MDedge Cardiology

A combination of simple interventions for acute patients with stroke attributable to intracerebral hemorrhage (ICH) has been shown to significantly improve the chances of survival without major disability.
 

The INTERACT3 study showed that timely administration of a care bundle that included early intensive lowering of systolic blood pressure, strict glucose control, treatment of fever, and rapid reversal of abnormal anticoagulation led to less disability, lower rates of death, and better overall quality of life.

“This is a groundbreaking result. It is the first-ever published trial in ICH patients to show a clear benefit on functional outcomes and on mortality,” lead investigator Craig Anderson, MD, director of global brain health at the George Institute for Global Health, Sydney, said in an interview.

“These results show that, if we can organize care and focus on optimal management of these four aspects of the health of the patient, they do better,” Dr. Anderson said.

‘Game changer’

“This is a game changer because now we have level A evidence showing something is definitely beneficial for these patients,” Dr. Anderson added. “That means hospitals have the imperative to organize their systems to do these things and maximize care. We have never had that before.”

Dr. Anderson noted that, while some previous studies have suggested benefit from various interventions, such as early lowering of blood pressure, the results have not been conclusive.

“This means the intervention has not always been implemented, leading to large variations in clinical practice. But now we have a package that is proven to work; this should become a guideline-recommended practice,” he commented.

The INTERACT-3 results were presented at the European Stroke Organisation conference in Munich. They were also simultaneously published online in The Lancet.

Dr. Anderson explained that, until now, there haven’t been any proven treatments for ICH. “There has been a lot of energy and research put into the field, but this has resulted in several interventions that are ‘probably useful’ or which have a level B recommendation,” he said. “No therapy has been shown to be beneficial in a totally conclusive way, so we are still not entirely sure exactly whether the treatments we use actually make a difference.”

The INTERACT3 researchers therefore decided to evaluate a care package consisting of a bundle of several treatments in the hope that they may have additive or synergistic effects.

The study involved 7,036 patients with imaging-confirmed spontaneous ICH who presented within 6 hours of symptom onset to one of 121 hospitals in 10 mainly low- and middle-income countries: Brazil, China, India, Mexico, Nigeria, Pakistan, Peru, Sri Lanka, Vietnam, and Chile.

Using a cluster design, all hospitals started with usual care as a control and then at some point during the study started using the care bundle intervention.

The care-bundle protocol included the early intensive lowering of systolic blood pressure (target, < 140 mm Hg), strict glucose control (target, 6.1-7.8 mmol/L in those without diabetes and 7.8-10.0 mmol/L in those with diabetes), antipyrexia treatment (target body temperature, ≤ 37.5° C), and rapid reversal of warfarin-related anticoagulation (target international normalized ratio, 1.5) in patients for whom these variables were abnormal.

Overall, the modified intention-to-treat population included 3,221 patients who were assigned to the care-bundle group and 3,815 who were assigned to the usual-care group. Primary outcome data were available for 2,892 patients in the care-bundle group and 3,363 patients in the usual-care group.

The primary outcome was functional recovery, measured with the Modified Rankin Scale at 6 months. Results show that the likelihood of a poor functional outcome was lower in the care-bundle group (common odds ratio, 0.86; P = .015).

Patients who received the interventional care bundle also had a significantly lower rate of serious adverse events (16.0% vs. 20.1%) and mortality (14.1% vs. 17.0%).

NNT of 35 to save one life free of disability

“The number needed to treat (NNT) is just 35 to save a life free of disability,” Dr. Anderson commented. “That’s pretty good. We estimate that this care bundle would save tens of thousands of lives a year if universally adopted.”

The intervention group also spent less time in hospital and had improved health-related quality of life.

Dr. Anderson pointed out that the interventions included in the care bundle were all relatively easy to perform.

“They just require a bit more nursing time and the use of a few inexpensive medicines and maybe infusion pumps, but we’re not talking about the need for skilled surgery or a new therapy costing hundreds of thousands of dollars, so this care bundle should be very straightforward to implement. While we haven’t done a formal cost-effectiveness analysis, I would say it will definitely be good value for money.”

Dr. Anderson believes the rapid lowering of blood pressure is a very important part of the care bundle. He noted that target levels were achieved, on average, in 2.3 hours, compared with 4.0 hours in the control group. But he stressed that this was not just a trial of blood pressure reduction and that the whole package is important.

He gave a couple of possible reasons why this trial was successful whereas previous trials did not show a clear benefit of blood pressure lowering in ICH.

“Firstly, it was a very large trial with more than 7,000 patients – that is more than three times larger than any other trial in ICH. And secondly, the package of care means there are several different interventions that together show a real benefit,” he said. “It’s like the polypill, or a rehabilitation program – if you put several different things together, the whole package can show really positive results.”

Dr. Anderson also pointed out that the study included a wide spectrum of ICH patients, and the benefit of the care bundle was seen across all groups and all stroke severities.

“There were a lot of patients with a large ICH, and if anything, they showed an even larger benefit with the bundle of care,” he said.

The researchers note that the burden of ICH is greatest in low- and middle-income countries. In 2019, 30% of all stroke cases in these countries were ICH, almost double the proportion seen in high-income countries (16%). This is in part attributable to high rates of hypertension and limited resources for primary prevention, including identification and management of stroke risk factors by health care services.

‘Outstanding example’ of less therapeutic negativity

Lili Song, MD, PhD, joint lead author and head of the Stroke Program at the George Institute China, Beijing, said, “A lack of proven treatments for ICH has led to a pessimistic view that not much can be done for these patients.

“However, with INTERACT3, we demonstrate on a large scale how readily available treatments can be used to improve outcomes in resource-limited settings,” she said. “We hope this evidence will inform clinical practice guidelines across the globe and help save many lives.”

In a comment that accompanied the article, Wendy Ziai, MD, Matthew Bower, MD, and Daniel Hanley, MD, Johns Hopkins University, Baltimore, say the INTERACT3 study shows that “an intracerebral hemorrhage care bundle focused on physiological control interventions, whether synergistic or not, might promote better outcomes in hospitals where care has not previously optimized sustained interventions.”

Pointing out that the care bundle has minimal risks of cost and coordination and a high public health effect, they conclude: “This effort is an outstanding example of why less therapeutic negativity, and more intervention might benefit survivors of intracerebral hemorrhage.”

The INTERACT3 study was funded by the Department of Health and Social Care, the Foreign, Commonwealth and Development Office, the Medical Research Council, and the Wellcome Trust (all in the United Kingdom), the West China Hospital Outstanding Discipline Development 1–3-5 Programme, the National Health and Medical Research Council of Australia, Sichuan Credit Pharmaceutical, and Takeda (China).

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

A combination of simple interventions for acute patients with stroke attributable to intracerebral hemorrhage (ICH) has been shown to significantly improve the chances of survival without major disability.
 

The INTERACT3 study showed that timely administration of a care bundle that included early intensive lowering of systolic blood pressure, strict glucose control, treatment of fever, and rapid reversal of abnormal anticoagulation led to less disability, lower rates of death, and better overall quality of life.

“This is a groundbreaking result. It is the first-ever published trial in ICH patients to show a clear benefit on functional outcomes and on mortality,” lead investigator Craig Anderson, MD, director of global brain health at the George Institute for Global Health, Sydney, said in an interview.

“These results show that, if we can organize care and focus on optimal management of these four aspects of the health of the patient, they do better,” Dr. Anderson said.

‘Game changer’

“This is a game changer because now we have level A evidence showing something is definitely beneficial for these patients,” Dr. Anderson added. “That means hospitals have the imperative to organize their systems to do these things and maximize care. We have never had that before.”

Dr. Anderson noted that, while some previous studies have suggested benefit from various interventions, such as early lowering of blood pressure, the results have not been conclusive.

“This means the intervention has not always been implemented, leading to large variations in clinical practice. But now we have a package that is proven to work; this should become a guideline-recommended practice,” he commented.

The INTERACT-3 results were presented at the European Stroke Organisation conference in Munich. They were also simultaneously published online in The Lancet.

Dr. Anderson explained that, until now, there haven’t been any proven treatments for ICH. “There has been a lot of energy and research put into the field, but this has resulted in several interventions that are ‘probably useful’ or which have a level B recommendation,” he said. “No therapy has been shown to be beneficial in a totally conclusive way, so we are still not entirely sure exactly whether the treatments we use actually make a difference.”

The INTERACT3 researchers therefore decided to evaluate a care package consisting of a bundle of several treatments in the hope that they may have additive or synergistic effects.

The study involved 7,036 patients with imaging-confirmed spontaneous ICH who presented within 6 hours of symptom onset to one of 121 hospitals in 10 mainly low- and middle-income countries: Brazil, China, India, Mexico, Nigeria, Pakistan, Peru, Sri Lanka, Vietnam, and Chile.

Using a cluster design, all hospitals started with usual care as a control and then at some point during the study started using the care bundle intervention.

The care-bundle protocol included the early intensive lowering of systolic blood pressure (target, < 140 mm Hg), strict glucose control (target, 6.1-7.8 mmol/L in those without diabetes and 7.8-10.0 mmol/L in those with diabetes), antipyrexia treatment (target body temperature, ≤ 37.5° C), and rapid reversal of warfarin-related anticoagulation (target international normalized ratio, 1.5) in patients for whom these variables were abnormal.

Overall, the modified intention-to-treat population included 3,221 patients who were assigned to the care-bundle group and 3,815 who were assigned to the usual-care group. Primary outcome data were available for 2,892 patients in the care-bundle group and 3,363 patients in the usual-care group.

The primary outcome was functional recovery, measured with the Modified Rankin Scale at 6 months. Results show that the likelihood of a poor functional outcome was lower in the care-bundle group (common odds ratio, 0.86; P = .015).

Patients who received the interventional care bundle also had a significantly lower rate of serious adverse events (16.0% vs. 20.1%) and mortality (14.1% vs. 17.0%).

NNT of 35 to save one life free of disability

“The number needed to treat (NNT) is just 35 to save a life free of disability,” Dr. Anderson commented. “That’s pretty good. We estimate that this care bundle would save tens of thousands of lives a year if universally adopted.”

The intervention group also spent less time in hospital and had improved health-related quality of life.

Dr. Anderson pointed out that the interventions included in the care bundle were all relatively easy to perform.

“They just require a bit more nursing time and the use of a few inexpensive medicines and maybe infusion pumps, but we’re not talking about the need for skilled surgery or a new therapy costing hundreds of thousands of dollars, so this care bundle should be very straightforward to implement. While we haven’t done a formal cost-effectiveness analysis, I would say it will definitely be good value for money.”

Dr. Anderson believes the rapid lowering of blood pressure is a very important part of the care bundle. He noted that target levels were achieved, on average, in 2.3 hours, compared with 4.0 hours in the control group. But he stressed that this was not just a trial of blood pressure reduction and that the whole package is important.

He gave a couple of possible reasons why this trial was successful whereas previous trials did not show a clear benefit of blood pressure lowering in ICH.

“Firstly, it was a very large trial with more than 7,000 patients – that is more than three times larger than any other trial in ICH. And secondly, the package of care means there are several different interventions that together show a real benefit,” he said. “It’s like the polypill, or a rehabilitation program – if you put several different things together, the whole package can show really positive results.”

Dr. Anderson also pointed out that the study included a wide spectrum of ICH patients, and the benefit of the care bundle was seen across all groups and all stroke severities.

“There were a lot of patients with a large ICH, and if anything, they showed an even larger benefit with the bundle of care,” he said.

The researchers note that the burden of ICH is greatest in low- and middle-income countries. In 2019, 30% of all stroke cases in these countries were ICH, almost double the proportion seen in high-income countries (16%). This is in part attributable to high rates of hypertension and limited resources for primary prevention, including identification and management of stroke risk factors by health care services.

‘Outstanding example’ of less therapeutic negativity

Lili Song, MD, PhD, joint lead author and head of the Stroke Program at the George Institute China, Beijing, said, “A lack of proven treatments for ICH has led to a pessimistic view that not much can be done for these patients.

“However, with INTERACT3, we demonstrate on a large scale how readily available treatments can be used to improve outcomes in resource-limited settings,” she said. “We hope this evidence will inform clinical practice guidelines across the globe and help save many lives.”

In a comment that accompanied the article, Wendy Ziai, MD, Matthew Bower, MD, and Daniel Hanley, MD, Johns Hopkins University, Baltimore, say the INTERACT3 study shows that “an intracerebral hemorrhage care bundle focused on physiological control interventions, whether synergistic or not, might promote better outcomes in hospitals where care has not previously optimized sustained interventions.”

Pointing out that the care bundle has minimal risks of cost and coordination and a high public health effect, they conclude: “This effort is an outstanding example of why less therapeutic negativity, and more intervention might benefit survivors of intracerebral hemorrhage.”

The INTERACT3 study was funded by the Department of Health and Social Care, the Foreign, Commonwealth and Development Office, the Medical Research Council, and the Wellcome Trust (all in the United Kingdom), the West China Hospital Outstanding Discipline Development 1–3-5 Programme, the National Health and Medical Research Council of Australia, Sichuan Credit Pharmaceutical, and Takeda (China).

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

A combination of simple interventions for acute patients with stroke attributable to intracerebral hemorrhage (ICH) has been shown to significantly improve the chances of survival without major disability.
 

The INTERACT3 study showed that timely administration of a care bundle that included early intensive lowering of systolic blood pressure, strict glucose control, treatment of fever, and rapid reversal of abnormal anticoagulation led to less disability, lower rates of death, and better overall quality of life.

“This is a groundbreaking result. It is the first-ever published trial in ICH patients to show a clear benefit on functional outcomes and on mortality,” lead investigator Craig Anderson, MD, director of global brain health at the George Institute for Global Health, Sydney, said in an interview.

“These results show that, if we can organize care and focus on optimal management of these four aspects of the health of the patient, they do better,” Dr. Anderson said.

‘Game changer’

“This is a game changer because now we have level A evidence showing something is definitely beneficial for these patients,” Dr. Anderson added. “That means hospitals have the imperative to organize their systems to do these things and maximize care. We have never had that before.”

Dr. Anderson noted that, while some previous studies have suggested benefit from various interventions, such as early lowering of blood pressure, the results have not been conclusive.

“This means the intervention has not always been implemented, leading to large variations in clinical practice. But now we have a package that is proven to work; this should become a guideline-recommended practice,” he commented.

The INTERACT-3 results were presented at the European Stroke Organisation conference in Munich. They were also simultaneously published online in The Lancet.

Dr. Anderson explained that, until now, there haven’t been any proven treatments for ICH. “There has been a lot of energy and research put into the field, but this has resulted in several interventions that are ‘probably useful’ or which have a level B recommendation,” he said. “No therapy has been shown to be beneficial in a totally conclusive way, so we are still not entirely sure exactly whether the treatments we use actually make a difference.”

The INTERACT3 researchers therefore decided to evaluate a care package consisting of a bundle of several treatments in the hope that they may have additive or synergistic effects.

The study involved 7,036 patients with imaging-confirmed spontaneous ICH who presented within 6 hours of symptom onset to one of 121 hospitals in 10 mainly low- and middle-income countries: Brazil, China, India, Mexico, Nigeria, Pakistan, Peru, Sri Lanka, Vietnam, and Chile.

Using a cluster design, all hospitals started with usual care as a control and then at some point during the study started using the care bundle intervention.

The care-bundle protocol included the early intensive lowering of systolic blood pressure (target, < 140 mm Hg), strict glucose control (target, 6.1-7.8 mmol/L in those without diabetes and 7.8-10.0 mmol/L in those with diabetes), antipyrexia treatment (target body temperature, ≤ 37.5° C), and rapid reversal of warfarin-related anticoagulation (target international normalized ratio, 1.5) in patients for whom these variables were abnormal.

Overall, the modified intention-to-treat population included 3,221 patients who were assigned to the care-bundle group and 3,815 who were assigned to the usual-care group. Primary outcome data were available for 2,892 patients in the care-bundle group and 3,363 patients in the usual-care group.

The primary outcome was functional recovery, measured with the Modified Rankin Scale at 6 months. Results show that the likelihood of a poor functional outcome was lower in the care-bundle group (common odds ratio, 0.86; P = .015).

Patients who received the interventional care bundle also had a significantly lower rate of serious adverse events (16.0% vs. 20.1%) and mortality (14.1% vs. 17.0%).

NNT of 35 to save one life free of disability

“The number needed to treat (NNT) is just 35 to save a life free of disability,” Dr. Anderson commented. “That’s pretty good. We estimate that this care bundle would save tens of thousands of lives a year if universally adopted.”

The intervention group also spent less time in hospital and had improved health-related quality of life.

Dr. Anderson pointed out that the interventions included in the care bundle were all relatively easy to perform.

“They just require a bit more nursing time and the use of a few inexpensive medicines and maybe infusion pumps, but we’re not talking about the need for skilled surgery or a new therapy costing hundreds of thousands of dollars, so this care bundle should be very straightforward to implement. While we haven’t done a formal cost-effectiveness analysis, I would say it will definitely be good value for money.”

Dr. Anderson believes the rapid lowering of blood pressure is a very important part of the care bundle. He noted that target levels were achieved, on average, in 2.3 hours, compared with 4.0 hours in the control group. But he stressed that this was not just a trial of blood pressure reduction and that the whole package is important.

He gave a couple of possible reasons why this trial was successful whereas previous trials did not show a clear benefit of blood pressure lowering in ICH.

“Firstly, it was a very large trial with more than 7,000 patients – that is more than three times larger than any other trial in ICH. And secondly, the package of care means there are several different interventions that together show a real benefit,” he said. “It’s like the polypill, or a rehabilitation program – if you put several different things together, the whole package can show really positive results.”

Dr. Anderson also pointed out that the study included a wide spectrum of ICH patients, and the benefit of the care bundle was seen across all groups and all stroke severities.

“There were a lot of patients with a large ICH, and if anything, they showed an even larger benefit with the bundle of care,” he said.

The researchers note that the burden of ICH is greatest in low- and middle-income countries. In 2019, 30% of all stroke cases in these countries were ICH, almost double the proportion seen in high-income countries (16%). This is in part attributable to high rates of hypertension and limited resources for primary prevention, including identification and management of stroke risk factors by health care services.

‘Outstanding example’ of less therapeutic negativity

Lili Song, MD, PhD, joint lead author and head of the Stroke Program at the George Institute China, Beijing, said, “A lack of proven treatments for ICH has led to a pessimistic view that not much can be done for these patients.

“However, with INTERACT3, we demonstrate on a large scale how readily available treatments can be used to improve outcomes in resource-limited settings,” she said. “We hope this evidence will inform clinical practice guidelines across the globe and help save many lives.”

In a comment that accompanied the article, Wendy Ziai, MD, Matthew Bower, MD, and Daniel Hanley, MD, Johns Hopkins University, Baltimore, say the INTERACT3 study shows that “an intracerebral hemorrhage care bundle focused on physiological control interventions, whether synergistic or not, might promote better outcomes in hospitals where care has not previously optimized sustained interventions.”

Pointing out that the care bundle has minimal risks of cost and coordination and a high public health effect, they conclude: “This effort is an outstanding example of why less therapeutic negativity, and more intervention might benefit survivors of intracerebral hemorrhage.”

The INTERACT3 study was funded by the Department of Health and Social Care, the Foreign, Commonwealth and Development Office, the Medical Research Council, and the Wellcome Trust (all in the United Kingdom), the West China Hospital Outstanding Discipline Development 1–3-5 Programme, the National Health and Medical Research Council of Australia, Sichuan Credit Pharmaceutical, and Takeda (China).

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

In patients with heart failure (HF) and reduced ejection fraction (HFrEF), the copper chelator trientine reduced NT-proBNP levels up to 8 weeks by restoring normal intracellular copper.

In models of HF, intracellular copper depletion is associated with myocardial hypertrophy and fibrosis, and thus an increased risk for cardiac remodeling, James Januzzi, MD, of Massachusetts General Hospital and Harvard Medical School in Boston, told attendees at the Heart Failure Association of the European Society of Cardiology (HFA-ESC) 2023 sessions.

