Arrhythmias & EP

The improved Los Angeles medical dispatch system prompted more callers with limited English proficiency to initiate telecommunicator-assisted cardiopulmonary resuscitation (T-CPR), compared with the previous system, a new study shows.

Chalabala/iStock/Getty Images Plus

The Los Angeles Tiered Dispatch System (LA-TDS), adopted in late 2014, used simplified questions aimed at identifying cardiac arrest, compared with the city’s earlier Medical Priority Dispatch System (MPDS).

The result was substantially decreased call processing times, decreased “undertriage” of out-of-hospital cardiac arrest (OHCA), and improved overall T-CPR rates (Resuscitation. 2020 Oct;155:74-81).

But now, a secondary analysis of the data shows there was a much higher jump in T-CPR rates among a small subset of callers with limited English proficiency, compared with those proficient in English (JAMA Network Open. 2021;4[6]:e216827).

“This was an unanticipated, significant, and disproportionate change, but fortunately a very good change,” lead author Stephen Sanko, MD, said in an interview.

While the T-CPR rate among English-proficient callers increased from 55% with the MPDS to 67% with the LA-TDS (odds ratio, 1.66; P = .007), it rose from 28% to 69% (OR, 5.66; P = .003) among callers with limited English proficiency. In the adjusted analysis, the new LA-TDS was associated with a 69% higher prevalence of T-CPR among English-proficient callers, compared with a 350% greater prevalence among callers with limited English proficiency.

“The emergency communication process between a caller and 911 telecommunicator is more complex than we thought, and likely constitutes a unique subsubspecialty that interacts with fields as diverse as medicine, health equity, linguistics, sociology, consumer behavior and others,” said Dr. Sanko, who is from the division of emergency medical services at the University of Southern California in Los Angeles.

“Yet in spite of this complexity, we’re starting to be able to reproducibly classify elements of the emergency conversation that we believe are tied to outcomes we all care about. ... Modulators of health disparities are present as early as the dispatch conversation, and, importantly, they can be intervened upon to promote improved outcomes,” he continued.

The retrospective cohort study was a predefined secondary analysis of a previously published study comparing telecommunicator management of out-of-hospital cardiac arrest over 3 months with the MPDS versus 3 months with the LA-TDS. The primary outcome was the number of patients who received telecommunicator-assisted chest compressions from callers with limited English proficiency.

Of the 597 emergency calls that met the inclusion criteria, 289 (48%) were in the MPDS cohort and 308 (52%) were in the LA-TDS cohort. In the MPDS cohort, 263 callers had English proficiency and 26 had limited proficiency; in the latter cohort, those figures were 273 and 35, respectively.

There were no significant differences between cohorts in the use of real-time translation services, which were employed 27%-31% of the time.

The reason for the overall T-CPR improvement is likely that the LA-TDS was tailored to the community needs, said Dr. Sanko. “Most people, including doctors, think of 911 dispatch as something simple and straightforward, like ordering a pizza or calling a ride share. [But] LA-TDS is a ‘home grown’ dispatch system whose structure, questions, and emergency instructions were all developed by EMS medical directors and telecommunicators with extensive experience in our community.”

That being said, the researchers acknowledge that the reason behind the bigger T-CPR boost in LEP callers remains unclear. Although the link between language and system was statistically significant, they noted “it was not an a priori hypothesis and appeared to be largely attributable to the low T-CPR rates for callers with limited English proficiency using MPDS.” Additionally, such callers were “remarkably under-represented” in the sample, “which included approximately 600 calls over two quarters in a large city,” said Dr Sanko.

“We hypothesize that a more direct structure, earlier commitment to treating patients with abnormal life status indicators as being suspected cardiac arrest cases, and earlier reassurance may have improved caller confidence that telecommunicators knew what they were doing. This in turn may have translated into an increased likelihood of bystander caller willingness to perform immediate life-saving maneuvers.”

Despite a number of limitations, “the study is important and highlights instructive topics for discussion that suggest potential next-step opportunities,” noted Richard Chocron, MD, PhD, Miranda Lewis, MD, and Thomas Rea, MD, MPH, in an invited commentary that accompanied the publication. Dr. Chocron is from the Paris University, Paris Research Cardiovascular Center, INSERM; Dr. Lewis is from the Georges Pompidou European Hospital in Paris; and Dr. Rea is from the Division of Emergency Medical Services, Public Health–Seattle & King County. Both Dr. Lewis and Dr. Rea are also at the University of Washington, Seattle.

“Sanko et al. found that approximately 10% of all emergency calls were classified as limited English proficiency calls in a community in which 19% of the population was considered to have limited English proficiency,” they added. “This finding suggests the possibility that populations with limited English proficiency are less likely to activate 911 for incidence of cardiac arrest. If true, this finding would compound the health disparity observed among those with limited English proficiency. This topic is important in that it transcends the role of EMS personnel and engages a broad spectrum of societal stakeholders. We must listen, learn, and ultimately deliver public safety resources to groups who have not been well served by conventional approaches.”

None of the authors or editorialists reported any conflicts of interest.

The improved Los Angeles medical dispatch system prompted more callers with limited English proficiency to initiate telecommunicator-assisted cardiopulmonary resuscitation (T-CPR), compared with the previous system, a new study shows.

Chalabala/iStock/Getty Images Plus

The Los Angeles Tiered Dispatch System (LA-TDS), adopted in late 2014, used simplified questions aimed at identifying cardiac arrest, compared with the city’s earlier Medical Priority Dispatch System (MPDS).

The result was substantially decreased call processing times, decreased “undertriage” of out-of-hospital cardiac arrest (OHCA), and improved overall T-CPR rates (Resuscitation. 2020 Oct;155:74-81).

But now, a secondary analysis of the data shows there was a much higher jump in T-CPR rates among a small subset of callers with limited English proficiency, compared with those proficient in English (JAMA Network Open. 2021;4[6]:e216827).

“This was an unanticipated, significant, and disproportionate change, but fortunately a very good change,” lead author Stephen Sanko, MD, said in an interview.

While the T-CPR rate among English-proficient callers increased from 55% with the MPDS to 67% with the LA-TDS (odds ratio, 1.66; P = .007), it rose from 28% to 69% (OR, 5.66; P = .003) among callers with limited English proficiency. In the adjusted analysis, the new LA-TDS was associated with a 69% higher prevalence of T-CPR among English-proficient callers, compared with a 350% greater prevalence among callers with limited English proficiency.

“The emergency communication process between a caller and 911 telecommunicator is more complex than we thought, and likely constitutes a unique subsubspecialty that interacts with fields as diverse as medicine, health equity, linguistics, sociology, consumer behavior and others,” said Dr. Sanko, who is from the division of emergency medical services at the University of Southern California in Los Angeles.

“Yet in spite of this complexity, we’re starting to be able to reproducibly classify elements of the emergency conversation that we believe are tied to outcomes we all care about. ... Modulators of health disparities are present as early as the dispatch conversation, and, importantly, they can be intervened upon to promote improved outcomes,” he continued.

The retrospective cohort study was a predefined secondary analysis of a previously published study comparing telecommunicator management of out-of-hospital cardiac arrest over 3 months with the MPDS versus 3 months with the LA-TDS. The primary outcome was the number of patients who received telecommunicator-assisted chest compressions from callers with limited English proficiency.

Of the 597 emergency calls that met the inclusion criteria, 289 (48%) were in the MPDS cohort and 308 (52%) were in the LA-TDS cohort. In the MPDS cohort, 263 callers had English proficiency and 26 had limited proficiency; in the latter cohort, those figures were 273 and 35, respectively.

There were no significant differences between cohorts in the use of real-time translation services, which were employed 27%-31% of the time.

The reason for the overall T-CPR improvement is likely that the LA-TDS was tailored to the community needs, said Dr. Sanko. “Most people, including doctors, think of 911 dispatch as something simple and straightforward, like ordering a pizza or calling a ride share. [But] LA-TDS is a ‘home grown’ dispatch system whose structure, questions, and emergency instructions were all developed by EMS medical directors and telecommunicators with extensive experience in our community.”

That being said, the researchers acknowledge that the reason behind the bigger T-CPR boost in LEP callers remains unclear. Although the link between language and system was statistically significant, they noted “it was not an a priori hypothesis and appeared to be largely attributable to the low T-CPR rates for callers with limited English proficiency using MPDS.” Additionally, such callers were “remarkably under-represented” in the sample, “which included approximately 600 calls over two quarters in a large city,” said Dr Sanko.

“We hypothesize that a more direct structure, earlier commitment to treating patients with abnormal life status indicators as being suspected cardiac arrest cases, and earlier reassurance may have improved caller confidence that telecommunicators knew what they were doing. This in turn may have translated into an increased likelihood of bystander caller willingness to perform immediate life-saving maneuvers.”

Despite a number of limitations, “the study is important and highlights instructive topics for discussion that suggest potential next-step opportunities,” noted Richard Chocron, MD, PhD, Miranda Lewis, MD, and Thomas Rea, MD, MPH, in an invited commentary that accompanied the publication. Dr. Chocron is from the Paris University, Paris Research Cardiovascular Center, INSERM; Dr. Lewis is from the Georges Pompidou European Hospital in Paris; and Dr. Rea is from the Division of Emergency Medical Services, Public Health–Seattle & King County. Both Dr. Lewis and Dr. Rea are also at the University of Washington, Seattle.

“Sanko et al. found that approximately 10% of all emergency calls were classified as limited English proficiency calls in a community in which 19% of the population was considered to have limited English proficiency,” they added. “This finding suggests the possibility that populations with limited English proficiency are less likely to activate 911 for incidence of cardiac arrest. If true, this finding would compound the health disparity observed among those with limited English proficiency. This topic is important in that it transcends the role of EMS personnel and engages a broad spectrum of societal stakeholders. We must listen, learn, and ultimately deliver public safety resources to groups who have not been well served by conventional approaches.”

None of the authors or editorialists reported any conflicts of interest.

The improved Los Angeles medical dispatch system prompted more callers with limited English proficiency to initiate telecommunicator-assisted cardiopulmonary resuscitation (T-CPR), compared with the previous system, a new study shows.

Chalabala/iStock/Getty Images Plus

The Los Angeles Tiered Dispatch System (LA-TDS), adopted in late 2014, used simplified questions aimed at identifying cardiac arrest, compared with the city’s earlier Medical Priority Dispatch System (MPDS).

The result was substantially decreased call processing times, decreased “undertriage” of out-of-hospital cardiac arrest (OHCA), and improved overall T-CPR rates (Resuscitation. 2020 Oct;155:74-81).

But now, a secondary analysis of the data shows there was a much higher jump in T-CPR rates among a small subset of callers with limited English proficiency, compared with those proficient in English (JAMA Network Open. 2021;4[6]:e216827).

“This was an unanticipated, significant, and disproportionate change, but fortunately a very good change,” lead author Stephen Sanko, MD, said in an interview.

While the T-CPR rate among English-proficient callers increased from 55% with the MPDS to 67% with the LA-TDS (odds ratio, 1.66; P = .007), it rose from 28% to 69% (OR, 5.66; P = .003) among callers with limited English proficiency. In the adjusted analysis, the new LA-TDS was associated with a 69% higher prevalence of T-CPR among English-proficient callers, compared with a 350% greater prevalence among callers with limited English proficiency.

“The emergency communication process between a caller and 911 telecommunicator is more complex than we thought, and likely constitutes a unique subsubspecialty that interacts with fields as diverse as medicine, health equity, linguistics, sociology, consumer behavior and others,” said Dr. Sanko, who is from the division of emergency medical services at the University of Southern California in Los Angeles.

“Yet in spite of this complexity, we’re starting to be able to reproducibly classify elements of the emergency conversation that we believe are tied to outcomes we all care about. ... Modulators of health disparities are present as early as the dispatch conversation, and, importantly, they can be intervened upon to promote improved outcomes,” he continued.

The retrospective cohort study was a predefined secondary analysis of a previously published study comparing telecommunicator management of out-of-hospital cardiac arrest over 3 months with the MPDS versus 3 months with the LA-TDS. The primary outcome was the number of patients who received telecommunicator-assisted chest compressions from callers with limited English proficiency.

Of the 597 emergency calls that met the inclusion criteria, 289 (48%) were in the MPDS cohort and 308 (52%) were in the LA-TDS cohort. In the MPDS cohort, 263 callers had English proficiency and 26 had limited proficiency; in the latter cohort, those figures were 273 and 35, respectively.

There were no significant differences between cohorts in the use of real-time translation services, which were employed 27%-31% of the time.

The reason for the overall T-CPR improvement is likely that the LA-TDS was tailored to the community needs, said Dr. Sanko. “Most people, including doctors, think of 911 dispatch as something simple and straightforward, like ordering a pizza or calling a ride share. [But] LA-TDS is a ‘home grown’ dispatch system whose structure, questions, and emergency instructions were all developed by EMS medical directors and telecommunicators with extensive experience in our community.”

That being said, the researchers acknowledge that the reason behind the bigger T-CPR boost in LEP callers remains unclear. Although the link between language and system was statistically significant, they noted “it was not an a priori hypothesis and appeared to be largely attributable to the low T-CPR rates for callers with limited English proficiency using MPDS.” Additionally, such callers were “remarkably under-represented” in the sample, “which included approximately 600 calls over two quarters in a large city,” said Dr Sanko.

“We hypothesize that a more direct structure, earlier commitment to treating patients with abnormal life status indicators as being suspected cardiac arrest cases, and earlier reassurance may have improved caller confidence that telecommunicators knew what they were doing. This in turn may have translated into an increased likelihood of bystander caller willingness to perform immediate life-saving maneuvers.”

Despite a number of limitations, “the study is important and highlights instructive topics for discussion that suggest potential next-step opportunities,” noted Richard Chocron, MD, PhD, Miranda Lewis, MD, and Thomas Rea, MD, MPH, in an invited commentary that accompanied the publication. Dr. Chocron is from the Paris University, Paris Research Cardiovascular Center, INSERM; Dr. Lewis is from the Georges Pompidou European Hospital in Paris; and Dr. Rea is from the Division of Emergency Medical Services, Public Health–Seattle & King County. Both Dr. Lewis and Dr. Rea are also at the University of Washington, Seattle.

“Sanko et al. found that approximately 10% of all emergency calls were classified as limited English proficiency calls in a community in which 19% of the population was considered to have limited English proficiency,” they added. “This finding suggests the possibility that populations with limited English proficiency are less likely to activate 911 for incidence of cardiac arrest. If true, this finding would compound the health disparity observed among those with limited English proficiency. This topic is important in that it transcends the role of EMS personnel and engages a broad spectrum of societal stakeholders. We must listen, learn, and ultimately deliver public safety resources to groups who have not been well served by conventional approaches.”

