Trends in Aspirin Use; Top Treatments for Localized Esophageal Cancer

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 a polygenic risk score and chronic obstructive pulmonary disease (COPD), an antibody to reduce bleeding risk in those with atrial fibrillation (Afib), aspirin use in cardiovascular risk reduction, and best treatments for local esophageal cancer.

Program notes:

0:37 Trends in aspirin use

1:37 Five cycles of National Health and Nutrition Examination Survey (NHANES) data

2:37 Takes a long time to change habits

3:01 Polygenic risk score added to strategies to identify COPD

4:01 Spirometry confirmed

5:01 Can improve quality of life

6:01 If questionnaire suggests

6:50 Reducing bleeding risk in those taking blood thinners

7:50 Antibody to factor XI

8:55 How to balance bleeding versus clotting

9:39 Strategies for treating esophageal cancer

10:39 Chemo and radiation before surgery

11:36 Incidence increasing worldwide

12:25 Adjuvant nivolumab (Opdivo) under investigation

13:23 End

Transcript:

Elizabeth: Does adding a polygenic risk score to looking for COPD help?

Rick: Lowering the risk of bleeding in individuals taking blood thinners.

Elizabeth: The best way to treat regional esophageal cancer.

Rick: And transient preventative aspirin use.

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, I’d like to turn first to JAMA to this research letter that’s taking a look at trends in aspirin use. It seems to bear witness to the idea that, wow, it takes a long time to change stuff. Doesn’t it?

Rick: This is based upon recommendations in 2019 by the American College of Cardiology and the American Heart Association to narrow the recommendations on who should receive preventative aspirin use. Now, when we say preventative, these are individuals that have not had any evidence of cardiovascular disease, but are considered to be at high risk for such, and aspirin could potentially lower that risk. Aspirin, although it seems like it’s an innocuous medication, is associated with bleeding episodes. We want to apply it to individuals that are likely to receive a benefit and avoid those that are likely to have complications.

In 2019, these organizations recommended that it only be used in individuals that have a high cardiovascular risk — if their 10-year risk of having a cardiovascular event is more than 10% — and a low bleeding risk as well. We have about 5 cycles of looking at the NHANES data from 2011 to 2023, which was conducted in all 50 states. One of the questions is, “Are you prescribed aspirin?”

They looked at four groups: those that have known cardiovascular disease — they should continue on aspirin; those who are older than 70 — they should not be on aspirin; adults with a 10-year cardiovascular risk less than 10% who shouldn’t be; and adults with a 10-year cardiovascular risk of over 10%, and they should be.

Those individuals who were receiving it for secondary prevention that should remain on it, they didn’t change over that 12-year period, and that’s good. Among adults older than 70, the use went down from 16% to 11%. For adults with cardiovascular disease risk of less than 10%, it went down from 34% to 28%. But unfortunately, it also went down in individuals who have a high cardiovascular risk as well. There are still 10% to 20% that are receiving aspirin and probably shouldn’t be.

Elizabeth: Once these things get into the popular consciousness, it seems to take a really long time to be able to get people to change their habits.

Rick: It does. It’s interesting because aspirin use did not decrease among those that didn’t have routine health insurance, those that weren’t on Medicaid or without insurance, and historically disadvantaged groups were less likely to reduce aspirin use as well.

Elizabeth: More work to be done and clearly more messaging that needs to get out there.

Staying in JAMA then, let’s turn to this notion that a polygenic risk score added to conventional case finding could help in identifying chronic obstructive pulmonary disease (COPD). The authors start with something that I was not aware of and that is that COPD is often undiagnosed. There is also a genetic risk that plays a role in susceptibility to developing this condition. They do have a questionnaire that’s used frequently to help find cases. This study takes a look at a COPD polygenic risk score to see if that adds to the ability of the questionnaire to identify these things.

This was a cross-sectional analysis of participants who were 35 years of age and older with no history of physician-diagnosed COPD. Data was used from the Framingham Heart Study and the COPD-enriched Genetic Epidemiology of COPD (COPDGene) study.

Their primary outcome measure was spirometry to find moderate to severe COPD, which I find again a little bit astonishing. It seems to me that somebody who had moderate to severe COPD would come forward to the medical establishment and say, “Hey, I’m having trouble breathing. Can we take a look at this?” But I guess that’s just my proclivity.

They have over 3,300 Framingham Heart Study participants reported in here and just shy of 4,100 of this COPDGene participants. What they showed was that this polygenic risk score significantly improved the area under the curve in the Framingham Heart group from 0.78 to 0.84, and from 0.69 to 0.72 in the COPDGene non-Hispanic African Americans, and 0.75 to 0.78 in the non-Hispanic white participants. The authors note, of course, that there are medications and interventions that can help these people to have a better quality of life, so it is important to identify them.

Rick: What’s interesting in this population, just in the general community at large, is about 5% had undiagnosed moderate or severe COPD and these were nonsmokers, but in the smoking group that you identified it was closer to about 20%. The polygenic risk score worked better in the community than it did in the smokers in identifying individuals with moderate to severe COPD.

This test costs about $35 to do. It does require a blood stick. The question is, is this any better than using handheld breathing tests — that is, spirometry — in the doctor’s office? It didn’t compare the polygenic risk score to using that.

Elizabeth: Right. I don’t know about you, but I have never been asked, except in allergy evaluation, to do spirometry. That 5% of folks who are out there, who have moderate to severe COPD that’s undiagnosed, I wonder if they’re being asked to do spirometry.

Rick: You would only be asked to do it if, in fact, your questionnaire suggested you were at an increased risk of having COPD. Now, the question is do you want to be doing blood tests on everybody to figure this out, or try to target more specific groups?

