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Promising first results with DNA editing to lower LDL
PHILADELPHIA –
While one of four patients in the highest-dose groups had a myocardial infarction the day after getting the treatment, investigators have enough confidence to go forward with the next phase of study.
“The HEART-1trial demonstrated the first human proof of concept for in vivo DNA-based editing,” said Andrew Bellinger, MD, PhD, chief scientific officer of Verve Therapeutics, the company developing the treatment. “We saw dose-dependent–based reductions in LDL and the PCSK9 protein.”
The HEART-1 study was a phase 1b trial of VERVE-101, a CRISPR-based gene editing mechanism designed to inactivate the liver gene PCSK9, which contributes to raising cholesterol. “Human genetics suggest that turning off the cholesterol-raising gene PCSK9 in the liver will durably reduce LDL cholesterol,” Dr. Bellinger said in presenting the results at the annual scientific sessions of the American Heart Association.
Lipid nanoparticle
VERVE-101 is designed to be a single-course treatment to specifically treat HeFH, Dr. Bellinger said. He explained how the therapy, given by intravenous infusion, differs from adeno-associated virus vectors that have dominated gene therapy platforms.
“It’s a lipid nanoparticle encapsulating two RNA nanoparticles that are taken up by hepatocytes in the liver from the blood by the LDL receptor,” he explained. “Then the A-to-G–based editor protein and the guide mRNA protein together find the PCSK9 gene in the liver.” That single DNA-base change in one position of the PCSK9 gene is able to turn off PCSK9 production in those liver cells.
Dr. Bellinger presented interim results of the first 10 patients treated in the open-label, single ascending dose study. The patients were male and female, ages 18-75, with HeFH, established atherosclerotic cardiovascular disease and uncontrolled hypercholesterolemia despite being on maximally tolerated lipid-lowering therapy.
They received four different doses: Three patients each received 0.1, 0.3, and 0.45 mg/kg; and one patient received 0.6 mg/kg.
Reductions in blood PCSK9 levels were measured across all dosing groups at 4 weeks, but they were most pronounced in the two highest groups, Dr. Bellinger said. Two patients in the 0.45-mg/kg group had reductions of 59% and 84%. The sole patient in the 0.6-mg/kg arm had a reduction of 47%.
Regarding the 84% reduction in one individual, Dr. Bellinger said, “Roughly 85% of PCSK9 comes from the liver. These data suggest that we have successfully made a single base pair change in both copies of the PCSK9 gene in nearly every hepatocyte in the liver of this individual.”
Those benefits carried over to LDL cholesterol measures, with the highest-dose patients registering 39%, 48% and 55% reductions.
Safety outcomes
Two patients had serious cardiovascular (CV) events. One in the 0.3-mg/kg arm died from cardiac arrest 5 weeks after receiving the infusion. A patient in the 0.45-mg/kg arm had a myocardial infarction a day after getting the infusion and then nonsustained ventricular tachycardia (NSVT) 4 weeks later. Dr. Bellinger said an independent review panel determined that the CV events were in line with outcomes for high-risk patients and weren’t directly related to treatment.
He added, “Increased liver transaminases were seen in patients treated in the higher-dose cohorts. It’s transient, asymptomatic, and it resolved quickly.”
The next step involves pursuing only the 0.45- and 0.6-mg/kg doses in the next dose-escalation phase and enrolling an expansion cohort in 2024, Dr. Bellinger said, with a plan to initiate a randomized, placebo-controlled phase 2 trial in 2025.
First, do no harm
Karol Watson, MD, PhD, a women’s cardiovascular disease specialist at UCLA, said the promise of gene therapy was “revolutionary,” but that proving safety was critical going forward.
“You’re changing the genome forever,” she said. “Safety is going to be of the utmost importance especially because there are currently safe and efficacious strategies available for lipid lowering. This is a strategy that could be revolutionary, but we have to make sure that it’s safe.”
She pointed to a multinational study from earlier this year that warned about pathogenic consequences from CRISPR-based gene editing. “There are concerns about gene editing,” Dr. Watson said. “This was a whole-genome analysis showing atypical nonhomologous on-target effects of genome editing. Of course this is a very different strategy from what we heard today, but, again, we have to know that this is safe.”
Despite the small sample size from the two highest-dose groups in the study, Dr. Watson said the investigators have reason for going forward. “I think the preclinical data supports moving forward, but the next studies will have to be scrutinized carefully,” she said. “This is a preventive therapy; the first tenet is to do no harm.”
Dr. Bellinger is an employee of Verve Therapeutics, which sponsored the trial. Dr. Watson disclosed relationships with Boehringer-Ingelheim, Amgen, Lilly and Novartis.
PHILADELPHIA –
While one of four patients in the highest-dose groups had a myocardial infarction the day after getting the treatment, investigators have enough confidence to go forward with the next phase of study.
“The HEART-1trial demonstrated the first human proof of concept for in vivo DNA-based editing,” said Andrew Bellinger, MD, PhD, chief scientific officer of Verve Therapeutics, the company developing the treatment. “We saw dose-dependent–based reductions in LDL and the PCSK9 protein.”
The HEART-1 study was a phase 1b trial of VERVE-101, a CRISPR-based gene editing mechanism designed to inactivate the liver gene PCSK9, which contributes to raising cholesterol. “Human genetics suggest that turning off the cholesterol-raising gene PCSK9 in the liver will durably reduce LDL cholesterol,” Dr. Bellinger said in presenting the results at the annual scientific sessions of the American Heart Association.
Lipid nanoparticle
VERVE-101 is designed to be a single-course treatment to specifically treat HeFH, Dr. Bellinger said. He explained how the therapy, given by intravenous infusion, differs from adeno-associated virus vectors that have dominated gene therapy platforms.
“It’s a lipid nanoparticle encapsulating two RNA nanoparticles that are taken up by hepatocytes in the liver from the blood by the LDL receptor,” he explained. “Then the A-to-G–based editor protein and the guide mRNA protein together find the PCSK9 gene in the liver.” That single DNA-base change in one position of the PCSK9 gene is able to turn off PCSK9 production in those liver cells.
Dr. Bellinger presented interim results of the first 10 patients treated in the open-label, single ascending dose study. The patients were male and female, ages 18-75, with HeFH, established atherosclerotic cardiovascular disease and uncontrolled hypercholesterolemia despite being on maximally tolerated lipid-lowering therapy.
They received four different doses: Three patients each received 0.1, 0.3, and 0.45 mg/kg; and one patient received 0.6 mg/kg.
Reductions in blood PCSK9 levels were measured across all dosing groups at 4 weeks, but they were most pronounced in the two highest groups, Dr. Bellinger said. Two patients in the 0.45-mg/kg group had reductions of 59% and 84%. The sole patient in the 0.6-mg/kg arm had a reduction of 47%.
Regarding the 84% reduction in one individual, Dr. Bellinger said, “Roughly 85% of PCSK9 comes from the liver. These data suggest that we have successfully made a single base pair change in both copies of the PCSK9 gene in nearly every hepatocyte in the liver of this individual.”
Those benefits carried over to LDL cholesterol measures, with the highest-dose patients registering 39%, 48% and 55% reductions.
Safety outcomes
Two patients had serious cardiovascular (CV) events. One in the 0.3-mg/kg arm died from cardiac arrest 5 weeks after receiving the infusion. A patient in the 0.45-mg/kg arm had a myocardial infarction a day after getting the infusion and then nonsustained ventricular tachycardia (NSVT) 4 weeks later. Dr. Bellinger said an independent review panel determined that the CV events were in line with outcomes for high-risk patients and weren’t directly related to treatment.
He added, “Increased liver transaminases were seen in patients treated in the higher-dose cohorts. It’s transient, asymptomatic, and it resolved quickly.”
The next step involves pursuing only the 0.45- and 0.6-mg/kg doses in the next dose-escalation phase and enrolling an expansion cohort in 2024, Dr. Bellinger said, with a plan to initiate a randomized, placebo-controlled phase 2 trial in 2025.
First, do no harm
Karol Watson, MD, PhD, a women’s cardiovascular disease specialist at UCLA, said the promise of gene therapy was “revolutionary,” but that proving safety was critical going forward.
“You’re changing the genome forever,” she said. “Safety is going to be of the utmost importance especially because there are currently safe and efficacious strategies available for lipid lowering. This is a strategy that could be revolutionary, but we have to make sure that it’s safe.”
She pointed to a multinational study from earlier this year that warned about pathogenic consequences from CRISPR-based gene editing. “There are concerns about gene editing,” Dr. Watson said. “This was a whole-genome analysis showing atypical nonhomologous on-target effects of genome editing. Of course this is a very different strategy from what we heard today, but, again, we have to know that this is safe.”
Despite the small sample size from the two highest-dose groups in the study, Dr. Watson said the investigators have reason for going forward. “I think the preclinical data supports moving forward, but the next studies will have to be scrutinized carefully,” she said. “This is a preventive therapy; the first tenet is to do no harm.”
Dr. Bellinger is an employee of Verve Therapeutics, which sponsored the trial. Dr. Watson disclosed relationships with Boehringer-Ingelheim, Amgen, Lilly and Novartis.
PHILADELPHIA –
While one of four patients in the highest-dose groups had a myocardial infarction the day after getting the treatment, investigators have enough confidence to go forward with the next phase of study.
“The HEART-1trial demonstrated the first human proof of concept for in vivo DNA-based editing,” said Andrew Bellinger, MD, PhD, chief scientific officer of Verve Therapeutics, the company developing the treatment. “We saw dose-dependent–based reductions in LDL and the PCSK9 protein.”
The HEART-1 study was a phase 1b trial of VERVE-101, a CRISPR-based gene editing mechanism designed to inactivate the liver gene PCSK9, which contributes to raising cholesterol. “Human genetics suggest that turning off the cholesterol-raising gene PCSK9 in the liver will durably reduce LDL cholesterol,” Dr. Bellinger said in presenting the results at the annual scientific sessions of the American Heart Association.
Lipid nanoparticle
VERVE-101 is designed to be a single-course treatment to specifically treat HeFH, Dr. Bellinger said. He explained how the therapy, given by intravenous infusion, differs from adeno-associated virus vectors that have dominated gene therapy platforms.
“It’s a lipid nanoparticle encapsulating two RNA nanoparticles that are taken up by hepatocytes in the liver from the blood by the LDL receptor,” he explained. “Then the A-to-G–based editor protein and the guide mRNA protein together find the PCSK9 gene in the liver.” That single DNA-base change in one position of the PCSK9 gene is able to turn off PCSK9 production in those liver cells.
Dr. Bellinger presented interim results of the first 10 patients treated in the open-label, single ascending dose study. The patients were male and female, ages 18-75, with HeFH, established atherosclerotic cardiovascular disease and uncontrolled hypercholesterolemia despite being on maximally tolerated lipid-lowering therapy.
They received four different doses: Three patients each received 0.1, 0.3, and 0.45 mg/kg; and one patient received 0.6 mg/kg.
Reductions in blood PCSK9 levels were measured across all dosing groups at 4 weeks, but they were most pronounced in the two highest groups, Dr. Bellinger said. Two patients in the 0.45-mg/kg group had reductions of 59% and 84%. The sole patient in the 0.6-mg/kg arm had a reduction of 47%.
Regarding the 84% reduction in one individual, Dr. Bellinger said, “Roughly 85% of PCSK9 comes from the liver. These data suggest that we have successfully made a single base pair change in both copies of the PCSK9 gene in nearly every hepatocyte in the liver of this individual.”
Those benefits carried over to LDL cholesterol measures, with the highest-dose patients registering 39%, 48% and 55% reductions.
Safety outcomes
Two patients had serious cardiovascular (CV) events. One in the 0.3-mg/kg arm died from cardiac arrest 5 weeks after receiving the infusion. A patient in the 0.45-mg/kg arm had a myocardial infarction a day after getting the infusion and then nonsustained ventricular tachycardia (NSVT) 4 weeks later. Dr. Bellinger said an independent review panel determined that the CV events were in line with outcomes for high-risk patients and weren’t directly related to treatment.
He added, “Increased liver transaminases were seen in patients treated in the higher-dose cohorts. It’s transient, asymptomatic, and it resolved quickly.”
The next step involves pursuing only the 0.45- and 0.6-mg/kg doses in the next dose-escalation phase and enrolling an expansion cohort in 2024, Dr. Bellinger said, with a plan to initiate a randomized, placebo-controlled phase 2 trial in 2025.
First, do no harm
Karol Watson, MD, PhD, a women’s cardiovascular disease specialist at UCLA, said the promise of gene therapy was “revolutionary,” but that proving safety was critical going forward.
“You’re changing the genome forever,” she said. “Safety is going to be of the utmost importance especially because there are currently safe and efficacious strategies available for lipid lowering. This is a strategy that could be revolutionary, but we have to make sure that it’s safe.”
She pointed to a multinational study from earlier this year that warned about pathogenic consequences from CRISPR-based gene editing. “There are concerns about gene editing,” Dr. Watson said. “This was a whole-genome analysis showing atypical nonhomologous on-target effects of genome editing. Of course this is a very different strategy from what we heard today, but, again, we have to know that this is safe.”
Despite the small sample size from the two highest-dose groups in the study, Dr. Watson said the investigators have reason for going forward. “I think the preclinical data supports moving forward, but the next studies will have to be scrutinized carefully,” she said. “This is a preventive therapy; the first tenet is to do no harm.”
Dr. Bellinger is an employee of Verve Therapeutics, which sponsored the trial. Dr. Watson disclosed relationships with Boehringer-Ingelheim, Amgen, Lilly and Novartis.
AT AHA 2023
AI-ECG gets STEMI patients to cath lab sooner
PHILADELPHIA – An artificial intelligence platform that sends alerts based on electrocardiography results enabled cardiologists and emergency department physicians at a major hospital in Taiwan to move patients with ST-elevation myocardial infarction (STEMI) into the catheterization laboratory 9 minutes sooner than the conventional protocol that did not use AI.
“This is the first randomized clinical trial to demonstrate the reduction of electrocardiography to coronary cath lab activation time" from 52.3 to 43.3 minutes (P = .003), Chin Sheng Lin, MD, PhD, director of cardiology at the National Defense Medical Center Tri-Service General Hospital in Taipei City, said in presenting the results at the American Heart Association scientific sessions.
Dr. Lin reported results from the Artificial Intelligence Enabled Rapid Identify of ST-Elevation Myocardial Infarction Using Electrocardiogram (ARISE) trial. The trial included 43,994 patients who came to the hospital’s emergency and inpatient departments with at least one ECG but no history of coronary angiography (CAG) in the previous 3 days between May 2022 and April 2023.
They were randomly assigned by date to either AI-ECG for rapid identification and triage of STEMI or standard care. Overall, 145 patients were finally diagnosed with STEMI based on CAG, 77 in the intervention group and 68 in the control group. All patients were seen by one of 20 cardiologists who participated in the study.
Dr. Lin and his group developed an AI algorithm that captures the ECG readout in the emergency department, analyzes the data and then sends a high-risk alarm to the front-line physician and on-duty cardiologist to activate the primary percutaneous coronary intervention (PCI).
Trial results
The differentiation between groups was even more pronounced in ED patients during regular working hours, Dr. Lin said, at 61.6 minutes for the intervention group vs. 33.1 minutes for controls (P = .001).*
He noted that the AI group showed a trend towards fewer cases of clinically suspected STEMI but not getting CAG, 6.5% vs. 15.8%, for an odds ratio of 0.37 (95% confidence interval, 0.14-0.94).
The AI-ECG model also demonstrated a high diagnostic accuracy. “With this AI-ECG system, because it has a very high accuracy and a high positive predictive variable that reach 88%, we can send a message to the on-duty cardiologists and also the emergency room physician and they can send the patients to receive the operation or the PCI as soon as possible,” Dr. Lin said in an interview.
The time differential is critical, Dr. Lin said. “For the patient with acute myocardial infarction, 1 minute is critical, because the patients can die within minutes,” he said. “If we can save 9 minutes I think we can save more lives, but it needs a larger study to evaluate that.”
Dr. Lin acknowledged a few limitations with the trial, among them its single-center nature, relatively small sample size of STEMI patients and the short-term of follow-up. Future study should involve multiple centers along with a prehospital, emergency medical services AI-ECG model.
‘Novel’ for an AI trial
“This is an incredible application of an AI technology in a real-world problem,” said Brahmajee K. Nallamothu, MD, MPH, an interventional cardiologist at the University of Michigan, Ann Arbor, who did not participate in the study. “What I really love about this study is it’s actually a clinical problem that has large implications, particularly for under-resourced areas.”
Using a randomized clinical trial to evaluate the AI platform is “very, very novel,” he said, and called the time improvement “enormous.” Referencing Dr. Lin’s next steps for studying the AI-ECG platform, Dr. Nallamothu said, “if we could push this up even earlier to paramedics and EMTs and prehospital systems, there would be a lot of excitement there.”
He noted the sensitivity analysis resulted in a rate of 88.8% along with the positive predictive value of 88%. “Missing 1 out of 10 ST-elevation MIs in my eyes can still be considered a big deal, so we need to know if this is happening in particular types of patients, for example women versus men, or other groups.”
However, some investigations reported false activation rates as high as 33%, he said. “So, to say that, the positive predictive value is at 88% is really exciting and I think it can make a real inroads,” Dr. Nallamothu said.
Dr. Lin and Dr. Nallamothu have no relevant disclosures.
*Correction, 11/20/23: An earlier version of this article misstated in both trial arms the time to coronary catheterization lab activation.
PHILADELPHIA – An artificial intelligence platform that sends alerts based on electrocardiography results enabled cardiologists and emergency department physicians at a major hospital in Taiwan to move patients with ST-elevation myocardial infarction (STEMI) into the catheterization laboratory 9 minutes sooner than the conventional protocol that did not use AI.
“This is the first randomized clinical trial to demonstrate the reduction of electrocardiography to coronary cath lab activation time" from 52.3 to 43.3 minutes (P = .003), Chin Sheng Lin, MD, PhD, director of cardiology at the National Defense Medical Center Tri-Service General Hospital in Taipei City, said in presenting the results at the American Heart Association scientific sessions.
Dr. Lin reported results from the Artificial Intelligence Enabled Rapid Identify of ST-Elevation Myocardial Infarction Using Electrocardiogram (ARISE) trial. The trial included 43,994 patients who came to the hospital’s emergency and inpatient departments with at least one ECG but no history of coronary angiography (CAG) in the previous 3 days between May 2022 and April 2023.
They were randomly assigned by date to either AI-ECG for rapid identification and triage of STEMI or standard care. Overall, 145 patients were finally diagnosed with STEMI based on CAG, 77 in the intervention group and 68 in the control group. All patients were seen by one of 20 cardiologists who participated in the study.
Dr. Lin and his group developed an AI algorithm that captures the ECG readout in the emergency department, analyzes the data and then sends a high-risk alarm to the front-line physician and on-duty cardiologist to activate the primary percutaneous coronary intervention (PCI).
Trial results
The differentiation between groups was even more pronounced in ED patients during regular working hours, Dr. Lin said, at 61.6 minutes for the intervention group vs. 33.1 minutes for controls (P = .001).*
He noted that the AI group showed a trend towards fewer cases of clinically suspected STEMI but not getting CAG, 6.5% vs. 15.8%, for an odds ratio of 0.37 (95% confidence interval, 0.14-0.94).
The AI-ECG model also demonstrated a high diagnostic accuracy. “With this AI-ECG system, because it has a very high accuracy and a high positive predictive variable that reach 88%, we can send a message to the on-duty cardiologists and also the emergency room physician and they can send the patients to receive the operation or the PCI as soon as possible,” Dr. Lin said in an interview.
The time differential is critical, Dr. Lin said. “For the patient with acute myocardial infarction, 1 minute is critical, because the patients can die within minutes,” he said. “If we can save 9 minutes I think we can save more lives, but it needs a larger study to evaluate that.”
