Heart Failure

A new review article highlights approaches for mechanical circulatory support in patients with high-risk acute pulmonary embolism (PE). Mechanical support has become an important treatment option for refractory shock resulting from acute right ventricular failure (RVF).

Pulmonary embolism with hemodynamic significance is widely underdiagnosed, and the mortality rate can be as high as 30%, but new therapeutic developments offer promise. “Over the past few years, a renewed interest in mechanical circulatory support (MCS; both percutaneous and surgical) for acute RVF has emerged, increasing viable treatment options for high-risk acute PE,” wrote the authors of the review, which was published online in Interventional Cardiology Clinics.

Poor outcomes are often driven by RVF, which is tricky to diagnose and manage, and it stems from a sudden increase in pulmonary vascular resistance (PVR) following PE. “The mechanism for increased PVR in acute PE is multifactorial, including direct blood flow impedance, local hypoxia-induced vasoconstriction, and platelet/thrombin-induced release of vasoactive peptides. The cascade of events that then leads to RVF includes decreased RV stoke volume, increased RV wall tension, and RV dilation,” the authors wrote.

The authors noted that diuretics help to correct changes to RV geometry and can improve left ventricle filling, which improves hemodynamics. Diuretics can be used in patients who are hypotensive and volume overloaded, but vasopressors should be employed to support blood pressure.

When using mechanical ventilation, strategies such as low tidal volumes, minimization of positive end expiratory pressure, and prevention of hypoxemia and acidemia should be employed to prevent an increase of pulmonary vascular resistance, which can worsen RV failure.

Pulmonary vasodilators aren’t recommended for acute PE, but inhaled pulmonary vasodilators may be considered in hemodynamically unstable patients.

Surgically implanted right ventricle assistance device are generally not used for acute RV failure in high-risk PE, unless the patient has not improved after medical management.
 

Percutaneous devices

Percutaneous mechanical circulatory support devices can be used for patients experiencing refractory shock. The review highlighted three such devices, including the Impella RP, tandem-heart right ventricular assist devices (TH-RVAD) or Protek Duo, and venoarterial extracorporeal membrane oxygenation (VA-ECMO), but they are not without limitations. “Challenges to using these devices in patients with acute PE include clot dislodgement, vascular complications, infections, device migration, and fracture of individual elements,” the authors wrote.

The Impella RP is easy to deploy and bypasses the RV, but it can’t provide blood oxygenation and may cause bleeding or hemolysis. TH-RVAD oxygenates the blood and bypasses the RV, but suffers from a large sheath size. VA-ECMO oxygenates the blood but may cause bleeding.

There are important differences among the mechanical support devices, according to Jonathan Ludmir, MD, who was asked to comment. “In reality, if someone has a large pulmonary embolism burden, to put in the Impella RP or the Protek Duo would be a little bit risky, because you’d be sometimes putting the device right where the clot is. At least what we do in our institution, when someone is in extremis despite using [intravenous] medications like vasopressors or inotropes, VA-ECMO is kind of the go to. This is both the quickest and probably most effective way to support the patient. I say the quickest because this is a procedure you can do at the bedside.”
 

Benefits of PERT

One message that the review only briefly mentions, but Dr. Ludmir believes is key, is employing a pulmonary embolism response team. “That’s been looked at extensively, and it’s a really key part of any decision-making. If someone presents to the emergency room or someone inside the hospital has an acute pulmonary embolism, you have a team of people that can respond and help assess the next step. Typically, that involves a cardiologist or an interventional cardiologist, a hematologist, vascular surgeon, often a cardiac surgeon, so it’s a whole slew of people. Based on the patient assessment they can quickly decide, can this patient just be okay with a blood thinner like heparin? Does this patient need something more aggressive, like a thrombectomy? Or is this a serious case where you involve the shock team or the ECMO team, and you have to stabilize the patient on mechanical circulatory support, so you can accomplish what you need to do to get rid of the pulmonary embolism,” said Dr. Ludmir, who is an assistant professor of medicine at Corrigan Minehan Heart Center at Massachusetts General Hospital and Harvard Medical School, both in Boston.

“Every case is individualized, hence the importance of having a team of a variety of different backgrounds and thoughts to approach it. And I think that’s kind of like the key takeaway. Yes, you have to be familiar with all the therapies, but at the end of the day, not every patient is going to fit into the algorithm for how you approach pulmonary embolism,” said Dr. Ludmir.

Dr. Ludmir has no relevant conflicts of interest.

A new review article highlights approaches for mechanical circulatory support in patients with high-risk acute pulmonary embolism (PE). Mechanical support has become an important treatment option for refractory shock resulting from acute right ventricular failure (RVF).

Pulmonary embolism with hemodynamic significance is widely underdiagnosed, and the mortality rate can be as high as 30%, but new therapeutic developments offer promise. “Over the past few years, a renewed interest in mechanical circulatory support (MCS; both percutaneous and surgical) for acute RVF has emerged, increasing viable treatment options for high-risk acute PE,” wrote the authors of the review, which was published online in Interventional Cardiology Clinics.

Poor outcomes are often driven by RVF, which is tricky to diagnose and manage, and it stems from a sudden increase in pulmonary vascular resistance (PVR) following PE. “The mechanism for increased PVR in acute PE is multifactorial, including direct blood flow impedance, local hypoxia-induced vasoconstriction, and platelet/thrombin-induced release of vasoactive peptides. The cascade of events that then leads to RVF includes decreased RV stoke volume, increased RV wall tension, and RV dilation,” the authors wrote.

The authors noted that diuretics help to correct changes to RV geometry and can improve left ventricle filling, which improves hemodynamics. Diuretics can be used in patients who are hypotensive and volume overloaded, but vasopressors should be employed to support blood pressure.

When using mechanical ventilation, strategies such as low tidal volumes, minimization of positive end expiratory pressure, and prevention of hypoxemia and acidemia should be employed to prevent an increase of pulmonary vascular resistance, which can worsen RV failure.

Pulmonary vasodilators aren’t recommended for acute PE, but inhaled pulmonary vasodilators may be considered in hemodynamically unstable patients.

Surgically implanted right ventricle assistance device are generally not used for acute RV failure in high-risk PE, unless the patient has not improved after medical management.
 

Percutaneous devices

Percutaneous mechanical circulatory support devices can be used for patients experiencing refractory shock. The review highlighted three such devices, including the Impella RP, tandem-heart right ventricular assist devices (TH-RVAD) or Protek Duo, and venoarterial extracorporeal membrane oxygenation (VA-ECMO), but they are not without limitations. “Challenges to using these devices in patients with acute PE include clot dislodgement, vascular complications, infections, device migration, and fracture of individual elements,” the authors wrote.

The Impella RP is easy to deploy and bypasses the RV, but it can’t provide blood oxygenation and may cause bleeding or hemolysis. TH-RVAD oxygenates the blood and bypasses the RV, but suffers from a large sheath size. VA-ECMO oxygenates the blood but may cause bleeding.

There are important differences among the mechanical support devices, according to Jonathan Ludmir, MD, who was asked to comment. “In reality, if someone has a large pulmonary embolism burden, to put in the Impella RP or the Protek Duo would be a little bit risky, because you’d be sometimes putting the device right where the clot is. At least what we do in our institution, when someone is in extremis despite using [intravenous] medications like vasopressors or inotropes, VA-ECMO is kind of the go to. This is both the quickest and probably most effective way to support the patient. I say the quickest because this is a procedure you can do at the bedside.”
 

Benefits of PERT

One message that the review only briefly mentions, but Dr. Ludmir believes is key, is employing a pulmonary embolism response team. “That’s been looked at extensively, and it’s a really key part of any decision-making. If someone presents to the emergency room or someone inside the hospital has an acute pulmonary embolism, you have a team of people that can respond and help assess the next step. Typically, that involves a cardiologist or an interventional cardiologist, a hematologist, vascular surgeon, often a cardiac surgeon, so it’s a whole slew of people. Based on the patient assessment they can quickly decide, can this patient just be okay with a blood thinner like heparin? Does this patient need something more aggressive, like a thrombectomy? Or is this a serious case where you involve the shock team or the ECMO team, and you have to stabilize the patient on mechanical circulatory support, so you can accomplish what you need to do to get rid of the pulmonary embolism,” said Dr. Ludmir, who is an assistant professor of medicine at Corrigan Minehan Heart Center at Massachusetts General Hospital and Harvard Medical School, both in Boston.

“Every case is individualized, hence the importance of having a team of a variety of different backgrounds and thoughts to approach it. And I think that’s kind of like the key takeaway. Yes, you have to be familiar with all the therapies, but at the end of the day, not every patient is going to fit into the algorithm for how you approach pulmonary embolism,” said Dr. Ludmir.

Dr. Ludmir has no relevant conflicts of interest.

A new review article highlights approaches for mechanical circulatory support in patients with high-risk acute pulmonary embolism (PE). Mechanical support has become an important treatment option for refractory shock resulting from acute right ventricular failure (RVF).

Pulmonary embolism with hemodynamic significance is widely underdiagnosed, and the mortality rate can be as high as 30%, but new therapeutic developments offer promise. “Over the past few years, a renewed interest in mechanical circulatory support (MCS; both percutaneous and surgical) for acute RVF has emerged, increasing viable treatment options for high-risk acute PE,” wrote the authors of the review, which was published online in Interventional Cardiology Clinics.

Poor outcomes are often driven by RVF, which is tricky to diagnose and manage, and it stems from a sudden increase in pulmonary vascular resistance (PVR) following PE. “The mechanism for increased PVR in acute PE is multifactorial, including direct blood flow impedance, local hypoxia-induced vasoconstriction, and platelet/thrombin-induced release of vasoactive peptides. The cascade of events that then leads to RVF includes decreased RV stoke volume, increased RV wall tension, and RV dilation,” the authors wrote.

The authors noted that diuretics help to correct changes to RV geometry and can improve left ventricle filling, which improves hemodynamics. Diuretics can be used in patients who are hypotensive and volume overloaded, but vasopressors should be employed to support blood pressure.

When using mechanical ventilation, strategies such as low tidal volumes, minimization of positive end expiratory pressure, and prevention of hypoxemia and acidemia should be employed to prevent an increase of pulmonary vascular resistance, which can worsen RV failure.

Pulmonary vasodilators aren’t recommended for acute PE, but inhaled pulmonary vasodilators may be considered in hemodynamically unstable patients.

Surgically implanted right ventricle assistance device are generally not used for acute RV failure in high-risk PE, unless the patient has not improved after medical management.
 

Percutaneous devices

Percutaneous mechanical circulatory support devices can be used for patients experiencing refractory shock. The review highlighted three such devices, including the Impella RP, tandem-heart right ventricular assist devices (TH-RVAD) or Protek Duo, and venoarterial extracorporeal membrane oxygenation (VA-ECMO), but they are not without limitations. “Challenges to using these devices in patients with acute PE include clot dislodgement, vascular complications, infections, device migration, and fracture of individual elements,” the authors wrote.

The Impella RP is easy to deploy and bypasses the RV, but it can’t provide blood oxygenation and may cause bleeding or hemolysis. TH-RVAD oxygenates the blood and bypasses the RV, but suffers from a large sheath size. VA-ECMO oxygenates the blood but may cause bleeding.

There are important differences among the mechanical support devices, according to Jonathan Ludmir, MD, who was asked to comment. “In reality, if someone has a large pulmonary embolism burden, to put in the Impella RP or the Protek Duo would be a little bit risky, because you’d be sometimes putting the device right where the clot is. At least what we do in our institution, when someone is in extremis despite using [intravenous] medications like vasopressors or inotropes, VA-ECMO is kind of the go to. This is both the quickest and probably most effective way to support the patient. I say the quickest because this is a procedure you can do at the bedside.”
 

Benefits of PERT

One message that the review only briefly mentions, but Dr. Ludmir believes is key, is employing a pulmonary embolism response team. “That’s been looked at extensively, and it’s a really key part of any decision-making. If someone presents to the emergency room or someone inside the hospital has an acute pulmonary embolism, you have a team of people that can respond and help assess the next step. Typically, that involves a cardiologist or an interventional cardiologist, a hematologist, vascular surgeon, often a cardiac surgeon, so it’s a whole slew of people. Based on the patient assessment they can quickly decide, can this patient just be okay with a blood thinner like heparin? Does this patient need something more aggressive, like a thrombectomy? Or is this a serious case where you involve the shock team or the ECMO team, and you have to stabilize the patient on mechanical circulatory support, so you can accomplish what you need to do to get rid of the pulmonary embolism,” said Dr. Ludmir, who is an assistant professor of medicine at Corrigan Minehan Heart Center at Massachusetts General Hospital and Harvard Medical School, both in Boston.

“Every case is individualized, hence the importance of having a team of a variety of different backgrounds and thoughts to approach it. And I think that’s kind of like the key takeaway. Yes, you have to be familiar with all the therapies, but at the end of the day, not every patient is going to fit into the algorithm for how you approach pulmonary embolism,” said Dr. Ludmir.

Dr. Ludmir has no relevant conflicts of interest.

Patients with an ejection fraction (EF) greater than 40% who were stabilized after recent worsening or de novo heart failure (HF) had a greater reduction in natriuretic peptides and less worsening renal function, but a higher rate of hypotension over 8 weeks with sacubitril-valsartan (Entresto) versus valsartan (Diovan) in the PARAGLIDE-HF trial.

A subgroup analysis showed evidence of a larger treatment effect among those with an EF of 60% or less, said Robert Mentz, MD, of the Duke Clinical Research Institute, Durham, N.C.

Dr. Mentz presented the findings at the Heart Failure Association of the European Society of Cardiology (HFA-ESC) scientific sessions. The study was also published online simultaneously in the Journal of the American College of Cardiology.

“Next steps will involve further assessment of the cardiovascular and renal benefits, as well as further exploration of the symptomatic hypotension that we observed,” Dr. Mentz said in an interview.

Meanwhile, he said, “clinicians should be aware of these new data – specifically, the incremental reduction in natriuretic peptide level, compared with valsartan, and potential benefits on cardiovascular and renal events,” particularly in those with an EF greater than 40% to 60% or less.
 

Larger benefit for EF > 40% to < 60%

PARAGLIDE-HF was a double-blind, randomized controlled trial with 466 patients with EF greater than 40% enrolled within 30 days of a worsening HF event. The median age was 71 years, 52% were women, and 22% were Black.

The trial was a follow-up to PARAGON-HF, which had shown that, in patients with an EF of at least 45%, sacubitril-valsartan did not result in a significantly lower rate of total hospitalizations for HF or death from cardiovascular causes, compared with valsartan.

The primary endpoint for PARAGLIDE was the time-averaged proportional change in N-terminal of the prohormone brain natriuretic peptide (NT-proBNP) from baseline through weeks 4 and 8, as in the PIONEER-HF trial. That trial showed that among patients hospitalized for acute decompensated HF with reduced EF (< 40%), the angiotensin receptor/neprilysin inhibitor (ARNI) led to a greater reduction in NT-proBNP concentration than the angiotensin receptor blocker (ARB).

Similarly, for PARAGLIDE, the time-averaged reduction in NT-proBNP was greater with sacubitril-valsartan, with a change ratio of 0.85 (15% greater reduction).

A secondary hierarchical outcome for PARAGLIDE, using the win ratio, consisted of time to cardiovascular death, number and timing of HF hospitalizations, number and timing of urgent HF visits, and time-averaged proportional change in NT-proBNP from baseline to weeks 4 and 8.

The hierarchical outcome favored sacubitril-valsartan, but was not significant (unmatched win ratio, 1.19).

As noted, sacubitril-valsartan reduced worsening renal function, compared with valsartan (odds ratio, 0.61), but increased symptomatic hypotension (OR, 1.73).

“We will work to better characterize the hypotension events that were observed to help identify those patients at greater risk and to provide further clarity around the timing and implications of these events,” Dr. Mentz said in an interview.

The team hypothesized that such events may be prevented by optimizing volume status and background therapies commonly used to treat hypertension in these patients.

“For instance,” Dr. Mentz suggested, “calcium channel blockers like amlodipine could be dose reduced or discontinued in patients with lower baseline blood pressures to better support sacubitril/valsartan initiation and titration.”