Although trientine has been used for over 40 years to treat Wilson disease – a rare inherited disease characterized by copper overload – “paradoxically, it acts as a copper chaperone and can restore intracellular copper concentrations at low doses,” Dr. Januzzi explained during his presentation of the TRACER-HF results.

Although the dose-ranging study found that at 300 mg twice daily trientine effectively reduced NT-proBNP levels at 4 and 8 weeks, by 12 weeks, the effect had disappeared.

Nevertheless, Dr. Januzzi told the meeting attendees that the same dose was “most consistently” associated with most favorable Kansas City Cardiomyopathy Questionnaire Overall Summary Score (KCCQ-OSS) changes, as well as improvements in left ventricular (LV) function and 6-minute walk distance.
 

‘Challenging is an understatement’

Asked why the improvement in NT-proBNP levels was no longer evident at week 12, Dr. Januzzi acknowledged, “We just don’t know.” However, the team speculates that the disrupted nature of the study might play a role.

The phase 2, placebo-controlled trial started recruiting at 27 sites in North America in 2019. When the pandemic hit in 2020, enrollment was suspended, then pivoted to China in 2021. A total of 190 participants were ultimately enrolled.

However, 91% of participants in China were finishing their follow-up in late 2022, when the country was hit by a COVID-19 surge, which might have affected the 12-week outcomes – though this is speculation for now.

Overall, participants had a mean age of 57 years; about 80% were men; 91% were Asian; the mean left ventricular ejection fraction (LVEF) was 30%; and most (77%) were New York Heart Association class II. All were stable on optimal drug therapy, including chronic loop diuretics.

All had elevated NT-proBNP: ≥ 400 pg/mL without atrial fibrillation or flutter, or ≥ 1200 pg/mL with atrial fibrillation or flutter.

Participants were randomized to placebo or twice-daily trientine doses of 50 mg, 150 mg, or 300 mg.

The primary endpoint was the proportional change in NT-proBNP from baseline to 12 weeks. Key secondary endpoints included the effect of trientine compared with placebo on mechanistic outcomes such as change in cardiac remodeling indices, 6-minute walk distance, and the KCCQ-OSS.

As noted, the greatest reduction in NT-proBNP at 4 and 8 weeks was in the 300-mg group, with a geometric mean ratio of 0.82 at week 4 vs. 1.03 for placebo; 0.92 for 50 mg; and 0.83 for 150 mg; and 0.79 at week 8 vs 1.02 for placebo; 0.85 for 50 mg; and 0.91 for 150 mg.

LV volumes improved at all doses, though by the most at 50 mg (–11.7 mL).

The change in 6-minute walk distance was greatest at the 300-mg dose at 42 meters.

The responder analysis showed that 300 mg was most consistently associated with most of the favorable KCCQ changes.

From a safety standpoint, trientine was well tolerated without any adverse outcomes. Notably, Dr. Januzzi told meeting attendees, blood pressure and heart rate were not affected by the addition of trientine to background medical care.

In addition, a post hoc interaction was identified between treatment response and a baseline LVEF ≤ 30%, data that, for now, are “compelling but hypothesis-generating,” he said. Data on secondary endpoints specifically for that group “are forthcoming.”
 

Looking ahead

Dr. Januzzi said in an interview that the team is now finalizing the main report “and will turn our attention to the interaction analyses suggesting exaggerated benefit in those with lower LVEF.

“We are examining all possible options for this novel therapy, which may include progressing to phase 3,” he said.

Challenges going forward include the need to understand which patients are most appropriate for the drug. “Given that it does not affect blood pressure or heart rate, it is an attractive consideration for any patient on guideline-directed medical therapy, but we need to have more clarity about the mechanism of benefit and understanding about the subgroup interactions that we have detected.

“Even in a well-managed population of patients with heart failure, there may still be room for therapies with benefit,” he concluded.

Danyaal Moin, MD, assistant professor of medicine at NYU Langone Health in New York and a specialist in advanced heart failure and transplantation, commented on these findings for this article.

“It is always exciting to consider new pathways to treat patients with systolic dysfunction, given the residual risk even for patients on contemporary quadruple therapy for HFrEF,” he said. “However, certain challenges with this phase 2 study will need to be addressed in an eventual phase 3 clinical trial.

“The study sample was predominately recruited in China and is not necessarily representative of a heart failure population in many clinical practices,” he said.

“It would be important that future studies with trientine-HCL assess endpoints such as heart failure hospitalizations and mortality that would help elucidate where this therapy would stand relative to current established heart failure therapies.”

Longer follow-up is needed and, he noted, “while it appears the investigators will ultimately favor the 300-mg dosage, it is interesting that left ventricular volume indices changed most favorably with the 50-mg dose of the therapy.” 

The study was sponsored by Innolife Pharmaceuticals and coordinated by the Baim Institute for Clinical Research in Boston. Dr. Januzzi has received grant support from Innolife. Dr. Moin declared no relevant financial relationships.

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

In patients with heart failure (HF) and reduced ejection fraction (HFrEF), the copper chelator trientine reduced NT-proBNP levels up to 8 weeks by restoring normal intracellular copper.

In models of HF, intracellular copper depletion is associated with myocardial hypertrophy and fibrosis, and thus an increased risk for cardiac remodeling, James Januzzi, MD, of Massachusetts General Hospital and Harvard Medical School in Boston, told attendees at the Heart Failure Association of the European Society of Cardiology (HFA-ESC) 2023 sessions.

Although trientine has been used for over 40 years to treat Wilson disease – a rare inherited disease characterized by copper overload – “paradoxically, it acts as a copper chaperone and can restore intracellular copper concentrations at low doses,” Dr. Januzzi explained during his presentation of the TRACER-HF results.

Although the dose-ranging study found that at 300 mg twice daily trientine effectively reduced NT-proBNP levels at 4 and 8 weeks, by 12 weeks, the effect had disappeared.

Nevertheless, Dr. Januzzi told the meeting attendees that the same dose was “most consistently” associated with most favorable Kansas City Cardiomyopathy Questionnaire Overall Summary Score (KCCQ-OSS) changes, as well as improvements in left ventricular (LV) function and 6-minute walk distance.
 

‘Challenging is an understatement’

Asked why the improvement in NT-proBNP levels was no longer evident at week 12, Dr. Januzzi acknowledged, “We just don’t know.” However, the team speculates that the disrupted nature of the study might play a role.

The phase 2, placebo-controlled trial started recruiting at 27 sites in North America in 2019. When the pandemic hit in 2020, enrollment was suspended, then pivoted to China in 2021. A total of 190 participants were ultimately enrolled.

However, 91% of participants in China were finishing their follow-up in late 2022, when the country was hit by a COVID-19 surge, which might have affected the 12-week outcomes – though this is speculation for now.

Overall, participants had a mean age of 57 years; about 80% were men; 91% were Asian; the mean left ventricular ejection fraction (LVEF) was 30%; and most (77%) were New York Heart Association class II. All were stable on optimal drug therapy, including chronic loop diuretics.

All had elevated NT-proBNP: ≥ 400 pg/mL without atrial fibrillation or flutter, or ≥ 1200 pg/mL with atrial fibrillation or flutter.

Participants were randomized to placebo or twice-daily trientine doses of 50 mg, 150 mg, or 300 mg.

The primary endpoint was the proportional change in NT-proBNP from baseline to 12 weeks. Key secondary endpoints included the effect of trientine compared with placebo on mechanistic outcomes such as change in cardiac remodeling indices, 6-minute walk distance, and the KCCQ-OSS.

As noted, the greatest reduction in NT-proBNP at 4 and 8 weeks was in the 300-mg group, with a geometric mean ratio of 0.82 at week 4 vs. 1.03 for placebo; 0.92 for 50 mg; and 0.83 for 150 mg; and 0.79 at week 8 vs 1.02 for placebo; 0.85 for 50 mg; and 0.91 for 150 mg.

LV volumes improved at all doses, though by the most at 50 mg (–11.7 mL).

The change in 6-minute walk distance was greatest at the 300-mg dose at 42 meters.

The responder analysis showed that 300 mg was most consistently associated with most of the favorable KCCQ changes.

From a safety standpoint, trientine was well tolerated without any adverse outcomes. Notably, Dr. Januzzi told meeting attendees, blood pressure and heart rate were not affected by the addition of trientine to background medical care.

In addition, a post hoc interaction was identified between treatment response and a baseline LVEF ≤ 30%, data that, for now, are “compelling but hypothesis-generating,” he said. Data on secondary endpoints specifically for that group “are forthcoming.”
 

Looking ahead

Dr. Januzzi said in an interview that the team is now finalizing the main report “and will turn our attention to the interaction analyses suggesting exaggerated benefit in those with lower LVEF.

“We are examining all possible options for this novel therapy, which may include progressing to phase 3,” he said.

Challenges going forward include the need to understand which patients are most appropriate for the drug. “Given that it does not affect blood pressure or heart rate, it is an attractive consideration for any patient on guideline-directed medical therapy, but we need to have more clarity about the mechanism of benefit and understanding about the subgroup interactions that we have detected.

“Even in a well-managed population of patients with heart failure, there may still be room for therapies with benefit,” he concluded.

Danyaal Moin, MD, assistant professor of medicine at NYU Langone Health in New York and a specialist in advanced heart failure and transplantation, commented on these findings for this article.

“It is always exciting to consider new pathways to treat patients with systolic dysfunction, given the residual risk even for patients on contemporary quadruple therapy for HFrEF,” he said. “However, certain challenges with this phase 2 study will need to be addressed in an eventual phase 3 clinical trial.

“The study sample was predominately recruited in China and is not necessarily representative of a heart failure population in many clinical practices,” he said.

“It would be important that future studies with trientine-HCL assess endpoints such as heart failure hospitalizations and mortality that would help elucidate where this therapy would stand relative to current established heart failure therapies.”

Longer follow-up is needed and, he noted, “while it appears the investigators will ultimately favor the 300-mg dosage, it is interesting that left ventricular volume indices changed most favorably with the 50-mg dose of the therapy.” 

The study was sponsored by Innolife Pharmaceuticals and coordinated by the Baim Institute for Clinical Research in Boston. Dr. Januzzi has received grant support from Innolife. Dr. Moin declared no relevant financial relationships.

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

In patients with heart failure (HF) and reduced ejection fraction (HFrEF), the copper chelator trientine reduced NT-proBNP levels up to 8 weeks by restoring normal intracellular copper.

In models of HF, intracellular copper depletion is associated with myocardial hypertrophy and fibrosis, and thus an increased risk for cardiac remodeling, James Januzzi, MD, of Massachusetts General Hospital and Harvard Medical School in Boston, told attendees at the Heart Failure Association of the European Society of Cardiology (HFA-ESC) 2023 sessions.

Although trientine has been used for over 40 years to treat Wilson disease – a rare inherited disease characterized by copper overload – “paradoxically, it acts as a copper chaperone and can restore intracellular copper concentrations at low doses,” Dr. Januzzi explained during his presentation of the TRACER-HF results.

Although the dose-ranging study found that at 300 mg twice daily trientine effectively reduced NT-proBNP levels at 4 and 8 weeks, by 12 weeks, the effect had disappeared.

Nevertheless, Dr. Januzzi told the meeting attendees that the same dose was “most consistently” associated with most favorable Kansas City Cardiomyopathy Questionnaire Overall Summary Score (KCCQ-OSS) changes, as well as improvements in left ventricular (LV) function and 6-minute walk distance.
 

‘Challenging is an understatement’

Asked why the improvement in NT-proBNP levels was no longer evident at week 12, Dr. Januzzi acknowledged, “We just don’t know.” However, the team speculates that the disrupted nature of the study might play a role.

The phase 2, placebo-controlled trial started recruiting at 27 sites in North America in 2019. When the pandemic hit in 2020, enrollment was suspended, then pivoted to China in 2021. A total of 190 participants were ultimately enrolled.

However, 91% of participants in China were finishing their follow-up in late 2022, when the country was hit by a COVID-19 surge, which might have affected the 12-week outcomes – though this is speculation for now.

Overall, participants had a mean age of 57 years; about 80% were men; 91% were Asian; the mean left ventricular ejection fraction (LVEF) was 30%; and most (77%) were New York Heart Association class II. All were stable on optimal drug therapy, including chronic loop diuretics.

All had elevated NT-proBNP: ≥ 400 pg/mL without atrial fibrillation or flutter, or ≥ 1200 pg/mL with atrial fibrillation or flutter.

Participants were randomized to placebo or twice-daily trientine doses of 50 mg, 150 mg, or 300 mg.

The primary endpoint was the proportional change in NT-proBNP from baseline to 12 weeks. Key secondary endpoints included the effect of trientine compared with placebo on mechanistic outcomes such as change in cardiac remodeling indices, 6-minute walk distance, and the KCCQ-OSS.

As noted, the greatest reduction in NT-proBNP at 4 and 8 weeks was in the 300-mg group, with a geometric mean ratio of 0.82 at week 4 vs. 1.03 for placebo; 0.92 for 50 mg; and 0.83 for 150 mg; and 0.79 at week 8 vs 1.02 for placebo; 0.85 for 50 mg; and 0.91 for 150 mg.

LV volumes improved at all doses, though by the most at 50 mg (–11.7 mL).

The change in 6-minute walk distance was greatest at the 300-mg dose at 42 meters.

The responder analysis showed that 300 mg was most consistently associated with most of the favorable KCCQ changes.

From a safety standpoint, trientine was well tolerated without any adverse outcomes. Notably, Dr. Januzzi told meeting attendees, blood pressure and heart rate were not affected by the addition of trientine to background medical care.

In addition, a post hoc interaction was identified between treatment response and a baseline LVEF ≤ 30%, data that, for now, are “compelling but hypothesis-generating,” he said. Data on secondary endpoints specifically for that group “are forthcoming.”
 

Looking ahead

Dr. Januzzi said in an interview that the team is now finalizing the main report “and will turn our attention to the interaction analyses suggesting exaggerated benefit in those with lower LVEF.

“We are examining all possible options for this novel therapy, which may include progressing to phase 3,” he said.

Challenges going forward include the need to understand which patients are most appropriate for the drug. “Given that it does not affect blood pressure or heart rate, it is an attractive consideration for any patient on guideline-directed medical therapy, but we need to have more clarity about the mechanism of benefit and understanding about the subgroup interactions that we have detected.

“Even in a well-managed population of patients with heart failure, there may still be room for therapies with benefit,” he concluded.

Danyaal Moin, MD, assistant professor of medicine at NYU Langone Health in New York and a specialist in advanced heart failure and transplantation, commented on these findings for this article.

“It is always exciting to consider new pathways to treat patients with systolic dysfunction, given the residual risk even for patients on contemporary quadruple therapy for HFrEF,” he said. “However, certain challenges with this phase 2 study will need to be addressed in an eventual phase 3 clinical trial.

“The study sample was predominately recruited in China and is not necessarily representative of a heart failure population in many clinical practices,” he said.

“It would be important that future studies with trientine-HCL assess endpoints such as heart failure hospitalizations and mortality that would help elucidate where this therapy would stand relative to current established heart failure therapies.”

Longer follow-up is needed and, he noted, “while it appears the investigators will ultimately favor the 300-mg dosage, it is interesting that left ventricular volume indices changed most favorably with the 50-mg dose of the therapy.” 

The study was sponsored by Innolife Pharmaceuticals and coordinated by the Baim Institute for Clinical Research in Boston. Dr. Januzzi has received grant support from Innolife. Dr. Moin declared no relevant financial relationships.

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

Patients undergoing bariatric surgery for obesity showed significant declines in the use of lipid-lowering and antidiabetic medications up to 15 years after the procedure compared with patients with obesity who did not have such an operation. However, these declines didn’t extend to cardiovascular medication use.

“In this study, undergoing bariatric surgery was associated with a substantial and long-lasting reduction in the use of lipid-lowering and antidiabetic medications, compared with no surgery for obesity, while for cardiovascular medications this reduction was only transient,” the authors report in research published in JAMA Surgery.

“The results can aid in informed decision-making when considering bariatric surgery for patients with morbid obesity and inform patients and professionals about the expected long-term effects of medication use for obesity-related comorbidities,” they write.

The study “highlights the benefits of mandated databases that report metabolic bariatric surgery, obesity-related comorbidities, and medications,” writes Paulina Salminen, MD, in an accompanying editorial.

However, key limitations include a lack of weight data, which is important in light of previous studies showing that suboptimal weight loss after bariatric surgery is linked to a higher incidence of type 2 diabetes, dyslipidemia, and hypertension, note Dr. Salminen, of the department of digestive surgery, University Hospital, Turku, Finland, and colleagues.
 

Swedish, Finnish obesity data probed

When significant weight loss is achieved, bariatric surgery has been well documented to be associated with improvements in a variety of comorbidities, quality of life, and even life expectancy.

Key comorbidities shown to improve with the surgery include hyperlipidemia, cardiovascular disease, and type 2 diabetes.

However, data are lacking on the association between bariatric surgery and the use of medications for those conditions, particularly compared with people with obesity who don’t have bariatric surgery.

To investigate, first author Joonas H. Kauppila, MD, PhD, of Upper Gastrointestinal Surgery, Karolinska University Hospital, Stockholm, and colleagues conducted a population-based cohort study, evaluating data on 26,396 patients who underwent bariatric surgery with gastric bypass or sleeve gastrectomy in Sweden between 2005 and 2020 or Finland between 1995 and 2018.

Overall, 66.4% of patients were women and their median age was 50.

They were compared with five times as many matched controls with obesity who had not had bariatric surgery from the same population databases, representing a total of 131,980 patients who were matched based on age, country, sex, calendar year, and medication use.  

In terms of lipid-lowering medication, rates of use after bariatric surgery decreased from 20.3% at baseline to 12.9% after 2 years and bounced back somewhat to 17.6% after 15 years. Comparatively, in the no surgery group, baseline lipid-lowering medication use of 21.0% increased to 44.6% after 15 years, more than twice the rate of usage in the bariatric surgery group in the same period.

Antidiabetic medications were used by 27.7% of patients in the bariatric surgery group at baseline, with a drop to 10.0% after 2 years, followed by an increase to 23.5% after 15 years. In the no surgery group, the rate of antidiabetic medication use steadily increased from 27.7% at baseline to 54.2% after 15 years, which again was nearly double the rate of antidiabetic medication use in the bariatric surgery group at 15 years.

Meanwhile, cardiovascular medications were used by 60.2% of patients receiving bariatric surgery at baseline, with the rate decreasing to 43.2% after 2 years but increasing to 74.6% after 15 years. Among the nonbariatric surgery patients, use of cardiovascular medications increased from 54.4% at baseline to 83.3% after 15 years.
 

Causes?

As for the cause of the lack of any decline in use of cardiovascular medications versus other medications in the surgery patients, the authors speculate that the effect “may be related to aging and regain of weight over time after bariatric surgery, a phenomenon caused by hormonal, dietary, physical, and behavioral factors.”

“In contrast, as expected, a gradual increase in the use of all three medication groups was observed over time among the patients treated with no surgery for obesity,” they note.

The lower medication use with bariatric surgery can also translate to economic benefits, the authors add.

“Economically, the long-lasting reductions in medication use for hyperlipidemia, cardiovascular morbidity, and diabetes suggest that surgical treatment of morbid obesity may infer savings in medication expenses for patients, health care, and society,” they report.

“Future research may focus on subgroups that are most likely to benefit from bariatric surgery, including resolution and severity of comorbidities,” they continue.

In their editorial, Dr. Salminen and colleagues note that previous research has shown remission of dyslipidemia in up to 70% of patients after bariatric surgery that was independent of weight loss, which appears to support the sustained reduction in lipid-lowering medications following surgery observed in the current study, suggesting some benefits on lipids beyond weight loss.

Other limitations, however, include that the bariatric surgery group in the study was older and had more comorbidities than those in previous bariatric surgery studies.

“Future studies should assess this in a younger cohort with less disease at baseline and differentiation within cardiovascular disease regarding at least hypertension, ischemic heart disease, and heart failure,” the authors conclude.

The authors have reported no relevant financial relationships. Dr. Salminen has reported receiving grants from the Sigrid Jusélius Foundation, Academy of Finland, Government Research Grant Foundation, and the University of Turku (Finland).

