← The Curbsiders Internal Medicine Podcast
The Curbsiders Internal Medicine Podcast
#506 DIGEST-Hotcakes: PSA Screening, Acetaminophen and Autism, COVID19 Vaccines and Cancer, Aspirin and Anticoagulation in Coronary Artery Disease
01:07:48
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A
Hey, before we get to the show, I wanted to remind you to check out our patreon@patreon.com curbsiders. If you haven't signed up yet, sign up now to get ad free episodes, twice monthly, bonus episodes, and a whole bunch of other cool stuff@patreon.com curbsiders.
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B
What'S up, Paul?
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C
Not much. What's up with you?
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B
Not much. This girl said she recognized me from the vegetarian club, but I'd never seen her before.
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C
What? I may have missed a punchline in there. Say that one more time.
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B
So I was going out and this girl, she said she recognized me from the vegetarian club, but I'd never seen her before.
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C
I genuinely don't understand.
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D
Herbivore.
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B
Herbivore.
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C
Oh, never seen herbivore. Okay. All right, great. Thank you, Rahul. Can I tell my quick joke? You guys may have heard this one already. It's one of my favorite dad jokes I was just reminded of recently. So a grasshopper walks into a bar and the bartender looks at him, he's like, hey, we got a drink named after you. And the grasshopper says, you have a drink named Larry. Anyway, the Curbsiders podcast is for entertainment, education and information purposes only. And the topics discussed should not be used solely diagnosed, treat, cure or prevent any diseases or conditions. Furthermore, 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 moral hospital and affiliate outreach programs, if indeed there are any. In fact, there are none. Pretty much.
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D
We aren't responsible if you screw up.
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C
You should always do your own homework and let us know when we're wrong. Welcome back to the Curbsiders. This is. That was a long run for a short slide. We are here tonight to do one of our Curbsiders Digest episodes. And I am joined by a large team and a special team. So on tonight's episode we talked about several studies and to do that we are joined by. What was the suggestion? Dr. Garnacha or a Live in epidemiologist? I'm not sure. Yeah, I like that.
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D
That's great.
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C
Our live in epidemiologist, Dr. Holgon. At we are joined by our chief editor of The Curbsiders Digest, Dr. Nora Taranto. Dr. Toronto, how are you?
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B
I am great. How are you, Paul?
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C
I am still well. And we are joined by Digest contributor, super producer, occasional co host, but always beloved expert hospitalist and digest associate editor, Dr. Laura Glick. Laura, how are you?
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E
Good, how are you? Doing.
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C
I'm so great. Still so, so good. We are joined by Dr. Adam Sifu.
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D
All right.
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C
We are also joined by a special guest, Dr. Adam Sifue. Dr. Adam Sifue is a professor of medicine and a general internist at the University of Chicago. And he is one of the most sensible medicine providers we know, a lover of evidence, active on social media, has a substack called Sensible Medicine, selected as a favorite faculty member by the graduating class of Pritzker School of medicine almost 20 times. And he joins us to provide additional perspective and expertise on some articles that we talked about tonight. Before we get to those articles, I should remind you that this and most episodes are available for CME credit for all health professionals through VCU healthsiders.org I will also just throw all kinds of out of order remind you that ordinarily we are the internal medicine podcast that use extra divinities to bring clinical pearls and practice changing knowledge. But tonight the experts are we. We are the experts. So we're going to talk you through some articles about, oh gosh, prostate cancer screening and whether or not we should be doing DOACs and aspirin and then some uncontroversial stuff like Covid vaccines and cancer and then maybe we'll even touc on acetaminophen and neurodevelopmental disorders. So without further ado, let's get to it. All right, well, we've been talking for a little while. We've got a large group, we have at least four articles to talk about to kind of really dive into and see if they're going to be changing our practice at all. Maybe if we're feeling sassy, we can give them some kind of rating. But Nora, why don't we start with you? You brought us an article about prostate cancer screening that has I think actually caught some general media buzz as well. So tell us what you read, what we're talking about and sort of what you thought about it.
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B
Great. So I'm going to be bringing us today a discussion of the European study of prostate cancer screening. This is the ERSPC and this study has actually now published its 23 year follow up, which is quite a bit of follow up for a screening study and just a study generally. It's published, published several prior updates to follow up since the study was initiated in 1993. And just as a little bit of background relating to the significance of this study, the study focused on prostate cancer screening, which obviously if caught early, before it's spread outside the prostate, remains curable and so that's with surgery or radiation, with or without other medications. Now it's also a disease of aging. And so there are many men who develop prostate cancer who may have other. And so the question has arisen over the last several decades about whether or not we're screening the right patients for prostate cancer, whether or not we're leading by screening too many patients to over diagnosis of prostate cancers that aren't ever going to actually cause patients problems or lead to prostate cancer mortality or mortality, broadly speaking. And so there have been a number of studies over the last several decades that have looked at prostate cancer screening with PSA or a prostate specific antigen. This is a blood test that can be drawn either once or multiple times over years. And what the effect of prostate cancer screening with this blood test, the PSA is on prostate cancer mortality. There were two other studies that are relevant besides the ERSPC and one of them was run in the UK over several decades. One of them was run in the US and then this one was run in eight countries in Europe. This study I believe, had the longest follow up of any of them and has the most recent and kind of modern follow up for lack of a better description. And in the erspc, this study randomized patients in those eight European countries to either an invitation to PSA screening between the ages of 55 and 69 or a control arm with no invitation to screening. Individuals in the screening arm were offered repeated testing that range I think between two and eight tests over 15 years with intervals anywhere between two and four years and ending around age 70, 71 to 74, positive PSA testing. So that's using typically a threshold of around 3 reflex to further diagnostic testing and standard care. From there, the primary outcome of the study was prostate cancer specific mortality. And then they did have secondary outcomes looking at the incidence of prostate cancer stratified by risk category of prostate cancer at the time of diagnosis. And so this overall was a positive study. They did find at this median follow up of 23 years that prostate cancer mortality was 13% lower in the screening group than in the control group. And that correlated with an absolute risk reduction of 0.22%. Now, I guess from there, I'm curious what you all thought about this study and kind of PSA screening, broadly speaking, and how this fits into what your recommendations are for patients. Obviously there have been a number of guidelines that, that have conflicting recommendations and have changed their recommendations. Paul, first off, what was your thought about the acronym?