He highlighted the subgroup analysis showing evidence of a larger treatment effect in study patients with an EF of 60% or less for the NT-proBNP change (0.78) and the hierarchical outcome (win ratio, 1.46). 

“These data may influence future guidance for sacubitril-valsartan in HF with EF greater than 40%, regardless of HF chronicity [acute or chronic vs. de novo] and treatment setting [hospital vs. clinic],” Dr. Mentz concluded.
 

Data ‘far from conclusive’

In a comment, Sean Pinney, MD, chief of cardiology at Mount Sinai Morningside, New York, said that the study results “help expand the current evidence base supporting the use of an ARNI in patients” with an EF greater than 40% up to 60%, and “provide confidence that ARNIs help to lower natriuretic peptides.

“It comes as little surprise that not everyone was able to tolerate these medications due to intolerable side effects like dizziness or hypotension,” he said.

Nevertheless, he added, “hopefully, these trial data help strengthen clinicians’ resolve to prescribe sacubitril/valsartan to a growing population of vulnerable patients.”

In a related editorial, Hector O. Ventura, MD, of the Ochsner Clinical School–University of Queensland, New Orleans, and colleagues express several concerns about the study.

Although the trial achieved significance for the primary endpoint, the margin of benefit was less than expected and the magnitude of the NT-proBNP reduction may not have been enough to reach the threshold for clinical benefit, they wrote.

Diuretic dosing in the two groups was not reported, and between-group differences may have contributed to both the differential NT-proBNP reduction and the rates of hypotension.

Furthermore, the sacubitril-valsartan group had a higher proportion of missing NT-proBNP data, which may have biased the results.

“In aggregate,” they wrote, “while the study suggests some evidence of a beneficial trend of sacubitril-valsartan in HFpEF and a recent episode of worsening HF, the data are far from conclusive.”

“Clinicians who elect to use sacubitril-valsartan in this population should be mindful of the risk for hypotension and select patients carefully, while providing close ambulatory follow up to ensure stability and adherence,” they noted.

“This important trial provides some wins that support selective use of sacubitril-valsartan in HFpEF [as well as] observed losses, which too may help to define better implementation strategies in appropriately selected patients,” the editorialists concluded.

The study was funded by Novartis. Dr. Mentz and other coauthors have received fees from Novartis. Dr. Pinney, Dr. Ventura, and the other editorialists disclosed no relevant financial relationships.

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

Patients with an ejection fraction (EF) greater than 40% who were stabilized after recent worsening or de novo heart failure (HF) had a greater reduction in natriuretic peptides and less worsening renal function, but a higher rate of hypotension over 8 weeks with sacubitril-valsartan (Entresto) versus valsartan (Diovan) in the PARAGLIDE-HF trial.

A subgroup analysis showed evidence of a larger treatment effect among those with an EF of 60% or less, said Robert Mentz, MD, of the Duke Clinical Research Institute, Durham, N.C.

Dr. Mentz presented the findings at the Heart Failure Association of the European Society of Cardiology (HFA-ESC) scientific sessions. The study was also published online simultaneously in the Journal of the American College of Cardiology.

“Next steps will involve further assessment of the cardiovascular and renal benefits, as well as further exploration of the symptomatic hypotension that we observed,” Dr. Mentz said in an interview.

Meanwhile, he said, “clinicians should be aware of these new data – specifically, the incremental reduction in natriuretic peptide level, compared with valsartan, and potential benefits on cardiovascular and renal events,” particularly in those with an EF greater than 40% to 60% or less.
 

Larger benefit for EF > 40% to < 60%

PARAGLIDE-HF was a double-blind, randomized controlled trial with 466 patients with EF greater than 40% enrolled within 30 days of a worsening HF event. The median age was 71 years, 52% were women, and 22% were Black.

The trial was a follow-up to PARAGON-HF, which had shown that, in patients with an EF of at least 45%, sacubitril-valsartan did not result in a significantly lower rate of total hospitalizations for HF or death from cardiovascular causes, compared with valsartan.

The primary endpoint for PARAGLIDE was the time-averaged proportional change in N-terminal of the prohormone brain natriuretic peptide (NT-proBNP) from baseline through weeks 4 and 8, as in the PIONEER-HF trial. That trial showed that among patients hospitalized for acute decompensated HF with reduced EF (< 40%), the angiotensin receptor/neprilysin inhibitor (ARNI) led to a greater reduction in NT-proBNP concentration than the angiotensin receptor blocker (ARB).

Similarly, for PARAGLIDE, the time-averaged reduction in NT-proBNP was greater with sacubitril-valsartan, with a change ratio of 0.85 (15% greater reduction).

A secondary hierarchical outcome for PARAGLIDE, using the win ratio, consisted of time to cardiovascular death, number and timing of HF hospitalizations, number and timing of urgent HF visits, and time-averaged proportional change in NT-proBNP from baseline to weeks 4 and 8.

The hierarchical outcome favored sacubitril-valsartan, but was not significant (unmatched win ratio, 1.19).

As noted, sacubitril-valsartan reduced worsening renal function, compared with valsartan (odds ratio, 0.61), but increased symptomatic hypotension (OR, 1.73).

“We will work to better characterize the hypotension events that were observed to help identify those patients at greater risk and to provide further clarity around the timing and implications of these events,” Dr. Mentz said in an interview.

The team hypothesized that such events may be prevented by optimizing volume status and background therapies commonly used to treat hypertension in these patients.

“For instance,” Dr. Mentz suggested, “calcium channel blockers like amlodipine could be dose reduced or discontinued in patients with lower baseline blood pressures to better support sacubitril/valsartan initiation and titration.”

He highlighted the subgroup analysis showing evidence of a larger treatment effect in study patients with an EF of 60% or less for the NT-proBNP change (0.78) and the hierarchical outcome (win ratio, 1.46). 

“These data may influence future guidance for sacubitril-valsartan in HF with EF greater than 40%, regardless of HF chronicity [acute or chronic vs. de novo] and treatment setting [hospital vs. clinic],” Dr. Mentz concluded.
 

Data ‘far from conclusive’

In a comment, Sean Pinney, MD, chief of cardiology at Mount Sinai Morningside, New York, said that the study results “help expand the current evidence base supporting the use of an ARNI in patients” with an EF greater than 40% up to 60%, and “provide confidence that ARNIs help to lower natriuretic peptides.

“It comes as little surprise that not everyone was able to tolerate these medications due to intolerable side effects like dizziness or hypotension,” he said.

Nevertheless, he added, “hopefully, these trial data help strengthen clinicians’ resolve to prescribe sacubitril/valsartan to a growing population of vulnerable patients.”

In a related editorial, Hector O. Ventura, MD, of the Ochsner Clinical School–University of Queensland, New Orleans, and colleagues express several concerns about the study.

Although the trial achieved significance for the primary endpoint, the margin of benefit was less than expected and the magnitude of the NT-proBNP reduction may not have been enough to reach the threshold for clinical benefit, they wrote.

Diuretic dosing in the two groups was not reported, and between-group differences may have contributed to both the differential NT-proBNP reduction and the rates of hypotension.

Furthermore, the sacubitril-valsartan group had a higher proportion of missing NT-proBNP data, which may have biased the results.

“In aggregate,” they wrote, “while the study suggests some evidence of a beneficial trend of sacubitril-valsartan in HFpEF and a recent episode of worsening HF, the data are far from conclusive.”

“Clinicians who elect to use sacubitril-valsartan in this population should be mindful of the risk for hypotension and select patients carefully, while providing close ambulatory follow up to ensure stability and adherence,” they noted.

“This important trial provides some wins that support selective use of sacubitril-valsartan in HFpEF [as well as] observed losses, which too may help to define better implementation strategies in appropriately selected patients,” the editorialists concluded.

The study was funded by Novartis. Dr. Mentz and other coauthors have received fees from Novartis. Dr. Pinney, Dr. Ventura, and the other editorialists disclosed no relevant financial relationships.

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

Patients with an ejection fraction (EF) greater than 40% who were stabilized after recent worsening or de novo heart failure (HF) had a greater reduction in natriuretic peptides and less worsening renal function, but a higher rate of hypotension over 8 weeks with sacubitril-valsartan (Entresto) versus valsartan (Diovan) in the PARAGLIDE-HF trial.

A subgroup analysis showed evidence of a larger treatment effect among those with an EF of 60% or less, said Robert Mentz, MD, of the Duke Clinical Research Institute, Durham, N.C.

Dr. Mentz presented the findings at the Heart Failure Association of the European Society of Cardiology (HFA-ESC) scientific sessions. The study was also published online simultaneously in the Journal of the American College of Cardiology.

“Next steps will involve further assessment of the cardiovascular and renal benefits, as well as further exploration of the symptomatic hypotension that we observed,” Dr. Mentz said in an interview.

Meanwhile, he said, “clinicians should be aware of these new data – specifically, the incremental reduction in natriuretic peptide level, compared with valsartan, and potential benefits on cardiovascular and renal events,” particularly in those with an EF greater than 40% to 60% or less.
 

Larger benefit for EF > 40% to < 60%

PARAGLIDE-HF was a double-blind, randomized controlled trial with 466 patients with EF greater than 40% enrolled within 30 days of a worsening HF event. The median age was 71 years, 52% were women, and 22% were Black.

The trial was a follow-up to PARAGON-HF, which had shown that, in patients with an EF of at least 45%, sacubitril-valsartan did not result in a significantly lower rate of total hospitalizations for HF or death from cardiovascular causes, compared with valsartan.

The primary endpoint for PARAGLIDE was the time-averaged proportional change in N-terminal of the prohormone brain natriuretic peptide (NT-proBNP) from baseline through weeks 4 and 8, as in the PIONEER-HF trial. That trial showed that among patients hospitalized for acute decompensated HF with reduced EF (< 40%), the angiotensin receptor/neprilysin inhibitor (ARNI) led to a greater reduction in NT-proBNP concentration than the angiotensin receptor blocker (ARB).

Similarly, for PARAGLIDE, the time-averaged reduction in NT-proBNP was greater with sacubitril-valsartan, with a change ratio of 0.85 (15% greater reduction).

A secondary hierarchical outcome for PARAGLIDE, using the win ratio, consisted of time to cardiovascular death, number and timing of HF hospitalizations, number and timing of urgent HF visits, and time-averaged proportional change in NT-proBNP from baseline to weeks 4 and 8.

The hierarchical outcome favored sacubitril-valsartan, but was not significant (unmatched win ratio, 1.19).

As noted, sacubitril-valsartan reduced worsening renal function, compared with valsartan (odds ratio, 0.61), but increased symptomatic hypotension (OR, 1.73).

“We will work to better characterize the hypotension events that were observed to help identify those patients at greater risk and to provide further clarity around the timing and implications of these events,” Dr. Mentz said in an interview.

The team hypothesized that such events may be prevented by optimizing volume status and background therapies commonly used to treat hypertension in these patients.

“For instance,” Dr. Mentz suggested, “calcium channel blockers like amlodipine could be dose reduced or discontinued in patients with lower baseline blood pressures to better support sacubitril/valsartan initiation and titration.”

He highlighted the subgroup analysis showing evidence of a larger treatment effect in study patients with an EF of 60% or less for the NT-proBNP change (0.78) and the hierarchical outcome (win ratio, 1.46). 

“These data may influence future guidance for sacubitril-valsartan in HF with EF greater than 40%, regardless of HF chronicity [acute or chronic vs. de novo] and treatment setting [hospital vs. clinic],” Dr. Mentz concluded.
 

Data ‘far from conclusive’

In a comment, Sean Pinney, MD, chief of cardiology at Mount Sinai Morningside, New York, said that the study results “help expand the current evidence base supporting the use of an ARNI in patients” with an EF greater than 40% up to 60%, and “provide confidence that ARNIs help to lower natriuretic peptides.

“It comes as little surprise that not everyone was able to tolerate these medications due to intolerable side effects like dizziness or hypotension,” he said.

Nevertheless, he added, “hopefully, these trial data help strengthen clinicians’ resolve to prescribe sacubitril/valsartan to a growing population of vulnerable patients.”

In a related editorial, Hector O. Ventura, MD, of the Ochsner Clinical School–University of Queensland, New Orleans, and colleagues express several concerns about the study.

Although the trial achieved significance for the primary endpoint, the margin of benefit was less than expected and the magnitude of the NT-proBNP reduction may not have been enough to reach the threshold for clinical benefit, they wrote.

Diuretic dosing in the two groups was not reported, and between-group differences may have contributed to both the differential NT-proBNP reduction and the rates of hypotension.

Furthermore, the sacubitril-valsartan group had a higher proportion of missing NT-proBNP data, which may have biased the results.

“In aggregate,” they wrote, “while the study suggests some evidence of a beneficial trend of sacubitril-valsartan in HFpEF and a recent episode of worsening HF, the data are far from conclusive.”

“Clinicians who elect to use sacubitril-valsartan in this population should be mindful of the risk for hypotension and select patients carefully, while providing close ambulatory follow up to ensure stability and adherence,” they noted.

“This important trial provides some wins that support selective use of sacubitril-valsartan in HFpEF [as well as] observed losses, which too may help to define better implementation strategies in appropriately selected patients,” the editorialists concluded.

The study was funded by Novartis. Dr. Mentz and other coauthors have received fees from Novartis. Dr. Pinney, Dr. Ventura, and the other editorialists disclosed no relevant financial relationships.

A version of this article originally 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.

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.

A novel antibody, NI006 (Neurimmune), was safe for the treatment of transthyretin amyloid cardiomyopathy (ATTR-CM) in a phase 1 trial and appeared to reduce the amount of amyloid protein deposited in the heart, a new study suggests.

Currently, the only drug approved to treat ATTR is tafamidis, which improves survival and reduces hospitalizations, but does not reverse disease symptoms, the authors noted.

NI006 is a recombinant human anti-ATTR antibody given by infusion that was developed to trigger removal of ATTR by the body’s phagocytic immune cells.

Use of the drug was not associated with serious drug-related adverse events, though mild and moderate adverse events did occur.

Median N-terminal pro–B-type natriuretic peptide (NT-proBNP) and troponin T levels also seemed to be reduced over the study period.

Given the success of the antibody in this initial 40-patient trial, a larger phase-3 placebo-controlled trial is planned and expected to launch in the second half of 2023, said lead author Pablo Garcia-Pavia, MD, of Hospital Universitario Puerta de Hierro and the Spanish National Cardiovascular Research Institute, Madrid.

However, “The design of appropriate phase-3 trials to demonstrate efficacy of drugs for ATTR-CM is becoming more complicated and challenging,” he said.

“Increased awareness of the disease and advances in cardiac imaging techniques have led to recognition of a larger number of patients with ATTR-CM who have a different clinical profile and a different prognosis than the patients who were diagnosed in previous years and were enrolled in the initial trials of stabilizers,” Dr. Garcia-Pavia added.

“Moreover, the availability of tafamidis, and hopefully soon other medications to treat ATTR-CM has complicated the design of new clinical trials because of the heterogenicity of treatments that patients might receive,” he said. “Therefore, it is critical to plan the design very well.”

Dr. Garcia-Pavia presented the findings on NI006 at the Heart Failure Association of the European Society of Cardiology (HFA-ESC) 2023 sessions. The study was published simultaneously in the New England Journal of Medicine.
 

No serious adverse events

For the phase-1, double-blind, multicenter study, the investigators randomly assigned (2:1 ratio) 40 patients (median age, 72 years; 98% men) with wild-type or variant ATTR cardiomyopathy and chronic heart failure to receive IV infusions of either NI006, at one of six doses ranging from 0.3 mg/kg to 60 mg/kg of body weight, or placebo every 4 weeks for 4 months.

After the four infusions, participants were enrolled in an open-label extension phase in which they received eight NI006 infusions with stepwise increases in the dose.

Participants had a confirmed diagnosis of ATTR-CM; left ventricular wall thickness of at least 14 mm; left ventricular ejection fraction of at least 40%; New York Heart Association class I, II, or III; estimated glomerular filtration rate of more than 30 mL/min per 1.73 m²; and an NT-proBNP level of 600 to 6,000 pg/mL.

Most (36) were receiving tafamidis, with a median treatment duration of 7 months; other ATTR-specific drugs were not permitted. Patients randomly assigned to receive NI006 seemed to have more advanced disease compared with those assigned to placebo.