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

Patients undergoing bariatric surgery for obesity showed significant declines in the use of lipid-lowering and antidiabetic medications up to 15 years after the procedure compared with patients with obesity who did not have such an operation. However, these declines didn’t extend to cardiovascular medication use.

“In this study, undergoing bariatric surgery was associated with a substantial and long-lasting reduction in the use of lipid-lowering and antidiabetic medications, compared with no surgery for obesity, while for cardiovascular medications this reduction was only transient,” the authors report in research published in JAMA Surgery.

“The results can aid in informed decision-making when considering bariatric surgery for patients with morbid obesity and inform patients and professionals about the expected long-term effects of medication use for obesity-related comorbidities,” they write.

The study “highlights the benefits of mandated databases that report metabolic bariatric surgery, obesity-related comorbidities, and medications,” writes Paulina Salminen, MD, in an accompanying editorial.

However, key limitations include a lack of weight data, which is important in light of previous studies showing that suboptimal weight loss after bariatric surgery is linked to a higher incidence of type 2 diabetes, dyslipidemia, and hypertension, note Dr. Salminen, of the department of digestive surgery, University Hospital, Turku, Finland, and colleagues.
 

Swedish, Finnish obesity data probed

When significant weight loss is achieved, bariatric surgery has been well documented to be associated with improvements in a variety of comorbidities, quality of life, and even life expectancy.

Key comorbidities shown to improve with the surgery include hyperlipidemia, cardiovascular disease, and type 2 diabetes.

However, data are lacking on the association between bariatric surgery and the use of medications for those conditions, particularly compared with people with obesity who don’t have bariatric surgery.

To investigate, first author Joonas H. Kauppila, MD, PhD, of Upper Gastrointestinal Surgery, Karolinska University Hospital, Stockholm, and colleagues conducted a population-based cohort study, evaluating data on 26,396 patients who underwent bariatric surgery with gastric bypass or sleeve gastrectomy in Sweden between 2005 and 2020 or Finland between 1995 and 2018.

Overall, 66.4% of patients were women and their median age was 50.

They were compared with five times as many matched controls with obesity who had not had bariatric surgery from the same population databases, representing a total of 131,980 patients who were matched based on age, country, sex, calendar year, and medication use.  

In terms of lipid-lowering medication, rates of use after bariatric surgery decreased from 20.3% at baseline to 12.9% after 2 years and bounced back somewhat to 17.6% after 15 years. Comparatively, in the no surgery group, baseline lipid-lowering medication use of 21.0% increased to 44.6% after 15 years, more than twice the rate of usage in the bariatric surgery group in the same period.

Antidiabetic medications were used by 27.7% of patients in the bariatric surgery group at baseline, with a drop to 10.0% after 2 years, followed by an increase to 23.5% after 15 years. In the no surgery group, the rate of antidiabetic medication use steadily increased from 27.7% at baseline to 54.2% after 15 years, which again was nearly double the rate of antidiabetic medication use in the bariatric surgery group at 15 years.

Meanwhile, cardiovascular medications were used by 60.2% of patients receiving bariatric surgery at baseline, with the rate decreasing to 43.2% after 2 years but increasing to 74.6% after 15 years. Among the nonbariatric surgery patients, use of cardiovascular medications increased from 54.4% at baseline to 83.3% after 15 years.
 

Causes?

As for the cause of the lack of any decline in use of cardiovascular medications versus other medications in the surgery patients, the authors speculate that the effect “may be related to aging and regain of weight over time after bariatric surgery, a phenomenon caused by hormonal, dietary, physical, and behavioral factors.”

“In contrast, as expected, a gradual increase in the use of all three medication groups was observed over time among the patients treated with no surgery for obesity,” they note.

The lower medication use with bariatric surgery can also translate to economic benefits, the authors add.

“Economically, the long-lasting reductions in medication use for hyperlipidemia, cardiovascular morbidity, and diabetes suggest that surgical treatment of morbid obesity may infer savings in medication expenses for patients, health care, and society,” they report.

“Future research may focus on subgroups that are most likely to benefit from bariatric surgery, including resolution and severity of comorbidities,” they continue.

In their editorial, Dr. Salminen and colleagues note that previous research has shown remission of dyslipidemia in up to 70% of patients after bariatric surgery that was independent of weight loss, which appears to support the sustained reduction in lipid-lowering medications following surgery observed in the current study, suggesting some benefits on lipids beyond weight loss.

Other limitations, however, include that the bariatric surgery group in the study was older and had more comorbidities than those in previous bariatric surgery studies.

“Future studies should assess this in a younger cohort with less disease at baseline and differentiation within cardiovascular disease regarding at least hypertension, ischemic heart disease, and heart failure,” the authors conclude.

The authors have reported no relevant financial relationships. Dr. Salminen has reported receiving grants from the Sigrid Jusélius Foundation, Academy of Finland, Government Research Grant Foundation, and the University of Turku (Finland).

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

Patients undergoing bariatric surgery for obesity showed significant declines in the use of lipid-lowering and antidiabetic medications up to 15 years after the procedure compared with patients with obesity who did not have such an operation. However, these declines didn’t extend to cardiovascular medication use.

“In this study, undergoing bariatric surgery was associated with a substantial and long-lasting reduction in the use of lipid-lowering and antidiabetic medications, compared with no surgery for obesity, while for cardiovascular medications this reduction was only transient,” the authors report in research published in JAMA Surgery.

“The results can aid in informed decision-making when considering bariatric surgery for patients with morbid obesity and inform patients and professionals about the expected long-term effects of medication use for obesity-related comorbidities,” they write.

The study “highlights the benefits of mandated databases that report metabolic bariatric surgery, obesity-related comorbidities, and medications,” writes Paulina Salminen, MD, in an accompanying editorial.

However, key limitations include a lack of weight data, which is important in light of previous studies showing that suboptimal weight loss after bariatric surgery is linked to a higher incidence of type 2 diabetes, dyslipidemia, and hypertension, note Dr. Salminen, of the department of digestive surgery, University Hospital, Turku, Finland, and colleagues.
 

Swedish, Finnish obesity data probed

When significant weight loss is achieved, bariatric surgery has been well documented to be associated with improvements in a variety of comorbidities, quality of life, and even life expectancy.

Key comorbidities shown to improve with the surgery include hyperlipidemia, cardiovascular disease, and type 2 diabetes.

However, data are lacking on the association between bariatric surgery and the use of medications for those conditions, particularly compared with people with obesity who don’t have bariatric surgery.

To investigate, first author Joonas H. Kauppila, MD, PhD, of Upper Gastrointestinal Surgery, Karolinska University Hospital, Stockholm, and colleagues conducted a population-based cohort study, evaluating data on 26,396 patients who underwent bariatric surgery with gastric bypass or sleeve gastrectomy in Sweden between 2005 and 2020 or Finland between 1995 and 2018.

Overall, 66.4% of patients were women and their median age was 50.

They were compared with five times as many matched controls with obesity who had not had bariatric surgery from the same population databases, representing a total of 131,980 patients who were matched based on age, country, sex, calendar year, and medication use.  

In terms of lipid-lowering medication, rates of use after bariatric surgery decreased from 20.3% at baseline to 12.9% after 2 years and bounced back somewhat to 17.6% after 15 years. Comparatively, in the no surgery group, baseline lipid-lowering medication use of 21.0% increased to 44.6% after 15 years, more than twice the rate of usage in the bariatric surgery group in the same period.

Antidiabetic medications were used by 27.7% of patients in the bariatric surgery group at baseline, with a drop to 10.0% after 2 years, followed by an increase to 23.5% after 15 years. In the no surgery group, the rate of antidiabetic medication use steadily increased from 27.7% at baseline to 54.2% after 15 years, which again was nearly double the rate of antidiabetic medication use in the bariatric surgery group at 15 years.

Meanwhile, cardiovascular medications were used by 60.2% of patients receiving bariatric surgery at baseline, with the rate decreasing to 43.2% after 2 years but increasing to 74.6% after 15 years. Among the nonbariatric surgery patients, use of cardiovascular medications increased from 54.4% at baseline to 83.3% after 15 years.
 

Causes?

As for the cause of the lack of any decline in use of cardiovascular medications versus other medications in the surgery patients, the authors speculate that the effect “may be related to aging and regain of weight over time after bariatric surgery, a phenomenon caused by hormonal, dietary, physical, and behavioral factors.”

“In contrast, as expected, a gradual increase in the use of all three medication groups was observed over time among the patients treated with no surgery for obesity,” they note.

The lower medication use with bariatric surgery can also translate to economic benefits, the authors add.

“Economically, the long-lasting reductions in medication use for hyperlipidemia, cardiovascular morbidity, and diabetes suggest that surgical treatment of morbid obesity may infer savings in medication expenses for patients, health care, and society,” they report.

“Future research may focus on subgroups that are most likely to benefit from bariatric surgery, including resolution and severity of comorbidities,” they continue.

In their editorial, Dr. Salminen and colleagues note that previous research has shown remission of dyslipidemia in up to 70% of patients after bariatric surgery that was independent of weight loss, which appears to support the sustained reduction in lipid-lowering medications following surgery observed in the current study, suggesting some benefits on lipids beyond weight loss.

Other limitations, however, include that the bariatric surgery group in the study was older and had more comorbidities than those in previous bariatric surgery studies.

“Future studies should assess this in a younger cohort with less disease at baseline and differentiation within cardiovascular disease regarding at least hypertension, ischemic heart disease, and heart failure,” the authors conclude.

The authors have reported no relevant financial relationships. Dr. Salminen has reported receiving grants from the Sigrid Jusélius Foundation, Academy of Finland, Government Research Grant Foundation, and the University of Turku (Finland).

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

A real-world study of more than 12,000 cases over 7 years has validated the predictive ability of the proposed guidelines for stratifying thrombotic risks at 1 year for patients with non–ST-elevated acute coronary syndrome (NSTE-ACS) undergoing percutaneous coronary intervention (PCI).

In research presented at the Society for Cardiovascular Angiography & Interventions annual scientific sessions, George Dangas, MD, PhD, current SCAI president and professor of cardiology and vascular surgery at the Icahn School of Medicine at Mount Sinai, New York, reported that the European Society of Cardiology risk stratification criteria appropriately predicted risk in 12,538 patients treated from 2012 to 2019.

Icahn School of Medicine

Despite these proposed guidelines put forward by the ESC in 2020, no consensus exists on criteria for ischemic or thrombotic risk in NSTE-ACS patients, Dr. Dangas noted.

The new study shows that the 1-year major adverse cardiovascular events (MACE) risk was four times greater in patients classified as medium risk (hazard ratio, 4.31; 95% confidence interval, 2.47-7.52) and six times greater in high-risk patients (HR, 6.16; 95% CI, 3.52-10.8), compared with the low-risk group, mostly because of higher rates of all-cause death and myocardial infarction, Dr. Dangas said in an interview.

“Indeed, we found some good correlation between the three risk categories and gradation of risk that validates essentially, but with the statistical testing that we need, that this classification is meaningful if not perfect,” Dr. Dangas said. “In the future we may perform calibrations to enhance its performance.”

The study used data on consecutive patients from the Angioplasty and Stent Procedures Database of Mount Sinai, grouping them into low, medium, and high thrombotic risk based on the proposed ESC guidelines for the management of NSTE-ACS.

The guidelines included a subset of criteria to identify patients with increased thrombotic risk who may benefit from extended treatment with a second antithrombotic agent.

This study aimed to evaluate the value of the criteria to identify patients at higher risk of ischemic events. “That’s why we went to our database to see how this might work,” Dr. Dangas said.

The researchers also found that high-risk patients had about a 40% greater risk of major bleeding (HR, 1.39; 95% CI, 1.06-1.84). Bleeding risks were similar between the low- and moderate-risk groups.

The risk categories reflected the rates of all-cause death, myocardial infarction, or stroke: 5.4%, 4.1%, and 1.6% in the high-, moderate-, and low-risks groups, respectively (P < .001).

“This identification of ischemic risks worked very well for all-cause mortality,” Dr. Dangas said. “I feel this is a strength because mortality is a leader of outcomes. And of course, we’ve had some associations with all events like mortality, myocardial infarction, repeat revascularization, which are interesting and valid, but I think a study result that indicates the mortality itself is known to be unidirectional and a very good correlation makes the result more robust.”
 

Critical role

Risk prediction models such as the proposed ESC guidelines will play a critical role as individualized medicine continues to evolve, Somjot Brar, MD, MPH, director of the regional department of cardiac catheterization at Kaiser Permanente, Los Angeles Medical Center, and associate clinical professor at the University of California, Los Angeles, said in an interview.

UCLA

“This study highlights again the importance of the value for predictive and precision medicine,” Dr. Brar said. “Everything is moving in this direction where we make decisions that are more appropriate for a given patient as opposed to a population of patients.”

Study strengths are the large sample size in a real-world setting and thorough 1-year follow-up, Dr. Brar said.

A limitation is the three risk categories the guidelines proposed. “These are still pretty big boxes,” he said. “The low-, moderate- and high-risk categorization is still very, very broad and can be very vague.”

The relatively low percentage of low-risk patients – 12% versus 56% and 32% for the moderate- and high-risk groups – in this data set may also skew results, Dr. Brar said.

“As we move toward predictive analytics and medicine, we want to make these boxes smaller and smaller and smaller to be able to better understand which treatments should be administered to which patients to maximize the benefit against the risk,” he said. That would be a focus for future analyses, Dr. Brar said.

Dr. Dangas and Dr. Brar have no relevant financial disclosures.


 

A real-world study of more than 12,000 cases over 7 years has validated the predictive ability of the proposed guidelines for stratifying thrombotic risks at 1 year for patients with non–ST-elevated acute coronary syndrome (NSTE-ACS) undergoing percutaneous coronary intervention (PCI).

In research presented at the Society for Cardiovascular Angiography & Interventions annual scientific sessions, George Dangas, MD, PhD, current SCAI president and professor of cardiology and vascular surgery at the Icahn School of Medicine at Mount Sinai, New York, reported that the European Society of Cardiology risk stratification criteria appropriately predicted risk in 12,538 patients treated from 2012 to 2019.

Icahn School of Medicine

Despite these proposed guidelines put forward by the ESC in 2020, no consensus exists on criteria for ischemic or thrombotic risk in NSTE-ACS patients, Dr. Dangas noted.

The new study shows that the 1-year major adverse cardiovascular events (MACE) risk was four times greater in patients classified as medium risk (hazard ratio, 4.31; 95% confidence interval, 2.47-7.52) and six times greater in high-risk patients (HR, 6.16; 95% CI, 3.52-10.8), compared with the low-risk group, mostly because of higher rates of all-cause death and myocardial infarction, Dr. Dangas said in an interview.

“Indeed, we found some good correlation between the three risk categories and gradation of risk that validates essentially, but with the statistical testing that we need, that this classification is meaningful if not perfect,” Dr. Dangas said. “In the future we may perform calibrations to enhance its performance.”

The study used data on consecutive patients from the Angioplasty and Stent Procedures Database of Mount Sinai, grouping them into low, medium, and high thrombotic risk based on the proposed ESC guidelines for the management of NSTE-ACS.

The guidelines included a subset of criteria to identify patients with increased thrombotic risk who may benefit from extended treatment with a second antithrombotic agent.

This study aimed to evaluate the value of the criteria to identify patients at higher risk of ischemic events. “That’s why we went to our database to see how this might work,” Dr. Dangas said.

The researchers also found that high-risk patients had about a 40% greater risk of major bleeding (HR, 1.39; 95% CI, 1.06-1.84). Bleeding risks were similar between the low- and moderate-risk groups.

The risk categories reflected the rates of all-cause death, myocardial infarction, or stroke: 5.4%, 4.1%, and 1.6% in the high-, moderate-, and low-risks groups, respectively (P < .001).

“This identification of ischemic risks worked very well for all-cause mortality,” Dr. Dangas said. “I feel this is a strength because mortality is a leader of outcomes. And of course, we’ve had some associations with all events like mortality, myocardial infarction, repeat revascularization, which are interesting and valid, but I think a study result that indicates the mortality itself is known to be unidirectional and a very good correlation makes the result more robust.”
 

Critical role

Risk prediction models such as the proposed ESC guidelines will play a critical role as individualized medicine continues to evolve, Somjot Brar, MD, MPH, director of the regional department of cardiac catheterization at Kaiser Permanente, Los Angeles Medical Center, and associate clinical professor at the University of California, Los Angeles, said in an interview.

UCLA

“This study highlights again the importance of the value for predictive and precision medicine,” Dr. Brar said. “Everything is moving in this direction where we make decisions that are more appropriate for a given patient as opposed to a population of patients.”

Study strengths are the large sample size in a real-world setting and thorough 1-year follow-up, Dr. Brar said.

A limitation is the three risk categories the guidelines proposed. “These are still pretty big boxes,” he said. “The low-, moderate- and high-risk categorization is still very, very broad and can be very vague.”

The relatively low percentage of low-risk patients – 12% versus 56% and 32% for the moderate- and high-risk groups – in this data set may also skew results, Dr. Brar said.

“As we move toward predictive analytics and medicine, we want to make these boxes smaller and smaller and smaller to be able to better understand which treatments should be administered to which patients to maximize the benefit against the risk,” he said. That would be a focus for future analyses, Dr. Brar said.

Dr. Dangas and Dr. Brar have no relevant financial disclosures.


 

A real-world study of more than 12,000 cases over 7 years has validated the predictive ability of the proposed guidelines for stratifying thrombotic risks at 1 year for patients with non–ST-elevated acute coronary syndrome (NSTE-ACS) undergoing percutaneous coronary intervention (PCI).

In research presented at the Society for Cardiovascular Angiography & Interventions annual scientific sessions, George Dangas, MD, PhD, current SCAI president and professor of cardiology and vascular surgery at the Icahn School of Medicine at Mount Sinai, New York, reported that the European Society of Cardiology risk stratification criteria appropriately predicted risk in 12,538 patients treated from 2012 to 2019.

Icahn School of Medicine

Despite these proposed guidelines put forward by the ESC in 2020, no consensus exists on criteria for ischemic or thrombotic risk in NSTE-ACS patients, Dr. Dangas noted.

The new study shows that the 1-year major adverse cardiovascular events (MACE) risk was four times greater in patients classified as medium risk (hazard ratio, 4.31; 95% confidence interval, 2.47-7.52) and six times greater in high-risk patients (HR, 6.16; 95% CI, 3.52-10.8), compared with the low-risk group, mostly because of higher rates of all-cause death and myocardial infarction, Dr. Dangas said in an interview.

“Indeed, we found some good correlation between the three risk categories and gradation of risk that validates essentially, but with the statistical testing that we need, that this classification is meaningful if not perfect,” Dr. Dangas said. “In the future we may perform calibrations to enhance its performance.”

The study used data on consecutive patients from the Angioplasty and Stent Procedures Database of Mount Sinai, grouping them into low, medium, and high thrombotic risk based on the proposed ESC guidelines for the management of NSTE-ACS.

The guidelines included a subset of criteria to identify patients with increased thrombotic risk who may benefit from extended treatment with a second antithrombotic agent.

This study aimed to evaluate the value of the criteria to identify patients at higher risk of ischemic events. “That’s why we went to our database to see how this might work,” Dr. Dangas said.

The researchers also found that high-risk patients had about a 40% greater risk of major bleeding (HR, 1.39; 95% CI, 1.06-1.84). Bleeding risks were similar between the low- and moderate-risk groups.

The risk categories reflected the rates of all-cause death, myocardial infarction, or stroke: 5.4%, 4.1%, and 1.6% in the high-, moderate-, and low-risks groups, respectively (P < .001).

“This identification of ischemic risks worked very well for all-cause mortality,” Dr. Dangas said. “I feel this is a strength because mortality is a leader of outcomes. And of course, we’ve had some associations with all events like mortality, myocardial infarction, repeat revascularization, which are interesting and valid, but I think a study result that indicates the mortality itself is known to be unidirectional and a very good correlation makes the result more robust.”
 

Critical role

Risk prediction models such as the proposed ESC guidelines will play a critical role as individualized medicine continues to evolve, Somjot Brar, MD, MPH, director of the regional department of cardiac catheterization at Kaiser Permanente, Los Angeles Medical Center, and associate clinical professor at the University of California, Los Angeles, said in an interview.

