Cardiothoracic

The design improvements introduced in the fourth-generation device for transcatheter mitral valve repair, called the MitraClip G4 (Abbott), appears to yield better outcomes than previous iterations, according to a multinational postapproval study with more than 1,000 patients.

Not least, the 1.3% all-cause mortality at 30 days in this series, called EXPAND G4, “is the lowest that has been reported to date,” reported Ralph Stephan von Bardeleben, MD, at the Transcatheter Cardiovascular Therapeutics annual meeting, sponsored by the Cardiovascular Research Foundation.

Ted Bosworth/MDedge News

The evidence of relative advantages was based on comparisons with historical data and a similar study of the previous-generation device. That previous study, called EXPAND, evaluated the MitraClip NTR and ETR systems.

Device times shorter with new device

“There were shorter device times with MitraClip G4,” said Dr. von Bardeleben, referring to a more than 10-minute advantage over the previous generation device (35 minutes in EXPAND G4 vs. 46 min in EXPAND). Although the reduction in overall median procedure time was more modest (77 vs. 80 minutes), Dr. von Bardeleben said these are “the shortest device and procedural times reported to date.”

He also reported what appeared to be incremental advantages across multiple other endpoints, such as procedural success (96.2% vs. 95.8%) and a reduction in the mean clip rate (1.4 vs. 1.5).

Compared with historical outcomes with other devices employed in transcatheter edge-to-edge repair (TEER) of mitral valves, Dr. von Bardeleben contended that the results support the premise that the MitraClip G4 system is a meaningful advance by incorporating such features as an expanded choice of clip sizes, a greater coaptation area, and a more advanced gripper actuation for leaflet grasping.
 

Over 90% achieve MR 1+

Not least, it appears to increase the proportion of patients who achieve a mitral regurgitation grade of 1+ (MR1+) or lower, which is increasingly recognized as the goal of TEER, said Dr. von Bardeleben, head of the Centre of Structure Heart Disease Interventions, Heart Valve Centre, Mainz, Germany.

He said the rates of 91% achieving MR1+ or less and 98% achieved 2+ or lower compare favorably with most other series and exceeds levels achieved with surgery.

Dr. von Bardeleben also contended that, because of its design features, the MitraClip G4 “expands the spectrum of TEER-suitable patients.” He noted that 5% of the patients in this real-world series had a high risk of stenosis owing to such issues as severe annular or leaflet calcification and another 5% had factors that would predict inadequate MR reduction, such as Barlow’s disease, bi-leaflet prolapse, and severe leaflet degeneration.

The 1,164 patients in EXPAND G4 were enrolled from sites in the United States, Europe, Canada, and Japan. For the key outcome measure of procedural success, echocardiograms were assessed by an independent core laboratory. Of the 1,164 patients enrolled, 1,044 (91%) had complete follow-up data at 30 days.

The procedural success rates were reflected in improvements in New York Heart Association (NYHA) functional classes and in the Kansas City Cardiomyopathy Questionnaire (KCCQ), a quality of life instrument. Prior to treatment, 69% were in NYHA class III or greater. Following treatment, the proportion was 17% (P < .0001). The 18-point improvement in the KCCQ was characterized by Dr. von Bardeleben as “both clinically and statistically significant [P < .0001].”

There were no strokes in this series, and the 30-day incidence of myocardial infarction was 0.2%. The proportion requiring cardiovascular surgery within 30 days was less than 1%. The rate of bleeding episodes, all of which were nonserious, was 7%.

The “EXPAND G4 study confirms the safety and effectiveness of the next generation MitraClip G4 system,” according to Dr. von Bardeleben, and it did so “in a contemporary real-world setting.”
 

Outcome data characterized as ‘excellent’

Several invited panelists participating in a discussion following the presentation agreed.

“These results are excellent,” said Raj Makkar, MD, associate director of interventional technologies at Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles. While he was impressed with the fact that only 2% missed the primary endpoint of MR 2+ or lower, he indicated that the 91% achieving MR 1+ or lower might be an even more apt signal that newer-generation devices are improving.

This was echoed by other panelists who appeared to form a general consensus over the premise that the target in TEER should no longer be MR 2+ for most patients.

“We should now be aiming for MR grade of 0-1,” stated panelist Stephan Windecker, MD, chairman, department of cardiology, University of Bern (Switzerland). He indicated that this goal is increasingly reasonable given the advances in device design and greater operator experience.

Dr. von Bardeleben reported financial relationships with Abbott Vascular, Edwards Lifesciences, Medtronic, and Neochord. Dr. Makkar reported financial relationships with Abbott Vascular, Cordis, Edwards Lifesciences, and Medtronic. Dr. Windecker reported financial relationships with more than 30 pharmaceutical companies, including Abbott Vascular, which manufactures MitraClip G4.
 

The design improvements introduced in the fourth-generation device for transcatheter mitral valve repair, called the MitraClip G4 (Abbott), appears to yield better outcomes than previous iterations, according to a multinational postapproval study with more than 1,000 patients.

Not least, the 1.3% all-cause mortality at 30 days in this series, called EXPAND G4, “is the lowest that has been reported to date,” reported Ralph Stephan von Bardeleben, MD, at the Transcatheter Cardiovascular Therapeutics annual meeting, sponsored by the Cardiovascular Research Foundation.

Ted Bosworth/MDedge News

The evidence of relative advantages was based on comparisons with historical data and a similar study of the previous-generation device. That previous study, called EXPAND, evaluated the MitraClip NTR and ETR systems.

Device times shorter with new device

“There were shorter device times with MitraClip G4,” said Dr. von Bardeleben, referring to a more than 10-minute advantage over the previous generation device (35 minutes in EXPAND G4 vs. 46 min in EXPAND). Although the reduction in overall median procedure time was more modest (77 vs. 80 minutes), Dr. von Bardeleben said these are “the shortest device and procedural times reported to date.”

He also reported what appeared to be incremental advantages across multiple other endpoints, such as procedural success (96.2% vs. 95.8%) and a reduction in the mean clip rate (1.4 vs. 1.5).

Compared with historical outcomes with other devices employed in transcatheter edge-to-edge repair (TEER) of mitral valves, Dr. von Bardeleben contended that the results support the premise that the MitraClip G4 system is a meaningful advance by incorporating such features as an expanded choice of clip sizes, a greater coaptation area, and a more advanced gripper actuation for leaflet grasping.
 

Over 90% achieve MR 1+

Not least, it appears to increase the proportion of patients who achieve a mitral regurgitation grade of 1+ (MR1+) or lower, which is increasingly recognized as the goal of TEER, said Dr. von Bardeleben, head of the Centre of Structure Heart Disease Interventions, Heart Valve Centre, Mainz, Germany.

He said the rates of 91% achieving MR1+ or less and 98% achieved 2+ or lower compare favorably with most other series and exceeds levels achieved with surgery.

Dr. von Bardeleben also contended that, because of its design features, the MitraClip G4 “expands the spectrum of TEER-suitable patients.” He noted that 5% of the patients in this real-world series had a high risk of stenosis owing to such issues as severe annular or leaflet calcification and another 5% had factors that would predict inadequate MR reduction, such as Barlow’s disease, bi-leaflet prolapse, and severe leaflet degeneration.

The 1,164 patients in EXPAND G4 were enrolled from sites in the United States, Europe, Canada, and Japan. For the key outcome measure of procedural success, echocardiograms were assessed by an independent core laboratory. Of the 1,164 patients enrolled, 1,044 (91%) had complete follow-up data at 30 days.

The procedural success rates were reflected in improvements in New York Heart Association (NYHA) functional classes and in the Kansas City Cardiomyopathy Questionnaire (KCCQ), a quality of life instrument. Prior to treatment, 69% were in NYHA class III or greater. Following treatment, the proportion was 17% (P < .0001). The 18-point improvement in the KCCQ was characterized by Dr. von Bardeleben as “both clinically and statistically significant [P < .0001].”

There were no strokes in this series, and the 30-day incidence of myocardial infarction was 0.2%. The proportion requiring cardiovascular surgery within 30 days was less than 1%. The rate of bleeding episodes, all of which were nonserious, was 7%.

The “EXPAND G4 study confirms the safety and effectiveness of the next generation MitraClip G4 system,” according to Dr. von Bardeleben, and it did so “in a contemporary real-world setting.”
 

Outcome data characterized as ‘excellent’

Several invited panelists participating in a discussion following the presentation agreed.

“These results are excellent,” said Raj Makkar, MD, associate director of interventional technologies at Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles. While he was impressed with the fact that only 2% missed the primary endpoint of MR 2+ or lower, he indicated that the 91% achieving MR 1+ or lower might be an even more apt signal that newer-generation devices are improving.

This was echoed by other panelists who appeared to form a general consensus over the premise that the target in TEER should no longer be MR 2+ for most patients.

“We should now be aiming for MR grade of 0-1,” stated panelist Stephan Windecker, MD, chairman, department of cardiology, University of Bern (Switzerland). He indicated that this goal is increasingly reasonable given the advances in device design and greater operator experience.

Dr. von Bardeleben reported financial relationships with Abbott Vascular, Edwards Lifesciences, Medtronic, and Neochord. Dr. Makkar reported financial relationships with Abbott Vascular, Cordis, Edwards Lifesciences, and Medtronic. Dr. Windecker reported financial relationships with more than 30 pharmaceutical companies, including Abbott Vascular, which manufactures MitraClip G4.
 

The design improvements introduced in the fourth-generation device for transcatheter mitral valve repair, called the MitraClip G4 (Abbott), appears to yield better outcomes than previous iterations, according to a multinational postapproval study with more than 1,000 patients.

Not least, the 1.3% all-cause mortality at 30 days in this series, called EXPAND G4, “is the lowest that has been reported to date,” reported Ralph Stephan von Bardeleben, MD, at the Transcatheter Cardiovascular Therapeutics annual meeting, sponsored by the Cardiovascular Research Foundation.

Ted Bosworth/MDedge News

The evidence of relative advantages was based on comparisons with historical data and a similar study of the previous-generation device. That previous study, called EXPAND, evaluated the MitraClip NTR and ETR systems.

Device times shorter with new device

“There were shorter device times with MitraClip G4,” said Dr. von Bardeleben, referring to a more than 10-minute advantage over the previous generation device (35 minutes in EXPAND G4 vs. 46 min in EXPAND). Although the reduction in overall median procedure time was more modest (77 vs. 80 minutes), Dr. von Bardeleben said these are “the shortest device and procedural times reported to date.”

He also reported what appeared to be incremental advantages across multiple other endpoints, such as procedural success (96.2% vs. 95.8%) and a reduction in the mean clip rate (1.4 vs. 1.5).

Compared with historical outcomes with other devices employed in transcatheter edge-to-edge repair (TEER) of mitral valves, Dr. von Bardeleben contended that the results support the premise that the MitraClip G4 system is a meaningful advance by incorporating such features as an expanded choice of clip sizes, a greater coaptation area, and a more advanced gripper actuation for leaflet grasping.
 

Over 90% achieve MR 1+

Not least, it appears to increase the proportion of patients who achieve a mitral regurgitation grade of 1+ (MR1+) or lower, which is increasingly recognized as the goal of TEER, said Dr. von Bardeleben, head of the Centre of Structure Heart Disease Interventions, Heart Valve Centre, Mainz, Germany.

He said the rates of 91% achieving MR1+ or less and 98% achieved 2+ or lower compare favorably with most other series and exceeds levels achieved with surgery.

Dr. von Bardeleben also contended that, because of its design features, the MitraClip G4 “expands the spectrum of TEER-suitable patients.” He noted that 5% of the patients in this real-world series had a high risk of stenosis owing to such issues as severe annular or leaflet calcification and another 5% had factors that would predict inadequate MR reduction, such as Barlow’s disease, bi-leaflet prolapse, and severe leaflet degeneration.

The 1,164 patients in EXPAND G4 were enrolled from sites in the United States, Europe, Canada, and Japan. For the key outcome measure of procedural success, echocardiograms were assessed by an independent core laboratory. Of the 1,164 patients enrolled, 1,044 (91%) had complete follow-up data at 30 days.

The procedural success rates were reflected in improvements in New York Heart Association (NYHA) functional classes and in the Kansas City Cardiomyopathy Questionnaire (KCCQ), a quality of life instrument. Prior to treatment, 69% were in NYHA class III or greater. Following treatment, the proportion was 17% (P < .0001). The 18-point improvement in the KCCQ was characterized by Dr. von Bardeleben as “both clinically and statistically significant [P < .0001].”

There were no strokes in this series, and the 30-day incidence of myocardial infarction was 0.2%. The proportion requiring cardiovascular surgery within 30 days was less than 1%. The rate of bleeding episodes, all of which were nonserious, was 7%.

The “EXPAND G4 study confirms the safety and effectiveness of the next generation MitraClip G4 system,” according to Dr. von Bardeleben, and it did so “in a contemporary real-world setting.”
 

Outcome data characterized as ‘excellent’

Several invited panelists participating in a discussion following the presentation agreed.

“These results are excellent,” said Raj Makkar, MD, associate director of interventional technologies at Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles. While he was impressed with the fact that only 2% missed the primary endpoint of MR 2+ or lower, he indicated that the 91% achieving MR 1+ or lower might be an even more apt signal that newer-generation devices are improving.

This was echoed by other panelists who appeared to form a general consensus over the premise that the target in TEER should no longer be MR 2+ for most patients.

“We should now be aiming for MR grade of 0-1,” stated panelist Stephan Windecker, MD, chairman, department of cardiology, University of Bern (Switzerland). He indicated that this goal is increasingly reasonable given the advances in device design and greater operator experience.

Dr. von Bardeleben reported financial relationships with Abbott Vascular, Edwards Lifesciences, Medtronic, and Neochord. Dr. Makkar reported financial relationships with Abbott Vascular, Cordis, Edwards Lifesciences, and Medtronic. Dr. Windecker reported financial relationships with more than 30 pharmaceutical companies, including Abbott Vascular, which manufactures MitraClip G4.
 

BARCELONA – A novel “extravascular” implantable cardioverter defibrillator (ICD) that uses substernally placed electrodes surpassed its prespecified efficacy and safety targets in the device’s pivotal trial with 299 patients who received an implant.

The results showed that the extravascular ICD “provides antitachycardia pacing and low energy defibrillation while avoiding the vascular space” for lead placement, Ian Crozier, MD, said at the annual congress of the European Society of Cardiology.

Mitchel L. Zoler/MDedge News

“The results are fantastic; they exceeded our expectations,” said Dr. Crozier in an interview, adding that he expects the new device to receive marketing approval from regulatory agencies based on the findings. “This will be the next generation of ICD going forward,” predicted Dr. Crozier, an electrophysiologist cardiologist at Christchurch (New Zealand) Hospital.
 

Moving beyond transvenous and subcutaneous ICDs

Traditional ICDs use transvenous leads, which can cause vascular injury, are prone to lead fracture over time, and can produce serious infections as well as other potential complications. The U.S. Food and Drug Administration first approved an alternative-design, subcutaneous ICD in 2012 that avoids the need for transvenous leads and the risks they pose. But subcutaneous ICDs have their own limitations: an inability to provide antitachycardia pacing or chronic pacing; a limited ability to provide bradycardia pacing; and an increased device size with shorter battery life, because of the high shock power needed for effective performance. These drawbacks have collectively hindered uptake, Dr. Crozier said.

Medtronic

This led to development of the extravascular ICD – 10 years in the making – which uses substernally placed leads that allow antitachycardia pacing and backup pacing in a device with the size of and the anticipated battery longevity of a transvenous ICD device, noted Dr. Crozier.
 

A 98.7% rate of arrhythmia termination at implant

The pivotal trial’s primary efficacy endpoint was successful defibrillation based on terminating an induced, sustained, shockable ventricular arrhythmia at the time of implantation. The rate was 98.7%, compared with a prespecified target of 88%. All patients had a class I or IIa indication for an ICD.

The primary safety endpoint was freedom from major system- or procedure-related complications at 6 months, which occurred at a rate of 92.6%, compared with the study’s prespecified target rate of 79%. Both targets were derived from the historical rates of ICDs with transvenous leads.

Simultaneously with Dr. Crozier’s report at the congress, the results also appeared online in the New England Journal of Medicine.

Although the pivotal study met both prespecified endpoints, the evidence has limitations that make it likely that regulatory bodies will seek additional data, commented Fred Kusumoto, MD, director of heart rhythm services for the Mayo Clinic in Jacksonville, Fla.
 

Short follow-up; questions remain

“Follow-up was relatively short, less than a year,” and “questions remain” about the extravascular ICD’s performance, Dr. Kusumoto said in an interview. “Inappropriate shocks occurred in nearly 10% of patients after 11 month follow-up,” he noted, and also cited the 29 patients who needed revisions including two cases with lead fractures.

“The extravascular lead strategy has an advantage over transvenous systems because of the lower risk for extraction or explant,” and it also provides the antitachycardia pacing that’s not available with subcutaneous ICDs, he granted. But in the new study, antitachycardia termination was delivered to only 10 patients and had “reasonable” effectiveness by resolving 70% of these episodes. “Wide adoption by clinicians will depend on results from larger studies with longer follow-up,” Dr. Kusumoto maintained. He also wanted to see confirmation of the ease of lead removal after longer periods of implantation.

Implantation ‘is not difficult’

The trial ran at 46 sites in 17 countries during September 2019 to October 2021. It enrolled patients with a class I or IIa indication for an ICD, excluding patients with a prior sternotomy or need for chronic pacing, and those unable to undergo defibrillation testing.

