TTHealthWatch is a weekly podcast from Texas Tech. In it, Elizabeth Tracey, director of electronic media for Johns Hopkins Medicine in Baltimore, and Rick Lange, MD, president of the Texas Tech University Health Sciences Center in El Paso, look at the top medical stories of the week.
This week’s topics include advances in treating early breast cancer, stroke after COVID vaccination, anti-seizure meds during pregnancy and ASD, and oxygen targets in critically ill people.
Program notes:
0:38 Stroke after bivalent COVID vaccine
1:35 No increased risk with this vaccine alone
2:32 Public messaging
2:41 Personalized oxygen settings for patients in the ICU
3:41 Lower level resulted in more days alive without life support
4:41 Lowering blood glucose?
5:42 Verify in randomized trials
6:43 Risk of autism in kids in moms on anti-seizure meds during pregnancy
7:43 Increased risk whether on medicine or not
8:46 Treatment of early breast cancer
9:46 CDK4/6 inhibitor
10:46 No significant side effects
11:37 Younger than median age at diagnosis
12:16 End
Transcript:
Elizabeth: Incremental advances in treating early breast cancer.
Rick: Risk of autism in kids whose mothers took anti-seizure medicines during pregnancy.
Elizabeth: Personalized oxygen settings if you’re in the ICU.
Rick: And does the COVID-19 bivalent vaccine cause stroke?
Elizabeth: That’s what we’re talking about this week on TTHealthWatch, your weekly look at the medical headlines from Texas Tech University Health Sciences Center in El Paso. I’m Elizabeth Tracey, a Baltimore-based medical journalist.
Rick: And I’m Rick Lange, president of Texas Tech University Health Sciences Center in El Paso, where I’m also Dean of the Paul L. Foster School of Medicine.
Elizabeth: Rick, how about if we turn right to JAMA, that’s taking a look at this issue of does the COVID vaccine increase one’s risk of stroke if one is an older adult?
Rick: This study comes on the heels of a report in January of 2023 where the FDA and the CDC both issued a joint public communication that there was a preliminary safety signal — and this was a signal within the Vaccine Safety Datalink surveillance system — that a stroke could be associated with the new COVID-19 bivalent vaccine.
What the investigators did is they used what’s called a self-controlled case series design in which individuals acted as their own controls. They looked at over 5 million recipients of either brand of the COVID-19 bivalent vaccine.
The study identified that there was 0.2% that had some type of a stroke, but then when they compared this to the general population there was no increased risk [of] stroke found with the bivalent vaccine alone. It’s consistent with other reports — for example, a similar report in France and Israel.
However, that’s for people that received the COVID vaccine alone. Those that received COVID vaccine and the flu shot, there was a slightly increased risk associated with the flu shot. I say a slightly increased risk; it wasn’t very consistent. For example, it didn’t happen in the first 21 days. It happened between 21 and 40 days and not after 40 days. But it’s very clear that the COVID-19 vaccine isn’t associated with increased stroke early on, in the mid-portion or later portion.
Elizabeth: I’m glad that there is surveillance of this, that people are taking a look at it and following out potentials like this that are serious, and putting the public’s mind at rest regarding getting vaccines. COVID has certainly provided us with a lot of new situations, concomitant vaccines with both flu and COVID.
Rick: Yep. I think, as you mentioned, the study was done and now we’re getting the public message out that the COVID-19 vaccine is safe and effective.
Elizabeth: Since we’re talking about COVID and we’re in JAMA, let’s stay there. There are going to be two studies that I’m kind of going to talk about together. Those are related to how much supplemental oxygen should we provide — what should our target be — for people who are in the intensive care unit.
The first of those deals with folks who had COVID-19 and it randomized people, 726 adults, with COVID-19 who were already receiving some oxygen or mechanical ventilation in 11 ICUs in Europe from August 2020 to March 2023. Can we use ventilator settings of 60 mm Hg — lower oxygen — or 90 mm Hg? They looked at their outcomes up to 90 days in the ICU. Their primary outcome measure was the number of days alive without life support, which I thought was a very curious outcome measure. They looked at 697 patients at the end, and they were able to demonstrate that in adult ICU patients with COVID-19 and severe hypoxemia, this lower level, 60 mm Hg of oxygen, resulted in more days alive without life support than targeting the higher level.
The other one is a modeling study, basically taking a look at a couple of studies and then producing a machine learning model on the predicted effect of treatment with lower versus higher oxygen levels for individual patients. They used that one data set to train their model and then they said, “How would this predict what the right thing to do with regard to these oxygen targets is?”
This study also used a number of more individualized factors to say, “Sometimes targeting a lower oxygen level is actually more beneficial than having the higher one.” Modeling certainly creates a hypothesis that needs to be tested in real people to see how it turns out.
This whole thing, of course, harkens back to me to studies we discussed years ago looking at the fact that people develop this high glucose level in their blood when they are critically ill. While we a priori think that it would have been a good idea to lower it into what we think are normal physiologic levels for people who are not in the ICU, that resulted in poorer outcomes.
One of the editorialists about these studies says if this modeling study is borne out and we individualize oxygen levels based on whether you have sepsis or you’ve got some other reason for being in the ICU, it would result in so much benefit, so many more patients staying alive, if it turns out to be true.
Rick: We think about the randomized controlled trial as being kind of the gold standard, but what happens if the treatment is effective in some individuals and harmful in others, and at the end it looks like there is no benefit? What these authors attempted to do is say, “Wait a minute — maybe giving everybody 100% oxygen isn’t the best thing.”
