The Curbsiders (00:01.066)
Hey Paul, my family told me to stop telling Thanksgiving jokes, but you know what? I said, I couldn't quit cold turkey.

The Curbsiders (00:11.818)
Are we going to make Nora go first, Paul? I feel like we should, yeah. Yeah, let's, Nora. Okay, just ripping off the band-aid. So Matt, what do you call rain on Turkey Day?

I don't know. Foul weather. That's not bad. Yeah, yeah. Paul? Nora. What sound does a turkey's phone make? What sound? Wing wing. That was good. That was good. I like it. It is not.

The Curbsiders (01:16.118)
Welcome back to the Curbsiders. I'm Dr. Matthew Otto here with my great friend and America's primary care physician, Dr. Paul Nelson Williams. Paul, how are you doing? I'm great, Matt. Thanks for asking. How are you? I'm doing great, Paul. Cause you know, this is a digest episode, but you know, it's close to Thanksgiving when this is going to be coming out. So this is like a Tofurkey cakes episode. I know it's not your favorite thing, Paul, but I really, I really enjoy the pun in the episode title. So it's yeah.

Now, Paul, we have with us a great co-host, but before we get there, can you please remind people what is it that we do on the Curbsiders? Sure, Matt. Always, we are the Internal Medicine Podcast, and ordinarily we use expert interviews to bring you clinical pearls and practice changing knowledge. Tonight, as you mentioned, we are actually reviewing some of our highlights from the Curbsiders Digest, which comes out, what, twice a month is it now, or is it just one time a month?

by Dr. Nora Toronto, who only puts out this voluminous work of current medicine once a month. Nora, how are you? I'm doing great, you know, getting excited for all of the festivities in November and December and the Philadelphia half marathon slash marathon. Is the 18th? 18th and 19th, right? Yeah.

which will have been, you know, in the past week or two at the time that this airs. But are you, which are you running, the half marathon or the marathon? Or are you just watching? I am running the half. I declined to run the full. You know, when you run the full and you, there's a part where you're running out towards Manny Onk and all the fast people are running past you and you know that you have like a really long way still to go. It's...

It's rough. And the grimace part is those people are running downhill as you're slogging uphill. Like they've already made it past the worst part and you're just trucking and dying in the cold weather. And it just, it's the worst. That sounds very emotionally distressing. Yeah, no. But Philly is a good marathon. If people in the audience are thinking of running it, it's pretty flat and people get good times there. I think they use it to qualify for some of the other bigger marathons, Boston, New York, et cetera. Yeah.

The Curbsiders (03:34.89)
I know a shocking number of people who are coming from out of town to run it, which I think is for that exact reason, maybe to qualify. And contrary to Philly's reputation, the people are delightful. Like it's like the one time where like the crowds are uniformly positive. They're cheering for you. They're not throwing anything at you. It's really, it's, it's lovely. So yeah, I will echo that, Matt, if you get a chance to run it, Marathons, your thing, that Philly is a good one to do. This message has been brought to you by the city of Philadelphia.

The Curbsiders (04:04.767)
Not sponsored. Where all of us live, kind of. And not the marathon, which I think is paid for by an insurance company of MemoryServe, so. Yeah. I think that's right. All right, so we have a lot of great articles to talk about. A reminder for the audience that this and most episodes are available for CME through VCU Health at curb Also wanted to thank everyone who has signed up for the Patreon.

where we're putting out bonus episodes each month, where you can get ad-free shows, you can hang out on our Discord, hear all about Paul's vinyl that he's been buying lately. And that's at patreon.com slash curbsiders. So with all that preamble, let's get into our first article. Nora, you're up first. And tell us the trial name, then maybe pause to let Paul critique it, and then we can go on.

the trial that we're going to talk about first today is Steph Heff Pef Paul comments. That was awful. Tell me where the P is. It just all blends together. We actually know that the P I guess is patients, but there's a T that I guess is smacked out in the middle of semaglutide to make the whole thing work. It's just a mess of an abbreviation. They should be ashamed of themselves. Yeah. There's another one coming. That's Steph Heff Pef.

DM. So don't worry, there's more. Great. So I'm guessing that in that version, they have HEPF-PEPH and diabetes, whereas in this version, they just had HEPF-PEPH. Indeed, that is one of the better names, I guess, in that context that you can tell that one of the inclusion criteria for that trial, which has not yet been published. So we're gonna talk about HEPF-PEPH.

to start, which Dr. Elissa Mancini covered in issue 46. And this is covering a randomized clinical trial that was just published in the New England Journal in the last couple of months. This trial looked at population with HEPF-PEPH, so that's heart failure with preserved ejection

The Curbsiders (06:23.33)
cutaneous weekly injectable medication versus placebo in this patient population with heart failure, looking at both symptom improvement as well as weight changes. Those were the two primary outcomes in the trial. This study was a positive trial. And in the patient population, which was 529 patients who were randomized equally to semaglutide weekly or placebo weekly over a year, we saw that

There was an improvement in symptom and physical limitation in the patient population that received semaglutide greater than with placebo. This was based on a Kansas City cardiomyopathy questionnaire clinical summary score or the KCCQ-CSS. There were also improvements in body weight change greater in the semaglutide group than in the placebo group.

and that was minus 13.3% with semaglutide compared to minus 2.6% with placebo. So what do you guys know about the KCCQ CSS? Well, we should point out that you're mentioning these, the KCCQ and there was a six minute walk distance and there was, you know, we knew the body weight was gonna get low. We already know it works for that, right? So that wasn't that exciting.

they didn't go after the hard endpoints here, you know, the heart failure, hospitalization, they didn't go after death or all-cause or cardiovascular death. So I think that's the big glaring thing to point out. But the KCCQ, Nora, I'd be curious to see, because I don't know that there's a standard answer to this. I looked up, you know, what is a clinically meaningful difference on the KCCQ? I found one article that was saying,

7 or greater would be, for HEP-PEPH would be considered significant, and 9 or greater would be significant for HEP-REF. I'm not sure if you found similar numbers or different numbers. Yeah, I've seen 5 according to some studies and then 10 according to others. And it seems plausible that those numbers are different in the HEP-PEPH and HEP-REF populations. So, I think that's right.