Dr. Lin acknowledged a few limitations with the trial, among them its single-center nature, relatively small sample size of STEMI patients and the short-term of follow-up. Future study should involve multiple centers along with a prehospital, emergency medical services AI-ECG model.
‘Novel’ for an AI trial
“This is an incredible application of an AI technology in a real-world problem,” said Brahmajee K. Nallamothu, MD, MPH, an interventional cardiologist at the University of Michigan, Ann Arbor, who did not participate in the study. “What I really love about this study is it’s actually a clinical problem that has large implications, particularly for under-resourced areas.”
Using a randomized clinical trial to evaluate the AI platform is “very, very novel,” he said, and called the time improvement “enormous.” Referencing Dr. Lin’s next steps for studying the AI-ECG platform, Dr. Nallamothu said, “if we could push this up even earlier to paramedics and EMTs and prehospital systems, there would be a lot of excitement there.”
He noted the sensitivity analysis resulted in a rate of 88.8% along with the positive predictive value of 88%. “Missing 1 out of 10 ST-elevation MIs in my eyes can still be considered a big deal, so we need to know if this is happening in particular types of patients, for example women versus men, or other groups.”
However, some investigations reported false activation rates as high as 33%, he said. “So, to say that, the positive predictive value is at 88% is really exciting and I think it can make a real inroads,” Dr. Nallamothu said.
Dr. Lin and Dr. Nallamothu have no relevant disclosures.
*Correction, 11/20/23: An earlier version of this article misstated in both trial arms the time to coronary catheterization lab activation.
PHILADELPHIA – An artificial intelligence platform that sends alerts based on electrocardiography results enabled cardiologists and emergency department physicians at a major hospital in Taiwan to move patients with ST-elevation myocardial infarction (STEMI) into the catheterization laboratory 9 minutes sooner than the conventional protocol that did not use AI.
“This is the first randomized clinical trial to demonstrate the reduction of electrocardiography to coronary cath lab activation time" from 52.3 to 43.3 minutes (P = .003), Chin Sheng Lin, MD, PhD, director of cardiology at the National Defense Medical Center Tri-Service General Hospital in Taipei City, said in presenting the results at the American Heart Association scientific sessions.
Dr. Lin reported results from the Artificial Intelligence Enabled Rapid Identify of ST-Elevation Myocardial Infarction Using Electrocardiogram (ARISE) trial. The trial included 43,994 patients who came to the hospital’s emergency and inpatient departments with at least one ECG but no history of coronary angiography (CAG) in the previous 3 days between May 2022 and April 2023.
They were randomly assigned by date to either AI-ECG for rapid identification and triage of STEMI or standard care. Overall, 145 patients were finally diagnosed with STEMI based on CAG, 77 in the intervention group and 68 in the control group. All patients were seen by one of 20 cardiologists who participated in the study.
Dr. Lin and his group developed an AI algorithm that captures the ECG readout in the emergency department, analyzes the data and then sends a high-risk alarm to the front-line physician and on-duty cardiologist to activate the primary percutaneous coronary intervention (PCI).
Trial results
The differentiation between groups was even more pronounced in ED patients during regular working hours, Dr. Lin said, at 61.6 minutes for the intervention group vs. 33.1 minutes for controls (P = .001).*
He noted that the AI group showed a trend towards fewer cases of clinically suspected STEMI but not getting CAG, 6.5% vs. 15.8%, for an odds ratio of 0.37 (95% confidence interval, 0.14-0.94).
The AI-ECG model also demonstrated a high diagnostic accuracy. “With this AI-ECG system, because it has a very high accuracy and a high positive predictive variable that reach 88%, we can send a message to the on-duty cardiologists and also the emergency room physician and they can send the patients to receive the operation or the PCI as soon as possible,” Dr. Lin said in an interview.
The time differential is critical, Dr. Lin said. “For the patient with acute myocardial infarction, 1 minute is critical, because the patients can die within minutes,” he said. “If we can save 9 minutes I think we can save more lives, but it needs a larger study to evaluate that.”
Dr. Lin acknowledged a few limitations with the trial, among them its single-center nature, relatively small sample size of STEMI patients and the short-term of follow-up. Future study should involve multiple centers along with a prehospital, emergency medical services AI-ECG model.
‘Novel’ for an AI trial
“This is an incredible application of an AI technology in a real-world problem,” said Brahmajee K. Nallamothu, MD, MPH, an interventional cardiologist at the University of Michigan, Ann Arbor, who did not participate in the study. “What I really love about this study is it’s actually a clinical problem that has large implications, particularly for under-resourced areas.”
Using a randomized clinical trial to evaluate the AI platform is “very, very novel,” he said, and called the time improvement “enormous.” Referencing Dr. Lin’s next steps for studying the AI-ECG platform, Dr. Nallamothu said, “if we could push this up even earlier to paramedics and EMTs and prehospital systems, there would be a lot of excitement there.”
He noted the sensitivity analysis resulted in a rate of 88.8% along with the positive predictive value of 88%. “Missing 1 out of 10 ST-elevation MIs in my eyes can still be considered a big deal, so we need to know if this is happening in particular types of patients, for example women versus men, or other groups.”
However, some investigations reported false activation rates as high as 33%, he said. “So, to say that, the positive predictive value is at 88% is really exciting and I think it can make a real inroads,” Dr. Nallamothu said.
Dr. Lin and Dr. Nallamothu have no relevant disclosures.
*Correction, 11/20/23: An earlier version of this article misstated in both trial arms the time to coronary catheterization lab activation.
AT AHA 2023
GLP-1s don’t appear to worsen diabetic retinopathy
SAN FRANCISCO – A large observational registry study of almost 100,000 eyes has found that the diabetes drug semaglutide, a GLP-1 agonist recently approved for weight loss, does not worsen the progression of potentially vision-threatening diabetic retinopathy in the long term in patients taking the drug. However, the researchers said, the findings do not obviate the need for providers to have a conversation about the potential risks to vision posed by the drug.
“In patients that have either no or early or relatively nonadvanced diabetic retinopathy, the absolute risk of having a worsening in their retinopathy is variable,” Zeeshan Haq, MD, a retina specialist at Retinal Consultants of Minnesota, told this news organization. Dr. Hag presented the findings Nov. 3 at the annual meeting of the American Academy of Ophthalmology.
“Based on this preliminary evidence and what we know so far, it suggests that there is a risk of worsening, but it’s quite low for most patients, and so a conversation needs to be had between anyone considering prescribing the drug, such as a general practitioner or a nurse practitioner, and that patient’s optometrist or comprehensive ophthalmologist or retina specialist.”
Methodology and results
Dr. Haq reported on a retrospective case series of 96,462 eyes from the Intelligent Research in Sight (IRIS) registry. Patients had type 2 diabetes and began taking injectable semaglutide between January 2013 and December 2021.
The study evaluated eyes with three levels of retinopathy:
- No retinopathy or background retinopathy (71.8%).
- Mild or moderate nonproliferative diabetic retinopathy (NPDR) (18.4%).
- Severe NPDR or proliferative diabetic retinopathy (PDR) (9.8%).
In eyes with no or background retinopathy, 1.3%, 1.2%, 1.6%, and 2.2% experienced a worsening in status of the condition at 3, 6, 12, and 24 months, respectively.
In eyes with mild or moderate NPDR, 2.4%, 3%, 3.4%, and 3.5% showed worsening retinopathy at the respective time intervals.
Improvement of retinopathy rather than worsening was evaluated in the eyes with severe NPDR or PDR. At 3, 6, 12, and 24 months, improvement was observed in 40%, 37.8%, 47.7%, and 58.7% of these eyes, respectively.
Most patients were aged 51-75 years (77.2%), female (55.0%), and White (63.8%).
The study found low rates of the following complications across the same time intervals: vitreous hemorrhage (from 0.1% to 0.15%); traction retinal detachment (0.02% to 0.05%); and neovascular glaucoma (0.03% to –0.04%), Dr. Haq reported.
Dr. Haq noted that understanding the possible consequences that semaglutide has on vision is important as the drug becomes more widely available for both diabetes and weight control. The Centers for Disease Control and Prevention reports that 37.3 million people in the United States have diabetes; 28.7 million cases have been diagnosed, and 8.5 million are undiagnosed.
Clinical implications
“Any patient in the United States with diabetes has to undergo screening for diabetic eye disease, and so they’re usually plugged into the eye-care system,” Dr. Haq said. “But if they’re going to be starting this drug and they don’t have any existing diabetic retinopathy, the discussion should be had between their doctor and the eye-care provider, and if they do have a history of DR, an evaluation with the eye-care provider should probably happen upon starting the drug.”
Vaidehi Dedania, MD, a retina specialist at NYU Langone Health in New York, said the findings underscore the importance of counseling patients who are taking semaglutide about potential vision outcomes.
“We know that when patients get rapid control of their diabetes, their diabetic retinopathy can worsen in the short term, although it always ends up doing better in long term anyway,” Dr. Dedania said in an interview. “We always educate our patients that if they get control of the diabetes to not feel discouraged if their diabetic retinopathy worsens despite getting good control, because we know in the long run it always get better.”
The new findings, however, may have masked some worsening of retinopathy because of how the researchers categorized the condition. “It’s hard to assess changes within a designation because they’re so broad,” Dr. Dedania said.
She also noted potential limitations with the IRIS database itself. “The data collected from it are not always as complete as you might need for the purpose of understanding this, so that’s a limitation,” she said. While the high number of patients is a strength of the study, she added, “I still think the limitations are pretty significant.”
Dr. Haq has disclosed no relevant financial relationships. Dr. Dedania has relationships with Genentech/Roche and Regeneron Pharmaceuticals.
A version of this article first appeared on Medscape.com.
SAN FRANCISCO – A large observational registry study of almost 100,000 eyes has found that the diabetes drug semaglutide, a GLP-1 agonist recently approved for weight loss, does not worsen the progression of potentially vision-threatening diabetic retinopathy in the long term in patients taking the drug. However, the researchers said, the findings do not obviate the need for providers to have a conversation about the potential risks to vision posed by the drug.
“In patients that have either no or early or relatively nonadvanced diabetic retinopathy, the absolute risk of having a worsening in their retinopathy is variable,” Zeeshan Haq, MD, a retina specialist at Retinal Consultants of Minnesota, told this news organization. Dr. Hag presented the findings Nov. 3 at the annual meeting of the American Academy of Ophthalmology.
“Based on this preliminary evidence and what we know so far, it suggests that there is a risk of worsening, but it’s quite low for most patients, and so a conversation needs to be had between anyone considering prescribing the drug, such as a general practitioner or a nurse practitioner, and that patient’s optometrist or comprehensive ophthalmologist or retina specialist.”
Methodology and results
Dr. Haq reported on a retrospective case series of 96,462 eyes from the Intelligent Research in Sight (IRIS) registry. Patients had type 2 diabetes and began taking injectable semaglutide between January 2013 and December 2021.
The study evaluated eyes with three levels of retinopathy:
- No retinopathy or background retinopathy (71.8%).
- Mild or moderate nonproliferative diabetic retinopathy (NPDR) (18.4%).
- Severe NPDR or proliferative diabetic retinopathy (PDR) (9.8%).
In eyes with no or background retinopathy, 1.3%, 1.2%, 1.6%, and 2.2% experienced a worsening in status of the condition at 3, 6, 12, and 24 months, respectively.
In eyes with mild or moderate NPDR, 2.4%, 3%, 3.4%, and 3.5% showed worsening retinopathy at the respective time intervals.
Improvement of retinopathy rather than worsening was evaluated in the eyes with severe NPDR or PDR. At 3, 6, 12, and 24 months, improvement was observed in 40%, 37.8%, 47.7%, and 58.7% of these eyes, respectively.
Most patients were aged 51-75 years (77.2%), female (55.0%), and White (63.8%).
The study found low rates of the following complications across the same time intervals: vitreous hemorrhage (from 0.1% to 0.15%); traction retinal detachment (0.02% to 0.05%); and neovascular glaucoma (0.03% to –0.04%), Dr. Haq reported.
Dr. Haq noted that understanding the possible consequences that semaglutide has on vision is important as the drug becomes more widely available for both diabetes and weight control. The Centers for Disease Control and Prevention reports that 37.3 million people in the United States have diabetes; 28.7 million cases have been diagnosed, and 8.5 million are undiagnosed.
Clinical implications
“Any patient in the United States with diabetes has to undergo screening for diabetic eye disease, and so they’re usually plugged into the eye-care system,” Dr. Haq said. “But if they’re going to be starting this drug and they don’t have any existing diabetic retinopathy, the discussion should be had between their doctor and the eye-care provider, and if they do have a history of DR, an evaluation with the eye-care provider should probably happen upon starting the drug.”
Vaidehi Dedania, MD, a retina specialist at NYU Langone Health in New York, said the findings underscore the importance of counseling patients who are taking semaglutide about potential vision outcomes.
“We know that when patients get rapid control of their diabetes, their diabetic retinopathy can worsen in the short term, although it always ends up doing better in long term anyway,” Dr. Dedania said in an interview. “We always educate our patients that if they get control of the diabetes to not feel discouraged if their diabetic retinopathy worsens despite getting good control, because we know in the long run it always get better.”
The new findings, however, may have masked some worsening of retinopathy because of how the researchers categorized the condition. “It’s hard to assess changes within a designation because they’re so broad,” Dr. Dedania said.
She also noted potential limitations with the IRIS database itself. “The data collected from it are not always as complete as you might need for the purpose of understanding this, so that’s a limitation,” she said. While the high number of patients is a strength of the study, she added, “I still think the limitations are pretty significant.”
Dr. Haq has disclosed no relevant financial relationships. Dr. Dedania has relationships with Genentech/Roche and Regeneron Pharmaceuticals.
A version of this article first appeared on Medscape.com.
SAN FRANCISCO – A large observational registry study of almost 100,000 eyes has found that the diabetes drug semaglutide, a GLP-1 agonist recently approved for weight loss, does not worsen the progression of potentially vision-threatening diabetic retinopathy in the long term in patients taking the drug. However, the researchers said, the findings do not obviate the need for providers to have a conversation about the potential risks to vision posed by the drug.
“In patients that have either no or early or relatively nonadvanced diabetic retinopathy, the absolute risk of having a worsening in their retinopathy is variable,” Zeeshan Haq, MD, a retina specialist at Retinal Consultants of Minnesota, told this news organization. Dr. Hag presented the findings Nov. 3 at the annual meeting of the American Academy of Ophthalmology.
“Based on this preliminary evidence and what we know so far, it suggests that there is a risk of worsening, but it’s quite low for most patients, and so a conversation needs to be had between anyone considering prescribing the drug, such as a general practitioner or a nurse practitioner, and that patient’s optometrist or comprehensive ophthalmologist or retina specialist.”
Methodology and results
Dr. Haq reported on a retrospective case series of 96,462 eyes from the Intelligent Research in Sight (IRIS) registry. Patients had type 2 diabetes and began taking injectable semaglutide between January 2013 and December 2021.
The study evaluated eyes with three levels of retinopathy:
- No retinopathy or background retinopathy (71.8%).
- Mild or moderate nonproliferative diabetic retinopathy (NPDR) (18.4%).
- Severe NPDR or proliferative diabetic retinopathy (PDR) (9.8%).
In eyes with no or background retinopathy, 1.3%, 1.2%, 1.6%, and 2.2% experienced a worsening in status of the condition at 3, 6, 12, and 24 months, respectively.
In eyes with mild or moderate NPDR, 2.4%, 3%, 3.4%, and 3.5% showed worsening retinopathy at the respective time intervals.
Improvement of retinopathy rather than worsening was evaluated in the eyes with severe NPDR or PDR. At 3, 6, 12, and 24 months, improvement was observed in 40%, 37.8%, 47.7%, and 58.7% of these eyes, respectively.
Most patients were aged 51-75 years (77.2%), female (55.0%), and White (63.8%).
The study found low rates of the following complications across the same time intervals: vitreous hemorrhage (from 0.1% to 0.15%); traction retinal detachment (0.02% to 0.05%); and neovascular glaucoma (0.03% to –0.04%), Dr. Haq reported.
Dr. Haq noted that understanding the possible consequences that semaglutide has on vision is important as the drug becomes more widely available for both diabetes and weight control. The Centers for Disease Control and Prevention reports that 37.3 million people in the United States have diabetes; 28.7 million cases have been diagnosed, and 8.5 million are undiagnosed.
Clinical implications
“Any patient in the United States with diabetes has to undergo screening for diabetic eye disease, and so they’re usually plugged into the eye-care system,” Dr. Haq said. “But if they’re going to be starting this drug and they don’t have any existing diabetic retinopathy, the discussion should be had between their doctor and the eye-care provider, and if they do have a history of DR, an evaluation with the eye-care provider should probably happen upon starting the drug.”
Vaidehi Dedania, MD, a retina specialist at NYU Langone Health in New York, said the findings underscore the importance of counseling patients who are taking semaglutide about potential vision outcomes.
“We know that when patients get rapid control of their diabetes, their diabetic retinopathy can worsen in the short term, although it always ends up doing better in long term anyway,” Dr. Dedania said in an interview. “We always educate our patients that if they get control of the diabetes to not feel discouraged if their diabetic retinopathy worsens despite getting good control, because we know in the long run it always get better.”
The new findings, however, may have masked some worsening of retinopathy because of how the researchers categorized the condition. “It’s hard to assess changes within a designation because they’re so broad,” Dr. Dedania said.
She also noted potential limitations with the IRIS database itself. “The data collected from it are not always as complete as you might need for the purpose of understanding this, so that’s a limitation,” she said. While the high number of patients is a strength of the study, she added, “I still think the limitations are pretty significant.”
Dr. Haq has disclosed no relevant financial relationships. Dr. Dedania has relationships with Genentech/Roche and Regeneron Pharmaceuticals.
A version of this article first appeared on Medscape.com.
Trial shows utility of small-volume blood collection tubes
A large Canadian clinical trial has found that using small-volume tubes to collect blood samples for laboratory testing of intensive care unit patients can reduce blood transfusions without affecting lab results.
“We showed in a large pragmatic cluster trial that automatically collect less blood for laboratory testing reduced red blood cell transfusions by about 10 units of red blood cells per 100 patients in the ICU,” lead study author Deborah M. Siegal, MD, associate professor at the University of Ottawa and scientist at the Ottawa Hospital Research Institute, said.
The study was coordinated by the Population Health Research Institute, an affiliate of McMaster University in Hamilton (Ont.) Health Sciences, where Dr. Siegal worked before moving to Ottawa.
The STRATUS randomized clinical trial, published in JAMA, involved 25 adult medical-surgical ICUs across Canada, where 21,201 patients were randomized to either standard-volume or small-volume tubes for collecting blood samples. During the course of the study, each site switched to the small-volume collection tubes.
“We also showed there were no negative effects on lab testing, and by that we measured the sufficiency of the specimens,” Dr. Siegal added. “We were able to show that there wasn’t a problem with the amount of blood that was available for the tests to be done.”
The samples were collected from February 2019 through January 2021, through the period of COVID-19 restrictions. Dr. Siegal explained that 6,210 patients admitted early in the COVID-19 pandemic were excluded from the primary analysis, but were included in secondary analyses.
Study results
While the study found no significant difference in RBC units per patient per ICU stage – a relative risk of .91 (95% confidence interval, 0.79-1.05; P = .19), it did find an absolute reduction of 7.24 RBC units/100 patients per ICU stay.
Findings from the secondary analyses, which included 27,411 patients, were:
- A 12% reduction in RBC units per patient per ICU stay after switching from standard-volume to small-volume tubes (RR, 0.88; 95% CI, 0.77-1; P = .04).
- An absolute reduction of 9.84 RBC units/100 patients per ICU stay (95% CI, 0.24-20.76).
