Richard Mark Kirkner

PHILADELPHIA – An investigational PCSK9 inhibitor that can be injected every 1-3 months as add-on therapy for patients with stubbornly high low-density lipoprotein (LDL) cholesterol has demonstrated cholesterol lowering for up to a year, in a clinical trial.

The results are from the phase 3 Recaticimab Add-On Therapy in Patients With Non-Familial Hypercholesterolemia and Mixed Hyperlipidemia (REMAIN-2) trial.

“It’s a new antibody that has a long half-life so each treatment can be prolonged,” investigator Xin Du, MD, professor of cardiology at Beijing Anzhen Hospital and the Capital Medical University, said in an interview. “Previous drugs like alirocumab and evolocumab have to be given every 2 weeks or every 4 weeks, and this new drug can be given even every 12 weeks, so it can get a very strong effect of LDL cholesterol lowering even when given every 3 months.”

Recaticimab has demonstrated a half-life of 18.6 to 27.4 days vs. 11 to 17 days for alirocumab and evolocumab, she said.

166105_Du_Xin_BEIJING_web.jpg

“Currently a high proportion of patients prescribed the PCSK9 inhibitors withdraw from therapy,” Dr. Du said. “After 36 months, only half of them are still on that therapy.”

Dr. Du presented the trial results at the annual scientific sessions of the American Heart Association.
 

Trial design and results

REMAIN-2 randomly assigned 692 patients to one of three recaticimab dosing arms vs. placebo: 150 mg/kg every 4 weeks; 300 mg/kg every 8 weeks; and 450 mg/kg every 12 weeks. The study was conducted from June 2021 to March 2023. The average age of the participants was 56 years and 64% were men. A high percentage of patients, 87% to 93.5%, completed the study across all groups. All participants had high LDL-C levels despite statin therapy: ≥ 70 mg/dL for those with cardiovascular disease and ≥ 100 mg/dL for those without.

Recaticimab enhanced LDL-C reduction by 53.4% to 62% vs. placebo at 24 weeks with a similar effect across all dosing regimens, Dr. Du said. That level of reduction was sustained out to 48 weeks, she said, at 48.4% to 64%.

At week 24, 86% to 94.5% of all patients across the three dosing arms achieved their LDL-C goal. The treatment had a positive impact on other lipid levels as well, Dr. Du said. Levels of non-HDL-C declined 55% to 47%. Apolipoprotein B (ApoB) levels fell 53% to 42% and lipoprotein (a), or Lp(a) readings declined 39.5% to 29%. The placebo arms had no change or small increases in non-HDL-C and ApoB levels and modest reductions in Lp(a).

The trial demonstrated acceptable safety and tolerability of recaticimab, Dr. Du said. At 48 weeks, the rates of injection site reactions were 3.9% in the treatment arms vs. 1.3% in the placebo arms. Common adverse events with a frequency ≥ 5% in patients receiving recaticimab were upper respiratory tract infection, hyperuricemia, urinary tract infection, increased blood creatine phosphokinase – a marker of damage to the heart – COVID-19 infection, and increased alanine transferase and aspartate transferase, both of which are markers of liver damage.
 

Larger, longer studies needed

Longer-term studies of recaticimab are still needed to determine its ability produce durable LDL-C reduction in a cost-effective manner, said discussant Stephen Nicholls, MD, director of Victorian Heart Institute and professor at Monash University in Australia. “It is important to note that these are still relatively short studies and the short treatment period cannot exclude the formation of neutralizing antibodies that have undermined development of other humanized antibodies,” he told attendees.

Nicholls_Stephen_AUSTRALIA_web.jpg

The every-12-week dosing, Dr. Nicholls said in an interview, “provides a dosing regimen that may be palatable to many patients.”

Besides the potential for the development of antibodies, Dr. Nicholls foresaw potential challenges with recaticimab. “The reality will lie in longer-term data,” he said. “If they can achieve durable lipid lowering without such neutralizing antibodies that would be very good.”

