was a thing and then subsequently learned more about it. So the listener Andrew had just listened to episode number 281, which was hypercalcemia.

where we did talk about this corrected calcium, but we were not aware of this information at the time. So that's why we wanted to update this now. And there's this PAYNES formula. That's the one that most people know where if you're using milligrams per deciliter, not millimoles, it's measured total calcium plus 0 .8 times the difference in an albumin of four and whatever the patient's albumin is. So basically,

If the patient's albumin is very low, then you're gonna have a bigger correction and it'll raise whatever your estimated calcium was. The problem is when they've actually looked at this corrected calcium formula and how it performs, Paul, it actually performs worse the lower the albumin is. That's exactly what you needed to perform well, Paul. That's when you would use it. So it seems problematic. Yeah, so like the uncorrected calcium,

The Curbsiders (15:47.554)
You know, so just the calcium that you just get correlates 70 to 80 % of the time with ionized, also called free calcium. That's not great, but actually the corrected calcium does worse than that. So there's no point in correcting the calcium because it's going to perform worse. So if you really are worried about a calcium disorder, you can either go by the uncorrected calcium or you can get an ionized calcium to confirm because you don't want to harm the person by treating them.

for hypercalcemia when they actually don't have it, or for treating them for hypocalcemia when they actually don't have it. Rahul, any comments, questions, concerns about this? No, I just feel like there's so much more I want to learn about this. But yeah, I can feel good about not taking the extra time required to do a corrected calcium now that I know this. What a gift.

to the third year medical students. What joy to have one less formula to have to have tucked in your brain. God bless. Now, Paul, you know, the one thing that the medical students might not like is ionized calcium or free calcium. You know, you really don't want to let that sample just sit around for a long time. So you might want to send them to the lab with it because it's sensitive to temperature. It's sensitive to like if it's exposed to the air, it's sensitive and pH. So basically.

You want to run the sample pretty quickly, like within 30 minutes. I tried to look this up. It's surprisingly hard to find like a source that very clearly, you know, spells out exactly what you should do. But if you're going to, if it's going to be sitting around for more than 30 minutes, Paul, you should put it in an ice slurry, uh, until it can be processed. Uh, but otherwise if, if you're going to process it right away, it's okay. And, um, or you get a bag of ice and then put it on the ice and then have the medical student run down to the lab. Yeah. Yeah.

But if it's going to be processed right away, you know, they, it wasn't clear to me that you need to do that all the time. They They can put it on ice. Okay. All right. That's, you heard it from Paul. You heard it from Paul. That's why it's a little bit of a pain to do the free calcium. So, all right. So thank you to Andrew. Thank you to Tony Brew for these corrections and omissions. And now, uh, let's get to, let's get to a hot cake, Paul. So you're, you're up first. Yeah. I, I once again set myself up for success by having a study that has hard to pronounce names and also some, um,

The Curbsiders (18:09.87)
complicated analyses. So this is from Edelstein et al. in 2023. This is November, so pretty recent from the Annals of Internal Medicine. This is SARS -CoV -2 Virologic Rebound with Neuromatril VIR, Retonovir Therapy and Observational Studies. So that's otherwise known as PaxLivid. We may go back and forth, so apologies in advance. And the reason I picked this paper, I don't know what it's been like for you all. I was on call for the practice the weekend before the holiday. And...

I was basically hammer paged by the answering service because everyone had tested positive for COVID. And there were lots of calls about, I'm going to say PaxLid, I'm going to beg indulgence because saying the generic is a challenge. You guys can break every so often and correct me. And it's always a little bit challenging. I know that this for patients who are at higher risk, there's great evidence for it, but there's the known concerns in terms of whether or not there's medication interactions. And then there's also the side effects. Then there is also.

This idea is, is there rebound COVID with these, with this agent or not? So if you have to take your course of, um, animatral veer or tonne of veer, do after that course, do your rebound, your COVID symptoms come back or do you have recurrence of sort of virologic shedding? And I think that's just sort of one more thing to talk about with patients before you start this medication, which we probably too often just kind of pull the trigger on without really doing our due diligence. So I was that, that's why I was interested in this particular study. Uh, and so basically what this is, is they looked at, they come through data from this thing called the positives.

cohort, which is the post vaccination viral characteristic study. I guess you can get positives out of that. I don't know, like B minus, I suppose. But it's this perspective longitudinal cohort study that enrolled patients who have acute COVID and they measure things. They do longitudinal assessments of their quantitative viral load. They do viral cultures. They track symptom data. And so they sort of poured through this data and sort of compared patients who were on this antiviral and patients who weren't and looked at there was evidence of rebound, if virologic rebound or not.