In the primary analysis population, the median transfusion-adjusted hemoglobin was not statistically different between the standard- and small-volume collection tube groups, with an average difference of 0.1 g/dL (95% CI, –0.04 to .23), but it was lower in the secondary population, with a mean difference of .17 g/dL (95% CI, 0.05-0.29).
“Those patients that we analyzed in the secondary analysis population received about 36,000 units of blood, just in 25 ICU units in Canada in less than 2 years,” Dr. Siegal said. “If we saved 10 units per 100 patients, that’s 1,500 units of blood. That really speaks to a small effect at the individual patient level but really potential for widespread effect. We are now in a period of blood product shortage not only in Canada but worldwide.”
First clinical trial for small tubes
Dr. Siegal noted this was the first clinical trial to compare standard- and small-volume blood collection tools, “and also to show there is both a benefit and a lack of harm,” Dr. Siegal said. “We thought that a randomized trial was the best way to move the needle. If we could design a trial of a large population of patients to show benefit and no harm, it would be a win, and that’s in fact what happened.”
She added, “The tubes essentially have the same cost, work the same, and go on the same equipment the same way the standard-volume tubes do, so it wasn’t a practice change for people in the hospital.”
The study also found an identical low rate of unusable specimens did not differ regardless of the type of collection tube: less than .03%.
Dr. Siegal said the study group is collaborating with hematology stakeholders in Canada, including Canadian Blood Services, which provides blood plasma to the country’s provincial and territorial health systems, and is reaching out to the American Society of Hematology.
“We’re going to target both hematologists and critical care providers and, even more broadly than the critical care community, hospitals, because anemia is big problem in hospitals,” Dr. Siegal said. “I think we can think about this more broadly.”
The study received funding from the Hamilton Academic Health Sciences Organization. Dr. Siegal disclosed relationships with Bristol-Myers Squibb-Pfizer, AstraZeneca and Roche.
A large Canadian clinical trial has found that using small-volume tubes to collect blood samples for laboratory testing of intensive care unit patients can reduce blood transfusions without affecting lab results.
“We showed in a large pragmatic cluster trial that automatically collect less blood for laboratory testing reduced red blood cell transfusions by about 10 units of red blood cells per 100 patients in the ICU,” lead study author Deborah M. Siegal, MD, associate professor at the University of Ottawa and scientist at the Ottawa Hospital Research Institute, said.
The study was coordinated by the Population Health Research Institute, an affiliate of McMaster University in Hamilton (Ont.) Health Sciences, where Dr. Siegal worked before moving to Ottawa.
The STRATUS randomized clinical trial, published in JAMA, involved 25 adult medical-surgical ICUs across Canada, where 21,201 patients were randomized to either standard-volume or small-volume tubes for collecting blood samples. During the course of the study, each site switched to the small-volume collection tubes.
“We also showed there were no negative effects on lab testing, and by that we measured the sufficiency of the specimens,” Dr. Siegal added. “We were able to show that there wasn’t a problem with the amount of blood that was available for the tests to be done.”
The samples were collected from February 2019 through January 2021, through the period of COVID-19 restrictions. Dr. Siegal explained that 6,210 patients admitted early in the COVID-19 pandemic were excluded from the primary analysis, but were included in secondary analyses.
Study results
While the study found no significant difference in RBC units per patient per ICU stage – a relative risk of .91 (95% confidence interval, 0.79-1.05; P = .19), it did find an absolute reduction of 7.24 RBC units/100 patients per ICU stay.
Findings from the secondary analyses, which included 27,411 patients, were:
- A 12% reduction in RBC units per patient per ICU stay after switching from standard-volume to small-volume tubes (RR, 0.88; 95% CI, 0.77-1; P = .04).
- An absolute reduction of 9.84 RBC units/100 patients per ICU stay (95% CI, 0.24-20.76).
In the primary analysis population, the median transfusion-adjusted hemoglobin was not statistically different between the standard- and small-volume collection tube groups, with an average difference of 0.1 g/dL (95% CI, –0.04 to .23), but it was lower in the secondary population, with a mean difference of .17 g/dL (95% CI, 0.05-0.29).
“Those patients that we analyzed in the secondary analysis population received about 36,000 units of blood, just in 25 ICU units in Canada in less than 2 years,” Dr. Siegal said. “If we saved 10 units per 100 patients, that’s 1,500 units of blood. That really speaks to a small effect at the individual patient level but really potential for widespread effect. We are now in a period of blood product shortage not only in Canada but worldwide.”
First clinical trial for small tubes
Dr. Siegal noted this was the first clinical trial to compare standard- and small-volume blood collection tools, “and also to show there is both a benefit and a lack of harm,” Dr. Siegal said. “We thought that a randomized trial was the best way to move the needle. If we could design a trial of a large population of patients to show benefit and no harm, it would be a win, and that’s in fact what happened.”
She added, “The tubes essentially have the same cost, work the same, and go on the same equipment the same way the standard-volume tubes do, so it wasn’t a practice change for people in the hospital.”
The study also found an identical low rate of unusable specimens did not differ regardless of the type of collection tube: less than .03%.
Dr. Siegal said the study group is collaborating with hematology stakeholders in Canada, including Canadian Blood Services, which provides blood plasma to the country’s provincial and territorial health systems, and is reaching out to the American Society of Hematology.
“We’re going to target both hematologists and critical care providers and, even more broadly than the critical care community, hospitals, because anemia is big problem in hospitals,” Dr. Siegal said. “I think we can think about this more broadly.”
The study received funding from the Hamilton Academic Health Sciences Organization. Dr. Siegal disclosed relationships with Bristol-Myers Squibb-Pfizer, AstraZeneca and Roche.
A large Canadian clinical trial has found that using small-volume tubes to collect blood samples for laboratory testing of intensive care unit patients can reduce blood transfusions without affecting lab results.
“We showed in a large pragmatic cluster trial that automatically collect less blood for laboratory testing reduced red blood cell transfusions by about 10 units of red blood cells per 100 patients in the ICU,” lead study author Deborah M. Siegal, MD, associate professor at the University of Ottawa and scientist at the Ottawa Hospital Research Institute, said.
The study was coordinated by the Population Health Research Institute, an affiliate of McMaster University in Hamilton (Ont.) Health Sciences, where Dr. Siegal worked before moving to Ottawa.
The STRATUS randomized clinical trial, published in JAMA, involved 25 adult medical-surgical ICUs across Canada, where 21,201 patients were randomized to either standard-volume or small-volume tubes for collecting blood samples. During the course of the study, each site switched to the small-volume collection tubes.
“We also showed there were no negative effects on lab testing, and by that we measured the sufficiency of the specimens,” Dr. Siegal added. “We were able to show that there wasn’t a problem with the amount of blood that was available for the tests to be done.”
The samples were collected from February 2019 through January 2021, through the period of COVID-19 restrictions. Dr. Siegal explained that 6,210 patients admitted early in the COVID-19 pandemic were excluded from the primary analysis, but were included in secondary analyses.
Study results
While the study found no significant difference in RBC units per patient per ICU stage – a relative risk of .91 (95% confidence interval, 0.79-1.05; P = .19), it did find an absolute reduction of 7.24 RBC units/100 patients per ICU stay.
Findings from the secondary analyses, which included 27,411 patients, were:
- A 12% reduction in RBC units per patient per ICU stay after switching from standard-volume to small-volume tubes (RR, 0.88; 95% CI, 0.77-1; P = .04).
- An absolute reduction of 9.84 RBC units/100 patients per ICU stay (95% CI, 0.24-20.76).
In the primary analysis population, the median transfusion-adjusted hemoglobin was not statistically different between the standard- and small-volume collection tube groups, with an average difference of 0.1 g/dL (95% CI, –0.04 to .23), but it was lower in the secondary population, with a mean difference of .17 g/dL (95% CI, 0.05-0.29).
“Those patients that we analyzed in the secondary analysis population received about 36,000 units of blood, just in 25 ICU units in Canada in less than 2 years,” Dr. Siegal said. “If we saved 10 units per 100 patients, that’s 1,500 units of blood. That really speaks to a small effect at the individual patient level but really potential for widespread effect. We are now in a period of blood product shortage not only in Canada but worldwide.”
First clinical trial for small tubes
Dr. Siegal noted this was the first clinical trial to compare standard- and small-volume blood collection tools, “and also to show there is both a benefit and a lack of harm,” Dr. Siegal said. “We thought that a randomized trial was the best way to move the needle. If we could design a trial of a large population of patients to show benefit and no harm, it would be a win, and that’s in fact what happened.”
She added, “The tubes essentially have the same cost, work the same, and go on the same equipment the same way the standard-volume tubes do, so it wasn’t a practice change for people in the hospital.”
The study also found an identical low rate of unusable specimens did not differ regardless of the type of collection tube: less than .03%.
Dr. Siegal said the study group is collaborating with hematology stakeholders in Canada, including Canadian Blood Services, which provides blood plasma to the country’s provincial and territorial health systems, and is reaching out to the American Society of Hematology.
“We’re going to target both hematologists and critical care providers and, even more broadly than the critical care community, hospitals, because anemia is big problem in hospitals,” Dr. Siegal said. “I think we can think about this more broadly.”
The study received funding from the Hamilton Academic Health Sciences Organization. Dr. Siegal disclosed relationships with Bristol-Myers Squibb-Pfizer, AstraZeneca and Roche.
FROM JAMA
Dropping aspirin cuts bleeding in LVAD patients: ARIES-HM3
PHILADELPHIA – particularly if it’s a newer device that does not use the centrifugal- or continuous-flow pump technology of conventional LVADs, new randomized results suggest.
“We’ve always thought that somehow aspirin prevents stroke and prevents clotting and that it’s anti-inflammatory, and what we found in ARIES was the exact opposite,” said Mandeep Mehra, MD, of Brigham and Women’s Hospital Heart and Vascular Center and Harvard Medical School, both in Boston, who reported results of the ARIES-HM3 trial of the HeartMate 3 LVAD, a device that uses a fully magnetically levitated rotor to maintain blood flow.
ARIES-HM3 randomly assigned 589 patients who received the HeartMate 3 device to vitamin K therapy with aspirin or to placebo. Dr. Mehra said it was the first international trial to conclusively evaluate medical therapy in patients who get an LVAD.
Unexpected findings
“To be honest with you, we set this up as a safety study to see if we could eliminate aspirin,” Dr. Mehra said in an interview. “We didn’t expect that the bleeding rates would decrease by 34% and that gastrointestinal bleeding in particular would decrease by 40%. We didn’t expect that it would nearly halve the days spent in the hospital, and we didn’t expect that the cost of care would decrease by 40%.”
Dr. Mehra reported the results at the annual scientific sessions of the American Heart Association. They were published simultaneously online in JAMA.
The researchers found that 74% of patients in the placebo group met the primary endpoint of being alive and not having any hemocompatibility events at 12 months vs 68% of the aspirin patients. The rate of nonsurgical bleeding events was 30% in the placebo group versus 42.4% in the aspirin patients. The rates of GI bleeding were 13% and 21.6% in the respective groups.
In his talk, Dr. Mehra noted the placebo group spent 47% fewer days in the hospital for bleeding, with hospitalization costs 41% lower than the aspirin group.
“We are very quick to throw things as deemed medical therapy at patients and this study outcome should give us pause that not everything we do may be right, and that we need to start building a stronger evidence base in medical therapy for what we do with patients that are on device support,” Dr. Mehra said.
Shift of focus to therapy
The study’s focus on aspirin therapy may be as significant as its evaluation of the HeartMate 3 LVAD, discussant Eric David Adler, MD, a cardiologist and section head of heart transplant at the University of California, San Diego, said in an interview.
“We focus so much on the device,” he said. “It’s like a set-it-and-forget-it kind of thing and we’re surprised that we see complications because we haven’t put a lot of effort into the medical therapy component.”
But he credited this study for doing just that, adding that it can serve as a model for future studies of LVADs, although such studies can face hurdles. “These studies are not trivial to accomplish,” he said. “Placebo medical therapy studies are very expensive, but I think this is a mandate for doing more studies. This is just the tip of the iceberg.”
Additionally, evaluating hospital stays in LVAD studies “is a really important endpoint,” Dr. Adler said.
“For me, one of the key things that we don’t think about enough is that lowering days in the hospital is a really big deal,” he said. “No one wants to spend time in the hospital, so anything we can do to lower the amount of hospital days is real impactful.”
Abbott funded and sponsored the ARIES-HM3 trial. Dr. Mehra disclosed relationships with Abbott, Moderna, Natera, Transmedics, Paragonix, NupulseCV, FineHeart, and Leviticus. Dr. Adler has disclosed no relevant financial relationships.
PHILADELPHIA – particularly if it’s a newer device that does not use the centrifugal- or continuous-flow pump technology of conventional LVADs, new randomized results suggest.
“We’ve always thought that somehow aspirin prevents stroke and prevents clotting and that it’s anti-inflammatory, and what we found in ARIES was the exact opposite,” said Mandeep Mehra, MD, of Brigham and Women’s Hospital Heart and Vascular Center and Harvard Medical School, both in Boston, who reported results of the ARIES-HM3 trial of the HeartMate 3 LVAD, a device that uses a fully magnetically levitated rotor to maintain blood flow.
ARIES-HM3 randomly assigned 589 patients who received the HeartMate 3 device to vitamin K therapy with aspirin or to placebo. Dr. Mehra said it was the first international trial to conclusively evaluate medical therapy in patients who get an LVAD.
Unexpected findings
“To be honest with you, we set this up as a safety study to see if we could eliminate aspirin,” Dr. Mehra said in an interview. “We didn’t expect that the bleeding rates would decrease by 34% and that gastrointestinal bleeding in particular would decrease by 40%. We didn’t expect that it would nearly halve the days spent in the hospital, and we didn’t expect that the cost of care would decrease by 40%.”
Dr. Mehra reported the results at the annual scientific sessions of the American Heart Association. They were published simultaneously online in JAMA.
The researchers found that 74% of patients in the placebo group met the primary endpoint of being alive and not having any hemocompatibility events at 12 months vs 68% of the aspirin patients. The rate of nonsurgical bleeding events was 30% in the placebo group versus 42.4% in the aspirin patients. The rates of GI bleeding were 13% and 21.6% in the respective groups.
In his talk, Dr. Mehra noted the placebo group spent 47% fewer days in the hospital for bleeding, with hospitalization costs 41% lower than the aspirin group.
“We are very quick to throw things as deemed medical therapy at patients and this study outcome should give us pause that not everything we do may be right, and that we need to start building a stronger evidence base in medical therapy for what we do with patients that are on device support,” Dr. Mehra said.
Shift of focus to therapy
The study’s focus on aspirin therapy may be as significant as its evaluation of the HeartMate 3 LVAD, discussant Eric David Adler, MD, a cardiologist and section head of heart transplant at the University of California, San Diego, said in an interview.
“We focus so much on the device,” he said. “It’s like a set-it-and-forget-it kind of thing and we’re surprised that we see complications because we haven’t put a lot of effort into the medical therapy component.”
But he credited this study for doing just that, adding that it can serve as a model for future studies of LVADs, although such studies can face hurdles. “These studies are not trivial to accomplish,” he said. “Placebo medical therapy studies are very expensive, but I think this is a mandate for doing more studies. This is just the tip of the iceberg.”
Additionally, evaluating hospital stays in LVAD studies “is a really important endpoint,” Dr. Adler said.
“For me, one of the key things that we don’t think about enough is that lowering days in the hospital is a really big deal,” he said. “No one wants to spend time in the hospital, so anything we can do to lower the amount of hospital days is real impactful.”
Abbott funded and sponsored the ARIES-HM3 trial. Dr. Mehra disclosed relationships with Abbott, Moderna, Natera, Transmedics, Paragonix, NupulseCV, FineHeart, and Leviticus. Dr. Adler has disclosed no relevant financial relationships.
PHILADELPHIA – particularly if it’s a newer device that does not use the centrifugal- or continuous-flow pump technology of conventional LVADs, new randomized results suggest.
“We’ve always thought that somehow aspirin prevents stroke and prevents clotting and that it’s anti-inflammatory, and what we found in ARIES was the exact opposite,” said Mandeep Mehra, MD, of Brigham and Women’s Hospital Heart and Vascular Center and Harvard Medical School, both in Boston, who reported results of the ARIES-HM3 trial of the HeartMate 3 LVAD, a device that uses a fully magnetically levitated rotor to maintain blood flow.
ARIES-HM3 randomly assigned 589 patients who received the HeartMate 3 device to vitamin K therapy with aspirin or to placebo. Dr. Mehra said it was the first international trial to conclusively evaluate medical therapy in patients who get an LVAD.
Unexpected findings
“To be honest with you, we set this up as a safety study to see if we could eliminate aspirin,” Dr. Mehra said in an interview. “We didn’t expect that the bleeding rates would decrease by 34% and that gastrointestinal bleeding in particular would decrease by 40%. We didn’t expect that it would nearly halve the days spent in the hospital, and we didn’t expect that the cost of care would decrease by 40%.”
Dr. Mehra reported the results at the annual scientific sessions of the American Heart Association. They were published simultaneously online in JAMA.
The researchers found that 74% of patients in the placebo group met the primary endpoint of being alive and not having any hemocompatibility events at 12 months vs 68% of the aspirin patients. The rate of nonsurgical bleeding events was 30% in the placebo group versus 42.4% in the aspirin patients. The rates of GI bleeding were 13% and 21.6% in the respective groups.
In his talk, Dr. Mehra noted the placebo group spent 47% fewer days in the hospital for bleeding, with hospitalization costs 41% lower than the aspirin group.
“We are very quick to throw things as deemed medical therapy at patients and this study outcome should give us pause that not everything we do may be right, and that we need to start building a stronger evidence base in medical therapy for what we do with patients that are on device support,” Dr. Mehra said.
Shift of focus to therapy
The study’s focus on aspirin therapy may be as significant as its evaluation of the HeartMate 3 LVAD, discussant Eric David Adler, MD, a cardiologist and section head of heart transplant at the University of California, San Diego, said in an interview.
“We focus so much on the device,” he said. “It’s like a set-it-and-forget-it kind of thing and we’re surprised that we see complications because we haven’t put a lot of effort into the medical therapy component.”
But he credited this study for doing just that, adding that it can serve as a model for future studies of LVADs, although such studies can face hurdles. “These studies are not trivial to accomplish,” he said. “Placebo medical therapy studies are very expensive, but I think this is a mandate for doing more studies. This is just the tip of the iceberg.”
Additionally, evaluating hospital stays in LVAD studies “is a really important endpoint,” Dr. Adler said.
“For me, one of the key things that we don’t think about enough is that lowering days in the hospital is a really big deal,” he said. “No one wants to spend time in the hospital, so anything we can do to lower the amount of hospital days is real impactful.”
Abbott funded and sponsored the ARIES-HM3 trial. Dr. Mehra disclosed relationships with Abbott, Moderna, Natera, Transmedics, Paragonix, NupulseCV, FineHeart, and Leviticus. Dr. Adler has disclosed no relevant financial relationships.
AT AHA 2023
Potential dapagliflozin benefit post MI is not a ‘mandate’
PHILADELPHIA – Giving the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin (Farxiga) to patients with acute myocardial infarction and impaired left ventricular systolic function but no diabetes or chronic heart failure significantly improved a composite of cardiovascular outcomes, a European registry-based randomized trial suggests.
In presenting these results from the DAPA-MI trial, Stefan James, MD, of Uppsala University (Sweden), noted that which the trial described as the hierarchical “win ratio” composite outcomes, compared with patients randomized to placebo plus standard of care.
“The ‘win ratio’ tells us that there’s a 34% higher likelihood of patients having a better cardiometabolic outcome with dapagliflozin vs placebo in terms of the seven components,” James said in an interview. The win ratio was achieved in 32.9% of dapagliflozin patients versus 24.6% of placebo (P < .001).