Elizabeth: It’s a good question. I also want to note something about the development of the polygenic risk score. It was based on the UK Biobank and spirometra [sic] database of European ancestry genome-wide association studies. That’s, of course, a limited population. It’s interesting the stuff that’s coming out of the UK Biobank. We’re going to see a lot more. We’ve seen a lot already that’s relative to this and it also — we have to admit — is a small slice of the population.

Rick: Absolutely. I mean, does it apply to other races or ethnicities? We don’t really know.

Elizabeth: Exactly. Let’s turn now to the New England Journal of Medicine. You’re going to talk about …

Rick: Is there a way to reduce bleeding risk in people that have to take blood thinners? I’m talking about people that have atrial fibrillation.

It’s about 50 million people worldwide that are affected by atrial fibrillation and the major difficulty is that it’s associated with a fivefold increased risk of stroke. People with atrial fibrillation are more likely to have a clot form in their heart. That clot can leave the heart and go throughout the body to cause a stroke. These individuals are typically placed on a blood thinner — a direct oral anticoagulant agent in most, or Coumadin, a vitamin K antagonist, in others. They are all associated with bleeding complications.

We’re searching for other ways to prevent clots, but to minimize bleeding and one of those is to inhibit various factors — Factor XI being one of those. It’s involved in the clotting cascade. The thought was, “Gosh, if we could inhibit this, we could actually decrease the bleeding and perhaps be just as effective in individual atrial fibrillation.”

They developed an antibody that binds to the inactive form of factor XI and it blocks its activation. In this study of almost 1300 patients, they randomized them to two different doses or to a routine oral anticoagulant. The antibody was effective in inhibiting factor XI by about 97% to 99%. Then when they followed these individuals, over the course of a couple of years, those that received the antibody had somewhere between 60% and 70% lower bleeding episodes, primarily gastrointestinal bleeding.

The unfortunate thing is, it looks like there was a slightly increased risk of stroke in those who took the antibody. Now to tease that out, we actually need to do a much larger study and there is currently a larger trial going on this particular agent or class of agents.

Elizabeth: Let’s talk more about this. It sounds to me like there are kind of two horses in the gate, one is the bleeding and one is the clotting. The question is, which of those horses are you going to allow to get ahead in terms of the management of the propensity for an ischemic stroke?

Rick: Exactly, and that’s always the balance. It seems like the agents that are most effective at preventing clots are also the ones that are most likely to cause bleeding. Those that are less likely to cause bleeding are often associated with a higher risk of a clot. Whether attacking this particular factor puts that balance in the favor of using it, we won’t know until we do additional studies.

Elizabeth: The other thing is that I remember how just ferociously complex the whole clotting cascade is, having both intrinsic and extrinsic pathways and a number of factors and cofactors involved. How do we know that Factor XI is really the right way to go?

Rick: It looks like in smaller studies there are some benefits.

Elizabeth: Okay. Staying in the New England Journal of Medicine then, let’s turn to this issue of perioperative chemotherapy or preoperative chemoradiotherapy for the treatment of locally advanced esophageal adenocarcinoma.

Let me just note that this is something that’s increasing in incidence. There is some evidence that it’s related to gastroesophageal reflux disease. Then there is some evidence that refutes that hypothesis. But in any case, we are seeing more cases of this and it does not have a great prognosis. So what is the best way to treat this when locally advanced esophageal cancer is identified?

This is a phase III, multicenter, randomized trial and they had two strategies here: perioperative chemotherapy with what’s called FLOT — i.e., fluorouracil, leucovorin, oxaliplatin, and docetaxel — plus surgery, or preoperative chemoradiotherapy — so radiotherapy and carboplatin and paclitaxel before surgery followed by the resection of this area. They had 221 patients in the FLOT group and 217 patients in the preoperative chemoradiotherapy group.

This difference between these folks was — in my mind, at least — really dramatic. Overall survival at 3 years was 57.4% in the FLOT group and 50.7% in the preoperative chemoradiotherapy group. Progression-free survival, another metric at 3 years, was just shy of 52% in the FLOT group and 35% in the preoperative group.

Lots of adverse events for both sides of this equation here. The mortality at 90 days after surgery was 3.1% in the FLOT group and 5.6% in the preoperative chemoradiotherapy group, clearly showing that this preoperative chemoradiotherapy was inferior to FLOT in this case.

Rick: Yep. Elizabeth, as you mentioned, esophageal cancer incidence is increasing worldwide, almost 450,000 deaths per year, and it’s particularly increasing in high-income countries. Surgery is the mainstay of treatment, but even after resection, the 5-year survival rate rarely exceeds 35%. We have to do something in addition to surgery. Do we do just chemotherapy or do we do radiation and chemotherapy? Neither one of these is innocuous. We want to try to find the ones that are most effective at the same time with reducing the side effects.

Elizabeth: I would note that this has been a worldwide investigation with this particular study being done in Germany. The authors say in their discussion that this chemoradiotherapy regimen that was used in this trial should no longer be considered the best treatment in these patients. They are showing that in other trials adjuvant nivolumab immunotherapy is probably going to be at least one of the choices relative to what’s selected for the management of this condition going forward.

Rick: Yep. As a result, we’ll take the best therapy — in this particular case FLOT — and then compare it to other therapies that are improving as well.

Elizabeth: Finally, I would note that this idea of preoperative chemoradiotherapy or immunotherapy is also something that’s evolving in the cancer treatment world and I think we’re going to see a good deal more of that and improvement of that strategy.

Rick: I totally agree.

Elizabeth: On that note then, that’s a 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.