UCLA

“This study highlights again the importance of the value for predictive and precision medicine,” Dr. Brar said. “Everything is moving in this direction where we make decisions that are more appropriate for a given patient as opposed to a population of patients.”

Study strengths are the large sample size in a real-world setting and thorough 1-year follow-up, Dr. Brar said.

A limitation is the three risk categories the guidelines proposed. “These are still pretty big boxes,” he said. “The low-, moderate- and high-risk categorization is still very, very broad and can be very vague.”

The relatively low percentage of low-risk patients – 12% versus 56% and 32% for the moderate- and high-risk groups – in this data set may also skew results, Dr. Brar said.

“As we move toward predictive analytics and medicine, we want to make these boxes smaller and smaller and smaller to be able to better understand which treatments should be administered to which patients to maximize the benefit against the risk,” he said. That would be a focus for future analyses, Dr. Brar said.

Dr. Dangas and Dr. Brar have no relevant financial disclosures.


 

How much atrial fibrillation (AFib) persists after catheter ablation makes a big difference to patients’ quality of life (QoL) as well as their need for cardioversion or repeat ablation procedures, suggests a new analysis.

It’s the first study tying those outcomes to residual AFib burden after ablation achieved using the emerging pulsed-field ablation (PFA) technology, say researchers. These associations are already established for cath ablation using traditional radiofrequency energy or cryoablation.

The new findings come from a secondary analysis of the recently published PULSED-AF study, which highlighted the ablation efficacy of Medtronic’s investigational PulseSelect PFA system in patients with either paroxysmal AFib (PAF) or persistent AFib.

The trial had entered 300 adult candidates for catheter ablation of recurrent, symptomatic PAF or persistent AFib at 41 centers in Australia, Canada, Europe, Japan, and the United States.

After ablation, 69% of PAF patients and 62% of those who had persistent AFib showed no sign of atrial arrhythmia (AA) over 12 months, based on the trial’s method for estimating AA burden.

Residual AA burden less than 10% was seen in 87% and 82% of those initially with PAF and persistent AFib, respectively. Burdens in that lowest range, compared with greater AA burden, predicted a “clinically meaningful” improvement in QoL scores in PAF patients.

Those who entered the study with persistent AFib showed such improvement – defined as a more than 19-point gain on the Atrial Fibrillation Effect on Quality-of-Life Questionnaire – regardless of postablation AA burden.

Moreover, patients initially with either type of AFib and residual burdens in the lowest range went on to have fewer cardioversions and repeat ablations (P < .01), Atul Verma, MD, McGill University Health Centre, Montreal, reported at the annual scientific sessions of the Heart Rhythm Society.

Dr. Verma, the trial’s principal investigator, is also lead author on the same-day publication of the secondary analysis in Heart Rhythm.
 

Binary endpoint lacks relevance

The PULSED-AF primary analysis defined ablation efficacy partly as freedom from AA recurrence lasting at least 30 seconds, with or without symptoms, a traditional AFib-ablation trial endpoint that is nonetheless considered clinically unhelpful.

The secondary analysis recasts that binary endpoint as degree of reduction in AFib burden, a continuous variable. That potentially allows AFib ablation efficacy to be assessed in a more nuanced way likely to be more meaningful to patients and the health care system, observed Dr. Verma and colleagues.

The “30-second endpoint” is limited in clinical usefulness and “doesn’t mean much to the patient,” he said at a press conference on the analysis before formally presenting it at the HRS sessions.

Recent AFib ablation trials have explored AA burden as possibly a superior way to assess the procedure’s success “but also to see if it’s better correlated with quality of life and health care outcomes,” Dr. Verma said. “So that’s exactly what we’ve tried to do here using the PULSED-AF data.”

In the secondary analysis, he said, patients’ rate of freedom from the 30-second endpoint was about 70%, but “more than 85% of them had an AFib burden of less than 10%.”

“This efficacy endpoint of 30 seconds of atrial arrhythmia has been challenged and has been seen clinically as insignificant,” agreed Rajeev Pathak, MBBS, PhD, of Australian National University and director of cardiac electrophysiology at Canberra (Australia) Hospital.

In AFib radiofrequency ablation and cryoablation studies “there is clear disconnect between these 30-second episodes of atrial arrhythmias we see and the clinical relevance of health care utilization and quality of life,” said Dr. Pathak, invited discussant for Dr. Verma’s presentation at the sessions.

Now an AFib ablation trial using PFA catheters has yielded similar results, finding AA burden to be “a more objective and relevant measure of success,” he said. “A 30-second endpoint is arbitrary, lacks significance, and is highly dependent on the monitoring strategy.”
 

The more you look, the more you see

The new secondary analysis included a demonstration that success rates based on the 30-second endpoint indeed vary depending on how subsequent arrhythmias are monitored.

As described by Dr. Verma, PULSED-AF data were assessed for the 30-second endpoint captured using three separate intermittent monitoring strategies that it and other recent ablation trials have used:

• Strategy A: Transtelephonic monitoring weekly and in the event of symptoms, plus 24-hour Holter monitoring at 6 and 12 months and 12-lead ECG at 3, 6, and 12 months
• Strategy B: Transtelephonic monitoring weekly and at symptoms for 3-6 months followed by monthly and at symptoms from 6 to 12 months, plus 24-hour Holter monitoring at 6 and 12 months, plus 12-lead ECG at 3, 6, and 12 months
• Strategy C: The median of two 24-hour Holter monitoring sessions per patient over 12 months

As Dr. Verma reported, rates of freedom from the 30-second endpoint climbed with successive monitoring strategies. The rates for PAF and persistent AFib patients, respectively, were: Strategy A – 70% and 62%, Strategy B – 71% and 68%, Strategy C – 91% and 86%.

“If you’re using the ‘freedom-from-30-seconds’ endpoint, the results that you are going to get are highly dependent on the monitoring strategy,” Dr. Verma said. “The more you look, the more you see.”
 

Valid estimation of burden

For the main PULSED-AF secondary analysis, the investigators defined AA burden according to findings on either Holter monitoring or the 12-lead ECG. “So as not to bias these results,” Dr. Verma said, “for every patient, we picked the method that gave us the highest atrial arrhythmia burden.”

Ideally, Dr. Verma said in an interview, arrhythmia burden would be determined using devices such as implantable loop recorders. “The problem is, this is expensive and not practical” in both clinical practice and many trials, so PULSED-AF investigators went with the intermittent monitoring strategy to estimate burdens.

Their method appears valid, he said, given that the study identified a statistically relevant 10% AA burden cut off for predicting quality of life improvement or less health care resource use.

“If their residual atrial arrhythmia burden was greater than 10%, they did not have a statistically significant improvement in quality of life,” Dr. Verma observed. And “very few” of them had cardioversions or repeat ablation.

“I couldn’t agree more” that residual AA burden is preferable to the 30-second endpoint for gauging AFib ablation success, Kenneth Ellenbogen, MD, Virginia Commonwealth University Medical Center, Richmond, said in an interview. Dr. Ellenbogen is also director of clinical cardiac electrophysiology and pacing at VCU Health Pauley Heart Center and not associated with PULSED-AF.

That AA burden was linked to health care resource use in the study “is absolutely brilliant,” he said, “because that’s what the bean counters really want at the end of the day. And as doctors we care about patients feeling better – improving quality of life.”

PULSED-AF was funded by Medtronic. Dr. Verma disclosed financial relationships with Bayer, Biosense Webster, Medtronic, Thermedical, Kardium, and Galaxy Medical, as well as and research grants from Adagio Medical. Dr. Ellenbogen disclosed financial relationships with Boston Scientific, Medtronic, Kestra, Hylomorph, Biotronik, MediLynx, Impulse Dynamics USA, Abbott, Biosense Webster, Milestone Pharmaceuticals, Sanofi, Medpace, and Elsevier. Dr. Pathak disclosed no relevant financial relationships.

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

How much atrial fibrillation (AFib) persists after catheter ablation makes a big difference to patients’ quality of life (QoL) as well as their need for cardioversion or repeat ablation procedures, suggests a new analysis.

It’s the first study tying those outcomes to residual AFib burden after ablation achieved using the emerging pulsed-field ablation (PFA) technology, say researchers. These associations are already established for cath ablation using traditional radiofrequency energy or cryoablation.

The new findings come from a secondary analysis of the recently published PULSED-AF study, which highlighted the ablation efficacy of Medtronic’s investigational PulseSelect PFA system in patients with either paroxysmal AFib (PAF) or persistent AFib.

The trial had entered 300 adult candidates for catheter ablation of recurrent, symptomatic PAF or persistent AFib at 41 centers in Australia, Canada, Europe, Japan, and the United States.

After ablation, 69% of PAF patients and 62% of those who had persistent AFib showed no sign of atrial arrhythmia (AA) over 12 months, based on the trial’s method for estimating AA burden.

Residual AA burden less than 10% was seen in 87% and 82% of those initially with PAF and persistent AFib, respectively. Burdens in that lowest range, compared with greater AA burden, predicted a “clinically meaningful” improvement in QoL scores in PAF patients.

Those who entered the study with persistent AFib showed such improvement – defined as a more than 19-point gain on the Atrial Fibrillation Effect on Quality-of-Life Questionnaire – regardless of postablation AA burden.

Moreover, patients initially with either type of AFib and residual burdens in the lowest range went on to have fewer cardioversions and repeat ablations (P < .01), Atul Verma, MD, McGill University Health Centre, Montreal, reported at the annual scientific sessions of the Heart Rhythm Society.

Dr. Verma, the trial’s principal investigator, is also lead author on the same-day publication of the secondary analysis in Heart Rhythm.
 

Binary endpoint lacks relevance

The PULSED-AF primary analysis defined ablation efficacy partly as freedom from AA recurrence lasting at least 30 seconds, with or without symptoms, a traditional AFib-ablation trial endpoint that is nonetheless considered clinically unhelpful.

The secondary analysis recasts that binary endpoint as degree of reduction in AFib burden, a continuous variable. That potentially allows AFib ablation efficacy to be assessed in a more nuanced way likely to be more meaningful to patients and the health care system, observed Dr. Verma and colleagues.

The “30-second endpoint” is limited in clinical usefulness and “doesn’t mean much to the patient,” he said at a press conference on the analysis before formally presenting it at the HRS sessions.

Recent AFib ablation trials have explored AA burden as possibly a superior way to assess the procedure’s success “but also to see if it’s better correlated with quality of life and health care outcomes,” Dr. Verma said. “So that’s exactly what we’ve tried to do here using the PULSED-AF data.”

In the secondary analysis, he said, patients’ rate of freedom from the 30-second endpoint was about 70%, but “more than 85% of them had an AFib burden of less than 10%.”

“This efficacy endpoint of 30 seconds of atrial arrhythmia has been challenged and has been seen clinically as insignificant,” agreed Rajeev Pathak, MBBS, PhD, of Australian National University and director of cardiac electrophysiology at Canberra (Australia) Hospital.

In AFib radiofrequency ablation and cryoablation studies “there is clear disconnect between these 30-second episodes of atrial arrhythmias we see and the clinical relevance of health care utilization and quality of life,” said Dr. Pathak, invited discussant for Dr. Verma’s presentation at the sessions.

Now an AFib ablation trial using PFA catheters has yielded similar results, finding AA burden to be “a more objective and relevant measure of success,” he said. “A 30-second endpoint is arbitrary, lacks significance, and is highly dependent on the monitoring strategy.”
 

The more you look, the more you see

The new secondary analysis included a demonstration that success rates based on the 30-second endpoint indeed vary depending on how subsequent arrhythmias are monitored.

As described by Dr. Verma, PULSED-AF data were assessed for the 30-second endpoint captured using three separate intermittent monitoring strategies that it and other recent ablation trials have used:

• Strategy A: Transtelephonic monitoring weekly and in the event of symptoms, plus 24-hour Holter monitoring at 6 and 12 months and 12-lead ECG at 3, 6, and 12 months
• Strategy B: Transtelephonic monitoring weekly and at symptoms for 3-6 months followed by monthly and at symptoms from 6 to 12 months, plus 24-hour Holter monitoring at 6 and 12 months, plus 12-lead ECG at 3, 6, and 12 months
• Strategy C: The median of two 24-hour Holter monitoring sessions per patient over 12 months

As Dr. Verma reported, rates of freedom from the 30-second endpoint climbed with successive monitoring strategies. The rates for PAF and persistent AFib patients, respectively, were: Strategy A – 70% and 62%, Strategy B – 71% and 68%, Strategy C – 91% and 86%.

“If you’re using the ‘freedom-from-30-seconds’ endpoint, the results that you are going to get are highly dependent on the monitoring strategy,” Dr. Verma said. “The more you look, the more you see.”
 

Valid estimation of burden

For the main PULSED-AF secondary analysis, the investigators defined AA burden according to findings on either Holter monitoring or the 12-lead ECG. “So as not to bias these results,” Dr. Verma said, “for every patient, we picked the method that gave us the highest atrial arrhythmia burden.”

Ideally, Dr. Verma said in an interview, arrhythmia burden would be determined using devices such as implantable loop recorders. “The problem is, this is expensive and not practical” in both clinical practice and many trials, so PULSED-AF investigators went with the intermittent monitoring strategy to estimate burdens.

Their method appears valid, he said, given that the study identified a statistically relevant 10% AA burden cut off for predicting quality of life improvement or less health care resource use.

“If their residual atrial arrhythmia burden was greater than 10%, they did not have a statistically significant improvement in quality of life,” Dr. Verma observed. And “very few” of them had cardioversions or repeat ablation.

“I couldn’t agree more” that residual AA burden is preferable to the 30-second endpoint for gauging AFib ablation success, Kenneth Ellenbogen, MD, Virginia Commonwealth University Medical Center, Richmond, said in an interview. Dr. Ellenbogen is also director of clinical cardiac electrophysiology and pacing at VCU Health Pauley Heart Center and not associated with PULSED-AF.

That AA burden was linked to health care resource use in the study “is absolutely brilliant,” he said, “because that’s what the bean counters really want at the end of the day. And as doctors we care about patients feeling better – improving quality of life.”

PULSED-AF was funded by Medtronic. Dr. Verma disclosed financial relationships with Bayer, Biosense Webster, Medtronic, Thermedical, Kardium, and Galaxy Medical, as well as and research grants from Adagio Medical. Dr. Ellenbogen disclosed financial relationships with Boston Scientific, Medtronic, Kestra, Hylomorph, Biotronik, MediLynx, Impulse Dynamics USA, Abbott, Biosense Webster, Milestone Pharmaceuticals, Sanofi, Medpace, and Elsevier. Dr. Pathak disclosed no relevant financial relationships.

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

How much atrial fibrillation (AFib) persists after catheter ablation makes a big difference to patients’ quality of life (QoL) as well as their need for cardioversion or repeat ablation procedures, suggests a new analysis.

It’s the first study tying those outcomes to residual AFib burden after ablation achieved using the emerging pulsed-field ablation (PFA) technology, say researchers. These associations are already established for cath ablation using traditional radiofrequency energy or cryoablation.

The new findings come from a secondary analysis of the recently published PULSED-AF study, which highlighted the ablation efficacy of Medtronic’s investigational PulseSelect PFA system in patients with either paroxysmal AFib (PAF) or persistent AFib.

The trial had entered 300 adult candidates for catheter ablation of recurrent, symptomatic PAF or persistent AFib at 41 centers in Australia, Canada, Europe, Japan, and the United States.

After ablation, 69% of PAF patients and 62% of those who had persistent AFib showed no sign of atrial arrhythmia (AA) over 12 months, based on the trial’s method for estimating AA burden.

Residual AA burden less than 10% was seen in 87% and 82% of those initially with PAF and persistent AFib, respectively. Burdens in that lowest range, compared with greater AA burden, predicted a “clinically meaningful” improvement in QoL scores in PAF patients.

Those who entered the study with persistent AFib showed such improvement – defined as a more than 19-point gain on the Atrial Fibrillation Effect on Quality-of-Life Questionnaire – regardless of postablation AA burden.

Moreover, patients initially with either type of AFib and residual burdens in the lowest range went on to have fewer cardioversions and repeat ablations (P < .01), Atul Verma, MD, McGill University Health Centre, Montreal, reported at the annual scientific sessions of the Heart Rhythm Society.

Dr. Verma, the trial’s principal investigator, is also lead author on the same-day publication of the secondary analysis in Heart Rhythm.
 

Binary endpoint lacks relevance

The PULSED-AF primary analysis defined ablation efficacy partly as freedom from AA recurrence lasting at least 30 seconds, with or without symptoms, a traditional AFib-ablation trial endpoint that is nonetheless considered clinically unhelpful.

The secondary analysis recasts that binary endpoint as degree of reduction in AFib burden, a continuous variable. That potentially allows AFib ablation efficacy to be assessed in a more nuanced way likely to be more meaningful to patients and the health care system, observed Dr. Verma and colleagues.

The “30-second endpoint” is limited in clinical usefulness and “doesn’t mean much to the patient,” he said at a press conference on the analysis before formally presenting it at the HRS sessions.

Recent AFib ablation trials have explored AA burden as possibly a superior way to assess the procedure’s success “but also to see if it’s better correlated with quality of life and health care outcomes,” Dr. Verma said. “So that’s exactly what we’ve tried to do here using the PULSED-AF data.”

In the secondary analysis, he said, patients’ rate of freedom from the 30-second endpoint was about 70%, but “more than 85% of them had an AFib burden of less than 10%.”

“This efficacy endpoint of 30 seconds of atrial arrhythmia has been challenged and has been seen clinically as insignificant,” agreed Rajeev Pathak, MBBS, PhD, of Australian National University and director of cardiac electrophysiology at Canberra (Australia) Hospital.

In AFib radiofrequency ablation and cryoablation studies “there is clear disconnect between these 30-second episodes of atrial arrhythmias we see and the clinical relevance of health care utilization and quality of life,” said Dr. Pathak, invited discussant for Dr. Verma’s presentation at the sessions.

Now an AFib ablation trial using PFA catheters has yielded similar results, finding AA burden to be “a more objective and relevant measure of success,” he said. “A 30-second endpoint is arbitrary, lacks significance, and is highly dependent on the monitoring strategy.”
 

The more you look, the more you see

The new secondary analysis included a demonstration that success rates based on the 30-second endpoint indeed vary depending on how subsequent arrhythmias are monitored.

As described by Dr. Verma, PULSED-AF data were assessed for the 30-second endpoint captured using three separate intermittent monitoring strategies that it and other recent ablation trials have used:

• Strategy A: Transtelephonic monitoring weekly and in the event of symptoms, plus 24-hour Holter monitoring at 6 and 12 months and 12-lead ECG at 3, 6, and 12 months
• Strategy B: Transtelephonic monitoring weekly and at symptoms for 3-6 months followed by monthly and at symptoms from 6 to 12 months, plus 24-hour Holter monitoring at 6 and 12 months, plus 12-lead ECG at 3, 6, and 12 months
• Strategy C: The median of two 24-hour Holter monitoring sessions per patient over 12 months

As Dr. Verma reported, rates of freedom from the 30-second endpoint climbed with successive monitoring strategies. The rates for PAF and persistent AFib patients, respectively, were: Strategy A – 70% and 62%, Strategy B – 71% and 68%, Strategy C – 91% and 86%.

“If you’re using the ‘freedom-from-30-seconds’ endpoint, the results that you are going to get are highly dependent on the monitoring strategy,” Dr. Verma said. “The more you look, the more you see.”
 

Valid estimation of burden

For the main PULSED-AF secondary analysis, the investigators defined AA burden according to findings on either Holter monitoring or the 12-lead ECG. “So as not to bias these results,” Dr. Verma said, “for every patient, we picked the method that gave us the highest atrial arrhythmia burden.”

Ideally, Dr. Verma said in an interview, arrhythmia burden would be determined using devices such as implantable loop recorders. “The problem is, this is expensive and not practical” in both clinical practice and many trials, so PULSED-AF investigators went with the intermittent monitoring strategy to estimate burdens.

Their method appears valid, he said, given that the study identified a statistically relevant 10% AA burden cut off for predicting quality of life improvement or less health care resource use.