The Curbsiders (08:43.346)
And in this one, what was the difference in that score? Like, did it meet, so did it meet significance? Yeah. So it met significance statistically, first off, the difference. There was a difference of 7.8 points between the semaglutide and the placebo group. And that was representative of an improvement of 16 and a half points with semaglutide compared to 8.7 points with placebo and just...

reminder for those of us who aren't looking at these scores every day, but it's a score spectrum of 100. And so patients were included if their score was lower than 90 in this study with higher scores correlating with better outcomes. So, and like we said, this was so the difference between the groups was 7.8. So that's right in that range of like, what would be considered clinically significant based on previously published things.

And then for this, for the six minute walk, I looked this up too, because I had no idea. And the patients in this, it looked like they had 300, they could all walk 300 meters or the mean or the median was 300 meters. And that was for a moderate improvement in that, with clinically significant improvement would be more than 25 meters. And then a large improvement would be considered more than 50 meters. So this, they walked about something like 20 meters more.

in the group that was given some agglutides. So not as impressive on that measure, but that was one of the things they were touting as like why this was a positive trial. Right. And as you said before, the trial was not powered to look at kind of important clinical outcomes like heart failure, hospitalization, or death.

cardiovascular event, but they did see a numerical increase in the placebo group compared to the simulatide group in terms of hospitalizations. Also kind of interesting, they saw an increase in...

The Curbsiders (10:43.438)
cardiac event, kind of looking at the adverse events in this population, saw this increase in cardiac events in the placebo group compared to semaglutide. It was almost all, it looked like a combination of heart failure and like exacerbations that were labeled in a couple of different ways. And then arrhythmia, so atrial flutter, atrial fibrillation, but just kind of interesting that did seem to be a difference in adverse event profile.

in this one? Not really, just because it's not that surprising to me. We were talking a little bit off air. I would be curious to know how direct the relationship was between the weight loss and sort of the improvement in outcomes. And then also, it's just, again, not surprising. Lower weight means sort of less risk for sort of heff-heff, less risk for OSA, less risk for atrial hip relation, which you actually saw an increase in those events in the placebo group. So these things all kind of line up with stuff that we know already. It's just nice to kind of see it laying out and studied specifically, but I would, of

be curious to see the hard outcomes that we talked about before. But in total, this is not terribly surprising to me, though. It's nice that someone studied it. And I thought that the path of physiology about how this works, too, is interesting. Nora, the editorialist, like there was an accompanying editorial for this one since it was a major study, and they were just talking about how, you know, a lot of the drugs for Hef-Ref work by

adjusting this sort of load to capacity mismatch that exists, you know, sort of the mechanical issue that exists with HFREF, but the fact that like SGLT2s work on HFPEF and GLP1s, if GLP1s show that they work in both, then maybe it's some other thing, it's maybe this, they said maybe it's working on a plethora of metabolic and inflammatory changes that are occurring, and you know, so maybe it's more of this, it's not that mechanical level that it's working on.

maybe there's something else going on that we just haven't identified yet. Like, it's not all just the weight loss. Because they did say with loraglutide, they tried to look at that. And in some calorie restriction studies where there was weight loss, they looked at markers of diastolic dysfunction. And it didn't seem like it was as strong as what we're seeing here with this. So maybe there's something different. Yeah, no, it's kind of interesting.

The Curbsiders (13:06.262)
both of those where we know that it's metabolic, it has metabolic effects, but it also clearly has more than metabolic effects or it seems to in this context. And so kind of parsing out what exactly those are and what patient populations in HEPF and then in other contexts these drugs work for is the question. The only two other small things.

to note with this trial is that the trial was ongoing as Emperor Preserved, which looked at SGLT2 inhibitors in HEPPF was published. And so a pretty low number of patients in this trial were on SGLT2 inhibitors. It was not an exclusion criteria. You could be on an SGLT2 inhibitor and on this trial, but just the drug hadn't yet kind of entered the toolbox for HEPPF. That's a great point.

Yeah, it was only like 4%. Yeah, exactly. Less than 4% even in total. So that's... Yeah. Which I don't think is a limitation necessarily. Like if anything, it would kind of muddy the waters that they're on it. So I think it's kind of hit the sweet spot to just look at GLP-1s in isolation. Anything else, Nora, before we get to your, I guess we're gonna give a Tofurky Cakes rating for this? I guess the only other thing to look out for is the select trial, which data yet to be published, but the company that...

makes semaglutide just published press release in August saying that semaglutide does appear to reduce the risk of major adverse cardiovascular events in patients with overweight or obesity. So I think that that's probably going to add to our interest in this drug in this context. Yeah. Is this practice changing for you? Do you think it's and how many toe-furky cakes do you give it out of out of five?

I do think it's going to be practice changing in this population where we don't have that many tools to treat symptoms or to improve outcomes. So I think probably like four and a half tofurkey cakes out of five. I can't say I'm going to be prescribing it for this indication all that often, but I am excited to see it prescribed very frequently.