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C
It's fine. I'm not sure I love catchy acronyms for life threatening diseases in general, but I don't know, it's certainly not memorable, but also not the point. So thank you for that. Excellent question. Yeah, I guess, I don't know, I've been doing this long enough that I've seen prostate cancer screening. The thinking around that kind of flipped back and forth a couple of times, but I can't think of many screenings that have as much consistent hate as prostate cancer screening has. Even when the guidelines flip more towards the shared decision making model. I think no one was really excited about that. I don't know that a lot of residents or trainees even know that that's the current model that's recommended. Even when the study came out, I heard a little bit of buzz about how well this is going to be spun the wrong way. And actually PSA screening is still awful. So I just, I think I'm glad the study was done and I think it's great to have the conversation. But yeah, in terms of a screening, something that we screened for, this is one that it's been hated for almost as long as I can remember. And I'm not entirely, I mean, I know why, but also I'm not entirely sure why. So those, even before getting into the n degree of the details, that was sort of the context I was bringing to this.
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F
I'll chime in and say I sort of celebrated this because I think it's the last time we'll have to deal with a prostate cancer screening trial. Right? Like this is the last study that the sort of placebo group, right, the unscreened group will actually be more or less unscreened. Right. That kind of doom the PLCO study, the American study, because so much of the non screen group got PSA testing and this, you know, we're 23 years out, you could never redo this study. So at least like we'll never have to talk about this again. And we talk about prostate cancer, which is a disease of older people. Right. 23 year follow up is enough. And then I can hate on it whenever we're ready for that.
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D
This reminds me of a prior study we've discussed on this show and that was the Nordic trial of colonoscopy screening. And you know, lots of parts of this kind of harken back to the discussion we had about that. In particular, something a little wonky, the use of what is called Zelen randomization, which is where informed consent happens after randomization. And that's something that's sort of typical of population Based or registry studies. But you could imagine that the act of consent itself might influence someone's behavior with regard to screening for a cancer. And so in this trial it was a relatively large proportion of patients who underwent the screening, which was not the case in the Nordic trial. So there's some important differences there. But I'm wondering for those of you who talk to patients about prostate cancer, screening is learning all of the details about the cancer and about the pros and cons of screening. I think that's sort of the intent that we're supposed to be having those discussions with patients now. But I could imagine that that is really something that would affect your behavior around vigilance and screening.
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F
I think it's a little bit of an issue of the design of the study as well as the results of the study. Because the fact that we're comparing intention to screen with not is very much producing population data rather than the kind of what would be considered probably per protocol in this, which is the patient level data, as like, yes, you were screened or you were not screened. And it's kind of irritating as like a primary care doctor where when you have that discussion, you know, my experience over the years has been just about every man says yes and the men who don't say yes after I've like, you know, brought them through this incredibly well planned, well articulated kind of consent, they're like, well, what would you do? And I'm like, God, you're right. It's so do that. Because I think about this all the time and you've thought about it for the 90 seconds I've been talking to you.
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E
I think it's also interesting to just mention that it's worthwhile thinking about how to use this data, given I think we mentioned this before, but how much change has happened in the screening and evaluation of prostate cancer in general? This likely reflects more of the older diagnostic biopsy and treatment pathways. I think now we use MRIs a lot more often in active surveillance to guide the biopsy decision. So I would love to hear your thoughts on how to use this data given that we have this newer diagnostic imaging and management approach which ideally balances the risks versus the benefits of screening, may be different now with how we use it.
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B
Yeah, and that's kind of one of the limitations that I think the authors raise and I think that the author of the editorialist of the editorial that kind of accompanied it raised as well, just that we do often with these like long term screening studies have this issue of like changes in standard of Care over the time of screening and changes to all of your points about kind of how recommendations have changed over time for PSA screening, like what the control arm, what the no invitation to screening arm was actually receiving over time. And so that makes it hard to parse out what the effect of like the screening test itself is here. But it is true. Totally, Laura. Like, we, we are not necessarily in prostate cancer management intervening on and kind of from a surgical perspective, actually removing every low risk prostate cancer. There are patients who actually do go on to active surveillance for, for years where they're getting repeat imaging, they're getting repeat testing before they actually undergo the surgery if they have other that are higher risk and that warrant more focus, or if they just have a really low risk cancer to begin with. And so I do think some of that worry about over treatment and the harms of over treatment have been mitigated by the kind of improvements in testing and management.
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F
Wait, I gotta jump in and call you on that because we do this all the time whenever we have a unimpressive screening study that everybody says, ah, well, come on, we do it so much better now. And like, is that ever actually born out? I'll just get into the data here. Right. I mean, this is. You gave the. Whatever it was 0.22% decrease in prostate cancer specific death. Right. That's tiny. Right. They give us a number needed to screen of 456. Right. That means that if I screen basically all the men in my clinic, you know, I save about one life over 23 years. That's nothing. The cost of that is that I diagnose 30% more men with prostate cancer than I would have otherwise. And then the number that like struck me so much in this study is that we save one life from prostate cancer cancer, save one person from prostate cancer death for every 12 men diagnosed. Right. So that means that 11 out of 12 men diagnosed with cancer I harm rather than help. Because even if we do a terrific job without selecting the right person, you've still given that person a diagnosis of cancer.