Adherence to the trial protocol was high: Thirty-four patients received the four scheduled infusions during the ascending-dose phase, and 34 of 35 patients who completed this phase subsequently enrolled in the open-label extension.

No apparent drug-related serious adverse events were reported. However, during the ascending-dose phase, 38 patients had at least one adverse event, most of which were mild or moderate; of the 191 total events, 124 were grade 1 and 60 were grade 2 (most commonly heart failure and arrhythmias). Three patients had cytokine release syndrome; all three completed treatment through the extension phase.

Musculoskeletal events increased with ascending doses of NI006, which led two patients to withdraw from the trial.

At doses of at least 10 mg/kg, cardiac tracer uptake on scintigraphy and extracellular volume on cardiac MRI, both of which are imaging-based surrogate markers of cardiac amyloid load, appeared to be reduced over 12 months.

Because NI006 stimulates the patient’s own immune system to eliminate cardiac amyloid fibrils, one session chair at the meeting wondered whether NI006 represented the “rise of immunology in cardiology,” and whether biologics might follow.

Another questioned how removing amyloid might affect cardiac function. The echocardiographic findings gathered so far don’t indicate dysfunction, “but this is a small trial, and we need more data,” Dr. Garcia-Pavia said.
 

Tempered excitement

In a comment, Ronald Witteles, MD, professor of cardiovascular medicine, Stanford (Calif.) University, and founder/codirector of the Stanford Amyloid Center, said that “antibody-based amyloid removal strategies are not currently clinically available and represent a fundamentally different mechanism to treat the disease from what we currently have.

“While the data are encouraging and will generate excitement for later-phase studies, we’re talking about small numbers of patients and nothing definitive should be drawn from this data,” said Dr. Witteles, deputy editor of JACC: CardioOncology.

“The biggest caveat is that similar approaches of antibody removal of amyloid deposits for other forms of amyloidosis — most notably AL amyloidosis (amyloid light chain or primary amyloidosis) – have failed in late-phase trials. Although there is reason to believe that ATTR amyloidosis may be more amenable to improvements with amyloid fibril removal than AL amyloidosis, the unimpressive results in other forms of amyloidosis still do temper the excitement to a degree.”

Like Dr. Garcia-Pavia, Dr. Witteles said, “Ultimately, we are going to need to see a phase 3 clinical trial which shows that NI006 – on top of standard-of-care treatment – improves hard outcomes in the disease. As treatment options likely expand in the coming years, that is likely to be a harder and harder bar to reach.”

Furthermore, although the safety profile was favorable overall, it “wasn’t entirely clean,” given cytokine release syndrome in three patients, a lowering of platelet counts in a couple of patients, and musculoskeletal side effects that triggered two to withdraw from the study. “Unless that changes,” he said, “that will be a barrier for some patients.”

Overall, he noted, “With the vast majority of patients being able to be diagnosed noninvasively, and with treatment options now available, we have seen a true explosion in the number of patients being diagnosed.

“But we also know that the large majority ... are still not getting diagnosed or are having huge delays in diagnosis. As such, the biggest thing we can do for patients with the disease is to continue to educate people about it,” Dr. Witteles concluded.

The study was funded by Neurimmune. Dr. Garcia-Pavia disclosed ties to Alexion, Alnylam Pharmaceuticals, AstraZeneca, Attralus, BridgeBio, General Electric, Intellia, Ionis Pharmaceuticals, Neurimmune, Novo Nordisk, and Pfizer. Dr. Witteles reported ties to Alexion, Alnylam, AstraZeneca, BridgeBio, Intellia, Ionis, Janssen, Novo Nordisk, and Pfizer.

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

A novel antibody, NI006 (Neurimmune), was safe for the treatment of transthyretin amyloid cardiomyopathy (ATTR-CM) in a phase 1 trial and appeared to reduce the amount of amyloid protein deposited in the heart, a new study suggests.

Currently, the only drug approved to treat ATTR is tafamidis, which improves survival and reduces hospitalizations, but does not reverse disease symptoms, the authors noted.

NI006 is a recombinant human anti-ATTR antibody given by infusion that was developed to trigger removal of ATTR by the body’s phagocytic immune cells.

Use of the drug was not associated with serious drug-related adverse events, though mild and moderate adverse events did occur.

Median N-terminal pro–B-type natriuretic peptide (NT-proBNP) and troponin T levels also seemed to be reduced over the study period.

Given the success of the antibody in this initial 40-patient trial, a larger phase-3 placebo-controlled trial is planned and expected to launch in the second half of 2023, said lead author Pablo Garcia-Pavia, MD, of Hospital Universitario Puerta de Hierro and the Spanish National Cardiovascular Research Institute, Madrid.

However, “The design of appropriate phase-3 trials to demonstrate efficacy of drugs for ATTR-CM is becoming more complicated and challenging,” he said.

“Increased awareness of the disease and advances in cardiac imaging techniques have led to recognition of a larger number of patients with ATTR-CM who have a different clinical profile and a different prognosis than the patients who were diagnosed in previous years and were enrolled in the initial trials of stabilizers,” Dr. Garcia-Pavia added.

“Moreover, the availability of tafamidis, and hopefully soon other medications to treat ATTR-CM has complicated the design of new clinical trials because of the heterogenicity of treatments that patients might receive,” he said. “Therefore, it is critical to plan the design very well.”

Dr. Garcia-Pavia presented the findings on NI006 at the Heart Failure Association of the European Society of Cardiology (HFA-ESC) 2023 sessions. The study was published simultaneously in the New England Journal of Medicine.
 

No serious adverse events

For the phase-1, double-blind, multicenter study, the investigators randomly assigned (2:1 ratio) 40 patients (median age, 72 years; 98% men) with wild-type or variant ATTR cardiomyopathy and chronic heart failure to receive IV infusions of either NI006, at one of six doses ranging from 0.3 mg/kg to 60 mg/kg of body weight, or placebo every 4 weeks for 4 months.

After the four infusions, participants were enrolled in an open-label extension phase in which they received eight NI006 infusions with stepwise increases in the dose.

Participants had a confirmed diagnosis of ATTR-CM; left ventricular wall thickness of at least 14 mm; left ventricular ejection fraction of at least 40%; New York Heart Association class I, II, or III; estimated glomerular filtration rate of more than 30 mL/min per 1.73 m²; and an NT-proBNP level of 600 to 6,000 pg/mL.

Most (36) were receiving tafamidis, with a median treatment duration of 7 months; other ATTR-specific drugs were not permitted. Patients randomly assigned to receive NI006 seemed to have more advanced disease compared with those assigned to placebo.

Adherence to the trial protocol was high: Thirty-four patients received the four scheduled infusions during the ascending-dose phase, and 34 of 35 patients who completed this phase subsequently enrolled in the open-label extension.

No apparent drug-related serious adverse events were reported. However, during the ascending-dose phase, 38 patients had at least one adverse event, most of which were mild or moderate; of the 191 total events, 124 were grade 1 and 60 were grade 2 (most commonly heart failure and arrhythmias). Three patients had cytokine release syndrome; all three completed treatment through the extension phase.

Musculoskeletal events increased with ascending doses of NI006, which led two patients to withdraw from the trial.

At doses of at least 10 mg/kg, cardiac tracer uptake on scintigraphy and extracellular volume on cardiac MRI, both of which are imaging-based surrogate markers of cardiac amyloid load, appeared to be reduced over 12 months.

Because NI006 stimulates the patient’s own immune system to eliminate cardiac amyloid fibrils, one session chair at the meeting wondered whether NI006 represented the “rise of immunology in cardiology,” and whether biologics might follow.

Another questioned how removing amyloid might affect cardiac function. The echocardiographic findings gathered so far don’t indicate dysfunction, “but this is a small trial, and we need more data,” Dr. Garcia-Pavia said.
 

Tempered excitement

In a comment, Ronald Witteles, MD, professor of cardiovascular medicine, Stanford (Calif.) University, and founder/codirector of the Stanford Amyloid Center, said that “antibody-based amyloid removal strategies are not currently clinically available and represent a fundamentally different mechanism to treat the disease from what we currently have.

“While the data are encouraging and will generate excitement for later-phase studies, we’re talking about small numbers of patients and nothing definitive should be drawn from this data,” said Dr. Witteles, deputy editor of JACC: CardioOncology.

“The biggest caveat is that similar approaches of antibody removal of amyloid deposits for other forms of amyloidosis — most notably AL amyloidosis (amyloid light chain or primary amyloidosis) – have failed in late-phase trials. Although there is reason to believe that ATTR amyloidosis may be more amenable to improvements with amyloid fibril removal than AL amyloidosis, the unimpressive results in other forms of amyloidosis still do temper the excitement to a degree.”

Like Dr. Garcia-Pavia, Dr. Witteles said, “Ultimately, we are going to need to see a phase 3 clinical trial which shows that NI006 – on top of standard-of-care treatment – improves hard outcomes in the disease. As treatment options likely expand in the coming years, that is likely to be a harder and harder bar to reach.”

Furthermore, although the safety profile was favorable overall, it “wasn’t entirely clean,” given cytokine release syndrome in three patients, a lowering of platelet counts in a couple of patients, and musculoskeletal side effects that triggered two to withdraw from the study. “Unless that changes,” he said, “that will be a barrier for some patients.”

Overall, he noted, “With the vast majority of patients being able to be diagnosed noninvasively, and with treatment options now available, we have seen a true explosion in the number of patients being diagnosed.

“But we also know that the large majority ... are still not getting diagnosed or are having huge delays in diagnosis. As such, the biggest thing we can do for patients with the disease is to continue to educate people about it,” Dr. Witteles concluded.

The study was funded by Neurimmune. Dr. Garcia-Pavia disclosed ties to Alexion, Alnylam Pharmaceuticals, AstraZeneca, Attralus, BridgeBio, General Electric, Intellia, Ionis Pharmaceuticals, Neurimmune, Novo Nordisk, and Pfizer. Dr. Witteles reported ties to Alexion, Alnylam, AstraZeneca, BridgeBio, Intellia, Ionis, Janssen, Novo Nordisk, and Pfizer.

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

A novel antibody, NI006 (Neurimmune), was safe for the treatment of transthyretin amyloid cardiomyopathy (ATTR-CM) in a phase 1 trial and appeared to reduce the amount of amyloid protein deposited in the heart, a new study suggests.

Currently, the only drug approved to treat ATTR is tafamidis, which improves survival and reduces hospitalizations, but does not reverse disease symptoms, the authors noted.

NI006 is a recombinant human anti-ATTR antibody given by infusion that was developed to trigger removal of ATTR by the body’s phagocytic immune cells.

Use of the drug was not associated with serious drug-related adverse events, though mild and moderate adverse events did occur.

Median N-terminal pro–B-type natriuretic peptide (NT-proBNP) and troponin T levels also seemed to be reduced over the study period.

Given the success of the antibody in this initial 40-patient trial, a larger phase-3 placebo-controlled trial is planned and expected to launch in the second half of 2023, said lead author Pablo Garcia-Pavia, MD, of Hospital Universitario Puerta de Hierro and the Spanish National Cardiovascular Research Institute, Madrid.

However, “The design of appropriate phase-3 trials to demonstrate efficacy of drugs for ATTR-CM is becoming more complicated and challenging,” he said.

“Increased awareness of the disease and advances in cardiac imaging techniques have led to recognition of a larger number of patients with ATTR-CM who have a different clinical profile and a different prognosis than the patients who were diagnosed in previous years and were enrolled in the initial trials of stabilizers,” Dr. Garcia-Pavia added.

“Moreover, the availability of tafamidis, and hopefully soon other medications to treat ATTR-CM has complicated the design of new clinical trials because of the heterogenicity of treatments that patients might receive,” he said. “Therefore, it is critical to plan the design very well.”

Dr. Garcia-Pavia presented the findings on NI006 at the Heart Failure Association of the European Society of Cardiology (HFA-ESC) 2023 sessions. The study was published simultaneously in the New England Journal of Medicine.
 

No serious adverse events

For the phase-1, double-blind, multicenter study, the investigators randomly assigned (2:1 ratio) 40 patients (median age, 72 years; 98% men) with wild-type or variant ATTR cardiomyopathy and chronic heart failure to receive IV infusions of either NI006, at one of six doses ranging from 0.3 mg/kg to 60 mg/kg of body weight, or placebo every 4 weeks for 4 months.

After the four infusions, participants were enrolled in an open-label extension phase in which they received eight NI006 infusions with stepwise increases in the dose.

Participants had a confirmed diagnosis of ATTR-CM; left ventricular wall thickness of at least 14 mm; left ventricular ejection fraction of at least 40%; New York Heart Association class I, II, or III; estimated glomerular filtration rate of more than 30 mL/min per 1.73 m²; and an NT-proBNP level of 600 to 6,000 pg/mL.

Most (36) were receiving tafamidis, with a median treatment duration of 7 months; other ATTR-specific drugs were not permitted. Patients randomly assigned to receive NI006 seemed to have more advanced disease compared with those assigned to placebo.

Adherence to the trial protocol was high: Thirty-four patients received the four scheduled infusions during the ascending-dose phase, and 34 of 35 patients who completed this phase subsequently enrolled in the open-label extension.

No apparent drug-related serious adverse events were reported. However, during the ascending-dose phase, 38 patients had at least one adverse event, most of which were mild or moderate; of the 191 total events, 124 were grade 1 and 60 were grade 2 (most commonly heart failure and arrhythmias). Three patients had cytokine release syndrome; all three completed treatment through the extension phase.

Musculoskeletal events increased with ascending doses of NI006, which led two patients to withdraw from the trial.

At doses of at least 10 mg/kg, cardiac tracer uptake on scintigraphy and extracellular volume on cardiac MRI, both of which are imaging-based surrogate markers of cardiac amyloid load, appeared to be reduced over 12 months.

Because NI006 stimulates the patient’s own immune system to eliminate cardiac amyloid fibrils, one session chair at the meeting wondered whether NI006 represented the “rise of immunology in cardiology,” and whether biologics might follow.

Another questioned how removing amyloid might affect cardiac function. The echocardiographic findings gathered so far don’t indicate dysfunction, “but this is a small trial, and we need more data,” Dr. Garcia-Pavia said.
 

Tempered excitement

In a comment, Ronald Witteles, MD, professor of cardiovascular medicine, Stanford (Calif.) University, and founder/codirector of the Stanford Amyloid Center, said that “antibody-based amyloid removal strategies are not currently clinically available and represent a fundamentally different mechanism to treat the disease from what we currently have.

“While the data are encouraging and will generate excitement for later-phase studies, we’re talking about small numbers of patients and nothing definitive should be drawn from this data,” said Dr. Witteles, deputy editor of JACC: CardioOncology.

“The biggest caveat is that similar approaches of antibody removal of amyloid deposits for other forms of amyloidosis — most notably AL amyloidosis (amyloid light chain or primary amyloidosis) – have failed in late-phase trials. Although there is reason to believe that ATTR amyloidosis may be more amenable to improvements with amyloid fibril removal than AL amyloidosis, the unimpressive results in other forms of amyloidosis still do temper the excitement to a degree.”

Like Dr. Garcia-Pavia, Dr. Witteles said, “Ultimately, we are going to need to see a phase 3 clinical trial which shows that NI006 – on top of standard-of-care treatment – improves hard outcomes in the disease. As treatment options likely expand in the coming years, that is likely to be a harder and harder bar to reach.”

Furthermore, although the safety profile was favorable overall, it “wasn’t entirely clean,” given cytokine release syndrome in three patients, a lowering of platelet counts in a couple of patients, and musculoskeletal side effects that triggered two to withdraw from the study. “Unless that changes,” he said, “that will be a barrier for some patients.”

Overall, he noted, “With the vast majority of patients being able to be diagnosed noninvasively, and with treatment options now available, we have seen a true explosion in the number of patients being diagnosed.

“But we also know that the large majority ... are still not getting diagnosed or are having huge delays in diagnosis. As such, the biggest thing we can do for patients with the disease is to continue to educate people about it,” Dr. Witteles concluded.