“If their residual atrial arrhythmia burden was greater than 10%, they did not have a statistically significant improvement in quality of life,” Dr. Verma observed. And “very few” of them had cardioversions or repeat ablation.

“I couldn’t agree more” that residual AA burden is preferable to the 30-second endpoint for gauging AFib ablation success, Kenneth Ellenbogen, MD, Virginia Commonwealth University Medical Center, Richmond, said in an interview. Dr. Ellenbogen is also director of clinical cardiac electrophysiology and pacing at VCU Health Pauley Heart Center and not associated with PULSED-AF.

That AA burden was linked to health care resource use in the study “is absolutely brilliant,” he said, “because that’s what the bean counters really want at the end of the day. And as doctors we care about patients feeling better – improving quality of life.”

PULSED-AF was funded by Medtronic. Dr. Verma disclosed financial relationships with Bayer, Biosense Webster, Medtronic, Thermedical, Kardium, and Galaxy Medical, as well as and research grants from Adagio Medical. Dr. Ellenbogen disclosed financial relationships with Boston Scientific, Medtronic, Kestra, Hylomorph, Biotronik, MediLynx, Impulse Dynamics USA, Abbott, Biosense Webster, Milestone Pharmaceuticals, Sanofi, Medpace, and Elsevier. Dr. Pathak disclosed no relevant financial relationships.

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

Patients presenting with an acute ischemic stroke and found to have atrial fibrillation (AFib) can be safely started on a direct oral anticoagulant (DOAC) much earlier than starting generally occurs in current clinical practice, a new study suggests.

The ELAN trial found that starting DOAC treatment earlier was not associated with an increased risk for intracranial hemorrhage (ICH) but rather was linked to a lower rate of ischemic events.

“We conclude that there is no reason to delay DOAC treatment in these patients. Our results suggest that early DOAC treatment is reasonable; it is unlikely to cause harm, and it is probably better at reducing ischemic events,” lead investigator of the study, Urs Fischer, MD, professor of neurology at University Hospital Basel (Switzerland), commented in an interview.

“This trial will change clinical practice in that we can feel much more reassured that starting DOAC treatment early in these patients will not cause harm,” he said.

Senior investigator Jesse Dawson, MD, professor of stroke medicine at Queen Elizabeth University Hospital, Glasgow, added: “This issue of timing of DOAC treatment causes a lot of anxiety in our daily workload. Clinicians are scared of causing an ICH, so they tend to wait. These results will ease a lot of that anxiety.”

Imaging-based assessment of stroke severity

In the ELAN trial, the definition of stroke severity was based on imaging rather than on the National Institutes of Health Stroke Scale (NIHSS).

“We took a cautious approach by using imaging to define stroke severity. So, when using these results in clinical practice, it is important that patients are selected for the timing of DOAC treatment based on the imaging results,” Dr. Dawson explained. “This is very straightforward, as the size of the stroke can be seen clearly on the routine CT imaging that all patients receive up front. This is a very pragmatic and simple protocol. And advanced imaging is not required.”

He noted that though clinicians tend to use the NIHSS clinical symptom score to define mild, moderate, and severe stroke, the imaging approach is actually more accurate when determining the risk for bleeding and ICH. And though imaging results often correlate with NIHSS scores, there can be some exceptions.

Commenting on the ELAN trial results at the ESOC meeting, Georgios Tsivgoulis, MD, professor of neurology, University of Athens, said that the trial showed that early administration of DOACs in these patients was safe and did not increase the rate of ICH.

“There was a very low ICH rate with only two events in each group. And then there was above a 1% reduction in the composite outcome including ischemic vascular events and bleeding,” he noted.

“This is important because there are many thousands of patients with acute ischemic stroke and AFib, and now we have a large study showing we can treat them with a DOAC early, and this appears to be safe and it appears also be more effective in terms of outcome events,” Dr. Tsivgoulis said.

But he highlighted one important caveat: The majority of patients had mild or moderate stroke.

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

Patients presenting with an acute ischemic stroke and found to have atrial fibrillation (AFib) can be safely started on a direct oral anticoagulant (DOAC) much earlier than starting generally occurs in current clinical practice, a new study suggests.

The ELAN trial found that starting DOAC treatment earlier was not associated with an increased risk for intracranial hemorrhage (ICH) but rather was linked to a lower rate of ischemic events.

“We conclude that there is no reason to delay DOAC treatment in these patients. Our results suggest that early DOAC treatment is reasonable; it is unlikely to cause harm, and it is probably better at reducing ischemic events,” lead investigator of the study, Urs Fischer, MD, professor of neurology at University Hospital Basel (Switzerland), commented in an interview.

“This trial will change clinical practice in that we can feel much more reassured that starting DOAC treatment early in these patients will not cause harm,” he said.

Senior investigator Jesse Dawson, MD, professor of stroke medicine at Queen Elizabeth University Hospital, Glasgow, added: “This issue of timing of DOAC treatment causes a lot of anxiety in our daily workload. Clinicians are scared of causing an ICH, so they tend to wait. These results will ease a lot of that anxiety.”

Imaging-based assessment of stroke severity

In the ELAN trial, the definition of stroke severity was based on imaging rather than on the National Institutes of Health Stroke Scale (NIHSS).

“We took a cautious approach by using imaging to define stroke severity. So, when using these results in clinical practice, it is important that patients are selected for the timing of DOAC treatment based on the imaging results,” Dr. Dawson explained. “This is very straightforward, as the size of the stroke can be seen clearly on the routine CT imaging that all patients receive up front. This is a very pragmatic and simple protocol. And advanced imaging is not required.”

He noted that though clinicians tend to use the NIHSS clinical symptom score to define mild, moderate, and severe stroke, the imaging approach is actually more accurate when determining the risk for bleeding and ICH. And though imaging results often correlate with NIHSS scores, there can be some exceptions.

Commenting on the ELAN trial results at the ESOC meeting, Georgios Tsivgoulis, MD, professor of neurology, University of Athens, said that the trial showed that early administration of DOACs in these patients was safe and did not increase the rate of ICH.

“There was a very low ICH rate with only two events in each group. And then there was above a 1% reduction in the composite outcome including ischemic vascular events and bleeding,” he noted.

“This is important because there are many thousands of patients with acute ischemic stroke and AFib, and now we have a large study showing we can treat them with a DOAC early, and this appears to be safe and it appears also be more effective in terms of outcome events,” Dr. Tsivgoulis said.

But he highlighted one important caveat: The majority of patients had mild or moderate stroke.

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

Patients presenting with an acute ischemic stroke and found to have atrial fibrillation (AFib) can be safely started on a direct oral anticoagulant (DOAC) much earlier than starting generally occurs in current clinical practice, a new study suggests.

The ELAN trial found that starting DOAC treatment earlier was not associated with an increased risk for intracranial hemorrhage (ICH) but rather was linked to a lower rate of ischemic events.

“We conclude that there is no reason to delay DOAC treatment in these patients. Our results suggest that early DOAC treatment is reasonable; it is unlikely to cause harm, and it is probably better at reducing ischemic events,” lead investigator of the study, Urs Fischer, MD, professor of neurology at University Hospital Basel (Switzerland), commented in an interview.

“This trial will change clinical practice in that we can feel much more reassured that starting DOAC treatment early in these patients will not cause harm,” he said.

Senior investigator Jesse Dawson, MD, professor of stroke medicine at Queen Elizabeth University Hospital, Glasgow, added: “This issue of timing of DOAC treatment causes a lot of anxiety in our daily workload. Clinicians are scared of causing an ICH, so they tend to wait. These results will ease a lot of that anxiety.”

Imaging-based assessment of stroke severity

In the ELAN trial, the definition of stroke severity was based on imaging rather than on the National Institutes of Health Stroke Scale (NIHSS).

“We took a cautious approach by using imaging to define stroke severity. So, when using these results in clinical practice, it is important that patients are selected for the timing of DOAC treatment based on the imaging results,” Dr. Dawson explained. “This is very straightforward, as the size of the stroke can be seen clearly on the routine CT imaging that all patients receive up front. This is a very pragmatic and simple protocol. And advanced imaging is not required.”

He noted that though clinicians tend to use the NIHSS clinical symptom score to define mild, moderate, and severe stroke, the imaging approach is actually more accurate when determining the risk for bleeding and ICH. And though imaging results often correlate with NIHSS scores, there can be some exceptions.

Commenting on the ELAN trial results at the ESOC meeting, Georgios Tsivgoulis, MD, professor of neurology, University of Athens, said that the trial showed that early administration of DOACs in these patients was safe and did not increase the rate of ICH.

“There was a very low ICH rate with only two events in each group. And then there was above a 1% reduction in the composite outcome including ischemic vascular events and bleeding,” he noted.

“This is important because there are many thousands of patients with acute ischemic stroke and AFib, and now we have a large study showing we can treat them with a DOAC early, and this appears to be safe and it appears also be more effective in terms of outcome events,” Dr. Tsivgoulis said.

But he highlighted one important caveat: The majority of patients had mild or moderate stroke.

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

MANNHEIM, GERMANY – Half of patients who die from homozygous familial hypercholesterolemia (HoFH) do so by age 32 years, new registry data show.

The researchers looked at almost 40 patients from the HoFH International Clinical Collaborators (HICC) registry who had died before data entry, finding that they had a mean age of diagnosis of 12 years.

Even those who received treatment had high LDL cholesterol levels, and 70% developed atherosclerotic cardiovascular disease (ASCVD) at a median age of 28 years.

Worryingly, the results showed that the median age at death was 32 years. Results were presented at the annual congress of the European Atherosclerosis Society.

Patients with HoFH “have severe atherosclerotic cardiovascular disease risk,” said study presenter Janneke Mulder, a PhD candidate at the department of internal medicine, Erasmus University Medical Center, Rotterdam, the Netherlands.

“Therefore, early diagnosis and initiation of treatments, and also a combination of treatments, is really crucial,” she added.
 

Call to action

Approached for comment, Maciej Banach, MD, PhD, full professor of cardiology, Polish Mother’s Memorial Hospital Research Institute, Lodz, and Secretary of the EAS, described the results as “terrifying.”

He said in an interview that they are a “call to action,” especially given that so few patients in the study received intensive combination lipid-lowering therapy despite having a baseline LDL cholesterol level that was “very, very high.”

Banach underlined that patients who receive triple lipid-lowering therapy with a high-intensity statin, ezetimibe (Nustendi), and a proprotein convertase subtilisin/kexin type 9 inhibitor, could expect, based on current evidence, to see their LDL cholesterol levels reduced by 85% and be on target.

“Obviously, this is kind of academic,” because in the real-world “this 85% is not observed very often,” but it offers a target for steep reductions in cholesterol levels.

“This is something that we should focus on for these patients from the beginning,” said Dr. Banach, either with a stepwise approach “or for experts in pediatric HoFH, “maybe immediately.”

He emphasized that clinicians have everything at hand to “be both effective in the early diagnosis of HoFH, the earlier the better, and obviously to be effective with its treatment.”

“We should do something to prolong the lives of those people,” because the current results are “terrifying,” Dr. Banach added.
 

Rare genetic condition

Presenting her findings, Ms. Mulder began by highlighting that HoFH is a “rare genetic condition that occurs due to mutations in cholesterol metabolism.”

This, she continued, leads to “severely increased LDL cholesterol levels, and consequently to very premature cardiovascular disease,” with patients potentially experiencing their first cardiovascular event before age 20 years.

Ms. Mulder pointed out that, although there have been case series in the literature on HoFH, they have had “limited numbers” and patients have typically spent decades being treated at the same lipid management clinic.

To broaden the understanding of the clinical characteristics and management of patients dying with HoFH, the team examined data from the HICC registry, which is “the largest contemporary database of homozygous FH patients,” Ms. Mulder said.

It includes 751 patients with HoFH from 88 centers in 38 countries who were alive in 2010 or later. Data entry was between 2016 and 2020. The current analysis focused on 37 patients who had already died by the time they were included on the registry.

Of those, 49% were women, 38% were of White ethnicity, and 43% were from high-income countries.

The median age at diagnosis was 12 years, Ms. Mulder said, explaining that this is similar to that seen in other studies. The majority (86%) underwent genetic testing, and 92% presented with xanthomas.

Ms. Mulder also noted that, at their final clinical evaluation, which was conducted a median age of 18 years after their initial diagnosis, 43% of patients were recorded as current or former smokers.

In terms of their lipid-lowering therapy, 94% were taking a statin, whereas 68% were on ezetimibe, and 23% were undergoing apheresis.

Ms. Mulder said that the median number of lipid-lowering therapies per patient was two, and that “sadly ... 26% of the deceased patients had only one or no treatment.”

Therefore, perhaps unsurprisingly even those patients who were receiving treatment had LDL cholesterol levels that were “too high,” at 9.4 mmol/L versus 15.6 mmol/L among those who were untreated.

There was a high prevalence of ASCVD, at 70% overall, or 41% for aortic stenosis, 30% for myocardial infarction, 30% for angina pectoris, and 22% each for aortic valve replacement and coronary artery bypass grafting. In addition, 19% underwent percutaneous coronary intervention.

The median age of onset for ASCVD was 28 years. Ms. Mulder pointed out, however, that, as data were not available for all patients, “this might be an underestimation.” About 70% of patients experienced recurrent ASCVD.

There was a wide range in the age at which patients with HoFH died, although the median was, “strikingly,” 32 years, Ms. Mulder said. Death was confirmed as stemming from cardiovascular causes in 76% of cases.

During the postpresentation discussion, session chair Antonio J. Vallejo-Vaz, PhD, from the Research Group of Clinical Epidemiology and Vascular Risk, Institute of Biomedicine of Seville (Spain), highlighted that, if 38% of the patients were of White ethnicity, then the remainder must therefore be from other ethnic groups.

“There could be potential issues with accessibility to lipid centers” for these patients, which could affect the findings, noted Dr. Vallejo-Vaz, who is also chief scientist of the EAS Familial Hypercholesterolaemia Studies Collaboration.

Ms. Mulder agreed, replying that their results, though already striking, may be an underestimation because the patients were all from either high or middle-income countries, “so it would be good to have some data on low-income countries.”

She was also asked about two patients who died at a much older age than did the others, at ages 70 years and 86 years, respectively, and whether they had, for example, a protective genetic mutation.

Ms. Mulder said that they do not yet know, but they are planning an extended case series on these and other long-lived patients so that they can be investigated further.

No funding or relevant financial relationships were declared.

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

MANNHEIM, GERMANY – Half of patients who die from homozygous familial hypercholesterolemia (HoFH) do so by age 32 years, new registry data show.

The researchers looked at almost 40 patients from the HoFH International Clinical Collaborators (HICC) registry who had died before data entry, finding that they had a mean age of diagnosis of 12 years.

Even those who received treatment had high LDL cholesterol levels, and 70% developed atherosclerotic cardiovascular disease (ASCVD) at a median age of 28 years.

Worryingly, the results showed that the median age at death was 32 years. Results were presented at the annual congress of the European Atherosclerosis Society.

Patients with HoFH “have severe atherosclerotic cardiovascular disease risk,” said study presenter Janneke Mulder, a PhD candidate at the department of internal medicine, Erasmus University Medical Center, Rotterdam, the Netherlands.

“Therefore, early diagnosis and initiation of treatments, and also a combination of treatments, is really crucial,” she added.
 

Call to action

Approached for comment, Maciej Banach, MD, PhD, full professor of cardiology, Polish Mother’s Memorial Hospital Research Institute, Lodz, and Secretary of the EAS, described the results as “terrifying.”

He said in an interview that they are a “call to action,” especially given that so few patients in the study received intensive combination lipid-lowering therapy despite having a baseline LDL cholesterol level that was “very, very high.”

Banach underlined that patients who receive triple lipid-lowering therapy with a high-intensity statin, ezetimibe (Nustendi), and a proprotein convertase subtilisin/kexin type 9 inhibitor, could expect, based on current evidence, to see their LDL cholesterol levels reduced by 85% and be on target.

“Obviously, this is kind of academic,” because in the real-world “this 85% is not observed very often,” but it offers a target for steep reductions in cholesterol levels.

“This is something that we should focus on for these patients from the beginning,” said Dr. Banach, either with a stepwise approach “or for experts in pediatric HoFH, “maybe immediately.”

He emphasized that clinicians have everything at hand to “be both effective in the early diagnosis of HoFH, the earlier the better, and obviously to be effective with its treatment.”

“We should do something to prolong the lives of those people,” because the current results are “terrifying,” Dr. Banach added.
 

Rare genetic condition

Presenting her findings, Ms. Mulder began by highlighting that HoFH is a “rare genetic condition that occurs due to mutations in cholesterol metabolism.”

This, she continued, leads to “severely increased LDL cholesterol levels, and consequently to very premature cardiovascular disease,” with patients potentially experiencing their first cardiovascular event before age 20 years.

Ms. Mulder pointed out that, although there have been case series in the literature on HoFH, they have had “limited numbers” and patients have typically spent decades being treated at the same lipid management clinic.

To broaden the understanding of the clinical characteristics and management of patients dying with HoFH, the team examined data from the HICC registry, which is “the largest contemporary database of homozygous FH patients,” Ms. Mulder said.

It includes 751 patients with HoFH from 88 centers in 38 countries who were alive in 2010 or later. Data entry was between 2016 and 2020. The current analysis focused on 37 patients who had already died by the time they were included on the registry.

Of those, 49% were women, 38% were of White ethnicity, and 43% were from high-income countries.

The median age at diagnosis was 12 years, Ms. Mulder said, explaining that this is similar to that seen in other studies. The majority (86%) underwent genetic testing, and 92% presented with xanthomas.

Ms. Mulder also noted that, at their final clinical evaluation, which was conducted a median age of 18 years after their initial diagnosis, 43% of patients were recorded as current or former smokers.

In terms of their lipid-lowering therapy, 94% were taking a statin, whereas 68% were on ezetimibe, and 23% were undergoing apheresis.

Ms. Mulder said that the median number of lipid-lowering therapies per patient was two, and that “sadly ... 26% of the deceased patients had only one or no treatment.”

Therefore, perhaps unsurprisingly even those patients who were receiving treatment had LDL cholesterol levels that were “too high,” at 9.4 mmol/L versus 15.6 mmol/L among those who were untreated.

There was a high prevalence of ASCVD, at 70% overall, or 41% for aortic stenosis, 30% for myocardial infarction, 30% for angina pectoris, and 22% each for aortic valve replacement and coronary artery bypass grafting. In addition, 19% underwent percutaneous coronary intervention.

The median age of onset for ASCVD was 28 years. Ms. Mulder pointed out, however, that, as data were not available for all patients, “this might be an underestimation.” About 70% of patients experienced recurrent ASCVD.

There was a wide range in the age at which patients with HoFH died, although the median was, “strikingly,” 32 years, Ms. Mulder said. Death was confirmed as stemming from cardiovascular causes in 76% of cases.

During the postpresentation discussion, session chair Antonio J. Vallejo-Vaz, PhD, from the Research Group of Clinical Epidemiology and Vascular Risk, Institute of Biomedicine of Seville (Spain), highlighted that, if 38% of the patients were of White ethnicity, then the remainder must therefore be from other ethnic groups.

“There could be potential issues with accessibility to lipid centers” for these patients, which could affect the findings, noted Dr. Vallejo-Vaz, who is also chief scientist of the EAS Familial Hypercholesterolaemia Studies Collaboration.

Ms. Mulder agreed, replying that their results, though already striking, may be an underestimation because the patients were all from either high or middle-income countries, “so it would be good to have some data on low-income countries.”

She was also asked about two patients who died at a much older age than did the others, at ages 70 years and 86 years, respectively, and whether they had, for example, a protective genetic mutation.

Ms. Mulder said that they do not yet know, but they are planning an extended case series on these and other long-lived patients so that they can be investigated further.

No funding or relevant financial relationships were declared.

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

MANNHEIM, GERMANY – Half of patients who die from homozygous familial hypercholesterolemia (HoFH) do so by age 32 years, new registry data show.

The researchers looked at almost 40 patients from the HoFH International Clinical Collaborators (HICC) registry who had died before data entry, finding that they had a mean age of diagnosis of 12 years.