Are you guys with me so far? I'm with you, Paul. And I'm very excited to dig into the results of this. It is. And the way they define virologic rama, that was also interesting. And it's a little bit tortuous. So again, I hope you'll stay with me for this. Because I think it's correct. But it's a positive SARS -CoV -2 viral culture after a prior negative result or a sustained elevated viral load characterized by a combination of a nadir viral load so that the viral load dropped and then came back.

The Curbsiders (20:30.574)
higher than four log 10 copies per milliliter, followed by an increase at least one above that. So it's a lot of numbers, what I'm not going to bother you with. So they had to have a dip in their viral load that went back up to a level that putatively can actually still transmit disease and can be capable of replication. So that's the important thing to know here. That's how they're defining virologic rebounds. Does that make sense? Yeah. So the study, it's interesting. The top line results is this was a positive trial. We can get into actually sort of what they looked at and how they did it.

it did show significantly more biologic rebound in patients who took the antiviral than those who did not. We're talking 20 % versus 2%. So like a markedly increased amount of virologic rebound. And this persisted even after you had sort of accounted for demographics and underlying immunosuppressions or other clinical states. It really, it does seem to be after all your fancy statistical finagling, it was the antiviral and not some other characteristic of the patient themselves that actually caused this virologic rebound. So as I mentioned, a perspective.

observational cohort study using the sort of data set they've been looking at. The patient self -collected their nasal swabs after diagnosis that were picked up by an unfortunate courier three times a week for the first two weeks, then weekly thereafter until their viral loads were persistently negative. And that's important because the other studies that showed a much lower level of virologic rebound, we're not checking that frequently. These did a lot more sort of spot checks as opposed to some of the other studies, which showed a couple of points in time.

The specimens were analyzed. They did a viral load, they did a viral culture, and the patients completed this survey log every time they actually sent their swabs off. So they're swabbing their nose, they're filling out surveys until their viral cultures are negative. The patients had acute COVID. They were ambulatory because that's who you're going to treat with the antiviral medication. They were from around the Master & Earl Brigham healthcare system for the most part. The patients could self -enroll. And it was a reasonably small study. So they enrolled a total of 173 patients.

But after exclusion criteria and some other stuff they ended up with 127 patients that they looked at and so not surprisingly The treated patients were were older because that's who you'd give the antiviral medication to they had received more COVID vaccines again That makes sense I'd be at good tracks my older patients tend to be a little bit more on top of their their vaccines and get more of the boosters and that kind of stuff and the older patients are more likely to be immunosuppressed which also makes sense because they're more likely to have immunosuppressing conditions and no one died in either group, so

The Curbsiders (22:46.83)
after sort of tracking all the stuff, the patients who receive the antiviral medication are much more likely to have this virologic rebound that persisted for like two weeks after the treatment. And Paul, what I found interesting about, because it's like, okay, so virologic rebound, what does this mean? Nobody was hospitalized for this rebound, right? No one died from this. And only about half the patients with rebound actually had symptoms of rebound, right? Like they were detecting like asymptomatic in...

in half of the patients, right? That's exactly right, Matt. Yeah. Yeah. So my concern, and I'm dying to hear a whole stake on this, but just in terms of my takeaway, and I won't give my hotcakes rating just yet, but my concern is less individual patient outcome and more public health outcome, right? Because as you're saying, these patients didn't present to the hospital. These patients may not even have rebounded their symptoms. But if they're still shedding virus up to two weeks later, that's past the time that we're telling patients to isolate. I worry about the...

the impact and the chance to actually sort of spread to others. So I worry about the treatment with the antiviral and what it means for how we're counseling patients after treatment in terms of when they're safe to serve in isolation and kind of go back out into the world. Does that make sense? Yeah, I mean, it makes sense to me. As you were describing the results, Paul, I was thinking in my head, you know, if I had to make a single sentence to sort of frame the results of the study, what is it? What do I take home?