Dr. Nicholls added, “There’s a lot going on in the PCSK9 inhibitor space and the challenge for any new therapeutic, including this one, is where will it fit in given the space is getting crowded. So, data is important and clinical uptake will be equally important.”

Dr. Du disclosed relationships with Sanofi, AstraZeneca and Bayer. Dr. Nicholls disclosed relationships with AstraZeneca, Akcea, Amarin, Amgen, Anthera, Boehringer Ingelheim, Cerenis, CSL Behring, Eli Lilly, Esperion, Novartis,  LipoScience, The Medicines Company, Merck, New Amsterdam Pharma, Omthera, Resverlogix, InfraReDx, Roche, Sanofi-Regeneron, Takeda, Vaxxinity, and Seqirus.

PHILADELPHIA – An investigational PCSK9 inhibitor that can be injected every 1-3 months as add-on therapy for patients with stubbornly high low-density lipoprotein (LDL) cholesterol has demonstrated cholesterol lowering for up to a year, in a clinical trial.

The results are from the phase 3 Recaticimab Add-On Therapy in Patients With Non-Familial Hypercholesterolemia and Mixed Hyperlipidemia (REMAIN-2) trial.

“It’s a new antibody that has a long half-life so each treatment can be prolonged,” investigator Xin Du, MD, professor of cardiology at Beijing Anzhen Hospital and the Capital Medical University, said in an interview. “Previous drugs like alirocumab and evolocumab have to be given every 2 weeks or every 4 weeks, and this new drug can be given even every 12 weeks, so it can get a very strong effect of LDL cholesterol lowering even when given every 3 months.”

Recaticimab has demonstrated a half-life of 18.6 to 27.4 days vs. 11 to 17 days for alirocumab and evolocumab, she said.

166105_Du_Xin_BEIJING_web.jpg

“Currently a high proportion of patients prescribed the PCSK9 inhibitors withdraw from therapy,” Dr. Du said. “After 36 months, only half of them are still on that therapy.”

Dr. Du presented the trial results at the annual scientific sessions of the American Heart Association.
 

Trial design and results

REMAIN-2 randomly assigned 692 patients to one of three recaticimab dosing arms vs. placebo: 150 mg/kg every 4 weeks; 300 mg/kg every 8 weeks; and 450 mg/kg every 12 weeks. The study was conducted from June 2021 to March 2023. The average age of the participants was 56 years and 64% were men. A high percentage of patients, 87% to 93.5%, completed the study across all groups. All participants had high LDL-C levels despite statin therapy: ≥ 70 mg/dL for those with cardiovascular disease and ≥ 100 mg/dL for those without.

Recaticimab enhanced LDL-C reduction by 53.4% to 62% vs. placebo at 24 weeks with a similar effect across all dosing regimens, Dr. Du said. That level of reduction was sustained out to 48 weeks, she said, at 48.4% to 64%.

At week 24, 86% to 94.5% of all patients across the three dosing arms achieved their LDL-C goal. The treatment had a positive impact on other lipid levels as well, Dr. Du said. Levels of non-HDL-C declined 55% to 47%. Apolipoprotein B (ApoB) levels fell 53% to 42% and lipoprotein (a), or Lp(a) readings declined 39.5% to 29%. The placebo arms had no change or small increases in non-HDL-C and ApoB levels and modest reductions in Lp(a).

The trial demonstrated acceptable safety and tolerability of recaticimab, Dr. Du said. At 48 weeks, the rates of injection site reactions were 3.9% in the treatment arms vs. 1.3% in the placebo arms. Common adverse events with a frequency ≥ 5% in patients receiving recaticimab were upper respiratory tract infection, hyperuricemia, urinary tract infection, increased blood creatine phosphokinase – a marker of damage to the heart – COVID-19 infection, and increased alanine transferase and aspartate transferase, both of which are markers of liver damage.
 

Larger, longer studies needed

Longer-term studies of recaticimab are still needed to determine its ability produce durable LDL-C reduction in a cost-effective manner, said discussant Stephen Nicholls, MD, director of Victorian Heart Institute and professor at Monash University in Australia. “It is important to note that these are still relatively short studies and the short treatment period cannot exclude the formation of neutralizing antibodies that have undermined development of other humanized antibodies,” he told attendees.