Clinicians attempted an implantation in 316 patients and had successful placement in 299 (314 had successful placement of their substernal leads), with 292 having a functional device after 6 months, and 284 completing their planned 6-month follow-up. The median procedure time was 66 minutes, including the time for defibrillation testing.

All of the cardiologists who did the implants had received a full day of training prior to performing the procedure. “This is not a difficult procedure, but it is not a region [the substernal space] that cardiologists are familiar working in,” noted Dr. Crozier, explaining the rationale behind a policy of required implantation training.

Twenty-five adverse events occurred in 23 patients. Eighteen of these events required a system revision, including nine lead dislodgments and five infections. The seven adverse events that did not require a revision included three wound-related episodes and three hospitalizations for inappropriate shock. No patients died, nor were there any cardiac injuries as result of the implant.

During average follow-up of 10.6 months, the implanted devices delivered antitachycardia pacing to 10 patients, successfully terminating 32 of 46 episodes (70%), a rate that Dr. Crozier called “very good, and very comparable to transvenous devices.” The devices also delivered 18 appropriate shocks that successfully converted all 18 episodes.
 

A 10% rate of inappropriate shocks

However, 29 patients (10% of the study cohort) received inappropriate shocks in 81 episodes, with a total of 118 inappropriate shocks delivered, including 34 episodes (42%) triggered by oversensing of a P wave.

“We fully acknowledge that the inappropriate shock rate is higher than what’s seen with transvenous ICDs, but the rate is comparable to what was seen in the early trials with subcutaneous ICDs,” said Dr. Crozier. “We have a number of strategies to reduce the inappropriate shock rate to what we’d expect with conventional devices,” such as making sure that P waves are not detected by the device at the time of implantation, using new algorithms to mitigate P wave sensing, and other programming changes, he added.

Two patients had lead fractures that Dr. Crozier attributed to atypical lead locations and that are likely avoidable in the future. He expressed optimism that the extravascular ICD will avoid the high lead fracture rate over time that remains a problem for ICDs with transvenous leads.

The study also followed a subgroup of 36 patients who underwent a prespecified protocol of chronic defibrillation testing that was successful in all 36.

Dr. Crozier conceded that the extravascular ICD cannot currently deliver chronic pacing, but he expressed optimism that this capability will be available in the future.

“This innovative [extravascular] ICD system would be particularly beneficial for patients with ventricular arrhythmias that can be reliably pace terminated and avoid a transvenous endocardial lead, but more information is required,” concluded Dr. Kusumoto.

The study was sponsored by Medtronic, the company that is developing the extravascular ICD. Dr. Crozier is a consultant to and has received research funding from Medtronic. Dr. Kusumoto had no disclosures.

BARCELONA – A novel “extravascular” implantable cardioverter defibrillator (ICD) that uses substernally placed electrodes surpassed its prespecified efficacy and safety targets in the device’s pivotal trial with 299 patients who received an implant.

The results showed that the extravascular ICD “provides antitachycardia pacing and low energy defibrillation while avoiding the vascular space” for lead placement, Ian Crozier, MD, said at the annual congress of the European Society of Cardiology.

Mitchel L. Zoler/MDedge News

“The results are fantastic; they exceeded our expectations,” said Dr. Crozier in an interview, adding that he expects the new device to receive marketing approval from regulatory agencies based on the findings. “This will be the next generation of ICD going forward,” predicted Dr. Crozier, an electrophysiologist cardiologist at Christchurch (New Zealand) Hospital.
 

Moving beyond transvenous and subcutaneous ICDs

Traditional ICDs use transvenous leads, which can cause vascular injury, are prone to lead fracture over time, and can produce serious infections as well as other potential complications. The U.S. Food and Drug Administration first approved an alternative-design, subcutaneous ICD in 2012 that avoids the need for transvenous leads and the risks they pose. But subcutaneous ICDs have their own limitations: an inability to provide antitachycardia pacing or chronic pacing; a limited ability to provide bradycardia pacing; and an increased device size with shorter battery life, because of the high shock power needed for effective performance. These drawbacks have collectively hindered uptake, Dr. Crozier said.

Medtronic

This led to development of the extravascular ICD – 10 years in the making – which uses substernally placed leads that allow antitachycardia pacing and backup pacing in a device with the size of and the anticipated battery longevity of a transvenous ICD device, noted Dr. Crozier.
 

A 98.7% rate of arrhythmia termination at implant

The pivotal trial’s primary efficacy endpoint was successful defibrillation based on terminating an induced, sustained, shockable ventricular arrhythmia at the time of implantation. The rate was 98.7%, compared with a prespecified target of 88%. All patients had a class I or IIa indication for an ICD.

The primary safety endpoint was freedom from major system- or procedure-related complications at 6 months, which occurred at a rate of 92.6%, compared with the study’s prespecified target rate of 79%. Both targets were derived from the historical rates of ICDs with transvenous leads.

Simultaneously with Dr. Crozier’s report at the congress, the results also appeared online in the New England Journal of Medicine.

Although the pivotal study met both prespecified endpoints, the evidence has limitations that make it likely that regulatory bodies will seek additional data, commented Fred Kusumoto, MD, director of heart rhythm services for the Mayo Clinic in Jacksonville, Fla.
 

Short follow-up; questions remain

“Follow-up was relatively short, less than a year,” and “questions remain” about the extravascular ICD’s performance, Dr. Kusumoto said in an interview. “Inappropriate shocks occurred in nearly 10% of patients after 11 month follow-up,” he noted, and also cited the 29 patients who needed revisions including two cases with lead fractures.

“The extravascular lead strategy has an advantage over transvenous systems because of the lower risk for extraction or explant,” and it also provides the antitachycardia pacing that’s not available with subcutaneous ICDs, he granted. But in the new study, antitachycardia termination was delivered to only 10 patients and had “reasonable” effectiveness by resolving 70% of these episodes. “Wide adoption by clinicians will depend on results from larger studies with longer follow-up,” Dr. Kusumoto maintained. He also wanted to see confirmation of the ease of lead removal after longer periods of implantation.

Implantation ‘is not difficult’

The trial ran at 46 sites in 17 countries during September 2019 to October 2021. It enrolled patients with a class I or IIa indication for an ICD, excluding patients with a prior sternotomy or need for chronic pacing, and those unable to undergo defibrillation testing.

Clinicians attempted an implantation in 316 patients and had successful placement in 299 (314 had successful placement of their substernal leads), with 292 having a functional device after 6 months, and 284 completing their planned 6-month follow-up. The median procedure time was 66 minutes, including the time for defibrillation testing.

All of the cardiologists who did the implants had received a full day of training prior to performing the procedure. “This is not a difficult procedure, but it is not a region [the substernal space] that cardiologists are familiar working in,” noted Dr. Crozier, explaining the rationale behind a policy of required implantation training.

Twenty-five adverse events occurred in 23 patients. Eighteen of these events required a system revision, including nine lead dislodgments and five infections. The seven adverse events that did not require a revision included three wound-related episodes and three hospitalizations for inappropriate shock. No patients died, nor were there any cardiac injuries as result of the implant.

During average follow-up of 10.6 months, the implanted devices delivered antitachycardia pacing to 10 patients, successfully terminating 32 of 46 episodes (70%), a rate that Dr. Crozier called “very good, and very comparable to transvenous devices.” The devices also delivered 18 appropriate shocks that successfully converted all 18 episodes.
 

A 10% rate of inappropriate shocks

However, 29 patients (10% of the study cohort) received inappropriate shocks in 81 episodes, with a total of 118 inappropriate shocks delivered, including 34 episodes (42%) triggered by oversensing of a P wave.

“We fully acknowledge that the inappropriate shock rate is higher than what’s seen with transvenous ICDs, but the rate is comparable to what was seen in the early trials with subcutaneous ICDs,” said Dr. Crozier. “We have a number of strategies to reduce the inappropriate shock rate to what we’d expect with conventional devices,” such as making sure that P waves are not detected by the device at the time of implantation, using new algorithms to mitigate P wave sensing, and other programming changes, he added.

Two patients had lead fractures that Dr. Crozier attributed to atypical lead locations and that are likely avoidable in the future. He expressed optimism that the extravascular ICD will avoid the high lead fracture rate over time that remains a problem for ICDs with transvenous leads.

The study also followed a subgroup of 36 patients who underwent a prespecified protocol of chronic defibrillation testing that was successful in all 36.

Dr. Crozier conceded that the extravascular ICD cannot currently deliver chronic pacing, but he expressed optimism that this capability will be available in the future.

“This innovative [extravascular] ICD system would be particularly beneficial for patients with ventricular arrhythmias that can be reliably pace terminated and avoid a transvenous endocardial lead, but more information is required,” concluded Dr. Kusumoto.

The study was sponsored by Medtronic, the company that is developing the extravascular ICD. Dr. Crozier is a consultant to and has received research funding from Medtronic. Dr. Kusumoto had no disclosures.

BARCELONA – A novel “extravascular” implantable cardioverter defibrillator (ICD) that uses substernally placed electrodes surpassed its prespecified efficacy and safety targets in the device’s pivotal trial with 299 patients who received an implant.

The results showed that the extravascular ICD “provides antitachycardia pacing and low energy defibrillation while avoiding the vascular space” for lead placement, Ian Crozier, MD, said at the annual congress of the European Society of Cardiology.

Mitchel L. Zoler/MDedge News

“The results are fantastic; they exceeded our expectations,” said Dr. Crozier in an interview, adding that he expects the new device to receive marketing approval from regulatory agencies based on the findings. “This will be the next generation of ICD going forward,” predicted Dr. Crozier, an electrophysiologist cardiologist at Christchurch (New Zealand) Hospital.
 

Moving beyond transvenous and subcutaneous ICDs

Traditional ICDs use transvenous leads, which can cause vascular injury, are prone to lead fracture over time, and can produce serious infections as well as other potential complications. The U.S. Food and Drug Administration first approved an alternative-design, subcutaneous ICD in 2012 that avoids the need for transvenous leads and the risks they pose. But subcutaneous ICDs have their own limitations: an inability to provide antitachycardia pacing or chronic pacing; a limited ability to provide bradycardia pacing; and an increased device size with shorter battery life, because of the high shock power needed for effective performance. These drawbacks have collectively hindered uptake, Dr. Crozier said.

Medtronic

This led to development of the extravascular ICD – 10 years in the making – which uses substernally placed leads that allow antitachycardia pacing and backup pacing in a device with the size of and the anticipated battery longevity of a transvenous ICD device, noted Dr. Crozier.
 

A 98.7% rate of arrhythmia termination at implant

The pivotal trial’s primary efficacy endpoint was successful defibrillation based on terminating an induced, sustained, shockable ventricular arrhythmia at the time of implantation. The rate was 98.7%, compared with a prespecified target of 88%. All patients had a class I or IIa indication for an ICD.

The primary safety endpoint was freedom from major system- or procedure-related complications at 6 months, which occurred at a rate of 92.6%, compared with the study’s prespecified target rate of 79%. Both targets were derived from the historical rates of ICDs with transvenous leads.

Simultaneously with Dr. Crozier’s report at the congress, the results also appeared online in the New England Journal of Medicine.

Although the pivotal study met both prespecified endpoints, the evidence has limitations that make it likely that regulatory bodies will seek additional data, commented Fred Kusumoto, MD, director of heart rhythm services for the Mayo Clinic in Jacksonville, Fla.
 

Short follow-up; questions remain

“Follow-up was relatively short, less than a year,” and “questions remain” about the extravascular ICD’s performance, Dr. Kusumoto said in an interview. “Inappropriate shocks occurred in nearly 10% of patients after 11 month follow-up,” he noted, and also cited the 29 patients who needed revisions including two cases with lead fractures.

“The extravascular lead strategy has an advantage over transvenous systems because of the lower risk for extraction or explant,” and it also provides the antitachycardia pacing that’s not available with subcutaneous ICDs, he granted. But in the new study, antitachycardia termination was delivered to only 10 patients and had “reasonable” effectiveness by resolving 70% of these episodes. “Wide adoption by clinicians will depend on results from larger studies with longer follow-up,” Dr. Kusumoto maintained. He also wanted to see confirmation of the ease of lead removal after longer periods of implantation.

Implantation ‘is not difficult’

The trial ran at 46 sites in 17 countries during September 2019 to October 2021. It enrolled patients with a class I or IIa indication for an ICD, excluding patients with a prior sternotomy or need for chronic pacing, and those unable to undergo defibrillation testing.

Clinicians attempted an implantation in 316 patients and had successful placement in 299 (314 had successful placement of their substernal leads), with 292 having a functional device after 6 months, and 284 completing their planned 6-month follow-up. The median procedure time was 66 minutes, including the time for defibrillation testing.

All of the cardiologists who did the implants had received a full day of training prior to performing the procedure. “This is not a difficult procedure, but it is not a region [the substernal space] that cardiologists are familiar working in,” noted Dr. Crozier, explaining the rationale behind a policy of required implantation training.

Twenty-five adverse events occurred in 23 patients. Eighteen of these events required a system revision, including nine lead dislodgments and five infections. The seven adverse events that did not require a revision included three wound-related episodes and three hospitalizations for inappropriate shock. No patients died, nor were there any cardiac injuries as result of the implant.

During average follow-up of 10.6 months, the implanted devices delivered antitachycardia pacing to 10 patients, successfully terminating 32 of 46 episodes (70%), a rate that Dr. Crozier called “very good, and very comparable to transvenous devices.” The devices also delivered 18 appropriate shocks that successfully converted all 18 episodes.
 

A 10% rate of inappropriate shocks

However, 29 patients (10% of the study cohort) received inappropriate shocks in 81 episodes, with a total of 118 inappropriate shocks delivered, including 34 episodes (42%) triggered by oversensing of a P wave.

“We fully acknowledge that the inappropriate shock rate is higher than what’s seen with transvenous ICDs, but the rate is comparable to what was seen in the early trials with subcutaneous ICDs,” said Dr. Crozier. “We have a number of strategies to reduce the inappropriate shock rate to what we’d expect with conventional devices,” such as making sure that P waves are not detected by the device at the time of implantation, using new algorithms to mitigate P wave sensing, and other programming changes, he added.

Two patients had lead fractures that Dr. Crozier attributed to atypical lead locations and that are likely avoidable in the future. He expressed optimism that the extravascular ICD will avoid the high lead fracture rate over time that remains a problem for ICDs with transvenous leads.

The study also followed a subgroup of 36 patients who underwent a prespecified protocol of chronic defibrillation testing that was successful in all 36.

Dr. Crozier conceded that the extravascular ICD cannot currently deliver chronic pacing, but he expressed optimism that this capability will be available in the future.

“This innovative [extravascular] ICD system would be particularly beneficial for patients with ventricular arrhythmias that can be reliably pace terminated and avoid a transvenous endocardial lead, but more information is required,” concluded Dr. Kusumoto.

The study was sponsored by Medtronic, the company that is developing the extravascular ICD. Dr. Crozier is a consultant to and has received research funding from Medtronic. Dr. Kusumoto had no disclosures.

BARCELONA – For patients with emphysema who are suitable candidates for lung volume reduction surgery, there were no differences at 1 year in either lung function, dyspnea, or exercise capacity between patients who were assigned to undergo standard lung volume reduction surgery (LVRS) or bronchoscopic lung volume reduction with endobrachial valves (BLVR-EBV) in a randomized trial.

Among patients with emphysema amenable to surgery, there were similar improvements between the treatment groups at 12-month follow-up as assessed by the iBODE score, a composite disease severity measure incorporating body mass index, airflow obstruction, dyspnea, and exercise capacity (incremental shuttle walk test), reported Sara Buttery, BSc, a research physiotherapist and PhD candidate at the National Heart and Lung Institute at Imperial College London.

“Until now there had been no direct comparison of the two to inform decision-making when a person seems to be suitable for either. Bronchoscopic lung volume reduction is a less invasive option and is thought to be ‘less risky’ but, until now, there has not been substantial research to support this,” she said at the annual congress of the European Respiratory Society.

Ms. Buttery and colleagues conducted a randomized, controlled, single-blinded superiority trial to see whether LVRS could be superior to BLVR with valves. They enrolled 88 patients (52% male) with a mean age of 64, and randomly assigned them to receive either LVRS (41 patients) or the less-invasive BLVR (47 patients).

As noted before, there were no significant differences in outcomes at 1 year, with similar degrees of improvement between the surgical techniques for both the composite iBODE score (–1.10 for LVRS vs. –0.82 for BLVR, nonsignificant), and for the individual components of the score.

In addition, the treatments were associated with similar reductions in gas trapping, with residual volume percentage predicted –36.1 with LVRS versus –30.5 with BLVR (nonsignificant).

One patient in each group died during the 12 months of follow-up. The death of the patient in the BLVR group was deemed to be treatment related; the death of the patient in the LVRS group was related to a noninfective exacerbation of chronic obstructive pulmonary disease.

Invited discussant Isabelle Opitz, MD, from University Hospital Zürich told Ms. Buttery: “I have to congratulate you for this very first randomized controlled trial comparing both procedures in a superiority design.”

She pointed out, however, that the number of patients lost to follow-up and crossover of some patients randomized to bronchoscopy raised questions about the powering of the study.

“We did a sensitivity analysis to have a look to see if there was any difference between the patients who did return and the ones who didn’t, and there was no difference at baseline between those patients.” Ms. Buttery said.

She noted that follow-up visits were hampered by the COVID-19 pandemic and the inability of many patients to come into the clinic.