The Curbsiders (15:22.866)
Is it okay if I ask America's primary care physician, like how he's gonna, what is this gonna, is this gonna change anything for you, Paul? I mean, only if you tell me what a Tofurky cake actually is. But I mean, it's, no, you're gonna get me talking, but like the SGLT2 inhibitors, I feel like are medications where the cardiologists often wait for the primary care doctor to start it and sort of vice versa. And as a result, the patient just never ends up getting this very high yield evidence-based medication. I do worry about this being in the same kind of category. So it might just.

tighten my interest in prescribing them and maybe change the way that I talk to patients about it. If someone has obesity, it's probably a conversation you should be having already. And then if you have comorbid hef-hef specifically, certainly that would be just one more reason to sort of be a little bit more, not aggressive, but it's sort of just more evidence to talk to the patient about actually starting this medication. I don't know, what's your take? These have been around for a while, right? We've been prescribing these for diabetes for over 10 years. I think my concern is just when you

suddenly expand the drugs to tens of millions of people, because now they're just every indication. People are saying they should put these in the water the way they would joke about, we should put statins in the water. Statins, yes. And I'm still worried. I'm just praying that we're not gonna find some just terrible issue that we overlooked that wasn't really, until you spun it out to tens of millions of people, that then becomes apparent. But as of right now, I mean,

You know, I'm cautiously optimistic. I would like to see a bigger trial of this. This was a small trial. I'd like to see the heart endpoints, you know, make sure that those are improving too. I think they probably will. And again, like you said, Paul, I don't know how much of this is just that the person was just, you know, losing weight, maybe eating less of bad things that were causing inflammation and, you know, exacerbating their heart failure. So maybe, you know, I don't know how much of this is that, but I think in general, these medications are...

You know, these are like the blockbuster drug of the 2020s for sure. It does feel hauntingly like the statin conversations back in the 20 yachts where we're like, what about statins for CBD exacerbations or how about statins for this or like you're just kind of like throwing it everything to see what it stuck and like we were just we were so excited about them as a class of medications and then the same sort of the atropic hand wavy conversations, like they do something. Yeah. So like, you know, it feels very much the same. So hopefully we'll kind of settle out and actually as the evidence grows, have very specific indications for them as opposed to the everything we're trying to make them work for right now.

The Curbsiders (17:49.33)
Yeah, I mean, I think you can wait until they get an official approval for heart failure with preserved ejection fraction before you start pushing out for that indication. But most of my patients in this boat either have diabetes or obesity, so you could prescribe it for those indications and not feel bad about it. And this is, you know, it seems like it's certainly safe in heart failure right now. So I think we can go with that.

All right, well, I think that warranted a bigger discussion just because it's such a hot topic and people are asking, like every other office visit, someone asking me about semaglutides, so better. Yeah, I feel like, whereas with the SGLT-2s, there was kind of hesitation, especially with the like genital candida infections, kind of the black box warning, whereas this, to some extent, except for the scarcity of the drug, like people are really excited about. And so I-

I do wonder whether there will be more uptake because of that actually. Yeah. All right, Paul. So the next, we're gonna be talking about tricyclic antidepressants for irritable bowel syndrome, Paul, IBS, and this is the Atlantis trial. Paul? Yeah, well, say what it stands for because I think this is important to see how they got to Atlantis.

Okay, so this was by Ford et al. And this is amitriptyline at low dose and titrated for irritable bowel syndrome as second line treatment in primary care, a randomized double-blind placebo controlled phase three trial published in the Lancet in 2023. Yeah, no, I mean, I think if we were being honest with ourselves, this would be like the, what, aldat fibs, six foot trial. Like, so it's just, I mean, this is tortured. Whoever came up with this.

should get millions of dollars. It's awful. I love it. So congratulations to the team that wrote this. I do like Atlantis. I mean, Atlantis, I'm a fan of Atlantis. Agree. That's a cool word. What Red Bull to be on isn't a fan of Atlantis though, the law city. Uh, so this trial, it was, it was a relatively small trial where this was one, one of those ones it was done in, uh, in England. They sent out like 15,000.

The Curbsiders (20:00.094)
invitations to patients to see if they were interested. And a little under 1,300 patients said they were interested and they ended up narrowing it down to 463 patients who were enrolled in the trial. And they split them between either placebo or low dose amitriptyline. The amitriptyline was started at 10 milligrams and over three weeks it could go up to 30 milligrams as the maximum dose in this trial.

And they were following people with this IBS severity scoring system, IBS-SSS, which was a score. This is a scoring system. It goes up to 500. And these were patients who had moderate to severe IBS. Most patients had, I guess the scores were in around the 270s in the groups at the start of the trial. And not surprisingly.

both groups showed improvement over the course of the trial. They followed these patients for six months and the between group difference at the end of the trial was 27 points. So that was statistically significant, but they were saying that they were expecting 35 points or more for a clinically meaningful difference between the groups. So I'll pause there.

Any questions, comments about this one? I'm glad they're studying it. It makes sense. We've talked about this before. I do wonder if the uptake wasn't so low just because of the stigma attached to this being an antidepressant, at least within that classification. I feel like that's always the hurdle that you get over when you're trying to prescribe medications like this for disorders of the gut-brain axis. So that's my genius commentary so far until we actually get to the results, I think. There was also one interesting piece of the.

just demographic information. I think it was a predominantly IBSD population and mixed. And there was some theory that maybe patients with IBSC were worried about this potential kind of constipation related side effects from the amitriptyline from the anticoelinergic effects, which I found kind of interesting and did make me wonder kind of about this election.

The Curbsiders (22:18.71)
Right. That patients. Yes. So it's funny that you bring this up. So they did pass this off as a positive trial. I told you that it was statistically significant. There was a statistically significant difference. There was 27 points on this scale that's out of 500. And remember, they were starting at a score of 270. But there may have been an issue with blinding, because patients definitely had more anti-cholinergic side effects in the group that was given the tricyclic antidepressants.

And there was also more dropout in the group that was given placebo. And I wonder how much of that was people that were just like, could kind of tell that they were getting a placebo and not getting an active drug. But it was a well-designed trial overall. I mean, it was intention to treat analysis and they did their due diligence to make sure that these patients didn't have like celiac or IBD or something else going on. That was part of how they screened a lot of the patients out of it.

And they also, these patients were also, had already tried first line therapies. So first line therapies being things like laxatives, changes in diet, anti-spasmatics and peppermint oil was also listed there. Have you guys used that? Yes, I have actually. Wow. I had no idea. No, no. So there's, we talked to the great Dr. Iris Wang. That was one of the ones that she mentioned.