Nicholls_Stephen_AUSTRALIA_web.jpg

The every-12-week dosing, Dr. Nicholls said in an interview, “provides a dosing regimen that may be palatable to many patients.”

Besides the potential for the development of antibodies, Dr. Nicholls foresaw potential challenges with recaticimab. “The reality will lie in longer-term data,” he said. “If they can achieve durable lipid lowering without such neutralizing antibodies that would be very good.”

Dr. Nicholls added, “There’s a lot going on in the PCSK9 inhibitor space and the challenge for any new therapeutic, including this one, is where will it fit in given the space is getting crowded. So, data is important and clinical uptake will be equally important.”

Dr. Du disclosed relationships with Sanofi, AstraZeneca and Bayer. Dr. Nicholls disclosed relationships with AstraZeneca, Akcea, Amarin, Amgen, Anthera, Boehringer Ingelheim, Cerenis, CSL Behring, Eli Lilly, Esperion, Novartis,  LipoScience, The Medicines Company, Merck, New Amsterdam Pharma, Omthera, Resverlogix, InfraReDx, Roche, Sanofi-Regeneron, Takeda, Vaxxinity, and Seqirus.

PHILADELPHIA – An investigational PCSK9 inhibitor that can be injected every 1-3 months as add-on therapy for patients with stubbornly high low-density lipoprotein (LDL) cholesterol has demonstrated cholesterol lowering for up to a year, in a clinical trial.

The results are from the phase 3 Recaticimab Add-On Therapy in Patients With Non-Familial Hypercholesterolemia and Mixed Hyperlipidemia (REMAIN-2) trial.

“It’s a new antibody that has a long half-life so each treatment can be prolonged,” investigator Xin Du, MD, professor of cardiology at Beijing Anzhen Hospital and the Capital Medical University, said in an interview. “Previous drugs like alirocumab and evolocumab have to be given every 2 weeks or every 4 weeks, and this new drug can be given even every 12 weeks, so it can get a very strong effect of LDL cholesterol lowering even when given every 3 months.”

Recaticimab has demonstrated a half-life of 18.6 to 27.4 days vs. 11 to 17 days for alirocumab and evolocumab, she said.

166105_Du_Xin_BEIJING_web.jpg

“Currently a high proportion of patients prescribed the PCSK9 inhibitors withdraw from therapy,” Dr. Du said. “After 36 months, only half of them are still on that therapy.”

Dr. Du presented the trial results at the annual scientific sessions of the American Heart Association.
 

Trial design and results

REMAIN-2 randomly assigned 692 patients to one of three recaticimab dosing arms vs. placebo: 150 mg/kg every 4 weeks; 300 mg/kg every 8 weeks; and 450 mg/kg every 12 weeks. The study was conducted from June 2021 to March 2023. The average age of the participants was 56 years and 64% were men. A high percentage of patients, 87% to 93.5%, completed the study across all groups. All participants had high LDL-C levels despite statin therapy: ≥ 70 mg/dL for those with cardiovascular disease and ≥ 100 mg/dL for those without.

Recaticimab enhanced LDL-C reduction by 53.4% to 62% vs. placebo at 24 weeks with a similar effect across all dosing regimens, Dr. Du said. That level of reduction was sustained out to 48 weeks, she said, at 48.4% to 64%.

At week 24, 86% to 94.5% of all patients across the three dosing arms achieved their LDL-C goal. The treatment had a positive impact on other lipid levels as well, Dr. Du said. Levels of non-HDL-C declined 55% to 47%. Apolipoprotein B (ApoB) levels fell 53% to 42% and lipoprotein (a), or Lp(a) readings declined 39.5% to 29%. The placebo arms had no change or small increases in non-HDL-C and ApoB levels and modest reductions in Lp(a).

