It has been three and a half years since the US Preventive Services Task Force (USPSTF) lowered the age to start colorectal cancer (CRC) screening from 50 to 45. As I mentioned in a previous commentary, two major medical groups — the American Academy of Family Physicians and the American College of Physicians — felt that the evidence was insufficient to support this change. 

Did doctors adjust their screening practices? A recent study suggests that they have. Comparing CRC screening rates in more than 10 million adults aged 45-49 during the 20 months preceding and 20 months following the USPSTF recommendation, researchers found significant increases during the latter time period, with the greatest increases among persons of high socioeconomic status or living in metropolitan areas.

Another study addressed concerns that younger adults may be less likely to follow up on positive screening results or more likely to have false positives on a fecal immunochemical test (FIT). Patients aged 45-49 years were slightly less likely to have a positive FIT result than 50-year-olds, but they had similar rates of colonoscopy completion and similar percentages of abnormal findings on colonoscopy.

Although the sensitivity and specificity of FIT varies quite a bit across different test brands, its overall effectiveness at reducing colorectal cancer deaths is well established. In 2024, the Food and Drug Administration approved three new screening options: a blood-based screening test (Shield), a next-generation multitarget stool DNA test (Cologuard Plus), and a multitarget stool RNA test (ColoSense) with similar performance characteristics as Cologuard Plus. The latter two tests will become available early next year.

This profusion of noninvasive options for CRC screening will challenge those tasked with developing the next iteration of the USPSTF recommendations. Not only must future guidelines establish what evidence threshold is sufficient to recommend a new screening strategy, but they also will need to consider the population-level consequences of relative utilization of different tests. For example, a cost-effectiveness analysis found that more CRC deaths would occur if people who would have otherwise accepted colonoscopy or fecal tests chose to be screened with Shield instead; however, this negative outcome could be offset if for every three of these test substitutions, two other people chose Shield who would otherwise have not been screened at all.

In the meantime, it is important for primary care clinicians to be familiar with evidence-based intervals for CRC screening tests and test eligibility criteria. A troubling study of patients who completed a multitarget stool DNA test in a Midwestern health system in 2021 found that more than one in five had the test ordered inappropriately, based on USPSTF guidelines. Reasons for inappropriate testing included having had a colonoscopy within the past 10 years, a family history of CRC, symptoms suggestive of possible CRC, age younger than 45, and a prior diagnosis of colonic adenomas. 

Just as a medication works best when the patient takes it as prescribed, a CRC screening test is most likely to yield more benefit than harm when it’s provided to the right patient at the right time.

Dr. Lin is Associate Director, Family Medicine Residency Program, at Lancaster General Hospital in Pennsylvania. He reported no relevant conflicts of interest.

A version of this article first appeared on Medscape.com.

It has been three and a half years since the US Preventive Services Task Force (USPSTF) lowered the age to start colorectal cancer (CRC) screening from 50 to 45. As I mentioned in a previous commentary, two major medical groups — the American Academy of Family Physicians and the American College of Physicians — felt that the evidence was insufficient to support this change. 

Did doctors adjust their screening practices? A recent study suggests that they have. Comparing CRC screening rates in more than 10 million adults aged 45-49 during the 20 months preceding and 20 months following the USPSTF recommendation, researchers found significant increases during the latter time period, with the greatest increases among persons of high socioeconomic status or living in metropolitan areas.

Another study addressed concerns that younger adults may be less likely to follow up on positive screening results or more likely to have false positives on a fecal immunochemical test (FIT). Patients aged 45-49 years were slightly less likely to have a positive FIT result than 50-year-olds, but they had similar rates of colonoscopy completion and similar percentages of abnormal findings on colonoscopy.

Although the sensitivity and specificity of FIT varies quite a bit across different test brands, its overall effectiveness at reducing colorectal cancer deaths is well established. In 2024, the Food and Drug Administration approved three new screening options: a blood-based screening test (Shield), a next-generation multitarget stool DNA test (Cologuard Plus), and a multitarget stool RNA test (ColoSense) with similar performance characteristics as Cologuard Plus. The latter two tests will become available early next year.

This profusion of noninvasive options for CRC screening will challenge those tasked with developing the next iteration of the USPSTF recommendations. Not only must future guidelines establish what evidence threshold is sufficient to recommend a new screening strategy, but they also will need to consider the population-level consequences of relative utilization of different tests. For example, a cost-effectiveness analysis found that more CRC deaths would occur if people who would have otherwise accepted colonoscopy or fecal tests chose to be screened with Shield instead; however, this negative outcome could be offset if for every three of these test substitutions, two other people chose Shield who would otherwise have not been screened at all.

In the meantime, it is important for primary care clinicians to be familiar with evidence-based intervals for CRC screening tests and test eligibility criteria. A troubling study of patients who completed a multitarget stool DNA test in a Midwestern health system in 2021 found that more than one in five had the test ordered inappropriately, based on USPSTF guidelines. Reasons for inappropriate testing included having had a colonoscopy within the past 10 years, a family history of CRC, symptoms suggestive of possible CRC, age younger than 45, and a prior diagnosis of colonic adenomas. 

Just as a medication works best when the patient takes it as prescribed, a CRC screening test is most likely to yield more benefit than harm when it’s provided to the right patient at the right time.

Dr. Lin is Associate Director, Family Medicine Residency Program, at Lancaster General Hospital in Pennsylvania. He reported no relevant conflicts of interest.

A version of this article first appeared on Medscape.com.

It has been three and a half years since the US Preventive Services Task Force (USPSTF) lowered the age to start colorectal cancer (CRC) screening from 50 to 45. As I mentioned in a previous commentary, two major medical groups — the American Academy of Family Physicians and the American College of Physicians — felt that the evidence was insufficient to support this change. 

Did doctors adjust their screening practices? A recent study suggests that they have. Comparing CRC screening rates in more than 10 million adults aged 45-49 during the 20 months preceding and 20 months following the USPSTF recommendation, researchers found significant increases during the latter time period, with the greatest increases among persons of high socioeconomic status or living in metropolitan areas.

Another study addressed concerns that younger adults may be less likely to follow up on positive screening results or more likely to have false positives on a fecal immunochemical test (FIT). Patients aged 45-49 years were slightly less likely to have a positive FIT result than 50-year-olds, but they had similar rates of colonoscopy completion and similar percentages of abnormal findings on colonoscopy.

Although the sensitivity and specificity of FIT varies quite a bit across different test brands, its overall effectiveness at reducing colorectal cancer deaths is well established. In 2024, the Food and Drug Administration approved three new screening options: a blood-based screening test (Shield), a next-generation multitarget stool DNA test (Cologuard Plus), and a multitarget stool RNA test (ColoSense) with similar performance characteristics as Cologuard Plus. The latter two tests will become available early next year.

This profusion of noninvasive options for CRC screening will challenge those tasked with developing the next iteration of the USPSTF recommendations. Not only must future guidelines establish what evidence threshold is sufficient to recommend a new screening strategy, but they also will need to consider the population-level consequences of relative utilization of different tests. For example, a cost-effectiveness analysis found that more CRC deaths would occur if people who would have otherwise accepted colonoscopy or fecal tests chose to be screened with Shield instead; however, this negative outcome could be offset if for every three of these test substitutions, two other people chose Shield who would otherwise have not been screened at all.

In the meantime, it is important for primary care clinicians to be familiar with evidence-based intervals for CRC screening tests and test eligibility criteria. A troubling study of patients who completed a multitarget stool DNA test in a Midwestern health system in 2021 found that more than one in five had the test ordered inappropriately, based on USPSTF guidelines. Reasons for inappropriate testing included having had a colonoscopy within the past 10 years, a family history of CRC, symptoms suggestive of possible CRC, age younger than 45, and a prior diagnosis of colonic adenomas. 

Just as a medication works best when the patient takes it as prescribed, a CRC screening test is most likely to yield more benefit than harm when it’s provided to the right patient at the right time.

Dr. Lin is Associate Director, Family Medicine Residency Program, at Lancaster General Hospital in Pennsylvania. He reported no relevant conflicts of interest.

A version of this article first appeared on Medscape.com.

This video transcript has been edited for clarity. 

Robert D. Glatter, MD: Hi and welcome. I’m Dr. Robert Glatter, medical adviser for Medscape Emergency Medicine. Joining me today to discuss a novel, plant-based approach to stopping moderate to severe bleeding is Joe Landolina, CEO and cofounder of Cresilon. Welcome, Joe. 

Joe Landolina, MS: Thank you so much for taking the time. It’s great to be here.

Educational Background and Inception of Cresilon

Glatter: It’s a pleasure to have you join me, and I want to congratulate you on your recent 510(k) FDA clearance for your novel product to save lives and stop bleeding. To begin with, can you explain how the idea for launching your company came about? 

Landolina: The way that Cresilon came about was a little bit unorthodox, because I was 17 years old when I invented the technology behind the product that eventually became Traumagel®. 

My grandfather was an ex-pharmaceutical executive, who later in life started a vineyard. I grew up on a vineyard with a winery chemistry lab across the street from my house and a grandfather who learned lab safety in the 60s. So, that meant that the day I learned how to walk, I was tossed into a lab and I fell head over heels in love with lab research.

That started experimentation and my academic pursuits. That led to discovering a blend of two plant-based polymers derived from algae that stop bleeding on contact, effectively creating a mechanical barrier and allowing anything from a gunshot wound to anything quite a bit more minor to stop in a matter of seconds.

Glatter: Your background is in biomedical engineering. How is it that you started tinkering and doing all this type of work? 

Landolina: That’s correct. I did my undergrad in chemical engineering, and my graduate studies were in biomedical engineering. For me, that was supposed to be a pathway into medical school. I always wanted to be a surgeon myself, and I love the field of medicine. 

As a freshman in college at NYU Engineering, I had this idea. I entered it into NYU’s business plan competition, and we won at the engineering school. That gave us just enough capital to start developing and researching Traumagel more, and Cresilon was born out of that research.

 

Techniques for Stopping Hemorrhage

Glatter: In terms of stopping hemorrhage, which takes so many lives in the United States and globally — certainly, uncontrolled hemorrhage — what are the techniques that you see, prior to the arrival of your product, as being effective? Can you elucidate some of these techniques? 

Landolina: In emergency medicine, the primary mode of controlling hemorrhage is passive. It’s what, in Brooklyn, we like to call “pressure and a prayer”, where you have a material that’s either gauze or an impregnated gauze in most cases, where the mode of action is absorbing blood, with the adjunct of pressure by the first responder or by the clinician who’s providing aid.

The idea is to stop the flow of blood to concentrate blood factors at the surface of the gauze product, and to promote either platelet activation or the production of fibrin to create a clot. 

These types of technologies are widespread. There are many versions of this technology carried by EMS agencies, trauma bays, US military soldiers, and soldiers across NATO countries. But these types of technologies tend to be relatively inefficient, meaning that they’re very difficult to get into wounds because of the gauze or the powder form of the devices, and it’s very hard to get them in contact with the form of bleeding.

On top of that, if the patient is clotting compromised or immunocompromised in some way, the ability to create a durable clot that will not be ripped off when you remove the product at the next level of care is also of concern. And so, this type of technology or the type of treatment of massive hemorrhage hasn’t changed in decades.

 

Current Applications and Potential Use

Glatter: I envision this product will be carried by paramedics, used on the battlefield at some point after your FDA clearance, and recently it went through.

Do you see any possibility that this could be an AED equivalent to Stop the Bleed? In other words, could the average lay person be trained to use your product if kits are available? 

Landolina: To be very clear, Traumagel today is only approved or cleared under a “prescription-only” indication, which means that it will not initially be available OTC. However, that is our goal. Our goal is to make this product available and usable by someone with no medical training whatsoever. 

The form factor of being a gel in a syringe lends itself well to that, meaning that we try to make it as easy as point and shoot to control hemorrhage, where there’s not as much technique to be learned in the application of a product like Traumagel as there is in current hemorrhage control techniques. 

 

Mechanism of Action and Physiology

Glatter: Once you apply Traumagel, can you explain what happens to the product after it’s applied and the bleeding has stopped? Does it get reabsorbed by the body? What’s the process here? 

Landolina: Under Traumagel’s indication, because it’s used in traumatic injury, it must be removed within 24 hours.

One of the big benefits of Traumagel is that when the patient produces a blood clot underneath Traumagel, it doesn’t become incorporated within the gel itself. To contrast that with the use of gauze, gauze is porous. The clot ends up wrapped around the fibers of the gauze, so if you peel the gauze away, it’s very likely that clot is coming off with it. The surgeon or the clinician at the next level of care is going to have to deal with the re-bleed. 

You can remove Traumagel cleanly and entirely without disturbing the underlying clot. That’s a major benefit, not only to the patient but also to the next level of care, to the next clinician or physician that is required to remove the product.

Glatter: How is it possible to remove the substance without disturbing the clot? Can you explain in more detail? 

Landolina: That’s one of the hallmarks of these plant-based polymers and the way that we design Traumagel itself. Traumagel is completely nonporous, and it has no fibrous nature to it. What that means is when the patient produces a blood clot or fibrin next to or on top of Traumagel, that fibrin ends up not incorporated within the polymers of Traumagel itself. 

Over time, because Traumagel is a hydrogel, meaning that by weight it’s mostly water, you end up having less adhesion to the clot over time. When it’s time to remove Traumagel from the injury, it has lost almost all of its adhesive capabilities, meaning that when you peel it away, that clot is going to stick better to tissue than it will to the gel itself. 

Glatter: Can you explain a little bit about the matrix that’s formed, the physiology, and how the polymers work to form this matrix? 

Landolina: Sure. Traumagel is made of two polysaccharides that are plant derived. One polysaccharide is polyanionic, and the other is polycationic, meaning one has negative charges and the other has positive charges, which together create almost a Lego block effect, where when the material comes in contact with tissue, it adheres strongly and allows for itself to effectively create a mechanical barrier against bleeding.

Courtesy of Cresilon

Landolina: Even in the face of major arterial blood flow, Traumagel will stay where it needs to stay, and it’s not going to get washed away. This means that it is much more easily appliable to these types of surfaces and will allow the patient to produce their own endogenous fibrin clot at that location.

Like I mentioned before, when that fibrin clot is formed, because the gel itself has no pores or fibers, it doesn’t become incorporated within the fibrin clot. You can take the gel away, leaving that clot behind without the chance of a rebleed.

 

Testing With Major Bleeds

Glatter: In terms of bleeding itself, have you tested your product with major aortic bleeds or carotid bleeds in preclinical work?

Landolina: We have used the US military’s model for lethal hemorrhage, and the idea there is to create a model that is just that — lethal. These are the worst types of bleeds that you can possibly imagine, where the patients are clotting compromised, and where you have, in most cases, a very strong arterial component, so something like a femoral artery bleed.

We’ve also tested in carotid artery, aortic applications, as well as combinations of venous and arterial bleeds. The idea here is to show the use of the product in the absolute worst-case scenario so that when this translates into the clinic, the models that we’ve used for evaluation, hopefully, are worse than what actually rolls into the trauma bay.

Glatter: Excellent. What’s the mean time to stop an arterial vs a venous bleed? Are we talking a matter of seconds?

Landolina: In the case of a healthy patient, meaning a patient without clotting compromise, you’re in a matter of seconds. It’s less than 10 seconds. 

In the case where you have clotting compromise, a deep, complicated wound geometry, we recommend holding a pressure bandage on for 3 minutes just because it increases the chance of Traumagel coming into contact with the bleed, especially when you can’t visualize the bleed in the bleed source. Because of that pressure time, that becomes the mean. But again, it’s highly dependent on the type of bleed and the style of application.

 

Failure Rates and Effectiveness

Glatter: As a segue to that, what is the failure rate based on your studies and internal research using Traumagel? Have there been cases where bleeding has not been able to be stopped? 

Landolina: It depends on the study, but the failure rates are incredibly low with Traumagel, assuming that it’s correctly used. That’s one of the benefits to this product, where with proper technique, with overwrap with gauze, you nearly always get control of hemorrhage with a product like this. 

Glatter: Is manual pressure required in that sense? From what you described earlier, manual pressure would not be required. 

Landolina: It depends on the injury. What we recommend is that, if you have a very deep wound where you cannot visualize the source of bleed, you use pressure to seat Traumagel into the source of bleeding, meaning that you’re following Committee on Tactical Combat Casualty Care (Co-TCCC) regulations or requirements, where you’re over wrapping with gauze, and you’re providing a pressure wrapping to ensure that the Traumagel is in contact with the bleed while it’s doing what it’s doing. 

In most cases, it doesn’t hurt to apply pressure on top of Traumagel as well. In more surface level bleeds, you don’t need pressure at all. 

 

Applications Beyond Trauma

Glatter: Interesting. In terms of further applications (eg, nose bleeds or GYN bleeding, which are life-threatening), do you see this coming as an application for the future? 

Landolina: That’s where we’re working. Traumagel is the successor to an animal health product called Vetigel. The formulations of the gel behind Vetigel and Traumagel are identical. Vetigel has a full surgical indication, and that’s everything from epistaxis to neuro and spine procedures, into cardiovascular and soft tissue surgeries, orthopedic medicine, and so on.

Cresilon’s goal is to eventually expand the indication of our technology to include surgical indications and other indications where we can help any patient that’s bleeding. 

Glatter: That’s important, because we use prehospital whole blood, low titer, specifically, when patients have life-threatening hemorrhage. With your product, that would reduce the amount of blood products that would need to be administered. This could be a real game changer. 