And the numbers you described translate to a 19 % absolute increase in the risk of virologic rebound and a tenfold increase in the odds of virologic rebound from Neurotelvir, Ritonavir. So it's big. And the whole question about an observational study like this is are the results explained by the exposure that we think explains the results? Or could there be confounding that is the influence of other variables, whether we know about them?

or not. And in a small observational study like this, you're kind of at risk for confounding and partially for the reasons you mentioned. I mean, patients who get treated with PaxLivid or Neuromotelbri or Rotonavir are gonna be older and with more comorbidities and at higher risk for severe outcomes because that's the NIH guideline recommendation is to treat people who are at greatest risk for progression to severe disease.

The Curbsiders (25:06.094)
So off to that, you know that there's gonna be differences in people who are treated with Paxilid and people who are not. So our interpretation of these results, whether there could be any confounding that really threatens the validity of this conclusion kind of depends on a close reading of the paper. And in their table one, they show you the characteristics of the cohort, of the two cohorts. And instead of a p -value, they have something called a standardized difference.

And this is something that is often encountered in observational studies where propensity matching is used to try to select comparison groups that are as similar as possible. And the authors talk about how in this study, they really didn't have enough people to do that. But the standardized mean differences really show you just how different these groups were. Typically, a difference of less than 0 .1 is considered to be kind of close for the purposes of comparison. And basically, all of these standardized differences differ by more than

So the groups were very different and patients who got treated were older, more COVID vaccines, more immunosuppression. So really, really a lot of differences. I can talk about this paper for a long time. Last thing I'll say is that there's one kind of interesting analysis they did, which I think kind of increases my confidence that this could be causal.

rather than just being associated with who gets treated with Neuromotorovir rotanivir. And that was the trend towards rebound if taken, if Neuromotorovir rotanivir was taken within two days of symptom onset compared with taken later. And that makes some mechanistic sense, right? Because you might need some, you know, initial time for your immune system to start to respond to a viral infection before just, you know, treating it with an antiviral and sort of,

that response. So the hypothesis is that if you start treatment too early, you know, maybe that's blunting our immune system's ability to clear the virus. And that kind of fits with, you know, why would these people shed virus longer? Well, maybe it's because by treating early, we're effectively blunting our own immune response. So that's kind of a nice feature of this study. It's by no means definitive, but it certainly makes mechanistic sense and it supports that this might be a causal association.

The Curbsiders (27:26.894)
There's an editorial that I think is worth reading that accompanies it in the annals by Myron Cohen and Elizabeth Brown. And they raised some interesting points and they also just have some interesting insight. You know, there's some authors are saying like, should we delay when we give it? Because Pfizer is actually studying the benefits of a second course, which is not surprising because they sell the drug. Sounds great. But the French research agency,

is also studying five days versus 10 days in immunocompromised patients. And then the authors mentioned that the full FDA approval of this drug, the price has been set at $1 ,390 for a five -day course. So if we're gonna do two five -day courses, Paul, that's big bucks. Cha -ching. Cha -ching. So hopefully Pfizer's not gonna charge twice that if they decide that we need to give a 10 -day course.

The other thing is there's another, I guess, longer acting antiviral called encetrelvir, which is in the pipeline, I guess, and it looks like it does not have viral rebound or clinical rebound so far. They have not seen that. So I thought those were interesting insights from someone with expert knowledge of the topic. I want to remind people, Rahul, you pointed this out. There was a press release, a Pfizer press release, because...

The high -risk trial that got this drug approved, right, it worked to prevent hospitalization and death, right? But in the standard risk group, they did not even go for that endpoint because they knew that people at standard risk are not getting hospitalized or dying from COVID, but they tried to go for, does it shorten the duration of symptoms? Because that's probably a reason a lot of people call and ask for it. And actually, it did not, and they never published that study.

But you can still find the press release, which I think we should put in the show notes here. So Paul, maybe this is getting to your question. I prescribe it for people over 65 who I think will not do well with COVID. And that's my practice as of now. And I'd be curious to hear what you guys do. That's exactly my practice. And I think that follows the data. I guess in terms of, I was going to ask you, how might this change your counseling about the patients you prescribe it to?

The Curbsiders (29:49.134)
or would it at all? One of the reasons I chose this paper is because I read it and I was like, hmm, that sounds important, but I don't know what to do with what they found. And I'm still not sure. So I'm asking people as far as me. Even the editorials and the journal watch are like, it's weird. I would still treat the patients who knew it the way that you would, which I think is correct. But I just don't know how this information changes things right now. But I feel like it should. I just don't know how. Yeah. I just tell them.