The trial demonstrated acceptable safety and tolerability of recaticimab, Dr. Du said. At 48 weeks, the rates of injection site reactions were 3.9% in the treatment arms vs. 1.3% in the placebo arms. Common adverse events with a frequency ≥ 5% in patients receiving recaticimab were upper respiratory tract infection, hyperuricemia, urinary tract infection, increased blood creatine phosphokinase – a marker of damage to the heart – COVID-19 infection, and increased alanine transferase and aspartate transferase, both of which are markers of liver damage.
 

Larger, longer studies needed

Longer-term studies of recaticimab are still needed to determine its ability produce durable LDL-C reduction in a cost-effective manner, said discussant Stephen Nicholls, MD, director of Victorian Heart Institute and professor at Monash University in Australia. “It is important to note that these are still relatively short studies and the short treatment period cannot exclude the formation of neutralizing antibodies that have undermined development of other humanized antibodies,” he told attendees.

Nicholls_Stephen_AUSTRALIA_web.jpg

The every-12-week dosing, Dr. Nicholls said in an interview, “provides a dosing regimen that may be palatable to many patients.”

Besides the potential for the development of antibodies, Dr. Nicholls foresaw potential challenges with recaticimab. “The reality will lie in longer-term data,” he said. “If they can achieve durable lipid lowering without such neutralizing antibodies that would be very good.”

Dr. Nicholls added, “There’s a lot going on in the PCSK9 inhibitor space and the challenge for any new therapeutic, including this one, is where will it fit in given the space is getting crowded. So, data is important and clinical uptake will be equally important.”

Dr. Du disclosed relationships with Sanofi, AstraZeneca and Bayer. Dr. Nicholls disclosed relationships with AstraZeneca, Akcea, Amarin, Amgen, Anthera, Boehringer Ingelheim, Cerenis, CSL Behring, Eli Lilly, Esperion, Novartis,  LipoScience, The Medicines Company, Merck, New Amsterdam Pharma, Omthera, Resverlogix, InfraReDx, Roche, Sanofi-Regeneron, Takeda, Vaxxinity, and Seqirus.

PHILADELPHIA – A carefully tailored program in which physicians talked with heart failure (HF) patients about the cost of their medications improved medication adherence and the likelihood that patients get the medications they’re prescribed, results of a pilot study show.

The POCKET-COST-HF trial integrated information about patient-specific out-of-pocket (OOP) drug costs into clinical encounters between cardiologists and patients with heart failure with reduced ejection fraction (HFrEF) at six clinic sites in two different health systems. Neil W. Dickert, MD, PhD, primary investigator of the trial, said OOP costs for HFrEF patients with Medicare Part D prescription drug coverage can run upwards of $2,600 a year for four-drug therapy. Dr. Dickert is a cardiologist at Emory University in Atlanta.

Dickert_Neil_W_ATLANTA_web.jpg

“The primary outcome for the study was whether patients and clinicians essentially talked about the cost of medications,” Dr. Dickert said in an interview. “The study was positive in that perspective; we saw an increase of about 19% in the encounters that had cost conversations related to heart failure medication.”

The trial, which Dr. Dickert presented at the annual scientific sessions of the American Heart Association, was designed to evaluate the effect of patient-specific OOP costs in the shared decision-making about heart failure medications, Dr. Dickert said.

The primary outcome was cost-informed decision-making, achieved in 68% of the intervention group encounters and 49% of control encounters (P = .021).
 

Fewer in-pharmacy adjustments

“We saw some really interesting signals of potential benefits in the space of actual decisions,” he said. “There were fewer, for example, contingency plans made in the intervention arm versus the control arm, and what that means is physicians were less likely to write a prescription and leave the decision about whether or not it’s worth it to the patient when they get to the pharmacy.”

The study intervention was a checklist of 19 heart failure medications that included OOP cost, ranging from minimal costs for generics such as diuretics and beta blockers to $617 for dapagliflozin. The checklist was based on an electronic medical records HF medications checklist. Researchers obtained drug cost estimates from TailorMed, a financial navigation company.