The study was funded by Neurimmune. Dr. Garcia-Pavia disclosed ties to Alexion, Alnylam Pharmaceuticals, AstraZeneca, Attralus, BridgeBio, General Electric, Intellia, Ionis Pharmaceuticals, Neurimmune, Novo Nordisk, and Pfizer. Dr. Witteles reported ties to Alexion, Alnylam, AstraZeneca, BridgeBio, Intellia, Ionis, Janssen, Novo Nordisk, and Pfizer.

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

New mechanisms underlying Takotsubo syndrome, often dubbed “broken heart syndrome,” are suggested from hemodynamic studies, which could lead to new treatment strategies for the condition.

Takotsubo syndrome is a form of acute heart failure that mimics acute coronary syndromes, with troponin elevation and symptoms including chest pain and dyspnea, but without a culprit lesion on coronary angiography.

However, echocardiography shows the heart to be massively enlarged. The condition was named by Japanese researchers as the shape of the left ventricle resembles the Takotsubo fishing pot used to trap octopi.

The condition affects mainly older women and accounts for about 6% of female patients presenting with acute coronary syndrome symptoms. In around two-thirds of cases there is a triggering stress event which can be physical, such as an acute disease, or emotional, such as an argument or the sudden death of someone close, hence the term “broken heart syndrome.” The emotional stress triggering the syndrome can also be positive such as a birthday party or the birth of a grandchild.

“The mechanisms involved in Takotsubo syndrome are unknown. Because there is often a stress trigger it is believed that sympathetic activation causes a surge of catecholamine release, but that is not fully understood,” lead author of the current study, Thomas Stiermaier, MD, University Heart Center Lübeck (Germany), explained in an interview.

“We wanted to look more closely at the hemodynamic effects in the hearts of patients with Takotsubo syndrome to see if we could identify novel mechanisms contributing to the condition,” he added.

The aptly named Optimized Characterization of Takotsubo Syndrome by Obtaining Pressure Volume Loops (OCTOPUS) study was published online in the Journal of the American College of Cardiology.

For the study, the researchers used a conductance catheter inserted into the left ventricle of the heart to analyze pressure-volume relationships in 24 consecutive patients with Takotsubo syndrome and a control population of 20 participants without cardiovascular disease.

These pressure-volume loops are “the gold standard for direct, real-time assessment of systolic and diastolic cardiac function independent of loading conditions,” and “provide in-depth information regarding ventricular-arterial coupling and cardiac energetics and efficiency,” the authors wrote.

“These parameters comprise a considerable amount of information on cardiac performance and help to advance our understanding of cardiac physiology and its pathophysiological role in various conditions,” they noted, adding that this is believed to be the first comprehensive hemodynamic analysis in patients with Takotsubo syndrome using such invasive tracing of pressure-volume loops.

Results showed that Takotsubo syndrome is associated with a severely impaired cardiac contractility and a shortened systolic period. In response, the heart compensates by increasing left ventricular end diastolic volume to preserve the stroke volume.

Diastolic function is characterized by prolonged active relaxation but unaltered passive elastic properties. The analysis of myocardial energetics revealed an inefficient system with increased potential and decreased kinetic energy (stroke work).

“These are new and important findings,” Dr. Stiermaier said, adding that these hemodynamic changes give clues as to the underlying mechanisms at play in Takotsubo syndrome, as well as possible treatment strategies that could be investigated.  

“Taking all this information together, we believe that it is likely that decreased phosphorylation of myofilament proteins – which may be caused by some kind of disturbance in calcium metabolism – may partially account for the impaired contractility and shortened systolic period seen in Takotsubo syndrome,” he commented.

The researchers suggested that Takotsubo syndrome may therefore be treated with medications such as omecamtiv (a drug that increases systolic duration) or the calcium sensitizer levosimendan, which improves contractility, possibly in combination with beta-blockers to protect against the intense adrenergic activation.

They noted that several studies have reported the use of levosimendan in Takotsubo syndrome and have suggested positive effects by accelerating recovery of ventricular function. But they added that prospective data are lacking, and, to their knowledge, omecamtiv has not been tested in Takotsubo syndrome.

“We need to clearly identify the mechanism involved in these changes at the cellular level, and then test these medications to see if they can help prevent or reverse the hemodynamic changes seen in Takotsubo syndrome,” Dr. Stiermaier said.

He explained that the contractile abnormalities in Takotsubo syndrome are transient and generally normalize after a few weeks or months, but while systolic function may appear normal in the long term there are other more subtle changes that can persist, and these patients have an increased rate of cardiovascular events, compared with the healthy population over the long term.

However, because Takotsubo syndrome patients generally have a high rate of other comorbidities, it is not known whether their increased event rate is caused by the syndrome or by these other comorbidities.

While some patients with Takotsubo syndrome have a mild disease course and a good prognosis, others have more complications, with around 10%-15% going on to develop severe disease with cardiogenic shock or pleural effusion, Dr. Stiermaier noted.

“These patients have a bad prognosis. Our aim is to try to identify the patients who are at high risk of these complications and treat them early to prevent cardiogenic shock and pleural effusion from developing,” he said. “We are hopeful that by identifying the hemodynamic changes occurring in Takotsubo syndrome we can figure out the mechanisms involved and give medications in the acute setting to prevent the complications that can arise down the road.”
 

Mechanisms ‘appealing but speculative’

In an editorial (J Am Coll Cardiol. 2023 May;81[20]:1992-5), Jorge Salamanca, MD, and Fernando Alfonso, MD, Hospital Universitario de La Princesa, Madrid, described this new study as “an important piece of research, providing a careful, systematic, and comprehensive set of sophisticated invasive hemodynamic data that shed new light on our understanding of this unique clinical entity.”

They said the researchers have provided “robust data on the acute hemodynamic behavior of the left ventricle in patients with Takotsubo syndrome that clearly advance the field but also raise new questions.”

But the editorialists cautioned that the hypotheses of the potential mechanisms linking a molecular basis for the metabolic dysregulation, resulting in increased potential energy coupled with a decreased kinetic energy, “are appealing but largely speculative.”

“Whether these hemodynamic findings could be the foundation and would support the use of novel and attractive drugs in Takotsubo syndrome, remains unsettled and can only be considered as hypothesis generating,” they wrote.

“Further studies are required to elucidate factors associated with a more severe hemodynamic derangement and to devise therapeutic strategies helping to rapidly restore an efficient left ventricular function in these challenging patients,” they concluded. 

The study authors and the editorialists reported no relevant financial relationships.

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

New mechanisms underlying Takotsubo syndrome, often dubbed “broken heart syndrome,” are suggested from hemodynamic studies, which could lead to new treatment strategies for the condition.

Takotsubo syndrome is a form of acute heart failure that mimics acute coronary syndromes, with troponin elevation and symptoms including chest pain and dyspnea, but without a culprit lesion on coronary angiography.

However, echocardiography shows the heart to be massively enlarged. The condition was named by Japanese researchers as the shape of the left ventricle resembles the Takotsubo fishing pot used to trap octopi.

The condition affects mainly older women and accounts for about 6% of female patients presenting with acute coronary syndrome symptoms. In around two-thirds of cases there is a triggering stress event which can be physical, such as an acute disease, or emotional, such as an argument or the sudden death of someone close, hence the term “broken heart syndrome.” The emotional stress triggering the syndrome can also be positive such as a birthday party or the birth of a grandchild.

“The mechanisms involved in Takotsubo syndrome are unknown. Because there is often a stress trigger it is believed that sympathetic activation causes a surge of catecholamine release, but that is not fully understood,” lead author of the current study, Thomas Stiermaier, MD, University Heart Center Lübeck (Germany), explained in an interview.

“We wanted to look more closely at the hemodynamic effects in the hearts of patients with Takotsubo syndrome to see if we could identify novel mechanisms contributing to the condition,” he added.

The aptly named Optimized Characterization of Takotsubo Syndrome by Obtaining Pressure Volume Loops (OCTOPUS) study was published online in the Journal of the American College of Cardiology.

For the study, the researchers used a conductance catheter inserted into the left ventricle of the heart to analyze pressure-volume relationships in 24 consecutive patients with Takotsubo syndrome and a control population of 20 participants without cardiovascular disease.

These pressure-volume loops are “the gold standard for direct, real-time assessment of systolic and diastolic cardiac function independent of loading conditions,” and “provide in-depth information regarding ventricular-arterial coupling and cardiac energetics and efficiency,” the authors wrote.

“These parameters comprise a considerable amount of information on cardiac performance and help to advance our understanding of cardiac physiology and its pathophysiological role in various conditions,” they noted, adding that this is believed to be the first comprehensive hemodynamic analysis in patients with Takotsubo syndrome using such invasive tracing of pressure-volume loops.

Results showed that Takotsubo syndrome is associated with a severely impaired cardiac contractility and a shortened systolic period. In response, the heart compensates by increasing left ventricular end diastolic volume to preserve the stroke volume.

Diastolic function is characterized by prolonged active relaxation but unaltered passive elastic properties. The analysis of myocardial energetics revealed an inefficient system with increased potential and decreased kinetic energy (stroke work).

“These are new and important findings,” Dr. Stiermaier said, adding that these hemodynamic changes give clues as to the underlying mechanisms at play in Takotsubo syndrome, as well as possible treatment strategies that could be investigated.  

“Taking all this information together, we believe that it is likely that decreased phosphorylation of myofilament proteins – which may be caused by some kind of disturbance in calcium metabolism – may partially account for the impaired contractility and shortened systolic period seen in Takotsubo syndrome,” he commented.

The researchers suggested that Takotsubo syndrome may therefore be treated with medications such as omecamtiv (a drug that increases systolic duration) or the calcium sensitizer levosimendan, which improves contractility, possibly in combination with beta-blockers to protect against the intense adrenergic activation.

They noted that several studies have reported the use of levosimendan in Takotsubo syndrome and have suggested positive effects by accelerating recovery of ventricular function. But they added that prospective data are lacking, and, to their knowledge, omecamtiv has not been tested in Takotsubo syndrome.

“We need to clearly identify the mechanism involved in these changes at the cellular level, and then test these medications to see if they can help prevent or reverse the hemodynamic changes seen in Takotsubo syndrome,” Dr. Stiermaier said.

He explained that the contractile abnormalities in Takotsubo syndrome are transient and generally normalize after a few weeks or months, but while systolic function may appear normal in the long term there are other more subtle changes that can persist, and these patients have an increased rate of cardiovascular events, compared with the healthy population over the long term.

However, because Takotsubo syndrome patients generally have a high rate of other comorbidities, it is not known whether their increased event rate is caused by the syndrome or by these other comorbidities.

While some patients with Takotsubo syndrome have a mild disease course and a good prognosis, others have more complications, with around 10%-15% going on to develop severe disease with cardiogenic shock or pleural effusion, Dr. Stiermaier noted.

“These patients have a bad prognosis. Our aim is to try to identify the patients who are at high risk of these complications and treat them early to prevent cardiogenic shock and pleural effusion from developing,” he said. “We are hopeful that by identifying the hemodynamic changes occurring in Takotsubo syndrome we can figure out the mechanisms involved and give medications in the acute setting to prevent the complications that can arise down the road.”
 

Mechanisms ‘appealing but speculative’

In an editorial (J Am Coll Cardiol. 2023 May;81[20]:1992-5), Jorge Salamanca, MD, and Fernando Alfonso, MD, Hospital Universitario de La Princesa, Madrid, described this new study as “an important piece of research, providing a careful, systematic, and comprehensive set of sophisticated invasive hemodynamic data that shed new light on our understanding of this unique clinical entity.”

They said the researchers have provided “robust data on the acute hemodynamic behavior of the left ventricle in patients with Takotsubo syndrome that clearly advance the field but also raise new questions.”

But the editorialists cautioned that the hypotheses of the potential mechanisms linking a molecular basis for the metabolic dysregulation, resulting in increased potential energy coupled with a decreased kinetic energy, “are appealing but largely speculative.”

“Whether these hemodynamic findings could be the foundation and would support the use of novel and attractive drugs in Takotsubo syndrome, remains unsettled and can only be considered as hypothesis generating,” they wrote.

“Further studies are required to elucidate factors associated with a more severe hemodynamic derangement and to devise therapeutic strategies helping to rapidly restore an efficient left ventricular function in these challenging patients,” they concluded. 

The study authors and the editorialists reported no relevant financial relationships.

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

New mechanisms underlying Takotsubo syndrome, often dubbed “broken heart syndrome,” are suggested from hemodynamic studies, which could lead to new treatment strategies for the condition.

Takotsubo syndrome is a form of acute heart failure that mimics acute coronary syndromes, with troponin elevation and symptoms including chest pain and dyspnea, but without a culprit lesion on coronary angiography.

However, echocardiography shows the heart to be massively enlarged. The condition was named by Japanese researchers as the shape of the left ventricle resembles the Takotsubo fishing pot used to trap octopi.

The condition affects mainly older women and accounts for about 6% of female patients presenting with acute coronary syndrome symptoms. In around two-thirds of cases there is a triggering stress event which can be physical, such as an acute disease, or emotional, such as an argument or the sudden death of someone close, hence the term “broken heart syndrome.” The emotional stress triggering the syndrome can also be positive such as a birthday party or the birth of a grandchild.

“The mechanisms involved in Takotsubo syndrome are unknown. Because there is often a stress trigger it is believed that sympathetic activation causes a surge of catecholamine release, but that is not fully understood,” lead author of the current study, Thomas Stiermaier, MD, University Heart Center Lübeck (Germany), explained in an interview.

“We wanted to look more closely at the hemodynamic effects in the hearts of patients with Takotsubo syndrome to see if we could identify novel mechanisms contributing to the condition,” he added.

The aptly named Optimized Characterization of Takotsubo Syndrome by Obtaining Pressure Volume Loops (OCTOPUS) study was published online in the Journal of the American College of Cardiology.

For the study, the researchers used a conductance catheter inserted into the left ventricle of the heart to analyze pressure-volume relationships in 24 consecutive patients with Takotsubo syndrome and a control population of 20 participants without cardiovascular disease.

These pressure-volume loops are “the gold standard for direct, real-time assessment of systolic and diastolic cardiac function independent of loading conditions,” and “provide in-depth information regarding ventricular-arterial coupling and cardiac energetics and efficiency,” the authors wrote.

“These parameters comprise a considerable amount of information on cardiac performance and help to advance our understanding of cardiac physiology and its pathophysiological role in various conditions,” they noted, adding that this is believed to be the first comprehensive hemodynamic analysis in patients with Takotsubo syndrome using such invasive tracing of pressure-volume loops.

Results showed that Takotsubo syndrome is associated with a severely impaired cardiac contractility and a shortened systolic period. In response, the heart compensates by increasing left ventricular end diastolic volume to preserve the stroke volume.

Diastolic function is characterized by prolonged active relaxation but unaltered passive elastic properties. The analysis of myocardial energetics revealed an inefficient system with increased potential and decreased kinetic energy (stroke work).

“These are new and important findings,” Dr. Stiermaier said, adding that these hemodynamic changes give clues as to the underlying mechanisms at play in Takotsubo syndrome, as well as possible treatment strategies that could be investigated.  

“Taking all this information together, we believe that it is likely that decreased phosphorylation of myofilament proteins – which may be caused by some kind of disturbance in calcium metabolism – may partially account for the impaired contractility and shortened systolic period seen in Takotsubo syndrome,” he commented.

The researchers suggested that Takotsubo syndrome may therefore be treated with medications such as omecamtiv (a drug that increases systolic duration) or the calcium sensitizer levosimendan, which improves contractility, possibly in combination with beta-blockers to protect against the intense adrenergic activation.

They noted that several studies have reported the use of levosimendan in Takotsubo syndrome and have suggested positive effects by accelerating recovery of ventricular function. But they added that prospective data are lacking, and, to their knowledge, omecamtiv has not been tested in Takotsubo syndrome.

“We need to clearly identify the mechanism involved in these changes at the cellular level, and then test these medications to see if they can help prevent or reverse the hemodynamic changes seen in Takotsubo syndrome,” Dr. Stiermaier said.

He explained that the contractile abnormalities in Takotsubo syndrome are transient and generally normalize after a few weeks or months, but while systolic function may appear normal in the long term there are other more subtle changes that can persist, and these patients have an increased rate of cardiovascular events, compared with the healthy population over the long term.

However, because Takotsubo syndrome patients generally have a high rate of other comorbidities, it is not known whether their increased event rate is caused by the syndrome or by these other comorbidities.