Dr. Opitz also asked about COPD Assessment Test (CAT) scores that were included in the trial design but not reported in the presentation. Ms. Buttery said that the CAT results favored the LVRS group, and that the results would be included in a future economic analysis.

“The results from this first randomized controlled trial suggest that BLVR may be a good therapeutic option for those patients for whom either procedure is suitable,” said Alexander Mathioudakis, MD, PhD, from the University of Manchester (England), who was not involved with this study but commented on it in a press statement. “Lung volume reduction surgery is an invasive operation as it requires a small incision to be made in the chest, which is stitched up after the procedure. As such, it has risks associated with surgery and it takes longer to recover from than bronchoscopic lung volume reduction. On the other hand, endobronchial valves placement is also associated with side effects, such as pneumonia, or valve displacement. Therefore, both the safety and effectiveness of the two procedures need to be investigated further, in larger groups of patients, but the results from this trial are very encouraging.”

The study is supported by the U.K. National Institute of Health Research. Ms. Buttery, Dr. Opitz, and Dr. Mathioudakis reported no relevant financial relationships.

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

BARCELONA – For patients with emphysema who are suitable candidates for lung volume reduction surgery, there were no differences at 1 year in either lung function, dyspnea, or exercise capacity between patients who were assigned to undergo standard lung volume reduction surgery (LVRS) or bronchoscopic lung volume reduction with endobrachial valves (BLVR-EBV) in a randomized trial.

Among patients with emphysema amenable to surgery, there were similar improvements between the treatment groups at 12-month follow-up as assessed by the iBODE score, a composite disease severity measure incorporating body mass index, airflow obstruction, dyspnea, and exercise capacity (incremental shuttle walk test), reported Sara Buttery, BSc, a research physiotherapist and PhD candidate at the National Heart and Lung Institute at Imperial College London.

“Until now there had been no direct comparison of the two to inform decision-making when a person seems to be suitable for either. Bronchoscopic lung volume reduction is a less invasive option and is thought to be ‘less risky’ but, until now, there has not been substantial research to support this,” she said at the annual congress of the European Respiratory Society.

Ms. Buttery and colleagues conducted a randomized, controlled, single-blinded superiority trial to see whether LVRS could be superior to BLVR with valves. They enrolled 88 patients (52% male) with a mean age of 64, and randomly assigned them to receive either LVRS (41 patients) or the less-invasive BLVR (47 patients).

As noted before, there were no significant differences in outcomes at 1 year, with similar degrees of improvement between the surgical techniques for both the composite iBODE score (–1.10 for LVRS vs. –0.82 for BLVR, nonsignificant), and for the individual components of the score.

In addition, the treatments were associated with similar reductions in gas trapping, with residual volume percentage predicted –36.1 with LVRS versus –30.5 with BLVR (nonsignificant).

One patient in each group died during the 12 months of follow-up. The death of the patient in the BLVR group was deemed to be treatment related; the death of the patient in the LVRS group was related to a noninfective exacerbation of chronic obstructive pulmonary disease.

Invited discussant Isabelle Opitz, MD, from University Hospital Zürich told Ms. Buttery: “I have to congratulate you for this very first randomized controlled trial comparing both procedures in a superiority design.”

She pointed out, however, that the number of patients lost to follow-up and crossover of some patients randomized to bronchoscopy raised questions about the powering of the study.

“We did a sensitivity analysis to have a look to see if there was any difference between the patients who did return and the ones who didn’t, and there was no difference at baseline between those patients.” Ms. Buttery said.

She noted that follow-up visits were hampered by the COVID-19 pandemic and the inability of many patients to come into the clinic.

Dr. Opitz also asked about COPD Assessment Test (CAT) scores that were included in the trial design but not reported in the presentation. Ms. Buttery said that the CAT results favored the LVRS group, and that the results would be included in a future economic analysis.

“The results from this first randomized controlled trial suggest that BLVR may be a good therapeutic option for those patients for whom either procedure is suitable,” said Alexander Mathioudakis, MD, PhD, from the University of Manchester (England), who was not involved with this study but commented on it in a press statement. “Lung volume reduction surgery is an invasive operation as it requires a small incision to be made in the chest, which is stitched up after the procedure. As such, it has risks associated with surgery and it takes longer to recover from than bronchoscopic lung volume reduction. On the other hand, endobronchial valves placement is also associated with side effects, such as pneumonia, or valve displacement. Therefore, both the safety and effectiveness of the two procedures need to be investigated further, in larger groups of patients, but the results from this trial are very encouraging.”

The study is supported by the U.K. National Institute of Health Research. Ms. Buttery, Dr. Opitz, and Dr. Mathioudakis reported no relevant financial relationships.

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

BARCELONA – For patients with emphysema who are suitable candidates for lung volume reduction surgery, there were no differences at 1 year in either lung function, dyspnea, or exercise capacity between patients who were assigned to undergo standard lung volume reduction surgery (LVRS) or bronchoscopic lung volume reduction with endobrachial valves (BLVR-EBV) in a randomized trial.

Among patients with emphysema amenable to surgery, there were similar improvements between the treatment groups at 12-month follow-up as assessed by the iBODE score, a composite disease severity measure incorporating body mass index, airflow obstruction, dyspnea, and exercise capacity (incremental shuttle walk test), reported Sara Buttery, BSc, a research physiotherapist and PhD candidate at the National Heart and Lung Institute at Imperial College London.

“Until now there had been no direct comparison of the two to inform decision-making when a person seems to be suitable for either. Bronchoscopic lung volume reduction is a less invasive option and is thought to be ‘less risky’ but, until now, there has not been substantial research to support this,” she said at the annual congress of the European Respiratory Society.

Ms. Buttery and colleagues conducted a randomized, controlled, single-blinded superiority trial to see whether LVRS could be superior to BLVR with valves. They enrolled 88 patients (52% male) with a mean age of 64, and randomly assigned them to receive either LVRS (41 patients) or the less-invasive BLVR (47 patients).

As noted before, there were no significant differences in outcomes at 1 year, with similar degrees of improvement between the surgical techniques for both the composite iBODE score (–1.10 for LVRS vs. –0.82 for BLVR, nonsignificant), and for the individual components of the score.

In addition, the treatments were associated with similar reductions in gas trapping, with residual volume percentage predicted –36.1 with LVRS versus –30.5 with BLVR (nonsignificant).

One patient in each group died during the 12 months of follow-up. The death of the patient in the BLVR group was deemed to be treatment related; the death of the patient in the LVRS group was related to a noninfective exacerbation of chronic obstructive pulmonary disease.

Invited discussant Isabelle Opitz, MD, from University Hospital Zürich told Ms. Buttery: “I have to congratulate you for this very first randomized controlled trial comparing both procedures in a superiority design.”

She pointed out, however, that the number of patients lost to follow-up and crossover of some patients randomized to bronchoscopy raised questions about the powering of the study.

“We did a sensitivity analysis to have a look to see if there was any difference between the patients who did return and the ones who didn’t, and there was no difference at baseline between those patients.” Ms. Buttery said.

She noted that follow-up visits were hampered by the COVID-19 pandemic and the inability of many patients to come into the clinic.

Dr. Opitz also asked about COPD Assessment Test (CAT) scores that were included in the trial design but not reported in the presentation. Ms. Buttery said that the CAT results favored the LVRS group, and that the results would be included in a future economic analysis.

“The results from this first randomized controlled trial suggest that BLVR may be a good therapeutic option for those patients for whom either procedure is suitable,” said Alexander Mathioudakis, MD, PhD, from the University of Manchester (England), who was not involved with this study but commented on it in a press statement. “Lung volume reduction surgery is an invasive operation as it requires a small incision to be made in the chest, which is stitched up after the procedure. As such, it has risks associated with surgery and it takes longer to recover from than bronchoscopic lung volume reduction. On the other hand, endobronchial valves placement is also associated with side effects, such as pneumonia, or valve displacement. Therefore, both the safety and effectiveness of the two procedures need to be investigated further, in larger groups of patients, but the results from this trial are very encouraging.”

The study is supported by the U.K. National Institute of Health Research. Ms. Buttery, Dr. Opitz, and Dr. Mathioudakis reported no relevant financial relationships.

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

The Food and Drug Administration is alerting health care providers about the potential for clip lock malfunctions with Abbott’s MitraClip’s delivery system.

“These events appear to occur in approximately 1.3% of MitraClip procedures and have been observed with all device models,” the FDA says in a letter posted on its website.

The MitraClip device was approved in 2013 for patients with symptomatic, degenerative mitral regurgitation (MR) deemed high risk for mitral-valve surgery.

In its own “urgent medical device correction letter” to providers, Abbott reports a recent increase in reports of the clips failing to “establish final arm angle (EFAA)” and of “clip opening while locked (COWL)” events.

During device preparation and prior to clip deployment, the operator intentionally attempts to open a locked clip to verify that the locking mechanism is engaged.

COWL describes when the clip arm angle increases postdeployment. “In these cases, users observe a slippage in the lock, resulting in an arm angle greater than 10 degrees from the angle observed at deployment,” which can be identified through fluoroscopy, Abbott says.

From February 2021 to January 2022, the EFAA failure rate was 0.51% and COWL rate 0.28%, increasing to 0.80% and 0.50%, respectively, from February 2022 to July 2022, according to the company.

Despite the increase in reports, the acute procedural success rate remains consistent with historical data, according to Abbott. “Further, EFAA failure or COWL most often results in no adverse patient outcomes. COWL may lead to less MR reduction, which is often treated with the use of one or more additional clips.”

Abbott says there is also a “low incidence” of required additional interventions. No immediate open surgical conversions have occurred as a result of EFAA/COWL events, whereas 0.53% of such events have resulted in nonurgent surgical conversions.

“In any case where significant residual MR is observed after clip deployment, a second clip should be considered and implanted in accordance with the IFU [instructions for use],” it advises.

Abbott says that a “change in the material properties of one of the clip locking components” has been identified as a contributing cause of EFAA/COWL events. It is working on producing new lots with updated manufacturing processing and raw material to mitigate the risk.

Certain use conditions can also contribute to EFAA/COWL events, and are referenced in the IFU, Appendix A, it notes.

The FDA is working with Abbott and recommends that health care providers do the following:

• Review the recall notice from Abbott for all MitraClip Clip Delivery Systems.
• Be aware of the potential for clip lock malfunctions before or after deployment with this device.
• Read and carefully follow the instructions for use and the recommendations provided in the recall notice to help minimize the chance of the clip failing to lock. These include recommendations about procedural steps for implant positioning, locking sequences, establishing clip arm angle, preparation for clip release, and avoiding excessive force and manipulation when unlocking the clip during device preparation and during the procedure.

Health care professionals can also report adverse reactions or quality problems they experience using these devices to the FDA’s MedWatch program.

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

The Food and Drug Administration is alerting health care providers about the potential for clip lock malfunctions with Abbott’s MitraClip’s delivery system.

“These events appear to occur in approximately 1.3% of MitraClip procedures and have been observed with all device models,” the FDA says in a letter posted on its website.

The MitraClip device was approved in 2013 for patients with symptomatic, degenerative mitral regurgitation (MR) deemed high risk for mitral-valve surgery.

In its own “urgent medical device correction letter” to providers, Abbott reports a recent increase in reports of the clips failing to “establish final arm angle (EFAA)” and of “clip opening while locked (COWL)” events.

During device preparation and prior to clip deployment, the operator intentionally attempts to open a locked clip to verify that the locking mechanism is engaged.

COWL describes when the clip arm angle increases postdeployment. “In these cases, users observe a slippage in the lock, resulting in an arm angle greater than 10 degrees from the angle observed at deployment,” which can be identified through fluoroscopy, Abbott says.

From February 2021 to January 2022, the EFAA failure rate was 0.51% and COWL rate 0.28%, increasing to 0.80% and 0.50%, respectively, from February 2022 to July 2022, according to the company.

Despite the increase in reports, the acute procedural success rate remains consistent with historical data, according to Abbott. “Further, EFAA failure or COWL most often results in no adverse patient outcomes. COWL may lead to less MR reduction, which is often treated with the use of one or more additional clips.”

Abbott says there is also a “low incidence” of required additional interventions. No immediate open surgical conversions have occurred as a result of EFAA/COWL events, whereas 0.53% of such events have resulted in nonurgent surgical conversions.

“In any case where significant residual MR is observed after clip deployment, a second clip should be considered and implanted in accordance with the IFU [instructions for use],” it advises.

Abbott says that a “change in the material properties of one of the clip locking components” has been identified as a contributing cause of EFAA/COWL events. It is working on producing new lots with updated manufacturing processing and raw material to mitigate the risk.

Certain use conditions can also contribute to EFAA/COWL events, and are referenced in the IFU, Appendix A, it notes.

The FDA is working with Abbott and recommends that health care providers do the following:

• Review the recall notice from Abbott for all MitraClip Clip Delivery Systems.
• Be aware of the potential for clip lock malfunctions before or after deployment with this device.
• Read and carefully follow the instructions for use and the recommendations provided in the recall notice to help minimize the chance of the clip failing to lock. These include recommendations about procedural steps for implant positioning, locking sequences, establishing clip arm angle, preparation for clip release, and avoiding excessive force and manipulation when unlocking the clip during device preparation and during the procedure.

Health care professionals can also report adverse reactions or quality problems they experience using these devices to the FDA’s MedWatch program.

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

The Food and Drug Administration is alerting health care providers about the potential for clip lock malfunctions with Abbott’s MitraClip’s delivery system.

“These events appear to occur in approximately 1.3% of MitraClip procedures and have been observed with all device models,” the FDA says in a letter posted on its website.

The MitraClip device was approved in 2013 for patients with symptomatic, degenerative mitral regurgitation (MR) deemed high risk for mitral-valve surgery.

In its own “urgent medical device correction letter” to providers, Abbott reports a recent increase in reports of the clips failing to “establish final arm angle (EFAA)” and of “clip opening while locked (COWL)” events.

During device preparation and prior to clip deployment, the operator intentionally attempts to open a locked clip to verify that the locking mechanism is engaged.

COWL describes when the clip arm angle increases postdeployment. “In these cases, users observe a slippage in the lock, resulting in an arm angle greater than 10 degrees from the angle observed at deployment,” which can be identified through fluoroscopy, Abbott says.

From February 2021 to January 2022, the EFAA failure rate was 0.51% and COWL rate 0.28%, increasing to 0.80% and 0.50%, respectively, from February 2022 to July 2022, according to the company.

Despite the increase in reports, the acute procedural success rate remains consistent with historical data, according to Abbott. “Further, EFAA failure or COWL most often results in no adverse patient outcomes. COWL may lead to less MR reduction, which is often treated with the use of one or more additional clips.”

Abbott says there is also a “low incidence” of required additional interventions. No immediate open surgical conversions have occurred as a result of EFAA/COWL events, whereas 0.53% of such events have resulted in nonurgent surgical conversions.

“In any case where significant residual MR is observed after clip deployment, a second clip should be considered and implanted in accordance with the IFU [instructions for use],” it advises.

Abbott says that a “change in the material properties of one of the clip locking components” has been identified as a contributing cause of EFAA/COWL events. It is working on producing new lots with updated manufacturing processing and raw material to mitigate the risk.

Certain use conditions can also contribute to EFAA/COWL events, and are referenced in the IFU, Appendix A, it notes.

The FDA is working with Abbott and recommends that health care providers do the following:

• Review the recall notice from Abbott for all MitraClip Clip Delivery Systems.
• Be aware of the potential for clip lock malfunctions before or after deployment with this device.
• Read and carefully follow the instructions for use and the recommendations provided in the recall notice to help minimize the chance of the clip failing to lock. These include recommendations about procedural steps for implant positioning, locking sequences, establishing clip arm angle, preparation for clip release, and avoiding excessive force and manipulation when unlocking the clip during device preparation and during the procedure.

Health care professionals can also report adverse reactions or quality problems they experience using these devices to the FDA’s MedWatch program.

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

Beta-blockers have long been recommended to prevent aortic dissection associated with Marfan syndrome despite limited evidence, but a new analysis also supports a benefit from angiotensin receptors blockers (ARBs) and further suggests that beta-blockers and ARBs exert independent effects.

For the endpoint of inhibition of growth of the aortic root, “there is no evidence of any interaction between the effects of ARBs with beta-blockers, and so we think that the treatment effects are likely to be additive,” reported Alex Pitcher, BMBCh, DPhil, Oxford (England) University Hospitals, NHS Trust.

Based on these data, Dr. Pitcher recommended considering ARBs and beta-blockers together soon after the diagnosis of Marfan syndrome. This includes young children.

“We think that medical treatments can delay surgery and dissection substantially if given for a number of years,” he added.

In this study, undertaken by the Marfan Treatment Trialists (MTT) collaboration, data were available from 1,442 Marfan syndrome patients participating in seven treatment trials. The primary outcome was aortic root enlargement, a predictor of life-threatening aortic dissection and rupture. Rather than a meta-analysis of the pooled data, the meta-analysis was conducted with individual patient data that involved collaboration with the original trialists.

Four of the studies with 746 patients compared ARBs to placebo or a control medication. A second group of three trials with 766 patients compared ARBs to beta-blockers.

From the two sets of data, a calculation of the effect of beta-blockers was indirectly estimated.
 

ARBs slow annualized aortic growth rate significantly

In the first set of trials, the analysis showed a significantly slower annualized aortic root growth rate for those treated with ARBs relative to controls (0.07 vs. 0.13), producing a statistically significant absolute difference (0.7%; P = .01) in favor of the ARB.