Dr. James presented the results at the annual scientific sessions of the American Heart Association, and they were published online simultaneously in NEJM Evidence.
Lower-risk patients
DAPA-MI enrolled 4,017 patients from the SWEDEHEART and Myocardial Ischemia National Audit Project registries in Sweden and the United Kingdom, randomly assigning patients to dapagliflozin 10 mg or placebo along with guideline-directed therapy for both groups.
Eligible patients were hemodynamically stable, had an acute MI within 10 days of enrollment, and impaired left ventricular systolic function or a Q-wave MI. Exclusion criteria included history of either type 1 or 2 diabetes, chronic heart failure, poor kidney function, or current treatment with an SGLT2 inhibitor. Baseline demographic characteristics were similar between trial arms.
- The hierarchical seven primary endpoints were:
- Death, with cardiovascular death ranked first followed by noncardiovascular death
- Hospitalization because of heart failure, with adjudicated first followed by investigator-reported HF
- Nonfatal MI
- Atrial fibrillation/flutter event
- New diagnosis of type 2 diabetes
- New York Heart Association functional class at the last visit
- Drop in body weight of at least 5% at the last visit
The key secondary endpoint, Dr. James said, was the primary outcome minus the body weight component, with time to first occurrence of hospitalization for HF or cardiovascular death.
When the seventh factor, body weight decrease, was removed, the differential narrowed: 20.3% versus 16.9% (P = .015). When two or more variables were removed from the composite, the differences were not statistically significant.
For 11 secondary and exploratory outcomes, ranging from CV death or hospitalization for HF to all-cause hospitalization, the outcomes were similar in both the dapagliflozin and placebo groups across the board.
However, the dapagliflozin patients had about half the rate of developing diabetes, compared with the placebo group: 2.1 % versus 3.9%.
The trial initially used the composite of CV death and hospitalization for HF as the primary endpoint, but switched to the seven-item composite endpoint in February because the number of primary composite outcomes was substantially lower than anticipated, Dr. James said.
He acknowledged the study was underpowered for the low-risk population it enrolled. “But if you extended the trial to a larger population and enriched it with a higher-risk population you would probably see an effect,” he said.
“The cardiometabolic benefit was consistent across all prespecified subgroups and there were no new safety concerns,” Dr. James told the attendees. “Clinical event rates were low with no significant difference between randomized groups.”
Not a ringing endorsement
But for invited discussant Stephen D. Wiviott, MD, a cardiologist at Brigham and Women’s Hospital and Harvard Medical School, both in Boston, the DAPA-MI trial result isn’t quite a ringing endorsement of SGLT2 inhibition in these patients.
“From my perspective, DAPA-MI does not suggest a new mandate to expand SGLT2 inhibition to an isolated MI population without other SGLT2 inhibitor indications,” Dr. Wiviott told attendees. “But it does support the safety of its use among patients with acute coronary syndromes.”
However, “these results do not indicate a lack of clinical benefit in patients with prior MI and any of those previously identified conditions – a history of diabetes, coronary heart failure or chronic kidney disease – where SGLT2 inhibition remains a pillar of guideline-directed medical therapy,” Dr. Wiviott said.
In an interview, Dr. Wiviott described the trial design as a “hybrid” in that it used a registry but then added, in his words, “some of the bells and whistles that we have with normal cardiovascular clinical trials.” He further explained: “This is a nice combination of those two things, where they use that as part of the endpoint for the trial but they’re able to add in some of the pieces that you would in a regular registration pathway trial.”
The trial design could serve as a model for future pragmatic therapeutic trials in acute MI, he said, but he acknowledged that DAPA-MI was underpowered to discern many key outcomes.
“They anticipated they were going to have a rate of around 11% of events so they needed to enroll about 6,000 people, but somewhere in the middle of the trial they saw the rate was 2.5%, not 11%, so they had to completely change the trial,” he said of the DAPA-MI investigators.
But an appropriately powered study of SGLT2 inhibition in this population would need about 28,000 patients. “This would be an enormous trial to actually clinically power, so in my sense it’s not going to happen,” Dr. Wiviott said.
The DAPA-MI trial was sponsored by AstraZeneca. Dr. James disclosed relationships with AstraZeneca, Janssen, and Amgen. Dr. Wiviott disclosed relationships with Amgen, AstraZeneca, Janssen, Merck, Pfizer, Icon Clinical, Novo Nordisk, and Varian.
PHILADELPHIA – Giving the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin (Farxiga) to patients with acute myocardial infarction and impaired left ventricular systolic function but no diabetes or chronic heart failure significantly improved a composite of cardiovascular outcomes, a European registry-based randomized trial suggests.
In presenting these results from the DAPA-MI trial, Stefan James, MD, of Uppsala University (Sweden), noted that which the trial described as the hierarchical “win ratio” composite outcomes, compared with patients randomized to placebo plus standard of care.
“The ‘win ratio’ tells us that there’s a 34% higher likelihood of patients having a better cardiometabolic outcome with dapagliflozin vs placebo in terms of the seven components,” James said in an interview. The win ratio was achieved in 32.9% of dapagliflozin patients versus 24.6% of placebo (P < .001).
Dr. James presented the results at the annual scientific sessions of the American Heart Association, and they were published online simultaneously in NEJM Evidence.
Lower-risk patients
DAPA-MI enrolled 4,017 patients from the SWEDEHEART and Myocardial Ischemia National Audit Project registries in Sweden and the United Kingdom, randomly assigning patients to dapagliflozin 10 mg or placebo along with guideline-directed therapy for both groups.
Eligible patients were hemodynamically stable, had an acute MI within 10 days of enrollment, and impaired left ventricular systolic function or a Q-wave MI. Exclusion criteria included history of either type 1 or 2 diabetes, chronic heart failure, poor kidney function, or current treatment with an SGLT2 inhibitor. Baseline demographic characteristics were similar between trial arms.
- The hierarchical seven primary endpoints were:
- Death, with cardiovascular death ranked first followed by noncardiovascular death
- Hospitalization because of heart failure, with adjudicated first followed by investigator-reported HF
- Nonfatal MI
- Atrial fibrillation/flutter event
- New diagnosis of type 2 diabetes
- New York Heart Association functional class at the last visit
- Drop in body weight of at least 5% at the last visit
The key secondary endpoint, Dr. James said, was the primary outcome minus the body weight component, with time to first occurrence of hospitalization for HF or cardiovascular death.
When the seventh factor, body weight decrease, was removed, the differential narrowed: 20.3% versus 16.9% (P = .015). When two or more variables were removed from the composite, the differences were not statistically significant.
For 11 secondary and exploratory outcomes, ranging from CV death or hospitalization for HF to all-cause hospitalization, the outcomes were similar in both the dapagliflozin and placebo groups across the board.
However, the dapagliflozin patients had about half the rate of developing diabetes, compared with the placebo group: 2.1 % versus 3.9%.
The trial initially used the composite of CV death and hospitalization for HF as the primary endpoint, but switched to the seven-item composite endpoint in February because the number of primary composite outcomes was substantially lower than anticipated, Dr. James said.
He acknowledged the study was underpowered for the low-risk population it enrolled. “But if you extended the trial to a larger population and enriched it with a higher-risk population you would probably see an effect,” he said.
“The cardiometabolic benefit was consistent across all prespecified subgroups and there were no new safety concerns,” Dr. James told the attendees. “Clinical event rates were low with no significant difference between randomized groups.”
Not a ringing endorsement
But for invited discussant Stephen D. Wiviott, MD, a cardiologist at Brigham and Women’s Hospital and Harvard Medical School, both in Boston, the DAPA-MI trial result isn’t quite a ringing endorsement of SGLT2 inhibition in these patients.
“From my perspective, DAPA-MI does not suggest a new mandate to expand SGLT2 inhibition to an isolated MI population without other SGLT2 inhibitor indications,” Dr. Wiviott told attendees. “But it does support the safety of its use among patients with acute coronary syndromes.”
However, “these results do not indicate a lack of clinical benefit in patients with prior MI and any of those previously identified conditions – a history of diabetes, coronary heart failure or chronic kidney disease – where SGLT2 inhibition remains a pillar of guideline-directed medical therapy,” Dr. Wiviott said.
In an interview, Dr. Wiviott described the trial design as a “hybrid” in that it used a registry but then added, in his words, “some of the bells and whistles that we have with normal cardiovascular clinical trials.” He further explained: “This is a nice combination of those two things, where they use that as part of the endpoint for the trial but they’re able to add in some of the pieces that you would in a regular registration pathway trial.”
The trial design could serve as a model for future pragmatic therapeutic trials in acute MI, he said, but he acknowledged that DAPA-MI was underpowered to discern many key outcomes.
“They anticipated they were going to have a rate of around 11% of events so they needed to enroll about 6,000 people, but somewhere in the middle of the trial they saw the rate was 2.5%, not 11%, so they had to completely change the trial,” he said of the DAPA-MI investigators.
But an appropriately powered study of SGLT2 inhibition in this population would need about 28,000 patients. “This would be an enormous trial to actually clinically power, so in my sense it’s not going to happen,” Dr. Wiviott said.
The DAPA-MI trial was sponsored by AstraZeneca. Dr. James disclosed relationships with AstraZeneca, Janssen, and Amgen. Dr. Wiviott disclosed relationships with Amgen, AstraZeneca, Janssen, Merck, Pfizer, Icon Clinical, Novo Nordisk, and Varian.
PHILADELPHIA – Giving the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin (Farxiga) to patients with acute myocardial infarction and impaired left ventricular systolic function but no diabetes or chronic heart failure significantly improved a composite of cardiovascular outcomes, a European registry-based randomized trial suggests.
In presenting these results from the DAPA-MI trial, Stefan James, MD, of Uppsala University (Sweden), noted that which the trial described as the hierarchical “win ratio” composite outcomes, compared with patients randomized to placebo plus standard of care.
“The ‘win ratio’ tells us that there’s a 34% higher likelihood of patients having a better cardiometabolic outcome with dapagliflozin vs placebo in terms of the seven components,” James said in an interview. The win ratio was achieved in 32.9% of dapagliflozin patients versus 24.6% of placebo (P < .001).
Dr. James presented the results at the annual scientific sessions of the American Heart Association, and they were published online simultaneously in NEJM Evidence.
Lower-risk patients
DAPA-MI enrolled 4,017 patients from the SWEDEHEART and Myocardial Ischemia National Audit Project registries in Sweden and the United Kingdom, randomly assigning patients to dapagliflozin 10 mg or placebo along with guideline-directed therapy for both groups.
Eligible patients were hemodynamically stable, had an acute MI within 10 days of enrollment, and impaired left ventricular systolic function or a Q-wave MI. Exclusion criteria included history of either type 1 or 2 diabetes, chronic heart failure, poor kidney function, or current treatment with an SGLT2 inhibitor. Baseline demographic characteristics were similar between trial arms.
- The hierarchical seven primary endpoints were:
- Death, with cardiovascular death ranked first followed by noncardiovascular death
- Hospitalization because of heart failure, with adjudicated first followed by investigator-reported HF
- Nonfatal MI
- Atrial fibrillation/flutter event
- New diagnosis of type 2 diabetes
- New York Heart Association functional class at the last visit
- Drop in body weight of at least 5% at the last visit
The key secondary endpoint, Dr. James said, was the primary outcome minus the body weight component, with time to first occurrence of hospitalization for HF or cardiovascular death.
When the seventh factor, body weight decrease, was removed, the differential narrowed: 20.3% versus 16.9% (P = .015). When two or more variables were removed from the composite, the differences were not statistically significant.
For 11 secondary and exploratory outcomes, ranging from CV death or hospitalization for HF to all-cause hospitalization, the outcomes were similar in both the dapagliflozin and placebo groups across the board.
However, the dapagliflozin patients had about half the rate of developing diabetes, compared with the placebo group: 2.1 % versus 3.9%.
The trial initially used the composite of CV death and hospitalization for HF as the primary endpoint, but switched to the seven-item composite endpoint in February because the number of primary composite outcomes was substantially lower than anticipated, Dr. James said.
He acknowledged the study was underpowered for the low-risk population it enrolled. “But if you extended the trial to a larger population and enriched it with a higher-risk population you would probably see an effect,” he said.
“The cardiometabolic benefit was consistent across all prespecified subgroups and there were no new safety concerns,” Dr. James told the attendees. “Clinical event rates were low with no significant difference between randomized groups.”
Not a ringing endorsement
But for invited discussant Stephen D. Wiviott, MD, a cardiologist at Brigham and Women’s Hospital and Harvard Medical School, both in Boston, the DAPA-MI trial result isn’t quite a ringing endorsement of SGLT2 inhibition in these patients.
“From my perspective, DAPA-MI does not suggest a new mandate to expand SGLT2 inhibition to an isolated MI population without other SGLT2 inhibitor indications,” Dr. Wiviott told attendees. “But it does support the safety of its use among patients with acute coronary syndromes.”
However, “these results do not indicate a lack of clinical benefit in patients with prior MI and any of those previously identified conditions – a history of diabetes, coronary heart failure or chronic kidney disease – where SGLT2 inhibition remains a pillar of guideline-directed medical therapy,” Dr. Wiviott said.
In an interview, Dr. Wiviott described the trial design as a “hybrid” in that it used a registry but then added, in his words, “some of the bells and whistles that we have with normal cardiovascular clinical trials.” He further explained: “This is a nice combination of those two things, where they use that as part of the endpoint for the trial but they’re able to add in some of the pieces that you would in a regular registration pathway trial.”
The trial design could serve as a model for future pragmatic therapeutic trials in acute MI, he said, but he acknowledged that DAPA-MI was underpowered to discern many key outcomes.
“They anticipated they were going to have a rate of around 11% of events so they needed to enroll about 6,000 people, but somewhere in the middle of the trial they saw the rate was 2.5%, not 11%, so they had to completely change the trial,” he said of the DAPA-MI investigators.
But an appropriately powered study of SGLT2 inhibition in this population would need about 28,000 patients. “This would be an enormous trial to actually clinically power, so in my sense it’s not going to happen,” Dr. Wiviott said.
The DAPA-MI trial was sponsored by AstraZeneca. Dr. James disclosed relationships with AstraZeneca, Janssen, and Amgen. Dr. Wiviott disclosed relationships with Amgen, AstraZeneca, Janssen, Merck, Pfizer, Icon Clinical, Novo Nordisk, and Varian.
AT AHA 2023
IPF pipeline crowded with new drug candidates
With the emergence of pirfenidone and nintedanib over the past decade or so, pulmonologists now have at their disposal two breakthrough antifibrotic agents for the treatment of idiopathic pulmonary fibrosis.
But these two drugs have a number of shortcomings that a host of investigative agents are aiming to address. For one, while pirfenidone and nintedanib have been shown to slow disease progression and improve symptoms, they don’t stop or reverse the disease. Also, a large number of patients with IPF don’t tolerate these drugs well. And, their high cost is a barrier for many patients.
in terms of therapies or interventions that have better efficacy, better long-term tolerability, and that improve symptoms and quality of life for our patients with IPF disease,” said Joyce Lee, MD, associate professor of medicine–pulmonary at the University of Colorado at Denver, Aurora, and senior medical adviser for research and health care quality for the Pulmonary Fibrosis Foundation.
The National Institutes of Health estimates that more than 30,000 new cases of IPF are diagnosed in the United States annually, and as many as 3 million people have the disease worldwide. The 5-year survival rate is less than 40% after diagnosis. Bloomberg News reported that more than 80 pharmaceutical companies are working on IPF treatments. iHealthcareAnalyst estimates the global market for IPF will reach $10.1 billion by 2029 thanks to rapidly increasing prevalence and incidence with age, premium-priced drugs, and rapid approval of new treatments.
The perils of phase 3 studies
A search on ClinicalTrials.gov turned up 89 investigative IPF treatments in human trials. However, the search for alternatives can be perilous. “In the field, we have gotten used to promising phase 2 studies that failed in the phase 3 stage of development,” Dr. Lee said. “I don’t hold my breath these days just in terms of trying to predict whether or not the efficacy will be present in the phase 3 clinical trial.”
Three notable phase 3 flops include the ISABELA 1 and 2 trials of the autotaxin inhibitor ziritaxestat, which failed to meet their primary endpoint and were halted early (JAMA. 2023;329:1567-78). The phase 3 ZEPHYRUS-1 trial failed to show any benefit of pamrevlumab to improve percent predicted force vital capacity (ppFVC) at week 48, causing discontinuation of a second phase 3 trial. The phase 3 STARSCAPE-OLE study of intravenous recombinant human pentraxin-2 was terminated earlier this year when the sponsor, Hoffmann-LaRoche, decided it was unable to meet its primary objective (NCT04594707).
In the meantime, these six other phase 3 programs in IPF are still in the field:
Anlotinib. A phase 2 and 3 trial in China is evaluating 1-year outcomes of once-daily oral anlotinib for treatment of IPF/progressive fibrosis-interstitial lung disease (PF-ILDS) (NCT05828953). Anlotinib is a tyrosine kinase inhibitor (TKI) that targets four factors: vascular endothelial growth factor receptor (VEGR), fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptors (PDGFR), and c-kit. It’s approved in China as a third-line therapy for non–small cell lung cancer (NSCLC).
BI 101550. Enrollment in the FIBRONEER-IPF trial commenced last fall (NCT05321069), with completion scheduled for late next year. BI 1015550 is an oral phosphodiesterase 4B (PDE4B) inhibitor. FIBRONEER-ILD is a separate phase 3 trial in fibrosing idiopathic lung disease (NCT05321082). In both trials, the primary endpoint is the absolute change from baseline in FVC at week 52.
BMS-986278. Results of a phase 2 trial showed that twice-daily treatment with oral BMS-986278 60 mg over 26 weeks reduced the rate of decline in ppFVC by 69% vs. placebo. The phase 3 ALOFT trial has been approved but hasn’t yet started recruiting patients (NCT06003426). BMS-986278 is a lysophosphatidic acid receptor 1 (LPA1) antagonist.
Lanxoprazole. Commonly used to treat and prevent gastrointestinal problems like stomach ulcers and esophagitis, this oral proton pump inhibitor (PPI) is the focus of a trial in the United Kingdom evaluating if PPIs can slow the progression of IPF (NCT04965298).
N-acetylcysteine (NAC). The PRECISIONS trial is evaluating the effect of NAC plus standard-of-care treatment in IPF patients who have the TOLLIP rs3750910 TT genotype (NCT04300920). Participants receive 600 mg NAC orally or matched placebo three times daily for 24 months. Trial completion is scheduled for 2025.
Treprostinil. Already approved to treat pulmonary arterial hypertension and pulmonary hypertension associated with interstitial lung disease, inhaled Treprostinil is the subject of the TETON 1 and 2 trials evaluating its impact on ppFVC after 52 weeks of treatment (NCT04708782, NCT05255991).
Phase 2 candidates
The primary endpoint in most of the phase 2 trials is change in ppFVC capacity from baseline to week 24. The following investigative therapies are in phase 2 trials:
Bexotegrast (PLN-74809), an oral, small molecule, dual-selective inhibitor of alphav/beta6 and alphav/beta1 (NCT04396756).
BBT-877, described as a potent autotaxin (ATX) inhibitor, demonstrated its ability to inhibit lysophosphatidic acid (LPA) production by as much as 90 percent (NCT05483907).
CC-90001, an oral, once-daily c-Jun N-terminal kinases (JNK) inhibitor. JNKs have been implicated in the underlying mechanisms of fibrosis, including epithelial cell death, inflammation and polarization of profibrotic macrophages, fibroblast activation, and collagen production (NCT03142191).
C21 targets the underlying fibrosis in IPF by stimulating the protective arm of the renin-angiotensin system. It also has an upstream effect by promoting alveolar repair by which it can reduce fibrosis formation, stabilize disease, and increase lung capacity (NCT04533022).