While some patients with Takotsubo syndrome have a mild disease course and a good prognosis, others have more complications, with around 10%-15% going on to develop severe disease with cardiogenic shock or pleural effusion, Dr. Stiermaier noted.

“These patients have a bad prognosis. Our aim is to try to identify the patients who are at high risk of these complications and treat them early to prevent cardiogenic shock and pleural effusion from developing,” he said. “We are hopeful that by identifying the hemodynamic changes occurring in Takotsubo syndrome we can figure out the mechanisms involved and give medications in the acute setting to prevent the complications that can arise down the road.”
 

Mechanisms ‘appealing but speculative’

In an editorial (J Am Coll Cardiol. 2023 May;81[20]:1992-5), Jorge Salamanca, MD, and Fernando Alfonso, MD, Hospital Universitario de La Princesa, Madrid, described this new study as “an important piece of research, providing a careful, systematic, and comprehensive set of sophisticated invasive hemodynamic data that shed new light on our understanding of this unique clinical entity.”

They said the researchers have provided “robust data on the acute hemodynamic behavior of the left ventricle in patients with Takotsubo syndrome that clearly advance the field but also raise new questions.”

But the editorialists cautioned that the hypotheses of the potential mechanisms linking a molecular basis for the metabolic dysregulation, resulting in increased potential energy coupled with a decreased kinetic energy, “are appealing but largely speculative.”

“Whether these hemodynamic findings could be the foundation and would support the use of novel and attractive drugs in Takotsubo syndrome, remains unsettled and can only be considered as hypothesis generating,” they wrote.

“Further studies are required to elucidate factors associated with a more severe hemodynamic derangement and to devise therapeutic strategies helping to rapidly restore an efficient left ventricular function in these challenging patients,” they concluded. 

The study authors and the editorialists reported no relevant financial relationships.

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

Women who experienced gestational hypertension or preeclampsia are at increased risk of developing nonischemic heart failure (HF) and especially ischemic HF over the next decade or two, an observational study suggests.

The risks were most pronounced, jumping more than sixfold in the case of ischemic HF, during the first 6 years after the pregnancy. They then receded to plateau at a lower, still significantly elevated level of risk that persisted even years later, in the analysis of women in a Swedish medical birth registry.

Jupiterimages/Thinkstock.com

The case-matching study compared women with no history of cardiovascular (CV) disease and a first successful pregnancy during which they either developed or did not experience gestational hypertension or preeclampsia.

It’s among the first studies to explore the impact of pregnancy-induced hypertensive disease on subsequent HF risk separately for both ischemic and nonischemic HF and to find that the severity of such risk differs for the two HF etiologies, according to a report published in JACC: Heart Failure.

The adjusted risk for any HF during a median of 13 years after the pregnancy rose 70% for those who had developed gestational hypertension or preeclampsia. Their risk of nonischemic HF went up 60%, and their risk of ischemic HF more than doubled.

Hypertensive disorders of pregnancy “are so much more than short-term disorders confined to the pregnancy period. They have long-term implications throughout a lifetime,” lead author Ängla Mantel, MD, PhD, said in an interview.

Obstetric history doesn’t figure into any formal HF risk scoring systems, observed Dr. Mantel of Karolinska Institutet, Stockholm. Still, women who develop gestational hypertension, preeclampsia, or other pregnancy complications “should be considered a high-risk population even after the pregnancy and monitored for cardiovascular risk factors regularly throughout life.”

In many studies, she said, “knowledge of women-specific risk factors for cardiovascular disease is poor among both clinicians and patients.” The current findings should help raise awareness about such obstetric risk factors for HF, “especially” in patients with HF with preserved ejection fraction (HFpEF), which isn’t closely related to a number of traditional CV risk factors.

Even though pregnancy complications such as gestational hypertension and preeclampsia don’t feature in risk calculators, “they are actually risk enhancers per the 2019 primary prevention guidelines,” Natalie A. Bello, MD, MPH, who was not involved in the current study, said in an interview.

“We’re working to educate physicians and cardiovascular team members to take a pregnancy history” for risk stratification of women in primary prevention,” said Dr. Bello, director of hypertension research at the Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles.

The current study, she said, “is an important step” for its finding that hypertensive disorders of pregnancy are associated separately with both ischemic and nonischemic HF.

She pointed out, however, that because the study excluded women with peripartum cardiomyopathy, a form of nonischemic HF, it may “underestimate the impact of hypertensive disorders on the short-term risk of nonischemic heart failure.” Women who had peripartum cardiomyopathy were excluded to avoid misclassification of other HF outcomes, the authors stated.

Also, Dr. Bello said, the study’s inclusion of patients with either gestational hypertension or preeclampsia may complicate its interpretation. Compared with the former condition, she said, preeclampsia “involves more inflammation and more endothelial dysfunction. It may cause a different impact on the heart and the vasculature.”

In the analysis, about 79,000 women with gestational hypertension or preeclampsia were identified among more than 1.4 million primiparous women who entered the Swedish Medical Birth Register over a period of about 30 years. They were matched with about 396,000 women in the registry who had normotensive pregnancies.

Excluded, besides women with peripartum cardiomyopathy, were women with a prepregnancy history of HF, hypertension, ischemic heart disease, atrial fibrillation, or valvular heart disease.

Hazard ratios (HRs) for HF, ischemic HF, and nonischemic HF were significantly elevated over among the women with gestational hypertension or preeclampsia compared to those with normotensive pregnancies:

• Any HF: HR, 1.70 (95% confidence interval [CI], 1.51-1.91)
• Nonischemic HF: HR, 1.60 (95% CI, 1.40-1.83)
• Ischemic HF: HR, 2.28 (95% CI, 1.74-2.98)

The analyses were adjusted for maternal age at delivery, year of delivery, prepregnancy comorbidities, maternal education level, smoking status, and body mass index.

Sharper risk increases were seen among women with gestational hypertension or preeclampsia who delivered prior to gestational week 34:

• Any HF: HR, 2.46 (95% CI, 1.82-3.32)
• Nonischemic HF: HR, 2.33 (95% CI, 1.65-3.31)
• Ischemic HF: HR, 3.64 (95% CI, 1.97-6.74)

Risks for HF developing within 6 years of pregnancy characterized by gestational hypertension or preeclampsia were far more pronounced for ischemic HF than for nonischemic HF:

• Any HF: HR, 2.09 (95% CI, 1.52-2.89)
• Nonischemic HF: HR, 1.86 (95% CI, 1.32-2.61)
• Ischemic HF: HR, 6.52 (95% CI, 2.00-12.34).

The study couldn’t directly explore potential mechanisms for the associations between pregnancy-induced hypertensive disorders and different forms of HF, but it may have provided clues, Dr. Mantel said.

The hypertensive disorders and ischemic HF appear to share risk factors that could lead to both conditions, she noted. Also, hypertension itself is a risk factor for ischemic heart disease.

In contrast, “the risk of nonischemic heart failure might be driven by other factors, such as the inflammatory profile, endothelial dysfunction, and cardiac remodeling induced by preeclampsia or gestational hypertension.”

Those disorders, moreover, are associated with cardiac structural changes that are also seen in HFpEF, Dr. Mantel said. And both HFpEF and preeclampsia are characterized by systemic inflammation and endothelial dysfunction.

“These pathophysiological similarities,” she proposed, “might explain the link between pregnancy-induced hypertensive disorder and HFpEF.”

The authors have disclosed no relevant financial relationships. Dr. Bello has received grants from the National Institutes of Health.
 

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

Women who experienced gestational hypertension or preeclampsia are at increased risk of developing nonischemic heart failure (HF) and especially ischemic HF over the next decade or two, an observational study suggests.

The risks were most pronounced, jumping more than sixfold in the case of ischemic HF, during the first 6 years after the pregnancy. They then receded to plateau at a lower, still significantly elevated level of risk that persisted even years later, in the analysis of women in a Swedish medical birth registry.

Jupiterimages/Thinkstock.com

The case-matching study compared women with no history of cardiovascular (CV) disease and a first successful pregnancy during which they either developed or did not experience gestational hypertension or preeclampsia.

It’s among the first studies to explore the impact of pregnancy-induced hypertensive disease on subsequent HF risk separately for both ischemic and nonischemic HF and to find that the severity of such risk differs for the two HF etiologies, according to a report published in JACC: Heart Failure.

The adjusted risk for any HF during a median of 13 years after the pregnancy rose 70% for those who had developed gestational hypertension or preeclampsia. Their risk of nonischemic HF went up 60%, and their risk of ischemic HF more than doubled.

Hypertensive disorders of pregnancy “are so much more than short-term disorders confined to the pregnancy period. They have long-term implications throughout a lifetime,” lead author Ängla Mantel, MD, PhD, said in an interview.

Obstetric history doesn’t figure into any formal HF risk scoring systems, observed Dr. Mantel of Karolinska Institutet, Stockholm. Still, women who develop gestational hypertension, preeclampsia, or other pregnancy complications “should be considered a high-risk population even after the pregnancy and monitored for cardiovascular risk factors regularly throughout life.”

In many studies, she said, “knowledge of women-specific risk factors for cardiovascular disease is poor among both clinicians and patients.” The current findings should help raise awareness about such obstetric risk factors for HF, “especially” in patients with HF with preserved ejection fraction (HFpEF), which isn’t closely related to a number of traditional CV risk factors.

Even though pregnancy complications such as gestational hypertension and preeclampsia don’t feature in risk calculators, “they are actually risk enhancers per the 2019 primary prevention guidelines,” Natalie A. Bello, MD, MPH, who was not involved in the current study, said in an interview.

“We’re working to educate physicians and cardiovascular team members to take a pregnancy history” for risk stratification of women in primary prevention,” said Dr. Bello, director of hypertension research at the Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles.

The current study, she said, “is an important step” for its finding that hypertensive disorders of pregnancy are associated separately with both ischemic and nonischemic HF.

She pointed out, however, that because the study excluded women with peripartum cardiomyopathy, a form of nonischemic HF, it may “underestimate the impact of hypertensive disorders on the short-term risk of nonischemic heart failure.” Women who had peripartum cardiomyopathy were excluded to avoid misclassification of other HF outcomes, the authors stated.

Also, Dr. Bello said, the study’s inclusion of patients with either gestational hypertension or preeclampsia may complicate its interpretation. Compared with the former condition, she said, preeclampsia “involves more inflammation and more endothelial dysfunction. It may cause a different impact on the heart and the vasculature.”

In the analysis, about 79,000 women with gestational hypertension or preeclampsia were identified among more than 1.4 million primiparous women who entered the Swedish Medical Birth Register over a period of about 30 years. They were matched with about 396,000 women in the registry who had normotensive pregnancies.

Excluded, besides women with peripartum cardiomyopathy, were women with a prepregnancy history of HF, hypertension, ischemic heart disease, atrial fibrillation, or valvular heart disease.

Hazard ratios (HRs) for HF, ischemic HF, and nonischemic HF were significantly elevated over among the women with gestational hypertension or preeclampsia compared to those with normotensive pregnancies:

• Any HF: HR, 1.70 (95% confidence interval [CI], 1.51-1.91)
• Nonischemic HF: HR, 1.60 (95% CI, 1.40-1.83)
• Ischemic HF: HR, 2.28 (95% CI, 1.74-2.98)

The analyses were adjusted for maternal age at delivery, year of delivery, prepregnancy comorbidities, maternal education level, smoking status, and body mass index.

Sharper risk increases were seen among women with gestational hypertension or preeclampsia who delivered prior to gestational week 34:

• Any HF: HR, 2.46 (95% CI, 1.82-3.32)
• Nonischemic HF: HR, 2.33 (95% CI, 1.65-3.31)
• Ischemic HF: HR, 3.64 (95% CI, 1.97-6.74)

Risks for HF developing within 6 years of pregnancy characterized by gestational hypertension or preeclampsia were far more pronounced for ischemic HF than for nonischemic HF:

• Any HF: HR, 2.09 (95% CI, 1.52-2.89)
• Nonischemic HF: HR, 1.86 (95% CI, 1.32-2.61)
• Ischemic HF: HR, 6.52 (95% CI, 2.00-12.34).

The study couldn’t directly explore potential mechanisms for the associations between pregnancy-induced hypertensive disorders and different forms of HF, but it may have provided clues, Dr. Mantel said.

The hypertensive disorders and ischemic HF appear to share risk factors that could lead to both conditions, she noted. Also, hypertension itself is a risk factor for ischemic heart disease.

In contrast, “the risk of nonischemic heart failure might be driven by other factors, such as the inflammatory profile, endothelial dysfunction, and cardiac remodeling induced by preeclampsia or gestational hypertension.”

Those disorders, moreover, are associated with cardiac structural changes that are also seen in HFpEF, Dr. Mantel said. And both HFpEF and preeclampsia are characterized by systemic inflammation and endothelial dysfunction.

“These pathophysiological similarities,” she proposed, “might explain the link between pregnancy-induced hypertensive disorder and HFpEF.”

The authors have disclosed no relevant financial relationships. Dr. Bello has received grants from the National Institutes of Health.
 

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

Women who experienced gestational hypertension or preeclampsia are at increased risk of developing nonischemic heart failure (HF) and especially ischemic HF over the next decade or two, an observational study suggests.

The risks were most pronounced, jumping more than sixfold in the case of ischemic HF, during the first 6 years after the pregnancy. They then receded to plateau at a lower, still significantly elevated level of risk that persisted even years later, in the analysis of women in a Swedish medical birth registry.

Jupiterimages/Thinkstock.com

The case-matching study compared women with no history of cardiovascular (CV) disease and a first successful pregnancy during which they either developed or did not experience gestational hypertension or preeclampsia.

It’s among the first studies to explore the impact of pregnancy-induced hypertensive disease on subsequent HF risk separately for both ischemic and nonischemic HF and to find that the severity of such risk differs for the two HF etiologies, according to a report published in JACC: Heart Failure.

The adjusted risk for any HF during a median of 13 years after the pregnancy rose 70% for those who had developed gestational hypertension or preeclampsia. Their risk of nonischemic HF went up 60%, and their risk of ischemic HF more than doubled.

Hypertensive disorders of pregnancy “are so much more than short-term disorders confined to the pregnancy period. They have long-term implications throughout a lifetime,” lead author Ängla Mantel, MD, PhD, said in an interview.

Obstetric history doesn’t figure into any formal HF risk scoring systems, observed Dr. Mantel of Karolinska Institutet, Stockholm. Still, women who develop gestational hypertension, preeclampsia, or other pregnancy complications “should be considered a high-risk population even after the pregnancy and monitored for cardiovascular risk factors regularly throughout life.”

In many studies, she said, “knowledge of women-specific risk factors for cardiovascular disease is poor among both clinicians and patients.” The current findings should help raise awareness about such obstetric risk factors for HF, “especially” in patients with HF with preserved ejection fraction (HFpEF), which isn’t closely related to a number of traditional CV risk factors.

Even though pregnancy complications such as gestational hypertension and preeclampsia don’t feature in risk calculators, “they are actually risk enhancers per the 2019 primary prevention guidelines,” Natalie A. Bello, MD, MPH, who was not involved in the current study, said in an interview.

“We’re working to educate physicians and cardiovascular team members to take a pregnancy history” for risk stratification of women in primary prevention,” said Dr. Bello, director of hypertension research at the Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles.

The current study, she said, “is an important step” for its finding that hypertensive disorders of pregnancy are associated separately with both ischemic and nonischemic HF.

She pointed out, however, that because the study excluded women with peripartum cardiomyopathy, a form of nonischemic HF, it may “underestimate the impact of hypertensive disorders on the short-term risk of nonischemic heart failure.” Women who had peripartum cardiomyopathy were excluded to avoid misclassification of other HF outcomes, the authors stated.

Also, Dr. Bello said, the study’s inclusion of patients with either gestational hypertension or preeclampsia may complicate its interpretation. Compared with the former condition, she said, preeclampsia “involves more inflammation and more endothelial dysfunction. It may cause a different impact on the heart and the vasculature.”

In the analysis, about 79,000 women with gestational hypertension or preeclampsia were identified among more than 1.4 million primiparous women who entered the Swedish Medical Birth Register over a period of about 30 years. They were matched with about 396,000 women in the registry who had normotensive pregnancies.