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D
Yeah, I mean, whether outcomes other than prostate cancer specific mortality are important, I think is is the point that you're bringing up, Adam. And I mean, the answer is definitely. And one outcome that I see as kind of missing from this study is some quantification of what is the harm that men experience who are diagnosed with either early stage or low risk prostate cancer. I mean, we know that the surgeries are morbid and come with complications. So I think. But a more nuanced Understanding for me of what exactly are the costs of the one life per 450 some people screened saved, in my view, it's one piece that's kind of missing from this study.
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C
This is my other question. Is mortality the right or the most important outcome for this particular cancer? I think is the other way that you're asking that question. And maybe this is salience bias, but the most impactful cases of prostate cancer I've seen have been, you know, bony metastases. And like, you know, is there other stuff that we could make better by doing a better job of screening that is not necessarily mortality? Because, again, this is happening in older patients where probably something may otherwise may get them anyway. So, you know, because I agree, because, like, the prostate cancer mortality in and of itself is probably not super duper impressive, but I think there are potential downstream benefits of actually catching sort of early prostate cancer in the right patient. But to have defined that is a challenge.
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B
Yeah, I was going to say, I think there's some. One of my open questions here is it feels like each of these studies has done the screening in different ways, slightly different ways, or very different ways, and then also kind of the exact population and the age thresholds for the population are different. And I don't know within the age range whether the age range is the correct one. That was chosen in the study to start and end between 55 and 69, as the prostate cancers that are the most aggressive and that we would theoretically want to catch the earliest are the ones that happen in younger men. That's one, I think, serious limitation to a number of these studies that I just can't. I had trouble parsing out in the data here, like where that population is within this bigger population, which it's obviously really hard to find those individuals. But I think those are the folks that I suspect would benefit the most from a screening approach at all.
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F
My struggle with this is that, and I think what I've already sort of hinted at, I think all this data is so underwhelming as to make me think the weight of this is that we've just done harm to now two, maybe three generations of men through prostate cancer screening. All that said, there are men in their 50s who I've sent PSAs on who've ended up having Gleason 7 prostate cancer, who I'm pretty sure I've saved their life. Right. And so although I can kind of sit here as, you know, like an EBM guy and be like, oh, my God, this is terrible, you know, We're we're diagnosing 11 out of 12 people with prostate cancer that wouldn't have hurt them to save one life. I also, when I'm actually sitting with a younger man, I do feel like maybe that cost is worthwhile, but it like behooves us to how we really should be doing significant counseling on with men, which I think the vast majority of people don't. This is just part of the Chem 30 that you get when you have a doctor and most women get screened for prostate cancer too, because of that.
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A
Yeah.
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B
I was going to ask what your practices are with the discussion at this point. It sounds like varying.
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C
Yeah, I mean, I do try to do counseling in certain forms and have the conversation around it with the appropriate patients. I just want to mention. And then we should wrap up and move on. I want to hear your Hotcakes rating, whether this is going to change. Are we doing hotcakes ratings this or you let us know if this leads to practice digest. But the decision to biopsy at a threshold of 3 nanograms per milliliter I just have to sort of comment on is not like that these days. Would be an insane thing to sort of practically do too. So I'd like just to Laura's point, there has been evolution, sort of now they're talking like reference ranges that are actually sort of age specific. So I just, I wonder how that impacts things to some extent. But that's maybe a conversation for a different time.
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B
So can we also just mention that they just threw out the whole country of France because they didn't comply with, with the protocol? That was, I, I, I was amused by that.
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C
It's worth mentioning.
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D
That's more typical of the US though. Like, apparently only like 30 to 40% of men in the US who are eligible undergo PSA screening.
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B
Interesting.
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D
I mean, in this study, like, and you know, they called it an intention to screen study, but I kind of wonder how fair that is because, you know, if over 80% of the people are doing the screening, that's definitely not what we're doing here. So just it makes me think that these mortality estimates might be more of an upper bound rather than kind of a lower bound.
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F
It's really more typical of Britain, though, to ignore everything from France.
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E
Very unfrench.
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C
All right, Nora, is this going to change your practice? What is your, what is your summary? Take us home.
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B
I don't think it's going to change my practice. I still have a number of questions about, to Adam's point, the right population in which to have this discussion. It's not going to lead me not to have that discussion.
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C
I have to parse that out.
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A
Yeah.
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B
But I do think it's still really hard to know how frequently to offer this to whom to offer this. And I completely agree that the number needed to screen is really not particularly impressive. And so I think it's a conversation as opposed to a mandate.
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C
My book, yeah, practically I don't see this actually changing any guidelines. I think they'll still just say talk to the patient and sort of leave it in the individual PCP's hands.
- [22:23]
A
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- [25:18]
C
All right, great, Great start. We are moving on to an article that generated quite a bit of lay buzz. There's been a lot of conversation about acetaminophen and autism. Rohol, so you brought us an article. No, I love that you chose this one. Tell us all about it and sort of how we should start to think about it.
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D
Sure. Okay friends, so for my selection for today, we're discussing a system without a meta analysis by Prada and colleagues. And I'll just note that the senior author is the dean for the School of Public Health at Harvard University. This is a systematic review that appears in a recent issue of Environmental Health. And the research question that this study was asking is whether maternal use of acetaminophen during pregnancy is associated with the subsequent development or I should say the subsequent diagnosis of autism, attention deficit hyperactivity disorder, or ADHD or other neurodevelopmental disorders in children. So why is this study important? Well, this study is important because it sort of formed the basis for the FDA's recommendation in September of 2025 to change the label for acetaminophen to reflect caution around these risks. And the FDA also sent a letter to physicians, which we can link in the show notes it's pretty short about the risks of acetaminophen use during pregnancy. Kind of independent of those actions, though it's my thought that clinicians with any stake in promoting maternal and child health are going to face questions about how seriously should people take these findings and how safe or harmful is acetaminophen in pregnancy? So before we get into the details, first of all, I'll just apologize to all of you for asking you to read this 45 page PDF with all the tables and supplements that this was kind of a doozy.