If they're over 65 and I think they're going to do fine and they're not feeling bad and they call me, they're like, I've had it for three or four days. I feel okay. It feels like a cold. You know, should I take this? And I'm usually like, you know, I wouldn't because I think you'll do fine and you have this chance to rebound. If they're over 65, COPD, heart failure, kidney failure, whatever, you know, I'm more likely to give it and just tell them you might get rebound symptoms, but I do, you know, my goal is to keep you alive and out of the hospital.

Yeah, the NIH guidelines are very conservative on this point. I reviewed them in advance of our recording and they basically say, as you pointed out, the recurrence of COVID symptoms and viral detection after treatment has not been associated with progression to severe disease. And so they recommend against using concern about recurrence or rebound to avoid, as a reason to avoid treatment.

So just like you all are saying, for patients who are high risk for progression to severe disease, it's still in line with NIH guidelines to treat them. Yeah. And I know we spent a lot of time on this, but I, there, there are also some data suggests that there might be prevention of, or a reduction in long -term COVID for patients who receive this medication as well. So I, I basically, my, my practice is to review these data with the patients and, and do share decision -making for everyone, which I know is.

an obvious thing to say, but truly this is one of the cases where I do talk about the evidence, what we know, what we don't know, just because I think it's important to be transparent about that stuff. Paul, would you like to give a hotcakes rating? I think it's important. I'm going to stand by that. So I'm going to give it four hotcakes. It's not practice changing, so it doesn't get to five, because I don't know what... I still don't fully appreciate the impact of my practice, but I'm glad that they did it, and I think it will eventually change practice. You know...

The Curbsiders (31:58.178)
I wonder if, because we're sort of in coffin cold land here, Rahul, if I should just go get into talking about phenylephrine here. Because have you guys seen people taking phenylephrine or have you noticed that it happens to be in a lot of products when you buy coffin cold over the counter? I feel like it's kind of everywhere. Or used to be everywhere. Yeah. So this happened in September.

where there's this FDA advisory committee recommended that oral phenylephrine be removed from the OTC monograph of drugs that have this GRACE designation, which stands for generally regarded as safe and effective because essentially oral phenylephrine has been proven to be ineffective, you know, quite convincingly. And there's been these two pharmacology experts, and I'll link to an article that talks all about them,

But they've, since 2005 or six, they've been really trying to get this drug removed from the market, just because it doesn't work. Not necessarily that it's dangerous. So if the FDA follows this recommendation from this advisory panel, it would have to be removed from lots of products. I mean, as you might imagine, the over -the -counter cough and cold medicines are like a $10 billion a year industry, and phenylephrine is, you know,

responsible for more than a billion dollars, probably closer to $2 billion of those sales. And this is a medicine, Paul, that does not work. And it's because it's so old that it was kind of grandfathered in before they had to prove that it worked well. Yeah, I don't know. It feels like there's some sort of agenda against it. The only reason I say that, Matt, is because none of them work. None of them Well, that's the point I'm getting to, too. Yeah. Sorry, I didn't mean to hijack you. No, no. It's weird that, like, phenylapherin is the...

is the thing that we're going after. And really a lot of the stuff that we sort of like, yeah, I guess you can try this if you want to, does not have a whole lot of compelling evidence behind it. Yeah, so why would they ever want to study these, Paul? Because there's like, you just put an antihistamine, an analgesic, a decongestant, and a mucolytic agent all in a product in all various combinations. Give it a fancy name or a fun name, cough, cold, flu, whatever. And then, you know, that's what's been happening. But...

The Curbsiders (34:16.717)
For pediatrics, they say don't give these to kids because, you know, we don't know that they work and give them honey and, you know, if they need antibiotics, that's one thing, but this—these medicines you shouldn't mess around with. Now, phenylephrine, the oral phenylephrine, it's deactivated. It can be deactivated in the gut. It can be deactivated in the liver. So, it's—it's not very bioavailable and they've known this for a long time. It's just—it's funny how long it's taken for it to be taken off the market. And these guys—

that had phenylephrine, you know, taken or that led this charge to take down phenylephrine. They're like, and that's not the only one out there. They're like, why Fennison, benzonatate? Why are those out there? They're like, we don't think those work either. So this is a whole industry that, you know, might be shooken up by this. I guess the hope would be that maybe we'll find stuff that is actually effective. You know, maybe they'll start actually studying to look for something. Cause this would be a huge market if you could actually find something that works.