Landolina: Definitely, that’s the goal we’re working on. 

Infection Risks and Biocompatibility

Glatter: In terms of any risk for infection, has that been studied as well? Does Traumagel in any way lead to increased rates of infection?

Landolina: Traumagel is biocompatible. It’s a sterile product. We’ve done the full suite of biocompatibility testing as required by FDA. On top of that, remember that Vetigel, which is the same formulation, is an implantable product. As a result, that has even extended biocompatibility testing beyond what would be necessary for an external product.

In Vetigel’s use case, which has been used now in over 60,000 patients, primarily companion animals, dogs and cats, we haven’t seen instances of infection. There’s no reason to believe that we would see that clinically with Traumagel.

 

Research Collaborations and Future Applications

Glatter: In terms of other research that your company’s embarked on preclinically, I understand there were some studies done at Walter Reed Army Institute of Research. I was wondering if you could expand on these, specifically, in terms of traumatic brain injury (TBI) and hemorrhage related to that. For example, with shrapnel or even a gunshot wound. 

Landolina: The Walter Reed collaboration with Cresilon is something that I’m particularly excited about, because it marks Cresilon’s first project that’s outside the scope of just hemostasis. Walter Reed came to us with this proposal where there’s a big challenge in a subset of TBI called penetrating ballistic-like brain injury, where the brain has been penetrated by a bullet, shrapnel, or some other projectile, and there’s an injury that exposes the brain to the outside. 

Today, there is no standard of care to treat patients with those types of injuries. In many cases, mortality is caused through swelling of the brain, or collapse of the brain. What they came to us with was the potential of using our technology, not primarily as a hemostatic agent, but to be able to stabilize that patient enough to get to the next level of care to be treated by a neurosurgeon.

That study Walter Reed did was just a pilot that was done in small animals. In that pilot, they showed that over the period of treatment, there was no negative change in vital signs, no increase in edema or in swelling, or in any of the biomarkers that were being monitored at that time. 

At the very least, this is not full indication that this indication will work for Cresilon, but it shows that there’s promise. It’s something that we’re working on and hopefully we’ll be able to bring to market soon.

Glatter: Certainly, maintaining intracranial pressure and cerebral perfusion pressures are very critical. In the future, do you think this product would be able to be deployed endovascularly? Imagine this in terms of stopping bleeding from some source, whether it’s from a stroke or another intracranial source. 

Landolina: That’s been an area of interest for us. We have no evidence to prove that indication works at this point, but there’s also nothing to say that it wouldn’t be possible for our technology. At this point, we’ve only looked at a cursory level at those indications. 

Glatter: Does the use of Traumagel obviate the need for a more definitive repair (eg, with sutures) or something that’s more permanent?

Landolina: I always say that Traumagel — and Vetigel, for that matter — is not a replacement for good surgical technique. The surgeon always needs to make his or her best judgment when reviewing the patient. That doesn’t mean that there won’t need to be sutures or vascular repair in most of these cases, especially in major trauma.

Final Takeaways

Glatter: Do you have some bullet points or pearls you could give our audience as a takeaway? 

Landolina: When Cresilon looks at Traumagel — and for us, Traumagel is the next generation of hemostatic agent, especially in trauma care and in emergency medicine — it allows for a far-simplified application of the product and much faster control of hemorrhage with better patient outcomes.

As we roll this out through EMS agencies, trauma hospitals, military agencies, and eventually to the general public through a future indication, it’s something we’re very excited about. Personally, I started this business 14 years ago, and so it’s great to see our mission of saving lives transitioning to saving human lives.

Glatter: I look forward to seeing this product in the emergency department, but also in other settings, such as in the operating room where we can really help patients who are dying from hemorrhage, certainly on the battlefield, and the lay public. If someone were to come upon a patient who’s bleeding out, this could be certainly a game changer and a lifesaver. 

I want to thank you for your time. This is a really important product that’s transformed the lives of so many animals, but also people in the future.

Dr. Glatter is an assistant professor of emergency medicine at Zucker School of Medicine at Hofstra/Northwell in Hempstead, New York. He reported no relevant conflicts of interest. Mr. Landolina is the CEO and co-founder of Cresilon, a biotechnology company specializing in plant-based solutions for emergency bleeding control.

A version of this article first appeared on Medscape.com.

This video transcript has been edited for clarity. 

Robert D. Glatter, MD: Hi and welcome. I’m Dr. Robert Glatter, medical adviser for Medscape Emergency Medicine. Joining me today to discuss a novel, plant-based approach to stopping moderate to severe bleeding is Joe Landolina, CEO and cofounder of Cresilon. Welcome, Joe. 

Joe Landolina, MS: Thank you so much for taking the time. It’s great to be here.

Educational Background and Inception of Cresilon

Glatter: It’s a pleasure to have you join me, and I want to congratulate you on your recent 510(k) FDA clearance for your novel product to save lives and stop bleeding. To begin with, can you explain how the idea for launching your company came about? 

Landolina: The way that Cresilon came about was a little bit unorthodox, because I was 17 years old when I invented the technology behind the product that eventually became Traumagel®. 

My grandfather was an ex-pharmaceutical executive, who later in life started a vineyard. I grew up on a vineyard with a winery chemistry lab across the street from my house and a grandfather who learned lab safety in the 60s. So, that meant that the day I learned how to walk, I was tossed into a lab and I fell head over heels in love with lab research.

That started experimentation and my academic pursuits. That led to discovering a blend of two plant-based polymers derived from algae that stop bleeding on contact, effectively creating a mechanical barrier and allowing anything from a gunshot wound to anything quite a bit more minor to stop in a matter of seconds.

Glatter: Your background is in biomedical engineering. How is it that you started tinkering and doing all this type of work? 

Landolina: That’s correct. I did my undergrad in chemical engineering, and my graduate studies were in biomedical engineering. For me, that was supposed to be a pathway into medical school. I always wanted to be a surgeon myself, and I love the field of medicine. 

As a freshman in college at NYU Engineering, I had this idea. I entered it into NYU’s business plan competition, and we won at the engineering school. That gave us just enough capital to start developing and researching Traumagel more, and Cresilon was born out of that research.

 

Techniques for Stopping Hemorrhage

Glatter: In terms of stopping hemorrhage, which takes so many lives in the United States and globally — certainly, uncontrolled hemorrhage — what are the techniques that you see, prior to the arrival of your product, as being effective? Can you elucidate some of these techniques? 

Landolina: In emergency medicine, the primary mode of controlling hemorrhage is passive. It’s what, in Brooklyn, we like to call “pressure and a prayer”, where you have a material that’s either gauze or an impregnated gauze in most cases, where the mode of action is absorbing blood, with the adjunct of pressure by the first responder or by the clinician who’s providing aid.

The idea is to stop the flow of blood to concentrate blood factors at the surface of the gauze product, and to promote either platelet activation or the production of fibrin to create a clot. 

These types of technologies are widespread. There are many versions of this technology carried by EMS agencies, trauma bays, US military soldiers, and soldiers across NATO countries. But these types of technologies tend to be relatively inefficient, meaning that they’re very difficult to get into wounds because of the gauze or the powder form of the devices, and it’s very hard to get them in contact with the form of bleeding.

On top of that, if the patient is clotting compromised or immunocompromised in some way, the ability to create a durable clot that will not be ripped off when you remove the product at the next level of care is also of concern. And so, this type of technology or the type of treatment of massive hemorrhage hasn’t changed in decades.

 

Current Applications and Potential Use

Glatter: I envision this product will be carried by paramedics, used on the battlefield at some point after your FDA clearance, and recently it went through.

Do you see any possibility that this could be an AED equivalent to Stop the Bleed? In other words, could the average lay person be trained to use your product if kits are available? 

Landolina: To be very clear, Traumagel today is only approved or cleared under a “prescription-only” indication, which means that it will not initially be available OTC. However, that is our goal. Our goal is to make this product available and usable by someone with no medical training whatsoever. 

The form factor of being a gel in a syringe lends itself well to that, meaning that we try to make it as easy as point and shoot to control hemorrhage, where there’s not as much technique to be learned in the application of a product like Traumagel as there is in current hemorrhage control techniques. 

 

Mechanism of Action and Physiology

Glatter: Once you apply Traumagel, can you explain what happens to the product after it’s applied and the bleeding has stopped? Does it get reabsorbed by the body? What’s the process here? 

Landolina: Under Traumagel’s indication, because it’s used in traumatic injury, it must be removed within 24 hours.

One of the big benefits of Traumagel is that when the patient produces a blood clot underneath Traumagel, it doesn’t become incorporated within the gel itself. To contrast that with the use of gauze, gauze is porous. The clot ends up wrapped around the fibers of the gauze, so if you peel the gauze away, it’s very likely that clot is coming off with it. The surgeon or the clinician at the next level of care is going to have to deal with the re-bleed. 

You can remove Traumagel cleanly and entirely without disturbing the underlying clot. That’s a major benefit, not only to the patient but also to the next level of care, to the next clinician or physician that is required to remove the product.

Glatter: How is it possible to remove the substance without disturbing the clot? Can you explain in more detail? 

Landolina: That’s one of the hallmarks of these plant-based polymers and the way that we design Traumagel itself. Traumagel is completely nonporous, and it has no fibrous nature to it. What that means is when the patient produces a blood clot or fibrin next to or on top of Traumagel, that fibrin ends up not incorporated within the polymers of Traumagel itself. 

Over time, because Traumagel is a hydrogel, meaning that by weight it’s mostly water, you end up having less adhesion to the clot over time. When it’s time to remove Traumagel from the injury, it has lost almost all of its adhesive capabilities, meaning that when you peel it away, that clot is going to stick better to tissue than it will to the gel itself. 

Glatter: Can you explain a little bit about the matrix that’s formed, the physiology, and how the polymers work to form this matrix? 

Landolina: Sure. Traumagel is made of two polysaccharides that are plant derived. One polysaccharide is polyanionic, and the other is polycationic, meaning one has negative charges and the other has positive charges, which together create almost a Lego block effect, where when the material comes in contact with tissue, it adheres strongly and allows for itself to effectively create a mechanical barrier against bleeding.

Courtesy of Cresilon

Landolina: Even in the face of major arterial blood flow, Traumagel will stay where it needs to stay, and it’s not going to get washed away. This means that it is much more easily appliable to these types of surfaces and will allow the patient to produce their own endogenous fibrin clot at that location.

Like I mentioned before, when that fibrin clot is formed, because the gel itself has no pores or fibers, it doesn’t become incorporated within the fibrin clot. You can take the gel away, leaving that clot behind without the chance of a rebleed.

 

Testing With Major Bleeds

Glatter: In terms of bleeding itself, have you tested your product with major aortic bleeds or carotid bleeds in preclinical work?

Landolina: We have used the US military’s model for lethal hemorrhage, and the idea there is to create a model that is just that — lethal. These are the worst types of bleeds that you can possibly imagine, where the patients are clotting compromised, and where you have, in most cases, a very strong arterial component, so something like a femoral artery bleed.

We’ve also tested in carotid artery, aortic applications, as well as combinations of venous and arterial bleeds. The idea here is to show the use of the product in the absolute worst-case scenario so that when this translates into the clinic, the models that we’ve used for evaluation, hopefully, are worse than what actually rolls into the trauma bay.

Glatter: Excellent. What’s the mean time to stop an arterial vs a venous bleed? Are we talking a matter of seconds?

Landolina: In the case of a healthy patient, meaning a patient without clotting compromise, you’re in a matter of seconds. It’s less than 10 seconds. 

In the case where you have clotting compromise, a deep, complicated wound geometry, we recommend holding a pressure bandage on for 3 minutes just because it increases the chance of Traumagel coming into contact with the bleed, especially when you can’t visualize the bleed in the bleed source. Because of that pressure time, that becomes the mean. But again, it’s highly dependent on the type of bleed and the style of application.

 

Failure Rates and Effectiveness

Glatter: As a segue to that, what is the failure rate based on your studies and internal research using Traumagel? Have there been cases where bleeding has not been able to be stopped? 

Landolina: It depends on the study, but the failure rates are incredibly low with Traumagel, assuming that it’s correctly used. That’s one of the benefits to this product, where with proper technique, with overwrap with gauze, you nearly always get control of hemorrhage with a product like this. 

Glatter: Is manual pressure required in that sense? From what you described earlier, manual pressure would not be required. 

Landolina: It depends on the injury. What we recommend is that, if you have a very deep wound where you cannot visualize the source of bleed, you use pressure to seat Traumagel into the source of bleeding, meaning that you’re following Committee on Tactical Combat Casualty Care (Co-TCCC) regulations or requirements, where you’re over wrapping with gauze, and you’re providing a pressure wrapping to ensure that the Traumagel is in contact with the bleed while it’s doing what it’s doing. 

In most cases, it doesn’t hurt to apply pressure on top of Traumagel as well. In more surface level bleeds, you don’t need pressure at all. 

 

Applications Beyond Trauma

Glatter: Interesting. In terms of further applications (eg, nose bleeds or GYN bleeding, which are life-threatening), do you see this coming as an application for the future? 

Landolina: That’s where we’re working. Traumagel is the successor to an animal health product called Vetigel. The formulations of the gel behind Vetigel and Traumagel are identical. Vetigel has a full surgical indication, and that’s everything from epistaxis to neuro and spine procedures, into cardiovascular and soft tissue surgeries, orthopedic medicine, and so on.

Cresilon’s goal is to eventually expand the indication of our technology to include surgical indications and other indications where we can help any patient that’s bleeding. 

Glatter: That’s important, because we use prehospital whole blood, low titer, specifically, when patients have life-threatening hemorrhage. With your product, that would reduce the amount of blood products that would need to be administered. This could be a real game changer. 

Landolina: Definitely, that’s the goal we’re working on. 

Infection Risks and Biocompatibility

Glatter: In terms of any risk for infection, has that been studied as well? Does Traumagel in any way lead to increased rates of infection?

Landolina: Traumagel is biocompatible. It’s a sterile product. We’ve done the full suite of biocompatibility testing as required by FDA. On top of that, remember that Vetigel, which is the same formulation, is an implantable product. As a result, that has even extended biocompatibility testing beyond what would be necessary for an external product.

In Vetigel’s use case, which has been used now in over 60,000 patients, primarily companion animals, dogs and cats, we haven’t seen instances of infection. There’s no reason to believe that we would see that clinically with Traumagel.

 

Research Collaborations and Future Applications

Glatter: In terms of other research that your company’s embarked on preclinically, I understand there were some studies done at Walter Reed Army Institute of Research. I was wondering if you could expand on these, specifically, in terms of traumatic brain injury (TBI) and hemorrhage related to that. For example, with shrapnel or even a gunshot wound. 

Landolina: The Walter Reed collaboration with Cresilon is something that I’m particularly excited about, because it marks Cresilon’s first project that’s outside the scope of just hemostasis. Walter Reed came to us with this proposal where there’s a big challenge in a subset of TBI called penetrating ballistic-like brain injury, where the brain has been penetrated by a bullet, shrapnel, or some other projectile, and there’s an injury that exposes the brain to the outside. 

Today, there is no standard of care to treat patients with those types of injuries. In many cases, mortality is caused through swelling of the brain, or collapse of the brain. What they came to us with was the potential of using our technology, not primarily as a hemostatic agent, but to be able to stabilize that patient enough to get to the next level of care to be treated by a neurosurgeon.

That study Walter Reed did was just a pilot that was done in small animals. In that pilot, they showed that over the period of treatment, there was no negative change in vital signs, no increase in edema or in swelling, or in any of the biomarkers that were being monitored at that time. 

At the very least, this is not full indication that this indication will work for Cresilon, but it shows that there’s promise. It’s something that we’re working on and hopefully we’ll be able to bring to market soon.

Glatter: Certainly, maintaining intracranial pressure and cerebral perfusion pressures are very critical. In the future, do you think this product would be able to be deployed endovascularly? Imagine this in terms of stopping bleeding from some source, whether it’s from a stroke or another intracranial source. 

Landolina: That’s been an area of interest for us. We have no evidence to prove that indication works at this point, but there’s also nothing to say that it wouldn’t be possible for our technology. At this point, we’ve only looked at a cursory level at those indications. 

Glatter: Does the use of Traumagel obviate the need for a more definitive repair (eg, with sutures) or something that’s more permanent?

Landolina: I always say that Traumagel — and Vetigel, for that matter — is not a replacement for good surgical technique. The surgeon always needs to make his or her best judgment when reviewing the patient. That doesn’t mean that there won’t need to be sutures or vascular repair in most of these cases, especially in major trauma.

Final Takeaways

Glatter: Do you have some bullet points or pearls you could give our audience as a takeaway? 

Landolina: When Cresilon looks at Traumagel — and for us, Traumagel is the next generation of hemostatic agent, especially in trauma care and in emergency medicine — it allows for a far-simplified application of the product and much faster control of hemorrhage with better patient outcomes.

As we roll this out through EMS agencies, trauma hospitals, military agencies, and eventually to the general public through a future indication, it’s something we’re very excited about. Personally, I started this business 14 years ago, and so it’s great to see our mission of saving lives transitioning to saving human lives.

Glatter: I look forward to seeing this product in the emergency department, but also in other settings, such as in the operating room where we can really help patients who are dying from hemorrhage, certainly on the battlefield, and the lay public. If someone were to come upon a patient who’s bleeding out, this could be certainly a game changer and a lifesaver. 

I want to thank you for your time. This is a really important product that’s transformed the lives of so many animals, but also people in the future.