I think if patients have GERD, you have to be a little careful because some patients don't tolerate it well, but there are some branded products that I think one of them has like Callaway seeds in it or something and the other one has peppermint in it and they're for IBS or dyspepsia, depending on which they have that patients can get. Sometimes I will recommend it, mention it to patients if it's the type of patient that wants that. But essentially these patients were, they had moderate to severe IBS.

They had already tried first line therapies. So this was a relevant study because in primary care, usually you would refer out at that point, but I think having this as a second line option would be something that would be reasonable to do. Even though they didn't meet that 35 point difference between the placebo group, there was in both groups, like the placebo group and the treatment group.

The Curbsiders (24:38.382)
there was a significant drop in that score, almost 100 points in the treatment group and 70 points or so in the placebo group. So the placebo effects with anything in IBS does have an effect as well. I think it's reasonable to try it. And if the person also has chronic pain of some other sort, that may also help.

Typically, if I'm reaching for a TCA, I'm trying to kill two birds with one stone. So I might have a migraineur with insomnia, or I might have somebody who has anxiety, maybe some neuropathic pain. And so I think what's interesting in this particular trial is that the baseline presence of depression had no impact on treatment response, and that also treatment did not improve the somatophore or the depression score. So even though, I'd be like, maybe I'll just try to get kind of two things here with one medication might be the reason I reached for that. Actually, this trial would maybe say that's not the way to think about it necessarily. So I...

I thought those results were fascinating and they kind of negated the way that I tend to think about using DCAs. The editorialist pointed out that the fact that it didn't improve what you would think of as like, you know, as depression, anxiety, some of the CNS related effects, you should use the language, this is a neuromodulator, and it's going to probably decrease your visceral hypersensitivity.

and your pain modulation in the gut. And that maybe that's how it's working. And again, like you said, did patients not wanna take an antidepressant for what is an organic issue? So I think talking to them about this as a neuromodulator and letting them know that it may have some benefit when added on to these other first line therapies that you should have tried before you get to this. So I will give this, I guess, a solid 3.5 Tofurky cakes.

And I think, you know, is it practice changing for me? I haven't used TCAs a lot for this. I was aware it was something that was something you could do. I'll still try the first line things. And usually I'm having success with that, or oftentimes patients are asking to see GI. So at some point, usually GI is becoming involved. But if you're, depending on the setting you're in, I think you should feel comfortable as a primary care prescribing TCAs as long as you, you know.

The Curbsiders (26:48.838)
It's at a low dose. You counsel them about the side effects that they might look out for. And yeah, so that's it. That's my take on this. Anything else before we go on to Paul's article?

All right, Paul, what do you got? I have, as per usual, made things more complicated for myself than I needed to. So I have from Yang et al in 2023, the comparison of antiplatelet monotherapies after a percutaneous coronary intervention, according to clinical ischemic and bleeding risks in Jack, which, as I mentioned, came out this year. So the reason I made this more complicated for myself, this was covered, by the way, by the great Dr. Jim DeSalvo in the digest.

is that you have to know about a different trial before you actually understand what they were doing with this one. So A plus work on my part, I gave myself two trials for the price of one because I am a brain genius. So this is a post-hoc analysis of the host exam trial, which I was glad for the chance to dig into it because probably that would be practice changing for me and I don't think I knew or thought much about it before kind of going into this post-hoc analysis. But the host exam trial for our listeners enrolled 55...

130 patients aged at least 20 years, which I think is a funny number, continuing the population, who were maintained on dual antiplatelet therapy six to 18 months after PCI with the drug-eluting stent. So these patients had some sort of PCI intervention and then were on dual antiplatelet therapy for at a minimum six months or as long as 18 months, and they could not have had a clinical event in that sort of post-PCI period. And what they did with these patients, they randomized them after the DAPT.

one-to-one to monotherapy with either clopidogrel 75 milligrams or aspen 100 milligrams for 24 months and we're looking at a primary composite endpoint of all-cause mortality non-fatal mi stroke readmission due to acs or a bleeding academic research consortium or bark type 3 or greater score bleed and just for you guys to know that's it's a big old bleed that is overt bleeding with a drop in hemoglobin greater than three grams like that's not like a nose like that is like you're like dumping out blood so it's not it's

The Curbsiders (28:49.73)
So a significant bleed is what I'm saying here. And basically for you to know about this initial trial, this host exam, is at the end of the trial, the primary outcome occurred in 5.7% of patients in the clopidogrel group and 7.7% in the aspirin group. In other words, the clopidogrel group had a lower rate of the primary composite endpoint and it was pretty clinically significant. It was statistically significant with a hazard ratio of 0.73 and a P value of less than like 0.0035. So.

Good study, interesting, argued in favor of clopidogrel after DAPT for patients of undergone PCI that had lower risks of bleeding and did not seem to have a higher recurrence of adverse cardiovascular events. So that's not the trial we're talking about, or at least it is indirectly. The authors actually extended the host exam trial out for five years after randomization. Turns out the effect persisted clopidogrel still seemed to do better in terms of fewer adverse outcomes and fewer ischemic events.

And before I get into the post-hoc analysis and sort of talk about that, any questions about the initial sort of post-exam stuff? Did that all make sense? Did I explain that okay? Yeah, I just, and this was done in Korea, right? Correct. Yep, so it's one of the arguments which can be extrapolated to say, not arguments, but limitations, is that may limit generalizability to sort of populations that we work with. So important point. So...

To the study that I'm talking about, this is the post-hoc analysis of the host exam. So we say, okay, clavidogrel might be better than aspirin monotherapy after dolentic platelet therapy, after someone's had a PCI. How does that apply to various sort of risk cohorts? So especially what does that look like in high risk groups? Does it do better in certain high risk versus low risk populations? And so what the authors did is looked at the data they already had and stratified patients by risk scores. They looked at this thing called the DAPT score.

dual antiplatelet therapy score, which is interesting because it's, I want to make sure that I say this right, the higher the DAP score is the higher the ischemic risk, but the lower the bleeding risk is what the authors say. And if you have a low DAP score, you have a lower ischemic risk, but a higher bleeding risk. So there's this sort of weird divergence that I still haven't quite figured out why that is. Paul, the score, if you look at the score on MDCalc, it's like you get minus points if your age is older.