None of the authors or editorialists reported any conflicts of interest.

The keys to effective resuscitation in the hospital setting include effective compression and early defibrillation, according to Jessica Nave Allen, MD, FHM, a hospitalist with Emory University Hospital in Atlanta. She spoke about best practices in resuscitation medicine recently at SHM Converge, the annual conference of the Society of Hospital Medicine.

“We know CPR [cardiopulmonary resuscitation] and shocking are the two biggest determinants of outcomes, so really strive to make those chest compressions really high quality,” said Dr. Allen. She urged hospitalists to consider mechanical piston compressions and even “reverse CPR” when appropriate.

Dr. Allen offered several other tips about effective in-hospital resuscitation.
 

Don’t overcrowd the hospital room

There shouldn’t be more than eight people inside the room during a code, she said. If you’re the code leader, “make sure that somebody has already started high-quality chest compressions. You want to make sure that somebody is already on the airway. It’s usually two people, one person to actually hold the mask down to make sure there’s a good seal, and the other person to deliver the breaths.”

Two to three people should be assigned to chest compressions, Dr. Allen said, “and you need one or two nurses for medication delivery and grabbing things from the runners. And then you need to have a recorder and the code leader. Everyone else who’s not in one of those formalized roles needs to be outside the room. That includes the pharmacist, who usually stands at the door if you don’t have a code pharmacist at your institution.”

A helpful mnemonic for the resuscitation process is I(CA)RAMBO, which was developed at Tufts Medical Center and published in 2020, she said. The mnemonic stands for the following:

• I: Identify yourself as code leader.
• CA: Compression, Airway.
• R: Roles (assign roles in the resuscitation).
• A: Access (intravenous access is preferred to intraosseous, per the American Heart Association’s , unless intravenous access is unavailable, Dr. Allen noted).
• M: Monitor (make sure pads are placed correctly; turn the defibrillator on).
• B: Backboard.
• O: Oxygen.

Focus on high-quality chest compressions

The number of chest compressions must be 100-120 per minute, Dr. Allen said. You can time them to the beat of a song, such as “Stayin’ Alive,” or with a metronome, she said, “but whatever it is, you need to stay in that window.”

The correct compression depth is 2-2.4 inches. “That’s very difficult to do during the middle of a code, which is why it’s important to allow full recoil,” she said. “This doesn’t mean taking your hands off of the chest: You should actually never take your hands off of the chest. But you should allow the chest wall to return to its normal state. Also, make sure you aren’t off the chest for more for 10 seconds whenever you’re doing a rhythm check.”

Audiovisual feedback devices can provide insight into the quality of chest compressions. For example, some defibrillators are equipped with sensors that urge users to push harder and faster when appropriate. “Studies have shown that the quality of chest compressions goes up when you use these devices,” she said.
 

Don’t be afraid of mechanical chest compression

Although early research raised questions about the quality of resuscitation outcomes when mechanical piston chest compression devices are used, a 2015 systematic review and meta-analysis found that “man was equal to machine,” Dr. Allen said. “The bottom line is that these devices may be a reasonable alternative to conventional CPR in specific settings.”

American Heart Association guidelines state that mechanical compressions may be appropriate in certain specific situations “where the delivery of high-quality manual compressions may be challenging or dangerous for the provider.”

According to Dr. Allen, “there are times when it’s useful,” such as for a patient with COVID-19, in the cath lab, or in a medical helicopter.
 

Move quickly to defibrillation

“Most of us know that you want to shock as early as possible in shockable rhythms,” Dr. Allen said. Support, she said, comes from a 2008 study that linked delayed defibrillation to lower survival rates. “We want to shock as soon as possible, because your chances of surviving go down for every minute you wait.”

Take special care for patients with confirmed or suspected COVID-19

“Not surprisingly, the goals here are to minimize exposure to staff,” Dr. Allen said.

Put on personal protective equipment before entering the room even if care is delayed, she advised, and reduce the number of staff members in the room below the typical maximum of eight. “In COVID, it should be a maximum of six, and some institutions have even gotten it down to four where the code leaders are outside the room with an iPad.”

Use mechanical compression devices, she advised, and place patients on ventilators as soon as possible. She added: “Use a HEPA [high-efficiency particulate air] filter for all your airway modalities.”

CPR may be challenging in some cases, such as when a large, intubated patient is prone and cannot be quickly or safely flipped over. In those cases, consider posterior chest compressions, also known as reverse CPR, at vertebral positions T7-T10. “We have done reverse CPR on several COVID patients throughout the Emory system,” she said.
 

Debrief right after codes

“You really want to debrief with the code team,” Dr. Allen said. “If you don’t already have a policy in place at your institution, you should help come up with one where you sit down with the team and talk about what could you have done better as a group. It’s not a time to place blame. It’s a time to learn.”

Dr. Allen has disclosed no relevant financial relationships.

This article was updated 7/26/21.

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

The keys to effective resuscitation in the hospital setting include effective compression and early defibrillation, according to Jessica Nave Allen, MD, FHM, a hospitalist with Emory University Hospital in Atlanta. She spoke about best practices in resuscitation medicine recently at SHM Converge, the annual conference of the Society of Hospital Medicine.

“We know CPR [cardiopulmonary resuscitation] and shocking are the two biggest determinants of outcomes, so really strive to make those chest compressions really high quality,” said Dr. Allen. She urged hospitalists to consider mechanical piston compressions and even “reverse CPR” when appropriate.

Dr. Allen offered several other tips about effective in-hospital resuscitation.
 

Don’t overcrowd the hospital room

There shouldn’t be more than eight people inside the room during a code, she said. If you’re the code leader, “make sure that somebody has already started high-quality chest compressions. You want to make sure that somebody is already on the airway. It’s usually two people, one person to actually hold the mask down to make sure there’s a good seal, and the other person to deliver the breaths.”

Two to three people should be assigned to chest compressions, Dr. Allen said, “and you need one or two nurses for medication delivery and grabbing things from the runners. And then you need to have a recorder and the code leader. Everyone else who’s not in one of those formalized roles needs to be outside the room. That includes the pharmacist, who usually stands at the door if you don’t have a code pharmacist at your institution.”

A helpful mnemonic for the resuscitation process is I(CA)RAMBO, which was developed at Tufts Medical Center and published in 2020, she said. The mnemonic stands for the following:

• I: Identify yourself as code leader.
• CA: Compression, Airway.
• R: Roles (assign roles in the resuscitation).
• A: Access (intravenous access is preferred to intraosseous, per the American Heart Association’s , unless intravenous access is unavailable, Dr. Allen noted).
• M: Monitor (make sure pads are placed correctly; turn the defibrillator on).
• B: Backboard.
• O: Oxygen.

Focus on high-quality chest compressions

The number of chest compressions must be 100-120 per minute, Dr. Allen said. You can time them to the beat of a song, such as “Stayin’ Alive,” or with a metronome, she said, “but whatever it is, you need to stay in that window.”

The correct compression depth is 2-2.4 inches. “That’s very difficult to do during the middle of a code, which is why it’s important to allow full recoil,” she said. “This doesn’t mean taking your hands off of the chest: You should actually never take your hands off of the chest. But you should allow the chest wall to return to its normal state. Also, make sure you aren’t off the chest for more for 10 seconds whenever you’re doing a rhythm check.”

Audiovisual feedback devices can provide insight into the quality of chest compressions. For example, some defibrillators are equipped with sensors that urge users to push harder and faster when appropriate. “Studies have shown that the quality of chest compressions goes up when you use these devices,” she said.
 

Don’t be afraid of mechanical chest compression

Although early research raised questions about the quality of resuscitation outcomes when mechanical piston chest compression devices are used, a 2015 systematic review and meta-analysis found that “man was equal to machine,” Dr. Allen said. “The bottom line is that these devices may be a reasonable alternative to conventional CPR in specific settings.”

American Heart Association guidelines state that mechanical compressions may be appropriate in certain specific situations “where the delivery of high-quality manual compressions may be challenging or dangerous for the provider.”

According to Dr. Allen, “there are times when it’s useful,” such as for a patient with COVID-19, in the cath lab, or in a medical helicopter.
 

Move quickly to defibrillation

“Most of us know that you want to shock as early as possible in shockable rhythms,” Dr. Allen said. Support, she said, comes from a 2008 study that linked delayed defibrillation to lower survival rates. “We want to shock as soon as possible, because your chances of surviving go down for every minute you wait.”

Take special care for patients with confirmed or suspected COVID-19

“Not surprisingly, the goals here are to minimize exposure to staff,” Dr. Allen said.

Put on personal protective equipment before entering the room even if care is delayed, she advised, and reduce the number of staff members in the room below the typical maximum of eight. “In COVID, it should be a maximum of six, and some institutions have even gotten it down to four where the code leaders are outside the room with an iPad.”

Use mechanical compression devices, she advised, and place patients on ventilators as soon as possible. She added: “Use a HEPA [high-efficiency particulate air] filter for all your airway modalities.”

CPR may be challenging in some cases, such as when a large, intubated patient is prone and cannot be quickly or safely flipped over. In those cases, consider posterior chest compressions, also known as reverse CPR, at vertebral positions T7-T10. “We have done reverse CPR on several COVID patients throughout the Emory system,” she said.
 

Debrief right after codes

“You really want to debrief with the code team,” Dr. Allen said. “If you don’t already have a policy in place at your institution, you should help come up with one where you sit down with the team and talk about what could you have done better as a group. It’s not a time to place blame. It’s a time to learn.”

Dr. Allen has disclosed no relevant financial relationships.

This article was updated 7/26/21.

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

The keys to effective resuscitation in the hospital setting include effective compression and early defibrillation, according to Jessica Nave Allen, MD, FHM, a hospitalist with Emory University Hospital in Atlanta. She spoke about best practices in resuscitation medicine recently at SHM Converge, the annual conference of the Society of Hospital Medicine.

“We know CPR [cardiopulmonary resuscitation] and shocking are the two biggest determinants of outcomes, so really strive to make those chest compressions really high quality,” said Dr. Allen. She urged hospitalists to consider mechanical piston compressions and even “reverse CPR” when appropriate.

Dr. Allen offered several other tips about effective in-hospital resuscitation.
 

Don’t overcrowd the hospital room

There shouldn’t be more than eight people inside the room during a code, she said. If you’re the code leader, “make sure that somebody has already started high-quality chest compressions. You want to make sure that somebody is already on the airway. It’s usually two people, one person to actually hold the mask down to make sure there’s a good seal, and the other person to deliver the breaths.”

Two to three people should be assigned to chest compressions, Dr. Allen said, “and you need one or two nurses for medication delivery and grabbing things from the runners. And then you need to have a recorder and the code leader. Everyone else who’s not in one of those formalized roles needs to be outside the room. That includes the pharmacist, who usually stands at the door if you don’t have a code pharmacist at your institution.”

A helpful mnemonic for the resuscitation process is I(CA)RAMBO, which was developed at Tufts Medical Center and published in 2020, she said. The mnemonic stands for the following:

• I: Identify yourself as code leader.
• CA: Compression, Airway.
• R: Roles (assign roles in the resuscitation).
• A: Access (intravenous access is preferred to intraosseous, per the American Heart Association’s , unless intravenous access is unavailable, Dr. Allen noted).
• M: Monitor (make sure pads are placed correctly; turn the defibrillator on).
• B: Backboard.
• O: Oxygen.

Focus on high-quality chest compressions

The number of chest compressions must be 100-120 per minute, Dr. Allen said. You can time them to the beat of a song, such as “Stayin’ Alive,” or with a metronome, she said, “but whatever it is, you need to stay in that window.”

The correct compression depth is 2-2.4 inches. “That’s very difficult to do during the middle of a code, which is why it’s important to allow full recoil,” she said. “This doesn’t mean taking your hands off of the chest: You should actually never take your hands off of the chest. But you should allow the chest wall to return to its normal state. Also, make sure you aren’t off the chest for more for 10 seconds whenever you’re doing a rhythm check.”

Audiovisual feedback devices can provide insight into the quality of chest compressions. For example, some defibrillators are equipped with sensors that urge users to push harder and faster when appropriate. “Studies have shown that the quality of chest compressions goes up when you use these devices,” she said.
 

Don’t be afraid of mechanical chest compression

Although early research raised questions about the quality of resuscitation outcomes when mechanical piston chest compression devices are used, a 2015 systematic review and meta-analysis found that “man was equal to machine,” Dr. Allen said. “The bottom line is that these devices may be a reasonable alternative to conventional CPR in specific settings.”

American Heart Association guidelines state that mechanical compressions may be appropriate in certain specific situations “where the delivery of high-quality manual compressions may be challenging or dangerous for the provider.”

According to Dr. Allen, “there are times when it’s useful,” such as for a patient with COVID-19, in the cath lab, or in a medical helicopter.
 

Move quickly to defibrillation

“Most of us know that you want to shock as early as possible in shockable rhythms,” Dr. Allen said. Support, she said, comes from a 2008 study that linked delayed defibrillation to lower survival rates. “We want to shock as soon as possible, because your chances of surviving go down for every minute you wait.”

Take special care for patients with confirmed or suspected COVID-19

“Not surprisingly, the goals here are to minimize exposure to staff,” Dr. Allen said.

Put on personal protective equipment before entering the room even if care is delayed, she advised, and reduce the number of staff members in the room below the typical maximum of eight. “In COVID, it should be a maximum of six, and some institutions have even gotten it down to four where the code leaders are outside the room with an iPad.”

Use mechanical compression devices, she advised, and place patients on ventilators as soon as possible. She added: “Use a HEPA [high-efficiency particulate air] filter for all your airway modalities.”

CPR may be challenging in some cases, such as when a large, intubated patient is prone and cannot be quickly or safely flipped over. In those cases, consider posterior chest compressions, also known as reverse CPR, at vertebral positions T7-T10. “We have done reverse CPR on several COVID patients throughout the Emory system,” she said.
 

Debrief right after codes

“You really want to debrief with the code team,” Dr. Allen said. “If you don’t already have a policy in place at your institution, you should help come up with one where you sit down with the team and talk about what could you have done better as a group. It’s not a time to place blame. It’s a time to learn.”

Dr. Allen has disclosed no relevant financial relationships.

This article was updated 7/26/21.

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

New data show for the first time that combining the DASH (Dietary Approaches to Stop Hypertension) diet with sodium restriction decreases myocardial injury and cardiac strain, which are associated with subclinical cardiac damage and long-term cardiovascular risk.