Dr. Glatter is an assistant professor of emergency medicine at Zucker School of Medicine at Hofstra/Northwell in Hempstead, New York. He reported no relevant conflicts of interest. Mr. Landolina is the CEO and co-founder of Cresilon, a biotechnology company specializing in plant-based solutions for emergency bleeding control.

A version of this article first appeared on Medscape.com.

This video transcript has been edited for clarity. 

Robert D. Glatter, MD: Hi and welcome. I’m Dr. Robert Glatter, medical adviser for Medscape Emergency Medicine. Joining me today to discuss a novel, plant-based approach to stopping moderate to severe bleeding is Joe Landolina, CEO and cofounder of Cresilon. Welcome, Joe. 

Joe Landolina, MS: Thank you so much for taking the time. It’s great to be here.

Educational Background and Inception of Cresilon

Glatter: It’s a pleasure to have you join me, and I want to congratulate you on your recent 510(k) FDA clearance for your novel product to save lives and stop bleeding. To begin with, can you explain how the idea for launching your company came about? 

Landolina: The way that Cresilon came about was a little bit unorthodox, because I was 17 years old when I invented the technology behind the product that eventually became Traumagel®. 

My grandfather was an ex-pharmaceutical executive, who later in life started a vineyard. I grew up on a vineyard with a winery chemistry lab across the street from my house and a grandfather who learned lab safety in the 60s. So, that meant that the day I learned how to walk, I was tossed into a lab and I fell head over heels in love with lab research.

That started experimentation and my academic pursuits. That led to discovering a blend of two plant-based polymers derived from algae that stop bleeding on contact, effectively creating a mechanical barrier and allowing anything from a gunshot wound to anything quite a bit more minor to stop in a matter of seconds.

Glatter: Your background is in biomedical engineering. How is it that you started tinkering and doing all this type of work? 

Landolina: That’s correct. I did my undergrad in chemical engineering, and my graduate studies were in biomedical engineering. For me, that was supposed to be a pathway into medical school. I always wanted to be a surgeon myself, and I love the field of medicine. 

As a freshman in college at NYU Engineering, I had this idea. I entered it into NYU’s business plan competition, and we won at the engineering school. That gave us just enough capital to start developing and researching Traumagel more, and Cresilon was born out of that research.

 

Techniques for Stopping Hemorrhage

Glatter: In terms of stopping hemorrhage, which takes so many lives in the United States and globally — certainly, uncontrolled hemorrhage — what are the techniques that you see, prior to the arrival of your product, as being effective? Can you elucidate some of these techniques? 

Landolina: In emergency medicine, the primary mode of controlling hemorrhage is passive. It’s what, in Brooklyn, we like to call “pressure and a prayer”, where you have a material that’s either gauze or an impregnated gauze in most cases, where the mode of action is absorbing blood, with the adjunct of pressure by the first responder or by the clinician who’s providing aid.

The idea is to stop the flow of blood to concentrate blood factors at the surface of the gauze product, and to promote either platelet activation or the production of fibrin to create a clot. 

These types of technologies are widespread. There are many versions of this technology carried by EMS agencies, trauma bays, US military soldiers, and soldiers across NATO countries. But these types of technologies tend to be relatively inefficient, meaning that they’re very difficult to get into wounds because of the gauze or the powder form of the devices, and it’s very hard to get them in contact with the form of bleeding.

On top of that, if the patient is clotting compromised or immunocompromised in some way, the ability to create a durable clot that will not be ripped off when you remove the product at the next level of care is also of concern. And so, this type of technology or the type of treatment of massive hemorrhage hasn’t changed in decades.

 

Current Applications and Potential Use

Glatter: I envision this product will be carried by paramedics, used on the battlefield at some point after your FDA clearance, and recently it went through.

Do you see any possibility that this could be an AED equivalent to Stop the Bleed? In other words, could the average lay person be trained to use your product if kits are available? 

Landolina: To be very clear, Traumagel today is only approved or cleared under a “prescription-only” indication, which means that it will not initially be available OTC. However, that is our goal. Our goal is to make this product available and usable by someone with no medical training whatsoever. 

The form factor of being a gel in a syringe lends itself well to that, meaning that we try to make it as easy as point and shoot to control hemorrhage, where there’s not as much technique to be learned in the application of a product like Traumagel as there is in current hemorrhage control techniques. 

 

Mechanism of Action and Physiology

Glatter: Once you apply Traumagel, can you explain what happens to the product after it’s applied and the bleeding has stopped? Does it get reabsorbed by the body? What’s the process here? 

Landolina: Under Traumagel’s indication, because it’s used in traumatic injury, it must be removed within 24 hours.

One of the big benefits of Traumagel is that when the patient produces a blood clot underneath Traumagel, it doesn’t become incorporated within the gel itself. To contrast that with the use of gauze, gauze is porous. The clot ends up wrapped around the fibers of the gauze, so if you peel the gauze away, it’s very likely that clot is coming off with it. The surgeon or the clinician at the next level of care is going to have to deal with the re-bleed. 

You can remove Traumagel cleanly and entirely without disturbing the underlying clot. That’s a major benefit, not only to the patient but also to the next level of care, to the next clinician or physician that is required to remove the product.

Glatter: How is it possible to remove the substance without disturbing the clot? Can you explain in more detail? 

Landolina: That’s one of the hallmarks of these plant-based polymers and the way that we design Traumagel itself. Traumagel is completely nonporous, and it has no fibrous nature to it. What that means is when the patient produces a blood clot or fibrin next to or on top of Traumagel, that fibrin ends up not incorporated within the polymers of Traumagel itself. 

Over time, because Traumagel is a hydrogel, meaning that by weight it’s mostly water, you end up having less adhesion to the clot over time. When it’s time to remove Traumagel from the injury, it has lost almost all of its adhesive capabilities, meaning that when you peel it away, that clot is going to stick better to tissue than it will to the gel itself. 

Glatter: Can you explain a little bit about the matrix that’s formed, the physiology, and how the polymers work to form this matrix? 

Landolina: Sure. Traumagel is made of two polysaccharides that are plant derived. One polysaccharide is polyanionic, and the other is polycationic, meaning one has negative charges and the other has positive charges, which together create almost a Lego block effect, where when the material comes in contact with tissue, it adheres strongly and allows for itself to effectively create a mechanical barrier against bleeding.

Courtesy of Cresilon

Landolina: Even in the face of major arterial blood flow, Traumagel will stay where it needs to stay, and it’s not going to get washed away. This means that it is much more easily appliable to these types of surfaces and will allow the patient to produce their own endogenous fibrin clot at that location.

Like I mentioned before, when that fibrin clot is formed, because the gel itself has no pores or fibers, it doesn’t become incorporated within the fibrin clot. You can take the gel away, leaving that clot behind without the chance of a rebleed.

 

Testing With Major Bleeds

Glatter: In terms of bleeding itself, have you tested your product with major aortic bleeds or carotid bleeds in preclinical work?

Landolina: We have used the US military’s model for lethal hemorrhage, and the idea there is to create a model that is just that — lethal. These are the worst types of bleeds that you can possibly imagine, where the patients are clotting compromised, and where you have, in most cases, a very strong arterial component, so something like a femoral artery bleed.

We’ve also tested in carotid artery, aortic applications, as well as combinations of venous and arterial bleeds. The idea here is to show the use of the product in the absolute worst-case scenario so that when this translates into the clinic, the models that we’ve used for evaluation, hopefully, are worse than what actually rolls into the trauma bay.

Glatter: Excellent. What’s the mean time to stop an arterial vs a venous bleed? Are we talking a matter of seconds?

Landolina: In the case of a healthy patient, meaning a patient without clotting compromise, you’re in a matter of seconds. It’s less than 10 seconds. 

In the case where you have clotting compromise, a deep, complicated wound geometry, we recommend holding a pressure bandage on for 3 minutes just because it increases the chance of Traumagel coming into contact with the bleed, especially when you can’t visualize the bleed in the bleed source. Because of that pressure time, that becomes the mean. But again, it’s highly dependent on the type of bleed and the style of application.

 

Failure Rates and Effectiveness

Glatter: As a segue to that, what is the failure rate based on your studies and internal research using Traumagel? Have there been cases where bleeding has not been able to be stopped? 

Landolina: It depends on the study, but the failure rates are incredibly low with Traumagel, assuming that it’s correctly used. That’s one of the benefits to this product, where with proper technique, with overwrap with gauze, you nearly always get control of hemorrhage with a product like this. 

Glatter: Is manual pressure required in that sense? From what you described earlier, manual pressure would not be required. 

Landolina: It depends on the injury. What we recommend is that, if you have a very deep wound where you cannot visualize the source of bleed, you use pressure to seat Traumagel into the source of bleeding, meaning that you’re following Committee on Tactical Combat Casualty Care (Co-TCCC) regulations or requirements, where you’re over wrapping with gauze, and you’re providing a pressure wrapping to ensure that the Traumagel is in contact with the bleed while it’s doing what it’s doing. 

In most cases, it doesn’t hurt to apply pressure on top of Traumagel as well. In more surface level bleeds, you don’t need pressure at all. 

 

Applications Beyond Trauma

Glatter: Interesting. In terms of further applications (eg, nose bleeds or GYN bleeding, which are life-threatening), do you see this coming as an application for the future? 

Landolina: That’s where we’re working. Traumagel is the successor to an animal health product called Vetigel. The formulations of the gel behind Vetigel and Traumagel are identical. Vetigel has a full surgical indication, and that’s everything from epistaxis to neuro and spine procedures, into cardiovascular and soft tissue surgeries, orthopedic medicine, and so on.

Cresilon’s goal is to eventually expand the indication of our technology to include surgical indications and other indications where we can help any patient that’s bleeding. 

Glatter: That’s important, because we use prehospital whole blood, low titer, specifically, when patients have life-threatening hemorrhage. With your product, that would reduce the amount of blood products that would need to be administered. This could be a real game changer. 

Landolina: Definitely, that’s the goal we’re working on. 

Infection Risks and Biocompatibility

Glatter: In terms of any risk for infection, has that been studied as well? Does Traumagel in any way lead to increased rates of infection?

Landolina: Traumagel is biocompatible. It’s a sterile product. We’ve done the full suite of biocompatibility testing as required by FDA. On top of that, remember that Vetigel, which is the same formulation, is an implantable product. As a result, that has even extended biocompatibility testing beyond what would be necessary for an external product.

In Vetigel’s use case, which has been used now in over 60,000 patients, primarily companion animals, dogs and cats, we haven’t seen instances of infection. There’s no reason to believe that we would see that clinically with Traumagel.

 

Research Collaborations and Future Applications

Glatter: In terms of other research that your company’s embarked on preclinically, I understand there were some studies done at Walter Reed Army Institute of Research. I was wondering if you could expand on these, specifically, in terms of traumatic brain injury (TBI) and hemorrhage related to that. For example, with shrapnel or even a gunshot wound. 

Landolina: The Walter Reed collaboration with Cresilon is something that I’m particularly excited about, because it marks Cresilon’s first project that’s outside the scope of just hemostasis. Walter Reed came to us with this proposal where there’s a big challenge in a subset of TBI called penetrating ballistic-like brain injury, where the brain has been penetrated by a bullet, shrapnel, or some other projectile, and there’s an injury that exposes the brain to the outside. 

Today, there is no standard of care to treat patients with those types of injuries. In many cases, mortality is caused through swelling of the brain, or collapse of the brain. What they came to us with was the potential of using our technology, not primarily as a hemostatic agent, but to be able to stabilize that patient enough to get to the next level of care to be treated by a neurosurgeon.

That study Walter Reed did was just a pilot that was done in small animals. In that pilot, they showed that over the period of treatment, there was no negative change in vital signs, no increase in edema or in swelling, or in any of the biomarkers that were being monitored at that time. 

At the very least, this is not full indication that this indication will work for Cresilon, but it shows that there’s promise. It’s something that we’re working on and hopefully we’ll be able to bring to market soon.

Glatter: Certainly, maintaining intracranial pressure and cerebral perfusion pressures are very critical. In the future, do you think this product would be able to be deployed endovascularly? Imagine this in terms of stopping bleeding from some source, whether it’s from a stroke or another intracranial source. 

Landolina: That’s been an area of interest for us. We have no evidence to prove that indication works at this point, but there’s also nothing to say that it wouldn’t be possible for our technology. At this point, we’ve only looked at a cursory level at those indications. 

Glatter: Does the use of Traumagel obviate the need for a more definitive repair (eg, with sutures) or something that’s more permanent?

Landolina: I always say that Traumagel — and Vetigel, for that matter — is not a replacement for good surgical technique. The surgeon always needs to make his or her best judgment when reviewing the patient. That doesn’t mean that there won’t need to be sutures or vascular repair in most of these cases, especially in major trauma.

Final Takeaways

Glatter: Do you have some bullet points or pearls you could give our audience as a takeaway? 

Landolina: When Cresilon looks at Traumagel — and for us, Traumagel is the next generation of hemostatic agent, especially in trauma care and in emergency medicine — it allows for a far-simplified application of the product and much faster control of hemorrhage with better patient outcomes.

As we roll this out through EMS agencies, trauma hospitals, military agencies, and eventually to the general public through a future indication, it’s something we’re very excited about. Personally, I started this business 14 years ago, and so it’s great to see our mission of saving lives transitioning to saving human lives.

Glatter: I look forward to seeing this product in the emergency department, but also in other settings, such as in the operating room where we can really help patients who are dying from hemorrhage, certainly on the battlefield, and the lay public. If someone were to come upon a patient who’s bleeding out, this could be certainly a game changer and a lifesaver. 

I want to thank you for your time. This is a really important product that’s transformed the lives of so many animals, but also people in the future.

Dr. Glatter is an assistant professor of emergency medicine at Zucker School of Medicine at Hofstra/Northwell in Hempstead, New York. He reported no relevant conflicts of interest. Mr. Landolina is the CEO and co-founder of Cresilon, a biotechnology company specializing in plant-based solutions for emergency bleeding control.

A version of this article first appeared on Medscape.com.

This transcript has been edited for clarity. 

It’s just about the easiest, safest medical advice you can give: “Drink more water.” You have a headache? Drink more water. Tired? Drink more water. Cold coming on? Drink more water. Tom Brady famously attributed his QB longevity to water drinking, among some other less ordinary practices.

I’m a nephrologist — a kidney doctor. I think about water all the time. I can tell you how your brain senses how much water is in your body and exactly how it communicates that information to your kidneys to control how dilute your urine is. I can explain the miraculous ability of the kidney to concentrate urine across a range from 50 mOsm/L to 1200 mOsm/L and the physiology that makes it all work.

 

But I can’t really tell you how much water you’re supposed to drink. And believe me, I get asked all the time.

I’m sure of a couple of things when it comes to water: You need to drink some. Though some animals, such as kangaroo rats, can get virtually all the water they need from the food they eat, we are not such animals. Without water, we die. I’m also sure that you can die from drinking too much water. Drinking excessive amounts of water dilutes the sodium in your blood, which messes with the electrical system in your brain and heart. I actually had a patient who went on a “water cleanse” and gave herself a seizure. 

But, to be fair, assuming your kidneys are working reasonably well and you’re otherwise healthy, you’d need to drink around 20 liters of water a day to get into mortal trouble. The dose is the poison, as they say.

So, somewhere between zero and 20 liters of water is the amount you should be drinking in a day. That much I’m sure of.

But the evidence on where in that range you should target is actually pretty skimpy. You wouldn’t think so if you look at the online wellness influencers, with their Stanleys and their strict water intake regimens. You’d think the evidence for the benefits of drinking extra water is overwhelming.

The venerated National Academy of Medicine suggests that men drink thirteen 8 oz cups a day (that’s about 3 liters) and women drink nine 8 oz cups a day (a bit more than 2 liters). From what I can tell, this recommendation — like the old “8 cups of water per day” recommendation — is pulled out of thin air.

I’m not arguing that we shouldn’t drink water. Of course, water is important. I’m just wondering what data there are to really prove that drinking more water is better. 

Fortunately, a team from UCSF has finally done the legwork for us. They break down the actual evidence in this paper, appearing in JAMA Network Open. 

The team scoured the medical literature for randomized controlled trials of water intake. This is critical; we don’t want anecdotes about how clear someone’s skin became after they increased their water intake. We want icy cold, clear data. Randomized trials take a group of people and, at random, assign some to the intervention — in this case, drinking more water — and others to keep doing what they would normally do.

 

The team reviewed nearly 1500 papers but only 18 (!) met the rigorous criteria to be included in the analysis, as you can see from this flow chart.

 

This is the first important finding; not many high-quality studies have investigated how much water we should drink. Of course, water isn’t a prescription product, so funding is likely hard to come by. Can we do a trial of Dasani?

In any case, these 18 trials all looked at different outcomes of interest. Four studies looked at the impact of drinking more water on weight loss, two on fasting blood glucose, two on headache, two on urinary tract infection, two on kidney stones, and six studies on various other outcomes. None of the studies looked at energy, skin tone, or overall wellness, though one did measure a quality-of-life score.

And if I could sum up all these studies in a word, that word would be “meh.”

 

One of four weight loss studies showed that increasing water intake had no effect on weight loss. Two studies showed an effect, but drinking extra water was combined with a low-calorie diet, so that feels a bit like cheating to me. One study randomized participants to drink half a liter of water before meals, and that group did lose more weight than the control group — about a kilogram more over 12 weeks. That’s not exactly Ozempic.

For fasting blood glucose, although one trial suggested that higher premeal water intake lowered glucose levels, the other study (which looked just at increasing water overall) didn’t.