CSL312 (garadacimab) is a humanized anti-FXIIa monoclonal antibody administrated intravenously (NCT05130970).
Cudetaxestat, a noncompetitive autotaxin inhibitor (NCT05373914).
Bersiposocin/DWN12088, an inhibitor of prolyl-tRNA synthetase 1 (PARS1), which is suspected to control the pathologic accumulation of collagen containing high amounts of proline in fibrotic diseases (NCT05389215).
ENV-101, a small-molecule inhibitor of the Hedgehog (Hh) signaling pathway, which plays a key role in IPF. This agent was originally developed to target Hh-driven cancers (NCT04968574).
GKT137831 (setanaxib) inhibits nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) isoforms. (NCT03865927).
HZN-825, a lysophosphatidic acid receptor 1 (LPAR1) antagonist. (NCT05032066)
Ifetroban, a potent and selective thromboxane-prostanoid receptor (TPr) antagonist, which exhibits a high affinity for TPr on platelets, vascular and airway smooth muscle, and fibroblasts, and lacks agonistic activity (NCT05571059).
INS018_055, a small-molecule, oral antifibrotic candidate notable for being the first entirely AI-generated drug to enter phase 2 trials. Trial enrollment started in October (NCT05975983, NCT05983920)
Jaktinib dihydrochloride monohydrate, an oral JAK1, JAK2, and JAK3 inhibitor (NCT04312594).
Leramistat, an anti–tumor necrosis factor (TNF) agent (NCT05951296).
LTP001, an oral, selectively deuterated form of pirfenidone designed to retain the antifibrotic and anti-inflammatory activity of pirfenidone with a differentiated pharmacokinetic profile (NCT05497284, NCT05321420).
ME-015 (suplatast tosilate) aims to stabilize ion channels in the neuronal endings in the lungs that mediate IPF-related cough (NCT05983471).
Nalbuphine, a small-molecule, dual-mechanism treatment for chronic cough in IPF. It acts as both a mu opioid receptor antagonist and a kappa opioid receptor agonist (NCT05964335). The CANAL trial, complete last year, is evaluating an extended-release formulation (NCT04030026).
NP-120 (ifenprodil), a small-molecule N-methyl-D-aspartate (NMDA) receptor antagonist, specifically targets the NMDA-type subunit 2B (GluN2B) (NCT04318704).
Orvepitant, a selective antagonist for the NK₁ receptor, is being evaluated to treat IPF-related cough (NCT05815089).
RXC007 (zelasudil), a Rho-associated coiled-coil–containing protein kinase 2 (ROCK2) selective inhibitor, was granted FDA orphan drug designation in August 2023 (NCT05570058).
Saracatinib, a selective Src kinase inhibitor originally developed for oncological indications (NCT04598919).
SHR-1906, an intravenous treatment, inhibits binding of a target protein to a variety of cytokines and growth factors, affects downstream signaling pathways, and reduces cell proliferation and migration (NCT05722964).
TTI-101, an oral, small-molecule inhibitor of signal transducer and activator of transcription (STAT3), which has been found to accumulate in the lungs of IPF patients (NCT05671835).
VAY736 (lanalumab), a BAFF-R inhibitor (NCT03287414).
Vixarelimab, a human monoclonal oncastatin M receptor beta antibody (NCT05785624).
Some investigative programs, however, didn’t make it out of phase 2. The trial evaluating inhaled GB0139, a selective functional antagonist of G-protein–coupled receptor 84, which plays a key role in fibrosis, failed to meet its primary endpoint (NCT03832946). Likewise, oral GLPG1205 failed to show a significant difference in FVC decline vs. placebo (NCT03725852). The program to develop SAR156597, also known as romilkimab, was halted (NCT02345070). ND-L02-s0201n, an siRNA oligonucleotide drug designed to inhibit heat shock protein 47 (HSP47), which regulates collagen synthesis and secretion that causes fibrosis, didn’t show the expected efficacy (NCT03538301).
Phase 1 trials
No fewer than 27 phase 1 trials are evaluating investigative treatments for IPF, many in the early phase or not yet recruiting. According to GlobalData, phase 1 drugs for IPF have a 66% chance of moving onto phase 2. Among the advanced phase 1 trials that have gained corporate backing are:
9MW3811, an anti–interleukin-11 monoclonal antibody IV injection (NCT05912049).
ANG-3070, an oral tyrosine kinase inhibitor targeting platelet-derived growth factor (PDGFR) alpha and beta (NCT05387785).
C106, an angiotensin II type 2 receptor agonist (NCT05427253).
HuL001, which targets alpha-enolase (NCT04540770).
LTI-03, a Caveolin-1 (Cav1)-related peptide designed to restore Cav1 expression in lung tissue (NCT05954988).
ORIN1001, a first-in-class small molecule that selectively blocks the inositol requiring enzyme 1alphase (IRE1) RNAse and blocks X-box binding protein 1 (XBP1) activation (NCT04643769).
PRS-220 is an orally inhaled anticalin protein targeting connective tissue growth factor (CTGF) (NTC05473533).
TRK-250, a single-strand, long-chain nucleic acid that selectively suppresses expression of transforming growth factor-beta 1 (TGF-beta1) protein (NCT03727802).
“While we have therapies that we’re able to give patients, we need to do more and we need to do better,” Dr. Lee said. “We’re all hopeful the next phase 3 clinical trial will be something that will help change the treatment paradigm for our patients. We’re very patient, and hopefully those that are interested in improving this treatment landscape will continue to persist.”
Dr. Lee disclosed financial relationships with Boehringer Ingelheim, Pliant Therapeutics, Blade Therapeutics, United Therapeutics, Eleven P15. and Avalyn Pharma.
With the emergence of pirfenidone and nintedanib over the past decade or so, pulmonologists now have at their disposal two breakthrough antifibrotic agents for the treatment of idiopathic pulmonary fibrosis.
But these two drugs have a number of shortcomings that a host of investigative agents are aiming to address. For one, while pirfenidone and nintedanib have been shown to slow disease progression and improve symptoms, they don’t stop or reverse the disease. Also, a large number of patients with IPF don’t tolerate these drugs well. And, their high cost is a barrier for many patients.
in terms of therapies or interventions that have better efficacy, better long-term tolerability, and that improve symptoms and quality of life for our patients with IPF disease,” said Joyce Lee, MD, associate professor of medicine–pulmonary at the University of Colorado at Denver, Aurora, and senior medical adviser for research and health care quality for the Pulmonary Fibrosis Foundation.
The National Institutes of Health estimates that more than 30,000 new cases of IPF are diagnosed in the United States annually, and as many as 3 million people have the disease worldwide. The 5-year survival rate is less than 40% after diagnosis. Bloomberg News reported that more than 80 pharmaceutical companies are working on IPF treatments. iHealthcareAnalyst estimates the global market for IPF will reach $10.1 billion by 2029 thanks to rapidly increasing prevalence and incidence with age, premium-priced drugs, and rapid approval of new treatments.
The perils of phase 3 studies
A search on ClinicalTrials.gov turned up 89 investigative IPF treatments in human trials. However, the search for alternatives can be perilous. “In the field, we have gotten used to promising phase 2 studies that failed in the phase 3 stage of development,” Dr. Lee said. “I don’t hold my breath these days just in terms of trying to predict whether or not the efficacy will be present in the phase 3 clinical trial.”
Three notable phase 3 flops include the ISABELA 1 and 2 trials of the autotaxin inhibitor ziritaxestat, which failed to meet their primary endpoint and were halted early (JAMA. 2023;329:1567-78). The phase 3 ZEPHYRUS-1 trial failed to show any benefit of pamrevlumab to improve percent predicted force vital capacity (ppFVC) at week 48, causing discontinuation of a second phase 3 trial. The phase 3 STARSCAPE-OLE study of intravenous recombinant human pentraxin-2 was terminated earlier this year when the sponsor, Hoffmann-LaRoche, decided it was unable to meet its primary objective (NCT04594707).
In the meantime, these six other phase 3 programs in IPF are still in the field:
Anlotinib. A phase 2 and 3 trial in China is evaluating 1-year outcomes of once-daily oral anlotinib for treatment of IPF/progressive fibrosis-interstitial lung disease (PF-ILDS) (NCT05828953). Anlotinib is a tyrosine kinase inhibitor (TKI) that targets four factors: vascular endothelial growth factor receptor (VEGR), fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptors (PDGFR), and c-kit. It’s approved in China as a third-line therapy for non–small cell lung cancer (NSCLC).
BI 101550. Enrollment in the FIBRONEER-IPF trial commenced last fall (NCT05321069), with completion scheduled for late next year. BI 1015550 is an oral phosphodiesterase 4B (PDE4B) inhibitor. FIBRONEER-ILD is a separate phase 3 trial in fibrosing idiopathic lung disease (NCT05321082). In both trials, the primary endpoint is the absolute change from baseline in FVC at week 52.
BMS-986278. Results of a phase 2 trial showed that twice-daily treatment with oral BMS-986278 60 mg over 26 weeks reduced the rate of decline in ppFVC by 69% vs. placebo. The phase 3 ALOFT trial has been approved but hasn’t yet started recruiting patients (NCT06003426). BMS-986278 is a lysophosphatidic acid receptor 1 (LPA1) antagonist.
Lanxoprazole. Commonly used to treat and prevent gastrointestinal problems like stomach ulcers and esophagitis, this oral proton pump inhibitor (PPI) is the focus of a trial in the United Kingdom evaluating if PPIs can slow the progression of IPF (NCT04965298).
N-acetylcysteine (NAC). The PRECISIONS trial is evaluating the effect of NAC plus standard-of-care treatment in IPF patients who have the TOLLIP rs3750910 TT genotype (NCT04300920). Participants receive 600 mg NAC orally or matched placebo three times daily for 24 months. Trial completion is scheduled for 2025.
Treprostinil. Already approved to treat pulmonary arterial hypertension and pulmonary hypertension associated with interstitial lung disease, inhaled Treprostinil is the subject of the TETON 1 and 2 trials evaluating its impact on ppFVC after 52 weeks of treatment (NCT04708782, NCT05255991).
Phase 2 candidates
The primary endpoint in most of the phase 2 trials is change in ppFVC capacity from baseline to week 24. The following investigative therapies are in phase 2 trials:
Bexotegrast (PLN-74809), an oral, small molecule, dual-selective inhibitor of alphav/beta6 and alphav/beta1 (NCT04396756).
BBT-877, described as a potent autotaxin (ATX) inhibitor, demonstrated its ability to inhibit lysophosphatidic acid (LPA) production by as much as 90 percent (NCT05483907).
CC-90001, an oral, once-daily c-Jun N-terminal kinases (JNK) inhibitor. JNKs have been implicated in the underlying mechanisms of fibrosis, including epithelial cell death, inflammation and polarization of profibrotic macrophages, fibroblast activation, and collagen production (NCT03142191).
C21 targets the underlying fibrosis in IPF by stimulating the protective arm of the renin-angiotensin system. It also has an upstream effect by promoting alveolar repair by which it can reduce fibrosis formation, stabilize disease, and increase lung capacity (NCT04533022).
CSL312 (garadacimab) is a humanized anti-FXIIa monoclonal antibody administrated intravenously (NCT05130970).
Cudetaxestat, a noncompetitive autotaxin inhibitor (NCT05373914).
Bersiposocin/DWN12088, an inhibitor of prolyl-tRNA synthetase 1 (PARS1), which is suspected to control the pathologic accumulation of collagen containing high amounts of proline in fibrotic diseases (NCT05389215).
ENV-101, a small-molecule inhibitor of the Hedgehog (Hh) signaling pathway, which plays a key role in IPF. This agent was originally developed to target Hh-driven cancers (NCT04968574).
GKT137831 (setanaxib) inhibits nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) isoforms. (NCT03865927).
HZN-825, a lysophosphatidic acid receptor 1 (LPAR1) antagonist. (NCT05032066)
Ifetroban, a potent and selective thromboxane-prostanoid receptor (TPr) antagonist, which exhibits a high affinity for TPr on platelets, vascular and airway smooth muscle, and fibroblasts, and lacks agonistic activity (NCT05571059).
INS018_055, a small-molecule, oral antifibrotic candidate notable for being the first entirely AI-generated drug to enter phase 2 trials. Trial enrollment started in October (NCT05975983, NCT05983920)
Jaktinib dihydrochloride monohydrate, an oral JAK1, JAK2, and JAK3 inhibitor (NCT04312594).
Leramistat, an anti–tumor necrosis factor (TNF) agent (NCT05951296).
LTP001, an oral, selectively deuterated form of pirfenidone designed to retain the antifibrotic and anti-inflammatory activity of pirfenidone with a differentiated pharmacokinetic profile (NCT05497284, NCT05321420).
ME-015 (suplatast tosilate) aims to stabilize ion channels in the neuronal endings in the lungs that mediate IPF-related cough (NCT05983471).
Nalbuphine, a small-molecule, dual-mechanism treatment for chronic cough in IPF. It acts as both a mu opioid receptor antagonist and a kappa opioid receptor agonist (NCT05964335). The CANAL trial, complete last year, is evaluating an extended-release formulation (NCT04030026).
NP-120 (ifenprodil), a small-molecule N-methyl-D-aspartate (NMDA) receptor antagonist, specifically targets the NMDA-type subunit 2B (GluN2B) (NCT04318704).
Orvepitant, a selective antagonist for the NK₁ receptor, is being evaluated to treat IPF-related cough (NCT05815089).
RXC007 (zelasudil), a Rho-associated coiled-coil–containing protein kinase 2 (ROCK2) selective inhibitor, was granted FDA orphan drug designation in August 2023 (NCT05570058).
Saracatinib, a selective Src kinase inhibitor originally developed for oncological indications (NCT04598919).
SHR-1906, an intravenous treatment, inhibits binding of a target protein to a variety of cytokines and growth factors, affects downstream signaling pathways, and reduces cell proliferation and migration (NCT05722964).
TTI-101, an oral, small-molecule inhibitor of signal transducer and activator of transcription (STAT3), which has been found to accumulate in the lungs of IPF patients (NCT05671835).
VAY736 (lanalumab), a BAFF-R inhibitor (NCT03287414).
Vixarelimab, a human monoclonal oncastatin M receptor beta antibody (NCT05785624).
Some investigative programs, however, didn’t make it out of phase 2. The trial evaluating inhaled GB0139, a selective functional antagonist of G-protein–coupled receptor 84, which plays a key role in fibrosis, failed to meet its primary endpoint (NCT03832946). Likewise, oral GLPG1205 failed to show a significant difference in FVC decline vs. placebo (NCT03725852). The program to develop SAR156597, also known as romilkimab, was halted (NCT02345070). ND-L02-s0201n, an siRNA oligonucleotide drug designed to inhibit heat shock protein 47 (HSP47), which regulates collagen synthesis and secretion that causes fibrosis, didn’t show the expected efficacy (NCT03538301).
Phase 1 trials
No fewer than 27 phase 1 trials are evaluating investigative treatments for IPF, many in the early phase or not yet recruiting. According to GlobalData, phase 1 drugs for IPF have a 66% chance of moving onto phase 2. Among the advanced phase 1 trials that have gained corporate backing are:
9MW3811, an anti–interleukin-11 monoclonal antibody IV injection (NCT05912049).
ANG-3070, an oral tyrosine kinase inhibitor targeting platelet-derived growth factor (PDGFR) alpha and beta (NCT05387785).
C106, an angiotensin II type 2 receptor agonist (NCT05427253).
HuL001, which targets alpha-enolase (NCT04540770).
LTI-03, a Caveolin-1 (Cav1)-related peptide designed to restore Cav1 expression in lung tissue (NCT05954988).
ORIN1001, a first-in-class small molecule that selectively blocks the inositol requiring enzyme 1alphase (IRE1) RNAse and blocks X-box binding protein 1 (XBP1) activation (NCT04643769).
PRS-220 is an orally inhaled anticalin protein targeting connective tissue growth factor (CTGF) (NTC05473533).
TRK-250, a single-strand, long-chain nucleic acid that selectively suppresses expression of transforming growth factor-beta 1 (TGF-beta1) protein (NCT03727802).
“While we have therapies that we’re able to give patients, we need to do more and we need to do better,” Dr. Lee said. “We’re all hopeful the next phase 3 clinical trial will be something that will help change the treatment paradigm for our patients. We’re very patient, and hopefully those that are interested in improving this treatment landscape will continue to persist.”
Dr. Lee disclosed financial relationships with Boehringer Ingelheim, Pliant Therapeutics, Blade Therapeutics, United Therapeutics, Eleven P15. and Avalyn Pharma.
With the emergence of pirfenidone and nintedanib over the past decade or so, pulmonologists now have at their disposal two breakthrough antifibrotic agents for the treatment of idiopathic pulmonary fibrosis.
But these two drugs have a number of shortcomings that a host of investigative agents are aiming to address. For one, while pirfenidone and nintedanib have been shown to slow disease progression and improve symptoms, they don’t stop or reverse the disease. Also, a large number of patients with IPF don’t tolerate these drugs well. And, their high cost is a barrier for many patients.
in terms of therapies or interventions that have better efficacy, better long-term tolerability, and that improve symptoms and quality of life for our patients with IPF disease,” said Joyce Lee, MD, associate professor of medicine–pulmonary at the University of Colorado at Denver, Aurora, and senior medical adviser for research and health care quality for the Pulmonary Fibrosis Foundation.
The National Institutes of Health estimates that more than 30,000 new cases of IPF are diagnosed in the United States annually, and as many as 3 million people have the disease worldwide. The 5-year survival rate is less than 40% after diagnosis. Bloomberg News reported that more than 80 pharmaceutical companies are working on IPF treatments. iHealthcareAnalyst estimates the global market for IPF will reach $10.1 billion by 2029 thanks to rapidly increasing prevalence and incidence with age, premium-priced drugs, and rapid approval of new treatments.
The perils of phase 3 studies
A search on ClinicalTrials.gov turned up 89 investigative IPF treatments in human trials. However, the search for alternatives can be perilous. “In the field, we have gotten used to promising phase 2 studies that failed in the phase 3 stage of development,” Dr. Lee said. “I don’t hold my breath these days just in terms of trying to predict whether or not the efficacy will be present in the phase 3 clinical trial.”
Three notable phase 3 flops include the ISABELA 1 and 2 trials of the autotaxin inhibitor ziritaxestat, which failed to meet their primary endpoint and were halted early (JAMA. 2023;329:1567-78). The phase 3 ZEPHYRUS-1 trial failed to show any benefit of pamrevlumab to improve percent predicted force vital capacity (ppFVC) at week 48, causing discontinuation of a second phase 3 trial. The phase 3 STARSCAPE-OLE study of intravenous recombinant human pentraxin-2 was terminated earlier this year when the sponsor, Hoffmann-LaRoche, decided it was unable to meet its primary objective (NCT04594707).
In the meantime, these six other phase 3 programs in IPF are still in the field:
Anlotinib. A phase 2 and 3 trial in China is evaluating 1-year outcomes of once-daily oral anlotinib for treatment of IPF/progressive fibrosis-interstitial lung disease (PF-ILDS) (NCT05828953). Anlotinib is a tyrosine kinase inhibitor (TKI) that targets four factors: vascular endothelial growth factor receptor (VEGR), fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptors (PDGFR), and c-kit. It’s approved in China as a third-line therapy for non–small cell lung cancer (NSCLC).
BI 101550. Enrollment in the FIBRONEER-IPF trial commenced last fall (NCT05321069), with completion scheduled for late next year. BI 1015550 is an oral phosphodiesterase 4B (PDE4B) inhibitor. FIBRONEER-ILD is a separate phase 3 trial in fibrosing idiopathic lung disease (NCT05321082). In both trials, the primary endpoint is the absolute change from baseline in FVC at week 52.