“The benefits of healthy eating are swift and direct. High sodium is not just about taste, it causes heart strain,” Stephen Juraschek, MD, PhD, from Beth Israel Deaconess Medical Center, Boston, said in an interview.

“We should consciously follow a diet enriched with fruit and vegetables and low in sodium. Collectively, we should think about how foods are promoted in society and what is an acceptable amount of sodium for food supplies,” said Dr. Juraschek.

The findings, from a secondary analysis of the DASH-Sodium trial, were published the Journal of the American College of Cardiology.
 

Renewed focus on diet

“These data should spur a renewed focus on the critical need for widespread adoption of the DASH–low-sodium diet in the United States,” wrote the coauthors of a linked editorial.

“The challenge remains moving the DASH–low-sodium diet from the research world into the real world, where its significant health benefits can be fully realized,” they added.

The researchers evaluated the impact of the DASH diet and sodium restriction, individually and combined, on biomarkers of cardiac injury (high-sensitivity cardiac troponin I [hs-cTnI]), cardiac strain (N-terminal of the prohormone brain natriuretic peptide [NT-proBNP]), and inflammation (high-sensitivity C-reactive protein [hs-CRP]).

The DASH-Sodium trial was a controlled feeding study that enrolled 412 adults (mean age, 48 years; 56% women, 56% Black) with untreated systolic blood pressure between 120 and 159 mm Hg and diastolic blood pressure between 80 and 95 mm Hg. Mean baseline BP was 135/86 mm Hg.

Participants were randomly allocated to a typical American diet (control) or the heart-healthy DASH diet. Further, participants in both groups were assigned to each of three sodium intake levels: low (0.5 mg/kcal), medium (1.1 mg/kcal) or high (1.6 mg/kcal) for 30 days using a crossover design with washout periods in between.

Compared with the control diet, the DASH diet reduced hs-cTnI by 18% and hs-CRP by 13% with no impact on NT-proBNP.

In contrast, lowering sodium from high to low levels reduced NT-proBNP independent of diet by 19%, but did not alter hs-cTnI and mildly increased hs-CRP (9%).

Combining the DASH diet with sodium reduction lowered hs-cTnI by 20% and NT-proBNP by 23%, with no significant change in hs-CRP, compared with the high-sodium-control diet.

“Together, these findings imply that two distinct dietary strategies might improve two key pathways of subclinical cardiac damage: injury and strain,” Dr. Juraschek and colleagues wrote.

“These findings should strengthen public resolve for public policies that promote the DASH dietary pattern and lower sodium intake in the United States and globally,” they concluded.

“We need to talk about DASH more. Most adults in the U.S. have never heard of it,” Dr. Juraschek said in an interview.

“We need to promote nutrition literacy with regard to nutrition facts. Labeling is not very transparent and hard to understand. Many people don’t know where salt is hiding in their diet,” he added.

It will also be important to address disparities in access to healthy foods and food insecurity, Dr. Juraschek said.

“If we don’t address food costs and access, disparities in healthy eating will persist. Greater equity is key. We should also be mindful about populations dependent on others for meal preparation [children in schools or older adults on meal plans]. This might be regulated in ways that promote healthier eating population wide, but for these patients, they may not have autonomy to choose what they eat,” Dr. Juraschek said.

In their editorial, Neha J. Pagidipati, MD, and Laura P. Svetkey, MD, from Duke University and Duke Clinical Research Institute, Durham, N.C., said an important caveat is that the beneficial effects of diet and sodium restriction on cardiac injury and strain occurred in people without any clinical evidence of coronary artery disease or heart failure at baseline, “suggesting that this dietary combination can improve subclinical metrics of cardiac health.”

“Further, the impact on these markers was seen within weeks, indicating a relatively rapid impact on cardiac damage,” they added.

The measurement of cardiac biomarkers was supported by the National Institutes of Health/National Heart, Lung, and Blood Institute. The original DASH trial was supported by the NHLBI, the Office of Research on Minority Health, and the National Center for Research Resources. Dr. Juraschek and coauthors disclosed no relevant conflicts of interest. Dr. Pagidipati has received research support to the institution from Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Novartis, Novo Nordisk, Regeneron, Sanofi, and Verily Life Sciences; and has received consultation fees from Boehringer Ingelheim, Eli Lilly, AstraZeneca, and Novo Nordisk. Dr. Svetkey has no relevant disclosures.

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

New data show for the first time that combining the DASH (Dietary Approaches to Stop Hypertension) diet with sodium restriction decreases myocardial injury and cardiac strain, which are associated with subclinical cardiac damage and long-term cardiovascular risk.

“The benefits of healthy eating are swift and direct. High sodium is not just about taste, it causes heart strain,” Stephen Juraschek, MD, PhD, from Beth Israel Deaconess Medical Center, Boston, said in an interview.

“We should consciously follow a diet enriched with fruit and vegetables and low in sodium. Collectively, we should think about how foods are promoted in society and what is an acceptable amount of sodium for food supplies,” said Dr. Juraschek.

The findings, from a secondary analysis of the DASH-Sodium trial, were published the Journal of the American College of Cardiology.
 

Renewed focus on diet

“These data should spur a renewed focus on the critical need for widespread adoption of the DASH–low-sodium diet in the United States,” wrote the coauthors of a linked editorial.

“The challenge remains moving the DASH–low-sodium diet from the research world into the real world, where its significant health benefits can be fully realized,” they added.

The researchers evaluated the impact of the DASH diet and sodium restriction, individually and combined, on biomarkers of cardiac injury (high-sensitivity cardiac troponin I [hs-cTnI]), cardiac strain (N-terminal of the prohormone brain natriuretic peptide [NT-proBNP]), and inflammation (high-sensitivity C-reactive protein [hs-CRP]).

The DASH-Sodium trial was a controlled feeding study that enrolled 412 adults (mean age, 48 years; 56% women, 56% Black) with untreated systolic blood pressure between 120 and 159 mm Hg and diastolic blood pressure between 80 and 95 mm Hg. Mean baseline BP was 135/86 mm Hg.

Participants were randomly allocated to a typical American diet (control) or the heart-healthy DASH diet. Further, participants in both groups were assigned to each of three sodium intake levels: low (0.5 mg/kcal), medium (1.1 mg/kcal) or high (1.6 mg/kcal) for 30 days using a crossover design with washout periods in between.

Compared with the control diet, the DASH diet reduced hs-cTnI by 18% and hs-CRP by 13% with no impact on NT-proBNP.

In contrast, lowering sodium from high to low levels reduced NT-proBNP independent of diet by 19%, but did not alter hs-cTnI and mildly increased hs-CRP (9%).

Combining the DASH diet with sodium reduction lowered hs-cTnI by 20% and NT-proBNP by 23%, with no significant change in hs-CRP, compared with the high-sodium-control diet.

“Together, these findings imply that two distinct dietary strategies might improve two key pathways of subclinical cardiac damage: injury and strain,” Dr. Juraschek and colleagues wrote.

“These findings should strengthen public resolve for public policies that promote the DASH dietary pattern and lower sodium intake in the United States and globally,” they concluded.

“We need to talk about DASH more. Most adults in the U.S. have never heard of it,” Dr. Juraschek said in an interview.

“We need to promote nutrition literacy with regard to nutrition facts. Labeling is not very transparent and hard to understand. Many people don’t know where salt is hiding in their diet,” he added.

It will also be important to address disparities in access to healthy foods and food insecurity, Dr. Juraschek said.

“If we don’t address food costs and access, disparities in healthy eating will persist. Greater equity is key. We should also be mindful about populations dependent on others for meal preparation [children in schools or older adults on meal plans]. This might be regulated in ways that promote healthier eating population wide, but for these patients, they may not have autonomy to choose what they eat,” Dr. Juraschek said.

In their editorial, Neha J. Pagidipati, MD, and Laura P. Svetkey, MD, from Duke University and Duke Clinical Research Institute, Durham, N.C., said an important caveat is that the beneficial effects of diet and sodium restriction on cardiac injury and strain occurred in people without any clinical evidence of coronary artery disease or heart failure at baseline, “suggesting that this dietary combination can improve subclinical metrics of cardiac health.”

“Further, the impact on these markers was seen within weeks, indicating a relatively rapid impact on cardiac damage,” they added.

The measurement of cardiac biomarkers was supported by the National Institutes of Health/National Heart, Lung, and Blood Institute. The original DASH trial was supported by the NHLBI, the Office of Research on Minority Health, and the National Center for Research Resources. Dr. Juraschek and coauthors disclosed no relevant conflicts of interest. Dr. Pagidipati has received research support to the institution from Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Novartis, Novo Nordisk, Regeneron, Sanofi, and Verily Life Sciences; and has received consultation fees from Boehringer Ingelheim, Eli Lilly, AstraZeneca, and Novo Nordisk. Dr. Svetkey has no relevant disclosures.

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

New data show for the first time that combining the DASH (Dietary Approaches to Stop Hypertension) diet with sodium restriction decreases myocardial injury and cardiac strain, which are associated with subclinical cardiac damage and long-term cardiovascular risk.

“The benefits of healthy eating are swift and direct. High sodium is not just about taste, it causes heart strain,” Stephen Juraschek, MD, PhD, from Beth Israel Deaconess Medical Center, Boston, said in an interview.

“We should consciously follow a diet enriched with fruit and vegetables and low in sodium. Collectively, we should think about how foods are promoted in society and what is an acceptable amount of sodium for food supplies,” said Dr. Juraschek.

The findings, from a secondary analysis of the DASH-Sodium trial, were published the Journal of the American College of Cardiology.
 

Renewed focus on diet

“These data should spur a renewed focus on the critical need for widespread adoption of the DASH–low-sodium diet in the United States,” wrote the coauthors of a linked editorial.

“The challenge remains moving the DASH–low-sodium diet from the research world into the real world, where its significant health benefits can be fully realized,” they added.

The researchers evaluated the impact of the DASH diet and sodium restriction, individually and combined, on biomarkers of cardiac injury (high-sensitivity cardiac troponin I [hs-cTnI]), cardiac strain (N-terminal of the prohormone brain natriuretic peptide [NT-proBNP]), and inflammation (high-sensitivity C-reactive protein [hs-CRP]).

The DASH-Sodium trial was a controlled feeding study that enrolled 412 adults (mean age, 48 years; 56% women, 56% Black) with untreated systolic blood pressure between 120 and 159 mm Hg and diastolic blood pressure between 80 and 95 mm Hg. Mean baseline BP was 135/86 mm Hg.

Participants were randomly allocated to a typical American diet (control) or the heart-healthy DASH diet. Further, participants in both groups were assigned to each of three sodium intake levels: low (0.5 mg/kcal), medium (1.1 mg/kcal) or high (1.6 mg/kcal) for 30 days using a crossover design with washout periods in between.

Compared with the control diet, the DASH diet reduced hs-cTnI by 18% and hs-CRP by 13% with no impact on NT-proBNP.

In contrast, lowering sodium from high to low levels reduced NT-proBNP independent of diet by 19%, but did not alter hs-cTnI and mildly increased hs-CRP (9%).

Combining the DASH diet with sodium reduction lowered hs-cTnI by 20% and NT-proBNP by 23%, with no significant change in hs-CRP, compared with the high-sodium-control diet.

“Together, these findings imply that two distinct dietary strategies might improve two key pathways of subclinical cardiac damage: injury and strain,” Dr. Juraschek and colleagues wrote.

“These findings should strengthen public resolve for public policies that promote the DASH dietary pattern and lower sodium intake in the United States and globally,” they concluded.

“We need to talk about DASH more. Most adults in the U.S. have never heard of it,” Dr. Juraschek said in an interview.

“We need to promote nutrition literacy with regard to nutrition facts. Labeling is not very transparent and hard to understand. Many people don’t know where salt is hiding in their diet,” he added.

It will also be important to address disparities in access to healthy foods and food insecurity, Dr. Juraschek said.

“If we don’t address food costs and access, disparities in healthy eating will persist. Greater equity is key. We should also be mindful about populations dependent on others for meal preparation [children in schools or older adults on meal plans]. This might be regulated in ways that promote healthier eating population wide, but for these patients, they may not have autonomy to choose what they eat,” Dr. Juraschek said.

In their editorial, Neha J. Pagidipati, MD, and Laura P. Svetkey, MD, from Duke University and Duke Clinical Research Institute, Durham, N.C., said an important caveat is that the beneficial effects of diet and sodium restriction on cardiac injury and strain occurred in people without any clinical evidence of coronary artery disease or heart failure at baseline, “suggesting that this dietary combination can improve subclinical metrics of cardiac health.”

“Further, the impact on these markers was seen within weeks, indicating a relatively rapid impact on cardiac damage,” they added.

The measurement of cardiac biomarkers was supported by the National Institutes of Health/National Heart, Lung, and Blood Institute. The original DASH trial was supported by the NHLBI, the Office of Research on Minority Health, and the National Center for Research Resources. Dr. Juraschek and coauthors disclosed no relevant conflicts of interest. Dr. Pagidipati has received research support to the institution from Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Novartis, Novo Nordisk, Regeneron, Sanofi, and Verily Life Sciences; and has received consultation fees from Boehringer Ingelheim, Eli Lilly, AstraZeneca, and Novo Nordisk. Dr. Svetkey has no relevant disclosures.

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

The first randomized controlled trial to compare specific temperatures for therapeutic hypothermia in comatose survivors of out-of-hospital cardiac arrest showed no differences in major outcomes, according to a single-center, double-blind study.

In the CAPITAL-CHILL trial, cooling temperatures of 31° C and 34° C were compared to explore the hypothesis that a lower temperature would improve major outcomes, explained Michel Le May, MD.

No differences for the primary composite outcome of all-cause mortality or poor neurologic outcome at 180 days were observed, he reported at the annual scientific sessions of the American College of Cardiology.

The study was completed over a period of almost 7 years in patients presumed to have had an out-of-hospital cardiac arrest and who were unconscious when they reached a center affiliated with the Ottawa Heart Institute, where Dr. Le May directs the regional STEMI (ST-elevation myocardial infarction) program. The initial rhythm at the time of the cardiac arrest was not an entry criterion.

Of 389 patients enrolled, the intention-to-treat analysis included 184 randomized to a cooling temperature of 31° C group and 183 to a temperature of 34° C. The assigned target temperature, reached with an endovascular device, was known only by the managing nurses.
 

31° C and 34° C are equivalent

There was a small numerical disadvantage for the lower temperature assignment, but none reached statistical significance. This was true of the primary outcome (48.4% vs. 45.4% for the higher temperature) and its components of mortality (43.5% vs. 41.0%) and poor neurologic outcome (4.9% vs. 4.4%). Poor neurologic outcome was defined as a Disability Rating Scale score of greater than 5.