Six clinic sites within two health systems, one in Georgia, the other in Colorado, participated in the study. Each cluster had 40 or so patients (n = 247) randomized to the intervention or control. About two-thirds were White, a quarter were Black and 4% and 2.5% in the control and intervention group were Hispanic/LatinX. Income ranges were similar across both arms.

For the study intervention, patients got a call from the clinic 2-3 weeks before their scheduled visit to obtain verbal consent to participate and their OOP costs for drugs. The visit itself, where patients randomized to the intervention received the checklist, was audio recorded. After the visit, patients took a follow-up telephone survey, then the clinic staff did an electronic health record 3 months after the visit.

Getting the patient drug price information was not easy, Dr. Dickert said. “It required a fair amount of work and a big list to get that information that we could then populate the checklist for people,” he said. “It was a behind-the-scenes thing that is not necessarily scalable as done.”

Dr. Dickert acknowledged an increasing emphasis on price transparency in medicine, but the trade-offs are unknown. “Depending upon how that’s carried out, that can have different implications,” he said. “I’m a believer that if we think good communication has the ability to enhance medical decision-making, it also means that either bad information or bad communication can undermine.

“So, I think it’s really important to study these interventions and to do them in rigorous ways where we can really get a sense of what kind of impact they have on patients and clinicians.”
 

Study strengths and limitations

Discussant Dhruv Kazi, MD, director of the cardiac critical care unit at Beth Israel Deaconess Medical Center and associate professor at Harvard Medical School, both in Boston, said in an interview that this study fulfills an important function in investigating how OOP costs influence medication adherence in HFrEF patients.

Kazi_Dhruv_BOSTON_web.jpg

“The total cost of drugs has often been a focus of policy discussions,” he said. “We talk about, how do we reduce drug costs?” He noted the Inflation Reduction Act will bring some of these drug costs down.

“On the flip side,” he added, “as a community we pay less attention to out-of-pocket costs because we assume those are not in our control, yet what the patient cares about is not the total cost of the drug, but, ‘What am I going to pay this month, and what am I going to pay cumulatively over the course of the year? Can I even afford this drug?”

POCKET-COST-HF provided a sound basis for making that investigation, he said, adding that its multisite design and mixed-methods approach – patient contact before and after visits and recording of encounters – are strengths. “Just looking at the logistics involved in pulling off something like this, the study investigators deserve to be congratulated,” he said.

One limitation, Dr. Kazi said, is its exclusion of non–English speakers. Adding them in, along with testing the intervention in community, rural, and primary care settings, are future goals for the intervention, he said. Within the trial itself, examining the cost-effectiveness of the intervention would be laudable, Dr. Kazi said.

The Agency for Healthcare Research and Quality funded the trial. Dr. Dickert disclosed relationships with Abiomed. Dr. Kazi has no relevant relationships to disclose.

PHILADELPHIA – A carefully tailored program in which physicians talked with heart failure (HF) patients about the cost of their medications improved medication adherence and the likelihood that patients get the medications they’re prescribed, results of a pilot study show.

The POCKET-COST-HF trial integrated information about patient-specific out-of-pocket (OOP) drug costs into clinical encounters between cardiologists and patients with heart failure with reduced ejection fraction (HFrEF) at six clinic sites in two different health systems. Neil W. Dickert, MD, PhD, primary investigator of the trial, said OOP costs for HFrEF patients with Medicare Part D prescription drug coverage can run upwards of $2,600 a year for four-drug therapy. Dr. Dickert is a cardiologist at Emory University in Atlanta.

Dickert_Neil_W_ATLANTA_web.jpg

“The primary outcome for the study was whether patients and clinicians essentially talked about the cost of medications,” Dr. Dickert said in an interview. “The study was positive in that perspective; we saw an increase of about 19% in the encounters that had cost conversations related to heart failure medication.”

The trial, which Dr. Dickert presented at the annual scientific sessions of the American Heart Association, was designed to evaluate the effect of patient-specific OOP costs in the shared decision-making about heart failure medications, Dr. Dickert said.