“In other words, the rate of growth was nearly double in the control arm,” Dr. Pitcher said.

In the three trials comparing ARBs to beta-blockers, the annualized growth rate among those taking an ARB was similar (0.8%) to that seen in the previous set of controlled trials. This rate of annualized growth was not significantly different from the 0.11% annualized rate of growth in patients receiving beta-blockers. When an analysis of the impact of beta-blockers was conducted by indirectly evaluating the change in growth relative to controls, the estimated impact was an annualized growth rate of 0.9% (P = .042).

A second set of data provided the basis for suggesting that the effects of beta ARBs and beta-blockers are independent and potentially additive.

“We were able to look at subgroups of patients in the ARB trials that were broken down by whether they were or were not on beta-blockers at baseline, and so by doing able to estimate independent effects,” Dr. Pitcher said. The lack of any interactions led Dr. Pitcher to conclude that benefits are likely additive.

Of patients genotyped in the ARB studies, more than 80% had the FBN1 pathogenic variant of Marfan syndrome. When the data were analyzed by subgroups, including age or blood pressure, there were no differences in treatment effect except for those with the FBN1 mutation in whom the benefit of ARB therapy was greater relative to those without.

As FBN1 is one of the most common genetic signatures of Marfan syndrome, the “greater effect of ARBs in this group makes it more plausible that the effect is real,” Dr. Pitcher said.
 

Results could change treatment guidelines

Current guidelines recommend beta-blockers in Marfan syndrome prior to a dilatation size of 4.5 to 5 cm when surgery is indicated, according to Dr. Pitcher, but he said these data might change guidelines. While reinforcing the benefit of beta-blockers, this analysis suggests ARBs should also be considered, possibly in combination with beta-blockers.

“What I hope this meta-analysis does is add substantially to the certainty with which physicians can discuss treatments with patients.”

As for the mechanism, it is reasonable to speculate the antihypertensive effect of both medications is relevant, but each has plausible independent activities that might contribute to modifying aortic growth, according to Roland R.J. van Kimmenade, MD, PhD, a specialist in aortic diseases and heart failure at Raboud University Medical Center, Nijmegan, the Netherlands.

Citing several studies, he suggested that the benefit of beta-blockers could also stem from their ability to reduce heart rate and aortic stiffness while ARBs are likely to inhibit the interaction between the renin-angiotensin system (RAS) and TGF-beta pathway. Each of these might participate in risk of aortic root growth, according to Dr. van Kimmenade, who was invited by ESC to discuss this study.

On the basis of these data as well as past studies, he agreed that the combination of beta-blockers and ARBs might not just be additive but “even a little bit synergistic.”

While Dr. Pitcher suggested that the evidence supports starting both beta-blockers and ARBs soon after the diagnosis, Dr. van Kimmenade said, “I don’t like using beta-blockers in young patients, but ARBs are now shown to be an excellent alternative.”

Ultimately, “the prescription pencil will not replace the surgical knife” in a disease that is likely to eventually require surgery to prevent life-threatening events, according to Dr. van Kimmenade, but he agreed that these data provide more certainty about the value of beta-blockers and ARBs for slowing progression.

Dr. Pitcher reports no potential conflicts of interest. Dr. van Kimmenade has financial relationships with Bayer and Novartis.

Beta-blockers have long been recommended to prevent aortic dissection associated with Marfan syndrome despite limited evidence, but a new analysis also supports a benefit from angiotensin receptors blockers (ARBs) and further suggests that beta-blockers and ARBs exert independent effects.

For the endpoint of inhibition of growth of the aortic root, “there is no evidence of any interaction between the effects of ARBs with beta-blockers, and so we think that the treatment effects are likely to be additive,” reported Alex Pitcher, BMBCh, DPhil, Oxford (England) University Hospitals, NHS Trust.

Based on these data, Dr. Pitcher recommended considering ARBs and beta-blockers together soon after the diagnosis of Marfan syndrome. This includes young children.

“We think that medical treatments can delay surgery and dissection substantially if given for a number of years,” he added.

In this study, undertaken by the Marfan Treatment Trialists (MTT) collaboration, data were available from 1,442 Marfan syndrome patients participating in seven treatment trials. The primary outcome was aortic root enlargement, a predictor of life-threatening aortic dissection and rupture. Rather than a meta-analysis of the pooled data, the meta-analysis was conducted with individual patient data that involved collaboration with the original trialists.

Four of the studies with 746 patients compared ARBs to placebo or a control medication. A second group of three trials with 766 patients compared ARBs to beta-blockers.

From the two sets of data, a calculation of the effect of beta-blockers was indirectly estimated.
 

ARBs slow annualized aortic growth rate significantly

In the first set of trials, the analysis showed a significantly slower annualized aortic root growth rate for those treated with ARBs relative to controls (0.07 vs. 0.13), producing a statistically significant absolute difference (0.7%; P = .01) in favor of the ARB.

“In other words, the rate of growth was nearly double in the control arm,” Dr. Pitcher said.

In the three trials comparing ARBs to beta-blockers, the annualized growth rate among those taking an ARB was similar (0.8%) to that seen in the previous set of controlled trials. This rate of annualized growth was not significantly different from the 0.11% annualized rate of growth in patients receiving beta-blockers. When an analysis of the impact of beta-blockers was conducted by indirectly evaluating the change in growth relative to controls, the estimated impact was an annualized growth rate of 0.9% (P = .042).

A second set of data provided the basis for suggesting that the effects of beta ARBs and beta-blockers are independent and potentially additive.

“We were able to look at subgroups of patients in the ARB trials that were broken down by whether they were or were not on beta-blockers at baseline, and so by doing able to estimate independent effects,” Dr. Pitcher said. The lack of any interactions led Dr. Pitcher to conclude that benefits are likely additive.

Of patients genotyped in the ARB studies, more than 80% had the FBN1 pathogenic variant of Marfan syndrome. When the data were analyzed by subgroups, including age or blood pressure, there were no differences in treatment effect except for those with the FBN1 mutation in whom the benefit of ARB therapy was greater relative to those without.

As FBN1 is one of the most common genetic signatures of Marfan syndrome, the “greater effect of ARBs in this group makes it more plausible that the effect is real,” Dr. Pitcher said.
 

Results could change treatment guidelines

Current guidelines recommend beta-blockers in Marfan syndrome prior to a dilatation size of 4.5 to 5 cm when surgery is indicated, according to Dr. Pitcher, but he said these data might change guidelines. While reinforcing the benefit of beta-blockers, this analysis suggests ARBs should also be considered, possibly in combination with beta-blockers.

“What I hope this meta-analysis does is add substantially to the certainty with which physicians can discuss treatments with patients.”

As for the mechanism, it is reasonable to speculate the antihypertensive effect of both medications is relevant, but each has plausible independent activities that might contribute to modifying aortic growth, according to Roland R.J. van Kimmenade, MD, PhD, a specialist in aortic diseases and heart failure at Raboud University Medical Center, Nijmegan, the Netherlands.

Citing several studies, he suggested that the benefit of beta-blockers could also stem from their ability to reduce heart rate and aortic stiffness while ARBs are likely to inhibit the interaction between the renin-angiotensin system (RAS) and TGF-beta pathway. Each of these might participate in risk of aortic root growth, according to Dr. van Kimmenade, who was invited by ESC to discuss this study.

On the basis of these data as well as past studies, he agreed that the combination of beta-blockers and ARBs might not just be additive but “even a little bit synergistic.”

While Dr. Pitcher suggested that the evidence supports starting both beta-blockers and ARBs soon after the diagnosis, Dr. van Kimmenade said, “I don’t like using beta-blockers in young patients, but ARBs are now shown to be an excellent alternative.”

Ultimately, “the prescription pencil will not replace the surgical knife” in a disease that is likely to eventually require surgery to prevent life-threatening events, according to Dr. van Kimmenade, but he agreed that these data provide more certainty about the value of beta-blockers and ARBs for slowing progression.

Dr. Pitcher reports no potential conflicts of interest. Dr. van Kimmenade has financial relationships with Bayer and Novartis.

Beta-blockers have long been recommended to prevent aortic dissection associated with Marfan syndrome despite limited evidence, but a new analysis also supports a benefit from angiotensin receptors blockers (ARBs) and further suggests that beta-blockers and ARBs exert independent effects.

For the endpoint of inhibition of growth of the aortic root, “there is no evidence of any interaction between the effects of ARBs with beta-blockers, and so we think that the treatment effects are likely to be additive,” reported Alex Pitcher, BMBCh, DPhil, Oxford (England) University Hospitals, NHS Trust.

Based on these data, Dr. Pitcher recommended considering ARBs and beta-blockers together soon after the diagnosis of Marfan syndrome. This includes young children.

“We think that medical treatments can delay surgery and dissection substantially if given for a number of years,” he added.

In this study, undertaken by the Marfan Treatment Trialists (MTT) collaboration, data were available from 1,442 Marfan syndrome patients participating in seven treatment trials. The primary outcome was aortic root enlargement, a predictor of life-threatening aortic dissection and rupture. Rather than a meta-analysis of the pooled data, the meta-analysis was conducted with individual patient data that involved collaboration with the original trialists.

Four of the studies with 746 patients compared ARBs to placebo or a control medication. A second group of three trials with 766 patients compared ARBs to beta-blockers.

From the two sets of data, a calculation of the effect of beta-blockers was indirectly estimated.
 

ARBs slow annualized aortic growth rate significantly

In the first set of trials, the analysis showed a significantly slower annualized aortic root growth rate for those treated with ARBs relative to controls (0.07 vs. 0.13), producing a statistically significant absolute difference (0.7%; P = .01) in favor of the ARB.

“In other words, the rate of growth was nearly double in the control arm,” Dr. Pitcher said.

In the three trials comparing ARBs to beta-blockers, the annualized growth rate among those taking an ARB was similar (0.8%) to that seen in the previous set of controlled trials. This rate of annualized growth was not significantly different from the 0.11% annualized rate of growth in patients receiving beta-blockers. When an analysis of the impact of beta-blockers was conducted by indirectly evaluating the change in growth relative to controls, the estimated impact was an annualized growth rate of 0.9% (P = .042).

A second set of data provided the basis for suggesting that the effects of beta ARBs and beta-blockers are independent and potentially additive.

“We were able to look at subgroups of patients in the ARB trials that were broken down by whether they were or were not on beta-blockers at baseline, and so by doing able to estimate independent effects,” Dr. Pitcher said. The lack of any interactions led Dr. Pitcher to conclude that benefits are likely additive.

Of patients genotyped in the ARB studies, more than 80% had the FBN1 pathogenic variant of Marfan syndrome. When the data were analyzed by subgroups, including age or blood pressure, there were no differences in treatment effect except for those with the FBN1 mutation in whom the benefit of ARB therapy was greater relative to those without.

As FBN1 is one of the most common genetic signatures of Marfan syndrome, the “greater effect of ARBs in this group makes it more plausible that the effect is real,” Dr. Pitcher said.
 

Results could change treatment guidelines

Current guidelines recommend beta-blockers in Marfan syndrome prior to a dilatation size of 4.5 to 5 cm when surgery is indicated, according to Dr. Pitcher, but he said these data might change guidelines. While reinforcing the benefit of beta-blockers, this analysis suggests ARBs should also be considered, possibly in combination with beta-blockers.

“What I hope this meta-analysis does is add substantially to the certainty with which physicians can discuss treatments with patients.”

As for the mechanism, it is reasonable to speculate the antihypertensive effect of both medications is relevant, but each has plausible independent activities that might contribute to modifying aortic growth, according to Roland R.J. van Kimmenade, MD, PhD, a specialist in aortic diseases and heart failure at Raboud University Medical Center, Nijmegan, the Netherlands.

Citing several studies, he suggested that the benefit of beta-blockers could also stem from their ability to reduce heart rate and aortic stiffness while ARBs are likely to inhibit the interaction between the renin-angiotensin system (RAS) and TGF-beta pathway. Each of these might participate in risk of aortic root growth, according to Dr. van Kimmenade, who was invited by ESC to discuss this study.

On the basis of these data as well as past studies, he agreed that the combination of beta-blockers and ARBs might not just be additive but “even a little bit synergistic.”

While Dr. Pitcher suggested that the evidence supports starting both beta-blockers and ARBs soon after the diagnosis, Dr. van Kimmenade said, “I don’t like using beta-blockers in young patients, but ARBs are now shown to be an excellent alternative.”

Ultimately, “the prescription pencil will not replace the surgical knife” in a disease that is likely to eventually require surgery to prevent life-threatening events, according to Dr. van Kimmenade, but he agreed that these data provide more certainty about the value of beta-blockers and ARBs for slowing progression.

Dr. Pitcher reports no potential conflicts of interest. Dr. van Kimmenade has financial relationships with Bayer and Novartis.

The study covered in this summary was published on ResearchSquare.com as a preprint and has not yet been peer reviewed.

Key takeaway

• High-dose furosemide after cardiac surgery is associated with increased mortality and other adverse outcomes.

Why this matters

• The influence of furosemide on prognosis after cardiac surgery is not fully understood.
• The current findings suggest that high-dose furosemide after cardiac surgery is associated with increased risk for death and other adverse events and therefore should be used cautiously in that setting.

Study design

• The retrospective cohort of 6,752 cardiac surgery patients was divided into two groups according to average daily furosemide dosage after cardiac surgery: less than 20 mg (low-dose group, n = 6,033) and at least 20 mg (high-dose group, n = 719).
• The group were compared for total furosemide dose, total furosemide dose of at least 200 mg, total dose of furosemide by patient weight, and average daily furosemide dose of at least 20 mg.
• The primary outcomes were in-hospital mortality and mortality at 1 year after cardiac surgery. Secondary outcomes were length of hospital stay of at least 14 days, length of ICU stay of at least 3 days, and mechanical ventilation for at least 48 hours.
• The study excluded patients aged younger than 18 whose weight data was missing or who had more than 5% of their data missing.

Key results

• Patients in the high-dose furosemide group tended to be older and have a higher body mass index (BMI) and higher rates of diabetes, chronic pulmonary diseases, heart failure, renal failure, blood transfusion, vasopressor use, and valvular surgery.
• They also tended have higher white cell counts and higher levels of blood urea nitrogen, creatinine, glucose, and lactate.
• Those in the high-dose group also were on vasopressors and ventilatory support longer.
• In adjusted multivariate analysis, increased in-hospital mortality was associated with average daily furosemide dose, average daily dose of at least 20 mg/d, and total dose of at least 200 mg.
• Increased mortality at 1 year was associated with total furosemide dose and average daily furosemide dose.
• Significant multivariate predictors of hospital stay of at least 14 days, length of ICU stay of at least 3 days, and mechanical ventilation for at least 48 hours after cardiac surgery included total furosemide dose, total dose by weight, average daily furosemide dose of at least 20 mg/d, and total dose of at least 200 mg.
• In subgroup analyses, average daily furosemide dose of at least 20 mg/d significantly increased risk for in-hospital mortality among patients younger than 60 years or with BMI of at least 28 who received vasopressors or blood transfusions, those with renal failure, and those with heart failure not involving congestion.

Limitations

• No limitations were discussed.

Disclosures

• The study was supported by grants from the National Natural Science Foundation of China, China Postdoctoral Science Foundation, and Jiangsu Postdoctoral Science Foundation.
• The authors declared that they have no competing interests.

This is a summary of a preprint research study, “Association between furosemide administration and outcomes in patients undergoing cardiac surgery,” from Jinghang Li, First Affiliated Hospital of Nanjing (China) Medical University, and colleagues on published on ResearchSquare.com. This study has not yet been peer reviewed. The full text of the study can be found on ResearchSquare.com. A version of this article first appeared on Medscape.com.

The study covered in this summary was published on ResearchSquare.com as a preprint and has not yet been peer reviewed.

Key takeaway

• High-dose furosemide after cardiac surgery is associated with increased mortality and other adverse outcomes.

Why this matters

• The influence of furosemide on prognosis after cardiac surgery is not fully understood.
• The current findings suggest that high-dose furosemide after cardiac surgery is associated with increased risk for death and other adverse events and therefore should be used cautiously in that setting.

Study design

• The retrospective cohort of 6,752 cardiac surgery patients was divided into two groups according to average daily furosemide dosage after cardiac surgery: less than 20 mg (low-dose group, n = 6,033) and at least 20 mg (high-dose group, n = 719).
• The group were compared for total furosemide dose, total furosemide dose of at least 200 mg, total dose of furosemide by patient weight, and average daily furosemide dose of at least 20 mg.
• The primary outcomes were in-hospital mortality and mortality at 1 year after cardiac surgery. Secondary outcomes were length of hospital stay of at least 14 days, length of ICU stay of at least 3 days, and mechanical ventilation for at least 48 hours.
• The study excluded patients aged younger than 18 whose weight data was missing or who had more than 5% of their data missing.