Yeah, for sure. But I think most patients know that stuff doesn't work that well. Paul, even Sudafed, which they keep behind the counter, if you look at the data for that, it's like a 6 % better than placebo or something is what I was seeing. So, probably just Yeah, the data is super compelling. Yeah. Yeah. I mean, I'm just struck by how it's an illustration of how much stuff there is out there that we do that we just kind of don't have the time or the sort of -

sufficiently high priority of the question to sort of look into the data. And there's just so many opportunities to kind of go deep down the rabbit hole. And this is great because this has a big slice of the financial pie. So yeah, I mean, nothing is too common. Nothing is too boring. The experts in these articles, Paul and Rahul, so for you just to give a clinical pearl what you can tell your patients, the topical decongestants, they do seem to work better.

Uh, certainly safer than the oral ones. So you can give the Oxymetazolam, which uh, Brandon is Afrin or the generic version of it. You can give if there's a, uh, intranasal phenolephrin that can be given too. And uh, I think good old, you know, saline irrigation, saline nasal spray, that sort of stuff, you know, works, works fine. Um, so I, I would just say the topical stuff is, is the way to go for, for sinus symptoms and uh, yeah.

The Curbsiders (36:42.444)
And it's a chance to, two weeks later, use the phrase, Rhenitis medica mentosa in clinic and feel good about yourself. Yeah. And yeah, so don't give oral phenylephrine along with the Paxlovid if you're going to be prescribing that agent. All right. So Rahul, last but not least, you have a trial to present. And I guess we'll have to ask Paul to comment on the name. So Rahul, do you want to tell them about the trial? Yes. Let's go back to blood land. So this is the Mint trial.

Paul, can I get your thoughts? Well, tell me what MINT stands for and then I'll report back. Ooh. Yeah, did you realize that the way that Paul evaluates trial names, most people just go, is it a cool word? And then that sounds like a cool trial. Paul goes by, the word has to be cool, but it also has to be like logical from what the, you know, the words in the study. Well, let me see if I can reverse engineer this. So this trial, this was a study.

in a recent issue of the New England Journal of Medicine. This was by Carson and colleagues, and this is called Restrictive or Liberal Transfusion Strategy in Myocardial Infarction and Anemia. So maybe myocardial infarction transfusion is where they Needing transfusion, maybe it would be in there. That would be, oh, yeah. So not great is my take. Sorry, go ahead. Okay, now that that's out of the way. So what was the research question?

Well, this study was asking for patients with acute MI and anemia, should we be using a liberal or a restrictive transfusion strategy? And that was defined as a liberal being transfusing for a hemoglobin of less than 10 and a restrictive strategy transfusing for a hemoglobin less than seven. Which of those should we be pursuing in order to reduce death and MI at 30 days?

So why is this study important? Well, the most recent professional society guidelines on blood transfusions to hospitalized patients actually don't take a stance on whether a liberal or a restrictive transfusion strategy is better for patients with acute MI and anemia due to a lack of evidence. But in response to this study, the up -to -date authors on the relevant topic actually now recommend a liberal transfusion strategy in this setting, even though this was a negative study. So...

The Curbsiders (39:03.534)
What were the top line results of this study? I'll just tell you, you know, what to take home from this paper and then I'll open it up for questions. So what do the authors find? Well, at 30 days, death or MI happened in 16 .9 % of patients in the restrictive group and 14 .5 % of patients in the liberal group. And that corresponded to a rate ratio of 1 .15 with a confidence interval of 0 .99 to 1 .34. Okay, the P value of 0 .07.

So crosses one. Crosses one. That's the thing to sort of interpret from that. And so the study was powered to look for a difference of 20%. And what they found was a non -significant point estimate of a difference of 15%. The other thing I'll say is among patients with a type 1 MI, meaning an MI due to vessel occlusion from plaque rupture, a benefit of a liberal transfusion strategy was seen. The rate ratio there was 1 .32, and the confidence interval did not include 1.

And that was, uh, corresponded to an absolute risk reduction in death, uh, or MI of 4 .4 % and number needed to treat of 23 over 30 days. So guys, what questions do you have before we get into the specifics of the study? So this study made headlines, but the, the primary endpoint was not, you know, was not statistically significant. And then there's this subgroup analysis of type one MI that looks like, Hey, maybe there's something there.