Excluded, besides women with peripartum cardiomyopathy, were women with a prepregnancy history of HF, hypertension, ischemic heart disease, atrial fibrillation, or valvular heart disease.

Hazard ratios (HRs) for HF, ischemic HF, and nonischemic HF were significantly elevated over among the women with gestational hypertension or preeclampsia compared to those with normotensive pregnancies:

• Any HF: HR, 1.70 (95% confidence interval [CI], 1.51-1.91)
• Nonischemic HF: HR, 1.60 (95% CI, 1.40-1.83)
• Ischemic HF: HR, 2.28 (95% CI, 1.74-2.98)

The analyses were adjusted for maternal age at delivery, year of delivery, prepregnancy comorbidities, maternal education level, smoking status, and body mass index.

Sharper risk increases were seen among women with gestational hypertension or preeclampsia who delivered prior to gestational week 34:

• Any HF: HR, 2.46 (95% CI, 1.82-3.32)
• Nonischemic HF: HR, 2.33 (95% CI, 1.65-3.31)
• Ischemic HF: HR, 3.64 (95% CI, 1.97-6.74)

Risks for HF developing within 6 years of pregnancy characterized by gestational hypertension or preeclampsia were far more pronounced for ischemic HF than for nonischemic HF:

• Any HF: HR, 2.09 (95% CI, 1.52-2.89)
• Nonischemic HF: HR, 1.86 (95% CI, 1.32-2.61)
• Ischemic HF: HR, 6.52 (95% CI, 2.00-12.34).

The study couldn’t directly explore potential mechanisms for the associations between pregnancy-induced hypertensive disorders and different forms of HF, but it may have provided clues, Dr. Mantel said.

The hypertensive disorders and ischemic HF appear to share risk factors that could lead to both conditions, she noted. Also, hypertension itself is a risk factor for ischemic heart disease.

In contrast, “the risk of nonischemic heart failure might be driven by other factors, such as the inflammatory profile, endothelial dysfunction, and cardiac remodeling induced by preeclampsia or gestational hypertension.”

Those disorders, moreover, are associated with cardiac structural changes that are also seen in HFpEF, Dr. Mantel said. And both HFpEF and preeclampsia are characterized by systemic inflammation and endothelial dysfunction.

“These pathophysiological similarities,” she proposed, “might explain the link between pregnancy-induced hypertensive disorder and HFpEF.”

The authors have disclosed no relevant financial relationships. Dr. Bello has received grants from the National Institutes of Health.
 

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

The Food and Drug Administration has expanded the indication of dapagliflozin (Farxiga, AstraZeneca) to include treatment of heart failure across the full spectrum of left ventricular ejection fraction (LVEF) – including HF with mildly reduced ejection fraction (HFmrEF) and with preserved ejection fraction (HFpEF).

The sodium-glucose cotransporter 2 (SGLT2) inhibitor was previously approved in the United States for adults with heart failure with reduced ejection fraction (HFrEF).

The expanded indication is based on data from the phase 3 DELIVER trial, which showed clear clinical benefits of the SGLT2 inhibitor for patients with HF regardless of left ventricular function.

In the trial, which included more than 6,200 patients, dapagliflozin led to a statistically significant and clinically meaningful early reduction in the primary composite endpoint of cardiovascular (CV) death or worsening HF for patients with HFmrEF or HFpEFF.

In addition, results of a pooled analysis of the DAPA-HF and DELIVER phase 3 trials showed a consistent benefit from dapagliflozin treatment in significantly reducing the combined endpoint of CV death or HF hospitalization across the range of LVEF.

The European Commission expanded the indication for dapagliflozin (Forxiga) to include HF across the full spectrum of LVEF in February.

The SGLT2 inhibitor is also approved for use by patients with chronic kidney disease. It was first approved in 2014 to improve glycemic control for patients with diabetes mellitus.

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

The Food and Drug Administration has expanded the indication of dapagliflozin (Farxiga, AstraZeneca) to include treatment of heart failure across the full spectrum of left ventricular ejection fraction (LVEF) – including HF with mildly reduced ejection fraction (HFmrEF) and with preserved ejection fraction (HFpEF).

The sodium-glucose cotransporter 2 (SGLT2) inhibitor was previously approved in the United States for adults with heart failure with reduced ejection fraction (HFrEF).

The expanded indication is based on data from the phase 3 DELIVER trial, which showed clear clinical benefits of the SGLT2 inhibitor for patients with HF regardless of left ventricular function.

In the trial, which included more than 6,200 patients, dapagliflozin led to a statistically significant and clinically meaningful early reduction in the primary composite endpoint of cardiovascular (CV) death or worsening HF for patients with HFmrEF or HFpEFF.

In addition, results of a pooled analysis of the DAPA-HF and DELIVER phase 3 trials showed a consistent benefit from dapagliflozin treatment in significantly reducing the combined endpoint of CV death or HF hospitalization across the range of LVEF.

The European Commission expanded the indication for dapagliflozin (Forxiga) to include HF across the full spectrum of LVEF in February.

The SGLT2 inhibitor is also approved for use by patients with chronic kidney disease. It was first approved in 2014 to improve glycemic control for patients with diabetes mellitus.

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

The Food and Drug Administration has expanded the indication of dapagliflozin (Farxiga, AstraZeneca) to include treatment of heart failure across the full spectrum of left ventricular ejection fraction (LVEF) – including HF with mildly reduced ejection fraction (HFmrEF) and with preserved ejection fraction (HFpEF).

The sodium-glucose cotransporter 2 (SGLT2) inhibitor was previously approved in the United States for adults with heart failure with reduced ejection fraction (HFrEF).

The expanded indication is based on data from the phase 3 DELIVER trial, which showed clear clinical benefits of the SGLT2 inhibitor for patients with HF regardless of left ventricular function.

In the trial, which included more than 6,200 patients, dapagliflozin led to a statistically significant and clinically meaningful early reduction in the primary composite endpoint of cardiovascular (CV) death or worsening HF for patients with HFmrEF or HFpEFF.

In addition, results of a pooled analysis of the DAPA-HF and DELIVER phase 3 trials showed a consistent benefit from dapagliflozin treatment in significantly reducing the combined endpoint of CV death or HF hospitalization across the range of LVEF.

The European Commission expanded the indication for dapagliflozin (Forxiga) to include HF across the full spectrum of LVEF in February.

The SGLT2 inhibitor is also approved for use by patients with chronic kidney disease. It was first approved in 2014 to improve glycemic control for patients with diabetes mellitus.

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

Understanding more about the gut microbiome and how it may affect the development and treatment of heart failure could lead to a more personalized approach to managing the condition, a new review article suggests.

ChrisChrisW/Getty Images

“The gut microbiome modulates heart failure pathophysiology, contributes to disease progression and therapeutic responses, and holds promise as a novel biomarker,” the authors note. “Interactions among the gut microbiome, diet, and medications offer potentially innovative modalities for management of patients with heart failure,” they add.

The review was published online in the Journal of the American College of Cardiology.

“Over the past years we have gathered more understanding about how important the gut microbiome is in relation to how our bodies function overall and even though the cardiovascular system and the heart itself may appear to be quite distant from the gut, we know the gut microbiome affects the cardiovascular system and the physiology of heart failure,” lead author Petra Mamic, MD, Stanford (Calif.) University, told this news organization.

“We’ve also learnt that the microbiome is very personalized. It seems to be affected by a lot of intrinsic and as well as extrinsic factors. For cardiovascular diseases in particular, we always knew that diet and lifestyle were part of the environmental risk, and we now believe that the gut microbiome may be one of the factors that mediates that risk,” she said.

“Studies on the gut microbiome are difficult to do and we are right at the beginning of this type of research. But we have learned that the microbiome is altered or dysregulated in many diseases including many cardiovascular diseases, and many of the changes in the microbiome we see in different cardiovascular diseases seem to overlap,” she added.

Dr. Mamic explained that patients with heart failure have a microbiome that appears different and dysregulated, compared with the microbiome in healthy individuals.

“The difficulty is teasing out whether the microbiome changes are causing heart failure or if they are a consequence of the heart failure and all the medications and comorbidities associated with heart failure,” she commented.

Animal studies have shown that many microbial products, small molecules made by the microbiome, seem to affect how the heart recovers from injury, for example after a myocardial infarction, and how much the heart scars and hypertrophies after an injury, Dr. Mamic reported. These microbiome-derived small molecules can also affect blood pressure, which is dysregulated in heart failure.

Other products of the microbiome can be pro-inflammatory or anti-inflammatory, which can again affect the cardiovascular physiology and the heart, she noted.
 

High-fiber diet may be beneficial

One area of particular interest at present involves the role of short-chain fatty acids, which are a byproduct of microbes in the gut that digest fiber.

“These short chain fatty acids seem to have positive effects on the host physiology. They are anti-inflammatory; they lower blood pressure; and they seem to protect the heart from scarring and hypertrophy after injury. In heart failure, the gut microbes that make these short-chain fatty acids are significantly depleted,” Dr. Mamic explained.

They are an obvious focus of interest because these short-chain fatty acids are produced when gut bacteria break down dietary fiber, raising the possibility of beneficial effects from eating a high-fiber diet.

Another product of the gut microbiome of interest is trimethylamine N-oxide, formed when gut bacteria break down nutrients such as L-carnitine and phosphatidyl choline, nutrients abundant in foods of animal origin, especially red meat. This metabolite has proatherogenic and prothrombotic effects, and negatively affected cardiac remodeling in a mouse heart failure model, the review notes.

However, though it is too early to make specific dietary recommendations based on these findings, Dr. Mamic points out that a high-fiber diet is thought to be beneficial.

“Nutritional research is very hard to do and the data is limited, but as best as we can summarize things, we know that plant-based diets such as the Mediterranean and DASH diets seem to prevent some of the risk factors for the development of heart failure and seem to slow the progression of heart failure,” she added.

One of the major recommendations in these diets is a high intake of fiber, including whole foods, vegetables, fruits, legumes, and nuts, and less intake of processed food and red meat. “In general, I think everyone should eat like that, but I specifically recommend a plant-based diet with a high amount of fiber to my heart failure patients,” Dr. Mamic said.
 

Large variation in microbiome composition

The review also explores the idea of personalization of diet or specific treatments dependent on an individual’s gut microbiome composition.

Dr. Mamic explains: “When we look at the microbiome composition between individuals, it is very different. There is very little overlap between individuals, even in people who are related. It seems to be more to do with the environment – people who are living together are more likely to have similarities in their microbiome. We are still trying to understand what drives these differences.”

It is thought that these differences may affect the response to a specific diet or medication. Dr. Mamic gives the example of fiber. “Not all bacteria can digest the same types of fiber, so not everyone responds in the same way to a high-fiber diet. That’s probably because of differences in their microbiome.”

Another example is the response to the heart failure drug digoxin, which is metabolized by one particular strain of bacteria in the gut. The toxicity or effectiveness of digoxin seems to be influenced by levels of this bacterial strain, and this again can be influenced by diet, Dr. Mamic says.
 

Manipulating the microbiome as a therapeutic strategy

Microbiome-targeting therapies may also become part of future treatment strategies for many conditions, including heart failure, the review authors say.

Probiotics (foods and dietary supplements that contain live microbes) interact with the gut microbiota to alter host physiology beneficially. Certain probiotics may specifically modulate processes dysregulated in heart failure, as was suggested in a rodent heart failure model in which supplementation with Lactobacillus-containing and Bifidobacterium-containing probiotics resulted in markedly improved cardiac function, the authors report.

However, a randomized trial (GutHeart) of probiotic yeast Saccharomyces boulardii in patients with heart failure found no improvement in cardiac function, compared with standard care.

Commenting on this, Dr. Mamic suggested that a more specific approach may be needed.

“Some of our preliminary data have shown people who have heart failure have severely depleted Bifidobacteria,” Dr. Mamic said. These bacteria are commercially available as a probiotic, and the researchers are planning a study to give patients with heart failure these specific probiotics. “We are trying to find practical ways forward and to be guided by the data. These people have very little Bifidobacteria, and we know that probiotics seem to be accepted best by the host where there is a specific need for them, so this seems like a sensible approach.”

Dr. Mamic does not recommend that heart failure patients take general probiotic products at present, but she tells her patients about the study she is doing. “Probiotics are quite different from each other. It is a very unregulated market. A general probiotic product may not contain the specific bacteria needed.”
 

Include microbiome data in biobanks

The review calls for more research on the subject and a more systematic approach to collecting data on the microbiome.

“At present for medical research, blood samples are collected, stored, and analyzed routinely. I think we should also be collecting stool samples in the same way to analyze the microbiome,” Dr. Mamic suggests.

“If we can combine that with data from blood tests on various metabolites/cytokines and look at how the microbiome changes over time or with medication, or with diet, and how the host responds including clinically relevant data, that would be really important. Given how quickly the field is growing I would think there would be biobanks including the microbiome in a few years’ time.”

“We need to gather this data. We would be looking for which bacteria are there, what their functionality is, how it changes over time, with diet or medication, and even whether we can use the microbiome data to predict who will respond to a specific drug.”

Dr. Mamic believes that in the future, analysis of the microbiome could be a routine part of deciding what people eat for good health and to characterize patients for personalized therapies.

“It is clear that the microbiome can influence health, and a dysregulated microbiome negatively affects the host, but there is lot of work to do. We need to learn a lot more about it, but we shouldn’t miss the opportunity to do this,” she concluded.

Dr. Mamic reported no disclosures.

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

Understanding more about the gut microbiome and how it may affect the development and treatment of heart failure could lead to a more personalized approach to managing the condition, a new review article suggests.

ChrisChrisW/Getty Images

“The gut microbiome modulates heart failure pathophysiology, contributes to disease progression and therapeutic responses, and holds promise as a novel biomarker,” the authors note. “Interactions among the gut microbiome, diet, and medications offer potentially innovative modalities for management of patients with heart failure,” they add.

The review was published online in the Journal of the American College of Cardiology.

“Over the past years we have gathered more understanding about how important the gut microbiome is in relation to how our bodies function overall and even though the cardiovascular system and the heart itself may appear to be quite distant from the gut, we know the gut microbiome affects the cardiovascular system and the physiology of heart failure,” lead author Petra Mamic, MD, Stanford (Calif.) University, told this news organization.

“We’ve also learnt that the microbiome is very personalized. It seems to be affected by a lot of intrinsic and as well as extrinsic factors. For cardiovascular diseases in particular, we always knew that diet and lifestyle were part of the environmental risk, and we now believe that the gut microbiome may be one of the factors that mediates that risk,” she said.

“Studies on the gut microbiome are difficult to do and we are right at the beginning of this type of research. But we have learned that the microbiome is altered or dysregulated in many diseases including many cardiovascular diseases, and many of the changes in the microbiome we see in different cardiovascular diseases seem to overlap,” she added.

Dr. Mamic explained that patients with heart failure have a microbiome that appears different and dysregulated, compared with the microbiome in healthy individuals.

“The difficulty is teasing out whether the microbiome changes are causing heart failure or if they are a consequence of the heart failure and all the medications and comorbidities associated with heart failure,” she commented.

Animal studies have shown that many microbial products, small molecules made by the microbiome, seem to affect how the heart recovers from injury, for example after a myocardial infarction, and how much the heart scars and hypertrophies after an injury, Dr. Mamic reported. These microbiome-derived small molecules can also affect blood pressure, which is dysregulated in heart failure.

Other products of the microbiome can be pro-inflammatory or anti-inflammatory, which can again affect the cardiovascular physiology and the heart, she noted.
 

High-fiber diet may be beneficial

One area of particular interest at present involves the role of short-chain fatty acids, which are a byproduct of microbes in the gut that digest fiber.

“These short chain fatty acids seem to have positive effects on the host physiology. They are anti-inflammatory; they lower blood pressure; and they seem to protect the heart from scarring and hypertrophy after injury. In heart failure, the gut microbes that make these short-chain fatty acids are significantly depleted,” Dr. Mamic explained.

They are an obvious focus of interest because these short-chain fatty acids are produced when gut bacteria break down dietary fiber, raising the possibility of beneficial effects from eating a high-fiber diet.