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C
Can I just I'm going to be the one to Say it. The table's unforgivable. Like, there's 20 pages of, like small tables, each one occupying a single page long. Oriented the wrong direction.
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B
Oriented the wrong direction.
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E
I can't handle it.
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D
Yeah, I mean, I knew that my contribution to this discussion would be simply having read the entire PDF, so you're welcome, everybody. So, and you know, we're kind of joking about this, but it really does get to why this is such a nuanced issue and such a difficult issue to really have as beliefs supported by evidence on, because it's really difficult to kind of wade through all the information that's contained. But anyway, what are the top line findings for us to start with? I'll just read you the conclusion from the abstract because I think that that really kind of encapsulates a lot of what people are reacting to about this paper. So the conclusion of the abstract reads. Our analysis supports evidence consistent with an association between acetaminophen exposure during pregnancy and increased incidence of NDDs neurodevelopmental disorders. They go on to say appropriate and immediate steps should be taken to advise pregnant women to limit acetaminophen consumption to protect their offspring's neurodevelopment. So before I get into the details of this, I'm just curious initial reactions to the language used in the conclusion of the abstract or to anything about the sort of setup of this that people have so far.
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F
I mean, it makes me want to just jump up and down and scream, right? I mean, this is like the greatest editorial failure ever. You know that first sentence, right? About there's evidence consistent with an association is true based on their data, and we can talk about how important that is. But then to make the jump from an association to causation and action is appalling and tells you that there was a whole lot else going on here other than science.
- [29:08]
D
I totally agree. I think that's a really crucial pickup about this. We haven't talked about the data at all yet, and already differentiating the use of causal language from language describing an association is a really critical part of the messaging about data like this. I'm curious what the rest of you think.
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B
Yeah, I had a similarly strong and critical reaction, mostly to that point, of making policy recommendations about management of patients based on an associational study or a set of associational studies primarily, and making recommendations that just seemed like entirely unhelpful. Like that patients who are pregnant with a fever instead of taking Tylenol, should cool themselves and seek medical consultation, which just like I Just couldn't. And I couldn't grapple with that being the recommendation here that came out of this study.
- [30:10]
C
Yeah.
- [30:11]
D
So I agree. So a lot of people's initial reactions to not only the use of causal language where it's maybe not warranted, and also kind of lack of consideration of what are the alternatives, I think those are very fair reactions. So I'm only going to tell you a little bit about how the study was done, because this is a systematic review. It's huge. We can't go into all the details without putting everyone to sleep. So I'm just going to tell you a few things, things about the highlights, and then we can discuss a little more. So basically, this was a systematic review that included 46 observational studies. 20 of those studies assessed the association between acetaminophen use and ADHD, eight assessed the association with autism, and then another 18 assessed the association with other neurodevelopmental disorders. Okay. And the authors, because they didn't undertake a meta analysis, really, all they can say by way of summarizing the results is how many studies showed a positive association, a null association, or no association, or a negative association, meaning a protective effect of acetaminophen. And Those numbers are 27 showed some indication of association, nine were null, and four indicated a protective effect. So to give you a sense of what the included studies were, I'm just going to tell you a little bit about one study that I think really exemplifies some of the problems with this systematic review, and then we can talk a little bit about some of the limitations therein. So one representative study that's included is a study that was in a 2024 issue of JAMA by Alkvist and colleagues. And this was a population based retrospective COHORT study of 2.5 million Swedish children who were born between 1995 and 2019. And these authors did something pretty cool. They did two analyses, one of which was a crude analysis just looking at rates of autism diagnosed by age 10 between children exposed to acetaminophen in utero compared with children not exposed in utero. Okay. Pretty standard stuff. They also did something called a sibling controlled analysis. And this is a substudy in which pairs of siblings with the same biological parents who were exposed to acetaminophen and were not exposed to acetaminophen were compared to each other. And that analysis is meant to control for unmeasured genetic and environmental confounders. And this type of study is really valuable when you're Looking at exposures to things in utero where we maybe don't know all of the exact confounders that could affect that. And that study, the crude analysis, found a very small increase in risk for autism. The hazard ratio was 1.05. Okay. And the absolute percentages were low. 1.33 versus 1.53. Okay. And that association was completely attenuated. In the sibling analysis, the hazard ratio was not significant. The absolute differences were not significant. So I'm curious now before we talk a little bit about some of the specific problems with this study. I mean, does this affect how you think about studying the association between acetaminophen and autism? Can people anticipate any problems in studying that association?
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F
These are incredibly difficult associations to pick up, right? Because these are generally the impact of a maternal exposure, and the relationship of that to a disease tends to be very small. When we've been successful with this in the past has been things like thalidomide or DES exposure, where we've been able to do case control studies or even case series to show a really clear effect, we get the sense from this that if there is an effect, which I have to say I don't think there is, the effect is minuscule. It is, unfortunately, I think, probably going to be impossible to detect. I love this study that you picked out here. And I also love it that you really made it clear that this is not a meta analysis. And although we were all tortured with these multiple tables, there were none of the forest plots that we always hear of look for it and say, like, what's the effect size and how does this all come to be. But even in this Swedish study, the Alquist, not The siblings study 2.4 million people, and they come up with a hazard ratio of 1.04. And I've always taught that in an observational study, in a cohort study, with all the noise there is, if the relationship is less than 2, a hazard ratio of less than 2, an odds ratio of less than 2, you should basically ignore it. And here we're getting news for an hazard ratio of 1.05. It just kind of got a shrug.