Deaths were most common in the early part of the 180-day follow-up in both arms. On a Kaplan-Meier survival graph, Dr. Le May showed curves that he characterized as “almost superimposable.”

There were no significant differences for any subgroup stratifications, such as age 75 years or older versus younger, males versus females, presence versus absence or an initial shockable rhythm, percutaneous coronary intervention (PCI) within 24 hours versus later, and STEMI versus non-STEMI. In these analyses, the higher temperature was associated with a potential trend for benefit among females and those with a shockable rhythm.

There was no signal for a difference in neurologic outcomes on the Disability Rating Scale or the Modified Rankin Scale. On the latter, for example, 46% of those in the 31° C group and 44% of these in the 34° C group had a score of four or greater at the end of follow-up.

The baseline characteristics of the two groups were similar. About 80% were male; the average age was roughly 62 years. More than 80% of the cardiac arrests were witnessed with CPR being administered by bystanders in nearly 70%. Nearly 40% had a STEMI.

Interventions were similar. Almost all patients underwent coronary angiography, of which nearly 60% received a percutaneous coronary intervention. More than 50% received a stent. The time from arrest to randomization was slightly longer in the 31° C group (228 vs. 204 minutes). The time to balloon inflation from arrival at the cardiac center was also slightly longer (73 vs. 60 minutes).

There was a trend for an increased rate of seizures in the 31° C group (12.5% vs. 7.1%; P = .08), but other secondary outcomes, including pneumonia (67.8% vs. 63.4%), renal replacement therapy (9.2% vs. 9.3%), and stroke (4.4% vs. 1.6%), were similar in the 31° C and 34° C groups, respectively.

Bleeding, whether measured by transfusion (19.6% vs. 22.4%) or TIMI major bleed (23.4% vs. 19.7%) were similar in the 31° C and 34° C groups, respectively. Thrombosis, whether measured by stent thrombosis (1.2% vs. 2.2%) or deep venous thrombosis (11.4% vs. 10.9%) were similar in these two groups, respectively.

The length of stay in the cardiac intensive care unit was significantly greater in the 31° C group (10 vs. 7 days; P = .004). Some of this increased length of stay can be attributed to the longer rewarming process required for the greater cooling, according to Dr. Le May, but he acknowledged that it is not clear this provides a full explanation.
 

More trials like CAPITAL-CHILL needed

The validity of these findings is supported by several strengths of the methodology, according to Jeanne E. Poole, MD, director of the arrhythmia service and electrophysiology laboratory, University of Washington, Seattle. This includes the reliance of an endovascular device, which can accelerate the time to the target temperature and assure the precision with which it is reached and maintained.

Dr. Poole did note that many of the primary and secondary measures, including the rates of stroke, seizures, and major bleeds, even though not significantly different, favored the higher temperature. The slightly longer door-to-balloon times might have been a factor. For the higher rate of pneumonia in the 31° C group, she questioned whether the longer period of ventilation linked to a longer period of rewarming might have been a factor.

However, Dr. Poole praised the CAPITAL-CHILL trial for drawing attention to a group of patients for whom survival rates remain “dismally low.” She indicated that these types of high-level trials are needed to look for strategies to improve outcomes.

Dr. Le May and Dr. Poole report no potential conflicts of interest.

The first randomized controlled trial to compare specific temperatures for therapeutic hypothermia in comatose survivors of out-of-hospital cardiac arrest showed no differences in major outcomes, according to a single-center, double-blind study.

In the CAPITAL-CHILL trial, cooling temperatures of 31° C and 34° C were compared to explore the hypothesis that a lower temperature would improve major outcomes, explained Michel Le May, MD.

No differences for the primary composite outcome of all-cause mortality or poor neurologic outcome at 180 days were observed, he reported at the annual scientific sessions of the American College of Cardiology.

The study was completed over a period of almost 7 years in patients presumed to have had an out-of-hospital cardiac arrest and who were unconscious when they reached a center affiliated with the Ottawa Heart Institute, where Dr. Le May directs the regional STEMI (ST-elevation myocardial infarction) program. The initial rhythm at the time of the cardiac arrest was not an entry criterion.

Of 389 patients enrolled, the intention-to-treat analysis included 184 randomized to a cooling temperature of 31° C group and 183 to a temperature of 34° C. The assigned target temperature, reached with an endovascular device, was known only by the managing nurses.
 

31° C and 34° C are equivalent

There was a small numerical disadvantage for the lower temperature assignment, but none reached statistical significance. This was true of the primary outcome (48.4% vs. 45.4% for the higher temperature) and its components of mortality (43.5% vs. 41.0%) and poor neurologic outcome (4.9% vs. 4.4%). Poor neurologic outcome was defined as a Disability Rating Scale score of greater than 5.

Deaths were most common in the early part of the 180-day follow-up in both arms. On a Kaplan-Meier survival graph, Dr. Le May showed curves that he characterized as “almost superimposable.”

There were no significant differences for any subgroup stratifications, such as age 75 years or older versus younger, males versus females, presence versus absence or an initial shockable rhythm, percutaneous coronary intervention (PCI) within 24 hours versus later, and STEMI versus non-STEMI. In these analyses, the higher temperature was associated with a potential trend for benefit among females and those with a shockable rhythm.

There was no signal for a difference in neurologic outcomes on the Disability Rating Scale or the Modified Rankin Scale. On the latter, for example, 46% of those in the 31° C group and 44% of these in the 34° C group had a score of four or greater at the end of follow-up.

The baseline characteristics of the two groups were similar. About 80% were male; the average age was roughly 62 years. More than 80% of the cardiac arrests were witnessed with CPR being administered by bystanders in nearly 70%. Nearly 40% had a STEMI.

Interventions were similar. Almost all patients underwent coronary angiography, of which nearly 60% received a percutaneous coronary intervention. More than 50% received a stent. The time from arrest to randomization was slightly longer in the 31° C group (228 vs. 204 minutes). The time to balloon inflation from arrival at the cardiac center was also slightly longer (73 vs. 60 minutes).

There was a trend for an increased rate of seizures in the 31° C group (12.5% vs. 7.1%; P = .08), but other secondary outcomes, including pneumonia (67.8% vs. 63.4%), renal replacement therapy (9.2% vs. 9.3%), and stroke (4.4% vs. 1.6%), were similar in the 31° C and 34° C groups, respectively.

Bleeding, whether measured by transfusion (19.6% vs. 22.4%) or TIMI major bleed (23.4% vs. 19.7%) were similar in the 31° C and 34° C groups, respectively. Thrombosis, whether measured by stent thrombosis (1.2% vs. 2.2%) or deep venous thrombosis (11.4% vs. 10.9%) were similar in these two groups, respectively.

The length of stay in the cardiac intensive care unit was significantly greater in the 31° C group (10 vs. 7 days; P = .004). Some of this increased length of stay can be attributed to the longer rewarming process required for the greater cooling, according to Dr. Le May, but he acknowledged that it is not clear this provides a full explanation.
 

More trials like CAPITAL-CHILL needed

The validity of these findings is supported by several strengths of the methodology, according to Jeanne E. Poole, MD, director of the arrhythmia service and electrophysiology laboratory, University of Washington, Seattle. This includes the reliance of an endovascular device, which can accelerate the time to the target temperature and assure the precision with which it is reached and maintained.

Dr. Poole did note that many of the primary and secondary measures, including the rates of stroke, seizures, and major bleeds, even though not significantly different, favored the higher temperature. The slightly longer door-to-balloon times might have been a factor. For the higher rate of pneumonia in the 31° C group, she questioned whether the longer period of ventilation linked to a longer period of rewarming might have been a factor.

However, Dr. Poole praised the CAPITAL-CHILL trial for drawing attention to a group of patients for whom survival rates remain “dismally low.” She indicated that these types of high-level trials are needed to look for strategies to improve outcomes.

Dr. Le May and Dr. Poole report no potential conflicts of interest.

The first randomized controlled trial to compare specific temperatures for therapeutic hypothermia in comatose survivors of out-of-hospital cardiac arrest showed no differences in major outcomes, according to a single-center, double-blind study.

In the CAPITAL-CHILL trial, cooling temperatures of 31° C and 34° C were compared to explore the hypothesis that a lower temperature would improve major outcomes, explained Michel Le May, MD.

No differences for the primary composite outcome of all-cause mortality or poor neurologic outcome at 180 days were observed, he reported at the annual scientific sessions of the American College of Cardiology.

The study was completed over a period of almost 7 years in patients presumed to have had an out-of-hospital cardiac arrest and who were unconscious when they reached a center affiliated with the Ottawa Heart Institute, where Dr. Le May directs the regional STEMI (ST-elevation myocardial infarction) program. The initial rhythm at the time of the cardiac arrest was not an entry criterion.

Of 389 patients enrolled, the intention-to-treat analysis included 184 randomized to a cooling temperature of 31° C group and 183 to a temperature of 34° C. The assigned target temperature, reached with an endovascular device, was known only by the managing nurses.
 

31° C and 34° C are equivalent

There was a small numerical disadvantage for the lower temperature assignment, but none reached statistical significance. This was true of the primary outcome (48.4% vs. 45.4% for the higher temperature) and its components of mortality (43.5% vs. 41.0%) and poor neurologic outcome (4.9% vs. 4.4%). Poor neurologic outcome was defined as a Disability Rating Scale score of greater than 5.

Deaths were most common in the early part of the 180-day follow-up in both arms. On a Kaplan-Meier survival graph, Dr. Le May showed curves that he characterized as “almost superimposable.”

There were no significant differences for any subgroup stratifications, such as age 75 years or older versus younger, males versus females, presence versus absence or an initial shockable rhythm, percutaneous coronary intervention (PCI) within 24 hours versus later, and STEMI versus non-STEMI. In these analyses, the higher temperature was associated with a potential trend for benefit among females and those with a shockable rhythm.

There was no signal for a difference in neurologic outcomes on the Disability Rating Scale or the Modified Rankin Scale. On the latter, for example, 46% of those in the 31° C group and 44% of these in the 34° C group had a score of four or greater at the end of follow-up.

The baseline characteristics of the two groups were similar. About 80% were male; the average age was roughly 62 years. More than 80% of the cardiac arrests were witnessed with CPR being administered by bystanders in nearly 70%. Nearly 40% had a STEMI.

Interventions were similar. Almost all patients underwent coronary angiography, of which nearly 60% received a percutaneous coronary intervention. More than 50% received a stent. The time from arrest to randomization was slightly longer in the 31° C group (228 vs. 204 minutes). The time to balloon inflation from arrival at the cardiac center was also slightly longer (73 vs. 60 minutes).

There was a trend for an increased rate of seizures in the 31° C group (12.5% vs. 7.1%; P = .08), but other secondary outcomes, including pneumonia (67.8% vs. 63.4%), renal replacement therapy (9.2% vs. 9.3%), and stroke (4.4% vs. 1.6%), were similar in the 31° C and 34° C groups, respectively.

Bleeding, whether measured by transfusion (19.6% vs. 22.4%) or TIMI major bleed (23.4% vs. 19.7%) were similar in the 31° C and 34° C groups, respectively. Thrombosis, whether measured by stent thrombosis (1.2% vs. 2.2%) or deep venous thrombosis (11.4% vs. 10.9%) were similar in these two groups, respectively.

The length of stay in the cardiac intensive care unit was significantly greater in the 31° C group (10 vs. 7 days; P = .004). Some of this increased length of stay can be attributed to the longer rewarming process required for the greater cooling, according to Dr. Le May, but he acknowledged that it is not clear this provides a full explanation.
 

More trials like CAPITAL-CHILL needed

The validity of these findings is supported by several strengths of the methodology, according to Jeanne E. Poole, MD, director of the arrhythmia service and electrophysiology laboratory, University of Washington, Seattle. This includes the reliance of an endovascular device, which can accelerate the time to the target temperature and assure the precision with which it is reached and maintained.

Dr. Poole did note that many of the primary and secondary measures, including the rates of stroke, seizures, and major bleeds, even though not significantly different, favored the higher temperature. The slightly longer door-to-balloon times might have been a factor. For the higher rate of pneumonia in the 31° C group, she questioned whether the longer period of ventilation linked to a longer period of rewarming might have been a factor.

However, Dr. Poole praised the CAPITAL-CHILL trial for drawing attention to a group of patients for whom survival rates remain “dismally low.” She indicated that these types of high-level trials are needed to look for strategies to improve outcomes.

Dr. Le May and Dr. Poole report no potential conflicts of interest.

Combined data from five implantable cardioverter-defibrillator (ICD) trials suggest that it is the underlying arrhythmic disorder, rather than the ICD therapy itself, that affects mortality in these patients.

Analysis of the MADIT II, MADIT-RISK, MADIT-CRT, MADIT-RIT, and RAID trials showed that the major determinant of mortality in patients receiving a primary prevention ICD was the arrhythmic substrate that leads to occurrence of fast ventricular tachycardia (VT), defined as ≥ 200 bpm, or ventricular fibrillation (VF), not adverse effects of the ICD shock therapy itself.

Patients experiencing an episode of VT had more than a twofold increased risk for death during a follow-up of 2½ years; however, ICD therapies for VT less than 200 bpm and inappropriate ICD shocks were not associated with a higher risk for death.

The findings were published online in the Journal of the American College of Cardiology.

“We know that patients receiving an ICD shock have increased mortality during subsequent follow-up,” first author Mehmet K. Aktas, MD, MBA, University of Rochester (N.Y.), said in an interview.

“There are conflicting data on the impact of ICD shocks on subsequent mortality, and in this study, we aimed to determine whether shocks per se increase subsequent mortality risk or whether the arrhythmic substrate that leads to ICD therapy results in subsequent risk of death,” Dr. Aktas said.

He and his team evaluated the association of ICD therapy with subsequent mortality according to the type of ICD therapy (model I), type of arrhythmia for which ICD therapy was delivered (model II), combined assessment of all arrhythmia and therapy types during follow-up (model III), and incremental risk associated with repeated ICD shocks (model IV).

The study cohort included 5,516 patients. Of these, 1,001 patients (18%) received appropriate ICD therapy and 561 (10%) received inappropriate ICD therapy during an average of 2.4 years.

Patients receiving an appropriate ICD therapy were more likely to be male and to have prior atrial arrhythmia and nonsustained VT compared with those without ICD therapy.

Patients receiving an inappropriate shock were more likely to be younger, to be African American, and to be less likely to have prior nonsustained VT, compared with those without ICD therapy.

Most patients (90%) were receiving beta-blockers and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers regardless of device therapy during follow-up, and 10% of patients were treated with amiodarone.