But that seems like there's got to be some risk in interpreting that and just giving everyone with type 1MI a liberal transfusion strategy based on this. That's perfect. And I like your framing of the overall trial result as negative. And I'll just remind listeners, the distinction of negative is a little arbitrary, but you've got to choose where you're going to draw the line somewhere. You could also call this inconclusive. You could call this null. In the main analysis, a benefit of the liberal transfusion strategy was not shown.

And as you pointed out, Matt, we did see a benefit in a subgroup analysis. So what we have to decide in our appraisal is are the results mechanistically sound? Could it be the case that this negative or null study was falsely negative or null? Are there sources of chance or bias that could explain that? And how do we take that into account in our appraisal? Paul, is there anything that stuck out to you about this? The framing of this, I find fascinating.

The Curbsiders (41:28.462)
Like, this may not even be the forum for it. I think we're sort of talking about methodology and the statistics, but the language used around it, this was discussed as if it were a positive trial. And even though at the end, when they're like, this is a negative trial, but still, we're changing practice based on it. Like, it's even, there's a notorious New England Journal of Medicine tweet about how this approach significance. You're like, oh, is that what we're doing now? We're just approaching significance? Better not touch it. It was presented as a positive study, even though it did not meet.

it's primary, which I'm not saying it's not important, it's not relevant, we shouldn't change practice based on it, but I think that the way that the evidence was framed, I thought was interesting to say the least. And I'm excited to hear sort of your specific breakdown as to why this would change practice, even though at the end of the day, the thing that they were looking for is not the thing that happened. Yeah. So yeah, I mean, you raise an important point that, you know, we could easily go off on a tangent. And so I'm going to have to try to keep my blinders on. So let me give you a little more detail about how the study was done and who the patients were and kind of.

sources of chance and bias. So this was a multi -center open -label randomized superiority trial in adults hospitalized with acute MI and hemoglobin of less than 10 were eligible for inclusion. And the included patients were randomized in a one -to -one fashion to either a liberal or restrictive transfusion strategy. The primary outcome in this study was all -cause death or recurrent MI 30 days. And this was assessed by phone and review of medical records.

And the protocol in this trial really worked. By day three, the mean hemoglobin in the liberal group was 10 .5, and in the restrictive group, it was 8 .9, so about a 1 .6 gram per deciliter difference. But this did come at kind of a high cost. People in the liberal group required about three and a half times as many units of blood as people in the restrictive group. So who were the patients? This was 3 ,500 older adults, mean age of 72.

mostly in the United States, Canada, and France. They were randomized about three days after their index MI. And by that time, 30 % of patients in this study had already been revascularized. And then they had a high burden of cardiac comorbidities, but I'll just point out that over half of patients in this study had a type 2 MI, meaning due to demand ischemia, and 40 % had a type 1 MI due to plaque rupture and vessel occlusion. So are there any...

The Curbsiders (43:50.892)
features of what I've described so far that sort of stick out to you. Any questions people have at this point? No, it makes sense. I'm just waiting for you to tell us like how, like what were the sources of chance and bias and like how much, how much stocks should we put in this trial? Yeah. Yeah. Okay. So the cliffhanger that we kind of left Paul's comment at. So what do we do with this, this negative or inconclusive study and why are the up -to -date authors making, you know, a definitive recommendation based on this?

So sources of chance, and by that I mean random variation from the truth. So I think that this study was effectively underpowered because they found a lower than expected risk reduction in the point estimate, okay? 15 % versus 20 % was, which is what the study was powered for. And this could be due to heterogeneity of the treatment effect if the effect of a liberal transfusion strategy is really only seen in patients with type 1 MI, okay?

And this hypothesis to me makes some mechanistic sense. Maybe perfusion really matters when the pipe is clogged, you know, and you're fighting to get any little bit of oxygen you can through, you know, a stenosed vessel. And maybe in a supply demand setting, maybe in that situation, increasing oxygen delivery through transfusion doesn't actually matter that much. Maybe just reducing the demand is what matters. So in my mind, this would leave the study underpowered because less than half of the

patients had a type 1 MI, and so this would bias towards a null finding. So that's one possibility. And then some potential sources of bias towards a null finding. It really stuck in my head that 30 % of patients in both groups were revascularized before randomization. And it's kind of that same idea that if maximizing oxygen delivery is what matters in a type 1 MI, it seems to me like that would matter the most when the pipe is clogged. And so that, I think, would also bias towards a null finding.