By the way, we know it’s not, for example, in kids. It can cause more lung issues. It looks like the same thing in adults as well. Let’s see which might benefit from higher oxygen, which might benefit from lower oxygen, because maybe not everybody should be treated the same. Now, we need to verify that in larger, randomized, controlled trials, but I think it shows that not everybody should be treated the same.
Elizabeth: That, of course, is the promise of AI in medicine, that somehow we’ll be able to integrate all of this data that comes from disparate populations, and integrate all of these different factors, and then say, “For you and your indication, the lower oxygen level would probably be better” and so forth. I just still am struck by the fact that the a priori hypothesis has turned out to be incorrect from years of practice in terms of oxygen levels in the ICU.
Rick: If you just take it as dogma and it hasn’t been really tested, sometimes you’re right and sometimes you’re not. Sometime over the next 2 years we’ll have about 50,000 additional patients that have been treated with higher or lower oxygen levels as well. We think about personalized medicine being related to the genes and the genetic makeup. Well, personalized medicine may be related to what brought you into the hospital in the first place and whether you should receive higher or lower oxygen based upon that.
Elizabeth: Let’s turn to NEJM.
Rick: I serve this up as the risk of autism in kids whose mothers took seizure medications during pregnancy. Anti-seizure medicines are actually fairly commonly prescribed to women of childbearing potential for epilepsy, for pain, and psychiatric disorders. Anything that’s given to a mother could affect the fetus. For example, fetal exposure to valproate is associated with neuropsychological impairments, whereas other anti-seizure medicines like lamotrigine or topiramate may not be.
What these investigators sought to look at is whether these seizure medicines are related to autism in the child. They looked at pregnant women and their children within two healthcare databases in the United States over about a 2-decade period from 2000 to 2020. They looked at the incidence of autism spectrum disorder at 8 years over these two large populations.
Some of these mothers had received topiramate, some had received lamotrigine, and some had received valproate. If a mother needed any of these or she just had this seizure condition, it increased the risk of having an autistic child. Children born to mothers with epilepsy across the population, the incidence of autism was 4.2% with no exposure to anti-seizure medication and it was three-fold higher in those who received valproate, but no difference in those that received lamotrigine or topiramate.
Elizabeth: This, of course, is a really important issue to consider because we have been seeing the rates of autism spectrum disorder rise a lot.
Rick: Yep. It doesn’t provide any insight into the mechanism.
Elizabeth: Is there any data in here on how often this single agent is really the only effective agent for women with seizure disorders?
Rick: There is not. It doesn’t provide any information about whether these mothers had been tried on multiple medications or why they were particularly put on valproate.
Elizabeth: Right now then what would you say to a woman who has a seizure disorder and is thinking of becoming pregnant?
Rick: I think those mothers should talk to their physicians and see if there is a possibility if they could be put on a different agent.
Elizabeth: Staying in the New England Journal of Medicine then, let’s look at this issue of treating early breast cancer with an agent called ribociclib and that’s added to another agent in this particular trial. This was an international, open-label, randomized, phase III trial with patients with HR-positive, HER2-negative, early breast cancer.
It turns out that this is the most common subtype of breast cancer out there, accounting for 70% to 75% of cases worldwide. Most of these cases are diagnosed early, stage 1 to 3, and this HR-positive, HER2-negative, early breast cancer is usually treated with surgery with or without radiotherapy or chemotherapy, followed by adjuvant endocrine therapy for 5 to 10 years. Even so, their recurrence occurs in 27% to 37% of patients with stage 2 disease and 46% to 57% of patients with stage 3 disease. That can continue up to 20 years after diagnosis, the risk of that.
They take a look at what are called CDK4/6 inhibitors and aromatase inhibitors in these folks who have this diagnosis. Interestingly, they do mention that men also with early-stage breast cancer account for some of the people who get this.
They had a total of 426 patients who had invasive disease recurrence or death during the time of this study. At 3 years, their invasive disease-free survival was 90.4% with the ribociclib group plus the aromatase inhibitor and 87.1% with the aromatase inhibitor alone. This sure sounds like adding ribociclib to this is probably a good idea.
Rick: Elizabeth, we’re talking about an oral medication that’s taken on a daily basis and these women took it for 3 years. That’s a 25% improvement and one would hope that even extended over a longer period of time, 5 years or 10 years, the survival would be even more marked. The nice thing is there weren’t any significant side effects associated with it.
Elizabeth: They do have side effects, however — neutropenia, arthralgia, liver-related events — and it did result in discontinuation in 3.3%. They also talk about this QT interval prolongation in 5.2% in the ribociclib group and 1.2% in those who just took the aromatase inhibitor alone.
Rick: 95% to 97% of the women tolerated this medicine pretty well for preventing recurrent breast disease. That’s pretty good.
Elizabeth: Yep, and adding to the benefits of breast cancer survival, at least in this country. I would give kudos to the authors for noting that some of their limitations include the fact that Black patients were underrepresented in this trial, even though they are overrepresented with regard to breast cancer. They were also, their patients, younger than the median age at diagnosis in the United States and so looking at those more expanded populations may change this benefit somewhat.
Rick: I agree. It needs to be tested in different populations to see whether the benefit extends to them as well.
Elizabeth: On that note then, that’s the look at this week’s medical headlines from Texas Tech. I’m Elizabeth Tracey.
Rick: And I’m Rick Lange. Y’all listen up and make healthy choices.
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