In model I, at 3 years, the cumulative probability of death following an appropriate ICD shock was 38% compared with no appropriate ICD shock (P < .001). Inappropriate shock alone was not associated with mortality risk.

In model II, which looked at the type of arrhythmia for which ICD therapy was delivered, the cumulative death rate at 3 years following the first occurrence of ICD therapy for VT ≥ 200 beats/min or VF was 27%, compared with 10% in patients not experiencing VT ≥ 200 beats/min or VF (P < .001).

In model III, the highest risk for death was observed following shocks delivered after a failed antitachycardia pacing (ATP) for fast VT (hazard ratio [HR], 3.05), followed by ICD shock for VF (HR, 2.86), ICD shock for fast VT without a prior ATP (HR, 2.83), and ICD shock for slower VT (< 200 beats/min) without a prior ATP (HR, 2.39).

In contrast, other types of appropriate and inappropriate shock or ATP therapies were not associated with a significant risk increase.

In model IV, which assessed the association of shock therapy counts with the risk for death, two or more ICD appropriate shocks were not associated with increased risk after the first appropriate ICD shock.

“Our findings shed light on the mechanisms associated with increased mortality risk in primary prevention ICD recipients,” Dr. Aktas said.

“Studies that evaluate interventions focused on treating and stabilizing the myocardial substrate, which promotes ventricular tachyarrhythmias, such as catheter ablation, are needed to improve survival in heart failure patients,” he added.
 

Thoughtful study design

In an accompanying editorial, Rajat Deo, MD, and Naga Venkata K. Pothineni, MD, both from the University of Pennsylvania, Philadelphia, praised the researchers for their “thoughtful study design.”

“The take-home message that is most relevant to our clinical practice is clear: Sustained ventricular arrhythmias are a prognostic marker of death and heart failure hospitalization,” they wrote.

The editorialists also commented on the higher rate of inappropriate ICD therapies in African Americans.

“It is concerning to observe that Black patients had a markedly higher rate of inappropriate ICD therapies compared with White patients – and this was in the setting of some of the most respectable, established, and well-funded clinical trials,” they wrote.

Reasons for disparities in outcomes include access to appropriate and affordable medical therapies, access to specialty clinics and caregivers, remote ICD monitoring, and compliance issues.

“Future work will need to understand how the social determinants of health including race affect the treatment and outcomes of our primary prevention ICD population,” they wrote.

Identifying and characterizing the arrhythmic substrate will become a key component of sudden cardiac death risk stratification, the editorialists predicted.

“Concurrently, we must continue to partner with industry colleagues and work with our professional societies to ensure health equity across our patient population,” they concluded.

Dr. Aktas has received research grants from Boston Scientific and Medtronic. Dr. Deo and his coeditorialists report no relevant financial relationships. The MADIT trials were funded by an unrestricted research grant from Boston Scientific to the University of Rochester Medical Center. The RAID trial was funded by the National Institutes of Health.

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

Combined data from five implantable cardioverter-defibrillator (ICD) trials suggest that it is the underlying arrhythmic disorder, rather than the ICD therapy itself, that affects mortality in these patients.

Analysis of the MADIT II, MADIT-RISK, MADIT-CRT, MADIT-RIT, and RAID trials showed that the major determinant of mortality in patients receiving a primary prevention ICD was the arrhythmic substrate that leads to occurrence of fast ventricular tachycardia (VT), defined as ≥ 200 bpm, or ventricular fibrillation (VF), not adverse effects of the ICD shock therapy itself.

Patients experiencing an episode of VT had more than a twofold increased risk for death during a follow-up of 2½ years; however, ICD therapies for VT less than 200 bpm and inappropriate ICD shocks were not associated with a higher risk for death.

The findings were published online in the Journal of the American College of Cardiology.

“We know that patients receiving an ICD shock have increased mortality during subsequent follow-up,” first author Mehmet K. Aktas, MD, MBA, University of Rochester (N.Y.), said in an interview.

“There are conflicting data on the impact of ICD shocks on subsequent mortality, and in this study, we aimed to determine whether shocks per se increase subsequent mortality risk or whether the arrhythmic substrate that leads to ICD therapy results in subsequent risk of death,” Dr. Aktas said.

He and his team evaluated the association of ICD therapy with subsequent mortality according to the type of ICD therapy (model I), type of arrhythmia for which ICD therapy was delivered (model II), combined assessment of all arrhythmia and therapy types during follow-up (model III), and incremental risk associated with repeated ICD shocks (model IV).

The study cohort included 5,516 patients. Of these, 1,001 patients (18%) received appropriate ICD therapy and 561 (10%) received inappropriate ICD therapy during an average of 2.4 years.

Patients receiving an appropriate ICD therapy were more likely to be male and to have prior atrial arrhythmia and nonsustained VT compared with those without ICD therapy.

Patients receiving an inappropriate shock were more likely to be younger, to be African American, and to be less likely to have prior nonsustained VT, compared with those without ICD therapy.

Most patients (90%) were receiving beta-blockers and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers regardless of device therapy during follow-up, and 10% of patients were treated with amiodarone.

In model I, at 3 years, the cumulative probability of death following an appropriate ICD shock was 38% compared with no appropriate ICD shock (P < .001). Inappropriate shock alone was not associated with mortality risk.

In model II, which looked at the type of arrhythmia for which ICD therapy was delivered, the cumulative death rate at 3 years following the first occurrence of ICD therapy for VT ≥ 200 beats/min or VF was 27%, compared with 10% in patients not experiencing VT ≥ 200 beats/min or VF (P < .001).

In model III, the highest risk for death was observed following shocks delivered after a failed antitachycardia pacing (ATP) for fast VT (hazard ratio [HR], 3.05), followed by ICD shock for VF (HR, 2.86), ICD shock for fast VT without a prior ATP (HR, 2.83), and ICD shock for slower VT (< 200 beats/min) without a prior ATP (HR, 2.39).

In contrast, other types of appropriate and inappropriate shock or ATP therapies were not associated with a significant risk increase.

In model IV, which assessed the association of shock therapy counts with the risk for death, two or more ICD appropriate shocks were not associated with increased risk after the first appropriate ICD shock.

“Our findings shed light on the mechanisms associated with increased mortality risk in primary prevention ICD recipients,” Dr. Aktas said.

“Studies that evaluate interventions focused on treating and stabilizing the myocardial substrate, which promotes ventricular tachyarrhythmias, such as catheter ablation, are needed to improve survival in heart failure patients,” he added.
 

Thoughtful study design

In an accompanying editorial, Rajat Deo, MD, and Naga Venkata K. Pothineni, MD, both from the University of Pennsylvania, Philadelphia, praised the researchers for their “thoughtful study design.”

“The take-home message that is most relevant to our clinical practice is clear: Sustained ventricular arrhythmias are a prognostic marker of death and heart failure hospitalization,” they wrote.

The editorialists also commented on the higher rate of inappropriate ICD therapies in African Americans.

“It is concerning to observe that Black patients had a markedly higher rate of inappropriate ICD therapies compared with White patients – and this was in the setting of some of the most respectable, established, and well-funded clinical trials,” they wrote.

Reasons for disparities in outcomes include access to appropriate and affordable medical therapies, access to specialty clinics and caregivers, remote ICD monitoring, and compliance issues.

“Future work will need to understand how the social determinants of health including race affect the treatment and outcomes of our primary prevention ICD population,” they wrote.

Identifying and characterizing the arrhythmic substrate will become a key component of sudden cardiac death risk stratification, the editorialists predicted.

“Concurrently, we must continue to partner with industry colleagues and work with our professional societies to ensure health equity across our patient population,” they concluded.

Dr. Aktas has received research grants from Boston Scientific and Medtronic. Dr. Deo and his coeditorialists report no relevant financial relationships. The MADIT trials were funded by an unrestricted research grant from Boston Scientific to the University of Rochester Medical Center. The RAID trial was funded by the National Institutes of Health.

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

Combined data from five implantable cardioverter-defibrillator (ICD) trials suggest that it is the underlying arrhythmic disorder, rather than the ICD therapy itself, that affects mortality in these patients.

Analysis of the MADIT II, MADIT-RISK, MADIT-CRT, MADIT-RIT, and RAID trials showed that the major determinant of mortality in patients receiving a primary prevention ICD was the arrhythmic substrate that leads to occurrence of fast ventricular tachycardia (VT), defined as ≥ 200 bpm, or ventricular fibrillation (VF), not adverse effects of the ICD shock therapy itself.

Patients experiencing an episode of VT had more than a twofold increased risk for death during a follow-up of 2½ years; however, ICD therapies for VT less than 200 bpm and inappropriate ICD shocks were not associated with a higher risk for death.

The findings were published online in the Journal of the American College of Cardiology.

“We know that patients receiving an ICD shock have increased mortality during subsequent follow-up,” first author Mehmet K. Aktas, MD, MBA, University of Rochester (N.Y.), said in an interview.

“There are conflicting data on the impact of ICD shocks on subsequent mortality, and in this study, we aimed to determine whether shocks per se increase subsequent mortality risk or whether the arrhythmic substrate that leads to ICD therapy results in subsequent risk of death,” Dr. Aktas said.

He and his team evaluated the association of ICD therapy with subsequent mortality according to the type of ICD therapy (model I), type of arrhythmia for which ICD therapy was delivered (model II), combined assessment of all arrhythmia and therapy types during follow-up (model III), and incremental risk associated with repeated ICD shocks (model IV).

The study cohort included 5,516 patients. Of these, 1,001 patients (18%) received appropriate ICD therapy and 561 (10%) received inappropriate ICD therapy during an average of 2.4 years.

Patients receiving an appropriate ICD therapy were more likely to be male and to have prior atrial arrhythmia and nonsustained VT compared with those without ICD therapy.

Patients receiving an inappropriate shock were more likely to be younger, to be African American, and to be less likely to have prior nonsustained VT, compared with those without ICD therapy.

Most patients (90%) were receiving beta-blockers and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers regardless of device therapy during follow-up, and 10% of patients were treated with amiodarone.

In model I, at 3 years, the cumulative probability of death following an appropriate ICD shock was 38% compared with no appropriate ICD shock (P < .001). Inappropriate shock alone was not associated with mortality risk.

In model II, which looked at the type of arrhythmia for which ICD therapy was delivered, the cumulative death rate at 3 years following the first occurrence of ICD therapy for VT ≥ 200 beats/min or VF was 27%, compared with 10% in patients not experiencing VT ≥ 200 beats/min or VF (P < .001).

In model III, the highest risk for death was observed following shocks delivered after a failed antitachycardia pacing (ATP) for fast VT (hazard ratio [HR], 3.05), followed by ICD shock for VF (HR, 2.86), ICD shock for fast VT without a prior ATP (HR, 2.83), and ICD shock for slower VT (< 200 beats/min) without a prior ATP (HR, 2.39).

In contrast, other types of appropriate and inappropriate shock or ATP therapies were not associated with a significant risk increase.

In model IV, which assessed the association of shock therapy counts with the risk for death, two or more ICD appropriate shocks were not associated with increased risk after the first appropriate ICD shock.

“Our findings shed light on the mechanisms associated with increased mortality risk in primary prevention ICD recipients,” Dr. Aktas said.

“Studies that evaluate interventions focused on treating and stabilizing the myocardial substrate, which promotes ventricular tachyarrhythmias, such as catheter ablation, are needed to improve survival in heart failure patients,” he added.
 

Thoughtful study design

In an accompanying editorial, Rajat Deo, MD, and Naga Venkata K. Pothineni, MD, both from the University of Pennsylvania, Philadelphia, praised the researchers for their “thoughtful study design.”

“The take-home message that is most relevant to our clinical practice is clear: Sustained ventricular arrhythmias are a prognostic marker of death and heart failure hospitalization,” they wrote.

The editorialists also commented on the higher rate of inappropriate ICD therapies in African Americans.

“It is concerning to observe that Black patients had a markedly higher rate of inappropriate ICD therapies compared with White patients – and this was in the setting of some of the most respectable, established, and well-funded clinical trials,” they wrote.

Reasons for disparities in outcomes include access to appropriate and affordable medical therapies, access to specialty clinics and caregivers, remote ICD monitoring, and compliance issues.

“Future work will need to understand how the social determinants of health including race affect the treatment and outcomes of our primary prevention ICD population,” they wrote.

Identifying and characterizing the arrhythmic substrate will become a key component of sudden cardiac death risk stratification, the editorialists predicted.

“Concurrently, we must continue to partner with industry colleagues and work with our professional societies to ensure health equity across our patient population,” they concluded.

Dr. Aktas has received research grants from Boston Scientific and Medtronic. Dr. Deo and his coeditorialists report no relevant financial relationships. The MADIT trials were funded by an unrestricted research grant from Boston Scientific to the University of Rochester Medical Center. The RAID trial was funded by the National Institutes of Health.

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

Finerenone treatment of patients with type 2 diabetes and diabetic kidney disease was linked to a significant drop in the incidence of new-onset atrial fibrillation as a prespecified, exploratory endpoint of the FIDELIO-DKD pivotal trial that randomized more than 5,700 patients.

Treatment with finerenone linked with a 29% relative reduction compared with placebo in incident cases of atrial fibrillation (AFib), Gerasimos Filippatos, MD, reported at the annual scientific sessions of the American College of Cardiology.

The absolute reduction was modest, a 1.3% reduction from the 4.5% incidence rate on placebo to a 3.2% rate on finerenone during a median 2.6 years of follow-up. Concurrently with the report, the results appeared online (J Am Coll Cardiol. 2021 May 17. doi: 10.1016/j.jacc.2021.04.079).

The analyses Dr. Filippatos presented also showed that whether or not patients had a history of AFib, there was no impact on either the primary benefit from finerenone treatment seen in FIDELIO-DKD, which was a significant 18% relative risk reduction compared with placebo in the combined rate of kidney failure, a 40% or greater decline from baseline in estimated glomerular filtration rate, or renal death.

Likewise, prior AFib status had no effect on the study’s key secondary endpoint, a significant 14% relative risk reduction in the combined rate of cardiovascular death, nonfatal MI, nonfatal stroke, or hospitalization for heart failure.

The primary results from FIDELIO-DKD (Efficacy and Safety of Finerenone in Subjects With Type 2 Diabetes Mellitus and Diabetic Kidney Disease) appeared in a 2020 report (N Engl J Med. 2020 Dec 3;383[23];2219-29).
 