Key results

• Patients in the high-dose furosemide group tended to be older and have a higher body mass index (BMI) and higher rates of diabetes, chronic pulmonary diseases, heart failure, renal failure, blood transfusion, vasopressor use, and valvular surgery.
• They also tended have higher white cell counts and higher levels of blood urea nitrogen, creatinine, glucose, and lactate.
• Those in the high-dose group also were on vasopressors and ventilatory support longer.
• In adjusted multivariate analysis, increased in-hospital mortality was associated with average daily furosemide dose, average daily dose of at least 20 mg/d, and total dose of at least 200 mg.
• Increased mortality at 1 year was associated with total furosemide dose and average daily furosemide dose.
• Significant multivariate predictors of hospital stay of at least 14 days, length of ICU stay of at least 3 days, and mechanical ventilation for at least 48 hours after cardiac surgery included total furosemide dose, total dose by weight, average daily furosemide dose of at least 20 mg/d, and total dose of at least 200 mg.
• In subgroup analyses, average daily furosemide dose of at least 20 mg/d significantly increased risk for in-hospital mortality among patients younger than 60 years or with BMI of at least 28 who received vasopressors or blood transfusions, those with renal failure, and those with heart failure not involving congestion.

Limitations

• No limitations were discussed.

Disclosures

• The study was supported by grants from the National Natural Science Foundation of China, China Postdoctoral Science Foundation, and Jiangsu Postdoctoral Science Foundation.
• The authors declared that they have no competing interests.

This is a summary of a preprint research study, “Association between furosemide administration and outcomes in patients undergoing cardiac surgery,” from Jinghang Li, First Affiliated Hospital of Nanjing (China) Medical University, and colleagues on published on ResearchSquare.com. This study has not yet been peer reviewed. The full text of the study can be found on ResearchSquare.com. A version of this article first appeared on Medscape.com.

The study covered in this summary was published on ResearchSquare.com as a preprint and has not yet been peer reviewed.

Key takeaway

• High-dose furosemide after cardiac surgery is associated with increased mortality and other adverse outcomes.

Why this matters

• The influence of furosemide on prognosis after cardiac surgery is not fully understood.
• The current findings suggest that high-dose furosemide after cardiac surgery is associated with increased risk for death and other adverse events and therefore should be used cautiously in that setting.

Study design

• The retrospective cohort of 6,752 cardiac surgery patients was divided into two groups according to average daily furosemide dosage after cardiac surgery: less than 20 mg (low-dose group, n = 6,033) and at least 20 mg (high-dose group, n = 719).
• The group were compared for total furosemide dose, total furosemide dose of at least 200 mg, total dose of furosemide by patient weight, and average daily furosemide dose of at least 20 mg.
• The primary outcomes were in-hospital mortality and mortality at 1 year after cardiac surgery. Secondary outcomes were length of hospital stay of at least 14 days, length of ICU stay of at least 3 days, and mechanical ventilation for at least 48 hours.
• The study excluded patients aged younger than 18 whose weight data was missing or who had more than 5% of their data missing.

Key results

• Patients in the high-dose furosemide group tended to be older and have a higher body mass index (BMI) and higher rates of diabetes, chronic pulmonary diseases, heart failure, renal failure, blood transfusion, vasopressor use, and valvular surgery.
• They also tended have higher white cell counts and higher levels of blood urea nitrogen, creatinine, glucose, and lactate.
• Those in the high-dose group also were on vasopressors and ventilatory support longer.
• In adjusted multivariate analysis, increased in-hospital mortality was associated with average daily furosemide dose, average daily dose of at least 20 mg/d, and total dose of at least 200 mg.
• Increased mortality at 1 year was associated with total furosemide dose and average daily furosemide dose.
• Significant multivariate predictors of hospital stay of at least 14 days, length of ICU stay of at least 3 days, and mechanical ventilation for at least 48 hours after cardiac surgery included total furosemide dose, total dose by weight, average daily furosemide dose of at least 20 mg/d, and total dose of at least 200 mg.
• In subgroup analyses, average daily furosemide dose of at least 20 mg/d significantly increased risk for in-hospital mortality among patients younger than 60 years or with BMI of at least 28 who received vasopressors or blood transfusions, those with renal failure, and those with heart failure not involving congestion.

Limitations

• No limitations were discussed.

Disclosures

• The study was supported by grants from the National Natural Science Foundation of China, China Postdoctoral Science Foundation, and Jiangsu Postdoctoral Science Foundation.
• The authors declared that they have no competing interests.

This is a summary of a preprint research study, “Association between furosemide administration and outcomes in patients undergoing cardiac surgery,” from Jinghang Li, First Affiliated Hospital of Nanjing (China) Medical University, and colleagues on published on ResearchSquare.com. This study has not yet been peer reviewed. The full text of the study can be found on ResearchSquare.com. A version of this article first appeared on Medscape.com.

A multibiomarker risk score helps predict increased risk for future cardiovascular (CV) events as well as high-risk anatomy at revascularization in stable patients with atherosclerotic cardiovascular disease (ASCVD), a FOURIER trial analysis suggests.

The risk score incorporates high-sensitivity C-reactive protein (hsCRP), N-terminal pro B-type natriuretic peptide (NT-proBNP), high-sensitivity troponin I (hsTnI), and growth differentiation factor 15 (GDF-15).

These routine biomarkers of inflammation and fibrosis, ventricular strain, and myocardial injury are individually associated with incident CV in stable ASCVD and were shown in earlier work to be a multimarker score to predict CV events in patients stabilized after an acute coronary syndrome in the IMPROVE-IT trial.

Validating the score, however, wasn’t really the intent here, explained senior author Brian Bergmark, MD, with the TIMI Study Group, Brigham and Women’s Hospital, and Harvard Medical School, both in Boston.

“We know broadly speaking people with high troponin, BNP, et cetera, are going to have broadly defined clinical events like MIs [myocardial infarctions], death. And we also know on a granular level at a single time point that people who, for example, get a coronary CT scan and have a contemporary troponin level tend to have a little bit more coronary disease,” he said.

“But that leaves this broad swath of, what if we follow people over time? Can biomarkers in some form actually predict specific coronary anatomical characteristics and revascularization procedures in conjunction with clinical events?” Dr. Bergmark continued. “That’s sort of an untouched link or translational step between some of the granular data and these clinical events.”

As published in the Journal of the American College of Cardiology, the post hoc study analyzed baseline blood samples from 21,644 FOURIER participants and adapted the previously studied multimarker score to use hsTnI in place of high-sensitivity troponin T (hsTnT). One point was assigned for each elevated biomarker: hsCRP ≥ 2 mg/L, NT-proBNP ≥ 450 pg/mL, hsTnI ≥ 6 ng/L, and GDF-15 ≥ 1,800 pg/mL.

A total of 6,444 patients had a low score (0 points), 12,439 an intermediate score (1-2 points), and 2,761 a high score (3-4 points). Patients with higher biomarker scores were older and were more likely to have hypertension, diabetes, multiple prior MIs, heart failure, prior coronary artery bypass grafting (CABG), and peripheral artery disease but were less likely to have prior percutaneous coronary intervention (PCI).

Results showed a stepwise increase in 3-year risk for major coronary events (coronary death, MI, or coronary revascularization) from 7.3% with a low score to 11.3% with an intermediate score and 21.0% with a high score. A near tripling of risk remained in those with a high score after adjustment (hazard ratio, 2.90).

Individuals with a high score had twice the risk for any coronary revascularization (HR, 2.10) and complex revascularization (HR, 2.07), as well as increased risks for complex PCI (HR, 1.80), CABG (HR, 2.57), and in-stent restenosis (ISR) revascularization (HR, 1.78).

The study is the first to show an association of these biomarkers with future ISR revascularization in a broad cohort of patients with stable ASCVD, the investigators observe.

It could be a random signal, but “it’s one piece of data as people start to look at other datasets, as we start to understand who’s at risk for ISR, as we understand this disease entity that’s really a pandemic at this point,” Dr. Bergmark said, “I think this is one piece of the puzzle that’s novel.”

Compared with those with a low score, patients with a high biomarker score had significantly higher risks for left main disease greater than 50% (HR, 2.22; P = .003), multivessel disease (HR, 1.99; P < .001), and chronic total occlusion (HR, 2.50; P < .001) at the time of revascularization.

There was no significant interaction between the biomarker score and the effect of evolocumab used in the trial; however, the assessment had limited statistical power, the authors note.

Dr. Bergmark said that the results can inform trial design to select a population at risk for specific types of events and when trying to risk adjust in a population for reimbursement purposes to understand quality metrics, for example, for people coming back with ISR.

“I think refining risk estimates has broad applicability clinically and academically,” he added. “This is one step, with one dataset, pushing these typically broad clinical endpoints to be more specific.”

In an related editorial, Giles Montalescot, MD, PhD, Pitié-Salpêtrière Hospital, Paris, and colleagues write, “Not only does this study validate the multibiomarker score in a new cohort of patients and with new coronary-focused outcomes, but it also opens novel and interesting avenues, on a global approach of cardiovascular risk.”

Possibilities include using this or another multibiomarker risk score to streamline enrichment or selection criteria for a trial or as a surrogate endpoint in proof-of-concept trials to test a new drug aimed at reducing CV risk.

“Beyond clinical research, we could imagine in the future to base our therapeutic decisions on such a score, just like we decide anticoagulation in patients with atrial fibrillation according to the CHA₂DS₂-VASc score,” the editorialists say.

This being said, Dr. Montalescot and colleagues point out that the current multibiomarker risk score assigned equal prognostic value to each of the components, whereas IMPROVE-IT and FOURIER both showed that elevated hsTnT and NT-proBNP were associated with much higher hazard ratios than hsCRP and GDF-15.

Other limitations, they say, are that the categorical nature of the variables, albeit user friendly, prevent any subtle analysis; the score does not include biological risk factors; and questions remain about the impact of the lipid-lowering intervention across risk categories.

FOURIER was funded by Amgen. The TIMI Study Group has received institutional grant support through Brigham and Women’s Hospital from Abbott, Amgen, Anthos Therapeutics, AstraZeneca, Bayer HealthCare Pharmaceuticals, Daiichi-Sankyo, Eisai, Intarcia, MedImmune, Merck, Novartis, Pfizer, Quark Pharmaceuticals, Regeneron Pharmaceuticals, Roche, Siemens Healthcare Diagnostics, The Medicines Company, and Zora Biosciences. Dr. Bergmark reports grant support from Pfizer, Ionis, AstraZeneca, and Abbott Vascular; and consulting fees from Philips, Abbott Vascular, Servier, Daiichi-Sankyo, Janssen, and Quark Pharmaceuticals. Dr. Montalescot reports research grants to his institution or consulting/lecture fees from Abbott, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cell Prothera, CSL Behring, Europa, Idorsia, IRIS-Servier, Medtronic, MSD, Novartis, Pfizer, Quantum Genomics, and Sanofi-Aventis.

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

A multibiomarker risk score helps predict increased risk for future cardiovascular (CV) events as well as high-risk anatomy at revascularization in stable patients with atherosclerotic cardiovascular disease (ASCVD), a FOURIER trial analysis suggests.

The risk score incorporates high-sensitivity C-reactive protein (hsCRP), N-terminal pro B-type natriuretic peptide (NT-proBNP), high-sensitivity troponin I (hsTnI), and growth differentiation factor 15 (GDF-15).

These routine biomarkers of inflammation and fibrosis, ventricular strain, and myocardial injury are individually associated with incident CV in stable ASCVD and were shown in earlier work to be a multimarker score to predict CV events in patients stabilized after an acute coronary syndrome in the IMPROVE-IT trial.

Validating the score, however, wasn’t really the intent here, explained senior author Brian Bergmark, MD, with the TIMI Study Group, Brigham and Women’s Hospital, and Harvard Medical School, both in Boston.

“We know broadly speaking people with high troponin, BNP, et cetera, are going to have broadly defined clinical events like MIs [myocardial infarctions], death. And we also know on a granular level at a single time point that people who, for example, get a coronary CT scan and have a contemporary troponin level tend to have a little bit more coronary disease,” he said.

“But that leaves this broad swath of, what if we follow people over time? Can biomarkers in some form actually predict specific coronary anatomical characteristics and revascularization procedures in conjunction with clinical events?” Dr. Bergmark continued. “That’s sort of an untouched link or translational step between some of the granular data and these clinical events.”

As published in the Journal of the American College of Cardiology, the post hoc study analyzed baseline blood samples from 21,644 FOURIER participants and adapted the previously studied multimarker score to use hsTnI in place of high-sensitivity troponin T (hsTnT). One point was assigned for each elevated biomarker: hsCRP ≥ 2 mg/L, NT-proBNP ≥ 450 pg/mL, hsTnI ≥ 6 ng/L, and GDF-15 ≥ 1,800 pg/mL.

A total of 6,444 patients had a low score (0 points), 12,439 an intermediate score (1-2 points), and 2,761 a high score (3-4 points). Patients with higher biomarker scores were older and were more likely to have hypertension, diabetes, multiple prior MIs, heart failure, prior coronary artery bypass grafting (CABG), and peripheral artery disease but were less likely to have prior percutaneous coronary intervention (PCI).

Results showed a stepwise increase in 3-year risk for major coronary events (coronary death, MI, or coronary revascularization) from 7.3% with a low score to 11.3% with an intermediate score and 21.0% with a high score. A near tripling of risk remained in those with a high score after adjustment (hazard ratio, 2.90).

Individuals with a high score had twice the risk for any coronary revascularization (HR, 2.10) and complex revascularization (HR, 2.07), as well as increased risks for complex PCI (HR, 1.80), CABG (HR, 2.57), and in-stent restenosis (ISR) revascularization (HR, 1.78).

The study is the first to show an association of these biomarkers with future ISR revascularization in a broad cohort of patients with stable ASCVD, the investigators observe.

It could be a random signal, but “it’s one piece of data as people start to look at other datasets, as we start to understand who’s at risk for ISR, as we understand this disease entity that’s really a pandemic at this point,” Dr. Bergmark said, “I think this is one piece of the puzzle that’s novel.”

Compared with those with a low score, patients with a high biomarker score had significantly higher risks for left main disease greater than 50% (HR, 2.22; P = .003), multivessel disease (HR, 1.99; P < .001), and chronic total occlusion (HR, 2.50; P < .001) at the time of revascularization.

There was no significant interaction between the biomarker score and the effect of evolocumab used in the trial; however, the assessment had limited statistical power, the authors note.

Dr. Bergmark said that the results can inform trial design to select a population at risk for specific types of events and when trying to risk adjust in a population for reimbursement purposes to understand quality metrics, for example, for people coming back with ISR.

“I think refining risk estimates has broad applicability clinically and academically,” he added. “This is one step, with one dataset, pushing these typically broad clinical endpoints to be more specific.”

In an related editorial, Giles Montalescot, MD, PhD, Pitié-Salpêtrière Hospital, Paris, and colleagues write, “Not only does this study validate the multibiomarker score in a new cohort of patients and with new coronary-focused outcomes, but it also opens novel and interesting avenues, on a global approach of cardiovascular risk.”

Possibilities include using this or another multibiomarker risk score to streamline enrichment or selection criteria for a trial or as a surrogate endpoint in proof-of-concept trials to test a new drug aimed at reducing CV risk.

“Beyond clinical research, we could imagine in the future to base our therapeutic decisions on such a score, just like we decide anticoagulation in patients with atrial fibrillation according to the CHA₂DS₂-VASc score,” the editorialists say.

This being said, Dr. Montalescot and colleagues point out that the current multibiomarker risk score assigned equal prognostic value to each of the components, whereas IMPROVE-IT and FOURIER both showed that elevated hsTnT and NT-proBNP were associated with much higher hazard ratios than hsCRP and GDF-15.

Other limitations, they say, are that the categorical nature of the variables, albeit user friendly, prevent any subtle analysis; the score does not include biological risk factors; and questions remain about the impact of the lipid-lowering intervention across risk categories.

FOURIER was funded by Amgen. The TIMI Study Group has received institutional grant support through Brigham and Women’s Hospital from Abbott, Amgen, Anthos Therapeutics, AstraZeneca, Bayer HealthCare Pharmaceuticals, Daiichi-Sankyo, Eisai, Intarcia, MedImmune, Merck, Novartis, Pfizer, Quark Pharmaceuticals, Regeneron Pharmaceuticals, Roche, Siemens Healthcare Diagnostics, The Medicines Company, and Zora Biosciences. Dr. Bergmark reports grant support from Pfizer, Ionis, AstraZeneca, and Abbott Vascular; and consulting fees from Philips, Abbott Vascular, Servier, Daiichi-Sankyo, Janssen, and Quark Pharmaceuticals. Dr. Montalescot reports research grants to his institution or consulting/lecture fees from Abbott, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cell Prothera, CSL Behring, Europa, Idorsia, IRIS-Servier, Medtronic, MSD, Novartis, Pfizer, Quantum Genomics, and Sanofi-Aventis.

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

A multibiomarker risk score helps predict increased risk for future cardiovascular (CV) events as well as high-risk anatomy at revascularization in stable patients with atherosclerotic cardiovascular disease (ASCVD), a FOURIER trial analysis suggests.

The risk score incorporates high-sensitivity C-reactive protein (hsCRP), N-terminal pro B-type natriuretic peptide (NT-proBNP), high-sensitivity troponin I (hsTnI), and growth differentiation factor 15 (GDF-15).

These routine biomarkers of inflammation and fibrosis, ventricular strain, and myocardial injury are individually associated with incident CV in stable ASCVD and were shown in earlier work to be a multimarker score to predict CV events in patients stabilized after an acute coronary syndrome in the IMPROVE-IT trial.

Validating the score, however, wasn’t really the intent here, explained senior author Brian Bergmark, MD, with the TIMI Study Group, Brigham and Women’s Hospital, and Harvard Medical School, both in Boston.

“We know broadly speaking people with high troponin, BNP, et cetera, are going to have broadly defined clinical events like MIs [myocardial infarctions], death. And we also know on a granular level at a single time point that people who, for example, get a coronary CT scan and have a contemporary troponin level tend to have a little bit more coronary disease,” he said.