For headache — and, cards on the table here, I’m a big believer in water for headaches — one study showed nothing. The other showed that increasing water intake by 1.5 liters per day improved migraine-related quality of life but didn’t change the number of headache days per month.

For urinary tract infections, one positive trial and one negative one.

The best evidence comes from the kidney stone trials. Increasing water intake to achieve more than two liters of urine a day was associated with a significant reduction in kidney stone recurrence. I consider this a positive finding, more or less. You would be hard-pressed to find a kidney doctor who doesn’t think that people with a history of kidney stones should drink more water.

What about that quality-of-life study? They randomized participants to either drink 1.5 liters of extra water per day (intervention group) or not (control group). Six months later, the scores on the quality-of-life survey were no different between those two groups.

Thirsty yet?

So, what’s going on here? There are a few possibilities.

First, I need to point out that clinical trials are really hard. All the studies in this review were relatively small, with most enrolling fewer than 100 people. The effect of extra water would need to be pretty potent to detect it with those small samples.

I can’t help but point out that our bodies are actually exquisitely tuned to manage how much water we carry. As we lose water throughout the day from sweat and exhalation, our blood becomes a tiny bit more concentrated — the sodium level goes up. Our brains detect that and create a sensation we call thirst. Thirst is one of the most powerful drives we have. Animals, including humans, when thirsty, will choose water over food, over drugs, and over sex. It is incredibly hard to resist, and assuming that we have ready access to water, there is no need to resist it. We drink when we are thirsty. And that may be enough.

Of course, pushing beyond thirst is possible. We are sapient beings who can drink more than we want to. But what we can’t do, assuming our kidneys work, is hold onto that water. It passes right through us. In the case of preventing kidney stones, this is a good thing. Putting more water into your body leads to more water coming out — more dilute urine — which means it’s harder for stones to form. 

But for all that other stuff? The wellness, the skin tone, and so on? It just doesn’t make much sense. If you drink an extra liter of water, you pee an extra liter of water. Net net? Zero.

Some folks will argue that the extra pee gets rid of extra toxins or something like that, but — sorry, kidney doctor Perry here again — that’s not how pee works. The clearance of toxins from the blood happens way upstream of where your urine is diluted or concentrated.

 

If you drink more, the same toxins come out, just with more water around them. In fact, one of the largest studies in this JAMA Network Open review assessed whether increasing water consumption in people with chronic kidney disease would improve kidney function. It didn’t.

I am left, then, with only a bit more confidence than when I began. I remain certain that you should drink more than zero liters and less than 20 liters every day (assuming you’re not losing a lot of water in some other way, like working in the heat). Beyond that, it seems reasonable to trust the millions of years of evolution that have made water homeostasis central to life itself. Give yourself access to water. Drink when you’re thirsty. Drink a bit more if you’d like. But no need to push it. Your kidneys won’t let you anyway.

F. Perry Wilson, MD, MSCE, is an associate professor of medicine and public health and director of Yale’s Clinical and Translational Research Accelerator in New Haven, Connecticut. He disclosed no relevant conflicts of interest.

A version of this article first appeared on Medscape.com.

This transcript has been edited for clarity. 

It’s just about the easiest, safest medical advice you can give: “Drink more water.” You have a headache? Drink more water. Tired? Drink more water. Cold coming on? Drink more water. Tom Brady famously attributed his QB longevity to water drinking, among some other less ordinary practices.

I’m a nephrologist — a kidney doctor. I think about water all the time. I can tell you how your brain senses how much water is in your body and exactly how it communicates that information to your kidneys to control how dilute your urine is. I can explain the miraculous ability of the kidney to concentrate urine across a range from 50 mOsm/L to 1200 mOsm/L and the physiology that makes it all work.

 

But I can’t really tell you how much water you’re supposed to drink. And believe me, I get asked all the time.

I’m sure of a couple of things when it comes to water: You need to drink some. Though some animals, such as kangaroo rats, can get virtually all the water they need from the food they eat, we are not such animals. Without water, we die. I’m also sure that you can die from drinking too much water. Drinking excessive amounts of water dilutes the sodium in your blood, which messes with the electrical system in your brain and heart. I actually had a patient who went on a “water cleanse” and gave herself a seizure. 

But, to be fair, assuming your kidneys are working reasonably well and you’re otherwise healthy, you’d need to drink around 20 liters of water a day to get into mortal trouble. The dose is the poison, as they say.

So, somewhere between zero and 20 liters of water is the amount you should be drinking in a day. That much I’m sure of.

But the evidence on where in that range you should target is actually pretty skimpy. You wouldn’t think so if you look at the online wellness influencers, with their Stanleys and their strict water intake regimens. You’d think the evidence for the benefits of drinking extra water is overwhelming.

The venerated National Academy of Medicine suggests that men drink thirteen 8 oz cups a day (that’s about 3 liters) and women drink nine 8 oz cups a day (a bit more than 2 liters). From what I can tell, this recommendation — like the old “8 cups of water per day” recommendation — is pulled out of thin air.

I’m not arguing that we shouldn’t drink water. Of course, water is important. I’m just wondering what data there are to really prove that drinking more water is better. 

Fortunately, a team from UCSF has finally done the legwork for us. They break down the actual evidence in this paper, appearing in JAMA Network Open. 

The team scoured the medical literature for randomized controlled trials of water intake. This is critical; we don’t want anecdotes about how clear someone’s skin became after they increased their water intake. We want icy cold, clear data. Randomized trials take a group of people and, at random, assign some to the intervention — in this case, drinking more water — and others to keep doing what they would normally do.

 

The team reviewed nearly 1500 papers but only 18 (!) met the rigorous criteria to be included in the analysis, as you can see from this flow chart.

 

This is the first important finding; not many high-quality studies have investigated how much water we should drink. Of course, water isn’t a prescription product, so funding is likely hard to come by. Can we do a trial of Dasani?

In any case, these 18 trials all looked at different outcomes of interest. Four studies looked at the impact of drinking more water on weight loss, two on fasting blood glucose, two on headache, two on urinary tract infection, two on kidney stones, and six studies on various other outcomes. None of the studies looked at energy, skin tone, or overall wellness, though one did measure a quality-of-life score.

And if I could sum up all these studies in a word, that word would be “meh.”

 

One of four weight loss studies showed that increasing water intake had no effect on weight loss. Two studies showed an effect, but drinking extra water was combined with a low-calorie diet, so that feels a bit like cheating to me. One study randomized participants to drink half a liter of water before meals, and that group did lose more weight than the control group — about a kilogram more over 12 weeks. That’s not exactly Ozempic.

For fasting blood glucose, although one trial suggested that higher premeal water intake lowered glucose levels, the other study (which looked just at increasing water overall) didn’t.

For headache — and, cards on the table here, I’m a big believer in water for headaches — one study showed nothing. The other showed that increasing water intake by 1.5 liters per day improved migraine-related quality of life but didn’t change the number of headache days per month.

For urinary tract infections, one positive trial and one negative one.

The best evidence comes from the kidney stone trials. Increasing water intake to achieve more than two liters of urine a day was associated with a significant reduction in kidney stone recurrence. I consider this a positive finding, more or less. You would be hard-pressed to find a kidney doctor who doesn’t think that people with a history of kidney stones should drink more water.

What about that quality-of-life study? They randomized participants to either drink 1.5 liters of extra water per day (intervention group) or not (control group). Six months later, the scores on the quality-of-life survey were no different between those two groups.

Thirsty yet?

So, what’s going on here? There are a few possibilities.

First, I need to point out that clinical trials are really hard. All the studies in this review were relatively small, with most enrolling fewer than 100 people. The effect of extra water would need to be pretty potent to detect it with those small samples.

I can’t help but point out that our bodies are actually exquisitely tuned to manage how much water we carry. As we lose water throughout the day from sweat and exhalation, our blood becomes a tiny bit more concentrated — the sodium level goes up. Our brains detect that and create a sensation we call thirst. Thirst is one of the most powerful drives we have. Animals, including humans, when thirsty, will choose water over food, over drugs, and over sex. It is incredibly hard to resist, and assuming that we have ready access to water, there is no need to resist it. We drink when we are thirsty. And that may be enough.

Of course, pushing beyond thirst is possible. We are sapient beings who can drink more than we want to. But what we can’t do, assuming our kidneys work, is hold onto that water. It passes right through us. In the case of preventing kidney stones, this is a good thing. Putting more water into your body leads to more water coming out — more dilute urine — which means it’s harder for stones to form. 

But for all that other stuff? The wellness, the skin tone, and so on? It just doesn’t make much sense. If you drink an extra liter of water, you pee an extra liter of water. Net net? Zero.

Some folks will argue that the extra pee gets rid of extra toxins or something like that, but — sorry, kidney doctor Perry here again — that’s not how pee works. The clearance of toxins from the blood happens way upstream of where your urine is diluted or concentrated.

 

If you drink more, the same toxins come out, just with more water around them. In fact, one of the largest studies in this JAMA Network Open review assessed whether increasing water consumption in people with chronic kidney disease would improve kidney function. It didn’t.

I am left, then, with only a bit more confidence than when I began. I remain certain that you should drink more than zero liters and less than 20 liters every day (assuming you’re not losing a lot of water in some other way, like working in the heat). Beyond that, it seems reasonable to trust the millions of years of evolution that have made water homeostasis central to life itself. Give yourself access to water. Drink when you’re thirsty. Drink a bit more if you’d like. But no need to push it. Your kidneys won’t let you anyway.

F. Perry Wilson, MD, MSCE, is an associate professor of medicine and public health and director of Yale’s Clinical and Translational Research Accelerator in New Haven, Connecticut. He disclosed no relevant conflicts of interest.

A version of this article first appeared on Medscape.com.

This transcript has been edited for clarity. 

It’s just about the easiest, safest medical advice you can give: “Drink more water.” You have a headache? Drink more water. Tired? Drink more water. Cold coming on? Drink more water. Tom Brady famously attributed his QB longevity to water drinking, among some other less ordinary practices.

I’m a nephrologist — a kidney doctor. I think about water all the time. I can tell you how your brain senses how much water is in your body and exactly how it communicates that information to your kidneys to control how dilute your urine is. I can explain the miraculous ability of the kidney to concentrate urine across a range from 50 mOsm/L to 1200 mOsm/L and the physiology that makes it all work.

 

But I can’t really tell you how much water you’re supposed to drink. And believe me, I get asked all the time.

I’m sure of a couple of things when it comes to water: You need to drink some. Though some animals, such as kangaroo rats, can get virtually all the water they need from the food they eat, we are not such animals. Without water, we die. I’m also sure that you can die from drinking too much water. Drinking excessive amounts of water dilutes the sodium in your blood, which messes with the electrical system in your brain and heart. I actually had a patient who went on a “water cleanse” and gave herself a seizure. 

But, to be fair, assuming your kidneys are working reasonably well and you’re otherwise healthy, you’d need to drink around 20 liters of water a day to get into mortal trouble. The dose is the poison, as they say.

So, somewhere between zero and 20 liters of water is the amount you should be drinking in a day. That much I’m sure of.

But the evidence on where in that range you should target is actually pretty skimpy. You wouldn’t think so if you look at the online wellness influencers, with their Stanleys and their strict water intake regimens. You’d think the evidence for the benefits of drinking extra water is overwhelming.

The venerated National Academy of Medicine suggests that men drink thirteen 8 oz cups a day (that’s about 3 liters) and women drink nine 8 oz cups a day (a bit more than 2 liters). From what I can tell, this recommendation — like the old “8 cups of water per day” recommendation — is pulled out of thin air.

I’m not arguing that we shouldn’t drink water. Of course, water is important. I’m just wondering what data there are to really prove that drinking more water is better. 

Fortunately, a team from UCSF has finally done the legwork for us. They break down the actual evidence in this paper, appearing in JAMA Network Open. 

The team scoured the medical literature for randomized controlled trials of water intake. This is critical; we don’t want anecdotes about how clear someone’s skin became after they increased their water intake. We want icy cold, clear data. Randomized trials take a group of people and, at random, assign some to the intervention — in this case, drinking more water — and others to keep doing what they would normally do.

 

The team reviewed nearly 1500 papers but only 18 (!) met the rigorous criteria to be included in the analysis, as you can see from this flow chart.

 

This is the first important finding; not many high-quality studies have investigated how much water we should drink. Of course, water isn’t a prescription product, so funding is likely hard to come by. Can we do a trial of Dasani?

In any case, these 18 trials all looked at different outcomes of interest. Four studies looked at the impact of drinking more water on weight loss, two on fasting blood glucose, two on headache, two on urinary tract infection, two on kidney stones, and six studies on various other outcomes. None of the studies looked at energy, skin tone, or overall wellness, though one did measure a quality-of-life score.

And if I could sum up all these studies in a word, that word would be “meh.”

 

One of four weight loss studies showed that increasing water intake had no effect on weight loss. Two studies showed an effect, but drinking extra water was combined with a low-calorie diet, so that feels a bit like cheating to me. One study randomized participants to drink half a liter of water before meals, and that group did lose more weight than the control group — about a kilogram more over 12 weeks. That’s not exactly Ozempic.

For fasting blood glucose, although one trial suggested that higher premeal water intake lowered glucose levels, the other study (which looked just at increasing water overall) didn’t.

For headache — and, cards on the table here, I’m a big believer in water for headaches — one study showed nothing. The other showed that increasing water intake by 1.5 liters per day improved migraine-related quality of life but didn’t change the number of headache days per month.

For urinary tract infections, one positive trial and one negative one.

The best evidence comes from the kidney stone trials. Increasing water intake to achieve more than two liters of urine a day was associated with a significant reduction in kidney stone recurrence. I consider this a positive finding, more or less. You would be hard-pressed to find a kidney doctor who doesn’t think that people with a history of kidney stones should drink more water.

What about that quality-of-life study? They randomized participants to either drink 1.5 liters of extra water per day (intervention group) or not (control group). Six months later, the scores on the quality-of-life survey were no different between those two groups.

Thirsty yet?

So, what’s going on here? There are a few possibilities.

First, I need to point out that clinical trials are really hard. All the studies in this review were relatively small, with most enrolling fewer than 100 people. The effect of extra water would need to be pretty potent to detect it with those small samples.

I can’t help but point out that our bodies are actually exquisitely tuned to manage how much water we carry. As we lose water throughout the day from sweat and exhalation, our blood becomes a tiny bit more concentrated — the sodium level goes up. Our brains detect that and create a sensation we call thirst. Thirst is one of the most powerful drives we have. Animals, including humans, when thirsty, will choose water over food, over drugs, and over sex. It is incredibly hard to resist, and assuming that we have ready access to water, there is no need to resist it. We drink when we are thirsty. And that may be enough.

Of course, pushing beyond thirst is possible. We are sapient beings who can drink more than we want to. But what we can’t do, assuming our kidneys work, is hold onto that water. It passes right through us. In the case of preventing kidney stones, this is a good thing. Putting more water into your body leads to more water coming out — more dilute urine — which means it’s harder for stones to form. 

But for all that other stuff? The wellness, the skin tone, and so on? It just doesn’t make much sense. If you drink an extra liter of water, you pee an extra liter of water. Net net? Zero.

Some folks will argue that the extra pee gets rid of extra toxins or something like that, but — sorry, kidney doctor Perry here again — that’s not how pee works. The clearance of toxins from the blood happens way upstream of where your urine is diluted or concentrated.

 

If you drink more, the same toxins come out, just with more water around them. In fact, one of the largest studies in this JAMA Network Open review assessed whether increasing water consumption in people with chronic kidney disease would improve kidney function. It didn’t.

I am left, then, with only a bit more confidence than when I began. I remain certain that you should drink more than zero liters and less than 20 liters every day (assuming you’re not losing a lot of water in some other way, like working in the heat). Beyond that, it seems reasonable to trust the millions of years of evolution that have made water homeostasis central to life itself. Give yourself access to water. Drink when you’re thirsty. Drink a bit more if you’d like. But no need to push it. Your kidneys won’t let you anyway.

F. Perry Wilson, MD, MSCE, is an associate professor of medicine and public health and director of Yale’s Clinical and Translational Research Accelerator in New Haven, Connecticut. He disclosed no relevant conflicts of interest.

A version of this article first appeared on Medscape.com.

This video transcript has been edited for clarity. 

Dear colleagues, I am Christoph Diener, from the Faculty of Medicine at the University Duisburg-Essen in Germany. In this video, I would like to cover six publications on stroke, which were published this fall. 

The Best Thrombolytic?

Let me start with systemic thrombolysis. We now have two thrombolytic agents available. One is the well-known alteplase, and newly approved for the treatment of stroke is tenecteplase. The ATTEST-2 study in the United Kingdom, published in The Lancet Neurology, compared tenecteplase 0.25 mg/kg body weight as a bolus with alteplase 0.9 mg/kg body weight as an infusion over 60 minutes in the 4.5-hour time window in 1777 patients with ischemic stroke.

There was no significant difference between the two thrombolytics for the primary endpoint of modified Rankin Scale score after 90 days. There was also no difference with respect to mortality, intracranial bleeding, or extracranial bleeding. 

We finally have 11 randomized controlled trials that compared tenecteplase and alteplase in acute ischemic stroke. A meta-analysis of these randomized trials was published in Neurology. The analysis included 3700 patients treated with tenecteplase and 3700 patients treated with alteplase. For the primary endpoint, excellent functional outcome defined as modified Rankin Scale score 0-1 after 90 days, there was a significant benefit for tenecteplase (relative risk, 1.05), but the absolute difference was very small, at 3%. There was no difference in mortality or bleeding complications. 