‘Side benefits can be very helpful’

“It’s important to know of finerenone’s benefits beyond the primary outcome of a trial because side benefits can be very helpful,” said Anne B. Curtis, MD, an electrophysiologist and professor and chair of medicine at the University of Buffalo (N.Y.) School of Medicine and Biomedical Sciences. “It’s not a huge benefit, but this could be an added benefit for selected patients,” she said during a press briefing. “Background studies had shown favorable remodeling of the heart [by finerenone] that could affect AFib.”

Possible mitigating effects by finerenone on inflammation and fibrosis might also mediate the drug’s apparent effect on AFib, said Dr. Filippatos, professor of cardiology and director of the Heart Failure and Cardio-Oncology Clinic at Attikon University Hospital and the University of Athens.

He noted that additional data addressing a possible AFib effect of finerenone will emerge soon from the FIGARO-DKD trial, which enrolled patients similar to those in FIDELIO-DKD but with more moderate stages of kidney disease, and from the FINEARTS-HF trial, which is examining the effect of finerenone in patients with heart failure with an ejection fraction of at least 40%.

“Heart failure and AFib go together tightly. It’s worth studying this specifically, so we can see whether there is an impact of finerenone on patients with heart failure who may not necessarily have kidney disease or diabetes,” Dr. Curtis said.
 

Hypothesis-generating findings

The new findings reported by Dr. Filippatos “should be considered hypothesis generating. Until we have more information, upstream therapies, including mineralocorticoid receptor antagonists [MRAs, the umbrella drug class that includes finerenone], should be used in appropriate patient populations based on defined benefits with the hope they will also reduce the development of AFib and atrial flutter over time,” Gerald V. Naccarelli, MD, and coauthors wrote in an editorial that accompanied the report (J Am Coll Cardiol. 2021 May 17. doi: 10.1016/j.jacc.2021.04.080).

The FIDELIO-DKD trial randomized 5,734 patients at 913 sites in 48 countries, including 461 patients with a history of AFib. The observed link of finerenone treatment with a reduced incidence of AFib appeared consistent regardless of patients’ age, sex, race, their kidney characteristics at baseline, baseline levels of systolic blood pressure, serum potassium, body mass index, A1c, or use of glucose-lowering medications.

Finerenone belongs to a new class of MRAs that have a nonsteroidal structure, in contrast with the MRAs spironolactone and eplerenone. This means that finerenone does not produce steroidal-associated adverse effects linked with certain other MRAs, such as gynecomastia, and may also differ in other actions.

FIDELIO-DKD was sponsored by Bayer, the company developing finerenone. Dr. Filippatos has received lecture fees from or participated in the direction of trials on behalf of Bayer, as well as for Amgen, Boehringer Ingelheim, Medtronic, Novartis, Servier, and Vifor. Dr. Curtis is an adviser to and receives honoraria from St. Jude Medical, and receives honoraria from Medtronic. Dr. Naccarelli has been a consultant to Acesion, ARCA, GlaxoSmithKline, Janssen, Milestone, Omeicos, and Sanofi. His coauthors had no disclosures.

[email protected]

Finerenone treatment of patients with type 2 diabetes and diabetic kidney disease was linked to a significant drop in the incidence of new-onset atrial fibrillation as a prespecified, exploratory endpoint of the FIDELIO-DKD pivotal trial that randomized more than 5,700 patients.

Treatment with finerenone linked with a 29% relative reduction compared with placebo in incident cases of atrial fibrillation (AFib), Gerasimos Filippatos, MD, reported at the annual scientific sessions of the American College of Cardiology.

The absolute reduction was modest, a 1.3% reduction from the 4.5% incidence rate on placebo to a 3.2% rate on finerenone during a median 2.6 years of follow-up. Concurrently with the report, the results appeared online (J Am Coll Cardiol. 2021 May 17. doi: 10.1016/j.jacc.2021.04.079).

The analyses Dr. Filippatos presented also showed that whether or not patients had a history of AFib, there was no impact on either the primary benefit from finerenone treatment seen in FIDELIO-DKD, which was a significant 18% relative risk reduction compared with placebo in the combined rate of kidney failure, a 40% or greater decline from baseline in estimated glomerular filtration rate, or renal death.

Likewise, prior AFib status had no effect on the study’s key secondary endpoint, a significant 14% relative risk reduction in the combined rate of cardiovascular death, nonfatal MI, nonfatal stroke, or hospitalization for heart failure.

The primary results from FIDELIO-DKD (Efficacy and Safety of Finerenone in Subjects With Type 2 Diabetes Mellitus and Diabetic Kidney Disease) appeared in a 2020 report (N Engl J Med. 2020 Dec 3;383[23];2219-29).
 

‘Side benefits can be very helpful’

“It’s important to know of finerenone’s benefits beyond the primary outcome of a trial because side benefits can be very helpful,” said Anne B. Curtis, MD, an electrophysiologist and professor and chair of medicine at the University of Buffalo (N.Y.) School of Medicine and Biomedical Sciences. “It’s not a huge benefit, but this could be an added benefit for selected patients,” she said during a press briefing. “Background studies had shown favorable remodeling of the heart [by finerenone] that could affect AFib.”

Possible mitigating effects by finerenone on inflammation and fibrosis might also mediate the drug’s apparent effect on AFib, said Dr. Filippatos, professor of cardiology and director of the Heart Failure and Cardio-Oncology Clinic at Attikon University Hospital and the University of Athens.

He noted that additional data addressing a possible AFib effect of finerenone will emerge soon from the FIGARO-DKD trial, which enrolled patients similar to those in FIDELIO-DKD but with more moderate stages of kidney disease, and from the FINEARTS-HF trial, which is examining the effect of finerenone in patients with heart failure with an ejection fraction of at least 40%.

“Heart failure and AFib go together tightly. It’s worth studying this specifically, so we can see whether there is an impact of finerenone on patients with heart failure who may not necessarily have kidney disease or diabetes,” Dr. Curtis said.
 

Hypothesis-generating findings

The new findings reported by Dr. Filippatos “should be considered hypothesis generating. Until we have more information, upstream therapies, including mineralocorticoid receptor antagonists [MRAs, the umbrella drug class that includes finerenone], should be used in appropriate patient populations based on defined benefits with the hope they will also reduce the development of AFib and atrial flutter over time,” Gerald V. Naccarelli, MD, and coauthors wrote in an editorial that accompanied the report (J Am Coll Cardiol. 2021 May 17. doi: 10.1016/j.jacc.2021.04.080).

The FIDELIO-DKD trial randomized 5,734 patients at 913 sites in 48 countries, including 461 patients with a history of AFib. The observed link of finerenone treatment with a reduced incidence of AFib appeared consistent regardless of patients’ age, sex, race, their kidney characteristics at baseline, baseline levels of systolic blood pressure, serum potassium, body mass index, A1c, or use of glucose-lowering medications.

Finerenone belongs to a new class of MRAs that have a nonsteroidal structure, in contrast with the MRAs spironolactone and eplerenone. This means that finerenone does not produce steroidal-associated adverse effects linked with certain other MRAs, such as gynecomastia, and may also differ in other actions.

FIDELIO-DKD was sponsored by Bayer, the company developing finerenone. Dr. Filippatos has received lecture fees from or participated in the direction of trials on behalf of Bayer, as well as for Amgen, Boehringer Ingelheim, Medtronic, Novartis, Servier, and Vifor. Dr. Curtis is an adviser to and receives honoraria from St. Jude Medical, and receives honoraria from Medtronic. Dr. Naccarelli has been a consultant to Acesion, ARCA, GlaxoSmithKline, Janssen, Milestone, Omeicos, and Sanofi. His coauthors had no disclosures.

[email protected]

Finerenone treatment of patients with type 2 diabetes and diabetic kidney disease was linked to a significant drop in the incidence of new-onset atrial fibrillation as a prespecified, exploratory endpoint of the FIDELIO-DKD pivotal trial that randomized more than 5,700 patients.

Treatment with finerenone linked with a 29% relative reduction compared with placebo in incident cases of atrial fibrillation (AFib), Gerasimos Filippatos, MD, reported at the annual scientific sessions of the American College of Cardiology.

The absolute reduction was modest, a 1.3% reduction from the 4.5% incidence rate on placebo to a 3.2% rate on finerenone during a median 2.6 years of follow-up. Concurrently with the report, the results appeared online (J Am Coll Cardiol. 2021 May 17. doi: 10.1016/j.jacc.2021.04.079).

The analyses Dr. Filippatos presented also showed that whether or not patients had a history of AFib, there was no impact on either the primary benefit from finerenone treatment seen in FIDELIO-DKD, which was a significant 18% relative risk reduction compared with placebo in the combined rate of kidney failure, a 40% or greater decline from baseline in estimated glomerular filtration rate, or renal death.

Likewise, prior AFib status had no effect on the study’s key secondary endpoint, a significant 14% relative risk reduction in the combined rate of cardiovascular death, nonfatal MI, nonfatal stroke, or hospitalization for heart failure.

The primary results from FIDELIO-DKD (Efficacy and Safety of Finerenone in Subjects With Type 2 Diabetes Mellitus and Diabetic Kidney Disease) appeared in a 2020 report (N Engl J Med. 2020 Dec 3;383[23];2219-29).
 

‘Side benefits can be very helpful’

“It’s important to know of finerenone’s benefits beyond the primary outcome of a trial because side benefits can be very helpful,” said Anne B. Curtis, MD, an electrophysiologist and professor and chair of medicine at the University of Buffalo (N.Y.) School of Medicine and Biomedical Sciences. “It’s not a huge benefit, but this could be an added benefit for selected patients,” she said during a press briefing. “Background studies had shown favorable remodeling of the heart [by finerenone] that could affect AFib.”

Possible mitigating effects by finerenone on inflammation and fibrosis might also mediate the drug’s apparent effect on AFib, said Dr. Filippatos, professor of cardiology and director of the Heart Failure and Cardio-Oncology Clinic at Attikon University Hospital and the University of Athens.

He noted that additional data addressing a possible AFib effect of finerenone will emerge soon from the FIGARO-DKD trial, which enrolled patients similar to those in FIDELIO-DKD but with more moderate stages of kidney disease, and from the FINEARTS-HF trial, which is examining the effect of finerenone in patients with heart failure with an ejection fraction of at least 40%.

“Heart failure and AFib go together tightly. It’s worth studying this specifically, so we can see whether there is an impact of finerenone on patients with heart failure who may not necessarily have kidney disease or diabetes,” Dr. Curtis said.
 

Hypothesis-generating findings

The new findings reported by Dr. Filippatos “should be considered hypothesis generating. Until we have more information, upstream therapies, including mineralocorticoid receptor antagonists [MRAs, the umbrella drug class that includes finerenone], should be used in appropriate patient populations based on defined benefits with the hope they will also reduce the development of AFib and atrial flutter over time,” Gerald V. Naccarelli, MD, and coauthors wrote in an editorial that accompanied the report (J Am Coll Cardiol. 2021 May 17. doi: 10.1016/j.jacc.2021.04.080).

The FIDELIO-DKD trial randomized 5,734 patients at 913 sites in 48 countries, including 461 patients with a history of AFib. The observed link of finerenone treatment with a reduced incidence of AFib appeared consistent regardless of patients’ age, sex, race, their kidney characteristics at baseline, baseline levels of systolic blood pressure, serum potassium, body mass index, A1c, or use of glucose-lowering medications.

Finerenone belongs to a new class of MRAs that have a nonsteroidal structure, in contrast with the MRAs spironolactone and eplerenone. This means that finerenone does not produce steroidal-associated adverse effects linked with certain other MRAs, such as gynecomastia, and may also differ in other actions.

FIDELIO-DKD was sponsored by Bayer, the company developing finerenone. Dr. Filippatos has received lecture fees from or participated in the direction of trials on behalf of Bayer, as well as for Amgen, Boehringer Ingelheim, Medtronic, Novartis, Servier, and Vifor. Dr. Curtis is an adviser to and receives honoraria from St. Jude Medical, and receives honoraria from Medtronic. Dr. Naccarelli has been a consultant to Acesion, ARCA, GlaxoSmithKline, Janssen, Milestone, Omeicos, and Sanofi. His coauthors had no disclosures.

[email protected]

Questions over the cardiovascular benefits shown in the REDUCE-IT trial with icosapent ethyl, a high-dose eicosapentaenoic acid (EPA) product, have been reignited with a new analysis from the STRENGTH trial showing no benefit of a high-dose combined omega-3 fatty acid product in patients who achieved the highest EPA levels and no harm in those with the highest levels of docosahexaenoic acid (DHA).

STRENGTH investigator Steven Nissen, MD, said these new results add to concerns about the positive result in the previously reported REDUCE-IT trial and suggest that “there is no strong evidence of a benefit of fish oil in preventing major cardiovascular events.”

But Dr. Nissen, who is chair of the department of cardiovascular medicine at the Cleveland Clinic in Ohio, pointed out evidence of harm, with both REDUCE-IT and STRENGTH showing an increase in atrial fibrillation with the high-dose omega-3 fatty acid products.

“Fish oils increase the risk of atrial fibrillation substantially, and there is no solid evidence that they help the heart in any way,” he stated.

The new STRENGTH analysis was presented at the annual scientific sessions of the American College of Cardiology. and was simultaneously published in JAMA Cardiology.

The REDUCE-IT trial showed a large 25% relative-risk reduction in cardiovascular events in patients taking icosapent ethyl (Vascepa, Amarin), a high-dose purified formulation of EPA, compared with patients taking a mineral oil placebo. But a similar trial, STRENGTH, showed no effect of a similar high dose of the mixed EPA/DHA product (Epanova, AstraZeneca), compared with a corn oil placebo.

The different results from these two studies have led to many questions about how the benefits seen in REDUCE-IT were brought about, and why they weren’t replicated in the STRENGTH study.

Dr. Nissen noted that several hypotheses have been proposed. These include a potential adverse effect of the mineral oil placebo in the REDUCE-IT trial, which may have elevated risk in the placebo treatment group and led to a false-positive result for icosapent ethyl. Another possibility is that the moderately higher plasma levels of EPA achieved in REDUCE-IT were responsible for the observed benefits or that the coadministration of DHA in STRENGTH may have counteracted the potential beneficial effects of EPA.

The current post hoc analysis of STRENGTH was conducted to address these latter two possibilities. It aimed to assess the association between cardiovascular outcomes and achieved levels of EPA, DHA, or changes in levels of these fatty acids.

“In our new analysis, among patients treated with fish oil, we found no evidence that EPA is beneficial or that DHA is harmful,” Dr. Nissen said.

Results of the new analysis showed an absence of a benefit from achieving high levels of EPA or harm from achieving high levels of DHA which, the authors say, “strengthens the concerns that the choice of comparator may have influenced the divergent results observed in the two trials.”