- [35:09]
B
I also was. I don't know whether any of you guys got a better sense of the. I was lacking a mechanistic explanation to this that I really struggled with. And the fact that it seemed like some of these studies found more effect kind of later in the. The pregnancy, when you don't think as much about neurodevelopment happening, though, obviously that's like simplifying it entirely. But I just really struggled with the lack of why this could be the case. And they really didn't provide that to me, at least that I could find in the discussion. And so that made me question all of these results even more, especially when they started talking about the kind of two hit hypothesis where like, Tylenol was actually the first hit and the second hit was the fever. Instead of thinking about, oh, why were they taking Tylenol? Probably because of the fever, I think.
- [36:09]
E
Nora, you brought up a good point about the heterogeneity of the different studies. So just in terms of how they're defining the exposure, some are using, some included any use of Tylenol. Some were duration, some was the timing, like the trimester. And, you know, some used biomarkers. But I think with all that heterogeneity of it's very hard to synthesize any.
- [36:31]
C
Results cards on the table. I tried very hard to kind of separate my own personal feelings about the politics surrounding this discussion with the actual outcomes and really tried to almost be devil's advocate and try to be on the side of, like, how can I believe that this is actually true? Because I know my inclination would be to think like, this is nonsense because, because of the source, if I'm being perfectly honest, not the authors themselves, but again, sort of the political environment from which this has sort of has stemmed. So that I struggled with. But even so, like, even the discussion seems sort of very. I'm just being reasonable here. There's a lot, a lot, a lot of details and sort of that I'm not sure that didn't fully line up. And I still didn't feel satisfied that there was a great explanation. At the end of the day, even the cited animal studies that talked about the neurotoxicity acetaminophen and leading to neurodevelopmental delays, that was not my read on the paper. When I actually went to the citation itself, I came away from this overall, to Adam's point, with a big shrug. There's a lot of words and a lot of stuff that was talked about, but nothing that felt especially compelling to me, which is not a very scientific way. But that is what I walked away from this gigantic paper with.
- [37:42]
D
Yeah, I mean, I'm hearing lots of very important limitations. You know, the strength of the association being small is a big problem for an observational study where confounding is virtually guaranteed. The presence of unmeasured confounding, we are very worried is happening as a result of what we saw in the Alkvist study. There's a couple other problems that I'll share with you before I give you my final take home on this. You know, autism is sort of a heterogeneous spectrum and a constellation of things. So the absence of a single unifying mechanistic pathophysiology here, I mean, you're not imagining that we're studying something that is a very heterogeneous label applied to many different things. So that's going to be a challenge. And then there's another problem that we haven't really discussed yet. And this is really getting into the weeds. And so I will leave listeners to kind of view the directed acyclic graph that we'll put in the show notes. But there's a big problem here which is confounding by indication. And what this basically gets at is how do we know that acetaminophen is the putative cause leading to the outcome and not the indication that acetaminophen is taken for? And I've tried to diagram this out a little bit. We can direct listeners to that. But I mean, this is particularly evident for febrile infections during pregnancy. I mean, we know that that is, especially when fever is untreated, is thought to increase risk for neurodevelopmental disorders, including autism. And disaggregating whether the increased risk comes from the acetaminophen or the reason the acetaminophen is being taken is a really subtle and not straightforward issue. So there's a bunch of reasons to doubt the conclusions as presented in the abstract.
- [39:34]
C
Thank you. I'm glad that you mentioned the confounded mind indication specifically. So, so what, Rahul, do we do with this? So does this change your management? How are we like, I guess where. What are you taking away from this after being the person who did the deep, deep dive? So what is your take home point? How do you. What should we do with this information such as this?
- [39:53]
D
Yeah, I mean, what I take away from this is that there unfortunately is really a dearth of high quality evidence to inform what pregnant women should do when it comes to weighing the risks and benefits of acetaminophen during pregnancy. I mean, I will say that there are clear harms to alternatives to acetaminophen like NSAIDs and aspirin that acetaminophen doesn't have. And there are harms to maternal fever, especially if it's prolonged and untreated during pregnancy. And the label already says to consult with a healthcare professional before use and that's a position that's supported by professional societies like acog. So to me this is not practice changing and if anything this is more of a cautionary tale about the harms of the careless application of causal language to low quality evidence for political gain.
- [40:39]
C
All right, beautifully said.
- [40:45]
A
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- [44:08]
C
Well, let's move on to our next article. So we're going to move away from controversy and just talk about COVID and cancer risk, which seems like much safer territory. But before we do that, I would actually, Adam, if you would indulge us, can I ask you to speak on the blue after visit summary framing of this? Because I just, I love it so, so much. I just want to make sure that our listeners actually have a chance to hear about this before we talk about.
- [44:31]
F
Maybe I'll save that since that gets so much to my interpretation of the article. But I was so proud of that. I'm glad you mentioned it. I can talk a little bit about the study and I'll try to be fast because I don't think it deserves actually a whole lot of attention. So this study was published in Biomarker research. It's called One Year Risks of Cancer associ with COVID 19 vaccination, a large population based cohort study in South Korea. And it was written by Kim and colleagues, actually on First Brush. Sort of seems like a pretty impressive study. It's a cohort study that compared about 2.4 million patients who received the COVID vaccine between 2021 and 2023. And it compared them with about 595,000 patients or people really who did not get the COVID vaccine. The data was obtained from the Korean National Health Insurance Database, which as far as I can tell is a pretty reliable database for getting that information. Who did and did not get the shot. The authors then categorized these people into vaccinated and not vaccinated. Vaccinated. And the authors then just examined the incidence of 30 different cancers in these two groups. What they found in the sort of highlight is that six cancer types, breast, gastric, prostate, colon, thyroid and lung, were more common in the vaccinated people. And the hazard ratios, they made the hazard ratios for acetaminophen and autism look like nothing. The hazard ratios went from 1.2 for breast cancer all the way up to 1.7 for prostate cancer. And I think, not surprisingly, because it's about the COVID vaccine, this got a lot of play both in the regular media and certainly on social media, among the sort of, I don't know, vaccine, skeptical, vaccine hesitant crowd. And so I wanted to cover it, to amplify it even more. I wanted to cover it because I thought that there were such clear and obvious errors in the data that I just thought was worth putting that out there because I think they packed a lot of mistakes into a four page paper. So maybe I'll open it up to people. Thoughts reading this?