BMS-986278. Results of a phase 2 trial showed that twice-daily treatment with oral BMS-986278 60 mg over 26 weeks reduced the rate of decline in ppFVC by 69% vs. placebo. The phase 3 ALOFT trial has been approved but hasn’t yet started recruiting patients (NCT06003426). BMS-986278 is a lysophosphatidic acid receptor 1 (LPA1) antagonist.
Lanxoprazole. Commonly used to treat and prevent gastrointestinal problems like stomach ulcers and esophagitis, this oral proton pump inhibitor (PPI) is the focus of a trial in the United Kingdom evaluating if PPIs can slow the progression of IPF (NCT04965298).
N-acetylcysteine (NAC). The PRECISIONS trial is evaluating the effect of NAC plus standard-of-care treatment in IPF patients who have the TOLLIP rs3750910 TT genotype (NCT04300920). Participants receive 600 mg NAC orally or matched placebo three times daily for 24 months. Trial completion is scheduled for 2025.
Treprostinil. Already approved to treat pulmonary arterial hypertension and pulmonary hypertension associated with interstitial lung disease, inhaled Treprostinil is the subject of the TETON 1 and 2 trials evaluating its impact on ppFVC after 52 weeks of treatment (NCT04708782, NCT05255991).
Phase 2 candidates
The primary endpoint in most of the phase 2 trials is change in ppFVC capacity from baseline to week 24. The following investigative therapies are in phase 2 trials:
Bexotegrast (PLN-74809), an oral, small molecule, dual-selective inhibitor of alphav/beta6 and alphav/beta1 (NCT04396756).
BBT-877, described as a potent autotaxin (ATX) inhibitor, demonstrated its ability to inhibit lysophosphatidic acid (LPA) production by as much as 90 percent (NCT05483907).
CC-90001, an oral, once-daily c-Jun N-terminal kinases (JNK) inhibitor. JNKs have been implicated in the underlying mechanisms of fibrosis, including epithelial cell death, inflammation and polarization of profibrotic macrophages, fibroblast activation, and collagen production (NCT03142191).
C21 targets the underlying fibrosis in IPF by stimulating the protective arm of the renin-angiotensin system. It also has an upstream effect by promoting alveolar repair by which it can reduce fibrosis formation, stabilize disease, and increase lung capacity (NCT04533022).
CSL312 (garadacimab) is a humanized anti-FXIIa monoclonal antibody administrated intravenously (NCT05130970).
Cudetaxestat, a noncompetitive autotaxin inhibitor (NCT05373914).
Bersiposocin/DWN12088, an inhibitor of prolyl-tRNA synthetase 1 (PARS1), which is suspected to control the pathologic accumulation of collagen containing high amounts of proline in fibrotic diseases (NCT05389215).
ENV-101, a small-molecule inhibitor of the Hedgehog (Hh) signaling pathway, which plays a key role in IPF. This agent was originally developed to target Hh-driven cancers (NCT04968574).
GKT137831 (setanaxib) inhibits nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) isoforms. (NCT03865927).
HZN-825, a lysophosphatidic acid receptor 1 (LPAR1) antagonist. (NCT05032066)
Ifetroban, a potent and selective thromboxane-prostanoid receptor (TPr) antagonist, which exhibits a high affinity for TPr on platelets, vascular and airway smooth muscle, and fibroblasts, and lacks agonistic activity (NCT05571059).
INS018_055, a small-molecule, oral antifibrotic candidate notable for being the first entirely AI-generated drug to enter phase 2 trials. Trial enrollment started in October (NCT05975983, NCT05983920)
Jaktinib dihydrochloride monohydrate, an oral JAK1, JAK2, and JAK3 inhibitor (NCT04312594).
Leramistat, an anti–tumor necrosis factor (TNF) agent (NCT05951296).
LTP001, an oral, selectively deuterated form of pirfenidone designed to retain the antifibrotic and anti-inflammatory activity of pirfenidone with a differentiated pharmacokinetic profile (NCT05497284, NCT05321420).
ME-015 (suplatast tosilate) aims to stabilize ion channels in the neuronal endings in the lungs that mediate IPF-related cough (NCT05983471).
Nalbuphine, a small-molecule, dual-mechanism treatment for chronic cough in IPF. It acts as both a mu opioid receptor antagonist and a kappa opioid receptor agonist (NCT05964335). The CANAL trial, complete last year, is evaluating an extended-release formulation (NCT04030026).
NP-120 (ifenprodil), a small-molecule N-methyl-D-aspartate (NMDA) receptor antagonist, specifically targets the NMDA-type subunit 2B (GluN2B) (NCT04318704).
Orvepitant, a selective antagonist for the NK₁ receptor, is being evaluated to treat IPF-related cough (NCT05815089).
RXC007 (zelasudil), a Rho-associated coiled-coil–containing protein kinase 2 (ROCK2) selective inhibitor, was granted FDA orphan drug designation in August 2023 (NCT05570058).
Saracatinib, a selective Src kinase inhibitor originally developed for oncological indications (NCT04598919).
SHR-1906, an intravenous treatment, inhibits binding of a target protein to a variety of cytokines and growth factors, affects downstream signaling pathways, and reduces cell proliferation and migration (NCT05722964).
TTI-101, an oral, small-molecule inhibitor of signal transducer and activator of transcription (STAT3), which has been found to accumulate in the lungs of IPF patients (NCT05671835).
VAY736 (lanalumab), a BAFF-R inhibitor (NCT03287414).
Vixarelimab, a human monoclonal oncastatin M receptor beta antibody (NCT05785624).
Some investigative programs, however, didn’t make it out of phase 2. The trial evaluating inhaled GB0139, a selective functional antagonist of G-protein–coupled receptor 84, which plays a key role in fibrosis, failed to meet its primary endpoint (NCT03832946). Likewise, oral GLPG1205 failed to show a significant difference in FVC decline vs. placebo (NCT03725852). The program to develop SAR156597, also known as romilkimab, was halted (NCT02345070). ND-L02-s0201n, an siRNA oligonucleotide drug designed to inhibit heat shock protein 47 (HSP47), which regulates collagen synthesis and secretion that causes fibrosis, didn’t show the expected efficacy (NCT03538301).
Phase 1 trials
No fewer than 27 phase 1 trials are evaluating investigative treatments for IPF, many in the early phase or not yet recruiting. According to GlobalData, phase 1 drugs for IPF have a 66% chance of moving onto phase 2. Among the advanced phase 1 trials that have gained corporate backing are:
9MW3811, an anti–interleukin-11 monoclonal antibody IV injection (NCT05912049).
ANG-3070, an oral tyrosine kinase inhibitor targeting platelet-derived growth factor (PDGFR) alpha and beta (NCT05387785).
C106, an angiotensin II type 2 receptor agonist (NCT05427253).
HuL001, which targets alpha-enolase (NCT04540770).
LTI-03, a Caveolin-1 (Cav1)-related peptide designed to restore Cav1 expression in lung tissue (NCT05954988).
ORIN1001, a first-in-class small molecule that selectively blocks the inositol requiring enzyme 1alphase (IRE1) RNAse and blocks X-box binding protein 1 (XBP1) activation (NCT04643769).
PRS-220 is an orally inhaled anticalin protein targeting connective tissue growth factor (CTGF) (NTC05473533).
TRK-250, a single-strand, long-chain nucleic acid that selectively suppresses expression of transforming growth factor-beta 1 (TGF-beta1) protein (NCT03727802).
“While we have therapies that we’re able to give patients, we need to do more and we need to do better,” Dr. Lee said. “We’re all hopeful the next phase 3 clinical trial will be something that will help change the treatment paradigm for our patients. We’re very patient, and hopefully those that are interested in improving this treatment landscape will continue to persist.”
Dr. Lee disclosed financial relationships with Boehringer Ingelheim, Pliant Therapeutics, Blade Therapeutics, United Therapeutics, Eleven P15. and Avalyn Pharma.
Residential move after a heart attack raises mortality risk
data suggest.
In a prospective study that followed more than 3,000 patients with AMI over 2 decades, each residential move was associated with a 12% higher rate of death.
“This study determined that residential mobility was more important than any other social factor that we studied,” investigator David Alter, MD, PhD, chair of cardiovascular and metabolic research at the University Health Network–Toronto Rehabilitation Institute and associate professor of medicine at the University of Toronto, said in an interview.
The results were published online in the Canadian Journal of Cardiology.
Moving and mortality
“There’s been very little work, surprisingly, on what happens when individuals move from community to community,” said Dr. Alter. “It is that movement from community to community that is a factor within the social context that needs to be explored better. To the best of our knowledge, up until our study, it has been studied very briefly in the literature.”
The prospective cohort study sample included 3,369 patients who had an AMI between Dec. 1, 1999, and March 30, 2023. The investigators followed participants until death or the last available follow-up date of March 30, 2020. They defined a residential move as a relocation from one postal code region to another.
The investigators drew data from multiple sources, including the prospective, observational Socio-Economic Status and Acute Myocardial Infarction study, which encompassed more than 35,000 patient life-years following hospitalization for a first heart attack in Ontario. Mortality data were collected from the Ontario Registered Persons Data Base. Other sources included Statistics Canada for information on neighborhood income, the Canadian Institutes for Health Information for patients’ clinical factors and comorbidities, and the Ontario Health Insurance Plan (OHIP) database for physician visits. Information on long-term care admissions came from the Continuous Care Reporting System-Long Term Care, OHIP, and the Ontario Drugs Benefit databases, the latter of which also provided information on medication prescriptions for individuals aged 65 years and older.
Patients’ ages ranged from 19 to 101 years (median age, 65 years). About 69% of patients were men. Of the study population, 1,828 patients (54.3%) had at least one residential move during the study period. Approximately 87% died in the community or moved from home into a long-term care facility as an end-of-life destination. Overall, 84.8% of patients who were admitted to long-term care facilities died.
The study also tracked the socioeconomic status of persons living in the postal code regions from and to which patients moved. About 32% of patients moved to a neighborhood with a lower socioeconomic status, and 30.5% moved to an area with a higher socioeconomic status.
Each residential move was associated with a 12% higher rate of death and a 26% higher rate of long-term institutionalization for end-of-life care. In unadjusted analyses, the rate of death was almost double for those who moved more frequently: 44.3% for those who moved two or more times versus 24.8% for those who moved once in 10 years.
Accounting for a multitude of variables, such as the socioeconomic status of areas that patients moved between, is a strength of the study, said Dr. Alter. But the study lacked information about why people moved.
“Where this study has a huge amount of strength is that it was designed specifically to really understand a patient’s clinical and psychosocial profile at the start of their journey, their first AMI. But the fact that we took it from heart attack onward is also a strength because it characterizes and anchors a clinical context in which we were following patients out,” said Dr. Alter.
‘An important marker’
In a comment, Paul Oh, MD, medical director of the cardiovascular disease prevention and rehabilitation program at University Health Network, said: “This is a very well-designed study and analysis from a cohort that has provided important insights about the role of socioeconomic factors and long-term outcomes post MI over many years.” Dr. Oh did not participate in the study.
“A few covariates that could impact on outcomes, like institutionalization, were not available to include in adjusted analyses – e.g., functional status, frailty, mild cognitive changes, and availability of social supports in the home,” he said.
The findings add another variable that cardiologists who care for post-MI patients need to be aware of, Dr. Oh added. “Clinicians need better awareness that the need to change residence is an important marker of changing health status and may portend end-of-life events in the near future. The need to change residence can signal an important change in physical, cognitive, and social circumstances that needs to be further explored during clinical encounters, with the goal of identifying and addressing any potentially reversible issues and identifying additional supports that may help that individual continue to live independently in their own home.”
The study was supported by ICES, which receives funding from the Ontario Ministry of Health. The investigators disclosed no relevant financial relationships. Dr. Oh serves on research boards for Lilly and Novartis and receives research funding from Apple.
A version of this article first appeared on Medscape.com.
data suggest.
In a prospective study that followed more than 3,000 patients with AMI over 2 decades, each residential move was associated with a 12% higher rate of death.
“This study determined that residential mobility was more important than any other social factor that we studied,” investigator David Alter, MD, PhD, chair of cardiovascular and metabolic research at the University Health Network–Toronto Rehabilitation Institute and associate professor of medicine at the University of Toronto, said in an interview.
The results were published online in the Canadian Journal of Cardiology.
Moving and mortality
“There’s been very little work, surprisingly, on what happens when individuals move from community to community,” said Dr. Alter. “It is that movement from community to community that is a factor within the social context that needs to be explored better. To the best of our knowledge, up until our study, it has been studied very briefly in the literature.”
The prospective cohort study sample included 3,369 patients who had an AMI between Dec. 1, 1999, and March 30, 2023. The investigators followed participants until death or the last available follow-up date of March 30, 2020. They defined a residential move as a relocation from one postal code region to another.
The investigators drew data from multiple sources, including the prospective, observational Socio-Economic Status and Acute Myocardial Infarction study, which encompassed more than 35,000 patient life-years following hospitalization for a first heart attack in Ontario. Mortality data were collected from the Ontario Registered Persons Data Base. Other sources included Statistics Canada for information on neighborhood income, the Canadian Institutes for Health Information for patients’ clinical factors and comorbidities, and the Ontario Health Insurance Plan (OHIP) database for physician visits. Information on long-term care admissions came from the Continuous Care Reporting System-Long Term Care, OHIP, and the Ontario Drugs Benefit databases, the latter of which also provided information on medication prescriptions for individuals aged 65 years and older.
Patients’ ages ranged from 19 to 101 years (median age, 65 years). About 69% of patients were men. Of the study population, 1,828 patients (54.3%) had at least one residential move during the study period. Approximately 87% died in the community or moved from home into a long-term care facility as an end-of-life destination. Overall, 84.8% of patients who were admitted to long-term care facilities died.
The study also tracked the socioeconomic status of persons living in the postal code regions from and to which patients moved. About 32% of patients moved to a neighborhood with a lower socioeconomic status, and 30.5% moved to an area with a higher socioeconomic status.
Each residential move was associated with a 12% higher rate of death and a 26% higher rate of long-term institutionalization for end-of-life care. In unadjusted analyses, the rate of death was almost double for those who moved more frequently: 44.3% for those who moved two or more times versus 24.8% for those who moved once in 10 years.
Accounting for a multitude of variables, such as the socioeconomic status of areas that patients moved between, is a strength of the study, said Dr. Alter. But the study lacked information about why people moved.
“Where this study has a huge amount of strength is that it was designed specifically to really understand a patient’s clinical and psychosocial profile at the start of their journey, their first AMI. But the fact that we took it from heart attack onward is also a strength because it characterizes and anchors a clinical context in which we were following patients out,” said Dr. Alter.
‘An important marker’
In a comment, Paul Oh, MD, medical director of the cardiovascular disease prevention and rehabilitation program at University Health Network, said: “This is a very well-designed study and analysis from a cohort that has provided important insights about the role of socioeconomic factors and long-term outcomes post MI over many years.” Dr. Oh did not participate in the study.
“A few covariates that could impact on outcomes, like institutionalization, were not available to include in adjusted analyses – e.g., functional status, frailty, mild cognitive changes, and availability of social supports in the home,” he said.
The findings add another variable that cardiologists who care for post-MI patients need to be aware of, Dr. Oh added. “Clinicians need better awareness that the need to change residence is an important marker of changing health status and may portend end-of-life events in the near future. The need to change residence can signal an important change in physical, cognitive, and social circumstances that needs to be further explored during clinical encounters, with the goal of identifying and addressing any potentially reversible issues and identifying additional supports that may help that individual continue to live independently in their own home.”
The study was supported by ICES, which receives funding from the Ontario Ministry of Health. The investigators disclosed no relevant financial relationships. Dr. Oh serves on research boards for Lilly and Novartis and receives research funding from Apple.
A version of this article first appeared on Medscape.com.
data suggest.
In a prospective study that followed more than 3,000 patients with AMI over 2 decades, each residential move was associated with a 12% higher rate of death.
“This study determined that residential mobility was more important than any other social factor that we studied,” investigator David Alter, MD, PhD, chair of cardiovascular and metabolic research at the University Health Network–Toronto Rehabilitation Institute and associate professor of medicine at the University of Toronto, said in an interview.
The results were published online in the Canadian Journal of Cardiology.
Moving and mortality
“There’s been very little work, surprisingly, on what happens when individuals move from community to community,” said Dr. Alter. “It is that movement from community to community that is a factor within the social context that needs to be explored better. To the best of our knowledge, up until our study, it has been studied very briefly in the literature.”
The prospective cohort study sample included 3,369 patients who had an AMI between Dec. 1, 1999, and March 30, 2023. The investigators followed participants until death or the last available follow-up date of March 30, 2020. They defined a residential move as a relocation from one postal code region to another.
The investigators drew data from multiple sources, including the prospective, observational Socio-Economic Status and Acute Myocardial Infarction study, which encompassed more than 35,000 patient life-years following hospitalization for a first heart attack in Ontario. Mortality data were collected from the Ontario Registered Persons Data Base. Other sources included Statistics Canada for information on neighborhood income, the Canadian Institutes for Health Information for patients’ clinical factors and comorbidities, and the Ontario Health Insurance Plan (OHIP) database for physician visits. Information on long-term care admissions came from the Continuous Care Reporting System-Long Term Care, OHIP, and the Ontario Drugs Benefit databases, the latter of which also provided information on medication prescriptions for individuals aged 65 years and older.
Patients’ ages ranged from 19 to 101 years (median age, 65 years). About 69% of patients were men. Of the study population, 1,828 patients (54.3%) had at least one residential move during the study period. Approximately 87% died in the community or moved from home into a long-term care facility as an end-of-life destination. Overall, 84.8% of patients who were admitted to long-term care facilities died.
The study also tracked the socioeconomic status of persons living in the postal code regions from and to which patients moved. About 32% of patients moved to a neighborhood with a lower socioeconomic status, and 30.5% moved to an area with a higher socioeconomic status.
Each residential move was associated with a 12% higher rate of death and a 26% higher rate of long-term institutionalization for end-of-life care. In unadjusted analyses, the rate of death was almost double for those who moved more frequently: 44.3% for those who moved two or more times versus 24.8% for those who moved once in 10 years.
Accounting for a multitude of variables, such as the socioeconomic status of areas that patients moved between, is a strength of the study, said Dr. Alter. But the study lacked information about why people moved.
“Where this study has a huge amount of strength is that it was designed specifically to really understand a patient’s clinical and psychosocial profile at the start of their journey, their first AMI. But the fact that we took it from heart attack onward is also a strength because it characterizes and anchors a clinical context in which we were following patients out,” said Dr. Alter.
‘An important marker’
In a comment, Paul Oh, MD, medical director of the cardiovascular disease prevention and rehabilitation program at University Health Network, said: “This is a very well-designed study and analysis from a cohort that has provided important insights about the role of socioeconomic factors and long-term outcomes post MI over many years.” Dr. Oh did not participate in the study.
“A few covariates that could impact on outcomes, like institutionalization, were not available to include in adjusted analyses – e.g., functional status, frailty, mild cognitive changes, and availability of social supports in the home,” he said.
The findings add another variable that cardiologists who care for post-MI patients need to be aware of, Dr. Oh added. “Clinicians need better awareness that the need to change residence is an important marker of changing health status and may portend end-of-life events in the near future. The need to change residence can signal an important change in physical, cognitive, and social circumstances that needs to be further explored during clinical encounters, with the goal of identifying and addressing any potentially reversible issues and identifying additional supports that may help that individual continue to live independently in their own home.”
The study was supported by ICES, which receives funding from the Ontario Ministry of Health. The investigators disclosed no relevant financial relationships. Dr. Oh serves on research boards for Lilly and Novartis and receives research funding from Apple.
A version of this article first appeared on Medscape.com.
FROM THE CANADIAN JOURNAL OF CARDIOLOGY
Few meet eligibility for newer Alzheimer’s drugs
, a cross sectional study has found.