The Curbsiders (30:59.806)
And then everything else is just an ischemic risk factor. So I feel like they're just like, if you're old, your bleeding risk is high. And then like how many, if you have less of these ischemic factors, then that's the only way to get a low score is to be old and not have- Have no other risk. Have ischemic risk. Yeah, and then you can start with a score of negative two, which is also just a weird quirk. Yeah, so that's the DAP score, which we'll come back to. And then the other one that they looked at was the thrombolysis and myocardial infarction risk score for secondary prevention, a mouthful. And then you try to abbreviate this.

like TRS2-prime-P or something awful like that. So I'm going to say that as little as possible. But that's a score which is basically used to predict recurrence of cardiovascular events. And it's based on age, grade and 75, presence of diabetes, high blood pressure, current tobacco use, sort of all the ACV risks that you would expect. And so looking at these risks and sort of risk stratifying the patients in this host exam trial, basically what they found is that the clavicular effect was fairly consistent across all these sort of risk strata. So if you had this high TRS,

risk score, which means high clinical risk, you had a lower primary composite outcome with clopidogrel compared to aspirin monotherapy. Same goes for low risk by that score. And then if you look at the DAP score, if you have a high ischemic risk and a low bleeding risk, you did better with clopidogrel, so you bled less and you had fewer ischemic events. And if that score was low, meaning a lower ischemic risk but a higher bleeding risk, you still did better off. And in fact, in the high TRS strata, so if someone has a high risk of clinical events,

they found that patients in the aspirin group had like, I think there were like nine hemorrhagic strokes, or maybe there were eight hemorrhagic strokes in that group, but something close to that compared to clopidogrel in that same group that had zero hemorrhagic strokes. So it just kind of reinforced the fact that there's probably a lower risk of intracranial bleeding with clopidogrel compared to aspirin therapy. So in sum total, and then I'll let you guys ask your questions and just make sure I explain this correctly, it seems like.

Low risk, high risk, bleeding or ischemic events, clopidogrel just seems to be better than aspirin, at least in this post-hoc analysis of this trial that looked at that exact same thing after someone has already undergone dolenta platelet therapy following PCI. So a lot of abbreviations, a lot of words that I just put out there, someone asked me a question or say something so it's not just me for like five straight minutes. Noor, was this talked about in your hematology, oncology, fellowship, you know, world of blood?

The Curbsiders (33:19.87)
I think that's a great question. So we often are at odds with the cardiologists about which agents to use and whether to use antiplatelet therapy at all. So this was not actually talked about in our conferences the last few months, but this is kind of an ongoing conversation in and around the dual antiplatelet kind of duration of therapy conversation.

which was one piece of this that I think they looked at as well. And they found that kind of regardless of how long you had been on dual antiplatelet therapy, the benefit to clopidogrel was the same that remained over aspirin. So that was kind of an interesting and I think probably important other analysis that they did. And that, yeah, the hemorrhagic strokes component was, was quite concerning and

a little bit surprising to me that it was so skewed in one direction over the other. Yeah. So, essentially, Paul, the top line result is that just like it doesn't matter what their risk is. Like the risk scores don't matter. Just like clopidogrel outperformed in all the risk groups compared to aspirin. Yeah, that's the takeaway. And this goes back because we were digging into this. There was the, you mentioned, host exam. And then like in the 1990s, there was the CAPRI trial.

where they looked at clopidogrel versus full dose aspirin. And there it outperformed it better as well. But back then clopidogrel was still, was not generic yet. So it was still, you know, cost prohibitive. And it wasn't, I think that much better that everybody just had to do it. And so I think that's where we've been at. But now the, it seems like the evidence has accumulated that the P2Y12 inhibitors are better or clopidogrel specifically.

in the host exam that we're talking about here. And, you know, Paul, in the back of my mind, because you always hear people talking about clopidogrel has to be converted from a pro drug into the active, and they always, they talk about like these certain medications that affect the metabolism and certain genetic, like loss of function mutations or gain of function mutations. And they actually did that Taylor PCI trial, which was published sometime in 2020.

The Curbsiders (35:43.39)
where they actually tried to look at the genetic mutations and said like, is this something we should be looking at? And does, is this going to improve outcomes? And in that one, it didn't improve outcomes. So I guess that's why we didn't, we don't do this all the time, but you know, once in a while, I don't know about Nora and Paul, but I feel like I interact with some specialists that like, they feel very strongly about, you know, whether or not clopidogrel is good enough for if we should be checking something before we just put someone on it.

So that's why I was kind of curious to dig into this a little bit. But it seems like for right now, you're OK to just put people on Clopidogrel if they have an indication. You don't have to worry about the genetics underlying it. Yeah, I think that's right. And you'll probably ask me at some point if this is practice changing for me. In practicality, probably the decision is because as to which...

antiplatelet medication is going to be used, it's going to be up to the cardiologist. And certainly I can have it put in that conversation or can at least prompt the discussion with the patient and their heart doctor. But in terms of my own personal practice, I don't know that much will change, but I'll be curious to see how this sort of changes the conversation across that specialist group, or if at all. One group I didn't think about, but somewhere in my reading here, they were just mentioning aspirin. Some patients with GI intolerance or dyspepsia, maybe they don't do as well with the aspirin, but the clopidogrel.

is a little more friendly in those situations. So that maybe that would be a tiebreaker for me. If the patient doesn't care and they're on dual antiplatelet and they're like, which one should I stop? And the interventionist is out of the picture for whatever reason, I guess I could push them towards clopidogrel of all other things being equal. So Paul, how many hotcakes or Tofurky cakes do you give this one? And I'm sorry, was it Tofurky cake? Tofurky cake. Well, it's a pancake, but it has

tofurkey in it. Oh, that classic food. It's very good, very appetizing. Well, Paul, you are familiar that on Thanksgiving if you are vegan you can get a tofurkey, which is a tofu turkey substance that I've actually tried and I have to say I'm sorry to the people at Tofu, I love tofu. Tofurkey is not for me. I did not like it. I like most foods, Paul, but that I could not do. I could not deal with it.