In conclusion, I think both substances are great. They are effective. Tenecteplase is most probably the drug which should be used in people who have to transfer from a primary stroke center to a dedicated stroke center that provides thrombectomy. Otherwise, I think it’s a choice of the physician as to which thrombolytic agent to use. 

 

Mobile Stroke Units

A highly debated topic is mobile stroke units. These stroke units have a CT scanner and laboratory on board, and this makes it possible to perform thrombolysis on the way to the hospital. A retrospective, observational study collected data between 2018 and 2023, and included 19,400 patients with acute stroke, of whom 1237, or 6.4%, were treated in a mobile stroke unit. This study was published in JAMA Neurology. 

The modified Rankin Scale score at the time of discharge was better in patients treated with a mobile stroke unit, but the absolute benefit was only 0.03 points on the modified Rankin Scale. The question is whether this is cost-effective, and can we really do this at times when there is a traumatic shortage of physicians and nursing staff in the hospital? 

 

DOAC Reversal Agents

Oral anticoagulation, as you know, is usually considered a contraindication for systemic thrombolysis. Idarucizumab, a monoclonal antibody, was developed to reverse the biological activity of dabigatran and then allow systemic thrombolysis.

A recent publication in Neurology analyzed 13 cohort studies with 553 stroke patients on dabigatran who received idarucizumab prior to systemic thrombolysis, and the rate of intracranial hemorrhage was 4%. This means it’s obviously possible to perform thrombolysis when the activity of dabigatran is neutralized by idarucizumab.

Unfortunately, until today, we have no data on whether this can also be done with andexanet alfa in people who are treated with a factor Xa inhibitor like, for example, apixaban, rivaroxaban, or edoxaban. 

 

Anticoagulation in ESUS 

My next topic is ESUS, or embolic stroke of undetermined source. We have four large randomized trials and three smaller trials that compared antiplatelet therapy with DOACs in patients with ESUS. A group in Neurology published a meta-analysis of seven randomized controlled studies with, altogether, 14,800 patients with ESUS. 

The comparison between antiplatelet therapy and anticoagulants showed no difference for recurrent ischemic stroke, and also not for major subgroups. This means that people with ESUS should receive antiplatelet therapy, most probably aspirin. 

 

Anticoagulation Post–Ischemic Stroke With AF 

My final topic is the optimal time to start anticoagulation in people with atrial fibrillation who suffer an ischemic stroke. The OPTIMAS study, published in The Lancet, randomized 3650 patients who were anticoagulated with DOACs early (which means less than 4 days) or delayed (between 7 and 14 days). There was no difference in the primary endpoint, which was recurrent ischemic stroke, intracranial hemorrhage, or systemic embolism at 90 days.

The conclusion is that, in most cases, we can probably initiate anticoagulation in people with ischemic stroke and atrial fibrillation within the first 4 days. 

Dear colleagues, this is an exciting time for the stroke field. I presented six new studies that have impact, I think, on the management of patients with ischemic stroke.

Dr. Diener is a professor in the Department of Neurology, Stroke Center-Headache Center, University Duisburg-Essen in Germany. He reported conflicts of interest with Abbott, AbbVie, Boehringer Ingelheim, Lundbeck, Novartis, Orion Pharma, Teva, WebMD, and The German Research Council. He also serves on the editorial boards of Cephalalgia, Lancet Neurology, and Drugs.

A version of this article first appeared on Medscape.com.

This video transcript has been edited for clarity. 

Dear colleagues, I am Christoph Diener, from the Faculty of Medicine at the University Duisburg-Essen in Germany. In this video, I would like to cover six publications on stroke, which were published this fall. 

The Best Thrombolytic?

Let me start with systemic thrombolysis. We now have two thrombolytic agents available. One is the well-known alteplase, and newly approved for the treatment of stroke is tenecteplase. The ATTEST-2 study in the United Kingdom, published in The Lancet Neurology, compared tenecteplase 0.25 mg/kg body weight as a bolus with alteplase 0.9 mg/kg body weight as an infusion over 60 minutes in the 4.5-hour time window in 1777 patients with ischemic stroke.

There was no significant difference between the two thrombolytics for the primary endpoint of modified Rankin Scale score after 90 days. There was also no difference with respect to mortality, intracranial bleeding, or extracranial bleeding. 

We finally have 11 randomized controlled trials that compared tenecteplase and alteplase in acute ischemic stroke. A meta-analysis of these randomized trials was published in Neurology. The analysis included 3700 patients treated with tenecteplase and 3700 patients treated with alteplase. For the primary endpoint, excellent functional outcome defined as modified Rankin Scale score 0-1 after 90 days, there was a significant benefit for tenecteplase (relative risk, 1.05), but the absolute difference was very small, at 3%. There was no difference in mortality or bleeding complications. 

In conclusion, I think both substances are great. They are effective. Tenecteplase is most probably the drug which should be used in people who have to transfer from a primary stroke center to a dedicated stroke center that provides thrombectomy. Otherwise, I think it’s a choice of the physician as to which thrombolytic agent to use. 

 

Mobile Stroke Units

A highly debated topic is mobile stroke units. These stroke units have a CT scanner and laboratory on board, and this makes it possible to perform thrombolysis on the way to the hospital. A retrospective, observational study collected data between 2018 and 2023, and included 19,400 patients with acute stroke, of whom 1237, or 6.4%, were treated in a mobile stroke unit. This study was published in JAMA Neurology. 

The modified Rankin Scale score at the time of discharge was better in patients treated with a mobile stroke unit, but the absolute benefit was only 0.03 points on the modified Rankin Scale. The question is whether this is cost-effective, and can we really do this at times when there is a traumatic shortage of physicians and nursing staff in the hospital? 

 

DOAC Reversal Agents

Oral anticoagulation, as you know, is usually considered a contraindication for systemic thrombolysis. Idarucizumab, a monoclonal antibody, was developed to reverse the biological activity of dabigatran and then allow systemic thrombolysis.

A recent publication in Neurology analyzed 13 cohort studies with 553 stroke patients on dabigatran who received idarucizumab prior to systemic thrombolysis, and the rate of intracranial hemorrhage was 4%. This means it’s obviously possible to perform thrombolysis when the activity of dabigatran is neutralized by idarucizumab.

Unfortunately, until today, we have no data on whether this can also be done with andexanet alfa in people who are treated with a factor Xa inhibitor like, for example, apixaban, rivaroxaban, or edoxaban. 

 

Anticoagulation in ESUS 

My next topic is ESUS, or embolic stroke of undetermined source. We have four large randomized trials and three smaller trials that compared antiplatelet therapy with DOACs in patients with ESUS. A group in Neurology published a meta-analysis of seven randomized controlled studies with, altogether, 14,800 patients with ESUS. 

The comparison between antiplatelet therapy and anticoagulants showed no difference for recurrent ischemic stroke, and also not for major subgroups. This means that people with ESUS should receive antiplatelet therapy, most probably aspirin. 

 

Anticoagulation Post–Ischemic Stroke With AF 

My final topic is the optimal time to start anticoagulation in people with atrial fibrillation who suffer an ischemic stroke. The OPTIMAS study, published in The Lancet, randomized 3650 patients who were anticoagulated with DOACs early (which means less than 4 days) or delayed (between 7 and 14 days). There was no difference in the primary endpoint, which was recurrent ischemic stroke, intracranial hemorrhage, or systemic embolism at 90 days.

The conclusion is that, in most cases, we can probably initiate anticoagulation in people with ischemic stroke and atrial fibrillation within the first 4 days. 

Dear colleagues, this is an exciting time for the stroke field. I presented six new studies that have impact, I think, on the management of patients with ischemic stroke.

Dr. Diener is a professor in the Department of Neurology, Stroke Center-Headache Center, University Duisburg-Essen in Germany. He reported conflicts of interest with Abbott, AbbVie, Boehringer Ingelheim, Lundbeck, Novartis, Orion Pharma, Teva, WebMD, and The German Research Council. He also serves on the editorial boards of Cephalalgia, Lancet Neurology, and Drugs.

A version of this article first appeared on Medscape.com.

This video transcript has been edited for clarity. 

Dear colleagues, I am Christoph Diener, from the Faculty of Medicine at the University Duisburg-Essen in Germany. In this video, I would like to cover six publications on stroke, which were published this fall. 

The Best Thrombolytic?

Let me start with systemic thrombolysis. We now have two thrombolytic agents available. One is the well-known alteplase, and newly approved for the treatment of stroke is tenecteplase. The ATTEST-2 study in the United Kingdom, published in The Lancet Neurology, compared tenecteplase 0.25 mg/kg body weight as a bolus with alteplase 0.9 mg/kg body weight as an infusion over 60 minutes in the 4.5-hour time window in 1777 patients with ischemic stroke.

There was no significant difference between the two thrombolytics for the primary endpoint of modified Rankin Scale score after 90 days. There was also no difference with respect to mortality, intracranial bleeding, or extracranial bleeding. 

We finally have 11 randomized controlled trials that compared tenecteplase and alteplase in acute ischemic stroke. A meta-analysis of these randomized trials was published in Neurology. The analysis included 3700 patients treated with tenecteplase and 3700 patients treated with alteplase. For the primary endpoint, excellent functional outcome defined as modified Rankin Scale score 0-1 after 90 days, there was a significant benefit for tenecteplase (relative risk, 1.05), but the absolute difference was very small, at 3%. There was no difference in mortality or bleeding complications. 

In conclusion, I think both substances are great. They are effective. Tenecteplase is most probably the drug which should be used in people who have to transfer from a primary stroke center to a dedicated stroke center that provides thrombectomy. Otherwise, I think it’s a choice of the physician as to which thrombolytic agent to use. 

 

Mobile Stroke Units

A highly debated topic is mobile stroke units. These stroke units have a CT scanner and laboratory on board, and this makes it possible to perform thrombolysis on the way to the hospital. A retrospective, observational study collected data between 2018 and 2023, and included 19,400 patients with acute stroke, of whom 1237, or 6.4%, were treated in a mobile stroke unit. This study was published in JAMA Neurology. 

The modified Rankin Scale score at the time of discharge was better in patients treated with a mobile stroke unit, but the absolute benefit was only 0.03 points on the modified Rankin Scale. The question is whether this is cost-effective, and can we really do this at times when there is a traumatic shortage of physicians and nursing staff in the hospital? 

 

DOAC Reversal Agents

Oral anticoagulation, as you know, is usually considered a contraindication for systemic thrombolysis. Idarucizumab, a monoclonal antibody, was developed to reverse the biological activity of dabigatran and then allow systemic thrombolysis.

A recent publication in Neurology analyzed 13 cohort studies with 553 stroke patients on dabigatran who received idarucizumab prior to systemic thrombolysis, and the rate of intracranial hemorrhage was 4%. This means it’s obviously possible to perform thrombolysis when the activity of dabigatran is neutralized by idarucizumab.

Unfortunately, until today, we have no data on whether this can also be done with andexanet alfa in people who are treated with a factor Xa inhibitor like, for example, apixaban, rivaroxaban, or edoxaban. 

 

Anticoagulation in ESUS 

My next topic is ESUS, or embolic stroke of undetermined source. We have four large randomized trials and three smaller trials that compared antiplatelet therapy with DOACs in patients with ESUS. A group in Neurology published a meta-analysis of seven randomized controlled studies with, altogether, 14,800 patients with ESUS. 

The comparison between antiplatelet therapy and anticoagulants showed no difference for recurrent ischemic stroke, and also not for major subgroups. This means that people with ESUS should receive antiplatelet therapy, most probably aspirin. 

 

Anticoagulation Post–Ischemic Stroke With AF 

My final topic is the optimal time to start anticoagulation in people with atrial fibrillation who suffer an ischemic stroke. The OPTIMAS study, published in The Lancet, randomized 3650 patients who were anticoagulated with DOACs early (which means less than 4 days) or delayed (between 7 and 14 days). There was no difference in the primary endpoint, which was recurrent ischemic stroke, intracranial hemorrhage, or systemic embolism at 90 days.

The conclusion is that, in most cases, we can probably initiate anticoagulation in people with ischemic stroke and atrial fibrillation within the first 4 days. 

Dear colleagues, this is an exciting time for the stroke field. I presented six new studies that have impact, I think, on the management of patients with ischemic stroke.

Dr. Diener is a professor in the Department of Neurology, Stroke Center-Headache Center, University Duisburg-Essen in Germany. He reported conflicts of interest with Abbott, AbbVie, Boehringer Ingelheim, Lundbeck, Novartis, Orion Pharma, Teva, WebMD, and The German Research Council. He also serves on the editorial boards of Cephalalgia, Lancet Neurology, and Drugs.

A version of this article first appeared on Medscape.com.

In a recent survey of 1259 mothers published in the journal Pediatrics, 28% reported they had fallen asleep while feeding their babies, and 83% of those mothers reported that the sleep was unplanned. Although the study sample was small, the investigators found that sociodemographic factors did not increase the odds that a mother would fall asleep while feeding.

These numbers are not surprising, but nonetheless they are concerning because co-sleeping is a known risk factor for sudden unexplained infant death (SUID). Every parent will tell you during the first 6 months of their adventure in parenting they didn’t get enough sleep. In fact some will tell you that sleep deprivation was their chronic state for the child’s first year. 

 

Falling asleep easily at times and places not intended for sleep is the primary symptom of sleep deprivation. SUID is the most tragic event associated with parental sleep deprivation, but it is certainly not the only one. Overtired parents are more likely to be involved in accidents and are more likely to make poor decisions, particularly those regarding how to respond to a crying or misbehaving child.

The investigators found that 24% of mothers who reported that their usual nighttime feeding location was a chair or sofa (14%). Not surprisingly, mothers who fed in chairs were less likely to fall asleep while feeding. Many of these mothers reported that they chose the chair because they thought they would be less likely to fall asleep and/or disturb other family members. One wonders how we should interpret these numbers in light of other research that has found it is “relatively less hazardous to fall asleep with an infant in the adult bed than on a chair or sofa.” Had these chair feeding mothers made the better choice under the circumstances? It would take a much larger and more granular study to answer that question.

Mothers who exclusively breastfed were more likely to fall asleep feeding than were those who partially breastfed or used formula. The investigators postulated that the infants of mothers who exclusively breastfed may have required more feedings because breast milk is more easily and quickly digested. I know this is a common explanation, but in my experience I have found that exclusively breastfed infants often use nursing as pacification and a sleep trigger and spend more time at the breast regardless of how quickly they emptied their stomachs.

This study also examined the effect of repeated educational interventions and support and found that mothers who received an intervention based on safe sleep practices were less likely to fall asleep while feeding than were the mothers who had received the intervention focused on exclusive breastfeeding value and barriers to its adoption.

Certainly, the problem of mothers falling asleep while feeding is one we should address more robustly than we have in the past. Education is one avenue, particularly when it includes the mother’s partner who can play an important role as standby lifeguard to make sure the mother doesn’t fall asleep. Obviously, this is easier said than done because when there is a new baby in the house sleep deprivation is usually a shared experience.

Although I believe that my family is on the verge of gifting me a smartwatch to protect me from my own misadventures, I don’t have any personal experience with these wonders of modern technology. However, I suspect with very little tweaking a wearable sensor could be easily programmed to detect when a mother is beginning to fall asleep while she is feeding her infant. A smartwatch would be an expensive intervention and is unlikely to filter down to economically challenged families. On the other hand, this paper has reinforced our suspicions that sleep-deprived infant feeding is a significant problem. A subsidized loaner program for those families that can’t afford a smartwatch is an option that should be considered. 

 

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].

In a recent survey of 1259 mothers published in the journal Pediatrics, 28% reported they had fallen asleep while feeding their babies, and 83% of those mothers reported that the sleep was unplanned. Although the study sample was small, the investigators found that sociodemographic factors did not increase the odds that a mother would fall asleep while feeding.

These numbers are not surprising, but nonetheless they are concerning because co-sleeping is a known risk factor for sudden unexplained infant death (SUID). Every parent will tell you during the first 6 months of their adventure in parenting they didn’t get enough sleep. In fact some will tell you that sleep deprivation was their chronic state for the child’s first year. 

 

Falling asleep easily at times and places not intended for sleep is the primary symptom of sleep deprivation. SUID is the most tragic event associated with parental sleep deprivation, but it is certainly not the only one. Overtired parents are more likely to be involved in accidents and are more likely to make poor decisions, particularly those regarding how to respond to a crying or misbehaving child.

The investigators found that 24% of mothers who reported that their usual nighttime feeding location was a chair or sofa (14%). Not surprisingly, mothers who fed in chairs were less likely to fall asleep while feeding. Many of these mothers reported that they chose the chair because they thought they would be less likely to fall asleep and/or disturb other family members. One wonders how we should interpret these numbers in light of other research that has found it is “relatively less hazardous to fall asleep with an infant in the adult bed than on a chair or sofa.” Had these chair feeding mothers made the better choice under the circumstances? It would take a much larger and more granular study to answer that question.

Mothers who exclusively breastfed were more likely to fall asleep feeding than were those who partially breastfed or used formula. The investigators postulated that the infants of mothers who exclusively breastfed may have required more feedings because breast milk is more easily and quickly digested. I know this is a common explanation, but in my experience I have found that exclusively breastfed infants often use nursing as pacification and a sleep trigger and spend more time at the breast regardless of how quickly they emptied their stomachs.