“But that leaves this broad swath of, what if we follow people over time? Can biomarkers in some form actually predict specific coronary anatomical characteristics and revascularization procedures in conjunction with clinical events?” Dr. Bergmark continued. “That’s sort of an untouched link or translational step between some of the granular data and these clinical events.”

As published in the Journal of the American College of Cardiology, the post hoc study analyzed baseline blood samples from 21,644 FOURIER participants and adapted the previously studied multimarker score to use hsTnI in place of high-sensitivity troponin T (hsTnT). One point was assigned for each elevated biomarker: hsCRP ≥ 2 mg/L, NT-proBNP ≥ 450 pg/mL, hsTnI ≥ 6 ng/L, and GDF-15 ≥ 1,800 pg/mL.

A total of 6,444 patients had a low score (0 points), 12,439 an intermediate score (1-2 points), and 2,761 a high score (3-4 points). Patients with higher biomarker scores were older and were more likely to have hypertension, diabetes, multiple prior MIs, heart failure, prior coronary artery bypass grafting (CABG), and peripheral artery disease but were less likely to have prior percutaneous coronary intervention (PCI).

Results showed a stepwise increase in 3-year risk for major coronary events (coronary death, MI, or coronary revascularization) from 7.3% with a low score to 11.3% with an intermediate score and 21.0% with a high score. A near tripling of risk remained in those with a high score after adjustment (hazard ratio, 2.90).

Individuals with a high score had twice the risk for any coronary revascularization (HR, 2.10) and complex revascularization (HR, 2.07), as well as increased risks for complex PCI (HR, 1.80), CABG (HR, 2.57), and in-stent restenosis (ISR) revascularization (HR, 1.78).

The study is the first to show an association of these biomarkers with future ISR revascularization in a broad cohort of patients with stable ASCVD, the investigators observe.

It could be a random signal, but “it’s one piece of data as people start to look at other datasets, as we start to understand who’s at risk for ISR, as we understand this disease entity that’s really a pandemic at this point,” Dr. Bergmark said, “I think this is one piece of the puzzle that’s novel.”

Compared with those with a low score, patients with a high biomarker score had significantly higher risks for left main disease greater than 50% (HR, 2.22; P = .003), multivessel disease (HR, 1.99; P < .001), and chronic total occlusion (HR, 2.50; P < .001) at the time of revascularization.

There was no significant interaction between the biomarker score and the effect of evolocumab used in the trial; however, the assessment had limited statistical power, the authors note.

Dr. Bergmark said that the results can inform trial design to select a population at risk for specific types of events and when trying to risk adjust in a population for reimbursement purposes to understand quality metrics, for example, for people coming back with ISR.

“I think refining risk estimates has broad applicability clinically and academically,” he added. “This is one step, with one dataset, pushing these typically broad clinical endpoints to be more specific.”

In an related editorial, Giles Montalescot, MD, PhD, Pitié-Salpêtrière Hospital, Paris, and colleagues write, “Not only does this study validate the multibiomarker score in a new cohort of patients and with new coronary-focused outcomes, but it also opens novel and interesting avenues, on a global approach of cardiovascular risk.”

Possibilities include using this or another multibiomarker risk score to streamline enrichment or selection criteria for a trial or as a surrogate endpoint in proof-of-concept trials to test a new drug aimed at reducing CV risk.

“Beyond clinical research, we could imagine in the future to base our therapeutic decisions on such a score, just like we decide anticoagulation in patients with atrial fibrillation according to the CHA₂DS₂-VASc score,” the editorialists say.

This being said, Dr. Montalescot and colleagues point out that the current multibiomarker risk score assigned equal prognostic value to each of the components, whereas IMPROVE-IT and FOURIER both showed that elevated hsTnT and NT-proBNP were associated with much higher hazard ratios than hsCRP and GDF-15.

Other limitations, they say, are that the categorical nature of the variables, albeit user friendly, prevent any subtle analysis; the score does not include biological risk factors; and questions remain about the impact of the lipid-lowering intervention across risk categories.

FOURIER was funded by Amgen. The TIMI Study Group has received institutional grant support through Brigham and Women’s Hospital from Abbott, Amgen, Anthos Therapeutics, AstraZeneca, Bayer HealthCare Pharmaceuticals, Daiichi-Sankyo, Eisai, Intarcia, MedImmune, Merck, Novartis, Pfizer, Quark Pharmaceuticals, Regeneron Pharmaceuticals, Roche, Siemens Healthcare Diagnostics, The Medicines Company, and Zora Biosciences. Dr. Bergmark reports grant support from Pfizer, Ionis, AstraZeneca, and Abbott Vascular; and consulting fees from Philips, Abbott Vascular, Servier, Daiichi-Sankyo, Janssen, and Quark Pharmaceuticals. Dr. Montalescot reports research grants to his institution or consulting/lecture fees from Abbott, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cell Prothera, CSL Behring, Europa, Idorsia, IRIS-Servier, Medtronic, MSD, Novartis, Pfizer, Quantum Genomics, and Sanofi-Aventis.

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

Wide variation in the cost of common cardiovascular (CV) tests and procedures, from stress tests to coronary interventions, was revealed in a cross-sectional analysis based on publicly available data from 20 top-ranked hospitals in the United States.

The analysis also suggested a low level of compliance with the 2021 Hospital Price Transparency Final Rule among the 20 centers.

“The variation we found in payer-negotiated prices for identical cardiovascular tests and procedures was stunning,” Rishi K. Wadhera, MD, MPP, MPhil, Beth Israel Deaconess Medical Center, Boston, told this news organization.

KatarzynaBialasiewicz/Thinkstock

Difficulties with data, interpretation

The researchers looked at payer and self-pay cash prices for noninvasive and invasive CV tests and procedures at the U.S. News & World Report 2021 top 20–ranked U.S. hospitals, based in part on Current Procedural Terminology codes.

Price differences among the hospitals were derived from median negotiated prices for each test and procedure at the centers across all payers. The interquartile ratio (IQR) of prices for each test or procedure across payers was used to evaluate within-hospital price variation.

“Only 80% of the hospitals reported prices for some cardiovascular tests and procedures,” Dr. Wadhera said. “For the most part, even among the hospitals that did report this information, it was extremely challenging to navigate and interpret the data provided.”

Further, the team found that only 7 of the 20 hospitals reported prices for all CV tests and procedures. Centers that did not post prices for some tests or procedures are named in the report’s Figure 1 and Figure 2.

The number of insurance plans listed for each test or procedure ranged from 1 to 432 in the analysis. Median prices ranged from $204 to $2,588 for an echocardiogram, $463 to $3,230 for a stress test, $2,821 to $9,382 for right heart catheterization, $2,868 to $9,203 for a coronary angiogram, $657 to $25,521 for a PCI, and $506 to $20,002 for pacemaker implantation, the report states.

A similar pattern was seen for self-pay cash prices.

Within-hospital variation also ranged broadly. For example, the widest IQR ranges were $3,143-$12,926 for a right heart catheterization, $4,011-$14,486 for a coronary angiogram, $11,325-$23,392 for a PCI, and $8,474-$22,694 for pacemaker implantation.

The report cites a number of limitations to the analysis, among those, the need to rely on the hospitals themselves for data quality and accuracy.
 

‘More needed besides transparency’

“As a means to better understand health care costs, many opined that full price transparency would leverage market dynamics and result in lower costs,” observed Clyde W. Yancy, MD, MSc, professor of medicine and chief of cardiology at Northwestern Medicine, Chicago. The findings “by an expert group of outcomes scientists make clear that more is needed besides price transparency to lower cost,” he said in an interview.

That said, he added, “there are sufficient variations and allowances made for data collection that it is preferable to hold the current findings circumspect at best. Importantly, the voice of the hospitals does not appear.”

Although “price variation among the top 20 hospitals is substantial,” he observed, “without a better assessment of root cause, actual charge capture, prevailing market dynamics – especially nursing and ancillary staff costs – and the general influence of inflation, it is too difficult to emerge with a precise interpretation.”

Across the 20 hospitals, “there are likely to be 20 different business models,” he added, with negotiated prices reflecting “at least regional, if not institutional, variations.”

“These are complex issues. The several-fold price differences in standard procedures are a concern and an area worth further study with the intention of lowering health care costs,” Dr. Yancy said. “But clearly our next efforts should not address lowering prices per se but understanding how prices are set [and] the connection with reimbursement and actual payments.”

Dr. Wadhera discloses receiving personal fees from Abbott and CVS Health unrelated to the current study; disclosures for the other authors are in the report. Dr. Yancy is deputy editor of JAMA Cardiology.

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

Wide variation in the cost of common cardiovascular (CV) tests and procedures, from stress tests to coronary interventions, was revealed in a cross-sectional analysis based on publicly available data from 20 top-ranked hospitals in the United States.

The analysis also suggested a low level of compliance with the 2021 Hospital Price Transparency Final Rule among the 20 centers.

“The variation we found in payer-negotiated prices for identical cardiovascular tests and procedures was stunning,” Rishi K. Wadhera, MD, MPP, MPhil, Beth Israel Deaconess Medical Center, Boston, told this news organization.

KatarzynaBialasiewicz/Thinkstock

Difficulties with data, interpretation

The researchers looked at payer and self-pay cash prices for noninvasive and invasive CV tests and procedures at the U.S. News & World Report 2021 top 20–ranked U.S. hospitals, based in part on Current Procedural Terminology codes.

Price differences among the hospitals were derived from median negotiated prices for each test and procedure at the centers across all payers. The interquartile ratio (IQR) of prices for each test or procedure across payers was used to evaluate within-hospital price variation.

“Only 80% of the hospitals reported prices for some cardiovascular tests and procedures,” Dr. Wadhera said. “For the most part, even among the hospitals that did report this information, it was extremely challenging to navigate and interpret the data provided.”

Further, the team found that only 7 of the 20 hospitals reported prices for all CV tests and procedures. Centers that did not post prices for some tests or procedures are named in the report’s Figure 1 and Figure 2.

The number of insurance plans listed for each test or procedure ranged from 1 to 432 in the analysis. Median prices ranged from $204 to $2,588 for an echocardiogram, $463 to $3,230 for a stress test, $2,821 to $9,382 for right heart catheterization, $2,868 to $9,203 for a coronary angiogram, $657 to $25,521 for a PCI, and $506 to $20,002 for pacemaker implantation, the report states.

A similar pattern was seen for self-pay cash prices.

Within-hospital variation also ranged broadly. For example, the widest IQR ranges were $3,143-$12,926 for a right heart catheterization, $4,011-$14,486 for a coronary angiogram, $11,325-$23,392 for a PCI, and $8,474-$22,694 for pacemaker implantation.

The report cites a number of limitations to the analysis, among those, the need to rely on the hospitals themselves for data quality and accuracy.
 

‘More needed besides transparency’

“As a means to better understand health care costs, many opined that full price transparency would leverage market dynamics and result in lower costs,” observed Clyde W. Yancy, MD, MSc, professor of medicine and chief of cardiology at Northwestern Medicine, Chicago. The findings “by an expert group of outcomes scientists make clear that more is needed besides price transparency to lower cost,” he said in an interview.

That said, he added, “there are sufficient variations and allowances made for data collection that it is preferable to hold the current findings circumspect at best. Importantly, the voice of the hospitals does not appear.”

Although “price variation among the top 20 hospitals is substantial,” he observed, “without a better assessment of root cause, actual charge capture, prevailing market dynamics – especially nursing and ancillary staff costs – and the general influence of inflation, it is too difficult to emerge with a precise interpretation.”

Across the 20 hospitals, “there are likely to be 20 different business models,” he added, with negotiated prices reflecting “at least regional, if not institutional, variations.”

“These are complex issues. The several-fold price differences in standard procedures are a concern and an area worth further study with the intention of lowering health care costs,” Dr. Yancy said. “But clearly our next efforts should not address lowering prices per se but understanding how prices are set [and] the connection with reimbursement and actual payments.”

Dr. Wadhera discloses receiving personal fees from Abbott and CVS Health unrelated to the current study; disclosures for the other authors are in the report. Dr. Yancy is deputy editor of JAMA Cardiology.

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

Wide variation in the cost of common cardiovascular (CV) tests and procedures, from stress tests to coronary interventions, was revealed in a cross-sectional analysis based on publicly available data from 20 top-ranked hospitals in the United States.

The analysis also suggested a low level of compliance with the 2021 Hospital Price Transparency Final Rule among the 20 centers.

“The variation we found in payer-negotiated prices for identical cardiovascular tests and procedures was stunning,” Rishi K. Wadhera, MD, MPP, MPhil, Beth Israel Deaconess Medical Center, Boston, told this news organization.

KatarzynaBialasiewicz/Thinkstock

Difficulties with data, interpretation

The researchers looked at payer and self-pay cash prices for noninvasive and invasive CV tests and procedures at the U.S. News & World Report 2021 top 20–ranked U.S. hospitals, based in part on Current Procedural Terminology codes.

Price differences among the hospitals were derived from median negotiated prices for each test and procedure at the centers across all payers. The interquartile ratio (IQR) of prices for each test or procedure across payers was used to evaluate within-hospital price variation.

“Only 80% of the hospitals reported prices for some cardiovascular tests and procedures,” Dr. Wadhera said. “For the most part, even among the hospitals that did report this information, it was extremely challenging to navigate and interpret the data provided.”

Further, the team found that only 7 of the 20 hospitals reported prices for all CV tests and procedures. Centers that did not post prices for some tests or procedures are named in the report’s Figure 1 and Figure 2.

The number of insurance plans listed for each test or procedure ranged from 1 to 432 in the analysis. Median prices ranged from $204 to $2,588 for an echocardiogram, $463 to $3,230 for a stress test, $2,821 to $9,382 for right heart catheterization, $2,868 to $9,203 for a coronary angiogram, $657 to $25,521 for a PCI, and $506 to $20,002 for pacemaker implantation, the report states.

A similar pattern was seen for self-pay cash prices.

Within-hospital variation also ranged broadly. For example, the widest IQR ranges were $3,143-$12,926 for a right heart catheterization, $4,011-$14,486 for a coronary angiogram, $11,325-$23,392 for a PCI, and $8,474-$22,694 for pacemaker implantation.

The report cites a number of limitations to the analysis, among those, the need to rely on the hospitals themselves for data quality and accuracy.
 

‘More needed besides transparency’

“As a means to better understand health care costs, many opined that full price transparency would leverage market dynamics and result in lower costs,” observed Clyde W. Yancy, MD, MSc, professor of medicine and chief of cardiology at Northwestern Medicine, Chicago. The findings “by an expert group of outcomes scientists make clear that more is needed besides price transparency to lower cost,” he said in an interview.

That said, he added, “there are sufficient variations and allowances made for data collection that it is preferable to hold the current findings circumspect at best. Importantly, the voice of the hospitals does not appear.”

Although “price variation among the top 20 hospitals is substantial,” he observed, “without a better assessment of root cause, actual charge capture, prevailing market dynamics – especially nursing and ancillary staff costs – and the general influence of inflation, it is too difficult to emerge with a precise interpretation.”

Across the 20 hospitals, “there are likely to be 20 different business models,” he added, with negotiated prices reflecting “at least regional, if not institutional, variations.”

“These are complex issues. The several-fold price differences in standard procedures are a concern and an area worth further study with the intention of lowering health care costs,” Dr. Yancy said. “But clearly our next efforts should not address lowering prices per se but understanding how prices are set [and] the connection with reimbursement and actual payments.”

Dr. Wadhera discloses receiving personal fees from Abbott and CVS Health unrelated to the current study; disclosures for the other authors are in the report. Dr. Yancy is deputy editor of JAMA Cardiology.

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

The long-struggling field of cardiac xenotransplantation has had a very good year.

In January, the University of Maryland made history by keeping a 57-year-old man deemed too sick for a human heart transplant alive for 2 months with a genetically engineered pig heart. On July 12, New York University surgeons reported that heart function was “completely normal with excellent contractility” in two brain-dead patients with pig hearts beating in their chests for 72 hours.

NYU Langone Health

The NYU team approached the project with a decedent model in mind and, after discussions with their IRB equivalent, settled on a 72-hour window because that’s the time they typically keep people ventilated when trying to place their organs, explained Robert A. Montgomery, MD, DPhil, director of the NYU Langone Transplant Institute.

“There’s no real ethical argument for that,” he said in an interview. The consideration is what the family is willing to do when trying to balance doing “something very altruistic and good versus having closure.”

Some families have religious beliefs that burial or interment has to occur very rapidly, whereas others, including one of the family donors, were willing to have the research go on much longer, Dr. Montgomery said. Indeed, the next protocol is being written to consider maintaining the bodies for 2-4 weeks.

“People do vary and you have to kind of accommodate that variation,” he said. “For some people, this isn’t going to be what they’re going to want and that’s why you have to go through the consent process.”
 

Informed authorization

Arthur L. Caplan, PhD, director of medical ethics at the NYU Langone Medical Center, said the Uniform Anatomical Gift Act recognizes an individual’s right to be an organ donor for transplant and research, but it “mentions nothing about maintaining you in a dead state artificially for research purposes.”

“It’s a major shift in what people are thinking about doing when they die or their relatives die,” he said.

Because organ donation is controlled at the state, not federal, level, the possibility of donating organs for xenotransplantation, like medical aid in dying, will vary between states, observed Dr. Caplan. The best way to ensure that patients whose organs are found to be unsuitable for transplantation have the option is to change state laws.