And there's a couple other things that kind of made the groups more similar than different. About a third of patients in both groups got an average of two to three units of red cells before randomization, which really reflects the sort of strong desire of people to have transfuse these patients. And there was differential adherence to the protocol. This continuation of the protocol happened in 2 .5 % of the restrictive group and 13 .7 % of the liberal group, which was mostly due to volume overload and transfusion reactions. So.

The Curbsiders (46:19.726)
I think taken together, all of these features, you know, at least open the possibility, this is far from conclusive, but this is kind of what we have to do with the data we have, at least open the possibility that it might be the case that patients with type 1 MI, vessel occlusion, they might experience a benefit from a liberal transfusion strategy, particularly before the pipe can be unclogged, particularly before revascularization. So to me, this study,

kind of makes me feel like if I thought that a patient was going to benefit from a transfusion in the setting of acute MI, as long as you're careful about volume overload, it's not clearly wrong to transfuse them to a liberal transfusion strategy. And I kind of wonder if it might be the kind of thing where we're exposing a lot of people to transfusions in order to try to get this intervention to the subset of people in whom it might actually have a benefit. Yeah, I think that's really well said, Rahul. And I...

My takeaway is not quite as nuanced as yours because you're much smarter than I am. But I think this is, I don't know, one of those things where there are so many factors that play into the decision to transfuse and not, and so many reasons to have anemia above and beyond, and what someone's acclimated to. And I know you can sort of make statistical adjustments for that. But I think having an absolute number, here transfuse, here no, I just don't know that it works that way. And I think that's why you're going to have so many heterogeneous results. So I think it's a challenge to parse out.

you're probably have to sort of divide and subdivide until you find the right patient population, but it's not, yeah, I'm glad in 30 days that there seemed to be an impact in the outcome, but like also being exposed to any transfusions, there's the development of antibodies and sort of longer term consequences. Blood is extraordinarily scarce right now. So sort of being willing to, so it's just, I don't know that it's going to be as straightforward as we'd like it to be ever. And I think that your subdivision makes a lot of sense to me more than anything else that I can think about with this trial.

Yeah, no, and it's a good reminder. I mean, there are costs to transfusion and harms and the adverse effects in this study. Transfusion associated circulatory overload or TACO and febrile non -hemolytic transfusion reactions, both were overall rare on the order of one to 2%, but they were more common in the liberal transfusion group. So it's important to kind of be upfront with ourselves about the cost of this strategy. Rahul, how many hotcakes?

The Curbsiders (48:39.214)
So I think this might be one of the most complete studies that we are gonna have in this space. And I think given the sort of totality of all the prior evidence, I think that this is a great exercise in us needing to use our expertise to make decisions in setting up imperfect data. So I just love this kind of thing. So I'm gonna give this four out of five hotcakes. Okay. Well, boys, I think we've did it. I think we've done it.

That's that's the show. I think we should get to an outro because I don't know Paul your cat seems like he wants your attention He's starving out of his mind. So apologies for all of that

The Curbsiders (49:20.206)
This has been another episode of The Curbsiders, bringing you a little knowledge food for your brain hole. Yummy. Nice. Distinguished, not surprisingly. Get your show notes at thecurbsiders .com. It's time 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 to do that, we need your feedback. So you can email us at askcurbsiders .gmail .com.

It also really helps to show a lot if you subscribe, rate, and review the show on YouTube, Spotify, or Apple Podcasts. It really does help new people find the show. A reminder that you can join our Patreon at patreon .com slash curbsiders. We can have bonus episodes and all sorts of other perks. A reminder that this and most episodes are available for CME for all health professionals through VCU Health at curbsiders .vcuhealth .org. And a special thanks to...

Dr. Rahul Ganatra and Dr. Paul Williams 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. Jen Watto runs our Patreon. Chris the Chew Man Chew moderates our Discord and Stuart Brigham composed our theme music. And with all that, until next time, I've been Dr. Matthew Frank Watto. I've been Dr. Rahul Balint Ganatra. And as always, our main Dr. Paul Nelson Williams. Thank you and goodbye.

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