This study also examined the effect of repeated educational interventions and support and found that mothers who received an intervention based on safe sleep practices were less likely to fall asleep while feeding than were the mothers who had received the intervention focused on exclusive breastfeeding value and barriers to its adoption.

Certainly, the problem of mothers falling asleep while feeding is one we should address more robustly than we have in the past. Education is one avenue, particularly when it includes the mother’s partner who can play an important role as standby lifeguard to make sure the mother doesn’t fall asleep. Obviously, this is easier said than done because when there is a new baby in the house sleep deprivation is usually a shared experience.

Although I believe that my family is on the verge of gifting me a smartwatch to protect me from my own misadventures, I don’t have any personal experience with these wonders of modern technology. However, I suspect with very little tweaking a wearable sensor could be easily programmed to detect when a mother is beginning to fall asleep while she is feeding her infant. A smartwatch would be an expensive intervention and is unlikely to filter down to economically challenged families. On the other hand, this paper has reinforced our suspicions that sleep-deprived infant feeding is a significant problem. A subsidized loaner program for those families that can’t afford a smartwatch is an option that should be considered. 

 

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].

In a recent survey of 1259 mothers published in the journal Pediatrics, 28% reported they had fallen asleep while feeding their babies, and 83% of those mothers reported that the sleep was unplanned. Although the study sample was small, the investigators found that sociodemographic factors did not increase the odds that a mother would fall asleep while feeding.

These numbers are not surprising, but nonetheless they are concerning because co-sleeping is a known risk factor for sudden unexplained infant death (SUID). Every parent will tell you during the first 6 months of their adventure in parenting they didn’t get enough sleep. In fact some will tell you that sleep deprivation was their chronic state for the child’s first year. 

 

Falling asleep easily at times and places not intended for sleep is the primary symptom of sleep deprivation. SUID is the most tragic event associated with parental sleep deprivation, but it is certainly not the only one. Overtired parents are more likely to be involved in accidents and are more likely to make poor decisions, particularly those regarding how to respond to a crying or misbehaving child.

The investigators found that 24% of mothers who reported that their usual nighttime feeding location was a chair or sofa (14%). Not surprisingly, mothers who fed in chairs were less likely to fall asleep while feeding. Many of these mothers reported that they chose the chair because they thought they would be less likely to fall asleep and/or disturb other family members. One wonders how we should interpret these numbers in light of other research that has found it is “relatively less hazardous to fall asleep with an infant in the adult bed than on a chair or sofa.” Had these chair feeding mothers made the better choice under the circumstances? It would take a much larger and more granular study to answer that question.

Mothers who exclusively breastfed were more likely to fall asleep feeding than were those who partially breastfed or used formula. The investigators postulated that the infants of mothers who exclusively breastfed may have required more feedings because breast milk is more easily and quickly digested. I know this is a common explanation, but in my experience I have found that exclusively breastfed infants often use nursing as pacification and a sleep trigger and spend more time at the breast regardless of how quickly they emptied their stomachs.

This study also examined the effect of repeated educational interventions and support and found that mothers who received an intervention based on safe sleep practices were less likely to fall asleep while feeding than were the mothers who had received the intervention focused on exclusive breastfeeding value and barriers to its adoption.

Certainly, the problem of mothers falling asleep while feeding is one we should address more robustly than we have in the past. Education is one avenue, particularly when it includes the mother’s partner who can play an important role as standby lifeguard to make sure the mother doesn’t fall asleep. Obviously, this is easier said than done because when there is a new baby in the house sleep deprivation is usually a shared experience.

Although I believe that my family is on the verge of gifting me a smartwatch to protect me from my own misadventures, I don’t have any personal experience with these wonders of modern technology. However, I suspect with very little tweaking a wearable sensor could be easily programmed to detect when a mother is beginning to fall asleep while she is feeding her infant. A smartwatch would be an expensive intervention and is unlikely to filter down to economically challenged families. On the other hand, this paper has reinforced our suspicions that sleep-deprived infant feeding is a significant problem. A subsidized loaner program for those families that can’t afford a smartwatch is an option that should be considered. 

 

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].

Case: 45-year-old woman comes to clinic and requests lipoprotein(a) [Lp(a)] testing. She has a family history of early coronary disease (mother age 50, sister age 48) and has hypertension with home blood pressure readings of 130-140/70-75. She had a lipid panel checked last year which showed a total cholesterol of 210 mg/dL, LDL 145 mg/dL, HDL 45 mg/dL, and triglycerides of 100 mg/dL. She does not smoke and is currently taking irbesartan, chlorthalidone, sertraline, a multivitamin, and vitamin D.

What do you recommend?

There has been a great deal of media attention on testing for Lp(a). Many of my patients are requesting testing although many of them do not need it. This patient is an exception. I think Lp(a) testing would help inform her medical care. She has a family history of early coronary disease in her mother and sister, but her own lipid profile is not worrisome.

Her 10-year cardiovascular disease risk is 2%. The cardiac risk calculator does not incorporate family history; I think this is a situation where testing for Lp(a)(as well as apolipoprotein B) can be helpful. If her Lp(a) is elevated, it helps reassess her risk and that information would be helpful in targeting aggressive interventions for other CV risk factors, including optimal blood pressure control. In her case, pushing for a goal systolic blood pressure below 120 mm Hg and making sure she is doing regular exercise and eating a heart-healthy diet. The current consensus statement on Lp(a) recommends that patients with elevated levels have aggressive lifestyle and cardiovascular risk management.¹

 

Currently, there are no medical treatments available for high Lp(a) for primary prevention. Apheresis has been approved by the US Food and Drug Administration (FDA) for patients with familial hyperlipidemia who have LDL ≥ 100 mg/dL, Lp(a) ≥ 60 mg/dL, and coronary or other artery disease. 

PCSK9 inhibitors have shown a reduction in major cardiovascular events in patients who have established coronary artery disease and high Lp(a) levels, albeit with limited data. Unlike statins, which increase Lp(a) levels, PCSK9 inhibitors reduce Lp(a) levels.² There are promising early results in a phase 2 trial of the oral drug muvalaplin lowering Lp(a) levels by up to 85% for the highest dose, but there are no peer-reviewed articles confirming these results and no outcome trials at this time.

In patients who are already recognized as high risk, especially those with established coronary artery disease, measuring Lp(a) levels offer little benefit. These patients should already be receiving aggressive medical therapy to reach blood pressure targets if hypertensive, maximal lifestyle modifications, and statin therapy. 

If these patients need more therapy because of continued coronary events, despite maximal conventional medical therapy, then adding a PCSK9 inhibitor would be appropriate whether or not a patient has a high Lp(a) level. Once Lp(a) targeted therapies are available and show clinical benefit, then the role of Lp(a) measurement and treatment in this population will be clearer.

Pearl: Most patients do not need Lp(a) testing. There are no FDA-approved treatments for high Lp(a) levels.

Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and he serves as third-year medical student clerkship director at the University of Washington. Contact Dr. Paauw at [email protected].

References

1. Kronenberg F et al. Lipoprotein(a) in atherosclerotic cardiovascular disease and aortic stenosis: A European Atherosclerosis Society consensus statement. Eur Heart J. 2022;43:3925-46.

2. Ruscica M et al. Lipoprotein(a) and PCSK9 inhibition: Clinical evidence Eur Heart J Suppl 2020;Nov 18(Suppl L):L53–L56.

Case: 45-year-old woman comes to clinic and requests lipoprotein(a) [Lp(a)] testing. She has a family history of early coronary disease (mother age 50, sister age 48) and has hypertension with home blood pressure readings of 130-140/70-75. She had a lipid panel checked last year which showed a total cholesterol of 210 mg/dL, LDL 145 mg/dL, HDL 45 mg/dL, and triglycerides of 100 mg/dL. She does not smoke and is currently taking irbesartan, chlorthalidone, sertraline, a multivitamin, and vitamin D.

What do you recommend?

There has been a great deal of media attention on testing for Lp(a). Many of my patients are requesting testing although many of them do not need it. This patient is an exception. I think Lp(a) testing would help inform her medical care. She has a family history of early coronary disease in her mother and sister, but her own lipid profile is not worrisome.

Her 10-year cardiovascular disease risk is 2%. The cardiac risk calculator does not incorporate family history; I think this is a situation where testing for Lp(a)(as well as apolipoprotein B) can be helpful. If her Lp(a) is elevated, it helps reassess her risk and that information would be helpful in targeting aggressive interventions for other CV risk factors, including optimal blood pressure control. In her case, pushing for a goal systolic blood pressure below 120 mm Hg and making sure she is doing regular exercise and eating a heart-healthy diet. The current consensus statement on Lp(a) recommends that patients with elevated levels have aggressive lifestyle and cardiovascular risk management.¹

 

Currently, there are no medical treatments available for high Lp(a) for primary prevention. Apheresis has been approved by the US Food and Drug Administration (FDA) for patients with familial hyperlipidemia who have LDL ≥ 100 mg/dL, Lp(a) ≥ 60 mg/dL, and coronary or other artery disease. 

PCSK9 inhibitors have shown a reduction in major cardiovascular events in patients who have established coronary artery disease and high Lp(a) levels, albeit with limited data. Unlike statins, which increase Lp(a) levels, PCSK9 inhibitors reduce Lp(a) levels.² There are promising early results in a phase 2 trial of the oral drug muvalaplin lowering Lp(a) levels by up to 85% for the highest dose, but there are no peer-reviewed articles confirming these results and no outcome trials at this time.

In patients who are already recognized as high risk, especially those with established coronary artery disease, measuring Lp(a) levels offer little benefit. These patients should already be receiving aggressive medical therapy to reach blood pressure targets if hypertensive, maximal lifestyle modifications, and statin therapy. 

If these patients need more therapy because of continued coronary events, despite maximal conventional medical therapy, then adding a PCSK9 inhibitor would be appropriate whether or not a patient has a high Lp(a) level. Once Lp(a) targeted therapies are available and show clinical benefit, then the role of Lp(a) measurement and treatment in this population will be clearer.

Pearl: Most patients do not need Lp(a) testing. There are no FDA-approved treatments for high Lp(a) levels.

Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and he serves as third-year medical student clerkship director at the University of Washington. Contact Dr. Paauw at [email protected].

References

1. Kronenberg F et al. Lipoprotein(a) in atherosclerotic cardiovascular disease and aortic stenosis: A European Atherosclerosis Society consensus statement. Eur Heart J. 2022;43:3925-46.

2. Ruscica M et al. Lipoprotein(a) and PCSK9 inhibition: Clinical evidence Eur Heart J Suppl 2020;Nov 18(Suppl L):L53–L56.

Case: 45-year-old woman comes to clinic and requests lipoprotein(a) [Lp(a)] testing. She has a family history of early coronary disease (mother age 50, sister age 48) and has hypertension with home blood pressure readings of 130-140/70-75. She had a lipid panel checked last year which showed a total cholesterol of 210 mg/dL, LDL 145 mg/dL, HDL 45 mg/dL, and triglycerides of 100 mg/dL. She does not smoke and is currently taking irbesartan, chlorthalidone, sertraline, a multivitamin, and vitamin D.

What do you recommend?

There has been a great deal of media attention on testing for Lp(a). Many of my patients are requesting testing although many of them do not need it. This patient is an exception. I think Lp(a) testing would help inform her medical care. She has a family history of early coronary disease in her mother and sister, but her own lipid profile is not worrisome.

Her 10-year cardiovascular disease risk is 2%. The cardiac risk calculator does not incorporate family history; I think this is a situation where testing for Lp(a)(as well as apolipoprotein B) can be helpful. If her Lp(a) is elevated, it helps reassess her risk and that information would be helpful in targeting aggressive interventions for other CV risk factors, including optimal blood pressure control. In her case, pushing for a goal systolic blood pressure below 120 mm Hg and making sure she is doing regular exercise and eating a heart-healthy diet. The current consensus statement on Lp(a) recommends that patients with elevated levels have aggressive lifestyle and cardiovascular risk management.¹

 

Currently, there are no medical treatments available for high Lp(a) for primary prevention. Apheresis has been approved by the US Food and Drug Administration (FDA) for patients with familial hyperlipidemia who have LDL ≥ 100 mg/dL, Lp(a) ≥ 60 mg/dL, and coronary or other artery disease. 

PCSK9 inhibitors have shown a reduction in major cardiovascular events in patients who have established coronary artery disease and high Lp(a) levels, albeit with limited data. Unlike statins, which increase Lp(a) levels, PCSK9 inhibitors reduce Lp(a) levels.² There are promising early results in a phase 2 trial of the oral drug muvalaplin lowering Lp(a) levels by up to 85% for the highest dose, but there are no peer-reviewed articles confirming these results and no outcome trials at this time.

In patients who are already recognized as high risk, especially those with established coronary artery disease, measuring Lp(a) levels offer little benefit. These patients should already be receiving aggressive medical therapy to reach blood pressure targets if hypertensive, maximal lifestyle modifications, and statin therapy. 

If these patients need more therapy because of continued coronary events, despite maximal conventional medical therapy, then adding a PCSK9 inhibitor would be appropriate whether or not a patient has a high Lp(a) level. Once Lp(a) targeted therapies are available and show clinical benefit, then the role of Lp(a) measurement and treatment in this population will be clearer.

Pearl: Most patients do not need Lp(a) testing. There are no FDA-approved treatments for high Lp(a) levels.

Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and he serves as third-year medical student clerkship director at the University of Washington. Contact Dr. Paauw at [email protected].

References

1. Kronenberg F et al. Lipoprotein(a) in atherosclerotic cardiovascular disease and aortic stenosis: A European Atherosclerosis Society consensus statement. Eur Heart J. 2022;43:3925-46.

2. Ruscica M et al. Lipoprotein(a) and PCSK9 inhibition: Clinical evidence Eur Heart J Suppl 2020;Nov 18(Suppl L):L53–L56.

Syphilis

Two biopsies by punch technique were performed; one for pathology and one for tissue culture (fungal and atypical mycobacteria). Tissue cultures showed no growth at 4 and 6 weeks, respectively. The lesions were swabbed for bacterial and viral cultures. Bacterial culture was positive for methicillin-resistant Staphylococcus aureus (MRSA), Pseudomonas aeruginosa, and group C Streptococcus. Viral culture for herpes simplex virus (HSV) and varicella zoster virus (VZV) was negative. Histopathology confirmed the diagnosis of syphilis. Immunoperoxidase stain was positive for Treponema pallidum, and negative for HSV-1, HSV-2, and VZV. Special stains for PAS, GMS, Fite, and AFB were negative for organisms. 

Syphilis, also known as Lues disease, is a contagious, sexually acquired disease caused by the spirochete T pallidum. The skin and mucous membranes are primarily infected. There are primary, secondary, and tertiary stages. In the primary or initial stage of syphilis, a chancre appears, usually 3-4 weeks after infection. The chancre is a painless papule or erosion that progresses to a firm ulceration. Lymphadenopathy may be present. Less often, multiple chancres may be present. Primary chancre on the finger has been reported in the literature, although it is far less common to have extragenital primary syphilis. The incidence ranges from 2% to 10%. Other extragenital areas that can be affected include lips, intraoral lesions, and the anus. Atypical chancres can be formed when other microbial agents are also present. Generally, an untreated chancre will heal spontaneously within a few months. 

The patient referred to the department of health for treatment with penicillin G and further workup of sexually transmitted diseases. He was also seen by infectious disease for treatment of the superimposed bacterial infections and treated with an antibiotic regimen. 



The case and photo were submitted by Dr. Bilu Martin.

 

Dr Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Florida. More diagnostic cases are available at mdedge.com/dermatology. To submit a case for possible publication, send an email to [email protected].

References

Ramoni S et al. Sex Transm Dis. 2010 Jul;37(7):468. doi: 10.1097/OLQ.0b013e3181e2cfac.

Starzycki Z. Br J Vener Dis. 1983 Jun;59(3):169-71. doi: 10.1136/sti.59.3.169.

Syphilis

Two biopsies by punch technique were performed; one for pathology and one for tissue culture (fungal and atypical mycobacteria). Tissue cultures showed no growth at 4 and 6 weeks, respectively. The lesions were swabbed for bacterial and viral cultures. Bacterial culture was positive for methicillin-resistant Staphylococcus aureus (MRSA), Pseudomonas aeruginosa, and group C Streptococcus. Viral culture for herpes simplex virus (HSV) and varicella zoster virus (VZV) was negative. Histopathology confirmed the diagnosis of syphilis. Immunoperoxidase stain was positive for Treponema pallidum, and negative for HSV-1, HSV-2, and VZV. Special stains for PAS, GMS, Fite, and AFB were negative for organisms. 

Syphilis, also known as Lues disease, is a contagious, sexually acquired disease caused by the spirochete T pallidum. The skin and mucous membranes are primarily infected. There are primary, secondary, and tertiary stages. In the primary or initial stage of syphilis, a chancre appears, usually 3-4 weeks after infection. The chancre is a painless papule or erosion that progresses to a firm ulceration. Lymphadenopathy may be present. Less often, multiple chancres may be present. Primary chancre on the finger has been reported in the literature, although it is far less common to have extragenital primary syphilis. The incidence ranges from 2% to 10%. Other extragenital areas that can be affected include lips, intraoral lesions, and the anus. Atypical chancres can be formed when other microbial agents are also present. Generally, an untreated chancre will heal spontaneously within a few months. 

The patient referred to the department of health for treatment with penicillin G and further workup of sexually transmitted diseases. He was also seen by infectious disease for treatment of the superimposed bacterial infections and treated with an antibiotic regimen. 