The primary outcome was cost-informed decision-making, achieved in 68% of the intervention group encounters and 49% of control encounters (P = .021).
 

Fewer in-pharmacy adjustments

“We saw some really interesting signals of potential benefits in the space of actual decisions,” he said. “There were fewer, for example, contingency plans made in the intervention arm versus the control arm, and what that means is physicians were less likely to write a prescription and leave the decision about whether or not it’s worth it to the patient when they get to the pharmacy.”

The study intervention was a checklist of 19 heart failure medications that included OOP cost, ranging from minimal costs for generics such as diuretics and beta blockers to $617 for dapagliflozin. The checklist was based on an electronic medical records HF medications checklist. Researchers obtained drug cost estimates from TailorMed, a financial navigation company.

Six clinic sites within two health systems, one in Georgia, the other in Colorado, participated in the study. Each cluster had 40 or so patients (n = 247) randomized to the intervention or control. About two-thirds were White, a quarter were Black and 4% and 2.5% in the control and intervention group were Hispanic/LatinX. Income ranges were similar across both arms.

For the study intervention, patients got a call from the clinic 2-3 weeks before their scheduled visit to obtain verbal consent to participate and their OOP costs for drugs. The visit itself, where patients randomized to the intervention received the checklist, was audio recorded. After the visit, patients took a follow-up telephone survey, then the clinic staff did an electronic health record 3 months after the visit.

Getting the patient drug price information was not easy, Dr. Dickert said. “It required a fair amount of work and a big list to get that information that we could then populate the checklist for people,” he said. “It was a behind-the-scenes thing that is not necessarily scalable as done.”

Dr. Dickert acknowledged an increasing emphasis on price transparency in medicine, but the trade-offs are unknown. “Depending upon how that’s carried out, that can have different implications,” he said. “I’m a believer that if we think good communication has the ability to enhance medical decision-making, it also means that either bad information or bad communication can undermine.

“So, I think it’s really important to study these interventions and to do them in rigorous ways where we can really get a sense of what kind of impact they have on patients and clinicians.”
 

Study strengths and limitations

Discussant Dhruv Kazi, MD, director of the cardiac critical care unit at Beth Israel Deaconess Medical Center and associate professor at Harvard Medical School, both in Boston, said in an interview that this study fulfills an important function in investigating how OOP costs influence medication adherence in HFrEF patients.

Kazi_Dhruv_BOSTON_web.jpg

“The total cost of drugs has often been a focus of policy discussions,” he said. “We talk about, how do we reduce drug costs?” He noted the Inflation Reduction Act will bring some of these drug costs down.

“On the flip side,” he added, “as a community we pay less attention to out-of-pocket costs because we assume those are not in our control, yet what the patient cares about is not the total cost of the drug, but, ‘What am I going to pay this month, and what am I going to pay cumulatively over the course of the year? Can I even afford this drug?”

POCKET-COST-HF provided a sound basis for making that investigation, he said, adding that its multisite design and mixed-methods approach – patient contact before and after visits and recording of encounters – are strengths. “Just looking at the logistics involved in pulling off something like this, the study investigators deserve to be congratulated,” he said.

One limitation, Dr. Kazi said, is its exclusion of non–English speakers. Adding them in, along with testing the intervention in community, rural, and primary care settings, are future goals for the intervention, he said. Within the trial itself, examining the cost-effectiveness of the intervention would be laudable, Dr. Kazi said.

The Agency for Healthcare Research and Quality funded the trial. Dr. Dickert disclosed relationships with Abiomed. Dr. Kazi has no relevant relationships to disclose.

PHILADELPHIA – A carefully tailored program in which physicians talked with heart failure (HF) patients about the cost of their medications improved medication adherence and the likelihood that patients get the medications they’re prescribed, results of a pilot study show.