The Curbsiders (38:00.094)
Well, with that, yeah, I'll do like three and a half, I guess. You know, this is a post-hoc analysis. If I was doing the host exam trial proper, I would probably actually give it like a four or four and a half, but the fact that this is sort of like the restratification and just give me an excuse to go back and dig into an older trial, I think this will probably give me like three and change of a Tufurki cake, even though I don't feel fully satisfied with the answer you gave me as to what that is. So I think this will contribute towards what will ultimately be some practice changing data, but maybe we're not quite there yet.

Now it's time to move on to the part of the show where we're just going to run through some hot takes, a couple shorter takes on some recent articles. Nora, you're first. And do you have a clever name to run by Paul? I always do. And I'm very curious for his insights into this one. So the trial we're going to be talking about now is called Reprieve. Paul, what do you think? I mean, I think that...

largely depends on how they derive reprieve. So tell me the full trial name and how they tortured this poor acronym out of it. And we've confirmed now that the way Paul judges the trial names is based on the derivation, which is not how everyone judges trial names, but. What, so now before you tell me the trial names, so what other metrics are we talking about then? Like otherwise we're just picking random words of a dictionary that we like and just kind of like. Yeah, that's what I would do.

It's too logical. Tell me how you got to reprieve. Yeah, OK. So the official title on clinicaltrials.gov is- These people get paid to write this stuff, you know? Like this is what their entire jobs are based on, is actually scholarship. And if we're just making up words. Sorry, what is it? I know, I wonder if they had a consulting firm kind of weigh in on this. But the name is randomized trial to prevent vascular events in HIV.

or reprieve, which does not have pitivastatin in it, unfortunately. Yeah, none of that works. Yeah. Sorry, go ahead. So not to jump to the trial design, but the trial looked at the benefit of pitivastatin or astatin in patients with HIV who were at low to moderate risk of cardiovascular disease.

The Curbsiders (40:19.75)
over a long time period. It looked at over 7,000, almost 8,000 adults aged 40 to 75 who were taking antiretroviral therapy for their HIV diagnosis. They had preserved CD4 counts and most of them actually had suppressed viral loads. And they all had a low to moderate cardiovascular disease risk on enrollment in the trial.

and they were randomized to either pitivastatin, four milligrams daily, or placebo. Just to remind ourselves, the ASCVD risk score that they used looked at a risk of less than five as low risk. So yeah, Nora, I wanted to ask, so in terms of estimating that cardiovascular risk, they used the pulled cohort equation, is that right? That's correct. OK, which I think if memory serves, did that actually include patients with HIV and its derivation? No, it doesn't.

derived calculator tool that is being used, but it actually, it's not yet kind of worked into all of the guidelines. So this is kind of the standard way they have historically measured ASCVD risk in the trial and kind of over the last 10 to 15 years, even in patients with HIV, though this may very well change in the coming next couple of years.

I did want to mention because we forgot to say this upfront, this was covered by Dr. Alyssa Mancini in Digest number 41 and 45. And the reason they're looking at statins for prevention of cardiovascular disease and HIV, it's, correct me if I'm wrong, Nora, but even if patients have a suppressed viral load, they're on ART, they still have a higher cardiovascular risk than...

you know, other people of the same age without HIV, right? Yeah, that's exactly right. And there's more data being assessed looking at the reasons for that and the actual path of physiology behind it. There's some thought that maybe it's immune activation related just chronically, even with a suppressed viral load. There was some thought that the drugs that were used were contributing to it, but it doesn't...

The Curbsiders (42:39.402)
seem like that is sufficient to explain the increased risk over time. And so because we have such effective therapies now for HIV, we're kind of running into these chronic conditions that are more common in this patient population and happen at different times than in patients without HIV. And then my other question would be, why pitivastatin? Is it because there's concern with interactions with other medications? Or is this just like a drug that...

people are looking to make money on getting it, you know, a specific FDA approval. I'm sure it's a little bit of everything, but. Great question. So I think the primary reason that pitivastatin was used for this trial is because it doesn't have interactions with the common antiretroviral therapy, which many other statins do. So I think that's the primary reason.

So is this practice changing for you? I mean, how are the numbers, any numbers needed to treat or things like that you wanted to point out and what you recommend to the audience? So I think we covered it actually twice in the digest. Once when the press release came out in the spring because the trial was actually stopped early for efficacy, which doesn't happen all that frequently. And this was at a median follow-up of 5.1 years in this patient population.

patient population of over 7,000 patients. And this was because at their interim analysis, they saw that the primary outcome, the major adverse cardiovascular events were significantly lower in the group that had received pitivastatin compared to the placebo group. That aligned to 4.81 per 1,000 person year events compared to 7.32 per 1,000 person year events. And that...

converts to a number needed to treat to prevent an event of 106. Yeah, and that's for primary prevention. Which is not, I mean, for a primary prevention, that's, you know, that seems like a reasonable number. It's perfectly fine. Yeah. It's kind of right in the ballpark of what we, the other things we do for primary prevention. They're like between 100 and 300 in general in terms of numbers needed to treat.