The case and photo were submitted by Dr. Bilu Martin.

 

Dr Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Florida. More diagnostic cases are available at mdedge.com/dermatology. To submit a case for possible publication, send an email to [email protected].

References

Ramoni S et al. Sex Transm Dis. 2010 Jul;37(7):468. doi: 10.1097/OLQ.0b013e3181e2cfac.

Starzycki Z. Br J Vener Dis. 1983 Jun;59(3):169-71. doi: 10.1136/sti.59.3.169.

Syphilis

Two biopsies by punch technique were performed; one for pathology and one for tissue culture (fungal and atypical mycobacteria). Tissue cultures showed no growth at 4 and 6 weeks, respectively. The lesions were swabbed for bacterial and viral cultures. Bacterial culture was positive for methicillin-resistant Staphylococcus aureus (MRSA), Pseudomonas aeruginosa, and group C Streptococcus. Viral culture for herpes simplex virus (HSV) and varicella zoster virus (VZV) was negative. Histopathology confirmed the diagnosis of syphilis. Immunoperoxidase stain was positive for Treponema pallidum, and negative for HSV-1, HSV-2, and VZV. Special stains for PAS, GMS, Fite, and AFB were negative for organisms. 

Syphilis, also known as Lues disease, is a contagious, sexually acquired disease caused by the spirochete T pallidum. The skin and mucous membranes are primarily infected. There are primary, secondary, and tertiary stages. In the primary or initial stage of syphilis, a chancre appears, usually 3-4 weeks after infection. The chancre is a painless papule or erosion that progresses to a firm ulceration. Lymphadenopathy may be present. Less often, multiple chancres may be present. Primary chancre on the finger has been reported in the literature, although it is far less common to have extragenital primary syphilis. The incidence ranges from 2% to 10%. Other extragenital areas that can be affected include lips, intraoral lesions, and the anus. Atypical chancres can be formed when other microbial agents are also present. Generally, an untreated chancre will heal spontaneously within a few months. 

The patient referred to the department of health for treatment with penicillin G and further workup of sexually transmitted diseases. He was also seen by infectious disease for treatment of the superimposed bacterial infections and treated with an antibiotic regimen. 



The case and photo were submitted by Dr. Bilu Martin.

 

Dr Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Florida. More diagnostic cases are available at mdedge.com/dermatology. To submit a case for possible publication, send an email to [email protected].

References

Ramoni S et al. Sex Transm Dis. 2010 Jul;37(7):468. doi: 10.1097/OLQ.0b013e3181e2cfac.

Starzycki Z. Br J Vener Dis. 1983 Jun;59(3):169-71. doi: 10.1136/sti.59.3.169.

As a doctor with a keen interest in myeloma who is looking ahead to the 2024 American Society of Hematology (ASH) annual meeting December 7-10 in San Diego, I’ve chosen 10 presentations that seem most likely to make the greatest impact on my thinking and practice.

First, let me place my selected studies in context by acknowledging my biases. As a clinician, I’m prone to choosing clinical rather than basic science or translational work — even if translational work might well end up exerting a pivotal impact on practice in the future. And now — in no particular order — here are my picks: 

 

IFM 2017-03 Phase 3 Study 

Frail patients are underrepresented in most myeloma studies, yet in this randomized trial for newly diagnosed myeloma, exclusively frail patients were enrolled. The trial compared daratumumab/lenalidomide to lenalidomide/dexamethasone, and the most recent follow/up shows a progression-free survival (PFS) (48.5 vs 21 months) and overall survival (OS) (not reached vs 36 months) benefit to daratumumab/lenalidomide. What I see in practice is that anti-CD38 monoclonal antibodies are the best-tolerated drugs in this space and should be the backbone of any regimen for frail patients. Steroids should be omitted as early as possible. Future trials may optimize what to give in addition to the anti-CD38 therapy, and how to adapt/escalate therapy to frailty and clinical status, as lenalidomide remains difficult for such patients to tolerate.

AQUILA Study 

This is a randomized, phase 3 comparison of daratumumab to observation for patients with smoldering myeloma. The endpoint was PFS. For context, similar studies done in asymptomatic CLL have shown improved PFS, but not OS, and the authors of such studies have concluded that improvement in PFS alone should not justify a change in approach.

This study shows that daratumumab can improve laboratory markers and reduce progression (60-month PFS rates of 63.1% for daratumumab vs 40.8% with observation). However, several important caveats remain. The protocol only mandated spine/pelvis MRI imaging, not whole-body MRI imaging, and such imaging was only performed once a year, which may not be frequent enough to catch lesions at an earlier stage. These details have important implications, as previous research shows that up to half of lesions can be missed by doing only a spine MRI, as opposed to a whole-body MRI. 

All of this means that had more comprehensive imaging been done, many more patients may have been diagnosed with myeloma. Such patients may have been undertreated, and single agent daratumumab, with a response rate of just 63%, may not have been enough. Conversely, some patients may also have been overtreated using this approach, as the protocol allowed patients who had been diagnosed with smoldering myeloma up to 5 years earlier to be enrolled. Many of these people could have had indolent disease for years prior to enrollment and may not have ever progressed. 

Further information is needed to help us understand this study better. What was the nature of the progression events: asymptomatic lab changes or morbid end organ damage? Was daratumumab given when patients in the control arm progressed to myeloma? My concern is that if patients in the control arm do not universally receive modern daratumumab-containing therapies when they develop myeloma, then an overall survival advantage may be shown simply because patients in the intervention arm are getting a good drug earlier in the disease, while those in the control arm are not getting a good drug at all. Nevertheless, despite these limitations, it is likely this trial will lead to regulatory approval of daratumumab in this space, and lots of discussions from patients and clinicians alike.

 

Extended Follow-Up of Anito-Cel in its First In-Human study 

Two chimeric antigen receptor therapy (CAR-T) products are currently approved for myeloma. Cilta-cel is clearly effective but is associated with problematic late-onset neurological toxicities. Ide-cel appears much less effective. There is clearly a need for a product that is both effective and safe.

Anito-cel has two relevant abstracts this meeting that show much promise. Extended follow-up of anito-cel from its first in human study shows a promising 27-month PFS of 52%, and with no cases of delayed neurotoxicity. I also eagerly await further information from the registrational single-arm study of anti-cel being presented at ASH 2024, which should (hopefully) lead to its accelerated approval.

 

Screening for Myeloma for all People With Vertebral Fractures Likely Unnecessary 

This elegant study of over 9,000 people with vertebral fractures shows that absolute risks for myeloma were 0.43% and 0.63% in women and men with grade 2-3 fractures, respectively, indicating that there is likely little benefit in evaluating asymptomatic individuals with incidentally discovered vertebral fractures for myeloma, unless other features are present. Spread the word.

Further Information on Cevostamab, Another Bispecific Option

We do need effective treatments for targets beyond just BCMA and GPRC5D. Cevostamab, a bispecific targeting FCRH5, represents another option, with updated data on 167 patients. With an overall response rate of 43% (duration of response, 10 months), and a response rate of about 30% in those with prior bispecific exposure, this data helps us contextualize expected benefits as we look forward to the eventual approval of this drug. The efficacy is relatively modest in those who have already progressed on bispecifics, but cevostamab would still be a welcome addition to our arsenal.

Is GPRC5D a Better Target for Car T Rather Than Bispecifics? 

Our currently available GPRC5D bispecific (talquetamab) leads to high rates of skin, oral, and nail toxicity. This drug can also bring significant weight loss. These side effects make me consider that continuous targeting of GPRC5D through a bispecific may not be ideal, and that GPRC5D may be better as a one-time CAR T target. At ASH 2024, we will have 15-month follow-up data from BMS-986393, a GPRC5D CAR T. Response rates for this heavily pretreated population (76% of whom had triple refractory disease) were at 87%, with a median PFS of 14.5 months. Only 6% of patients experienced treatment-related weight loss, and nail (19%), skin (30%), and oral (31%) toxicities were relatively low. I look forward to updated data, as well as data on the resolution of the toxicities seen.

Daratumumab, a Game-Changer for AL Amyloidosis 

A truly effective drug given early can change the natural history of disease, even if patients in the control arm only receive the drug later. A case in point is daratumumab. The 5-year survival rate was 76.1% for the daratumumab/cyclophosphamide/bortezomib/dexamethasone arm and 64.7% for cyclophosphamide/bortezomib/dexamethasone arm. This happened despite the fact that 67% of the control arm patients (among those who received therapy) went on to receive daratumumab later in the disease course.

Understanding how SMM Progresses to MM 

We often hear that we should treat SMM and not just watch carefully because fractures may suddenly happen, or a patient may end up on dialysis. What this retrospective study tells us that amongst 427 patients with SMM, 42 had progression to myeloma, and amongst those 42, only 1 developed renal dysfunction (unclear if this resolved), and only 1 had lytic lesions that were symptomatic. The remainder were all asymptomatic lab and imaging changes. This is a retrospective study, and one should assume that follow-up was thus highly variable. It does not appear that diffusion weighted whole-body MRI imaging (our most sensitive imaging test) was employed universally or very frequently. Nevertheless, these powerful findings reassure us that, with close observation, morbidity is unlikely. Our group has designed a prospective study incorporating frequent diffusion weighted whole body MRI imaging to formally test this hypothesis (SPOTLIGHT, NCT06212323). 

The Underperformance of Daratumumab/Lenalidomide/Dexamethasone in the Real World 

At every major meeting I am reminded of the disconnect between real-world efficacy and clinical trial efficacy. Case in point: In this Austrian experience, daratumumab/lenalidomide/dexamethasone led to a PFS of 22.7 months vs 61.9 months in the MAIA trial of daratumumab/lenalidomide/dexamethasone. Such a sobering difference! And if you think this is an isolated experience, even in a US real-world cohort, consider that in a recently published comparative study dara/len/dex underperformed, although the time to next treatment or death was longer (37.8 months).

Delayed Neurotoxicity may not be Just a Consequence of high tumor burden 

We currently think that some of the scariest side effects of cilta-cel, such as delayed neurotoxicity, may be a consequence of a high number of cancer cells and may be prevented by better disease control at the time of infusion. This study, a sobering analysis of 52 patients with delayed neurotoxicity occurring after CAR T, included 8 patients (15%) who were not heavily pretreated, and all had less than 5% plasma cells at the time of infusion. None of these patients had extramedullary disease. This result worries me, especially because cilta-cel is being studied and is poised for future approval in earlier line settings. It suggests that this toxicity may not always be a product of disease burden, contrary to our current belief.

I will be paying close attention to these 10 myeloma studies at ASH 2024, where I look forward to meeting you and learning more.Dr. Mohyuddin is assistant professor in the multiple myeloma program at the Huntsman Cancer Institute at the University of Utah, Salt Lake City.

As a doctor with a keen interest in myeloma who is looking ahead to the 2024 American Society of Hematology (ASH) annual meeting December 7-10 in San Diego, I’ve chosen 10 presentations that seem most likely to make the greatest impact on my thinking and practice.

First, let me place my selected studies in context by acknowledging my biases. As a clinician, I’m prone to choosing clinical rather than basic science or translational work — even if translational work might well end up exerting a pivotal impact on practice in the future. And now — in no particular order — here are my picks: 

 

IFM 2017-03 Phase 3 Study 

Frail patients are underrepresented in most myeloma studies, yet in this randomized trial for newly diagnosed myeloma, exclusively frail patients were enrolled. The trial compared daratumumab/lenalidomide to lenalidomide/dexamethasone, and the most recent follow/up shows a progression-free survival (PFS) (48.5 vs 21 months) and overall survival (OS) (not reached vs 36 months) benefit to daratumumab/lenalidomide. What I see in practice is that anti-CD38 monoclonal antibodies are the best-tolerated drugs in this space and should be the backbone of any regimen for frail patients. Steroids should be omitted as early as possible. Future trials may optimize what to give in addition to the anti-CD38 therapy, and how to adapt/escalate therapy to frailty and clinical status, as lenalidomide remains difficult for such patients to tolerate.

AQUILA Study 

This is a randomized, phase 3 comparison of daratumumab to observation for patients with smoldering myeloma. The endpoint was PFS. For context, similar studies done in asymptomatic CLL have shown improved PFS, but not OS, and the authors of such studies have concluded that improvement in PFS alone should not justify a change in approach.

This study shows that daratumumab can improve laboratory markers and reduce progression (60-month PFS rates of 63.1% for daratumumab vs 40.8% with observation). However, several important caveats remain. The protocol only mandated spine/pelvis MRI imaging, not whole-body MRI imaging, and such imaging was only performed once a year, which may not be frequent enough to catch lesions at an earlier stage. These details have important implications, as previous research shows that up to half of lesions can be missed by doing only a spine MRI, as opposed to a whole-body MRI. 

All of this means that had more comprehensive imaging been done, many more patients may have been diagnosed with myeloma. Such patients may have been undertreated, and single agent daratumumab, with a response rate of just 63%, may not have been enough. Conversely, some patients may also have been overtreated using this approach, as the protocol allowed patients who had been diagnosed with smoldering myeloma up to 5 years earlier to be enrolled. Many of these people could have had indolent disease for years prior to enrollment and may not have ever progressed. 

Further information is needed to help us understand this study better. What was the nature of the progression events: asymptomatic lab changes or morbid end organ damage? Was daratumumab given when patients in the control arm progressed to myeloma? My concern is that if patients in the control arm do not universally receive modern daratumumab-containing therapies when they develop myeloma, then an overall survival advantage may be shown simply because patients in the intervention arm are getting a good drug earlier in the disease, while those in the control arm are not getting a good drug at all. Nevertheless, despite these limitations, it is likely this trial will lead to regulatory approval of daratumumab in this space, and lots of discussions from patients and clinicians alike.

 

Extended Follow-Up of Anito-Cel in its First In-Human study 

Two chimeric antigen receptor therapy (CAR-T) products are currently approved for myeloma. Cilta-cel is clearly effective but is associated with problematic late-onset neurological toxicities. Ide-cel appears much less effective. There is clearly a need for a product that is both effective and safe.

Anito-cel has two relevant abstracts this meeting that show much promise. Extended follow-up of anito-cel from its first in human study shows a promising 27-month PFS of 52%, and with no cases of delayed neurotoxicity. I also eagerly await further information from the registrational single-arm study of anti-cel being presented at ASH 2024, which should (hopefully) lead to its accelerated approval.

 

Screening for Myeloma for all People With Vertebral Fractures Likely Unnecessary 

This elegant study of over 9,000 people with vertebral fractures shows that absolute risks for myeloma were 0.43% and 0.63% in women and men with grade 2-3 fractures, respectively, indicating that there is likely little benefit in evaluating asymptomatic individuals with incidentally discovered vertebral fractures for myeloma, unless other features are present. Spread the word.

Further Information on Cevostamab, Another Bispecific Option

We do need effective treatments for targets beyond just BCMA and GPRC5D. Cevostamab, a bispecific targeting FCRH5, represents another option, with updated data on 167 patients. With an overall response rate of 43% (duration of response, 10 months), and a response rate of about 30% in those with prior bispecific exposure, this data helps us contextualize expected benefits as we look forward to the eventual approval of this drug. The efficacy is relatively modest in those who have already progressed on bispecifics, but cevostamab would still be a welcome addition to our arsenal.

Is GPRC5D a Better Target for Car T Rather Than Bispecifics? 

Our currently available GPRC5D bispecific (talquetamab) leads to high rates of skin, oral, and nail toxicity. This drug can also bring significant weight loss. These side effects make me consider that continuous targeting of GPRC5D through a bispecific may not be ideal, and that GPRC5D may be better as a one-time CAR T target. At ASH 2024, we will have 15-month follow-up data from BMS-986393, a GPRC5D CAR T. Response rates for this heavily pretreated population (76% of whom had triple refractory disease) were at 87%, with a median PFS of 14.5 months. Only 6% of patients experienced treatment-related weight loss, and nail (19%), skin (30%), and oral (31%) toxicities were relatively low. I look forward to updated data, as well as data on the resolution of the toxicities seen.

Daratumumab, a Game-Changer for AL Amyloidosis 

A truly effective drug given early can change the natural history of disease, even if patients in the control arm only receive the drug later. A case in point is daratumumab. The 5-year survival rate was 76.1% for the daratumumab/cyclophosphamide/bortezomib/dexamethasone arm and 64.7% for cyclophosphamide/bortezomib/dexamethasone arm. This happened despite the fact that 67% of the control arm patients (among those who received therapy) went on to receive daratumumab later in the disease course.

Understanding how SMM Progresses to MM 

We often hear that we should treat SMM and not just watch carefully because fractures may suddenly happen, or a patient may end up on dialysis. What this retrospective study tells us that amongst 427 patients with SMM, 42 had progression to myeloma, and amongst those 42, only 1 developed renal dysfunction (unclear if this resolved), and only 1 had lytic lesions that were symptomatic. The remainder were all asymptomatic lab and imaging changes. This is a retrospective study, and one should assume that follow-up was thus highly variable. It does not appear that diffusion weighted whole-body MRI imaging (our most sensitive imaging test) was employed universally or very frequently. Nevertheless, these powerful findings reassure us that, with close observation, morbidity is unlikely. Our group has designed a prospective study incorporating frequent diffusion weighted whole body MRI imaging to formally test this hypothesis (SPOTLIGHT, NCT06212323). 