Another product of the gut microbiome of interest is trimethylamine N-oxide, formed when gut bacteria break down nutrients such as L-carnitine and phosphatidyl choline, nutrients abundant in foods of animal origin, especially red meat. This metabolite has proatherogenic and prothrombotic effects, and negatively affected cardiac remodeling in a mouse heart failure model, the review notes.

However, though it is too early to make specific dietary recommendations based on these findings, Dr. Mamic points out that a high-fiber diet is thought to be beneficial.

“Nutritional research is very hard to do and the data is limited, but as best as we can summarize things, we know that plant-based diets such as the Mediterranean and DASH diets seem to prevent some of the risk factors for the development of heart failure and seem to slow the progression of heart failure,” she added.

One of the major recommendations in these diets is a high intake of fiber, including whole foods, vegetables, fruits, legumes, and nuts, and less intake of processed food and red meat. “In general, I think everyone should eat like that, but I specifically recommend a plant-based diet with a high amount of fiber to my heart failure patients,” Dr. Mamic said.
 

Large variation in microbiome composition

The review also explores the idea of personalization of diet or specific treatments dependent on an individual’s gut microbiome composition.

Dr. Mamic explains: “When we look at the microbiome composition between individuals, it is very different. There is very little overlap between individuals, even in people who are related. It seems to be more to do with the environment – people who are living together are more likely to have similarities in their microbiome. We are still trying to understand what drives these differences.”

It is thought that these differences may affect the response to a specific diet or medication. Dr. Mamic gives the example of fiber. “Not all bacteria can digest the same types of fiber, so not everyone responds in the same way to a high-fiber diet. That’s probably because of differences in their microbiome.”

Another example is the response to the heart failure drug digoxin, which is metabolized by one particular strain of bacteria in the gut. The toxicity or effectiveness of digoxin seems to be influenced by levels of this bacterial strain, and this again can be influenced by diet, Dr. Mamic says.
 

Manipulating the microbiome as a therapeutic strategy

Microbiome-targeting therapies may also become part of future treatment strategies for many conditions, including heart failure, the review authors say.

Probiotics (foods and dietary supplements that contain live microbes) interact with the gut microbiota to alter host physiology beneficially. Certain probiotics may specifically modulate processes dysregulated in heart failure, as was suggested in a rodent heart failure model in which supplementation with Lactobacillus-containing and Bifidobacterium-containing probiotics resulted in markedly improved cardiac function, the authors report.

However, a randomized trial (GutHeart) of probiotic yeast Saccharomyces boulardii in patients with heart failure found no improvement in cardiac function, compared with standard care.

Commenting on this, Dr. Mamic suggested that a more specific approach may be needed.

“Some of our preliminary data have shown people who have heart failure have severely depleted Bifidobacteria,” Dr. Mamic said. These bacteria are commercially available as a probiotic, and the researchers are planning a study to give patients with heart failure these specific probiotics. “We are trying to find practical ways forward and to be guided by the data. These people have very little Bifidobacteria, and we know that probiotics seem to be accepted best by the host where there is a specific need for them, so this seems like a sensible approach.”

Dr. Mamic does not recommend that heart failure patients take general probiotic products at present, but she tells her patients about the study she is doing. “Probiotics are quite different from each other. It is a very unregulated market. A general probiotic product may not contain the specific bacteria needed.”
 

Include microbiome data in biobanks

The review calls for more research on the subject and a more systematic approach to collecting data on the microbiome.

“At present for medical research, blood samples are collected, stored, and analyzed routinely. I think we should also be collecting stool samples in the same way to analyze the microbiome,” Dr. Mamic suggests.

“If we can combine that with data from blood tests on various metabolites/cytokines and look at how the microbiome changes over time or with medication, or with diet, and how the host responds including clinically relevant data, that would be really important. Given how quickly the field is growing I would think there would be biobanks including the microbiome in a few years’ time.”

“We need to gather this data. We would be looking for which bacteria are there, what their functionality is, how it changes over time, with diet or medication, and even whether we can use the microbiome data to predict who will respond to a specific drug.”

Dr. Mamic believes that in the future, analysis of the microbiome could be a routine part of deciding what people eat for good health and to characterize patients for personalized therapies.

“It is clear that the microbiome can influence health, and a dysregulated microbiome negatively affects the host, but there is lot of work to do. We need to learn a lot more about it, but we shouldn’t miss the opportunity to do this,” she concluded.

Dr. Mamic reported no disclosures.

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

Understanding more about the gut microbiome and how it may affect the development and treatment of heart failure could lead to a more personalized approach to managing the condition, a new review article suggests.

ChrisChrisW/Getty Images

“The gut microbiome modulates heart failure pathophysiology, contributes to disease progression and therapeutic responses, and holds promise as a novel biomarker,” the authors note. “Interactions among the gut microbiome, diet, and medications offer potentially innovative modalities for management of patients with heart failure,” they add.

The review was published online in the Journal of the American College of Cardiology.

“Over the past years we have gathered more understanding about how important the gut microbiome is in relation to how our bodies function overall and even though the cardiovascular system and the heart itself may appear to be quite distant from the gut, we know the gut microbiome affects the cardiovascular system and the physiology of heart failure,” lead author Petra Mamic, MD, Stanford (Calif.) University, told this news organization.

“We’ve also learnt that the microbiome is very personalized. It seems to be affected by a lot of intrinsic and as well as extrinsic factors. For cardiovascular diseases in particular, we always knew that diet and lifestyle were part of the environmental risk, and we now believe that the gut microbiome may be one of the factors that mediates that risk,” she said.

“Studies on the gut microbiome are difficult to do and we are right at the beginning of this type of research. But we have learned that the microbiome is altered or dysregulated in many diseases including many cardiovascular diseases, and many of the changes in the microbiome we see in different cardiovascular diseases seem to overlap,” she added.

Dr. Mamic explained that patients with heart failure have a microbiome that appears different and dysregulated, compared with the microbiome in healthy individuals.

“The difficulty is teasing out whether the microbiome changes are causing heart failure or if they are a consequence of the heart failure and all the medications and comorbidities associated with heart failure,” she commented.

Animal studies have shown that many microbial products, small molecules made by the microbiome, seem to affect how the heart recovers from injury, for example after a myocardial infarction, and how much the heart scars and hypertrophies after an injury, Dr. Mamic reported. These microbiome-derived small molecules can also affect blood pressure, which is dysregulated in heart failure.

Other products of the microbiome can be pro-inflammatory or anti-inflammatory, which can again affect the cardiovascular physiology and the heart, she noted.
 

High-fiber diet may be beneficial

One area of particular interest at present involves the role of short-chain fatty acids, which are a byproduct of microbes in the gut that digest fiber.

“These short chain fatty acids seem to have positive effects on the host physiology. They are anti-inflammatory; they lower blood pressure; and they seem to protect the heart from scarring and hypertrophy after injury. In heart failure, the gut microbes that make these short-chain fatty acids are significantly depleted,” Dr. Mamic explained.

They are an obvious focus of interest because these short-chain fatty acids are produced when gut bacteria break down dietary fiber, raising the possibility of beneficial effects from eating a high-fiber diet.

Another product of the gut microbiome of interest is trimethylamine N-oxide, formed when gut bacteria break down nutrients such as L-carnitine and phosphatidyl choline, nutrients abundant in foods of animal origin, especially red meat. This metabolite has proatherogenic and prothrombotic effects, and negatively affected cardiac remodeling in a mouse heart failure model, the review notes.

However, though it is too early to make specific dietary recommendations based on these findings, Dr. Mamic points out that a high-fiber diet is thought to be beneficial.

“Nutritional research is very hard to do and the data is limited, but as best as we can summarize things, we know that plant-based diets such as the Mediterranean and DASH diets seem to prevent some of the risk factors for the development of heart failure and seem to slow the progression of heart failure,” she added.

One of the major recommendations in these diets is a high intake of fiber, including whole foods, vegetables, fruits, legumes, and nuts, and less intake of processed food and red meat. “In general, I think everyone should eat like that, but I specifically recommend a plant-based diet with a high amount of fiber to my heart failure patients,” Dr. Mamic said.
 

Large variation in microbiome composition

The review also explores the idea of personalization of diet or specific treatments dependent on an individual’s gut microbiome composition.

Dr. Mamic explains: “When we look at the microbiome composition between individuals, it is very different. There is very little overlap between individuals, even in people who are related. It seems to be more to do with the environment – people who are living together are more likely to have similarities in their microbiome. We are still trying to understand what drives these differences.”

It is thought that these differences may affect the response to a specific diet or medication. Dr. Mamic gives the example of fiber. “Not all bacteria can digest the same types of fiber, so not everyone responds in the same way to a high-fiber diet. That’s probably because of differences in their microbiome.”

Another example is the response to the heart failure drug digoxin, which is metabolized by one particular strain of bacteria in the gut. The toxicity or effectiveness of digoxin seems to be influenced by levels of this bacterial strain, and this again can be influenced by diet, Dr. Mamic says.
 

Manipulating the microbiome as a therapeutic strategy

Microbiome-targeting therapies may also become part of future treatment strategies for many conditions, including heart failure, the review authors say.

Probiotics (foods and dietary supplements that contain live microbes) interact with the gut microbiota to alter host physiology beneficially. Certain probiotics may specifically modulate processes dysregulated in heart failure, as was suggested in a rodent heart failure model in which supplementation with Lactobacillus-containing and Bifidobacterium-containing probiotics resulted in markedly improved cardiac function, the authors report.

However, a randomized trial (GutHeart) of probiotic yeast Saccharomyces boulardii in patients with heart failure found no improvement in cardiac function, compared with standard care.

Commenting on this, Dr. Mamic suggested that a more specific approach may be needed.

“Some of our preliminary data have shown people who have heart failure have severely depleted Bifidobacteria,” Dr. Mamic said. These bacteria are commercially available as a probiotic, and the researchers are planning a study to give patients with heart failure these specific probiotics. “We are trying to find practical ways forward and to be guided by the data. These people have very little Bifidobacteria, and we know that probiotics seem to be accepted best by the host where there is a specific need for them, so this seems like a sensible approach.”

Dr. Mamic does not recommend that heart failure patients take general probiotic products at present, but she tells her patients about the study she is doing. “Probiotics are quite different from each other. It is a very unregulated market. A general probiotic product may not contain the specific bacteria needed.”
 

Include microbiome data in biobanks

The review calls for more research on the subject and a more systematic approach to collecting data on the microbiome.

“At present for medical research, blood samples are collected, stored, and analyzed routinely. I think we should also be collecting stool samples in the same way to analyze the microbiome,” Dr. Mamic suggests.

“If we can combine that with data from blood tests on various metabolites/cytokines and look at how the microbiome changes over time or with medication, or with diet, and how the host responds including clinically relevant data, that would be really important. Given how quickly the field is growing I would think there would be biobanks including the microbiome in a few years’ time.”

“We need to gather this data. We would be looking for which bacteria are there, what their functionality is, how it changes over time, with diet or medication, and even whether we can use the microbiome data to predict who will respond to a specific drug.”

Dr. Mamic believes that in the future, analysis of the microbiome could be a routine part of deciding what people eat for good health and to characterize patients for personalized therapies.

“It is clear that the microbiome can influence health, and a dysregulated microbiome negatively affects the host, but there is lot of work to do. We need to learn a lot more about it, but we shouldn’t miss the opportunity to do this,” she concluded.

Dr. Mamic reported no disclosures.

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

Prediction models that incorporate more than just treatment status could rank order heart transplant candidates by urgency more effectively than the current system, a modeling study suggests.

Since 2018, the U.S. heart transplant allocation system has ranked heart candidates according to six treatment-based “statuses” (up from three used previously), ignoring many objective patient characteristics, the authors write.

Their study showed no significant difference in survival between statuses four and six, and status five had lower survival than status four.

“We expected multivariable prediction models to outperform the six-status system when it comes to rank ordering patients by how likely they are to die on the wait list (medical urgency),” William F. Parker, MD, MS, PhD, of the University of Chicago, told this news organization.

“However, we were surprised to see that the statuses were out of order,” he said. “Status five patients are more urgent than status three or status four patients,” mainly because most are in renal failure and listed for multiorgan transplantation with a kidney.

Objective physiologic measurements, such as glomerular filtration rate (GFR), had high variable importance, offering a minimally invasive measurement with predictive power in assessing medical urgency. Therefore, including GFR and other variables such as extracorporeal membrane oxygenation (ECMO) could improve the accuracy of the allocation system in identifying the most medically urgent candidates, Dr. Parker and colleagues suggest.

The study was published online in JACC: Heart Failure.
 

‘Moderate ability’ to rank order

The investigators assessed the effectiveness of the standard six-status ranking system and several novel prediction models in identifying the most urgent heart transplant candidates. The primary outcome was death before receipt of a heart transplant.

The final data set contained 32,294 candidates (mean age, 53 years; 74%, men); 27,200 made up the prepolicy training set and 5,094 were included in the postpolicy test set.

The team evaluated the accuracy of the six-status system using Harrell’s C-index and log-rank tests of Kaplan-Meier estimated survival by status for candidates listed after the policy change (November 2018 to March 2020) in the Scientific Registry of Transplant Recipients data set.

They then developed Cox proportional hazards models and random survival forest models using prepolicy data (2010-2017). Predictor variables included age, diagnosis, laboratory measurements, hemodynamics, and supportive treatment at the time of listing.

They found that the six-status ranking at listing has had “moderate ability” to rank order candidates.

As Dr. Parker indicated, statuses four and six had no significant difference in survival, and status five had lower survival than status four.

The investigators’ multivariable prediction models derived with prepolicy data ranked candidates correctly more often than the six-status rankings. Objective physiologic measurements, such as GFR and ECMO, were identified as having significant importance with regard to ranking by urgency.

“The novel prediction models we developed … could be implemented by the Organ Procurement and Transplantation Network (OPTN) as allocation policy and would be better than the status quo,” Dr. Parker said. “However, I think we could do even better using the newer data collected after 2018.” 
 

Modifications underway

The OPTN Heart Transplantation Committee is currently working on developing a new framework for allocating deceased donor hearts called Continuous Distribution.

“The six-tiered system works well, and it better stratifies the most medically urgent candidates than the previous allocation framework,” the leadership of the United Network for Organ Sharing Heart Transplantation Committee, including Chair Richard C. Daly, MD, Mayo Clinic; Vice-Chair Jondavid Menteer, MD, University of Southern California, Los Angeles; and former Chair Shelley Hall, MD, Baylor University Medical Center, told this news organization.

“That said, it is always appropriate to review and adjust variables that affect the medical urgency attribute for heart allocation.”

The new framework will change how patients are prioritized, they said. “Continuous distribution will consider all patient factors, including medical urgency, together to determine the order of an organ offer, and no single factor will decide an organ match.

“The goal is to increase fairness by moving to a points-based allocation framework that allows candidates to be compared using a single score composed of multiple factors.

“Furthermore,” they added, “continuous distribution provides a framework that will allow modifications of the criteria defining medical urgency (and other attributes of allocation) to a finer degree than the current policy. … Once continuous distribution is in place and the OPTN has policy monitoring data, the committee may consider and model different ways of defining medical urgency.”

Kiran K. Khush, MD, of Stanford (Calif.) University School of Medicine, coauthor of a related commentary, elaborated. “The composite allocation score (CAS) will consist of a ‘points-based system,’ in which candidates will be assigned points based on (1) medical urgency, (2) anticipated posttransplant survival, (3) candidate biology (eg., special characteristics that may result in higher prioritization, such as blood type O and allosensitization), (4) access (eg., prior living donor, pediatric patient), and (5) placement efficacy (travel, proximity).”

Candidates will be assigned points based on these categories, and will be rank ordered for each donor offer.

Dr. Khush and colleagues propose that a multivariable model – such as the ones described in the study – would be the best way to assign points for medical urgency.

“This system will be more equitable than the current system,” Dr. Khush said, “because it will better prioritize the sickest candidates while improving access for patients who are currently at a disadvantage [for example, blood O, highly sensitized patients], and will also remove artificial geographic boundaries [for example, the current 500-mile rule for heart allocation].”
 

Going further

Jesse D. Schold, PhD, of the University of Colorado at Denver, Aurora, raises concerns about other aspects of the heart allocation system in another related commentary.