Reporting in the journal Neurology, researchers from the Mayo Clinic in Rochester, Minn., and the University of Chicago found that only a small percentage of patients in the Mayo Clinic Study of Aging (MCSA) with mild cognitive impairment (MCI) or mild dementia due to Alzheimer’s disease would meet the clinical trial eligibility requirements of either agent.
“Our study results show only a small percentage of people with early Alzheimer’s disease may be eligible to receive treatment, mostly due to chronic health conditions and brain scan abnormalities common in older adults,” said lead researcher Maria Vassilaki, MD, PhD, an epidemiologist at Mayo Clinic in Rochester, Minn.
Applying clinical trial exclusion criteria to a broader population
The study included 237 people aged 50-90, 222 who had MCI and 15 with mild dementia, and whose brain scans showed increased amounts of amyloid-beta plaques. Average age of the participants was 80.9 years and 97.5% were White (99.6% not Hispanic or Latino).
The researchers then looked at the eligibility criteria for the pivotal clinical trials for lecanemab, which the U.S. Food and Drug Administration approved in January this year, and aducanumab, which the FDA cleared in 2021. Both drugs received FDA accelerated approval.
For lecanemab, clinical trial inclusion required specific scores for the Clinical Dementia Rating (CDR) (other than 0.5 or 1.0), Wechsler Memory Scale (WMS-R) Logical Memory II (which varied with age group), or Mini-Mental State Examination (MMSE) (22 to 30). A body mass index between 17 and 35 kg/m2 was also an inclusion criteria. Only 112 people, or 47%, met the inclusion criteria. Exclusion criteria included a history of cardiovascular disease or cancer, Parkinson’s disease, or brain injury, or a positive brain scan. When the exclusion criteria were applied, only 19 people, or 8%, qualified for the lecanemab trial.
When the researchers modified the exclusion criteria to include all study participants with MCI but not applying results from additional cognitive tests, 17.4% of MCSA patients would have been eligible for the lecanemab trial.
Aducanumab clinical trial inclusion criteria were a CDR global score other than 0.5 and an MMSE below 24, with an age cutoff of 85 years. Only 104 of the MCSA population, or 44%, met the clinical trial criteria. When the researchers applied the exclusion criteria for cardiovascular disease, central nervous system-related exclusions (such as brain cancer or epilepsy), a history of cancer, or brain scan abnormalities, they found that only 12 people, or 5%, would have been eligible for an aducanumab trial.
“Clinical trials often have strict eligibility criteria and could exclude those with other conditions that could be common in older adults,” Dr. Vassilaki said in emailed comments. “Thus, we wanted to examine if we apply these criteria to a study that recruits participants from the community, how many of the individuals in the early symptomatic stages, mild cognitive impairment or mild dementia due to Alzheimer’s disease, would be eligible for the treatment.”
Dr. Vassilaki said these drugs need to be studied in larger, more diverse populations, as well as in less healthy populations, before they’re more widely available to people with Alzheimer’s disease. “In addition,” she said, “we can learn more from the postmarketing surveillance of side effects and also from registries of patients receiving these treatments.”
One limitation of the study Dr. Vassilaki pointed out is the overwhelmingly White population. Evaluating the clinical trial eligibility criteria in more diverse populations is crucial, she said.
Estimating the number of patients who would qualify for treatment
In an accompanying commentary, Matthew Howes, MD, of Butler Hospital and Brown University in Providence, R.I., and colleagues wrote that the study findings provide health systems planning to offer amyloid-lowering antibodies for Alzheimer’s disease an estimate of how many patients would be eligible for the treatments. “Providers must exercise clinical judgment in selecting patients for treatment with shared decision-making with patients and families,” the commentators wrote.
The study was supported by the National Institutes of Health, the National Institute on Aging, the Alexander Family Alzheimer’s Disease Research Professorship of the Mayo Clinic, the Mayo Foundation for Medical Education and Research, the Liston Award, the GHR Foundation, and the Schuler Foundation. Dr. Vassilaki disclosed relationships with F. Hoffmann-La Roche, Abbott Laboratories, Johnson & Johnson, Medtronic, Merck, and Amgen. Dr. Howe has no relevant disclosures.
, a cross sectional study has found.
Reporting in the journal Neurology, researchers from the Mayo Clinic in Rochester, Minn., and the University of Chicago found that only a small percentage of patients in the Mayo Clinic Study of Aging (MCSA) with mild cognitive impairment (MCI) or mild dementia due to Alzheimer’s disease would meet the clinical trial eligibility requirements of either agent.
“Our study results show only a small percentage of people with early Alzheimer’s disease may be eligible to receive treatment, mostly due to chronic health conditions and brain scan abnormalities common in older adults,” said lead researcher Maria Vassilaki, MD, PhD, an epidemiologist at Mayo Clinic in Rochester, Minn.
Applying clinical trial exclusion criteria to a broader population
The study included 237 people aged 50-90, 222 who had MCI and 15 with mild dementia, and whose brain scans showed increased amounts of amyloid-beta plaques. Average age of the participants was 80.9 years and 97.5% were White (99.6% not Hispanic or Latino).
The researchers then looked at the eligibility criteria for the pivotal clinical trials for lecanemab, which the U.S. Food and Drug Administration approved in January this year, and aducanumab, which the FDA cleared in 2021. Both drugs received FDA accelerated approval.
For lecanemab, clinical trial inclusion required specific scores for the Clinical Dementia Rating (CDR) (other than 0.5 or 1.0), Wechsler Memory Scale (WMS-R) Logical Memory II (which varied with age group), or Mini-Mental State Examination (MMSE) (22 to 30). A body mass index between 17 and 35 kg/m2 was also an inclusion criteria. Only 112 people, or 47%, met the inclusion criteria. Exclusion criteria included a history of cardiovascular disease or cancer, Parkinson’s disease, or brain injury, or a positive brain scan. When the exclusion criteria were applied, only 19 people, or 8%, qualified for the lecanemab trial.
When the researchers modified the exclusion criteria to include all study participants with MCI but not applying results from additional cognitive tests, 17.4% of MCSA patients would have been eligible for the lecanemab trial.
Aducanumab clinical trial inclusion criteria were a CDR global score other than 0.5 and an MMSE below 24, with an age cutoff of 85 years. Only 104 of the MCSA population, or 44%, met the clinical trial criteria. When the researchers applied the exclusion criteria for cardiovascular disease, central nervous system-related exclusions (such as brain cancer or epilepsy), a history of cancer, or brain scan abnormalities, they found that only 12 people, or 5%, would have been eligible for an aducanumab trial.
“Clinical trials often have strict eligibility criteria and could exclude those with other conditions that could be common in older adults,” Dr. Vassilaki said in emailed comments. “Thus, we wanted to examine if we apply these criteria to a study that recruits participants from the community, how many of the individuals in the early symptomatic stages, mild cognitive impairment or mild dementia due to Alzheimer’s disease, would be eligible for the treatment.”
Dr. Vassilaki said these drugs need to be studied in larger, more diverse populations, as well as in less healthy populations, before they’re more widely available to people with Alzheimer’s disease. “In addition,” she said, “we can learn more from the postmarketing surveillance of side effects and also from registries of patients receiving these treatments.”
One limitation of the study Dr. Vassilaki pointed out is the overwhelmingly White population. Evaluating the clinical trial eligibility criteria in more diverse populations is crucial, she said.
Estimating the number of patients who would qualify for treatment
In an accompanying commentary, Matthew Howes, MD, of Butler Hospital and Brown University in Providence, R.I., and colleagues wrote that the study findings provide health systems planning to offer amyloid-lowering antibodies for Alzheimer’s disease an estimate of how many patients would be eligible for the treatments. “Providers must exercise clinical judgment in selecting patients for treatment with shared decision-making with patients and families,” the commentators wrote.
The study was supported by the National Institutes of Health, the National Institute on Aging, the Alexander Family Alzheimer’s Disease Research Professorship of the Mayo Clinic, the Mayo Foundation for Medical Education and Research, the Liston Award, the GHR Foundation, and the Schuler Foundation. Dr. Vassilaki disclosed relationships with F. Hoffmann-La Roche, Abbott Laboratories, Johnson & Johnson, Medtronic, Merck, and Amgen. Dr. Howe has no relevant disclosures.
, a cross sectional study has found.
Reporting in the journal Neurology, researchers from the Mayo Clinic in Rochester, Minn., and the University of Chicago found that only a small percentage of patients in the Mayo Clinic Study of Aging (MCSA) with mild cognitive impairment (MCI) or mild dementia due to Alzheimer’s disease would meet the clinical trial eligibility requirements of either agent.
“Our study results show only a small percentage of people with early Alzheimer’s disease may be eligible to receive treatment, mostly due to chronic health conditions and brain scan abnormalities common in older adults,” said lead researcher Maria Vassilaki, MD, PhD, an epidemiologist at Mayo Clinic in Rochester, Minn.
Applying clinical trial exclusion criteria to a broader population
The study included 237 people aged 50-90, 222 who had MCI and 15 with mild dementia, and whose brain scans showed increased amounts of amyloid-beta plaques. Average age of the participants was 80.9 years and 97.5% were White (99.6% not Hispanic or Latino).
The researchers then looked at the eligibility criteria for the pivotal clinical trials for lecanemab, which the U.S. Food and Drug Administration approved in January this year, and aducanumab, which the FDA cleared in 2021. Both drugs received FDA accelerated approval.
For lecanemab, clinical trial inclusion required specific scores for the Clinical Dementia Rating (CDR) (other than 0.5 or 1.0), Wechsler Memory Scale (WMS-R) Logical Memory II (which varied with age group), or Mini-Mental State Examination (MMSE) (22 to 30). A body mass index between 17 and 35 kg/m2 was also an inclusion criteria. Only 112 people, or 47%, met the inclusion criteria. Exclusion criteria included a history of cardiovascular disease or cancer, Parkinson’s disease, or brain injury, or a positive brain scan. When the exclusion criteria were applied, only 19 people, or 8%, qualified for the lecanemab trial.
When the researchers modified the exclusion criteria to include all study participants with MCI but not applying results from additional cognitive tests, 17.4% of MCSA patients would have been eligible for the lecanemab trial.
Aducanumab clinical trial inclusion criteria were a CDR global score other than 0.5 and an MMSE below 24, with an age cutoff of 85 years. Only 104 of the MCSA population, or 44%, met the clinical trial criteria. When the researchers applied the exclusion criteria for cardiovascular disease, central nervous system-related exclusions (such as brain cancer or epilepsy), a history of cancer, or brain scan abnormalities, they found that only 12 people, or 5%, would have been eligible for an aducanumab trial.
“Clinical trials often have strict eligibility criteria and could exclude those with other conditions that could be common in older adults,” Dr. Vassilaki said in emailed comments. “Thus, we wanted to examine if we apply these criteria to a study that recruits participants from the community, how many of the individuals in the early symptomatic stages, mild cognitive impairment or mild dementia due to Alzheimer’s disease, would be eligible for the treatment.”
Dr. Vassilaki said these drugs need to be studied in larger, more diverse populations, as well as in less healthy populations, before they’re more widely available to people with Alzheimer’s disease. “In addition,” she said, “we can learn more from the postmarketing surveillance of side effects and also from registries of patients receiving these treatments.”
One limitation of the study Dr. Vassilaki pointed out is the overwhelmingly White population. Evaluating the clinical trial eligibility criteria in more diverse populations is crucial, she said.
Estimating the number of patients who would qualify for treatment
In an accompanying commentary, Matthew Howes, MD, of Butler Hospital and Brown University in Providence, R.I., and colleagues wrote that the study findings provide health systems planning to offer amyloid-lowering antibodies for Alzheimer’s disease an estimate of how many patients would be eligible for the treatments. “Providers must exercise clinical judgment in selecting patients for treatment with shared decision-making with patients and families,” the commentators wrote.
The study was supported by the National Institutes of Health, the National Institute on Aging, the Alexander Family Alzheimer’s Disease Research Professorship of the Mayo Clinic, the Mayo Foundation for Medical Education and Research, the Liston Award, the GHR Foundation, and the Schuler Foundation. Dr. Vassilaki disclosed relationships with F. Hoffmann-La Roche, Abbott Laboratories, Johnson & Johnson, Medtronic, Merck, and Amgen. Dr. Howe has no relevant disclosures.
FROM NEUROLOGY
AI in pulmonary medicine – imaging and beyond
The utility of artificial intelligence in pulmonology has focused mainly on using image datasets to detect and diagnose lung malignancies, but now a growing number of AI models are emerging that apply machine learning to improve predictability for other pulmonary conditions, including pulmonary infections, pulmonary fibrosis, and chronic obstructive pulmonary disease (COPD).
These applications are moving beyond the traditional AI model of collecting data from a multitude of images to cast a wider data net that includes electronic health records.
Also on the horizon, ChatGPT technology is poised to have an impact. But pulmonologists and their practices have a number of barriers to clear before they feel a meaningful impact from AI.
The imperative, said AI researcher Ishanu Chattopadhyay, PhD, is to create transformative models that can detect lung disease early on. Dr. Chattopadhyay, an assistant professor of medicine at the University of Chicago and its Institute for Genomics and Systems Biology, and fellow researchers developed an AI algorithm that uses comorbidity signatures in electronic health records to screen for idiopathic pulmonary fibrosis (IPF) (Nature Med. 2022 Sep 29. doi: 10.1038/s41591-022-02010-y).
“If you could do this when somebody walks into a primary care setting and they are barely suspecting something is going on with them or when they don’t have the typical risk factors, there is a certain fraction of these people who do have IPF and they will almost invariably be diagnosed late and/or misdiagnosed,” Dr. Chattopadhyay said, citing a study that found 55% of patients with IPF have had at least one misdiagnosis and 38% have two or more misdiagnoses (BMC Pulm Med. 2018 Jan 17. doi: 10.1186/s12890-017-0560-x).
Harnessing massive data sets
AI models cull data sets, whether banks of radiographic images or files in an EHR, to extract telltale signatures of a disease state. Dr. Chattopadhyay and his team’s model used three databases with almost 3 million participants and 54,247 positive cases of IPF. Hospitals in Scotland have deployed what they’ve claimed are the first AI models to predict COPD built with 55,000 patient records from a regional National Health Service database. Another AI model for staging COPD, developed by researchers in the United States and Romania, used more than 18,000 medical records from 588 patients to identify physiological signals predictive of COPD (Advanced Sci. 2023 Feb 19. doi: 10.1002/advs.202203485).
Said Dr. Chattopadhyay: “If I can bring in AI which doesn’t just look at radiological images but actually gets it back where someone walks into primary care using only the information that is available at that point in the patient files and asking for nothing more, it raises a flag reliably that gets you a pulmonary referral that will hopefully reduce the misdiagnosis and late diagnosis.”
Victor Tseng, MD, medical director for pulmonology at Ansible Health in Mountain View, Calif., who’s researching the potential of AI in pulmonology, speculated on what functions AI can perform in the clinic. “I think you will start to see much more interventional sort of clinically patient care–facing applications,” he said. That would include acting as a triage layer to direct patient queries to a nurse, physician, or another practitioner, providing patient instructions, serving as therapeutic software, coordinating care, integrating supply chain issues,” he said.
AI vs. spirometry for COPD
Researchers in the United States and Romania, led by Paul Bogdan, PhD, at the University of Southern California Viterbi School of Engineering, developed a model that predicted COPD with an accuracy of almost 99% (98.66%) and avoids many of the shortcomings of spirometry, Dr. Bogdan said.
The models developed by Dr. Bogdan and collaborators use a different principle than existing AI platforms, Dr. Bogdan said. They analyze the properties of the data. As he explained it, they exploit what he called the “geometry of these data” to make inferences and decisions on a patient’s risk for COPD.
“Deep learning is very good for images, for videos, but it doesn’t work that well for signals,” said Mihai Udrescu, PhD, one of the Romanian collaborators. “But if we process the data with the technique brought up by Paul [Bogdan] and his team at USC, deep learning also works well on physiological signals.”
Said Dr. Bogdan, “Nobody thought about using physiological signals to predict COPD before this work. They used spirometry, but spirometry is cumbersome and several steps have to be performed in order to have an accurate spirometry.” His team’s AI models extract and analyze risk data based on 10 minutes of monitoring.
This technology also has the potential to improve accessibility of COPD screening, Dr. Udrescu said. “It can democratize the access to the health care because you don’t need to travel for 100 or 200 miles to see a specialist,” he said. “You just send an app to the mobile phone of a patient, the person puts on a smart watch and wears it for a couple of minutes and the data is either recorded locally or is transmitted and it is analyzed.” The computations can be done locally and in a matter of minutes, he said.
In Scotland, a 12-month feasibility study is underway to evaluate an AI model to identify COPD patients at greatest risk for adverse events. A press release from Lenus, the company developing the technology, said the study will use a COPD multidisciplinary team to consider real-time AI model outputs to enable proactive patient encounters and reduce emergency care visits.
Researchers in Paris built an AI model that showed a 68% accuracy in distinguishing people with asthma from people with COPD in administrative medical databases (BMC Pulmon Med. 2022 Sep 20. doi: 10.1186/s12890-022-02144-2). They found that asthma patients were younger than those with COPD (a mean of 49.9 vs. 72.1 years) and that COPD occurred mostly in men (68% vs. 33%). And an international team of researchers reported that an AI model that used chest CT scans determined that ever-smokers with COPD who met the imaging criteria for bronchiectasis were more prone to disease exacerbations (Radiology. 2022 Dec 13. doi: 10.1148/radiol.221109).
AI in idiopathic pulmonary fibrosis
The AI model that Dr. Chattopadhyay and collaborators developed had an 88% accuracy in predicting IPF. The model, known as the zero-burden comorbidity risk score for IPF (ZCoR-IPF), identified IPF cases in adults age 45 and older 1-4 years sooner than in a variety of pulmonology practice settings.
The model accounted for about 700 different features of IPF, Dr. Chattopadhyay said, but it deviated from standard AI risk models in that it used a machine learning algorithm to extract disease features that aren’t well understood or even known. “We do not know what all the risk factors of IPF are,” he said. “People who don’t have all the risk factors still get IPF. So we have to step back from the raw EHR data from where the features are being generated automatically, and then you can apply standard ML tools.”
Researchers at Nagoya University in Japan also reported on an AI algorithm for predicting IPF that used 646,800 high-resolution CT images and medical records data from 1,068 patients. Their algorithm had an average diagnostic accuracy of 83.6% and, they reported, demonstrated good accuracy even in patients with signs of interstitial pneumonia or who had surgical lung biopsies (Respirology. 2022 Dec 13. doi: 10.1111/resp.14310).
Chat GPT: The next frontier in AI
Dr. Tseng last year led a group of researchers that fed questions from the United States Medical Licensing Exam to a ChatGPT model, which found it answered 60%-65% of questions correctly (PLOS Digit Health. 2023 Feb 9. doi: 10.1371/journal.pdig.0000198). As Dr. Tseng pointed out, that’s good enough to get a medical license.
It may be a matter of time before ChatGPT technology finds its way into the clinic, Dr. Tseng said. A quick ChatGPT query of how it could be used in medicine yielded 12 different answers, from patient triage to providing basic first aid instructions in an emergency.
Dr. Tseng, who’s pulmonology practice places an emphasis on virtual care delivery, went deeper than the ChatGPT answer. “If you’re a respiratory therapist and you’re trying to execute a complicated medical care plan written by a physician, there’s a natural disconnect between our language and their language,” he said. “What we have found is that GPT has significantly harmonized the care plan. And that’s amazing because you end up with this single-stream understanding of the care plan, where the language is halfway between a bedside clinician, like the respiratory therapist or nurse, and is also something that a physician can understand and take the bigger sort of direction of care from.”
Barriers to AI in clinic
Numerous barriers face widespread adoption of AI tools in the clinic, Dr. Tseng said, including physician and staff anxiety about learning new technology. “AI tools, for all purposes, are supposed to allay the cognitive burden and the tedium burden on clinicians, but end up actually costing more time,” he said.