The Curbsiders (44:58.146)
So this seems like the kind of thing we were talking off air that where statins for patients with diabetes, statins are just sort of a standard, modern intensity statin for all patients with diabetes. It seems like they're moving towards that with statins for, or maybe just pitivastatin or if there's another statin that can be.

easily co-prescribed with ART, then those would be, you know, this would be practice changing. It's not something that I'm thinking of right now, oh, this patient has HIV. I need to start them on a statin. That's not something that I've been doing. Right. Yeah, I think it shows that there's benefit even in the lower risk cohort within this study. And so it's worth probably thinking about starting and...

a statin or at least having a conversation with patients about starting one, even in a group of patients that you wouldn't necessarily, based on their ASCVD risk otherwise, be thinking about it. Yeah, because the range of risk was between like 0 and 20 percent. So this is a wide swath of cardiovascular risk that they were sort of looking at. But I think even at the lower end of the spectrum, you still saw benefits. So the question that you have, Matt, is they are on this question, like what do you do for patient selection?

Is it just easier to just go with all patients who are looking with HIV? Because we know that cardiovascular risk is elevated and we just don't have data to be more selective. Yeah, it sounds like a big trial. And so we'll, of course, keep covering this in the digest or on hotcakes. And maybe this will make it into future guidelines. Let's move on to another article. Paul, this one was about starchy vegetables. Did you get a chance to look at this one too? It looks like it is dense, dude. I was.

Ready for some light reading about how potato chips are bad. And instead, I was glad that you picked this one and not me. So maybe you'll tell me what this is about, because I had a hard time teasing things apart. Right. So I found out about this one because it was covered by Hannah Smith in the digest number 46, and this was by Juan et al. The association between changes in carbohydrate intake and long-term weight changes. This was a prospective cohort study. It appeared in the BMJ in September, 2023. And I'm not used to reading.

The Curbsiders (47:15.69)
literature about nutrition and this was like, you know, these were they were scraping like NHANES data sets and this one is a little bit dense to go through, but I'll give you my dumbed down version, which I mean dumbed down for me, not for you audience. You're smart. So in healthy middle-aged adults, they found that increasing intake, not surprisingly, in increasing intake of fiber, natural sugars.

whole grains, fruit and non-starchy vegetables was associated with less weight gain when you compared it to refined grains and potatoes and other starchy vegetables and sugar sweetened beverages. That's not really that surprising, but I guess what made this one get headlines was the fact that they were saying, not only do you have to worry about eating vegetables, but you should worry about which type of vegetables you're eating because the starchy vegetables, which...

they were including as like peas, potatoes, corn, and I'm sure I'm missing another one, but those are the ones that were associated with more weight gain. So I'll pause there, Nora, Paul, any thoughts or concerns, questions about this? I agree that most of it seemed relatively obvious and it seemed like the overarching message was that the-

Fried potatoes are the worst, number one. And then beyond that, trying to limit some quantities of these starchier products and balancing it out with better things like whole grains is the most specific recommendation we can take away from this. Yeah. I think some people are concerned, like I wouldn't slice and dice.

the vegetables up too much and be specific, which vegetables are good and which vegetables are bad. I think that was sort of one of the potential criticisms of this, like it's, yes, obviously French fries, not great. But I think, you know, rather than saying, you know, rather than getting parsing things down too much, vegetables are probably still better than just sort of drinking sodas. And I just be careful in terms of the messaging around what you're trying to say, I guess, would be the only thought I had about this study. Yeah, this was a hard one. They were saying, let's say every extra hundred grams of starch that someone ate,

The Curbsiders (49:36.582)
over a four-year period, they would gain an extra 1.5 kilograms and that's 100 grams per day of starch, which is a lot. I mean that's a lot. You know, we've talked about carbs a little bit recently on the show. So like 15 grams is like a serving of a carb. So when you're talking 100 grams, that's several servings. So yeah, people that are... It's at least two. Yeah. And they said that people that were eating carbohydrates...

from starchy vegetables for every extra 100 grams per day, they estimated that over a four year period, they would gain 2.6 kilograms compared to people who were eating an extra 100 grams a day of non-starchy vegetables. Those people would have three kilograms of weight loss. So kind of like that they have the graphics showing that. Now I will just say there were some.

pretty entertaining responses in the BMJ, you know, underneath the article linked to it. And the valid points that they were making, which I thought is that they were saying like, if you look in the supplement that the patients that were eating more of the starchy type vegetables tended to be eating more calories in general, there was some suggestion of that. So it would make sense that they would gain more. And the other thing is that they were just saying that culturally,

you know, certain foods are just eaten. And so to tell people not to eat potatoes or corn or peas, whatever, if that's part of how they cook, you know, that's might not be the most helpful thing and is not really, it might not be realistic or culturally, I don't know, I'm not sure what the right word is. Probably people are not just gaining all this extra weight just because they're eating peas and corn and potatoes. Maybe it's- Right.

the company, maybe it's because it's doused in, you know, with other, there's other greasy foods or they're frying it, whatever. It's probably the way they're preparing it that's causing it. I don't think it's the vegetables themselves. That would be my take. And of course we all know that refined sugars and sugar sweetened beverages are gonna put weight on people. So, you know, I'm not gonna tell people to be too specific about the way that they're eating their vegetables, but I will.

The Curbsiders (51:54.474)
you know, the way they prepare their vegetables, I think, is probably more of what you should be talking to people about. It's really well said. I think that's exactly right. So rather than assume that french fries is the same thing as a baked sweet potato, which is obviously bananas on the face of it. When we talked to Michelle McMackin on our, we were talking about nutrition, you know, she's like, I don't have a problem with potatoes. Like, she's not telling people not to eat potatoes. So enough said about that. Paul, to round it out here.

Can you tell me a little bit about cannabis and heavy metals? Should I be worried about this? Yes. Put my cap down. So this is an article that was initially covered by Beth Garbs Garbatelli. This is from McGraw et al. in 2023 in environmental health perspectives, which I'm sure that, Matt, you read on the weekly basis. Robert Garb is published. I have an RSS. Sure. Google notification. But this is a.