“Unlike corn oil, which is inert, mineral oil has major adverse effects, increasing LDL by 10.9% and CRP [C-reactive protein] by 32% in the REDUCE-IT trial,” Dr. Nissen said. “If you give a toxic placebo, then the active drug may falsely look really good.”  

The STRENGTH trial randomly assigned 13,078 individuals at high risk for major cardiovascular events to receive 4 g daily of the EPA/DHA combined product (omega-3 carboxylic acid) or corn oil as the placebo. Main results, reported previously, showed no difference between the two groups in terms of the primary outcome – a composite of cardiovascular death, myocardial infarction, stroke, coronary revascularization, or unstable angina requiring hospitalization.

The current analysis, in 10,382 patients with available omega-3 fatty acid levels, looked at event rates according to tertiles of achieved EPA and DHA levels. The median plasma EPA level for patients taking the omega-3 product was 89 mcg/mL, with the top tertile achieving levels of 151 mcg/mL (a 443% increase). Dr. Nissen pointed out that this was higher than the median level of EPA reported in the REDUCE-IT trial (144 mcg/mL).

The median level of DHA was 91 mcg/mL, rising to 118 mcg/mL (a 68% increase) in the top tertile in the STRENGTH analysis.

Results showed no difference in the occurrence of the prespecified primary outcome among patients treated with omega-3 carboxylic acid who were in the top tertile of achieved EPA levels at 1 year (event rate, 11.3%), compared with patients treated with corn oil (11.0%), a nonsignificant difference (hazard ratio, 0.98; P = .81).

For DHA, patients in the top tertile of achieved DHA levels had an event rate of 11.4% vs. 11.0% in the corn oil group, also a nonsignificant difference (HR, 1.02; P = .85)    

Sensitivity analyses based on the highest tertile of change in EPA or DHA levels showed similarly neutral results.

Because plasma levels may not reflect tissue levels of EPA or DHA, additional analyses assessed red blood cell EPA and DHA levels, neither of which showed any evidence of benefit or harm.

“These findings suggest that supplementation of omega-3 fatty acids in high-risk cardiovascular patients is neutral even at the highest achieved levels,” Dr. Nissen said. “And, in the context of increased risk of atrial fibrillation in omega-3 trials, they cast uncertainty over whether there is net benefit or harm with any omega-3 preparation,” he concluded.

He suggested that the choice of placebo comparator may play an important role in determining outcome for trials of omega-3 products, adding that further research is needed with trials specifically designed to compare corn oil with mineral oil and compare purified EPA with other formulations of omega-3 fatty acids.

At an press conference, Dr. Nissen said he could not recommend use of omega-3 fatty acid products for cardiovascular risk reduction given the uncertainty over the benefit in REDUCE-IT.

“We need replication, and the problem is STRENGTH did not replicate REDUCE-IT,” he stated.

 REDUCE-IT investigator responds

The discussant of the STRENGTH analysis at the ACC presentation, Deepak L. Bhatt, MD, who was lead investigator of the REDUCE-IT trial, suggested that one conclusion could be that “an absence of a relationship in a negative trial doesn’t tell us that much other than that specific drug doesn’t work.”

Dr. Bhatt, who is executive director of interventional cardiovascular programs at Brigham and Women’s Hospital Heart & Vascular Center, Boston, said in an interview that comparisons should not be made between different trials using different products.  

“I commend the STRENGTH investigators on a well-conducted trial that provided a definitive answer about the specific drug they studied, finding no benefit. But in a completely negative trial, I wouldn’t necessarily expect to see a relationship between any biomarker and outcome,” he said.

“With respect to icosapent ethyl (pure EPA), every cardiovascular trial to date has been positive: REDUCE-IT (randomized, placebo-controlled), JELIS (randomized, no placebo), EVAPORATE (randomized, placebo-controlled), CHERRY (randomized, no placebo), and some smaller ones,” Dr. Bhatt added. “Both REDUCE-IT and JELIS found associations between higher levels of EPA and lower rates of cardiovascular events, suggesting that higher EPA levels attained specifically with icosapent ethyl are beneficial.”

Pointing out that all the glucagonlike peptide–1 agonists lower glucose, for example, but not all reduce cardiovascular events, Dr. Bhatt said it was best to focus on clinical trial results and not overly focus on biomarker changes.

“Yes, the drug in STRENGTH raised EPA (and raised DHA, as well as lowering triglycerides), but the drug in REDUCE-IT and JELIS raised EPA much more, without raising DHA – and more importantly, the increase in EPA was via a totally different drug, with many different properties,” he added.

In his discussion of the study at the ACC presentation, Dr. Bhatt pointed out that in the STRENGTH trial overall there was no reduction in major adverse cardiovascular events despite a 19% reduction in triglycerides, which he said was a “very interesting disconnect.” He asked Dr. Nissen what he thought the reason was for the observation in this analysis of no relationship between EPA or DHA level and triglyceride reduction. 

Dr. Nissen said that was an interesting point. “When we look at the two trials, they both reduced triglyceride levels by an almost identical amount, 19%, but we don’t see a relationship with that and EPA levels achieved.” He suggested this may be because of different threshold levels.

Dr. Bhatt also noted that high-intensity statin use was lower in the patients with higher EPA levels in the STRENGTH analysis, but Dr. Nissen countered: “I don’t think that was enough of a difference to explain the lack of an effect.”

Invited commentator on the new analysis at an ACC press conference, Eileen Handberg, PhD, said it was important to try to understand the reasons behind the different results of the STRENGTH and REDUCE-IT trials. “These new findings are important because they explain potentially why these outcomes are different,” she stated.

Dr. Handberg, who is professor of medicine at the University of Florida, Gainesville, said she hoped the additional research called for by Dr. Nissen would go ahead as a head-to-head study of the two omega-3 products or of the two different placebo oils.

The STRENGTH trial was sponsored by Astra Zeneca. Dr. Nissen reports research grants from AbbVie, Amgen, Astra Zeneca, Eli Lilly, Esperion Therapeutics, MEDTRONIC, MyoKardia, Novartis, Novo Nordisk, Pfizer, and Silence Therapeutics. Dr. Bhatt reports constant fees/honoraria from CellProthera, Elsevier Practice Update Cardiology, K2P, Level Ex, Medtelligence, MJH Life Sciences, and WebMD; data safety monitoring board activities with Contego; other roles with TobeSoft, Belvoir Publications, Cardax, Cereno Scientific, Clinical Cardiology, Elsevier, HMP Global, Janssen Pharmaceuticals, Journal of Invasive Cardiology, Medscape Cardiology, Merck, MyoKardia, Novo Nordisk, PhaseBio, PLx Pharma, Regado Biosciences, and Slack Publications/Cardiology Research Foundation; and research grants from Abbott, Afimmune, Amarin, Amgen, Astra Zeneca, Bayer Healthcare Pharmaceuticals, Boehringer Ingelheim Pharmaceuticals,  Bristol-Myers Squibb, Cardax, Chiesi, Eisai, Eli Lilly, Ethicon, FlowCo, Forest Laboratories, Fractyl, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Lexicon, MEDTRONIC, MyoKardia, Owkin, Pfizer, PhaseBio, PLx Pharma, Regeneron, Roche, Sanofi Aventis, Synaptic, Takeda, and The Medicines Company.  

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

Questions over the cardiovascular benefits shown in the REDUCE-IT trial with icosapent ethyl, a high-dose eicosapentaenoic acid (EPA) product, have been reignited with a new analysis from the STRENGTH trial showing no benefit of a high-dose combined omega-3 fatty acid product in patients who achieved the highest EPA levels and no harm in those with the highest levels of docosahexaenoic acid (DHA).

STRENGTH investigator Steven Nissen, MD, said these new results add to concerns about the positive result in the previously reported REDUCE-IT trial and suggest that “there is no strong evidence of a benefit of fish oil in preventing major cardiovascular events.”

But Dr. Nissen, who is chair of the department of cardiovascular medicine at the Cleveland Clinic in Ohio, pointed out evidence of harm, with both REDUCE-IT and STRENGTH showing an increase in atrial fibrillation with the high-dose omega-3 fatty acid products.

“Fish oils increase the risk of atrial fibrillation substantially, and there is no solid evidence that they help the heart in any way,” he stated.

The new STRENGTH analysis was presented at the annual scientific sessions of the American College of Cardiology. and was simultaneously published in JAMA Cardiology.

The REDUCE-IT trial showed a large 25% relative-risk reduction in cardiovascular events in patients taking icosapent ethyl (Vascepa, Amarin), a high-dose purified formulation of EPA, compared with patients taking a mineral oil placebo. But a similar trial, STRENGTH, showed no effect of a similar high dose of the mixed EPA/DHA product (Epanova, AstraZeneca), compared with a corn oil placebo.

The different results from these two studies have led to many questions about how the benefits seen in REDUCE-IT were brought about, and why they weren’t replicated in the STRENGTH study.

Dr. Nissen noted that several hypotheses have been proposed. These include a potential adverse effect of the mineral oil placebo in the REDUCE-IT trial, which may have elevated risk in the placebo treatment group and led to a false-positive result for icosapent ethyl. Another possibility is that the moderately higher plasma levels of EPA achieved in REDUCE-IT were responsible for the observed benefits or that the coadministration of DHA in STRENGTH may have counteracted the potential beneficial effects of EPA.

The current post hoc analysis of STRENGTH was conducted to address these latter two possibilities. It aimed to assess the association between cardiovascular outcomes and achieved levels of EPA, DHA, or changes in levels of these fatty acids.

“In our new analysis, among patients treated with fish oil, we found no evidence that EPA is beneficial or that DHA is harmful,” Dr. Nissen said.

Results of the new analysis showed an absence of a benefit from achieving high levels of EPA or harm from achieving high levels of DHA which, the authors say, “strengthens the concerns that the choice of comparator may have influenced the divergent results observed in the two trials.”

“Unlike corn oil, which is inert, mineral oil has major adverse effects, increasing LDL by 10.9% and CRP [C-reactive protein] by 32% in the REDUCE-IT trial,” Dr. Nissen said. “If you give a toxic placebo, then the active drug may falsely look really good.”  

The STRENGTH trial randomly assigned 13,078 individuals at high risk for major cardiovascular events to receive 4 g daily of the EPA/DHA combined product (omega-3 carboxylic acid) or corn oil as the placebo. Main results, reported previously, showed no difference between the two groups in terms of the primary outcome – a composite of cardiovascular death, myocardial infarction, stroke, coronary revascularization, or unstable angina requiring hospitalization.

The current analysis, in 10,382 patients with available omega-3 fatty acid levels, looked at event rates according to tertiles of achieved EPA and DHA levels. The median plasma EPA level for patients taking the omega-3 product was 89 mcg/mL, with the top tertile achieving levels of 151 mcg/mL (a 443% increase). Dr. Nissen pointed out that this was higher than the median level of EPA reported in the REDUCE-IT trial (144 mcg/mL).

The median level of DHA was 91 mcg/mL, rising to 118 mcg/mL (a 68% increase) in the top tertile in the STRENGTH analysis.

Results showed no difference in the occurrence of the prespecified primary outcome among patients treated with omega-3 carboxylic acid who were in the top tertile of achieved EPA levels at 1 year (event rate, 11.3%), compared with patients treated with corn oil (11.0%), a nonsignificant difference (hazard ratio, 0.98; P = .81).

For DHA, patients in the top tertile of achieved DHA levels had an event rate of 11.4% vs. 11.0% in the corn oil group, also a nonsignificant difference (HR, 1.02; P = .85)    

Sensitivity analyses based on the highest tertile of change in EPA or DHA levels showed similarly neutral results.

Because plasma levels may not reflect tissue levels of EPA or DHA, additional analyses assessed red blood cell EPA and DHA levels, neither of which showed any evidence of benefit or harm.

“These findings suggest that supplementation of omega-3 fatty acids in high-risk cardiovascular patients is neutral even at the highest achieved levels,” Dr. Nissen said. “And, in the context of increased risk of atrial fibrillation in omega-3 trials, they cast uncertainty over whether there is net benefit or harm with any omega-3 preparation,” he concluded.

He suggested that the choice of placebo comparator may play an important role in determining outcome for trials of omega-3 products, adding that further research is needed with trials specifically designed to compare corn oil with mineral oil and compare purified EPA with other formulations of omega-3 fatty acids.

At an press conference, Dr. Nissen said he could not recommend use of omega-3 fatty acid products for cardiovascular risk reduction given the uncertainty over the benefit in REDUCE-IT.

“We need replication, and the problem is STRENGTH did not replicate REDUCE-IT,” he stated.

 REDUCE-IT investigator responds

The discussant of the STRENGTH analysis at the ACC presentation, Deepak L. Bhatt, MD, who was lead investigator of the REDUCE-IT trial, suggested that one conclusion could be that “an absence of a relationship in a negative trial doesn’t tell us that much other than that specific drug doesn’t work.”

Dr. Bhatt, who is executive director of interventional cardiovascular programs at Brigham and Women’s Hospital Heart & Vascular Center, Boston, said in an interview that comparisons should not be made between different trials using different products.  

“I commend the STRENGTH investigators on a well-conducted trial that provided a definitive answer about the specific drug they studied, finding no benefit. But in a completely negative trial, I wouldn’t necessarily expect to see a relationship between any biomarker and outcome,” he said.

“With respect to icosapent ethyl (pure EPA), every cardiovascular trial to date has been positive: REDUCE-IT (randomized, placebo-controlled), JELIS (randomized, no placebo), EVAPORATE (randomized, placebo-controlled), CHERRY (randomized, no placebo), and some smaller ones,” Dr. Bhatt added. “Both REDUCE-IT and JELIS found associations between higher levels of EPA and lower rates of cardiovascular events, suggesting that higher EPA levels attained specifically with icosapent ethyl are beneficial.”

Pointing out that all the glucagonlike peptide–1 agonists lower glucose, for example, but not all reduce cardiovascular events, Dr. Bhatt said it was best to focus on clinical trial results and not overly focus on biomarker changes.

“Yes, the drug in STRENGTH raised EPA (and raised DHA, as well as lowering triglycerides), but the drug in REDUCE-IT and JELIS raised EPA much more, without raising DHA – and more importantly, the increase in EPA was via a totally different drug, with many different properties,” he added.

In his discussion of the study at the ACC presentation, Dr. Bhatt pointed out that in the STRENGTH trial overall there was no reduction in major adverse cardiovascular events despite a 19% reduction in triglycerides, which he said was a “very interesting disconnect.” He asked Dr. Nissen what he thought the reason was for the observation in this analysis of no relationship between EPA or DHA level and triglyceride reduction. 