- [47:09]
D
Yeah, I mean, I really like the exercise of reading a paper where you don't agree with the conclusion, just to sort of diagram your. Your thinking and your thought process. I mean I. You're preaching to the choir with that. And you know, Paul, something you said, thinking about the acetaminophen paper really got me thinking, you know, just to play devil's advocate, like how could you, you know, what would you need to accept these results as true? In my mind, Adam, that is exactly like how I approach a paper like this is thinking, like, okay, what would need to be true? What would I need to believe about the analysis in order to accept these results? Results. So I'm looking forward to hearing how you walk through a paper like this.
- [47:50]
F
So as I read this, I think the first thing I always think about is bioplausibility. Right? How likely is this to be an issue? I am certainly not a molecular biologist, but from everything I know about vaccinations, even the quote unquote dreaded MRNA vaccination, is because it's hard to believe there is going to be impact on human DNA from vaccination, which I'd expect is what would happen if we were seeing cancer. I'd also expect there to be a long lag time between vaccination and cancer. And so certainly even if this is true, I don't think we would See this in tunnel analysis sort of 20 years hence. And so those two things were the first things that really raised alarm bells in me is that when you look at this data, the curves between the vaccinated group and the non vaccinated groups separate essentially immediately. And even with studies of survivors of the Hiroshima and Nagasaki bombs, we didn't see that sort of injury. And so that's kind of shocking. And interestingly, all of that ill effect seems to happen in the first six months. The curves separate over six months and then become parallel after six months. So it seems like the putative harm, I guess I would call it happens immediately and then sort of disappears. And then the next step for me is, well, what could be the difference? Like, why are we seeing this? And this took a little bit of research for me, because certainly primary care in South Korea is a little bit different than primary care in the United States. And it turns out that the six cancers that did increase are things that are, if not routinely screened for, commonly screened for in South Korea. So for us, certainly breast, lung, colon, and prostate are things that are screened at doctor's visits or soon after once you can get your patient in for a colonoscopy. That's actually true as well with gastric cancer and thyroid cancer in Korea. So I think it becomes very clear that what we're doing is we're comparing people who went to the doctor, got screened for cancer, and often also got a Covid shot with people who didn't see a doctor, didn't get screened for cancer, and also didn't get a Covid shot.
- [50:15]
B
I feel like, for me looking at this, one of the things that kind of immediately raised red flags that I'm curious whether this is kind of how you guys interpret it as well, is just seeing the effect primarily, like, all in the same direction across everything they looked at at, and seeing it in everything they looked at, pretty much even if it wasn't a significant association. And so that was kind of one interesting reflection I had. I was like, oh, yeah, this does raise some flags. And perhaps this is a good tool with which to kind of look at, look at results when people are doing multiple analyses in this kind of exploratory way.
- [51:00]
D
Yeah, I mean, it does kind of beg the question, you know, what, apart from receipt of the COVID vaccine, could explain a difference and a difference that becomes apparent, you know, quickly in rates of cancer diagnosis between these two groups. And, you know, I mean, Adam, you, having looked into this paper the most, are kind of in the best position to Speak on that. And me as a non subject matter expert, all I bring to this are questions about, you know, does this make sense or not? But I'm trying to think biologically from a mechanistic standpoint, what could explain oncogenesis on the timeframe of months? I mean, Nora, I don't think you need to go to oncology fellowship to sort of know that that's really fast for solid cancers. So, I mean, it does raise the question, is this about oncogenesis or is this about detection of cancers? And something about the people who got vaccinated that is reflective of their underlying propensity to seek care as being different from people who did not get vaccinated? Unfortunately, there weren't really any indicators of that in the paper. I mean, there are things that could be measured to try to get at that, like the number of visits a person had in the year preceding their diagnosis, how up to date a person was with recommended cancer screenings. Like, there's ways this could have been assessed. And I kind of expect that had those been included as covariates in the propensity score, that this association across all the cancer types might have been attenuated.
- [52:32]
F
Well, I think that's a great point. I came away from this study a little bit amused and just a little bit depressed at the state of the medical literature because we know that journal editors pay attention to clicks and citations. It's kind of their job. And I had to come away from this thinking that, that a short paper like this, the problems of which are so obvious, and that there's not even a nod to what you mentioned, other things that could be controlled for, to try to control for confounders, wasn't done. You feel like this was almost knowingly seeking attention rather than trying to improve our understanding of biomedicine five years after the beginning of the pandemic.
- [53:22]
E
Yeah, I think in my opinion, if there's one thing that I learned from Adam Sifu's class my first year of medical school, it was to digest these articles or dissect the articles and try and figure out potential sources of bias. And I think this one has plenty. So I see why you chose it. I think one that really stood out to me, which we kind of mentioned, is this healthy user bias, which is the type of selection bias when people engage. Engage in a particular behavior are just inherently either healthy or at least have different characteristics compared to those who do not, independent of that exposure being studied. And I think what we've gotten to. And I think Rahul's point is we don't have great understanding of the whole picture. But people who are more likely to take the preventative measures like the vaccine are likely also more likely to be seeing a doctor and then undergoing those cancer screenings. And as such, they're more likely to have those cancers detected.
- [54:17]
F
Boy, that warms my heart just to hear my course. A hat tip to the course and you talking about that so perfectly well.