Blood and urinary levels among exclusive marijuana users, a phrase I love, and a haze from 2005, 2018. So basically, it turns out, Matt, I don't know if you've heard about this cannabis stuff, but people like it. It's becoming popular, I've heard, and it's legal in like, it was 21 states, at least the publishing of the article, which accounts for over half the US population at this point. So lots and lots of people are using it empirically, like you just anecdotally talking to patients like they, a lot of my patients either have

prescribed cannabis or just use it recreationally. It's just very, very prevalent. And what we know about cannabis is it is a hyperaccumulator of heavy metals. So what that means is it actually leeches heavy metals in the soils and the water that it uses gets stored in the vacuoles and it's not well regulated. It may shock you to hear because it's still illegal at the federal level. So we don't have the FDA weighing in on what permissible levels of cadmium and lead are in cannabis. So it's just this wild west out there of this plant that can hyperaccumulate these.

potentially toxic metals that can impact neurodevelopment can cause malignancy and can have other kinds of effects. So basically what the researchers did is they did, they combed through NHANES data from 2005, 2018, and looked at blood levels of cadmium, lead, mercury, manganese, and selenium, and then also urinary levels of 15 different heavy metals. And they sort of stratified these levels among patients' exposure to tobacco and cannabis use. So they had four big categories. They had folks who never used tobacco

The Curbsiders (54:17.75)
had at least not recently used tobacco or cannabis. That's group one. They had exclusive cannabis use, but not tobacco use. They had exclusive tobacco use, or they had dual use of these things. So before I move on in terms of what they found in terms of having metals in the blood or urine, your takeaway here is that they found that cadmium and lead levels were higher among those who used cannabis exclusively compared to people who did not use tobacco or cannabis. So basically cannabis does expose you to higher levels of,

lead and cadmium. These levels are higher the more recently that you had actually used cannabis. Which is not surprising. Then the exposure kind of decays as time elapses between last use. If you used tobacco, you had higher cadmium levels than other groups. The lead levels were comparable among exclusive tobacco use and exclusive cannabis use. In other words, whether you only smoke tobacco or you only smoke cannabis, your blood levels of lead were about the same.

In summary, your takeaway point, rather than kind of parsing through a lot of confusing cross-referencing, cannabis is a source of lead and cadmium exposure, at least according to the data set that they scraped down. Yeah, and they didn't really try to look at any clinical effects of that, or they didn't really... I was trying to find, is this a concerning level of cadmium? Is this a concern? Yeah, right. The answer for lead is, any level of lead is not good, is what I found, but I couldn't really find any specific way to quantify...

is this cadmium gonna cause problems? It's hard to know how to use this clinically. So will this change anything that you do when you're talking to patients about this? Yeah, the conversations around cannabis use in general, I do talk about safety specifically. And my usual take-home point is like, please don't use cannabis and drive. Like that is the one health outcome that we know is measurably worse.

The pendulum is swung that we're very permissive about cannabis use and because it's so prevalent, I think we almost don't comment on it now. This might prompt me to just use it or don't, but I should at least let you know that there are heavy metals that you may be being exposed to and I don't think we know what the clinical impacts of those things are. If you are going to use it, at least be mindful that there are potential duct exposures there if that is a consideration in terms of you decide to use it or not. I will probably mention it, but in terms of how I practice medicine, it's not going to change all that much.

The Curbsiders (56:34.834)
And are you going to give any advice about kind of mechanism of using it in terms of ingestion, inhalation? Good question. It's a great question. I don't know, based on these data that I can actually make any specific recommendations on, I don't know if eating lead is better or worse than inhaling it. It's hard for me to know. So I could dante down the rabbit hole. So I think it's probably a blanket recommendation so far.

So I'm sure the listeners are a little bit familiar with what like lead toxicity might look like, but cadmium toxicity, I just looked it up, Paul, just for fun. And this one, it can apparently cause kidney dysfunction and issues with bone mineral density, specifically it can decrease bone mineral density. So Paul, have you heard of e-tie disease? Matt, that rings a-

Weird Bell, like I want to say that it's Japanese for ouch ouch, but I can't, I can't remember much more than that. Am I making that up? I am shocked that you know this. So Paul, this gets its name given to a mass cadmium poisoning that occurred in the Toyama prefecture of Japan starting around 1912 because there were, cadmium was being released into rivers by mining companies in the mountains and people were getting this just terribly painful

disease where they were having severe back pain and joint pain, and it was related to this cadmium toxicity. I doubt people are getting that much cadmium from their cannabis, but I'm sure there will be a case report if it ever happens. Right. Well, now, thanks for our show. Vigilance will be increased. Vigilance. So if anyone has diagnosed Itai disease because of cannabis exposure, I bet you can get...

I bet you can get that published. Just think of it as an acknowledgment session.

The Curbsiders (58:28.69)
This has been another episode of The Curbsiders bringing you a little knowledge food for your brain hole. Yummy. All right. Get your show notes at thecurbsiders.com and sign up for our mailing list to get our weekly show notes in your inbox. Plus, once each month, you'll get our Curbsiders Digest, which recaps the latest practice changing articles, guidelines, and news in internal medicine. And we're committed to high value practice changing knowledge. And to do that, we need your feedback. So please subscribe, rate, and review the show on YouTube, Spotify, or Apple podcasts. It really does help people find the show.

You can also send us an email at askcurbsiders at gmail.com. A reminder that we have a Patreon. If you want to get bonus episodes, add free shows, hang out on our Discord, that's patreon.com slash curbsiders. And this episode and most episodes are available for CME for all health professionals through VCU health at curb Wanted to give a special thanks to...

Drs. Williams and Toronto for helping to write and produce this episode. Our technical production is done by the team at PodPaste. Elizabeth Proto runs our social media. Chris the Chew Man Chew moderates our Discord. Stuart Brigham composed our theme music. And with all that, until next time, I've been Dr. Matthew Frank Watto. I've been Dr. Nora Toronto. And as always, our main Dr. Paul Nelson Williams. Thank you and goodbye.