“One big issue with our data in transplantation … is that, while it is very comprehensive for capturing transplant candidates and recipients, there is no data collection for patients and processes of care for patients prior to wait list placement,” he told this news organization. This phase of care is subject to wide variation in practice, he said, “and is likely as important as any to patients – the ability to be referred, evaluated, and placed on a waiting list.”

Report cards that measure quality of care after wait list placement ignore key phases prior to wait list placement, he said. “This may have the unintended consequences of limiting access to care and to the waiting list for patients perceived to be at higher risk, or the use of higher-risk donors, despite their potential survival advantage.

“In contrast,” he said, “quality report cards that incentivize treatment for all patients who may benefit would likely have a greater beneficial impact on patients with end-organ disease.”

There is also significant risk of underlying differences in patient populations between centers, despite the use of multivariable models, he added. This heterogeneity “may not be reflected accurately in the report cards [which] have significant impact for regulatory review, private payer contracting, and center reputation.”

Some of these concerns may be addressed in the new OPTN Modernization Initiative, according to David Bowman, a public affairs specialist at the Health Resources and Services Administration. One of the goals of the initiative “is to ensure that the OPTN Board of Directors is high functioning, has greater independence, and represents the diversity of communities served by the OPTN,” he told this news organization. “Strengthened governance will lead to effective policy development and implementation, and enhanced transparency and accountability of the process.”

Addressing another concern about the system, Savitri Fedson, MD, of the Michael E. DeBakey VA Medical Center and Baylor College of Medicine, Houston, wonders in a related editorial whether organ donors and recipients should know more about each other, and if so, could that reverse the ongoing downward trend in organ acceptance?

Although some organizations are in favor of sharing more information, Dr. Fedson notes that “less information may have the greater benefit.” She writes, “We might realize that the simplest approach is often the best: a fulsome thank you for the donor’s gift that is willingly given to a stranger without expectation of payment, and on the recipient side, the knowledge that an organ is of good quality.

“The transplant patient can be comforted with the understanding that the risk of disease transmission, while not zero, is low, and that their survival following acceptance of an organ is better than languishing on a waiting list.”

The study received no commercial funding. Dr. Parker, Dr. Khush, Dr. Schold, and Dr. Fedson report no relevant financial relationships.

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

Prediction models that incorporate more than just treatment status could rank order heart transplant candidates by urgency more effectively than the current system, a modeling study suggests.

Since 2018, the U.S. heart transplant allocation system has ranked heart candidates according to six treatment-based “statuses” (up from three used previously), ignoring many objective patient characteristics, the authors write.

Their study showed no significant difference in survival between statuses four and six, and status five had lower survival than status four.

“We expected multivariable prediction models to outperform the six-status system when it comes to rank ordering patients by how likely they are to die on the wait list (medical urgency),” William F. Parker, MD, MS, PhD, of the University of Chicago, told this news organization.

“However, we were surprised to see that the statuses were out of order,” he said. “Status five patients are more urgent than status three or status four patients,” mainly because most are in renal failure and listed for multiorgan transplantation with a kidney.

Objective physiologic measurements, such as glomerular filtration rate (GFR), had high variable importance, offering a minimally invasive measurement with predictive power in assessing medical urgency. Therefore, including GFR and other variables such as extracorporeal membrane oxygenation (ECMO) could improve the accuracy of the allocation system in identifying the most medically urgent candidates, Dr. Parker and colleagues suggest.

The study was published online in JACC: Heart Failure.
 

‘Moderate ability’ to rank order

The investigators assessed the effectiveness of the standard six-status ranking system and several novel prediction models in identifying the most urgent heart transplant candidates. The primary outcome was death before receipt of a heart transplant.

The final data set contained 32,294 candidates (mean age, 53 years; 74%, men); 27,200 made up the prepolicy training set and 5,094 were included in the postpolicy test set.

The team evaluated the accuracy of the six-status system using Harrell’s C-index and log-rank tests of Kaplan-Meier estimated survival by status for candidates listed after the policy change (November 2018 to March 2020) in the Scientific Registry of Transplant Recipients data set.

They then developed Cox proportional hazards models and random survival forest models using prepolicy data (2010-2017). Predictor variables included age, diagnosis, laboratory measurements, hemodynamics, and supportive treatment at the time of listing.

They found that the six-status ranking at listing has had “moderate ability” to rank order candidates.

As Dr. Parker indicated, statuses four and six had no significant difference in survival, and status five had lower survival than status four.

The investigators’ multivariable prediction models derived with prepolicy data ranked candidates correctly more often than the six-status rankings. Objective physiologic measurements, such as GFR and ECMO, were identified as having significant importance with regard to ranking by urgency.

“The novel prediction models we developed … could be implemented by the Organ Procurement and Transplantation Network (OPTN) as allocation policy and would be better than the status quo,” Dr. Parker said. “However, I think we could do even better using the newer data collected after 2018.” 
 

Modifications underway

The OPTN Heart Transplantation Committee is currently working on developing a new framework for allocating deceased donor hearts called Continuous Distribution.

“The six-tiered system works well, and it better stratifies the most medically urgent candidates than the previous allocation framework,” the leadership of the United Network for Organ Sharing Heart Transplantation Committee, including Chair Richard C. Daly, MD, Mayo Clinic; Vice-Chair Jondavid Menteer, MD, University of Southern California, Los Angeles; and former Chair Shelley Hall, MD, Baylor University Medical Center, told this news organization.

“That said, it is always appropriate to review and adjust variables that affect the medical urgency attribute for heart allocation.”

The new framework will change how patients are prioritized, they said. “Continuous distribution will consider all patient factors, including medical urgency, together to determine the order of an organ offer, and no single factor will decide an organ match.

“The goal is to increase fairness by moving to a points-based allocation framework that allows candidates to be compared using a single score composed of multiple factors.

“Furthermore,” they added, “continuous distribution provides a framework that will allow modifications of the criteria defining medical urgency (and other attributes of allocation) to a finer degree than the current policy. … Once continuous distribution is in place and the OPTN has policy monitoring data, the committee may consider and model different ways of defining medical urgency.”

Kiran K. Khush, MD, of Stanford (Calif.) University School of Medicine, coauthor of a related commentary, elaborated. “The composite allocation score (CAS) will consist of a ‘points-based system,’ in which candidates will be assigned points based on (1) medical urgency, (2) anticipated posttransplant survival, (3) candidate biology (eg., special characteristics that may result in higher prioritization, such as blood type O and allosensitization), (4) access (eg., prior living donor, pediatric patient), and (5) placement efficacy (travel, proximity).”

Candidates will be assigned points based on these categories, and will be rank ordered for each donor offer.

Dr. Khush and colleagues propose that a multivariable model – such as the ones described in the study – would be the best way to assign points for medical urgency.

“This system will be more equitable than the current system,” Dr. Khush said, “because it will better prioritize the sickest candidates while improving access for patients who are currently at a disadvantage [for example, blood O, highly sensitized patients], and will also remove artificial geographic boundaries [for example, the current 500-mile rule for heart allocation].”
 

Going further

Jesse D. Schold, PhD, of the University of Colorado at Denver, Aurora, raises concerns about other aspects of the heart allocation system in another related commentary.

“One big issue with our data in transplantation … is that, while it is very comprehensive for capturing transplant candidates and recipients, there is no data collection for patients and processes of care for patients prior to wait list placement,” he told this news organization. This phase of care is subject to wide variation in practice, he said, “and is likely as important as any to patients – the ability to be referred, evaluated, and placed on a waiting list.”

Report cards that measure quality of care after wait list placement ignore key phases prior to wait list placement, he said. “This may have the unintended consequences of limiting access to care and to the waiting list for patients perceived to be at higher risk, or the use of higher-risk donors, despite their potential survival advantage.

“In contrast,” he said, “quality report cards that incentivize treatment for all patients who may benefit would likely have a greater beneficial impact on patients with end-organ disease.”

There is also significant risk of underlying differences in patient populations between centers, despite the use of multivariable models, he added. This heterogeneity “may not be reflected accurately in the report cards [which] have significant impact for regulatory review, private payer contracting, and center reputation.”

Some of these concerns may be addressed in the new OPTN Modernization Initiative, according to David Bowman, a public affairs specialist at the Health Resources and Services Administration. One of the goals of the initiative “is to ensure that the OPTN Board of Directors is high functioning, has greater independence, and represents the diversity of communities served by the OPTN,” he told this news organization. “Strengthened governance will lead to effective policy development and implementation, and enhanced transparency and accountability of the process.”

Addressing another concern about the system, Savitri Fedson, MD, of the Michael E. DeBakey VA Medical Center and Baylor College of Medicine, Houston, wonders in a related editorial whether organ donors and recipients should know more about each other, and if so, could that reverse the ongoing downward trend in organ acceptance?

Although some organizations are in favor of sharing more information, Dr. Fedson notes that “less information may have the greater benefit.” She writes, “We might realize that the simplest approach is often the best: a fulsome thank you for the donor’s gift that is willingly given to a stranger without expectation of payment, and on the recipient side, the knowledge that an organ is of good quality.

“The transplant patient can be comforted with the understanding that the risk of disease transmission, while not zero, is low, and that their survival following acceptance of an organ is better than languishing on a waiting list.”

The study received no commercial funding. Dr. Parker, Dr. Khush, Dr. Schold, and Dr. Fedson report no relevant financial relationships.

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

Prediction models that incorporate more than just treatment status could rank order heart transplant candidates by urgency more effectively than the current system, a modeling study suggests.

Since 2018, the U.S. heart transplant allocation system has ranked heart candidates according to six treatment-based “statuses” (up from three used previously), ignoring many objective patient characteristics, the authors write.

Their study showed no significant difference in survival between statuses four and six, and status five had lower survival than status four.

“We expected multivariable prediction models to outperform the six-status system when it comes to rank ordering patients by how likely they are to die on the wait list (medical urgency),” William F. Parker, MD, MS, PhD, of the University of Chicago, told this news organization.

“However, we were surprised to see that the statuses were out of order,” he said. “Status five patients are more urgent than status three or status four patients,” mainly because most are in renal failure and listed for multiorgan transplantation with a kidney.

Objective physiologic measurements, such as glomerular filtration rate (GFR), had high variable importance, offering a minimally invasive measurement with predictive power in assessing medical urgency. Therefore, including GFR and other variables such as extracorporeal membrane oxygenation (ECMO) could improve the accuracy of the allocation system in identifying the most medically urgent candidates, Dr. Parker and colleagues suggest.

The study was published online in JACC: Heart Failure.
 

‘Moderate ability’ to rank order

The investigators assessed the effectiveness of the standard six-status ranking system and several novel prediction models in identifying the most urgent heart transplant candidates. The primary outcome was death before receipt of a heart transplant.

The final data set contained 32,294 candidates (mean age, 53 years; 74%, men); 27,200 made up the prepolicy training set and 5,094 were included in the postpolicy test set.

The team evaluated the accuracy of the six-status system using Harrell’s C-index and log-rank tests of Kaplan-Meier estimated survival by status for candidates listed after the policy change (November 2018 to March 2020) in the Scientific Registry of Transplant Recipients data set.

They then developed Cox proportional hazards models and random survival forest models using prepolicy data (2010-2017). Predictor variables included age, diagnosis, laboratory measurements, hemodynamics, and supportive treatment at the time of listing.

They found that the six-status ranking at listing has had “moderate ability” to rank order candidates.

As Dr. Parker indicated, statuses four and six had no significant difference in survival, and status five had lower survival than status four.

The investigators’ multivariable prediction models derived with prepolicy data ranked candidates correctly more often than the six-status rankings. Objective physiologic measurements, such as GFR and ECMO, were identified as having significant importance with regard to ranking by urgency.

“The novel prediction models we developed … could be implemented by the Organ Procurement and Transplantation Network (OPTN) as allocation policy and would be better than the status quo,” Dr. Parker said. “However, I think we could do even better using the newer data collected after 2018.” 
 

Modifications underway

The OPTN Heart Transplantation Committee is currently working on developing a new framework for allocating deceased donor hearts called Continuous Distribution.

“The six-tiered system works well, and it better stratifies the most medically urgent candidates than the previous allocation framework,” the leadership of the United Network for Organ Sharing Heart Transplantation Committee, including Chair Richard C. Daly, MD, Mayo Clinic; Vice-Chair Jondavid Menteer, MD, University of Southern California, Los Angeles; and former Chair Shelley Hall, MD, Baylor University Medical Center, told this news organization.

“That said, it is always appropriate to review and adjust variables that affect the medical urgency attribute for heart allocation.”

The new framework will change how patients are prioritized, they said. “Continuous distribution will consider all patient factors, including medical urgency, together to determine the order of an organ offer, and no single factor will decide an organ match.

“The goal is to increase fairness by moving to a points-based allocation framework that allows candidates to be compared using a single score composed of multiple factors.

“Furthermore,” they added, “continuous distribution provides a framework that will allow modifications of the criteria defining medical urgency (and other attributes of allocation) to a finer degree than the current policy. … Once continuous distribution is in place and the OPTN has policy monitoring data, the committee may consider and model different ways of defining medical urgency.”

Kiran K. Khush, MD, of Stanford (Calif.) University School of Medicine, coauthor of a related commentary, elaborated. “The composite allocation score (CAS) will consist of a ‘points-based system,’ in which candidates will be assigned points based on (1) medical urgency, (2) anticipated posttransplant survival, (3) candidate biology (eg., special characteristics that may result in higher prioritization, such as blood type O and allosensitization), (4) access (eg., prior living donor, pediatric patient), and (5) placement efficacy (travel, proximity).”

Candidates will be assigned points based on these categories, and will be rank ordered for each donor offer.

Dr. Khush and colleagues propose that a multivariable model – such as the ones described in the study – would be the best way to assign points for medical urgency.

“This system will be more equitable than the current system,” Dr. Khush said, “because it will better prioritize the sickest candidates while improving access for patients who are currently at a disadvantage [for example, blood O, highly sensitized patients], and will also remove artificial geographic boundaries [for example, the current 500-mile rule for heart allocation].”
 

Going further

Jesse D. Schold, PhD, of the University of Colorado at Denver, Aurora, raises concerns about other aspects of the heart allocation system in another related commentary.

“One big issue with our data in transplantation … is that, while it is very comprehensive for capturing transplant candidates and recipients, there is no data collection for patients and processes of care for patients prior to wait list placement,” he told this news organization. This phase of care is subject to wide variation in practice, he said, “and is likely as important as any to patients – the ability to be referred, evaluated, and placed on a waiting list.”

Report cards that measure quality of care after wait list placement ignore key phases prior to wait list placement, he said. “This may have the unintended consequences of limiting access to care and to the waiting list for patients perceived to be at higher risk, or the use of higher-risk donors, despite their potential survival advantage.

“In contrast,” he said, “quality report cards that incentivize treatment for all patients who may benefit would likely have a greater beneficial impact on patients with end-organ disease.”

There is also significant risk of underlying differences in patient populations between centers, despite the use of multivariable models, he added. This heterogeneity “may not be reflected accurately in the report cards [which] have significant impact for regulatory review, private payer contracting, and center reputation.”

Some of these concerns may be addressed in the new OPTN Modernization Initiative, according to David Bowman, a public affairs specialist at the Health Resources and Services Administration. One of the goals of the initiative “is to ensure that the OPTN Board of Directors is high functioning, has greater independence, and represents the diversity of communities served by the OPTN,” he told this news organization. “Strengthened governance will lead to effective policy development and implementation, and enhanced transparency and accountability of the process.”

Addressing another concern about the system, Savitri Fedson, MD, of the Michael E. DeBakey VA Medical Center and Baylor College of Medicine, Houston, wonders in a related editorial whether organ donors and recipients should know more about each other, and if so, could that reverse the ongoing downward trend in organ acceptance?

Although some organizations are in favor of sharing more information, Dr. Fedson notes that “less information may have the greater benefit.” She writes, “We might realize that the simplest approach is often the best: a fulsome thank you for the donor’s gift that is willingly given to a stranger without expectation of payment, and on the recipient side, the knowledge that an organ is of good quality.

“The transplant patient can be comforted with the understanding that the risk of disease transmission, while not zero, is low, and that their survival following acceptance of an organ is better than languishing on a waiting list.”

The study received no commercial funding. Dr. Parker, Dr. Khush, Dr. Schold, and Dr. Fedson report no relevant financial relationships.

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