- [54:27]
C
And while we're buttering your bread, I will just encourage our listeners to head to your substack and read the blue after visit summaries, which kind of frames this type of conversation a way that I found really helpful to think about. So, Adam, in terms of what to do with this information, I guess the big question for you is should we, should we screen patients who've received the COVID vaccine for cancer? Is that or I guess more broadly, what should we do with this information, if anything, other than just be cautious with what we read?
- [54:50]
F
I think if they are in your office and you're considering giving them the COVID vaccine, it should not affect your decision to screen them. You should screen them as you would otherwise. And I would use this paper maybe as a teaching tool in the future and otherwise ignore it.
- [55:08]
C
All right, excellent. Let's move on to our last article. Laura, you brought us an article about patients with chronic coronary syndrome. And today I learned that we're calling it chronic coronary syndrome and not. Yes, we are not something else. And what to do with their potentially with their aspirin and oral anticoagulants if they're on them. So tell us a little bit about what you brought to us and what we should do with it.
- [55:30]
B
Yeah.
- [55:30]
E
So to end this episode, let's talk a little bit about some of the new evidence regarding the use of long term aspirin on top of oral anticoagulation in patients, patients with high atherothrombotic risk. So this is the Aquatic trial. It's a multicenter, double blinded, randomized controlled trial. It was done in France and published in New England Journal of Medicine. And it was comparing aspirin versus placebo in addition to oral anticoagulation in patients with chronic coronary syndrome who had previous previously undergone PCI over six months prior to enrollment and were at a high atherothrombotic risk and also requiring long term oral anticoagulation. So the study included a total of 872 patients and they were randomly assigned to receive either Aspen 100mg daily or placebo in Addition to their oral anticoagulation with the primary outcome of major adverse cardiovascular event. So the trial was actually stopped early after a median about two years due to harm in a dual therapy group with about a 50% relative increase in major adverse cardiovascular events, mostly driven by cardiovascular death and also a tripling in bleeding risk in that group.
- [56:46]
D
I mean, I'm confused. I understand the increase in bleeding risk. I feel like that has been demonstrated in other related literature. But maybe some of you, you smart people can help me understand, like, why would there be an increase in cardiovascular death? Like, is there some mechanism outside of bleeding that biologically could explain that? That was one thing that sort of struck me, you know, upfront about the results of this paper. I expected the harm to be, you know, increased risk of bleeding, which there was. But I was unprepared and still am kind of struggling to explain this increase in cardiovascular mortality.
- [57:26]
E
You know, honestly, I also struggled with that. And I think it's interesting to note too, that the risk of the events in this aquatic trial were actually like seven to eight times higher than in previous trials in the field. The groups studied in those trials were slightly different, but in general, that's a pretty big increase in the number of events. And I'm not sure I have a great explanation for that either.
- [57:50]
B
Yeah, I was kind of in my mind, like, oh, maybe it would have been interesting to understand a little more the patients who had those events and whether or not they had concomitant bleeding events. That was one, I think, Rahul, you had also been kind of thinking along those potential lines that sometimes, you know, hypoperfusion, bleeding causing a cardiac event, something like that, and I don't think they kind of showed that data. That was the, like, best mechanistic explanation I could come up with. But I don't know that that. That is enough to explain what we saw.
- [58:30]
F
It's funny. Maybe I'll sort of play devil's advocate because I don't care.
- [58:36]
B
Fair enough.
- [58:38]
F
I think this is something I'm going to. Because I have to, like, you know, push my brand whenever I can. You know, my whole shtick is medical reversal, right? It's things that we do because they've kind of got a good story, right? Like, there's bio plausibility and then there's generally, you know, some bad data, observational data, inadequate data, or maybe no data at all. And we haven't really tested it with a randomized control trial. Right. And here we are, you know, with a randomized control trial showing that we've what. What we've been doing without data, but with sort of bioplausibility. Oh, you know, we're blocking platelet, you know, clotting, and we're blocking stasis, clotting, you know, but finding. We study it. Right. And there's an overwhelming difference. Right. This is frightening. This is like, I don't know, one in 20 people we treat this way. We actually kill. And we all know, you know, we've all filled out death certificates. We know how bad those death certificates are. The one thing that we know is that when a death certificate is filled out, the person's actually dead. And so the one really robust endpoint here is to say this is a dangerous therapy and we shouldn't have been doing all this time, and we should be sort of embarrassed and we should definitely stop. And I kind of feel like this, like, as a general internist, man, this is the most important paper I've read all year.
- [60:00]
D
Yeah, I am heavily influenced by your buddy John Mandrola's thoughts on this paper. I agree. It's a really important paper. And I also agree with the premise that data trumps theory every day. But just for love of the game, man, I'm so curious. Why. Why is it the case? I mean, you know, Nora, you kind of brought up. I mean, could it be that. And I unfortunately think I missed the deadline for a letter to the editor on this, because I'm really curious, you know, what the authors would say in clarification about this. Like, if we knew that, you know, these cardiovascular events were in people who did have preceding or concomitant bleeding, that might support the sort of thrombogenesis of bleeding. How? Hypothesis, you know, also, I mean, aspirin is an NSAID. I mean, this is 100 milligrams a day, so that seems unlikely to be the culprit. But I agree, data trumps theory every day.
- [60:54]
B
I'm also curious how you got. So the patient population was. Was high risk and kind of how does this translate to patients who are not quite as high risk and are.
- [61:06]
E
Is.
- [61:07]
B
Was this. They were obviously high risk from an atherothrombotic perspective, but does it. I don't know the extent to which they were high risk from a bleeding perspective. And kind of how do we extend. Are we. Are we willing to. Going to extend this to a broader population based on this trial?
- [61:27]
F
Boy, Nora, I think that is such a good question. Right? Because we get ourselves into trouble a lot. Often it seems like in the opposite direction, Right. Where something works in A high risk population. And we extrapolate that to a low risk population. That was our whole problem with PCA for stemi. All of a sudden we're doing it for stable coronary disease.