The Underperformance of Daratumumab/Lenalidomide/Dexamethasone in the Real World 

At every major meeting I am reminded of the disconnect between real-world efficacy and clinical trial efficacy. Case in point: In this Austrian experience, daratumumab/lenalidomide/dexamethasone led to a PFS of 22.7 months vs 61.9 months in the MAIA trial of daratumumab/lenalidomide/dexamethasone. Such a sobering difference! And if you think this is an isolated experience, even in a US real-world cohort, consider that in a recently published comparative study dara/len/dex underperformed, although the time to next treatment or death was longer (37.8 months).

Delayed Neurotoxicity may not be Just a Consequence of high tumor burden 

We currently think that some of the scariest side effects of cilta-cel, such as delayed neurotoxicity, may be a consequence of a high number of cancer cells and may be prevented by better disease control at the time of infusion. This study, a sobering analysis of 52 patients with delayed neurotoxicity occurring after CAR T, included 8 patients (15%) who were not heavily pretreated, and all had less than 5% plasma cells at the time of infusion. None of these patients had extramedullary disease. This result worries me, especially because cilta-cel is being studied and is poised for future approval in earlier line settings. It suggests that this toxicity may not always be a product of disease burden, contrary to our current belief.

I will be paying close attention to these 10 myeloma studies at ASH 2024, where I look forward to meeting you and learning more.Dr. Mohyuddin is assistant professor in the multiple myeloma program at the Huntsman Cancer Institute at the University of Utah, Salt Lake City.

As a doctor with a keen interest in myeloma who is looking ahead to the 2024 American Society of Hematology (ASH) annual meeting December 7-10 in San Diego, I’ve chosen 10 presentations that seem most likely to make the greatest impact on my thinking and practice.

First, let me place my selected studies in context by acknowledging my biases. As a clinician, I’m prone to choosing clinical rather than basic science or translational work — even if translational work might well end up exerting a pivotal impact on practice in the future. And now — in no particular order — here are my picks: 

 

IFM 2017-03 Phase 3 Study 

Frail patients are underrepresented in most myeloma studies, yet in this randomized trial for newly diagnosed myeloma, exclusively frail patients were enrolled. The trial compared daratumumab/lenalidomide to lenalidomide/dexamethasone, and the most recent follow/up shows a progression-free survival (PFS) (48.5 vs 21 months) and overall survival (OS) (not reached vs 36 months) benefit to daratumumab/lenalidomide. What I see in practice is that anti-CD38 monoclonal antibodies are the best-tolerated drugs in this space and should be the backbone of any regimen for frail patients. Steroids should be omitted as early as possible. Future trials may optimize what to give in addition to the anti-CD38 therapy, and how to adapt/escalate therapy to frailty and clinical status, as lenalidomide remains difficult for such patients to tolerate.

AQUILA Study 

This is a randomized, phase 3 comparison of daratumumab to observation for patients with smoldering myeloma. The endpoint was PFS. For context, similar studies done in asymptomatic CLL have shown improved PFS, but not OS, and the authors of such studies have concluded that improvement in PFS alone should not justify a change in approach.

This study shows that daratumumab can improve laboratory markers and reduce progression (60-month PFS rates of 63.1% for daratumumab vs 40.8% with observation). However, several important caveats remain. The protocol only mandated spine/pelvis MRI imaging, not whole-body MRI imaging, and such imaging was only performed once a year, which may not be frequent enough to catch lesions at an earlier stage. These details have important implications, as previous research shows that up to half of lesions can be missed by doing only a spine MRI, as opposed to a whole-body MRI. 

All of this means that had more comprehensive imaging been done, many more patients may have been diagnosed with myeloma. Such patients may have been undertreated, and single agent daratumumab, with a response rate of just 63%, may not have been enough. Conversely, some patients may also have been overtreated using this approach, as the protocol allowed patients who had been diagnosed with smoldering myeloma up to 5 years earlier to be enrolled. Many of these people could have had indolent disease for years prior to enrollment and may not have ever progressed. 

Further information is needed to help us understand this study better. What was the nature of the progression events: asymptomatic lab changes or morbid end organ damage? Was daratumumab given when patients in the control arm progressed to myeloma? My concern is that if patients in the control arm do not universally receive modern daratumumab-containing therapies when they develop myeloma, then an overall survival advantage may be shown simply because patients in the intervention arm are getting a good drug earlier in the disease, while those in the control arm are not getting a good drug at all. Nevertheless, despite these limitations, it is likely this trial will lead to regulatory approval of daratumumab in this space, and lots of discussions from patients and clinicians alike.

 

Extended Follow-Up of Anito-Cel in its First In-Human study 

Two chimeric antigen receptor therapy (CAR-T) products are currently approved for myeloma. Cilta-cel is clearly effective but is associated with problematic late-onset neurological toxicities. Ide-cel appears much less effective. There is clearly a need for a product that is both effective and safe.

Anito-cel has two relevant abstracts this meeting that show much promise. Extended follow-up of anito-cel from its first in human study shows a promising 27-month PFS of 52%, and with no cases of delayed neurotoxicity. I also eagerly await further information from the registrational single-arm study of anti-cel being presented at ASH 2024, which should (hopefully) lead to its accelerated approval.

 

Screening for Myeloma for all People With Vertebral Fractures Likely Unnecessary 

This elegant study of over 9,000 people with vertebral fractures shows that absolute risks for myeloma were 0.43% and 0.63% in women and men with grade 2-3 fractures, respectively, indicating that there is likely little benefit in evaluating asymptomatic individuals with incidentally discovered vertebral fractures for myeloma, unless other features are present. Spread the word.

Further Information on Cevostamab, Another Bispecific Option

We do need effective treatments for targets beyond just BCMA and GPRC5D. Cevostamab, a bispecific targeting FCRH5, represents another option, with updated data on 167 patients. With an overall response rate of 43% (duration of response, 10 months), and a response rate of about 30% in those with prior bispecific exposure, this data helps us contextualize expected benefits as we look forward to the eventual approval of this drug. The efficacy is relatively modest in those who have already progressed on bispecifics, but cevostamab would still be a welcome addition to our arsenal.

Is GPRC5D a Better Target for Car T Rather Than Bispecifics? 

Our currently available GPRC5D bispecific (talquetamab) leads to high rates of skin, oral, and nail toxicity. This drug can also bring significant weight loss. These side effects make me consider that continuous targeting of GPRC5D through a bispecific may not be ideal, and that GPRC5D may be better as a one-time CAR T target. At ASH 2024, we will have 15-month follow-up data from BMS-986393, a GPRC5D CAR T. Response rates for this heavily pretreated population (76% of whom had triple refractory disease) were at 87%, with a median PFS of 14.5 months. Only 6% of patients experienced treatment-related weight loss, and nail (19%), skin (30%), and oral (31%) toxicities were relatively low. I look forward to updated data, as well as data on the resolution of the toxicities seen.

Daratumumab, a Game-Changer for AL Amyloidosis 

A truly effective drug given early can change the natural history of disease, even if patients in the control arm only receive the drug later. A case in point is daratumumab. The 5-year survival rate was 76.1% for the daratumumab/cyclophosphamide/bortezomib/dexamethasone arm and 64.7% for cyclophosphamide/bortezomib/dexamethasone arm. This happened despite the fact that 67% of the control arm patients (among those who received therapy) went on to receive daratumumab later in the disease course.

Understanding how SMM Progresses to MM 

We often hear that we should treat SMM and not just watch carefully because fractures may suddenly happen, or a patient may end up on dialysis. What this retrospective study tells us that amongst 427 patients with SMM, 42 had progression to myeloma, and amongst those 42, only 1 developed renal dysfunction (unclear if this resolved), and only 1 had lytic lesions that were symptomatic. The remainder were all asymptomatic lab and imaging changes. This is a retrospective study, and one should assume that follow-up was thus highly variable. It does not appear that diffusion weighted whole-body MRI imaging (our most sensitive imaging test) was employed universally or very frequently. Nevertheless, these powerful findings reassure us that, with close observation, morbidity is unlikely. Our group has designed a prospective study incorporating frequent diffusion weighted whole body MRI imaging to formally test this hypothesis (SPOTLIGHT, NCT06212323). 

The Underperformance of Daratumumab/Lenalidomide/Dexamethasone in the Real World 

At every major meeting I am reminded of the disconnect between real-world efficacy and clinical trial efficacy. Case in point: In this Austrian experience, daratumumab/lenalidomide/dexamethasone led to a PFS of 22.7 months vs 61.9 months in the MAIA trial of daratumumab/lenalidomide/dexamethasone. Such a sobering difference! And if you think this is an isolated experience, even in a US real-world cohort, consider that in a recently published comparative study dara/len/dex underperformed, although the time to next treatment or death was longer (37.8 months).

Delayed Neurotoxicity may not be Just a Consequence of high tumor burden 

We currently think that some of the scariest side effects of cilta-cel, such as delayed neurotoxicity, may be a consequence of a high number of cancer cells and may be prevented by better disease control at the time of infusion. This study, a sobering analysis of 52 patients with delayed neurotoxicity occurring after CAR T, included 8 patients (15%) who were not heavily pretreated, and all had less than 5% plasma cells at the time of infusion. None of these patients had extramedullary disease. This result worries me, especially because cilta-cel is being studied and is poised for future approval in earlier line settings. It suggests that this toxicity may not always be a product of disease burden, contrary to our current belief.

I will be paying close attention to these 10 myeloma studies at ASH 2024, where I look forward to meeting you and learning more.Dr. Mohyuddin is assistant professor in the multiple myeloma program at the Huntsman Cancer Institute at the University of Utah, Salt Lake City.

Summary and Key Highlights

Summary: This section explores why physicians often struggle to recognize burnout within themselves, partly due to stigma and a tendency to focus on productivity over well-being. Dr. Tyra Fainstad shares personal experiences of burnout symptoms, emphasizing the importance of awareness and self-reflection. Recognizing and addressing burnout early can help physicians find healthier coping strategies, avoid productivity traps, and seek support.

Key Takeaways:

• Many physicians struggle to identify burnout due to stigma and self-blame.
• Awareness of burnout symptoms is essential for early intervention and healthy coping.
• Seeking support can prevent burnout from worsening and improve quality of life.

Our Editors Also Recommend: 

Medscape Physician Burnout & Depression Report 2024: ‘We Have Much Work to Do’

Medscape Hospitalist Burnout & Depression Report 2024: Seeking Progress, Balance 

Medscape Physician Lifestyle & Happiness Report 2024: The Ongoing Struggle for Balance 

A Transformative Rx for Burnout, Grief, and Illness: Dance 

 

Next Medscape Masters Event:

Stay at the forefront of obesity care. Register for exclusive insights and the latest treatment innovations.

Lotte Dyrbye, has disclosed the following relevant financial relationships: Co-inventor of the Well-being Index and its derivatives, which Mayo Clinic has licensed. Dyrbye receives royalties.

A version of this article first appeared on Medscape.com.

Summary and Key Highlights

Summary: This section explores why physicians often struggle to recognize burnout within themselves, partly due to stigma and a tendency to focus on productivity over well-being. Dr. Tyra Fainstad shares personal experiences of burnout symptoms, emphasizing the importance of awareness and self-reflection. Recognizing and addressing burnout early can help physicians find healthier coping strategies, avoid productivity traps, and seek support.

Key Takeaways:

• Many physicians struggle to identify burnout due to stigma and self-blame.
• Awareness of burnout symptoms is essential for early intervention and healthy coping.
• Seeking support can prevent burnout from worsening and improve quality of life.

Our Editors Also Recommend: 

Medscape Physician Burnout & Depression Report 2024: ‘We Have Much Work to Do’

Medscape Hospitalist Burnout & Depression Report 2024: Seeking Progress, Balance 

Medscape Physician Lifestyle & Happiness Report 2024: The Ongoing Struggle for Balance 

A Transformative Rx for Burnout, Grief, and Illness: Dance 

 

Next Medscape Masters Event:

Stay at the forefront of obesity care. Register for exclusive insights and the latest treatment innovations.

Lotte Dyrbye, has disclosed the following relevant financial relationships: Co-inventor of the Well-being Index and its derivatives, which Mayo Clinic has licensed. Dyrbye receives royalties.

A version of this article first appeared on Medscape.com.

Summary and Key Highlights

Summary: This section explores why physicians often struggle to recognize burnout within themselves, partly due to stigma and a tendency to focus on productivity over well-being. Dr. Tyra Fainstad shares personal experiences of burnout symptoms, emphasizing the importance of awareness and self-reflection. Recognizing and addressing burnout early can help physicians find healthier coping strategies, avoid productivity traps, and seek support.

Key Takeaways:

• Many physicians struggle to identify burnout due to stigma and self-blame.
• Awareness of burnout symptoms is essential for early intervention and healthy coping.
• Seeking support can prevent burnout from worsening and improve quality of life.

Our Editors Also Recommend: 

Medscape Physician Burnout & Depression Report 2024: ‘We Have Much Work to Do’

Medscape Hospitalist Burnout & Depression Report 2024: Seeking Progress, Balance 

Medscape Physician Lifestyle & Happiness Report 2024: The Ongoing Struggle for Balance 

A Transformative Rx for Burnout, Grief, and Illness: Dance 

 

Next Medscape Masters Event:

Stay at the forefront of obesity care. Register for exclusive insights and the latest treatment innovations.

Lotte Dyrbye, has disclosed the following relevant financial relationships: Co-inventor of the Well-being Index and its derivatives, which Mayo Clinic has licensed. Dyrbye receives royalties.

A version of this article first appeared on Medscape.com.

Summary and Key Highlights

Summary: Dr Tyra Fainstad explores the ingrained culture in medicine that encourages self-criticism, with many physicians feeling that they must be hard on themselves to succeed. Dr Fainstad challenges this belief, advocating for self-compassion as a healthier alternative. The evolving medical field now includes physicians who prioritize well-being without sacrificing quality of care, underscoring the importance of self-kindness for sustainable practice.

Key Takeaways:

• Many physicians believe that self-criticism is necessary for success, a mindset rooted in medical culture.
• Practicing self-compassion can improve long-term resilience and prevent burnout.
• The changing landscape of healthcare supports a more balanced approach to physician well-being.

Our Editors Also Recommend: 

Medscape Physician Burnout & Depression Report 2024: ‘We Have Much Work to Do’

Medscape Hospitalist Burnout & Depression Report 2024: Seeking Progress, Balance 

Medscape Physician Lifestyle & Happiness Report 2024: The Ongoing Struggle for Balance 

A Transformative Rx for Burnout, Grief, and Illness: Dance 

 

Next Medscape Masters Event:

Stay at the forefront of obesity care. Register for exclusive insights and the latest treatment innovations. 

Lotte Dyrbye, has disclosed the following relevant financial relationships: Co-inventor of the Well-being Index and its derivatives, which Mayo Clinic has licensed. Dyrbye receives royalties.

A version of this article first appeared on Medscape.com.

Summary and Key Highlights

Summary: Dr Tyra Fainstad explores the ingrained culture in medicine that encourages self-criticism, with many physicians feeling that they must be hard on themselves to succeed. Dr Fainstad challenges this belief, advocating for self-compassion as a healthier alternative. The evolving medical field now includes physicians who prioritize well-being without sacrificing quality of care, underscoring the importance of self-kindness for sustainable practice.

Key Takeaways:

• Many physicians believe that self-criticism is necessary for success, a mindset rooted in medical culture.
• Practicing self-compassion can improve long-term resilience and prevent burnout.
• The changing landscape of healthcare supports a more balanced approach to physician well-being.

Our Editors Also Recommend: 

Medscape Physician Burnout & Depression Report 2024: ‘We Have Much Work to Do’

Medscape Hospitalist Burnout & Depression Report 2024: Seeking Progress, Balance 

Medscape Physician Lifestyle & Happiness Report 2024: The Ongoing Struggle for Balance 

A Transformative Rx for Burnout, Grief, and Illness: Dance 

 

Next Medscape Masters Event:

Stay at the forefront of obesity care. Register for exclusive insights and the latest treatment innovations. 

Lotte Dyrbye, has disclosed the following relevant financial relationships: Co-inventor of the Well-being Index and its derivatives, which Mayo Clinic has licensed. Dyrbye receives royalties.

A version of this article first appeared on Medscape.com.

Summary and Key Highlights

Summary: Dr Tyra Fainstad explores the ingrained culture in medicine that encourages self-criticism, with many physicians feeling that they must be hard on themselves to succeed. Dr Fainstad challenges this belief, advocating for self-compassion as a healthier alternative. The evolving medical field now includes physicians who prioritize well-being without sacrificing quality of care, underscoring the importance of self-kindness for sustainable practice.

Key Takeaways:

• Many physicians believe that self-criticism is necessary for success, a mindset rooted in medical culture.
• Practicing self-compassion can improve long-term resilience and prevent burnout.
• The changing landscape of healthcare supports a more balanced approach to physician well-being.

Our Editors Also Recommend: 

Medscape Physician Burnout & Depression Report 2024: ‘We Have Much Work to Do’

Medscape Hospitalist Burnout & Depression Report 2024: Seeking Progress, Balance 

Medscape Physician Lifestyle & Happiness Report 2024: The Ongoing Struggle for Balance 

A Transformative Rx for Burnout, Grief, and Illness: Dance 

 

Next Medscape Masters Event:

Stay at the forefront of obesity care. Register for exclusive insights and the latest treatment innovations. 

Lotte Dyrbye, has disclosed the following relevant financial relationships: Co-inventor of the Well-being Index and its derivatives, which Mayo Clinic has licensed. Dyrbye receives royalties.

A version of this article first appeared on Medscape.com.