He noted that cases are already springing up where people are requesting postmortem sperm or egg donations without direct consents from the person who died. “So we have this new area opening up of handling the use of the dead body and we need to bring the law into sync with the possibilities that are out there.”

In terms of informed authorization (informed consent is reserved for the living), Dr. Caplan said there should be written evidence the person wanted to be a donor and, while not required by law, all survivors should give their permission and understand what’s going to be done in terms of the experiment, such as the use of animal parts, when the body will be returned, and the possibility of zoonotic viral infection.

“They have to fully accept that the person is dead and we’re just maintaining them artificially,” he said. “There’s no maintaining anyone who’s alive. That’s a source of a lot of confusion.”

Special committees also need to be appointed with voices from people in organ procurement, law, theology, and patient groups to monitor practice to ensure people who have given permission understood the process, that families have their questions answered independent of the research team, and that clear limits are set on how long experiments will last.

As to what those limits should be: “I think in terms of a week or 2,” Dr. Caplan said. “Obviously we could maintain bodies longer and people have. But I think, culturally in our society, going much past that starts to perhaps stress emotionally, psychologically, family and friends about getting closure.”

“I’m not as comfortable when people say things like, ‘How about 2 months?’ ” he said. “That’s a long time to sort of accept the fact that somebody has died but you can’t complete all the things that go along with the death.”

Dr. Caplan is also uncomfortable with the use of one-off emergency authorizations, as used for Maryland resident David Bennett Sr., who was rejected for standard heart transplantation and required mechanical circulatory support to stay alive.

“It’s too premature, I believe, even to try and rescue someone,” he said. “We need to learn more from the deceased models.”
 

A better model

Dr. Montgomery noted that primates are very imperfect models for predicting what’s going to happen in humans, and that in order to do xenotransplantation in living humans, there are only two pathways – the one-off emergency authorization or a clinical phase 1 trial.

The decedent model, he said, “will make human trials safer because it’s an intermediate step. You don’t have a living human’s life on the line when you’re trying to do iterative changes and improve the procedure.”

Joe Carrotta for NYU Langone Health

The team, for example, omitted a perfusion pump that was used in the Maryland case and would likely have made its way into phase 1 trials based on baboon data that suggested it was important to have the heart on the pump for hours before it was transplanted, he said. “We didn’t do any of that. We just did it like we would do a regular heart transplant and it started right up, immediately, and started to work.”

The researchers did not release details on the immunosuppression regimen, but noted that, unlike Maryland, they also did not use the experimental anti-CD40 antibody to tamp down the recipients’ immune system.

Although Mr. Bennett’s autopsy did not show any conventional sign of graft rejection, the transplanted pig heart was infected with porcine cytomegalovirus (PCMV) and Mr. Bennett showed traces of DNA from PCMV in his circulation.
 

Nailing down safety

Dr. Montgomery said he wouldn’t rule out xenotransplantation in a living human, but that the safety issues need to be nailed down. “I think that the tests used on the pig that was the donor for the Bennett case were not sensitive enough for latent virus, and that’s how it slipped through. So there was a bit of going back to the drawing board, really looking at each of the tests, and being sure we had the sensitivity to pick up a latent virus.”

He noted that United Therapeutics, which funded the research and provided the engineered pigs through its subsidiary Revivicor, has created and validated a more sensitive polymerase chain reaction test that covers some 35 different pathogens, microbes, and parasites. NYU has also developed its own platform to repeat the testing and for monitoring after the transplant. “The ones that we’re currently using would have picked up the virus.”

Stuart Russell, MD, a professor of medicine who specializes in advanced HF at Duke University, Durham, N.C., said “the biggest thing from my perspective is those two amazing families that were willing let this happen. ... If 20 years from now, this is what we’re doing, it’s related to these families being this generous at a really tough time in their lives.”

Dr. Russell said he awaits publication of the data on what the pathology of the heart looks like, but that the experiments “help to give us a lot of reassurance that we don’t need to worry about hyperacute rejection,” which by definition is going to happen in the first 24-48 hours.

That said, longer-term data is essential to potential safety issues. Notably, among the 10 genetic modifications made to the pigs, four were porcine gene knockouts, including a growth hormone receptor knockout to prevent abnormal organ growth inside the recipient’s chest. As a result, the organs seem to be small for the age of the pig and just don’t grow that well, admitted Dr. Montgomery, who said they are currently analyzing this with echocardiography.

Dr. Russell said this may create a sizing issue, but also “if you have a heart that’s more stressed in the pig, from the point of being a donor, maybe it’s not as good a heart as if it was growing normally. But that kind of stuff, I think, is going to take more than two cases and longer-term data to sort out.”

Sharon Hunt, MD, professor emerita, Stanford (Calif.) University Medical Center, and past president of the International Society for Heart Lung Transplantation, said it’s not the technical aspects, but the biology of xenotransplantation that’s really daunting.

“It’s not the physical act of doing it, like they needed a bigger heart or a smaller heart. Those are technical problems but they’ll manage them,” she said. “The big problem is biological – and the bottom line is we don’t really know. We may have overcome hyperacute rejection, which is great, but the rest remains to be seen.”

Dr. Hunt, who worked with heart transplantation pioneer Norman Shumway, MD, and spent decades caring for patients after transplantation, said most families will consent to 24 or 48 hours or even a week of experimentation on a brain-dead loved one, but what the transplant community wants to know is whether this is workable for many months.

“So the fact that the xenotransplant works for 72 hours, yeah, that’s groovy. But, you know, the answer is kind of ‘so what,’ ” she said. “I’d like to see this go for months, like they were trying to do in the human in Maryland.”

For phase 1 trials, even longer-term survival with or without rejection or with rejection that’s treatable is needed, Dr. Hunt suggested.

“We haven’t seen that yet. The Maryland people were very valiant but they lost the cause,” she said. “There’s just so much more to do before we have a viable model to start anything like a phase 1 trial. I’d love it if that happens in my lifetime, but I’m not sure it’s going to.”

Dr. Russell and Dr. Hunt reported no relevant financial relationships. Dr. Caplan reported serving as a director, officer, partner, employee, advisor, consultant, or trustee for Johnson & Johnson’s Panel for Compassionate Drug Use (unpaid position) and is a contributing author and adviser for Medscape.

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

The long-struggling field of cardiac xenotransplantation has had a very good year.

In January, the University of Maryland made history by keeping a 57-year-old man deemed too sick for a human heart transplant alive for 2 months with a genetically engineered pig heart. On July 12, New York University surgeons reported that heart function was “completely normal with excellent contractility” in two brain-dead patients with pig hearts beating in their chests for 72 hours.

NYU Langone Health

The NYU team approached the project with a decedent model in mind and, after discussions with their IRB equivalent, settled on a 72-hour window because that’s the time they typically keep people ventilated when trying to place their organs, explained Robert A. Montgomery, MD, DPhil, director of the NYU Langone Transplant Institute.

“There’s no real ethical argument for that,” he said in an interview. The consideration is what the family is willing to do when trying to balance doing “something very altruistic and good versus having closure.”

Some families have religious beliefs that burial or interment has to occur very rapidly, whereas others, including one of the family donors, were willing to have the research go on much longer, Dr. Montgomery said. Indeed, the next protocol is being written to consider maintaining the bodies for 2-4 weeks.

“People do vary and you have to kind of accommodate that variation,” he said. “For some people, this isn’t going to be what they’re going to want and that’s why you have to go through the consent process.”
 

Informed authorization

Arthur L. Caplan, PhD, director of medical ethics at the NYU Langone Medical Center, said the Uniform Anatomical Gift Act recognizes an individual’s right to be an organ donor for transplant and research, but it “mentions nothing about maintaining you in a dead state artificially for research purposes.”

“It’s a major shift in what people are thinking about doing when they die or their relatives die,” he said.

Because organ donation is controlled at the state, not federal, level, the possibility of donating organs for xenotransplantation, like medical aid in dying, will vary between states, observed Dr. Caplan. The best way to ensure that patients whose organs are found to be unsuitable for transplantation have the option is to change state laws.

He noted that cases are already springing up where people are requesting postmortem sperm or egg donations without direct consents from the person who died. “So we have this new area opening up of handling the use of the dead body and we need to bring the law into sync with the possibilities that are out there.”

In terms of informed authorization (informed consent is reserved for the living), Dr. Caplan said there should be written evidence the person wanted to be a donor and, while not required by law, all survivors should give their permission and understand what’s going to be done in terms of the experiment, such as the use of animal parts, when the body will be returned, and the possibility of zoonotic viral infection.

“They have to fully accept that the person is dead and we’re just maintaining them artificially,” he said. “There’s no maintaining anyone who’s alive. That’s a source of a lot of confusion.”

Special committees also need to be appointed with voices from people in organ procurement, law, theology, and patient groups to monitor practice to ensure people who have given permission understood the process, that families have their questions answered independent of the research team, and that clear limits are set on how long experiments will last.

As to what those limits should be: “I think in terms of a week or 2,” Dr. Caplan said. “Obviously we could maintain bodies longer and people have. But I think, culturally in our society, going much past that starts to perhaps stress emotionally, psychologically, family and friends about getting closure.”

“I’m not as comfortable when people say things like, ‘How about 2 months?’ ” he said. “That’s a long time to sort of accept the fact that somebody has died but you can’t complete all the things that go along with the death.”

Dr. Caplan is also uncomfortable with the use of one-off emergency authorizations, as used for Maryland resident David Bennett Sr., who was rejected for standard heart transplantation and required mechanical circulatory support to stay alive.

“It’s too premature, I believe, even to try and rescue someone,” he said. “We need to learn more from the deceased models.”
 

A better model

Dr. Montgomery noted that primates are very imperfect models for predicting what’s going to happen in humans, and that in order to do xenotransplantation in living humans, there are only two pathways – the one-off emergency authorization or a clinical phase 1 trial.

The decedent model, he said, “will make human trials safer because it’s an intermediate step. You don’t have a living human’s life on the line when you’re trying to do iterative changes and improve the procedure.”

Joe Carrotta for NYU Langone Health

The team, for example, omitted a perfusion pump that was used in the Maryland case and would likely have made its way into phase 1 trials based on baboon data that suggested it was important to have the heart on the pump for hours before it was transplanted, he said. “We didn’t do any of that. We just did it like we would do a regular heart transplant and it started right up, immediately, and started to work.”

The researchers did not release details on the immunosuppression regimen, but noted that, unlike Maryland, they also did not use the experimental anti-CD40 antibody to tamp down the recipients’ immune system.

Although Mr. Bennett’s autopsy did not show any conventional sign of graft rejection, the transplanted pig heart was infected with porcine cytomegalovirus (PCMV) and Mr. Bennett showed traces of DNA from PCMV in his circulation.
 

Nailing down safety

Dr. Montgomery said he wouldn’t rule out xenotransplantation in a living human, but that the safety issues need to be nailed down. “I think that the tests used on the pig that was the donor for the Bennett case were not sensitive enough for latent virus, and that’s how it slipped through. So there was a bit of going back to the drawing board, really looking at each of the tests, and being sure we had the sensitivity to pick up a latent virus.”

He noted that United Therapeutics, which funded the research and provided the engineered pigs through its subsidiary Revivicor, has created and validated a more sensitive polymerase chain reaction test that covers some 35 different pathogens, microbes, and parasites. NYU has also developed its own platform to repeat the testing and for monitoring after the transplant. “The ones that we’re currently using would have picked up the virus.”

Stuart Russell, MD, a professor of medicine who specializes in advanced HF at Duke University, Durham, N.C., said “the biggest thing from my perspective is those two amazing families that were willing let this happen. ... If 20 years from now, this is what we’re doing, it’s related to these families being this generous at a really tough time in their lives.”

Dr. Russell said he awaits publication of the data on what the pathology of the heart looks like, but that the experiments “help to give us a lot of reassurance that we don’t need to worry about hyperacute rejection,” which by definition is going to happen in the first 24-48 hours.

That said, longer-term data is essential to potential safety issues. Notably, among the 10 genetic modifications made to the pigs, four were porcine gene knockouts, including a growth hormone receptor knockout to prevent abnormal organ growth inside the recipient’s chest. As a result, the organs seem to be small for the age of the pig and just don’t grow that well, admitted Dr. Montgomery, who said they are currently analyzing this with echocardiography.

Dr. Russell said this may create a sizing issue, but also “if you have a heart that’s more stressed in the pig, from the point of being a donor, maybe it’s not as good a heart as if it was growing normally. But that kind of stuff, I think, is going to take more than two cases and longer-term data to sort out.”

Sharon Hunt, MD, professor emerita, Stanford (Calif.) University Medical Center, and past president of the International Society for Heart Lung Transplantation, said it’s not the technical aspects, but the biology of xenotransplantation that’s really daunting.

“It’s not the physical act of doing it, like they needed a bigger heart or a smaller heart. Those are technical problems but they’ll manage them,” she said. “The big problem is biological – and the bottom line is we don’t really know. We may have overcome hyperacute rejection, which is great, but the rest remains to be seen.”

Dr. Hunt, who worked with heart transplantation pioneer Norman Shumway, MD, and spent decades caring for patients after transplantation, said most families will consent to 24 or 48 hours or even a week of experimentation on a brain-dead loved one, but what the transplant community wants to know is whether this is workable for many months.

“So the fact that the xenotransplant works for 72 hours, yeah, that’s groovy. But, you know, the answer is kind of ‘so what,’ ” she said. “I’d like to see this go for months, like they were trying to do in the human in Maryland.”

For phase 1 trials, even longer-term survival with or without rejection or with rejection that’s treatable is needed, Dr. Hunt suggested.

“We haven’t seen that yet. The Maryland people were very valiant but they lost the cause,” she said. “There’s just so much more to do before we have a viable model to start anything like a phase 1 trial. I’d love it if that happens in my lifetime, but I’m not sure it’s going to.”

Dr. Russell and Dr. Hunt reported no relevant financial relationships. Dr. Caplan reported serving as a director, officer, partner, employee, advisor, consultant, or trustee for Johnson & Johnson’s Panel for Compassionate Drug Use (unpaid position) and is a contributing author and adviser for Medscape.

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

The long-struggling field of cardiac xenotransplantation has had a very good year.

In January, the University of Maryland made history by keeping a 57-year-old man deemed too sick for a human heart transplant alive for 2 months with a genetically engineered pig heart. On July 12, New York University surgeons reported that heart function was “completely normal with excellent contractility” in two brain-dead patients with pig hearts beating in their chests for 72 hours.

NYU Langone Health

The NYU team approached the project with a decedent model in mind and, after discussions with their IRB equivalent, settled on a 72-hour window because that’s the time they typically keep people ventilated when trying to place their organs, explained Robert A. Montgomery, MD, DPhil, director of the NYU Langone Transplant Institute.

“There’s no real ethical argument for that,” he said in an interview. The consideration is what the family is willing to do when trying to balance doing “something very altruistic and good versus having closure.”

Some families have religious beliefs that burial or interment has to occur very rapidly, whereas others, including one of the family donors, were willing to have the research go on much longer, Dr. Montgomery said. Indeed, the next protocol is being written to consider maintaining the bodies for 2-4 weeks.

“People do vary and you have to kind of accommodate that variation,” he said. “For some people, this isn’t going to be what they’re going to want and that’s why you have to go through the consent process.”
 

Informed authorization

Arthur L. Caplan, PhD, director of medical ethics at the NYU Langone Medical Center, said the Uniform Anatomical Gift Act recognizes an individual’s right to be an organ donor for transplant and research, but it “mentions nothing about maintaining you in a dead state artificially for research purposes.”

“It’s a major shift in what people are thinking about doing when they die or their relatives die,” he said.

Because organ donation is controlled at the state, not federal, level, the possibility of donating organs for xenotransplantation, like medical aid in dying, will vary between states, observed Dr. Caplan. The best way to ensure that patients whose organs are found to be unsuitable for transplantation have the option is to change state laws.

He noted that cases are already springing up where people are requesting postmortem sperm or egg donations without direct consents from the person who died. “So we have this new area opening up of handling the use of the dead body and we need to bring the law into sync with the possibilities that are out there.”

In terms of informed authorization (informed consent is reserved for the living), Dr. Caplan said there should be written evidence the person wanted to be a donor and, while not required by law, all survivors should give their permission and understand what’s going to be done in terms of the experiment, such as the use of animal parts, when the body will be returned, and the possibility of zoonotic viral infection.

“They have to fully accept that the person is dead and we’re just maintaining them artificially,” he said. “There’s no maintaining anyone who’s alive. That’s a source of a lot of confusion.”

Special committees also need to be appointed with voices from people in organ procurement, law, theology, and patient groups to monitor practice to ensure people who have given permission understood the process, that families have their questions answered independent of the research team, and that clear limits are set on how long experiments will last.

As to what those limits should be: “I think in terms of a week or 2,” Dr. Caplan said. “Obviously we could maintain bodies longer and people have. But I think, culturally in our society, going much past that starts to perhaps stress emotionally, psychologically, family and friends about getting closure.”

“I’m not as comfortable when people say things like, ‘How about 2 months?’ ” he said. “That’s a long time to sort of accept the fact that somebody has died but you can’t complete all the things that go along with the death.”

Dr. Caplan is also uncomfortable with the use of one-off emergency authorizations, as used for Maryland resident David Bennett Sr., who was rejected for standard heart transplantation and required mechanical circulatory support to stay alive.