Health care organizations will also need to retool for AI, a group of medical informatics and digital health experts, led by Laurie Lovett Novak, PhD, reported (JAMIA Open. 2023 May 3. doi: 10.1093/jamiaopen/ooad028). But it’s coming nonetheless, Dr. Novak, an associate professor of biomedical informatics at Vanderbilt University Medical Center in Nashville, Tenn., said in an interview.
“In the near future, managers in clinics and inpatient units will be overseeing care that involves numerous AI-based technologies, including predictive analytics, imaging tools, language models, and others,” she said. “Organizations need to support managers by implementing capabilities for algorithmo-vigilance.”
That would include dealing with what she called “algorithmic drift” – when the accuracy of an AI model wanes because of changes in the underlying data – and ensuring that models are unbiased and aren’t used in a way that contributes to inequities in health care. “These new organizational capabilities will demand new tools and new competencies,” she said. That would include policies and processes drawing guidance from medical societies for legal and regulatory direction for managers, staff training, and software documentation.
Dr. Tseng envisioned how AI would work in the clinic. “I personally think that, at some time in the near future, AI-driven care coordination, where the AI basically handles appointment scheduling, patient motivation, patient engagement and acts as their health navigator, will be superior to any human health navigator on the whole, only for the reason that AI is indefatigable,” Dr. Tseng said. “It doesn’t get tired, it doesn’t get burned out, and these health navigation care coordination roles are notoriously difficult.”
The physicians and researchers interviewed for this report had no relevant relationships to disclose.
The utility of artificial intelligence in pulmonology has focused mainly on using image datasets to detect and diagnose lung malignancies, but now a growing number of AI models are emerging that apply machine learning to improve predictability for other pulmonary conditions, including pulmonary infections, pulmonary fibrosis, and chronic obstructive pulmonary disease (COPD).
These applications are moving beyond the traditional AI model of collecting data from a multitude of images to cast a wider data net that includes electronic health records.
Also on the horizon, ChatGPT technology is poised to have an impact. But pulmonologists and their practices have a number of barriers to clear before they feel a meaningful impact from AI.
The imperative, said AI researcher Ishanu Chattopadhyay, PhD, is to create transformative models that can detect lung disease early on. Dr. Chattopadhyay, an assistant professor of medicine at the University of Chicago and its Institute for Genomics and Systems Biology, and fellow researchers developed an AI algorithm that uses comorbidity signatures in electronic health records to screen for idiopathic pulmonary fibrosis (IPF) (Nature Med. 2022 Sep 29. doi: 10.1038/s41591-022-02010-y).
“If you could do this when somebody walks into a primary care setting and they are barely suspecting something is going on with them or when they don’t have the typical risk factors, there is a certain fraction of these people who do have IPF and they will almost invariably be diagnosed late and/or misdiagnosed,” Dr. Chattopadhyay said, citing a study that found 55% of patients with IPF have had at least one misdiagnosis and 38% have two or more misdiagnoses (BMC Pulm Med. 2018 Jan 17. doi: 10.1186/s12890-017-0560-x).
Harnessing massive data sets
AI models cull data sets, whether banks of radiographic images or files in an EHR, to extract telltale signatures of a disease state. Dr. Chattopadhyay and his team’s model used three databases with almost 3 million participants and 54,247 positive cases of IPF. Hospitals in Scotland have deployed what they’ve claimed are the first AI models to predict COPD built with 55,000 patient records from a regional National Health Service database. Another AI model for staging COPD, developed by researchers in the United States and Romania, used more than 18,000 medical records from 588 patients to identify physiological signals predictive of COPD (Advanced Sci. 2023 Feb 19. doi: 10.1002/advs.202203485).
Said Dr. Chattopadhyay: “If I can bring in AI which doesn’t just look at radiological images but actually gets it back where someone walks into primary care using only the information that is available at that point in the patient files and asking for nothing more, it raises a flag reliably that gets you a pulmonary referral that will hopefully reduce the misdiagnosis and late diagnosis.”
Victor Tseng, MD, medical director for pulmonology at Ansible Health in Mountain View, Calif., who’s researching the potential of AI in pulmonology, speculated on what functions AI can perform in the clinic. “I think you will start to see much more interventional sort of clinically patient care–facing applications,” he said. That would include acting as a triage layer to direct patient queries to a nurse, physician, or another practitioner, providing patient instructions, serving as therapeutic software, coordinating care, integrating supply chain issues,” he said.
AI vs. spirometry for COPD
Researchers in the United States and Romania, led by Paul Bogdan, PhD, at the University of Southern California Viterbi School of Engineering, developed a model that predicted COPD with an accuracy of almost 99% (98.66%) and avoids many of the shortcomings of spirometry, Dr. Bogdan said.
The models developed by Dr. Bogdan and collaborators use a different principle than existing AI platforms, Dr. Bogdan said. They analyze the properties of the data. As he explained it, they exploit what he called the “geometry of these data” to make inferences and decisions on a patient’s risk for COPD.
“Deep learning is very good for images, for videos, but it doesn’t work that well for signals,” said Mihai Udrescu, PhD, one of the Romanian collaborators. “But if we process the data with the technique brought up by Paul [Bogdan] and his team at USC, deep learning also works well on physiological signals.”
Said Dr. Bogdan, “Nobody thought about using physiological signals to predict COPD before this work. They used spirometry, but spirometry is cumbersome and several steps have to be performed in order to have an accurate spirometry.” His team’s AI models extract and analyze risk data based on 10 minutes of monitoring.
This technology also has the potential to improve accessibility of COPD screening, Dr. Udrescu said. “It can democratize the access to the health care because you don’t need to travel for 100 or 200 miles to see a specialist,” he said. “You just send an app to the mobile phone of a patient, the person puts on a smart watch and wears it for a couple of minutes and the data is either recorded locally or is transmitted and it is analyzed.” The computations can be done locally and in a matter of minutes, he said.
In Scotland, a 12-month feasibility study is underway to evaluate an AI model to identify COPD patients at greatest risk for adverse events. A press release from Lenus, the company developing the technology, said the study will use a COPD multidisciplinary team to consider real-time AI model outputs to enable proactive patient encounters and reduce emergency care visits.
Researchers in Paris built an AI model that showed a 68% accuracy in distinguishing people with asthma from people with COPD in administrative medical databases (BMC Pulmon Med. 2022 Sep 20. doi: 10.1186/s12890-022-02144-2). They found that asthma patients were younger than those with COPD (a mean of 49.9 vs. 72.1 years) and that COPD occurred mostly in men (68% vs. 33%). And an international team of researchers reported that an AI model that used chest CT scans determined that ever-smokers with COPD who met the imaging criteria for bronchiectasis were more prone to disease exacerbations (Radiology. 2022 Dec 13. doi: 10.1148/radiol.221109).
AI in idiopathic pulmonary fibrosis
The AI model that Dr. Chattopadhyay and collaborators developed had an 88% accuracy in predicting IPF. The model, known as the zero-burden comorbidity risk score for IPF (ZCoR-IPF), identified IPF cases in adults age 45 and older 1-4 years sooner than in a variety of pulmonology practice settings.
The model accounted for about 700 different features of IPF, Dr. Chattopadhyay said, but it deviated from standard AI risk models in that it used a machine learning algorithm to extract disease features that aren’t well understood or even known. “We do not know what all the risk factors of IPF are,” he said. “People who don’t have all the risk factors still get IPF. So we have to step back from the raw EHR data from where the features are being generated automatically, and then you can apply standard ML tools.”
Researchers at Nagoya University in Japan also reported on an AI algorithm for predicting IPF that used 646,800 high-resolution CT images and medical records data from 1,068 patients. Their algorithm had an average diagnostic accuracy of 83.6% and, they reported, demonstrated good accuracy even in patients with signs of interstitial pneumonia or who had surgical lung biopsies (Respirology. 2022 Dec 13. doi: 10.1111/resp.14310).
Chat GPT: The next frontier in AI
Dr. Tseng last year led a group of researchers that fed questions from the United States Medical Licensing Exam to a ChatGPT model, which found it answered 60%-65% of questions correctly (PLOS Digit Health. 2023 Feb 9. doi: 10.1371/journal.pdig.0000198). As Dr. Tseng pointed out, that’s good enough to get a medical license.
It may be a matter of time before ChatGPT technology finds its way into the clinic, Dr. Tseng said. A quick ChatGPT query of how it could be used in medicine yielded 12 different answers, from patient triage to providing basic first aid instructions in an emergency.
Dr. Tseng, who’s pulmonology practice places an emphasis on virtual care delivery, went deeper than the ChatGPT answer. “If you’re a respiratory therapist and you’re trying to execute a complicated medical care plan written by a physician, there’s a natural disconnect between our language and their language,” he said. “What we have found is that GPT has significantly harmonized the care plan. And that’s amazing because you end up with this single-stream understanding of the care plan, where the language is halfway between a bedside clinician, like the respiratory therapist or nurse, and is also something that a physician can understand and take the bigger sort of direction of care from.”
Barriers to AI in clinic
Numerous barriers face widespread adoption of AI tools in the clinic, Dr. Tseng said, including physician and staff anxiety about learning new technology. “AI tools, for all purposes, are supposed to allay the cognitive burden and the tedium burden on clinicians, but end up actually costing more time,” he said.
Health care organizations will also need to retool for AI, a group of medical informatics and digital health experts, led by Laurie Lovett Novak, PhD, reported (JAMIA Open. 2023 May 3. doi: 10.1093/jamiaopen/ooad028). But it’s coming nonetheless, Dr. Novak, an associate professor of biomedical informatics at Vanderbilt University Medical Center in Nashville, Tenn., said in an interview.
“In the near future, managers in clinics and inpatient units will be overseeing care that involves numerous AI-based technologies, including predictive analytics, imaging tools, language models, and others,” she said. “Organizations need to support managers by implementing capabilities for algorithmo-vigilance.”
That would include dealing with what she called “algorithmic drift” – when the accuracy of an AI model wanes because of changes in the underlying data – and ensuring that models are unbiased and aren’t used in a way that contributes to inequities in health care. “These new organizational capabilities will demand new tools and new competencies,” she said. That would include policies and processes drawing guidance from medical societies for legal and regulatory direction for managers, staff training, and software documentation.
Dr. Tseng envisioned how AI would work in the clinic. “I personally think that, at some time in the near future, AI-driven care coordination, where the AI basically handles appointment scheduling, patient motivation, patient engagement and acts as their health navigator, will be superior to any human health navigator on the whole, only for the reason that AI is indefatigable,” Dr. Tseng said. “It doesn’t get tired, it doesn’t get burned out, and these health navigation care coordination roles are notoriously difficult.”
The physicians and researchers interviewed for this report had no relevant relationships to disclose.
The utility of artificial intelligence in pulmonology has focused mainly on using image datasets to detect and diagnose lung malignancies, but now a growing number of AI models are emerging that apply machine learning to improve predictability for other pulmonary conditions, including pulmonary infections, pulmonary fibrosis, and chronic obstructive pulmonary disease (COPD).
These applications are moving beyond the traditional AI model of collecting data from a multitude of images to cast a wider data net that includes electronic health records.
Also on the horizon, ChatGPT technology is poised to have an impact. But pulmonologists and their practices have a number of barriers to clear before they feel a meaningful impact from AI.
The imperative, said AI researcher Ishanu Chattopadhyay, PhD, is to create transformative models that can detect lung disease early on. Dr. Chattopadhyay, an assistant professor of medicine at the University of Chicago and its Institute for Genomics and Systems Biology, and fellow researchers developed an AI algorithm that uses comorbidity signatures in electronic health records to screen for idiopathic pulmonary fibrosis (IPF) (Nature Med. 2022 Sep 29. doi: 10.1038/s41591-022-02010-y).
“If you could do this when somebody walks into a primary care setting and they are barely suspecting something is going on with them or when they don’t have the typical risk factors, there is a certain fraction of these people who do have IPF and they will almost invariably be diagnosed late and/or misdiagnosed,” Dr. Chattopadhyay said, citing a study that found 55% of patients with IPF have had at least one misdiagnosis and 38% have two or more misdiagnoses (BMC Pulm Med. 2018 Jan 17. doi: 10.1186/s12890-017-0560-x).
Harnessing massive data sets
AI models cull data sets, whether banks of radiographic images or files in an EHR, to extract telltale signatures of a disease state. Dr. Chattopadhyay and his team’s model used three databases with almost 3 million participants and 54,247 positive cases of IPF. Hospitals in Scotland have deployed what they’ve claimed are the first AI models to predict COPD built with 55,000 patient records from a regional National Health Service database. Another AI model for staging COPD, developed by researchers in the United States and Romania, used more than 18,000 medical records from 588 patients to identify physiological signals predictive of COPD (Advanced Sci. 2023 Feb 19. doi: 10.1002/advs.202203485).
Said Dr. Chattopadhyay: “If I can bring in AI which doesn’t just look at radiological images but actually gets it back where someone walks into primary care using only the information that is available at that point in the patient files and asking for nothing more, it raises a flag reliably that gets you a pulmonary referral that will hopefully reduce the misdiagnosis and late diagnosis.”
Victor Tseng, MD, medical director for pulmonology at Ansible Health in Mountain View, Calif., who’s researching the potential of AI in pulmonology, speculated on what functions AI can perform in the clinic. “I think you will start to see much more interventional sort of clinically patient care–facing applications,” he said. That would include acting as a triage layer to direct patient queries to a nurse, physician, or another practitioner, providing patient instructions, serving as therapeutic software, coordinating care, integrating supply chain issues,” he said.
AI vs. spirometry for COPD
Researchers in the United States and Romania, led by Paul Bogdan, PhD, at the University of Southern California Viterbi School of Engineering, developed a model that predicted COPD with an accuracy of almost 99% (98.66%) and avoids many of the shortcomings of spirometry, Dr. Bogdan said.
The models developed by Dr. Bogdan and collaborators use a different principle than existing AI platforms, Dr. Bogdan said. They analyze the properties of the data. As he explained it, they exploit what he called the “geometry of these data” to make inferences and decisions on a patient’s risk for COPD.
“Deep learning is very good for images, for videos, but it doesn’t work that well for signals,” said Mihai Udrescu, PhD, one of the Romanian collaborators. “But if we process the data with the technique brought up by Paul [Bogdan] and his team at USC, deep learning also works well on physiological signals.”
Said Dr. Bogdan, “Nobody thought about using physiological signals to predict COPD before this work. They used spirometry, but spirometry is cumbersome and several steps have to be performed in order to have an accurate spirometry.” His team’s AI models extract and analyze risk data based on 10 minutes of monitoring.
This technology also has the potential to improve accessibility of COPD screening, Dr. Udrescu said. “It can democratize the access to the health care because you don’t need to travel for 100 or 200 miles to see a specialist,” he said. “You just send an app to the mobile phone of a patient, the person puts on a smart watch and wears it for a couple of minutes and the data is either recorded locally or is transmitted and it is analyzed.” The computations can be done locally and in a matter of minutes, he said.
In Scotland, a 12-month feasibility study is underway to evaluate an AI model to identify COPD patients at greatest risk for adverse events. A press release from Lenus, the company developing the technology, said the study will use a COPD multidisciplinary team to consider real-time AI model outputs to enable proactive patient encounters and reduce emergency care visits.
Researchers in Paris built an AI model that showed a 68% accuracy in distinguishing people with asthma from people with COPD in administrative medical databases (BMC Pulmon Med. 2022 Sep 20. doi: 10.1186/s12890-022-02144-2). They found that asthma patients were younger than those with COPD (a mean of 49.9 vs. 72.1 years) and that COPD occurred mostly in men (68% vs. 33%). And an international team of researchers reported that an AI model that used chest CT scans determined that ever-smokers with COPD who met the imaging criteria for bronchiectasis were more prone to disease exacerbations (Radiology. 2022 Dec 13. doi: 10.1148/radiol.221109).
AI in idiopathic pulmonary fibrosis
The AI model that Dr. Chattopadhyay and collaborators developed had an 88% accuracy in predicting IPF. The model, known as the zero-burden comorbidity risk score for IPF (ZCoR-IPF), identified IPF cases in adults age 45 and older 1-4 years sooner than in a variety of pulmonology practice settings.
The model accounted for about 700 different features of IPF, Dr. Chattopadhyay said, but it deviated from standard AI risk models in that it used a machine learning algorithm to extract disease features that aren’t well understood or even known. “We do not know what all the risk factors of IPF are,” he said. “People who don’t have all the risk factors still get IPF. So we have to step back from the raw EHR data from where the features are being generated automatically, and then you can apply standard ML tools.”
Researchers at Nagoya University in Japan also reported on an AI algorithm for predicting IPF that used 646,800 high-resolution CT images and medical records data from 1,068 patients. Their algorithm had an average diagnostic accuracy of 83.6% and, they reported, demonstrated good accuracy even in patients with signs of interstitial pneumonia or who had surgical lung biopsies (Respirology. 2022 Dec 13. doi: 10.1111/resp.14310).
Chat GPT: The next frontier in AI
Dr. Tseng last year led a group of researchers that fed questions from the United States Medical Licensing Exam to a ChatGPT model, which found it answered 60%-65% of questions correctly (PLOS Digit Health. 2023 Feb 9. doi: 10.1371/journal.pdig.0000198). As Dr. Tseng pointed out, that’s good enough to get a medical license.
It may be a matter of time before ChatGPT technology finds its way into the clinic, Dr. Tseng said. A quick ChatGPT query of how it could be used in medicine yielded 12 different answers, from patient triage to providing basic first aid instructions in an emergency.
Dr. Tseng, who’s pulmonology practice places an emphasis on virtual care delivery, went deeper than the ChatGPT answer. “If you’re a respiratory therapist and you’re trying to execute a complicated medical care plan written by a physician, there’s a natural disconnect between our language and their language,” he said. “What we have found is that GPT has significantly harmonized the care plan. And that’s amazing because you end up with this single-stream understanding of the care plan, where the language is halfway between a bedside clinician, like the respiratory therapist or nurse, and is also something that a physician can understand and take the bigger sort of direction of care from.”
Barriers to AI in clinic
Numerous barriers face widespread adoption of AI tools in the clinic, Dr. Tseng said, including physician and staff anxiety about learning new technology. “AI tools, for all purposes, are supposed to allay the cognitive burden and the tedium burden on clinicians, but end up actually costing more time,” he said.
Health care organizations will also need to retool for AI, a group of medical informatics and digital health experts, led by Laurie Lovett Novak, PhD, reported (JAMIA Open. 2023 May 3. doi: 10.1093/jamiaopen/ooad028). But it’s coming nonetheless, Dr. Novak, an associate professor of biomedical informatics at Vanderbilt University Medical Center in Nashville, Tenn., said in an interview.
“In the near future, managers in clinics and inpatient units will be overseeing care that involves numerous AI-based technologies, including predictive analytics, imaging tools, language models, and others,” she said. “Organizations need to support managers by implementing capabilities for algorithmo-vigilance.”
That would include dealing with what she called “algorithmic drift” – when the accuracy of an AI model wanes because of changes in the underlying data – and ensuring that models are unbiased and aren’t used in a way that contributes to inequities in health care. “These new organizational capabilities will demand new tools and new competencies,” she said. That would include policies and processes drawing guidance from medical societies for legal and regulatory direction for managers, staff training, and software documentation.
Dr. Tseng envisioned how AI would work in the clinic. “I personally think that, at some time in the near future, AI-driven care coordination, where the AI basically handles appointment scheduling, patient motivation, patient engagement and acts as their health navigator, will be superior to any human health navigator on the whole, only for the reason that AI is indefatigable,” Dr. Tseng said. “It doesn’t get tired, it doesn’t get burned out, and these health navigation care coordination roles are notoriously difficult.”
The physicians and researchers interviewed for this report had no relevant relationships to disclose.