Even those who received treatment had high LDL cholesterol levels, and 70% developed atherosclerotic cardiovascular disease (ASCVD) at a median age of 28 years.

Worryingly, the results showed that the median age at death was 32 years. Results were presented at the annual congress of the European Atherosclerosis Society.

Patients with HoFH “have severe atherosclerotic cardiovascular disease risk,” said study presenter Janneke Mulder, a PhD candidate at the department of internal medicine, Erasmus University Medical Center, Rotterdam, the Netherlands.

“Therefore, early diagnosis and initiation of treatments, and also a combination of treatments, is really crucial,” she added.
 

Call to action

Approached for comment, Maciej Banach, MD, PhD, full professor of cardiology, Polish Mother’s Memorial Hospital Research Institute, Lodz, and Secretary of the EAS, described the results as “terrifying.”

He said in an interview that they are a “call to action,” especially given that so few patients in the study received intensive combination lipid-lowering therapy despite having a baseline LDL cholesterol level that was “very, very high.”

Banach underlined that patients who receive triple lipid-lowering therapy with a high-intensity statin, ezetimibe (Nustendi), and a proprotein convertase subtilisin/kexin type 9 inhibitor, could expect, based on current evidence, to see their LDL cholesterol levels reduced by 85% and be on target.

“Obviously, this is kind of academic,” because in the real-world “this 85% is not observed very often,” but it offers a target for steep reductions in cholesterol levels.

“This is something that we should focus on for these patients from the beginning,” said Dr. Banach, either with a stepwise approach “or for experts in pediatric HoFH, “maybe immediately.”

He emphasized that clinicians have everything at hand to “be both effective in the early diagnosis of HoFH, the earlier the better, and obviously to be effective with its treatment.”

“We should do something to prolong the lives of those people,” because the current results are “terrifying,” Dr. Banach added.
 

Rare genetic condition

Presenting her findings, Ms. Mulder began by highlighting that HoFH is a “rare genetic condition that occurs due to mutations in cholesterol metabolism.”

This, she continued, leads to “severely increased LDL cholesterol levels, and consequently to very premature cardiovascular disease,” with patients potentially experiencing their first cardiovascular event before age 20 years.

Ms. Mulder pointed out that, although there have been case series in the literature on HoFH, they have had “limited numbers” and patients have typically spent decades being treated at the same lipid management clinic.

To broaden the understanding of the clinical characteristics and management of patients dying with HoFH, the team examined data from the HICC registry, which is “the largest contemporary database of homozygous FH patients,” Ms. Mulder said.

It includes 751 patients with HoFH from 88 centers in 38 countries who were alive in 2010 or later. Data entry was between 2016 and 2020. The current analysis focused on 37 patients who had already died by the time they were included on the registry.

Of those, 49% were women, 38% were of White ethnicity, and 43% were from high-income countries.

The median age at diagnosis was 12 years, Ms. Mulder said, explaining that this is similar to that seen in other studies. The majority (86%) underwent genetic testing, and 92% presented with xanthomas.

Ms. Mulder also noted that, at their final clinical evaluation, which was conducted a median age of 18 years after their initial diagnosis, 43% of patients were recorded as current or former smokers.

In terms of their lipid-lowering therapy, 94% were taking a statin, whereas 68% were on ezetimibe, and 23% were undergoing apheresis.

Ms. Mulder said that the median number of lipid-lowering therapies per patient was two, and that “sadly ... 26% of the deceased patients had only one or no treatment.”

Therefore, perhaps unsurprisingly even those patients who were receiving treatment had LDL cholesterol levels that were “too high,” at 9.4 mmol/L versus 15.6 mmol/L among those who were untreated.

There was a high prevalence of ASCVD, at 70% overall, or 41% for aortic stenosis, 30% for myocardial infarction, 30% for angina pectoris, and 22% each for aortic valve replacement and coronary artery bypass grafting. In addition, 19% underwent percutaneous coronary intervention.

The median age of onset for ASCVD was 28 years. Ms. Mulder pointed out, however, that, as data were not available for all patients, “this might be an underestimation.” About 70% of patients experienced recurrent ASCVD.

There was a wide range in the age at which patients with HoFH died, although the median was, “strikingly,” 32 years, Ms. Mulder said. Death was confirmed as stemming from cardiovascular causes in 76% of cases.

During the postpresentation discussion, session chair Antonio J. Vallejo-Vaz, PhD, from the Research Group of Clinical Epidemiology and Vascular Risk, Institute of Biomedicine of Seville (Spain), highlighted that, if 38% of the patients were of White ethnicity, then the remainder must therefore be from other ethnic groups.

“There could be potential issues with accessibility to lipid centers” for these patients, which could affect the findings, noted Dr. Vallejo-Vaz, who is also chief scientist of the EAS Familial Hypercholesterolaemia Studies Collaboration.

Ms. Mulder agreed, replying that their results, though already striking, may be an underestimation because the patients were all from either high or middle-income countries, “so it would be good to have some data on low-income countries.”

She was also asked about two patients who died at a much older age than did the others, at ages 70 years and 86 years, respectively, and whether they had, for example, a protective genetic mutation.

Ms. Mulder said that they do not yet know, but they are planning an extended case series on these and other long-lived patients so that they can be investigated further.

No funding or relevant financial relationships were declared.

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

Doctors or AI? Lukewarm vote of confidence goes to …

Well, we’ve got some good news for the physicians out there, and we’ve got some bad news. Which do you want first? Okay, we’re mostly hearing good news, so here goes: Most people would choose a human doctor over artificial intelligence for the diagnosis and treatment of their medical conditions.

Alexandra_Koch/Pixabay

And the bad news? In the survey we’re talking about, “most” was 53%, so not exactly a huge victory for the carbon-based life forms. Yup, about 47% of the 2,472 respondents said they would prefer an AI-based clinic over a human specialist, and that number went up if individuals were told that their primary care physicians were on board with AI, “or otherwise nudged to consider AI as good,” the research team said in a written statement released by the University of Arizona, Tucson.

They went on to add that “this signaled the significance of the human physician in guiding a patient’s decision.” So patients will still need their doctors in the future to … um … this is a bit awkward … tell them how good the AI is?

And yes, we know that ChatGPT is already doing the same thing to journalists, but could it write a medical-humor column? Not a chance. Probably can’t even tell a joke.

How do ghosts get rid of wrinkles? Boo-tox. There, let’s see ChatGPT do that.
 

Explaining the joke makes it funnier, right?

Here at LOTME headquarters, we live by one simple rule, passed down directly from the Buddha himself: “Never let a good presurgical assessment of refractory epilepsy go to waste. Also, don’t believe everything you read on the Internet.”

Amy/Pixabay

This human-created joke has been brought to you by the leading theory of humor, which states that comedy stems from our brain reacting to an incongruous part of reality in a positive way. These positive emotions light up our neurons in a specific fashion, and boom, comedy is achieved.

Previous studies into the science of comedy have typically used functional MRI to analyze the brain while it was gripped in the throes of a comedic reaction. Unfortunately, fMRI cannot detect the entirety of the electromagnetic spectrum generated by the brain during these moments, so observing scientists have been, quite literally, missing out on some of the joke. And that’s where a new study from France comes in.

In the study, the researchers showed a group of patients with epilepsy who were hooked up to deep brain electrodes and a high-tech neuroimaging machine – part of the aforementioned presurgical assessment – a 3-minute excerpt from a Charlie Chaplin movie and analyzed their brain activity. Why Charlie Chaplin? Simple. Slapstick is perhaps the most accessible form of comedy across cultures. We can all appreciate a man getting hit in the head with a coconut. The world’s oldest bar joke or whatever this is? Not so much.

During the funniest scenes, all study participants showed increased high-frequency gamma waves (indicating high cognitive engagement) and a decrease in low-frequency waves (indicating reduced inattention and introspection). During unfunny scenes, such as transition moments, the opposite occurred. Importantly, this inverse relationship occurred in the temporal lobe but not in other regions, supporting previous research that indicated humor was mainly processed in the temporal lobe.

The investigators suggested future research should focus on longer videos with more complex forms of comedy, such as jokes, irony, sarcasm, or reference humor. So, uh, a guy getting hit in the head with two coconuts? That’s high-brow stuff right there.
 

Hot take: Humans aren’t that special

We humans have always prided ourselves on being different from “the animals” in an exceptional way. News flash! We aren’t. We may be the apex predator, but new research shows that humans, as part of the animal kingdom, just aren’t special.

jacoblund/iStock/Getty Images

Not special? How can they say that? Are gorillas doing open-heart surgery? Do wolverines tell jokes? At a more basic level, though, the way we operate as mammals in societies is not unique or even new. Elephants are known to mourn their deceased and to have funeral-like practices, ants invented agriculture, and we’re certainly not the only species that has figured out how to use tools.

This new research just demonstrates another way we aren’t exceptional, and that’s in our mating practices and outcomes.

“Humans appear to resemble mammals that live in monogamous partnerships and to some extent, those classified as cooperative breeders, where breeding individuals have to rely on the help of others to raise their offspring,” Monique Borgerhoff Mulder, PhD, professor emerita of anthropology at the University of California, Davis, said in a written statement.

The research team, which consisted of over 100 investigators, looked at 90 human populations based on data from over 80,000 people globally and compared the human data with 49 different nonhuman mammal species. In polygynous societies in which men take several wives, they found, women have more access to resources like food, shelter, and parenting help. Monogamy, on the other hand, “can drive significant inequalities among women,” Dr. Borgerhoff Mulder said, by promoting large differences in the number of children couples produce.

Human day-to-day behavior and child-rearing habits – one parent taking a daughter to ballet class and fixing dinner so the other parent can get to exercise class before picking up the son from soccer practice – may have us thinking that we are part of an evolved society, but really we are not much different than other mammals that hunt, forage for food, and rear and teach their children, the researchers suggested.

So, yes, humans can travel to the moon, create a vaccine for smallpox, and hit other humans with coconuts, but when it comes to simply having offspring or raising them, we’re not all that special. Get over it.

Doctors or AI? Lukewarm vote of confidence goes to …

Well, we’ve got some good news for the physicians out there, and we’ve got some bad news. Which do you want first? Okay, we’re mostly hearing good news, so here goes: Most people would choose a human doctor over artificial intelligence for the diagnosis and treatment of their medical conditions.

Alexandra_Koch/Pixabay

And the bad news? In the survey we’re talking about, “most” was 53%, so not exactly a huge victory for the carbon-based life forms. Yup, about 47% of the 2,472 respondents said they would prefer an AI-based clinic over a human specialist, and that number went up if individuals were told that their primary care physicians were on board with AI, “or otherwise nudged to consider AI as good,” the research team said in a written statement released by the University of Arizona, Tucson.

They went on to add that “this signaled the significance of the human physician in guiding a patient’s decision.” So patients will still need their doctors in the future to … um … this is a bit awkward … tell them how good the AI is?

And yes, we know that ChatGPT is already doing the same thing to journalists, but could it write a medical-humor column? Not a chance. Probably can’t even tell a joke.

How do ghosts get rid of wrinkles? Boo-tox. There, let’s see ChatGPT do that.
 

Explaining the joke makes it funnier, right?

Here at LOTME headquarters, we live by one simple rule, passed down directly from the Buddha himself: “Never let a good presurgical assessment of refractory epilepsy go to waste. Also, don’t believe everything you read on the Internet.”

Amy/Pixabay

This human-created joke has been brought to you by the leading theory of humor, which states that comedy stems from our brain reacting to an incongruous part of reality in a positive way. These positive emotions light up our neurons in a specific fashion, and boom, comedy is achieved.

Previous studies into the science of comedy have typically used functional MRI to analyze the brain while it was gripped in the throes of a comedic reaction. Unfortunately, fMRI cannot detect the entirety of the electromagnetic spectrum generated by the brain during these moments, so observing scientists have been, quite literally, missing out on some of the joke. And that’s where a new study from France comes in.

In the study, the researchers showed a group of patients with epilepsy who were hooked up to deep brain electrodes and a high-tech neuroimaging machine – part of the aforementioned presurgical assessment – a 3-minute excerpt from a Charlie Chaplin movie and analyzed their brain activity. Why Charlie Chaplin? Simple. Slapstick is perhaps the most accessible form of comedy across cultures. We can all appreciate a man getting hit in the head with a coconut. The world’s oldest bar joke or whatever this is? Not so much.

During the funniest scenes, all study participants showed increased high-frequency gamma waves (indicating high cognitive engagement) and a decrease in low-frequency waves (indicating reduced inattention and introspection). During unfunny scenes, such as transition moments, the opposite occurred. Importantly, this inverse relationship occurred in the temporal lobe but not in other regions, supporting previous research that indicated humor was mainly processed in the temporal lobe.

The investigators suggested future research should focus on longer videos with more complex forms of comedy, such as jokes, irony, sarcasm, or reference humor. So, uh, a guy getting hit in the head with two coconuts? That’s high-brow stuff right there.
 

Hot take: Humans aren’t that special

We humans have always prided ourselves on being different from “the animals” in an exceptional way. News flash! We aren’t. We may be the apex predator, but new research shows that humans, as part of the animal kingdom, just aren’t special.

jacoblund/iStock/Getty Images

Not special? How can they say that? Are gorillas doing open-heart surgery? Do wolverines tell jokes? At a more basic level, though, the way we operate as mammals in societies is not unique or even new. Elephants are known to mourn their deceased and to have funeral-like practices, ants invented agriculture, and we’re certainly not the only species that has figured out how to use tools.

This new research just demonstrates another way we aren’t exceptional, and that’s in our mating practices and outcomes.

“Humans appear to resemble mammals that live in monogamous partnerships and to some extent, those classified as cooperative breeders, where breeding individuals have to rely on the help of others to raise their offspring,” Monique Borgerhoff Mulder, PhD, professor emerita of anthropology at the University of California, Davis, said in a written statement.

The research team, which consisted of over 100 investigators, looked at 90 human populations based on data from over 80,000 people globally and compared the human data with 49 different nonhuman mammal species. In polygynous societies in which men take several wives, they found, women have more access to resources like food, shelter, and parenting help. Monogamy, on the other hand, “can drive significant inequalities among women,” Dr. Borgerhoff Mulder said, by promoting large differences in the number of children couples produce.

Human day-to-day behavior and child-rearing habits – one parent taking a daughter to ballet class and fixing dinner so the other parent can get to exercise class before picking up the son from soccer practice – may have us thinking that we are part of an evolved society, but really we are not much different than other mammals that hunt, forage for food, and rear and teach their children, the researchers suggested.

So, yes, humans can travel to the moon, create a vaccine for smallpox, and hit other humans with coconuts, but when it comes to simply having offspring or raising them, we’re not all that special. Get over it.

Doctors or AI? Lukewarm vote of confidence goes to …

Well, we’ve got some good news for the physicians out there, and we’ve got some bad news. Which do you want first? Okay, we’re mostly hearing good news, so here goes: Most people would choose a human doctor over artificial intelligence for the diagnosis and treatment of their medical conditions.

Alexandra_Koch/Pixabay

And the bad news? In the survey we’re talking about, “most” was 53%, so not exactly a huge victory for the carbon-based life forms. Yup, about 47% of the 2,472 respondents said they would prefer an AI-based clinic over a human specialist, and that number went up if individuals were told that their primary care physicians were on board with AI, “or otherwise nudged to consider AI as good,” the research team said in a written statement released by the University of Arizona, Tucson.

They went on to add that “this signaled the significance of the human physician in guiding a patient’s decision.” So patients will still need their doctors in the future to … um … this is a bit awkward … tell them how good the AI is?

And yes, we know that ChatGPT is already doing the same thing to journalists, but could it write a medical-humor column? Not a chance. Probably can’t even tell a joke.

How do ghosts get rid of wrinkles? Boo-tox. There, let’s see ChatGPT do that.
 

Explaining the joke makes it funnier, right?

Here at LOTME headquarters, we live by one simple rule, passed down directly from the Buddha himself: “Never let a good presurgical assessment of refractory epilepsy go to waste. Also, don’t believe everything you read on the Internet.”

Amy/Pixabay

This human-created joke has been brought to you by the leading theory of humor, which states that comedy stems from our brain reacting to an incongruous part of reality in a positive way. These positive emotions light up our neurons in a specific fashion, and boom, comedy is achieved.

Previous studies into the science of comedy have typically used functional MRI to analyze the brain while it was gripped in the throes of a comedic reaction. Unfortunately, fMRI cannot detect the entirety of the electromagnetic spectrum generated by the brain during these moments, so observing scientists have been, quite literally, missing out on some of the joke. And that’s where a new study from France comes in.

In the study, the researchers showed a group of patients with epilepsy who were hooked up to deep brain electrodes and a high-tech neuroimaging machine – part of the aforementioned presurgical assessment – a 3-minute excerpt from a Charlie Chaplin movie and analyzed their brain activity. Why Charlie Chaplin? Simple. Slapstick is perhaps the most accessible form of comedy across cultures. We can all appreciate a man getting hit in the head with a coconut. The world’s oldest bar joke or whatever this is? Not so much.

During the funniest scenes, all study participants showed increased high-frequency gamma waves (indicating high cognitive engagement) and a decrease in low-frequency waves (indicating reduced inattention and introspection). During unfunny scenes, such as transition moments, the opposite occurred. Importantly, this inverse relationship occurred in the temporal lobe but not in other regions, supporting previous research that indicated humor was mainly processed in the temporal lobe.

The investigators suggested future research should focus on longer videos with more complex forms of comedy, such as jokes, irony, sarcasm, or reference humor. So, uh, a guy getting hit in the head with two coconuts? That’s high-brow stuff right there.
 

Hot take: Humans aren’t that special

We humans have always prided ourselves on being different from “the animals” in an exceptional way. News flash! We aren’t. We may be the apex predator, but new research shows that humans, as part of the animal kingdom, just aren’t special.

jacoblund/iStock/Getty Images

Not special? How can they say that? Are gorillas doing open-heart surgery? Do wolverines tell jokes? At a more basic level, though, the way we operate as mammals in societies is not unique or even new. Elephants are known to mourn their deceased and to have funeral-like practices, ants invented agriculture, and we’re certainly not the only species that has figured out how to use tools.

This new research just demonstrates another way we aren’t exceptional, and that’s in our mating practices and outcomes.

“Humans appear to resemble mammals that live in monogamous partnerships and to some extent, those classified as cooperative breeders, where breeding individuals have to rely on the help of others to raise their offspring,” Monique Borgerhoff Mulder, PhD, professor emerita of anthropology at the University of California, Davis, said in a written statement.

The research team, which consisted of over 100 investigators, looked at 90 human populations based on data from over 80,000 people globally and compared the human data with 49 different nonhuman mammal species. In polygynous societies in which men take several wives, they found, women have more access to resources like food, shelter, and parenting help. Monogamy, on the other hand, “can drive significant inequalities among women,” Dr. Borgerhoff Mulder said, by promoting large differences in the number of children couples produce.

Human day-to-day behavior and child-rearing habits – one parent taking a daughter to ballet class and fixing dinner so the other parent can get to exercise class before picking up the son from soccer practice – may have us thinking that we are part of an evolved society, but really we are not much different than other mammals that hunt, forage for food, and rear and teach their children, the researchers suggested.

So, yes, humans can travel to the moon, create a vaccine for smallpox, and hit other humans with coconuts, but when it comes to simply having offspring or raising them, we’re not all that special. Get over it.

In a first-of-its-kind in utero surgery, researchers have successfully repaired a cerebrovascular malformation, which often leads to heart failure, severe brain injury, or possibly death soon after birth.
 

The team from Boston Children’s Hospital and Brigham and Women’s Hospital used ultrasound guidance to repair the vein of Galen malformation, which causes excessively high blood flow, resulting in both neurologic and cardiac complications. 

The surgery was performed in a fetus at 34 weeks’ gestational age, with remarkable results. Since birth, the baby girl, who was identified in utero as being at high risk of suffering serious complications of the malformation, has required no medication to treat heart failure and no postnatal surgery.

Repeated echocardiograms after birth displayed marked improvement in cardiac output, and brain MRI showed no brain injury and a normal neurologic exam.