The POCKET-COST-HF trial integrated information about patient-specific out-of-pocket (OOP) drug costs into clinical encounters between cardiologists and patients with heart failure with reduced ejection fraction (HFrEF) at six clinic sites in two different health systems. Neil W. Dickert, MD, PhD, primary investigator of the trial, said OOP costs for HFrEF patients with Medicare Part D prescription drug coverage can run upwards of $2,600 a year for four-drug therapy. Dr. Dickert is a cardiologist at Emory University in Atlanta.

Dickert_Neil_W_ATLANTA_web.jpg

“The primary outcome for the study was whether patients and clinicians essentially talked about the cost of medications,” Dr. Dickert said in an interview. “The study was positive in that perspective; we saw an increase of about 19% in the encounters that had cost conversations related to heart failure medication.”

The trial, which Dr. Dickert presented at the annual scientific sessions of the American Heart Association, was designed to evaluate the effect of patient-specific OOP costs in the shared decision-making about heart failure medications, Dr. Dickert said.

The primary outcome was cost-informed decision-making, achieved in 68% of the intervention group encounters and 49% of control encounters (P = .021).
 

Fewer in-pharmacy adjustments

“We saw some really interesting signals of potential benefits in the space of actual decisions,” he said. “There were fewer, for example, contingency plans made in the intervention arm versus the control arm, and what that means is physicians were less likely to write a prescription and leave the decision about whether or not it’s worth it to the patient when they get to the pharmacy.”

The study intervention was a checklist of 19 heart failure medications that included OOP cost, ranging from minimal costs for generics such as diuretics and beta blockers to $617 for dapagliflozin. The checklist was based on an electronic medical records HF medications checklist. Researchers obtained drug cost estimates from TailorMed, a financial navigation company.

Six clinic sites within two health systems, one in Georgia, the other in Colorado, participated in the study. Each cluster had 40 or so patients (n = 247) randomized to the intervention or control. About two-thirds were White, a quarter were Black and 4% and 2.5% in the control and intervention group were Hispanic/LatinX. Income ranges were similar across both arms.

For the study intervention, patients got a call from the clinic 2-3 weeks before their scheduled visit to obtain verbal consent to participate and their OOP costs for drugs. The visit itself, where patients randomized to the intervention received the checklist, was audio recorded. After the visit, patients took a follow-up telephone survey, then the clinic staff did an electronic health record 3 months after the visit.

Getting the patient drug price information was not easy, Dr. Dickert said. “It required a fair amount of work and a big list to get that information that we could then populate the checklist for people,” he said. “It was a behind-the-scenes thing that is not necessarily scalable as done.”

Dr. Dickert acknowledged an increasing emphasis on price transparency in medicine, but the trade-offs are unknown. “Depending upon how that’s carried out, that can have different implications,” he said. “I’m a believer that if we think good communication has the ability to enhance medical decision-making, it also means that either bad information or bad communication can undermine.

“So, I think it’s really important to study these interventions and to do them in rigorous ways where we can really get a sense of what kind of impact they have on patients and clinicians.”
 

Study strengths and limitations

Discussant Dhruv Kazi, MD, director of the cardiac critical care unit at Beth Israel Deaconess Medical Center and associate professor at Harvard Medical School, both in Boston, said in an interview that this study fulfills an important function in investigating how OOP costs influence medication adherence in HFrEF patients.

Kazi_Dhruv_BOSTON_web.jpg

“The total cost of drugs has often been a focus of policy discussions,” he said. “We talk about, how do we reduce drug costs?” He noted the Inflation Reduction Act will bring some of these drug costs down.

“On the flip side,” he added, “as a community we pay less attention to out-of-pocket costs because we assume those are not in our control, yet what the patient cares about is not the total cost of the drug, but, ‘What am I going to pay this month, and what am I going to pay cumulatively over the course of the year? Can I even afford this drug?”

POCKET-COST-HF provided a sound basis for making that investigation, he said, adding that its multisite design and mixed-methods approach – patient contact before and after visits and recording of encounters – are strengths. “Just looking at the logistics involved in pulling off something like this, the study investigators deserve to be congratulated,” he said.