- [61:57]
A
Here.
- [61:57]
F
I almost feel like, yeah, this population is probably most at risk of us doing harm to them, but they were probably most at risk of benefit or most likely to have benefit. I almost feel like a lower risk population. And here I'm doing what I just cautioned us not to do is both extrapolate and to use theory. But I'm sucked into a holes camp with just for the good of the game is that, wow, a low risk population seems like they'd have very little chance of benefit and maybe would get all the harm without any of the benefit. But it's just a great question.
- [62:38]
E
Yeah. And I think some of the other studies did look at more lower risk populations in general. Those were a little bit different, those studies because they were open label conducted in different population in general, but they included patients that weren't at as high risk and not all of them had undergone stent implantation. And actually, actually, you know, this is to look at the higher risk. And I think regardless looking at those studies, they had a very similar outcome and that there's, you know, there's really not much benefit and a lot of harm that can be done. And I think we're seeing that just as much, you know, in the same population. So I think regardless of the different, you know, the different studies that have been done and the different, you know, what we're looking at, it does seem overall that the harm is very serious and that the, that there's not, if any, very limited benefit.
- [63:29]
C
Yeah, I don't know why we're not carrying the authors of this study around on our shoulders and holding grades for them. I feel like this is such a common scenario and I think it's a question that's sort of asked all the time. And now we have a good study and important data. I don't know why we're not talking about it more. I'm just very excited to read through this and think through this and hear everyone's conversation about it because that just this seems critically important. But I don't remember hearing as much buzz about this as I do about. Well, I will not cite other papers that we discussed tonight, but it just seems like this is pretty important and I hope to hear more about it as we spread the good news.
- [64:05]
E
Yeah, and I think it'll be really interesting to see because the data seems very Obvious that this is very harmful or causes more harm than good, for sure. But I'm interested to see how that actually plays out in the real world and if people are really going to start giving aspirin on top. And I'm not sure that that that's going to happen. It's, you know, changing practice is difficult, and I think that the. The data is very good, and this is a very strong paper. But I wonder, you know, is what's going to happen and what will happen in the real world.
- [64:33]
B
I also think from a, like, time perspective, I feel like I'm getting a throwback to my days on cardiology service, but, you know, triplet therapy upfront and for how long and then when can you de escalate? And so this just. I think these patients were like, on therapy for over several years on average. And so kind of at what point is it really is the ideal point to de escalate antiplatelet therapy? I'm not entirely sure at this point, but it seems like definitely sooner rather than never.
- [65:05]
E
Yeah. And I think that these studies are definitely showing that DOAC monotherapy is much safer.
- [65:11]
F
Who on this podcast can we blame for having discussed Tylenol, sorry, acetaminophen and autism and the COVID vaccine in cancer before? We've discussed the aquatic trial.
- [65:21]
B
Right.
- [65:22]
D
It's almost like you're saying there should be a press conference touting the harms of dual therapy in patients with chronic coronary syndrome above all else.
- [65:30]
F
And a ticker tape parade.
- [65:34]
C
All right, well, I feel like I'm picking up the vibes here, Laura, but just to be concrete and explicit, does this change your practice and how do we feel about this paper?
- [65:41]
E
Yeah, I mean, I think the takeaway from the aquatic trial is very clear. As we mentioned, combination therapy with an oral anticoagulant and aspirin leads to more harm than good. So let's just stop it and move on.
- [65:55]
C
All right, well said. And I think so that was our last paper and we ended with a bang. But, I mean, I think all these were incredibly fun conversations.
- [66:02]
D
I learned so much from you. Thank you so much, Dr. Sifu, for joining us.
- [66:06]
F
Thank you. This was a lot of fun.
- [66:08]
B
Yeah, this was amazing.
- [66:14]
C
This has been another episode of the Curbsiders bringing you a little knowledge food for your brain hole.
- [66:21]
B
Yummy.
- [66:22]
C
That went just as well as I was hoping it would. Still hungry for more? Join our Patreon and get all of our episodes ad free, plus twice monthly bonus episodes at patreon.com curbsiders you can find our show notes@thecbsiders.com and sign up for our mailing list to get our weekly show notes in your inbox. This includes our Curbsiders Digestive edited by one Dr. Nora Toronto which recaps you that is practice changing articles, guidelines and news and internal medicine. We are committed to high value practice changing knowledge and to do that we need your feedback so please email us@askcurbsidersmail.com it also helps a lot when you subscribe, rate and review the show on YouTube, Spotify or Apple Podcasts. A reminder that this and most episodes are available for CME Credit for all healthcare professionals through VCU Health at curbsiders vcuhealth.org A special thanks to our writer producer for this episode which is everyone present here today. So Hol Ganacha North Toronto Laura Glick we can even throw me in there and then also special guest Adam Seafue. We'd also like to thank our techno production team which is done by Podpaste. Elizabeth Proto does her social media, Jen Watto runs our Patreon, Chris the Chew Manchu moderates our Discord and Stuart Brigitte post our theme music. Until next time. I've been Dr. Paul Nelson Williams.
- [67:27]
D
I've been Dr. Rahul Prime Bhavan Ganatra.
- [67:29]
E
I've been Dr. Laura Glick.
- [67:31]
B
And I've been Dr. Nora Taranto. Hey, this is Sarah.
- [67:51]
E
Look, I'm standing out front of a.m. p.m. Right now and well, you're sweet and all but I found something more fulfilling, even kind of cheesy. But I like it. Sure you met some of my dietary needs but they've just got it all. So farewell Oatmeal so long you strange.
- [68:07]
D
Soggy Break up with bland breakfast and.
- [68:09]
F
Taste AMPM's bacon, egg and cheese biscuit made with cage free eggs, smoked bacon and melty cheese on a buttery biscuit. AMPM Too much good stuff.