“This is incredibly exciting. The hope is that this baby, and others with this condition who receive this in utero surgery in future, will go on to have a normal life,” lead researcher Darren B. Orbach, MD, PhD, said in an interview.

“We were thrilled to see that the aggressive decline usually seen after birth simply did not appear. We are pleased to report that at 6 weeks, the infant is progressing remarkably well, on no medications, eating normally, gaining weight and is back home. There are no signs of any negative effects on the brain,” he added.

Dr. Orbach, codirector of the Cerebrovascular Surgery & Interventions Center at Boston Children’s Hospital, and colleagues described this first case report of the in utero vein of Galen malformation repair in a research letter, published online in the journal Stroke.
 

Vein of Galen malformation

Dr. Orbach explained that vein of Galen malformation, which occurs in around 1 in every 60,000 births, is a cerebrovascular anomaly in which the arterial system is directly connected to the venous system rather than to capillaries that are necessary to slow blood flow and deliver oxygen to surrounding brain tissue.

“The arterial and venous systems are fundamentally very different. The arterial system is high pressure, high flow; while the venous system is low pressure, low flow. They shouldn’t be directly connected,” he noted.

The vein of Galen malformation is the most extreme version of such an anomaly. Developing in early gestation, it is associated with a large increase in blood flow through the brain which grows over time and can sometimes result in twice the total cardiac output of the body or even more, Dr. Orbach said.

The placenta is believed to be protective as most babies don’t have overt physiologic problems in utero, but they can run into crisis after birth, with the abnormally high blood flow causing an immense stress to the heart.

Babies typically present with heart failure as their first major symptom soon after birth, Dr. Orbach said. “Although the anatomical problem is in the brain, the clinical manifestation is high-output heart failure. The heart is trying to do double its normal work, pumping the blood to the malformation and immediately back to the heart and that blood is not performing any useful function.

“These newborns can get very sick. They need multiple medications to support their cardiovascular system and we need to do procedures to try and reduce the blood flow,” he explained. 

Brain injury is also a common problem. “The brain circulation is very abnormal. The blood is being shunted through the malformation rather than circulating through the brain tissue which can become ischemic,” Dr. Orbach commented.

“The babies who get sick would have a very high mortality (up to 90%) without expert care. Even those who do receive expert care at a specialty center have a mortality rate of 30% to 40% and those who survive have a high risk of neurologic and cognitive impairment,” he added.

The current treatment for babies born with the condition involves transarterial embolization, by which a catheter is inserted into the arterial system to enable the malformation to be occluded by various techniques. 

But Dr. Orbach pointed out that some babies are born too sick to have the postnatal intervention. “The heart failure and brain injury is so overwhelming that no matter what we do, we cannot reverse it, and these babies normally do not survive. What we are doing with the fetal surgery is trying to help those babies who cannot be treated with the current postnatal approach,” he said.

The first stage of this research involved trying to identify these very-high-risk babies in utero, and the researchers found that on fetal MRI a particular measurement of one of the venous sinuses that drains the main malformation was a good predictor of how the baby would fare after birth. The babies predicted to do poorly from this test are the targets for the fetal surgery.

The technique used for the postnatal intervention is too technically challenging to perform in utero. “So we have developed a different approach for the in utero surgery that involves navigating into the accepting vein in the malformation with a needle under ultrasound guidance, and then packing the vein with metal coils to dramatically reduce the blood flow,” Dr. Orbach explained.

This procedure was performed in this first patient on March 15. The surgery was part of a clinical trial that is planned to include 20 cases in total.

“The immediate goal is to see whether we can transform those fetuses who are at very high risk of getting sick after birth into babies who do well in the [neonatal] ICU and are able to be sent home for elective treatment at a few months of age,” Dr. Orbach noted. “The study is continuing as it is vital that we continue and show efficacy and safety in other patients as well,” he added.

Dr. Orbach said the results of this first case were extremely encouraging. “Each stage was exciting – the technical success of the procedure, and then seeing the [blood] flow diminish on the ultrasound right there during the procedure; then the next day we did a fetal echocardiogram, and we could see that the abnormal cardiac output was dramatically reduced, and a fetal MRI scan also showed the malformation was already coming down in size.”

The baby was born prematurely 2 days after the procedure because of ruptured membranes with a birth weight of 1.9 kg (4.2 lb). She has not required any cardiovascular support or postnatal embolization.

“We were waiting with bated breath until the baby was born to see how she did clinically. I was trying to be conservative in my expectations, but it was quickly apparent that she was going to do great,” he said. Now at home, she has some oxygen treatment for the first few weeks, “but right now her neurological status is completely intact and essentially she looks like any other baby,” Dr. Orbach commented.

It is not yet known whether the infant will need any additional procedures. “We will follow her closely and make a decision on whether further treatment is needed based on whether the malformation is growing or not,” Dr. Orbach said. Longer term follow-up will also assess secondary problems sometimes seen, such as learning problems and seizures.

Although other fetal surgeries are now routinely performed, this is believed to be the first in utero surgery aimed at the cerebrovascular system.

“There were a lot of uncertainties,” Dr. Orbach said. “We didn’t even know if we would be able to see our instruments on ultrasound.” To model the procedure, the researchers had a phantom fetal skull and brain constructed with a vein of Galen malformation, which was key to obtaining Food and Drug Administration approval for the study.

If the study shows success in the other patients too, the technique could be rolled out to other centers. “There definitely needs to be fetal surgery and neurointerventional teams familiar with vein of Galen malformation in place, and ready to manage complications after delivery regardless of outcome. But we are not the only center with those capabilities, so if our trial pans out, yes, the hope is that other teams in specialist children’s hospitals around the world could do this too,” he added.
 

Pioneering work

Commenting on the case report in an American Heart Association press release, Colin Derdeyn, MD, a neurointerventional radiologist at University of Iowa Health Care, Iowa City, who performs vein of Galen malformation embolizations on neonates, said: “The key advance here is to intervene before the physiologic events of birth can cause life-threatening heart failure.”

Dr. Derdeyn, who is a past chair of the American Heart Association’s Stroke Council, cautioned that one successful case is not enough experience to conclude that the risks of this procedure are worth the benefits.

But, he added: “The positive hemodynamic changes that they observed in utero and after birth – reduction in flow, reduction in size of the draining vein, reversal of the abnormal reversed flow in the aorta – are really encouraging. These are some of the most exciting and surprising aspects of this case report. This is pioneering work being done in a very careful and responsible way.”

The study was funded by a grant from the Sage Schermerhorn Chair for Image-Guided Therapy.

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

In a first-of-its-kind in utero surgery, researchers have successfully repaired a cerebrovascular malformation, which often leads to heart failure, severe brain injury, or possibly death soon after birth.
 

The team from Boston Children’s Hospital and Brigham and Women’s Hospital used ultrasound guidance to repair the vein of Galen malformation, which causes excessively high blood flow, resulting in both neurologic and cardiac complications. 

The surgery was performed in a fetus at 34 weeks’ gestational age, with remarkable results. Since birth, the baby girl, who was identified in utero as being at high risk of suffering serious complications of the malformation, has required no medication to treat heart failure and no postnatal surgery.

Repeated echocardiograms after birth displayed marked improvement in cardiac output, and brain MRI showed no brain injury and a normal neurologic exam.

“This is incredibly exciting. The hope is that this baby, and others with this condition who receive this in utero surgery in future, will go on to have a normal life,” lead researcher Darren B. Orbach, MD, PhD, said in an interview.

“We were thrilled to see that the aggressive decline usually seen after birth simply did not appear. We are pleased to report that at 6 weeks, the infant is progressing remarkably well, on no medications, eating normally, gaining weight and is back home. There are no signs of any negative effects on the brain,” he added.

Dr. Orbach, codirector of the Cerebrovascular Surgery & Interventions Center at Boston Children’s Hospital, and colleagues described this first case report of the in utero vein of Galen malformation repair in a research letter, published online in the journal Stroke.
 

Vein of Galen malformation

Dr. Orbach explained that vein of Galen malformation, which occurs in around 1 in every 60,000 births, is a cerebrovascular anomaly in which the arterial system is directly connected to the venous system rather than to capillaries that are necessary to slow blood flow and deliver oxygen to surrounding brain tissue.

“The arterial and venous systems are fundamentally very different. The arterial system is high pressure, high flow; while the venous system is low pressure, low flow. They shouldn’t be directly connected,” he noted.

The vein of Galen malformation is the most extreme version of such an anomaly. Developing in early gestation, it is associated with a large increase in blood flow through the brain which grows over time and can sometimes result in twice the total cardiac output of the body or even more, Dr. Orbach said.

The placenta is believed to be protective as most babies don’t have overt physiologic problems in utero, but they can run into crisis after birth, with the abnormally high blood flow causing an immense stress to the heart.

Babies typically present with heart failure as their first major symptom soon after birth, Dr. Orbach said. “Although the anatomical problem is in the brain, the clinical manifestation is high-output heart failure. The heart is trying to do double its normal work, pumping the blood to the malformation and immediately back to the heart and that blood is not performing any useful function.

“These newborns can get very sick. They need multiple medications to support their cardiovascular system and we need to do procedures to try and reduce the blood flow,” he explained. 

Brain injury is also a common problem. “The brain circulation is very abnormal. The blood is being shunted through the malformation rather than circulating through the brain tissue which can become ischemic,” Dr. Orbach commented.

“The babies who get sick would have a very high mortality (up to 90%) without expert care. Even those who do receive expert care at a specialty center have a mortality rate of 30% to 40% and those who survive have a high risk of neurologic and cognitive impairment,” he added.

The current treatment for babies born with the condition involves transarterial embolization, by which a catheter is inserted into the arterial system to enable the malformation to be occluded by various techniques. 

But Dr. Orbach pointed out that some babies are born too sick to have the postnatal intervention. “The heart failure and brain injury is so overwhelming that no matter what we do, we cannot reverse it, and these babies normally do not survive. What we are doing with the fetal surgery is trying to help those babies who cannot be treated with the current postnatal approach,” he said.

The first stage of this research involved trying to identify these very-high-risk babies in utero, and the researchers found that on fetal MRI a particular measurement of one of the venous sinuses that drains the main malformation was a good predictor of how the baby would fare after birth. The babies predicted to do poorly from this test are the targets for the fetal surgery.

The technique used for the postnatal intervention is too technically challenging to perform in utero. “So we have developed a different approach for the in utero surgery that involves navigating into the accepting vein in the malformation with a needle under ultrasound guidance, and then packing the vein with metal coils to dramatically reduce the blood flow,” Dr. Orbach explained.

This procedure was performed in this first patient on March 15. The surgery was part of a clinical trial that is planned to include 20 cases in total.

“The immediate goal is to see whether we can transform those fetuses who are at very high risk of getting sick after birth into babies who do well in the [neonatal] ICU and are able to be sent home for elective treatment at a few months of age,” Dr. Orbach noted. “The study is continuing as it is vital that we continue and show efficacy and safety in other patients as well,” he added.

Dr. Orbach said the results of this first case were extremely encouraging. “Each stage was exciting – the technical success of the procedure, and then seeing the [blood] flow diminish on the ultrasound right there during the procedure; then the next day we did a fetal echocardiogram, and we could see that the abnormal cardiac output was dramatically reduced, and a fetal MRI scan also showed the malformation was already coming down in size.”

The baby was born prematurely 2 days after the procedure because of ruptured membranes with a birth weight of 1.9 kg (4.2 lb). She has not required any cardiovascular support or postnatal embolization.

“We were waiting with bated breath until the baby was born to see how she did clinically. I was trying to be conservative in my expectations, but it was quickly apparent that she was going to do great,” he said. Now at home, she has some oxygen treatment for the first few weeks, “but right now her neurological status is completely intact and essentially she looks like any other baby,” Dr. Orbach commented.

It is not yet known whether the infant will need any additional procedures. “We will follow her closely and make a decision on whether further treatment is needed based on whether the malformation is growing or not,” Dr. Orbach said. Longer term follow-up will also assess secondary problems sometimes seen, such as learning problems and seizures.

Although other fetal surgeries are now routinely performed, this is believed to be the first in utero surgery aimed at the cerebrovascular system.

“There were a lot of uncertainties,” Dr. Orbach said. “We didn’t even know if we would be able to see our instruments on ultrasound.” To model the procedure, the researchers had a phantom fetal skull and brain constructed with a vein of Galen malformation, which was key to obtaining Food and Drug Administration approval for the study.

If the study shows success in the other patients too, the technique could be rolled out to other centers. “There definitely needs to be fetal surgery and neurointerventional teams familiar with vein of Galen malformation in place, and ready to manage complications after delivery regardless of outcome. But we are not the only center with those capabilities, so if our trial pans out, yes, the hope is that other teams in specialist children’s hospitals around the world could do this too,” he added.
 

Pioneering work

Commenting on the case report in an American Heart Association press release, Colin Derdeyn, MD, a neurointerventional radiologist at University of Iowa Health Care, Iowa City, who performs vein of Galen malformation embolizations on neonates, said: “The key advance here is to intervene before the physiologic events of birth can cause life-threatening heart failure.”

Dr. Derdeyn, who is a past chair of the American Heart Association’s Stroke Council, cautioned that one successful case is not enough experience to conclude that the risks of this procedure are worth the benefits.

But, he added: “The positive hemodynamic changes that they observed in utero and after birth – reduction in flow, reduction in size of the draining vein, reversal of the abnormal reversed flow in the aorta – are really encouraging. These are some of the most exciting and surprising aspects of this case report. This is pioneering work being done in a very careful and responsible way.”

The study was funded by a grant from the Sage Schermerhorn Chair for Image-Guided Therapy.

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

In a first-of-its-kind in utero surgery, researchers have successfully repaired a cerebrovascular malformation, which often leads to heart failure, severe brain injury, or possibly death soon after birth.
 

The team from Boston Children’s Hospital and Brigham and Women’s Hospital used ultrasound guidance to repair the vein of Galen malformation, which causes excessively high blood flow, resulting in both neurologic and cardiac complications. 

The surgery was performed in a fetus at 34 weeks’ gestational age, with remarkable results. Since birth, the baby girl, who was identified in utero as being at high risk of suffering serious complications of the malformation, has required no medication to treat heart failure and no postnatal surgery.

Repeated echocardiograms after birth displayed marked improvement in cardiac output, and brain MRI showed no brain injury and a normal neurologic exam.

“This is incredibly exciting. The hope is that this baby, and others with this condition who receive this in utero surgery in future, will go on to have a normal life,” lead researcher Darren B. Orbach, MD, PhD, said in an interview.

“We were thrilled to see that the aggressive decline usually seen after birth simply did not appear. We are pleased to report that at 6 weeks, the infant is progressing remarkably well, on no medications, eating normally, gaining weight and is back home. There are no signs of any negative effects on the brain,” he added.

Dr. Orbach, codirector of the Cerebrovascular Surgery & Interventions Center at Boston Children’s Hospital, and colleagues described this first case report of the in utero vein of Galen malformation repair in a research letter, published online in the journal Stroke.
 

Vein of Galen malformation

Dr. Orbach explained that vein of Galen malformation, which occurs in around 1 in every 60,000 births, is a cerebrovascular anomaly in which the arterial system is directly connected to the venous system rather than to capillaries that are necessary to slow blood flow and deliver oxygen to surrounding brain tissue.

“The arterial and venous systems are fundamentally very different. The arterial system is high pressure, high flow; while the venous system is low pressure, low flow. They shouldn’t be directly connected,” he noted.

The vein of Galen malformation is the most extreme version of such an anomaly. Developing in early gestation, it is associated with a large increase in blood flow through the brain which grows over time and can sometimes result in twice the total cardiac output of the body or even more, Dr. Orbach said.

The placenta is believed to be protective as most babies don’t have overt physiologic problems in utero, but they can run into crisis after birth, with the abnormally high blood flow causing an immense stress to the heart.

Babies typically present with heart failure as their first major symptom soon after birth, Dr. Orbach said. “Although the anatomical problem is in the brain, the clinical manifestation is high-output heart failure. The heart is trying to do double its normal work, pumping the blood to the malformation and immediately back to the heart and that blood is not performing any useful function.

“These newborns can get very sick. They need multiple medications to support their cardiovascular system and we need to do procedures to try and reduce the blood flow,” he explained. 

Brain injury is also a common problem. “The brain circulation is very abnormal. The blood is being shunted through the malformation rather than circulating through the brain tissue which can become ischemic,” Dr. Orbach commented.

“The babies who get sick would have a very high mortality (up to 90%) without expert care. Even those who do receive expert care at a specialty center have a mortality rate of 30% to 40% and those who survive have a high risk of neurologic and cognitive impairment,” he added.

The current treatment for babies born with the condition involves transarterial embolization, by which a catheter is inserted into the arterial system to enable the malformation to be occluded by various techniques. 

But Dr. Orbach pointed out that some babies are born too sick to have the postnatal intervention. “The heart failure and brain injury is so overwhelming that no matter what we do, we cannot reverse it, and these babies normally do not survive. What we are doing with the fetal surgery is trying to help those babies who cannot be treated with the current postnatal approach,” he said.

The first stage of this research involved trying to identify these very-high-risk babies in utero, and the researchers found that on fetal MRI a particular measurement of one of the venous sinuses that drains the main malformation was a good predictor of how the baby would fare after birth. The babies predicted to do poorly from this test are the targets for the fetal surgery.

The technique used for the postnatal intervention is too technically challenging to perform in utero. “So we have developed a different approach for the in utero surgery that involves navigating into the accepting vein in the malformation with a needle under ultrasound guidance, and then packing the vein with metal coils to dramatically reduce the blood flow,” Dr. Orbach explained.

This procedure was performed in this first patient on March 15. The surgery was part of a clinical trial that is planned to include 20 cases in total.

“The immediate goal is to see whether we can transform those fetuses who are at very high risk of getting sick after birth into babies who do well in the [neonatal] ICU and are able to be sent home for elective treatment at a few months of age,” Dr. Orbach noted. “The study is continuing as it is vital that we continue and show efficacy and safety in other patients as well,” he added.

Dr. Orbach said the results of this first case were extremely encouraging. “Each stage was exciting – the technical success of the procedure, and then seeing the [blood] flow diminish on the ultrasound right there during the procedure; then the next day we did a fetal echocardiogram, and we could see that the abnormal cardiac output was dramatically reduced, and a fetal MRI scan also showed the malformation was already coming down in size.”

The baby was born prematurely 2 days after the procedure because of ruptured membranes with a birth weight of 1.9 kg (4.2 lb). She has not required any cardiovascular support or postnatal embolization.

“We were waiting with bated breath until the baby was born to see how she did clinically. I was trying to be conservative in my expectations, but it was quickly apparent that she was going to do great,” he said. Now at home, she has some oxygen treatment for the first few weeks, “but right now her neurological status is completely intact and essentially she looks like any other baby,” Dr. Orbach commented.

It is not yet known whether the infant will need any additional procedures. “We will follow her closely and make a decision on whether further treatment is needed based on whether the malformation is growing or not,” Dr. Orbach said. Longer term follow-up will also assess secondary problems sometimes seen, such as learning problems and seizures.

Although other fetal surgeries are now routinely performed, this is believed to be the first in utero surgery aimed at the cerebrovascular system.

“There were a lot of uncertainties,” Dr. Orbach said. “We didn’t even know if we would be able to see our instruments on ultrasound.” To model the procedure, the researchers had a phantom fetal skull and brain constructed with a vein of Galen malformation, which was key to obtaining Food and Drug Administration approval for the study.

If the study shows success in the other patients too, the technique could be rolled out to other centers. “There definitely needs to be fetal surgery and neurointerventional teams familiar with vein of Galen malformation in place, and ready to manage complications after delivery regardless of outcome. But we are not the only center with those capabilities, so if our trial pans out, yes, the hope is that other teams in specialist children’s hospitals around the world could do this too,” he added.
 

Pioneering work

Commenting on the case report in an American Heart Association press release, Colin Derdeyn, MD, a neurointerventional radiologist at University of Iowa Health Care, Iowa City, who performs vein of Galen malformation embolizations on neonates, said: “The key advance here is to intervene before the physiologic events of birth can cause life-threatening heart failure.”