One limitation, Dr. Kazi said, is its exclusion of non–English speakers. Adding them in, along with testing the intervention in community, rural, and primary care settings, are future goals for the intervention, he said. Within the trial itself, examining the cost-effectiveness of the intervention would be laudable, Dr. Kazi said.

The Agency for Healthcare Research and Quality funded the trial. Dr. Dickert disclosed relationships with Abiomed. Dr. Kazi has no relevant relationships to disclose.

PHILADELPHIA – The first in-human study of a gene therapy designed to reduce low-density lipoprotein cholesterol has shown a signal that the treatment works in a small group of patients with heterozygous familial hypercholesterolemia (HeFH).

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 – The first in-human study of a gene therapy designed to reduce low-density lipoprotein cholesterol has shown a signal that the treatment works in a small group of patients with heterozygous familial hypercholesterolemia (HeFH).

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 – The first in-human study of a gene therapy designed to reduce low-density lipoprotein cholesterol has shown a signal that the treatment works in a small group of patients with heterozygous familial hypercholesterolemia (HeFH).

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 – 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.

Lin_Chin_Sheng_TAPEI_web.jpg

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.”

Nallamothu_Brahmajee_K_MICH_web.jpg

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.

Lin_Chin_Sheng_TAPEI_web.jpg

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.”

Nallamothu_Brahmajee_K_MICH_web.jpg

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.

Lin_Chin_Sheng_TAPEI_web.jpg

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.”

Nallamothu_Brahmajee_K_MICH_web.jpg

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.

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.

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.

Siegal_Deborah_M_web.jpg

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.

Siegal_Deborah_M_web.jpg

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.

Siegal_Deborah_M_web.jpg

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.

PHILADELPHIA – Aspirin may not be necessary or beneficial in patients with advanced heart failure who get a left ventricular assist device (LVAD), 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 – Aspirin may not be necessary or beneficial in patients with advanced heart failure who get a left ventricular assist device (LVAD), 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 – Aspirin may not be necessary or beneficial in patients with advanced heart failure who get a left ventricular assist device (LVAD), 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 – 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 patients randomly assigned to dapagliflozin 10 mg along with the standard of care had improved outcomes based on a composite of seven primary endpoints, which the trial described as the hierarchical “win ratio” composite outcomes, compared with patients randomized to placebo plus standard of care.

165916_James_Stefan_web.jpg

“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.

Wiviott_Stephen_MASS_web.PNG

“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 patients randomly assigned to dapagliflozin 10 mg along with the standard of care had improved outcomes based on a composite of seven primary endpoints, which the trial described as the hierarchical “win ratio” composite outcomes, compared with patients randomized to placebo plus standard of care.

165916_James_Stefan_web.jpg

“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.

Wiviott_Stephen_MASS_web.PNG

“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 patients randomly assigned to dapagliflozin 10 mg along with the standard of care had improved outcomes based on a composite of seven primary endpoints, which the trial described as the hierarchical “win ratio” composite outcomes, compared with patients randomized to placebo plus standard of care.

165916_James_Stefan_web.jpg

“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.

Wiviott_Stephen_MASS_web.PNG

“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.
 

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.

pills_520225198_web.jpg

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.

Lee_Joyce_CO_web.jpg

“There are no curative therapies that improve lung function or improve symptoms, so there remains a very large unmet need 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.

pills_520225198_web.jpg

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.

Lee_Joyce_CO_web.jpg

“There are no curative therapies that improve lung function or improve symptoms, so there remains a very large unmet need 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.

pills_520225198_web.jpg

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.

Lee_Joyce_CO_web.jpg

“There are no curative therapies that improve lung function or improve symptoms, so there remains a very large unmet need 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.

Moving from one residence to another after an acute myocardial infarction (AMI) significantly increases the risk for death or transition to a long-term care facility as an end-of-life measure, 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.

Moving from one residence to another after an acute myocardial infarction (AMI) significantly increases the risk for death or transition to a long-term care facility as an end-of-life measure, 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.

Moving from one residence to another after an acute myocardial infarction (AMI) significantly increases the risk for death or transition to a long-term care facility as an end-of-life measure, 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.