“It’s too premature, I believe, even to try and rescue someone,” he said. “We need to learn more from the deceased models.”
 

A better model

Dr. Montgomery noted that primates are very imperfect models for predicting what’s going to happen in humans, and that in order to do xenotransplantation in living humans, there are only two pathways – the one-off emergency authorization or a clinical phase 1 trial.

The decedent model, he said, “will make human trials safer because it’s an intermediate step. You don’t have a living human’s life on the line when you’re trying to do iterative changes and improve the procedure.”

Joe Carrotta for NYU Langone Health

The team, for example, omitted a perfusion pump that was used in the Maryland case and would likely have made its way into phase 1 trials based on baboon data that suggested it was important to have the heart on the pump for hours before it was transplanted, he said. “We didn’t do any of that. We just did it like we would do a regular heart transplant and it started right up, immediately, and started to work.”

The researchers did not release details on the immunosuppression regimen, but noted that, unlike Maryland, they also did not use the experimental anti-CD40 antibody to tamp down the recipients’ immune system.

Although Mr. Bennett’s autopsy did not show any conventional sign of graft rejection, the transplanted pig heart was infected with porcine cytomegalovirus (PCMV) and Mr. Bennett showed traces of DNA from PCMV in his circulation.
 

Nailing down safety

Dr. Montgomery said he wouldn’t rule out xenotransplantation in a living human, but that the safety issues need to be nailed down. “I think that the tests used on the pig that was the donor for the Bennett case were not sensitive enough for latent virus, and that’s how it slipped through. So there was a bit of going back to the drawing board, really looking at each of the tests, and being sure we had the sensitivity to pick up a latent virus.”

He noted that United Therapeutics, which funded the research and provided the engineered pigs through its subsidiary Revivicor, has created and validated a more sensitive polymerase chain reaction test that covers some 35 different pathogens, microbes, and parasites. NYU has also developed its own platform to repeat the testing and for monitoring after the transplant. “The ones that we’re currently using would have picked up the virus.”

Stuart Russell, MD, a professor of medicine who specializes in advanced HF at Duke University, Durham, N.C., said “the biggest thing from my perspective is those two amazing families that were willing let this happen. ... If 20 years from now, this is what we’re doing, it’s related to these families being this generous at a really tough time in their lives.”

Dr. Russell said he awaits publication of the data on what the pathology of the heart looks like, but that the experiments “help to give us a lot of reassurance that we don’t need to worry about hyperacute rejection,” which by definition is going to happen in the first 24-48 hours.

That said, longer-term data is essential to potential safety issues. Notably, among the 10 genetic modifications made to the pigs, four were porcine gene knockouts, including a growth hormone receptor knockout to prevent abnormal organ growth inside the recipient’s chest. As a result, the organs seem to be small for the age of the pig and just don’t grow that well, admitted Dr. Montgomery, who said they are currently analyzing this with echocardiography.

Dr. Russell said this may create a sizing issue, but also “if you have a heart that’s more stressed in the pig, from the point of being a donor, maybe it’s not as good a heart as if it was growing normally. But that kind of stuff, I think, is going to take more than two cases and longer-term data to sort out.”

Sharon Hunt, MD, professor emerita, Stanford (Calif.) University Medical Center, and past president of the International Society for Heart Lung Transplantation, said it’s not the technical aspects, but the biology of xenotransplantation that’s really daunting.

“It’s not the physical act of doing it, like they needed a bigger heart or a smaller heart. Those are technical problems but they’ll manage them,” she said. “The big problem is biological – and the bottom line is we don’t really know. We may have overcome hyperacute rejection, which is great, but the rest remains to be seen.”

Dr. Hunt, who worked with heart transplantation pioneer Norman Shumway, MD, and spent decades caring for patients after transplantation, said most families will consent to 24 or 48 hours or even a week of experimentation on a brain-dead loved one, but what the transplant community wants to know is whether this is workable for many months.

“So the fact that the xenotransplant works for 72 hours, yeah, that’s groovy. But, you know, the answer is kind of ‘so what,’ ” she said. “I’d like to see this go for months, like they were trying to do in the human in Maryland.”

For phase 1 trials, even longer-term survival with or without rejection or with rejection that’s treatable is needed, Dr. Hunt suggested.

“We haven’t seen that yet. The Maryland people were very valiant but they lost the cause,” she said. “There’s just so much more to do before we have a viable model to start anything like a phase 1 trial. I’d love it if that happens in my lifetime, but I’m not sure it’s going to.”

Dr. Russell and Dr. Hunt reported no relevant financial relationships. Dr. Caplan reported serving as a director, officer, partner, employee, advisor, consultant, or trustee for Johnson & Johnson’s Panel for Compassionate Drug Use (unpaid position) and is a contributing author and adviser for Medscape.

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

A team of surgeons successfully transplanted genetically engineered pig hearts into two recently deceased people whose bodies were being maintained on ventilatory support – not in the hope of restoring life, but as a proof-of-concept experiment in xenotransplantation that could eventually help to ease the critical shortage of donor organs.

The surgeries were performed on June 16 and July 6, 2022, using porcine hearts from animals genetically engineered to prevent organ rejection and promote adaptive immunity by human recipients

“From the very beginning our goal was to be able to create a model where we actually mimicked what is now done clinically in human transplantation, without utilizing unapproved devices or techniques or medications,” said Nader Moazami, MD, surgical director of heart transplantation and chief of the division of heart and lung transplantation and mechanical circulatory support at NYU Langone Health, New York.

Joe Carrotta for NYU Langone Health

Through 72 hours of postoperative monitoring “we evaluated the heart for functionality and the heart function was completely normal with excellent contractility,” he said at a press briefing announcing early results of the experimental program.

He acknowledged that for the first of the two procedures some surgical modification of the pig heart was required, primarily because of size differences between the donor and recipient.

“Nevertheless, we learned a tremendous amount from the first operation, and when that experience was translated into the second operation it even performed better,” he said.

Alex Reyentovich, MD, medical director of heart transplantation and director of the NYU Langone advanced heart failure program noted that “there are 6 million individuals with heart failure in the United States. About 100,000 of those individuals have end-stage heart failure, and we only do about 3,500 heart transplants a year in the United States, so we have a tremendous deficiency in organs, and there are many people dying waiting for a heart.”

Infection protocols

To date there has been only one xenotransplant of a genetically modified pig heart into a living human recipient, David Bennett Sr., age 57. The surgery, performed at the University of Maryland in January 2022, was initially successful, with the patient able to sit up in bed a few days after the procedure, and the heart performing like a “rock star” according to transplant surgeon Bartley Griffith, MD.

However, Mr. Bennett died 2 months after the procedure from compromise of the organ by an as yet undetermined cause, of which one may have been the heart's infection by porcine cytomegalovirus (CMV).

Joe Carrotta for NYU Langone Health

The NYU team, mindful of this potential setback, used more sensitive assays to screen the donor organs for porcine CMV, and implemented protocols to prevent and to monitor for potential zoonotic transmission of porcine endogenous retrovirus.

The procedure used a dedicated operating room and equipment that will not be used for clinical procedures, the team emphasized.

An organ transplant specialist who was not involved in the study commented that there can be unwelcome surprises even with the most rigorous infection prophylaxis protocols.

“I think these are important steps, but they don’t resolve the question of infectious risk. Sometimes viruses or latent infections are only manifested later,” said Jay A. Fishman, MD, associate director of the Massachusetts General Hospital Transplant Center and director of the transplant infectious diseases and compromised host program at the hospital, which is in Boston.

“I think these are important steps, but as you may recall from the Maryland heart transplant experience, when porcine cytomegalovirus was activated, it was a long way into that patient’s course, and so we just don’t know whether something would have been reactivated later,” he said in an interview.

Dr. Fishman noted that experience with xenotransplantation at the University of Maryland and other centers has suggested that immunosuppressive regimens used for human-to-human transplants may not be suited for animal-to-human grafts.

The hearts were taken from pigs genetically modified with knockouts of four porcine genes to prevent rejection – including a gene for a growth hormone that would otherwise cause the heart to continue to expand in the recipient’s chest – and with the addition of six human transgenes encoding for expression of proteins regulating biologic pathways that might be disrupted by incompatibilities across species.

Vietnam veteran

The organ recipients were recently deceased patients who had expressed the clear wish to be organ donors but whose organs were for clinical reasons unsuitable for transplant.

The first recipient was Lawrence Kelly, a Vietnam War veteran and welder who died from heart failure at the age of 72.

“He was an organ donor, and would be so happy to know how much his contribution to this research will help people like him with this heart disease. He was a hero his whole life, and he went out a hero,” said Alice Michael, Mr. Kelly’s partner of 33 years, who also spoke at the briefing.

“It was, I think, one of the most incredible things to see a pig heart pounding away and beating inside the chest of a human being,” said Robert A. Montgomery, MD, DPhil, director of the NYU Transplant Institute, and himself a heart transplant recipient.

Dr. Fishman said he had no relevant conflicts of interest.

This article was updated on 7/12/22 and 7/14/22.

A team of surgeons successfully transplanted genetically engineered pig hearts into two recently deceased people whose bodies were being maintained on ventilatory support – not in the hope of restoring life, but as a proof-of-concept experiment in xenotransplantation that could eventually help to ease the critical shortage of donor organs.

The surgeries were performed on June 16 and July 6, 2022, using porcine hearts from animals genetically engineered to prevent organ rejection and promote adaptive immunity by human recipients

“From the very beginning our goal was to be able to create a model where we actually mimicked what is now done clinically in human transplantation, without utilizing unapproved devices or techniques or medications,” said Nader Moazami, MD, surgical director of heart transplantation and chief of the division of heart and lung transplantation and mechanical circulatory support at NYU Langone Health, New York.

Joe Carrotta for NYU Langone Health

Through 72 hours of postoperative monitoring “we evaluated the heart for functionality and the heart function was completely normal with excellent contractility,” he said at a press briefing announcing early results of the experimental program.

He acknowledged that for the first of the two procedures some surgical modification of the pig heart was required, primarily because of size differences between the donor and recipient.

“Nevertheless, we learned a tremendous amount from the first operation, and when that experience was translated into the second operation it even performed better,” he said.

Alex Reyentovich, MD, medical director of heart transplantation and director of the NYU Langone advanced heart failure program noted that “there are 6 million individuals with heart failure in the United States. About 100,000 of those individuals have end-stage heart failure, and we only do about 3,500 heart transplants a year in the United States, so we have a tremendous deficiency in organs, and there are many people dying waiting for a heart.”

Infection protocols

To date there has been only one xenotransplant of a genetically modified pig heart into a living human recipient, David Bennett Sr., age 57. The surgery, performed at the University of Maryland in January 2022, was initially successful, with the patient able to sit up in bed a few days after the procedure, and the heart performing like a “rock star” according to transplant surgeon Bartley Griffith, MD.

However, Mr. Bennett died 2 months after the procedure from compromise of the organ by an as yet undetermined cause, of which one may have been the heart's infection by porcine cytomegalovirus (CMV).

Joe Carrotta for NYU Langone Health

The NYU team, mindful of this potential setback, used more sensitive assays to screen the donor organs for porcine CMV, and implemented protocols to prevent and to monitor for potential zoonotic transmission of porcine endogenous retrovirus.

The procedure used a dedicated operating room and equipment that will not be used for clinical procedures, the team emphasized.

An organ transplant specialist who was not involved in the study commented that there can be unwelcome surprises even with the most rigorous infection prophylaxis protocols.

“I think these are important steps, but they don’t resolve the question of infectious risk. Sometimes viruses or latent infections are only manifested later,” said Jay A. Fishman, MD, associate director of the Massachusetts General Hospital Transplant Center and director of the transplant infectious diseases and compromised host program at the hospital, which is in Boston.

“I think these are important steps, but as you may recall from the Maryland heart transplant experience, when porcine cytomegalovirus was activated, it was a long way into that patient’s course, and so we just don’t know whether something would have been reactivated later,” he said in an interview.

Dr. Fishman noted that experience with xenotransplantation at the University of Maryland and other centers has suggested that immunosuppressive regimens used for human-to-human transplants may not be suited for animal-to-human grafts.

The hearts were taken from pigs genetically modified with knockouts of four porcine genes to prevent rejection – including a gene for a growth hormone that would otherwise cause the heart to continue to expand in the recipient’s chest – and with the addition of six human transgenes encoding for expression of proteins regulating biologic pathways that might be disrupted by incompatibilities across species.

Vietnam veteran

The organ recipients were recently deceased patients who had expressed the clear wish to be organ donors but whose organs were for clinical reasons unsuitable for transplant.

The first recipient was Lawrence Kelly, a Vietnam War veteran and welder who died from heart failure at the age of 72.

“He was an organ donor, and would be so happy to know how much his contribution to this research will help people like him with this heart disease. He was a hero his whole life, and he went out a hero,” said Alice Michael, Mr. Kelly’s partner of 33 years, who also spoke at the briefing.

“It was, I think, one of the most incredible things to see a pig heart pounding away and beating inside the chest of a human being,” said Robert A. Montgomery, MD, DPhil, director of the NYU Transplant Institute, and himself a heart transplant recipient.

Dr. Fishman said he had no relevant conflicts of interest.

This article was updated on 7/12/22 and 7/14/22.

A team of surgeons successfully transplanted genetically engineered pig hearts into two recently deceased people whose bodies were being maintained on ventilatory support – not in the hope of restoring life, but as a proof-of-concept experiment in xenotransplantation that could eventually help to ease the critical shortage of donor organs.

The surgeries were performed on June 16 and July 6, 2022, using porcine hearts from animals genetically engineered to prevent organ rejection and promote adaptive immunity by human recipients

“From the very beginning our goal was to be able to create a model where we actually mimicked what is now done clinically in human transplantation, without utilizing unapproved devices or techniques or medications,” said Nader Moazami, MD, surgical director of heart transplantation and chief of the division of heart and lung transplantation and mechanical circulatory support at NYU Langone Health, New York.

Joe Carrotta for NYU Langone Health

Through 72 hours of postoperative monitoring “we evaluated the heart for functionality and the heart function was completely normal with excellent contractility,” he said at a press briefing announcing early results of the experimental program.

He acknowledged that for the first of the two procedures some surgical modification of the pig heart was required, primarily because of size differences between the donor and recipient.

“Nevertheless, we learned a tremendous amount from the first operation, and when that experience was translated into the second operation it even performed better,” he said.

Alex Reyentovich, MD, medical director of heart transplantation and director of the NYU Langone advanced heart failure program noted that “there are 6 million individuals with heart failure in the United States. About 100,000 of those individuals have end-stage heart failure, and we only do about 3,500 heart transplants a year in the United States, so we have a tremendous deficiency in organs, and there are many people dying waiting for a heart.”

Infection protocols

To date there has been only one xenotransplant of a genetically modified pig heart into a living human recipient, David Bennett Sr., age 57. The surgery, performed at the University of Maryland in January 2022, was initially successful, with the patient able to sit up in bed a few days after the procedure, and the heart performing like a “rock star” according to transplant surgeon Bartley Griffith, MD.

However, Mr. Bennett died 2 months after the procedure from compromise of the organ by an as yet undetermined cause, of which one may have been the heart's infection by porcine cytomegalovirus (CMV).

Joe Carrotta for NYU Langone Health

The NYU team, mindful of this potential setback, used more sensitive assays to screen the donor organs for porcine CMV, and implemented protocols to prevent and to monitor for potential zoonotic transmission of porcine endogenous retrovirus.

The procedure used a dedicated operating room and equipment that will not be used for clinical procedures, the team emphasized.

An organ transplant specialist who was not involved in the study commented that there can be unwelcome surprises even with the most rigorous infection prophylaxis protocols.

“I think these are important steps, but they don’t resolve the question of infectious risk. Sometimes viruses or latent infections are only manifested later,” said Jay A. Fishman, MD, associate director of the Massachusetts General Hospital Transplant Center and director of the transplant infectious diseases and compromised host program at the hospital, which is in Boston.

“I think these are important steps, but as you may recall from the Maryland heart transplant experience, when porcine cytomegalovirus was activated, it was a long way into that patient’s course, and so we just don’t know whether something would have been reactivated later,” he said in an interview.

Dr. Fishman noted that experience with xenotransplantation at the University of Maryland and other centers has suggested that immunosuppressive regimens used for human-to-human transplants may not be suited for animal-to-human grafts.

The hearts were taken from pigs genetically modified with knockouts of four porcine genes to prevent rejection – including a gene for a growth hormone that would otherwise cause the heart to continue to expand in the recipient’s chest – and with the addition of six human transgenes encoding for expression of proteins regulating biologic pathways that might be disrupted by incompatibilities across species.

Vietnam veteran

The organ recipients were recently deceased patients who had expressed the clear wish to be organ donors but whose organs were for clinical reasons unsuitable for transplant.

The first recipient was Lawrence Kelly, a Vietnam War veteran and welder who died from heart failure at the age of 72.

“He was an organ donor, and would be so happy to know how much his contribution to this research will help people like him with this heart disease. He was a hero his whole life, and he went out a hero,” said Alice Michael, Mr. Kelly’s partner of 33 years, who also spoke at the briefing.

“It was, I think, one of the most incredible things to see a pig heart pounding away and beating inside the chest of a human being,” said Robert A. Montgomery, MD, DPhil, director of the NYU Transplant Institute, and himself a heart transplant recipient.

Dr. Fishman said he had no relevant conflicts of interest.

This article was updated on 7/12/22 and 7/14/22.