Dr. Derdeyn, who is a past chair of the American Heart Association’s Stroke Council, cautioned that one successful case is not enough experience to conclude that the risks of this procedure are worth the benefits.

But, he added: “The positive hemodynamic changes that they observed in utero and after birth – reduction in flow, reduction in size of the draining vein, reversal of the abnormal reversed flow in the aorta – are really encouraging. These are some of the most exciting and surprising aspects of this case report. This is pioneering work being done in a very careful and responsible way.”

The study was funded by a grant from the Sage Schermerhorn Chair for Image-Guided Therapy.

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

In the first randomized clinical trial of remote pulmonary artery pressure–guided monitoring and management of chronic heart failure (HF) in Europe, the intervention “substantially” improved quality of life (QoL) and reduced HF hospitalizations, new data show.

The CardioMEMS-HF system (Abbot Laboratories) used in the trial, called MONITOR-HF, remotely monitors changes in pulmonary artery pressure and provides an early warning of worsening HF.

Jasper Brugts, MD, PhD, of Erasmus MC University Medical Centre, Rotterdam, the Netherlands, said in an interview, “The concordance on outcomes of the three CardioMEMS trials across different eras, evolving GDMT [guideline-directed medical therapy], different conditions (pandemic), and different health care systems is reassuring and supportive of technologies such as CardioMEMS to improve patient monitoring to prevent HF hospitalizations and improve QoL.”

Dr. Brugts presented the study at the Heart Failure Association of the European Society of Cardiology (HFA-ESC) 2023 sessions.

The system “improved QoL in all six domains of the Kansas City Cardiomyopathy Questionnaire” and resulted in fewer HF-related hospitalizations (117 vs. 212) and fewer urgent visits (11 vs. 17), in comparison with standard of care, Dr. Brugts told meeting attendees.

Furthermore, CardioMEMS monitors hypervolemia as well as hypovolemia, enabling “fine-tuning of diuretics.”

The presentation drew such applause that one chairperson described it as “close to a standing ovation.” The study was published simultaneously in The Lancet.
 

Aggregate evidence

Early clinical evidence of the benefits of remote monitoring with the CardioMEMS-HF system was provided by the CHAMPION trial, which included patients with New York Heart Association (NYHA) class III heart failure.

Results of the subsequent GUIDE-HF trial, which aimed to test a broader population of patients with NYHA class II–IV heart failure and either increased N-terminal-pro-B-type natriuretic peptide (NT-proBNP) concentrations or hospitalization, were inconclusive.

However, a pre–COVID-19 impact analysis of GUIDE-HF indicated a possible benefit, which was primarily driven by a lower HF hospitalization rate, compared with the control group. That finding was the basis for an expanded indication for the system from the U.S. Food and Drug Administration.

The 2022 FDA indication permits the use of CardioMEMS for patients with NYHA class II HF and for those with worsening HF, as assessed by elevated natriuretic peptide levels.
 

From United States to Europe

Aware that most CardioMEMS data came from U.S. trials, the investigators embarked on the current trial, MONITOR-HF, an open-label, randomized trial in 25 centers in the Netherlands. Eligible patients had chronic NYHA class III HF, irrespective of ejection fraction, and had previously undergone hospitalization for HF.

A total of 348 patients were randomly assigned to either CardioMEMS-HF or standard of care (SoC) between 2019 and 2022.The median age of the patients was 69 years, and the median ejection fraction was 30%.

All patients were scheduled to be seen by their clinician at 3 months, 6 months, and every 6 months thereafter for up to 48 months.

The primary endpoint was the mean difference in the Kansas City Cardiomyopathy Questionnaire (KCCQ) summary score at 12 months

That difference between groups was 7.13 (+7.05 in the CardioMEMS group and –0.08 in the SoC group).

In the responder analysis, the odds ratio of an improvement of at least 5 points in the KCCQ overall summary score was 1.69 in the CardioMEMS group vs. the SoC group; the OR of a deterioration of at least 5 points was 0.45.

Subgroup analyses showed no relevant heterogeneity in the treatment effect on total HF hospitalizations and, notably, no significant interaction in patients with an EF below 40% and an EF above 40%.

There was a significant reduction in the median NT-proBNP change from baseline only in the remote monitoring group (800 pg/mL) and a smaller, nonsignificant difference with SoC.

Both groups received highly appropriate background guideline–directed medical therapy throughout the study. There were no significant between-group differences at 12 months.

Freedom from device-related or system-related complications and sensor failure were 97.7% and 98.8%, respectively.

Two sensor failures occurred during a mean follow-up 1.8 years. The percentage of failures was comparable to CHAMPION and GUIDE-HF trials.

The trial was not powered to assess a mortality benefit.
 

Pick the right patients

“As in the U.S. trials, there will be side effects, so select the right patients, because [remote monitoring] is not without risk,” Dr. Brugts told meeting attendees.

That point also was made by Christiane E. Angermann of University and University Hospital Würzburg, Germany, in a related editorial in The Lancet.

“To reproduce these results on a large scale in real-life health care, diligent patient selection should identify those at high risk of heart failure–related hospitalization who agree with the concept of daily data collection and are able and motivated to comply with treatment recommendations even if asymptomatic,” Dr. Angermann writes.

“Without direct interaction between health care providers and patients, and timely treatment modification triggered by abnormal monitoring results, the care cycle might break and the potential benefits from early detection of decompensation would be lost.”

Val Rakita, MD, assistant professor of medicine at Temple University, Philadelphia, a specialist in advanced heart failure and main implanter of the CardioMEMS device at Temple University Hospital, commented on the study for this article.

“This study confirms the previous data that the device is very safe and effective in preventing HF hospitalizations and improving patients’ quality of life, even in a different population with more modern background guideline-directed medical therapy.”

Nevertheless, he noted, “Studies have yet to confirm a mortality benefit, despite logic telling us that preventing heart failure hospitalizations should also improve patient survival. More studies are needed to see if a survival benefit can be proven over a longer follow-up period.”

Overall, he said, “Remote monitoring allows more precise management of medications, prevention of hospitalizations, and improvement in quality of life, and I am an advocate for it in my practice.”

Not everyone is an advocate, however. In a commentary published last year, John M. Mandrola, MD, a cardiac electrophysiologist at Baptist Medical Associates in Louisville, Ky., said the expanded FDA indication for the device is the result of “dubious trial analysis, spin, lax regulation, and the growth of low-value care.”

Others also have questioned the device’s value in the clinic.

But at least for now, as Dr. Angermann writes, “Scientific evidence supports the use of the CardioMEMS-HF system to enhance remote patient management in heart failure care. For more widespread application, technological advancements are desirable to provide more comfort for patients and reusable external device components, thereby improving care experience and saving resources.”

The MONITOR-HF trial is funded by the Dutch Ministry of Health and Health Care institute. Dr. Brugts has an independent research grant from Abbott (investigator-sponsored study) and has had speaker engagements or has participated in advisory boards for Abbott and other pharmaceutical companies. Dr. Angermann has received personal fees from Abbott for serving as chair of the steering committee for the CardioMEMS European Monitoring Study for Heart Failure (MEMS-HF) and consulting fees, honoraria, and travel costs from Abbott. Dr. Rakita has disclosed no relevant financial relationships.

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

In the first randomized clinical trial of remote pulmonary artery pressure–guided monitoring and management of chronic heart failure (HF) in Europe, the intervention “substantially” improved quality of life (QoL) and reduced HF hospitalizations, new data show.

The CardioMEMS-HF system (Abbot Laboratories) used in the trial, called MONITOR-HF, remotely monitors changes in pulmonary artery pressure and provides an early warning of worsening HF.

Jasper Brugts, MD, PhD, of Erasmus MC University Medical Centre, Rotterdam, the Netherlands, said in an interview, “The concordance on outcomes of the three CardioMEMS trials across different eras, evolving GDMT [guideline-directed medical therapy], different conditions (pandemic), and different health care systems is reassuring and supportive of technologies such as CardioMEMS to improve patient monitoring to prevent HF hospitalizations and improve QoL.”

Dr. Brugts presented the study at the Heart Failure Association of the European Society of Cardiology (HFA-ESC) 2023 sessions.

The system “improved QoL in all six domains of the Kansas City Cardiomyopathy Questionnaire” and resulted in fewer HF-related hospitalizations (117 vs. 212) and fewer urgent visits (11 vs. 17), in comparison with standard of care, Dr. Brugts told meeting attendees.

Furthermore, CardioMEMS monitors hypervolemia as well as hypovolemia, enabling “fine-tuning of diuretics.”

The presentation drew such applause that one chairperson described it as “close to a standing ovation.” The study was published simultaneously in The Lancet.
 

Aggregate evidence

Early clinical evidence of the benefits of remote monitoring with the CardioMEMS-HF system was provided by the CHAMPION trial, which included patients with New York Heart Association (NYHA) class III heart failure.

Results of the subsequent GUIDE-HF trial, which aimed to test a broader population of patients with NYHA class II–IV heart failure and either increased N-terminal-pro-B-type natriuretic peptide (NT-proBNP) concentrations or hospitalization, were inconclusive.

However, a pre–COVID-19 impact analysis of GUIDE-HF indicated a possible benefit, which was primarily driven by a lower HF hospitalization rate, compared with the control group. That finding was the basis for an expanded indication for the system from the U.S. Food and Drug Administration.

The 2022 FDA indication permits the use of CardioMEMS for patients with NYHA class II HF and for those with worsening HF, as assessed by elevated natriuretic peptide levels.
 

From United States to Europe

Aware that most CardioMEMS data came from U.S. trials, the investigators embarked on the current trial, MONITOR-HF, an open-label, randomized trial in 25 centers in the Netherlands. Eligible patients had chronic NYHA class III HF, irrespective of ejection fraction, and had previously undergone hospitalization for HF.

A total of 348 patients were randomly assigned to either CardioMEMS-HF or standard of care (SoC) between 2019 and 2022.The median age of the patients was 69 years, and the median ejection fraction was 30%.

All patients were scheduled to be seen by their clinician at 3 months, 6 months, and every 6 months thereafter for up to 48 months.

The primary endpoint was the mean difference in the Kansas City Cardiomyopathy Questionnaire (KCCQ) summary score at 12 months

That difference between groups was 7.13 (+7.05 in the CardioMEMS group and –0.08 in the SoC group).

In the responder analysis, the odds ratio of an improvement of at least 5 points in the KCCQ overall summary score was 1.69 in the CardioMEMS group vs. the SoC group; the OR of a deterioration of at least 5 points was 0.45.

Subgroup analyses showed no relevant heterogeneity in the treatment effect on total HF hospitalizations and, notably, no significant interaction in patients with an EF below 40% and an EF above 40%.

There was a significant reduction in the median NT-proBNP change from baseline only in the remote monitoring group (800 pg/mL) and a smaller, nonsignificant difference with SoC.

Both groups received highly appropriate background guideline–directed medical therapy throughout the study. There were no significant between-group differences at 12 months.

Freedom from device-related or system-related complications and sensor failure were 97.7% and 98.8%, respectively.

Two sensor failures occurred during a mean follow-up 1.8 years. The percentage of failures was comparable to CHAMPION and GUIDE-HF trials.

The trial was not powered to assess a mortality benefit.
 

Pick the right patients

“As in the U.S. trials, there will be side effects, so select the right patients, because [remote monitoring] is not without risk,” Dr. Brugts told meeting attendees.

That point also was made by Christiane E. Angermann of University and University Hospital Würzburg, Germany, in a related editorial in The Lancet.

“To reproduce these results on a large scale in real-life health care, diligent patient selection should identify those at high risk of heart failure–related hospitalization who agree with the concept of daily data collection and are able and motivated to comply with treatment recommendations even if asymptomatic,” Dr. Angermann writes.

“Without direct interaction between health care providers and patients, and timely treatment modification triggered by abnormal monitoring results, the care cycle might break and the potential benefits from early detection of decompensation would be lost.”

Val Rakita, MD, assistant professor of medicine at Temple University, Philadelphia, a specialist in advanced heart failure and main implanter of the CardioMEMS device at Temple University Hospital, commented on the study for this article.

“This study confirms the previous data that the device is very safe and effective in preventing HF hospitalizations and improving patients’ quality of life, even in a different population with more modern background guideline-directed medical therapy.”

Nevertheless, he noted, “Studies have yet to confirm a mortality benefit, despite logic telling us that preventing heart failure hospitalizations should also improve patient survival. More studies are needed to see if a survival benefit can be proven over a longer follow-up period.”

Overall, he said, “Remote monitoring allows more precise management of medications, prevention of hospitalizations, and improvement in quality of life, and I am an advocate for it in my practice.”

Not everyone is an advocate, however. In a commentary published last year, John M. Mandrola, MD, a cardiac electrophysiologist at Baptist Medical Associates in Louisville, Ky., said the expanded FDA indication for the device is the result of “dubious trial analysis, spin, lax regulation, and the growth of low-value care.”

Others also have questioned the device’s value in the clinic.

But at least for now, as Dr. Angermann writes, “Scientific evidence supports the use of the CardioMEMS-HF system to enhance remote patient management in heart failure care. For more widespread application, technological advancements are desirable to provide more comfort for patients and reusable external device components, thereby improving care experience and saving resources.”

The MONITOR-HF trial is funded by the Dutch Ministry of Health and Health Care institute. Dr. Brugts has an independent research grant from Abbott (investigator-sponsored study) and has had speaker engagements or has participated in advisory boards for Abbott and other pharmaceutical companies. Dr. Angermann has received personal fees from Abbott for serving as chair of the steering committee for the CardioMEMS European Monitoring Study for Heart Failure (MEMS-HF) and consulting fees, honoraria, and travel costs from Abbott. Dr. Rakita has disclosed no relevant financial relationships.

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

In the first randomized clinical trial of remote pulmonary artery pressure–guided monitoring and management of chronic heart failure (HF) in Europe, the intervention “substantially” improved quality of life (QoL) and reduced HF hospitalizations, new data show.

The CardioMEMS-HF system (Abbot Laboratories) used in the trial, called MONITOR-HF, remotely monitors changes in pulmonary artery pressure and provides an early warning of worsening HF.

Jasper Brugts, MD, PhD, of Erasmus MC University Medical Centre, Rotterdam, the Netherlands, said in an interview, “The concordance on outcomes of the three CardioMEMS trials across different eras, evolving GDMT [guideline-directed medical therapy], different conditions (pandemic), and different health care systems is reassuring and supportive of technologies such as CardioMEMS to improve patient monitoring to prevent HF hospitalizations and improve QoL.”

Dr. Brugts presented the study at the Heart Failure Association of the European Society of Cardiology (HFA-ESC) 2023 sessions.

The system “improved QoL in all six domains of the Kansas City Cardiomyopathy Questionnaire” and resulted in fewer HF-related hospitalizations (117 vs. 212) and fewer urgent visits (11 vs. 17), in comparison with standard of care, Dr. Brugts told meeting attendees.

Furthermore, CardioMEMS monitors hypervolemia as well as hypovolemia, enabling “fine-tuning of diuretics.”

The presentation drew such applause that one chairperson described it as “close to a standing ovation.” The study was published simultaneously in The Lancet.
 

Aggregate evidence

Early clinical evidence of the benefits of remote monitoring with the CardioMEMS-HF system was provided by the CHAMPION trial, which included patients with New York Heart Association (NYHA) class III heart failure.

Results of the subsequent GUIDE-HF trial, which aimed to test a broader population of patients with NYHA class II–IV heart failure and either increased N-terminal-pro-B-type natriuretic peptide (NT-proBNP) concentrations or hospitalization, were inconclusive.

However, a pre–COVID-19 impact analysis of GUIDE-HF indicated a possible benefit, which was primarily driven by a lower HF hospitalization rate, compared with the control group. That finding was the basis for an expanded indication for the system from the U.S. Food and Drug Administration.

The 2022 FDA indication permits the use of CardioMEMS for patients with NYHA class II HF and for those with worsening HF, as assessed by elevated natriuretic peptide levels.
 

From United States to Europe

Aware that most CardioMEMS data came from U.S. trials, the investigators embarked on the current trial, MONITOR-HF, an open-label, randomized trial in 25 centers in the Netherlands. Eligible patients had chronic NYHA class III HF, irrespective of ejection fraction, and had previously undergone hospitalization for HF.

A total of 348 patients were randomly assigned to either CardioMEMS-HF or standard of care (SoC) between 2019 and 2022.The median age of the patients was 69 years, and the median ejection fraction was 30%.

All patients were scheduled to be seen by their clinician at 3 months, 6 months, and every 6 months thereafter for up to 48 months.

The primary endpoint was the mean difference in the Kansas City Cardiomyopathy Questionnaire (KCCQ) summary score at 12 months

That difference between groups was 7.13 (+7.05 in the CardioMEMS group and –0.08 in the SoC group).

In the responder analysis, the odds ratio of an improvement of at least 5 points in the KCCQ overall summary score was 1.69 in the CardioMEMS group vs. the SoC group; the OR of a deterioration of at least 5 points was 0.45.

Subgroup analyses showed no relevant heterogeneity in the treatment effect on total HF hospitalizations and, notably, no significant interaction in patients with an EF below 40% and an EF above 40%.

There was a significant reduction in the median NT-proBNP change from baseline only in the remote monitoring group (800 pg/mL) and a smaller, nonsignificant difference with SoC.

Both groups received highly appropriate background guideline–directed medical therapy throughout the study. There were no significant between-group differences at 12 months.

Freedom from device-related or system-related complications and sensor failure were 97.7% and 98.8%, respectively.

Two sensor failures occurred during a mean follow-up 1.8 years. The percentage of failures was comparable to CHAMPION and GUIDE-HF trials.

The trial was not powered to assess a mortality benefit.
 

Pick the right patients

“As in the U.S. trials, there will be side effects, so select the right patients, because [remote monitoring] is not without risk,” Dr. Brugts told meeting attendees.

That point also was made by Christiane E. Angermann of University and University Hospital Würzburg, Germany, in a related editorial in The Lancet.

“To reproduce these results on a large scale in real-life health care, diligent patient selection should identify those at high risk of heart failure–related hospitalization who agree with the concept of daily data collection and are able and motivated to comply with treatment recommendations even if asymptomatic,” Dr. Angermann writes.

“Without direct interaction between health care providers and patients, and timely treatment modification triggered by abnormal monitoring results, the care cycle might break and the potential benefits from early detection of decompensation would be lost.”

Val Rakita, MD, assistant professor of medicine at Temple University, Philadelphia, a specialist in advanced heart failure and main implanter of the CardioMEMS device at Temple University Hospital, commented on the study for this article.

“This study confirms the previous data that the device is very safe and effective in preventing HF hospitalizations and improving patients’ quality of life, even in a different population with more modern background guideline-directed medical therapy.”

Nevertheless, he noted, “Studies have yet to confirm a mortality benefit, despite logic telling us that preventing heart failure hospitalizations should also improve patient survival. More studies are needed to see if a survival benefit can be proven over a longer follow-up period.”

Overall, he said, “Remote monitoring allows more precise management of medications, prevention of hospitalizations, and improvement in quality of life, and I am an advocate for it in my practice.”

Not everyone is an advocate, however. In a commentary published last year, John M. Mandrola, MD, a cardiac electrophysiologist at Baptist Medical Associates in Louisville, Ky., said the expanded FDA indication for the device is the result of “dubious trial analysis, spin, lax regulation, and the growth of low-value care.”

Others also have questioned the device’s value in the clinic.

But at least for now, as Dr. Angermann writes, “Scientific evidence supports the use of the CardioMEMS-HF system to enhance remote patient management in heart failure care. For more widespread application, technological advancements are desirable to provide more comfort for patients and reusable external device components, thereby improving care experience and saving resources.”

The MONITOR-HF trial is funded by the Dutch Ministry of Health and Health Care institute. Dr. Brugts has an independent research grant from Abbott (investigator-sponsored study) and has had speaker engagements or has participated in advisory boards for Abbott and other pharmaceutical companies. Dr. Angermann has received personal fees from Abbott for serving as chair of the steering committee for the CardioMEMS European Monitoring Study for Heart Failure (MEMS-HF) and consulting fees, honoraria, and travel costs from Abbott. Dr. Rakita has disclosed no relevant financial relationships.

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