Dr. Nissen said that was an interesting point. “When we look at the two trials, they both reduced triglyceride levels by an almost identical amount, 19%, but we don’t see a relationship with that and EPA levels achieved.” He suggested this may be because of different threshold levels.

Dr. Bhatt also noted that high-intensity statin use was lower in the patients with higher EPA levels in the STRENGTH analysis, but Dr. Nissen countered: “I don’t think that was enough of a difference to explain the lack of an effect.”

Invited commentator on the new analysis at an ACC press conference, Eileen Handberg, PhD, said it was important to try to understand the reasons behind the different results of the STRENGTH and REDUCE-IT trials. “These new findings are important because they explain potentially why these outcomes are different,” she stated.

Dr. Handberg, who is professor of medicine at the University of Florida, Gainesville, said she hoped the additional research called for by Dr. Nissen would go ahead as a head-to-head study of the two omega-3 products or of the two different placebo oils.

The STRENGTH trial was sponsored by Astra Zeneca. Dr. Nissen reports research grants from AbbVie, Amgen, Astra Zeneca, Eli Lilly, Esperion Therapeutics, MEDTRONIC, MyoKardia, Novartis, Novo Nordisk, Pfizer, and Silence Therapeutics. Dr. Bhatt reports constant fees/honoraria from CellProthera, Elsevier Practice Update Cardiology, K2P, Level Ex, Medtelligence, MJH Life Sciences, and WebMD; data safety monitoring board activities with Contego; other roles with TobeSoft, Belvoir Publications, Cardax, Cereno Scientific, Clinical Cardiology, Elsevier, HMP Global, Janssen Pharmaceuticals, Journal of Invasive Cardiology, Medscape Cardiology, Merck, MyoKardia, Novo Nordisk, PhaseBio, PLx Pharma, Regado Biosciences, and Slack Publications/Cardiology Research Foundation; and research grants from Abbott, Afimmune, Amarin, Amgen, Astra Zeneca, Bayer Healthcare Pharmaceuticals, Boehringer Ingelheim Pharmaceuticals,  Bristol-Myers Squibb, Cardax, Chiesi, Eisai, Eli Lilly, Ethicon, FlowCo, Forest Laboratories, Fractyl, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Lexicon, MEDTRONIC, MyoKardia, Owkin, Pfizer, PhaseBio, PLx Pharma, Regeneron, Roche, Sanofi Aventis, Synaptic, Takeda, and The Medicines Company.  

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

Questions over the cardiovascular benefits shown in the REDUCE-IT trial with icosapent ethyl, a high-dose eicosapentaenoic acid (EPA) product, have been reignited with a new analysis from the STRENGTH trial showing no benefit of a high-dose combined omega-3 fatty acid product in patients who achieved the highest EPA levels and no harm in those with the highest levels of docosahexaenoic acid (DHA).

STRENGTH investigator Steven Nissen, MD, said these new results add to concerns about the positive result in the previously reported REDUCE-IT trial and suggest that “there is no strong evidence of a benefit of fish oil in preventing major cardiovascular events.”

But Dr. Nissen, who is chair of the department of cardiovascular medicine at the Cleveland Clinic in Ohio, pointed out evidence of harm, with both REDUCE-IT and STRENGTH showing an increase in atrial fibrillation with the high-dose omega-3 fatty acid products.

“Fish oils increase the risk of atrial fibrillation substantially, and there is no solid evidence that they help the heart in any way,” he stated.

The new STRENGTH analysis was presented at the annual scientific sessions of the American College of Cardiology. and was simultaneously published in JAMA Cardiology.

The REDUCE-IT trial showed a large 25% relative-risk reduction in cardiovascular events in patients taking icosapent ethyl (Vascepa, Amarin), a high-dose purified formulation of EPA, compared with patients taking a mineral oil placebo. But a similar trial, STRENGTH, showed no effect of a similar high dose of the mixed EPA/DHA product (Epanova, AstraZeneca), compared with a corn oil placebo.

The different results from these two studies have led to many questions about how the benefits seen in REDUCE-IT were brought about, and why they weren’t replicated in the STRENGTH study.

Dr. Nissen noted that several hypotheses have been proposed. These include a potential adverse effect of the mineral oil placebo in the REDUCE-IT trial, which may have elevated risk in the placebo treatment group and led to a false-positive result for icosapent ethyl. Another possibility is that the moderately higher plasma levels of EPA achieved in REDUCE-IT were responsible for the observed benefits or that the coadministration of DHA in STRENGTH may have counteracted the potential beneficial effects of EPA.

The current post hoc analysis of STRENGTH was conducted to address these latter two possibilities. It aimed to assess the association between cardiovascular outcomes and achieved levels of EPA, DHA, or changes in levels of these fatty acids.

“In our new analysis, among patients treated with fish oil, we found no evidence that EPA is beneficial or that DHA is harmful,” Dr. Nissen said.

Results of the new analysis showed an absence of a benefit from achieving high levels of EPA or harm from achieving high levels of DHA which, the authors say, “strengthens the concerns that the choice of comparator may have influenced the divergent results observed in the two trials.”

“Unlike corn oil, which is inert, mineral oil has major adverse effects, increasing LDL by 10.9% and CRP [C-reactive protein] by 32% in the REDUCE-IT trial,” Dr. Nissen said. “If you give a toxic placebo, then the active drug may falsely look really good.”  

The STRENGTH trial randomly assigned 13,078 individuals at high risk for major cardiovascular events to receive 4 g daily of the EPA/DHA combined product (omega-3 carboxylic acid) or corn oil as the placebo. Main results, reported previously, showed no difference between the two groups in terms of the primary outcome – a composite of cardiovascular death, myocardial infarction, stroke, coronary revascularization, or unstable angina requiring hospitalization.

The current analysis, in 10,382 patients with available omega-3 fatty acid levels, looked at event rates according to tertiles of achieved EPA and DHA levels. The median plasma EPA level for patients taking the omega-3 product was 89 mcg/mL, with the top tertile achieving levels of 151 mcg/mL (a 443% increase). Dr. Nissen pointed out that this was higher than the median level of EPA reported in the REDUCE-IT trial (144 mcg/mL).

The median level of DHA was 91 mcg/mL, rising to 118 mcg/mL (a 68% increase) in the top tertile in the STRENGTH analysis.

Results showed no difference in the occurrence of the prespecified primary outcome among patients treated with omega-3 carboxylic acid who were in the top tertile of achieved EPA levels at 1 year (event rate, 11.3%), compared with patients treated with corn oil (11.0%), a nonsignificant difference (hazard ratio, 0.98; P = .81).

For DHA, patients in the top tertile of achieved DHA levels had an event rate of 11.4% vs. 11.0% in the corn oil group, also a nonsignificant difference (HR, 1.02; P = .85)    

Sensitivity analyses based on the highest tertile of change in EPA or DHA levels showed similarly neutral results.

Because plasma levels may not reflect tissue levels of EPA or DHA, additional analyses assessed red blood cell EPA and DHA levels, neither of which showed any evidence of benefit or harm.

“These findings suggest that supplementation of omega-3 fatty acids in high-risk cardiovascular patients is neutral even at the highest achieved levels,” Dr. Nissen said. “And, in the context of increased risk of atrial fibrillation in omega-3 trials, they cast uncertainty over whether there is net benefit or harm with any omega-3 preparation,” he concluded.

He suggested that the choice of placebo comparator may play an important role in determining outcome for trials of omega-3 products, adding that further research is needed with trials specifically designed to compare corn oil with mineral oil and compare purified EPA with other formulations of omega-3 fatty acids.

At an press conference, Dr. Nissen said he could not recommend use of omega-3 fatty acid products for cardiovascular risk reduction given the uncertainty over the benefit in REDUCE-IT.

“We need replication, and the problem is STRENGTH did not replicate REDUCE-IT,” he stated.

 REDUCE-IT investigator responds

The discussant of the STRENGTH analysis at the ACC presentation, Deepak L. Bhatt, MD, who was lead investigator of the REDUCE-IT trial, suggested that one conclusion could be that “an absence of a relationship in a negative trial doesn’t tell us that much other than that specific drug doesn’t work.”

Dr. Bhatt, who is executive director of interventional cardiovascular programs at Brigham and Women’s Hospital Heart & Vascular Center, Boston, said in an interview that comparisons should not be made between different trials using different products.  

“I commend the STRENGTH investigators on a well-conducted trial that provided a definitive answer about the specific drug they studied, finding no benefit. But in a completely negative trial, I wouldn’t necessarily expect to see a relationship between any biomarker and outcome,” he said.

“With respect to icosapent ethyl (pure EPA), every cardiovascular trial to date has been positive: REDUCE-IT (randomized, placebo-controlled), JELIS (randomized, no placebo), EVAPORATE (randomized, placebo-controlled), CHERRY (randomized, no placebo), and some smaller ones,” Dr. Bhatt added. “Both REDUCE-IT and JELIS found associations between higher levels of EPA and lower rates of cardiovascular events, suggesting that higher EPA levels attained specifically with icosapent ethyl are beneficial.”

Pointing out that all the glucagonlike peptide–1 agonists lower glucose, for example, but not all reduce cardiovascular events, Dr. Bhatt said it was best to focus on clinical trial results and not overly focus on biomarker changes.

“Yes, the drug in STRENGTH raised EPA (and raised DHA, as well as lowering triglycerides), but the drug in REDUCE-IT and JELIS raised EPA much more, without raising DHA – and more importantly, the increase in EPA was via a totally different drug, with many different properties,” he added.

In his discussion of the study at the ACC presentation, Dr. Bhatt pointed out that in the STRENGTH trial overall there was no reduction in major adverse cardiovascular events despite a 19% reduction in triglycerides, which he said was a “very interesting disconnect.” He asked Dr. Nissen what he thought the reason was for the observation in this analysis of no relationship between EPA or DHA level and triglyceride reduction. 

Dr. Nissen said that was an interesting point. “When we look at the two trials, they both reduced triglyceride levels by an almost identical amount, 19%, but we don’t see a relationship with that and EPA levels achieved.” He suggested this may be because of different threshold levels.

Dr. Bhatt also noted that high-intensity statin use was lower in the patients with higher EPA levels in the STRENGTH analysis, but Dr. Nissen countered: “I don’t think that was enough of a difference to explain the lack of an effect.”

Invited commentator on the new analysis at an ACC press conference, Eileen Handberg, PhD, said it was important to try to understand the reasons behind the different results of the STRENGTH and REDUCE-IT trials. “These new findings are important because they explain potentially why these outcomes are different,” she stated.

Dr. Handberg, who is professor of medicine at the University of Florida, Gainesville, said she hoped the additional research called for by Dr. Nissen would go ahead as a head-to-head study of the two omega-3 products or of the two different placebo oils.

The STRENGTH trial was sponsored by Astra Zeneca. Dr. Nissen reports research grants from AbbVie, Amgen, Astra Zeneca, Eli Lilly, Esperion Therapeutics, MEDTRONIC, MyoKardia, Novartis, Novo Nordisk, Pfizer, and Silence Therapeutics. Dr. Bhatt reports constant fees/honoraria from CellProthera, Elsevier Practice Update Cardiology, K2P, Level Ex, Medtelligence, MJH Life Sciences, and WebMD; data safety monitoring board activities with Contego; other roles with TobeSoft, Belvoir Publications, Cardax, Cereno Scientific, Clinical Cardiology, Elsevier, HMP Global, Janssen Pharmaceuticals, Journal of Invasive Cardiology, Medscape Cardiology, Merck, MyoKardia, Novo Nordisk, PhaseBio, PLx Pharma, Regado Biosciences, and Slack Publications/Cardiology Research Foundation; and research grants from Abbott, Afimmune, Amarin, Amgen, Astra Zeneca, Bayer Healthcare Pharmaceuticals, Boehringer Ingelheim Pharmaceuticals,  Bristol-Myers Squibb, Cardax, Chiesi, Eisai, Eli Lilly, Ethicon, FlowCo, Forest Laboratories, Fractyl, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Lexicon, MEDTRONIC, MyoKardia, Owkin, Pfizer, PhaseBio, PLx Pharma, Regeneron, Roche, Sanofi Aventis, Synaptic, Takeda, and The Medicines Company.  

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

Significant improvement in the control of symptoms related to paroxysmal supraventricular tachycardia (PSVT) is resurrecting etripamil as a self-administered nasal spray a year after it failed to meet the primary endpoint in a phase 3 trial, according to a new analysis from this same study presented at the annual scientific sessions of the American College of Cardiology.

Thinkstock

In the phase 3 NODE-301 trial, presented at the 2020 Heart Rhythm Society annual meeting, etripamil did not show an advantage over placebo at 5 hours for achieving sinus rhythm. Nevertheless, a new presentation of the secondary outcomes suggests substantial clinical benefit.

These advantages include significant reductions in PSVT symptoms, a trend for fewer emergency room visits, and a degree of patient satisfaction that appears meaningful, according to Bruce S. Stambler, MD, an electrophysiologist affiliated with Piedmont Heart Institute, Atlanta.

The data, despite the phase 3 trial results, “support continued development of etripamil nasal spray acute treatment of PSVT,” Dr. Stambler said.
Etripamil is an L-type calcium channel blocker. When administered by nasal spray, it reaches peak effects within about 10 minutes. But the action is short, with a decline in antiarrhythmia effects beginning about 30 minutes after the peak effect. 

In the NODE-301 trial, which employed a 2:1 randomization ratio, 138 patients self-administered 70 mg of etripamil or placebo immediately upon experiencing a suspected episode of PSVT.

Up until 45 minutes, the proportion of episodes that converted to sinus rhythm was about 66% greater (hazard ratio, 1.66; P = .02) on etripamil than placebo, but the advantage was then lost. By predefined primary endpoint of 5 hours, when 100% of placebo patients but not all etripamil patients had converted, there was a slight but nonstatistical advantage for placebo (HR 1.08; P = .1212).

However, because of the rapid onset and then the rapid offset of this agent, the 5-hour time point for comparing effects might not have been the optimal duration to compare effects, according to Dr. Stambler.

On the basis of safety of etripamil, which was not associated with any significant adverse events in NODE-301, and the early clinical effect, the investigators have looked again at the data.

For relief of patient-reported symptoms and patient-reported satisfaction, which were secondary endpoints of the study, the data support a clinical role, according to this new analysis. 

Specifically, there were large differences on a 7-point scale for all of the measured symptoms of PSVT in favor of etripamil, including rapid pulse (P = .002), palpitations (P = .0001), dizziness (P = 0.01), shortness of breath (P = 0.008), and anxiety (P = 0.006). A numerical advantage for chest pain did not reach significance.

“In general, patients reported scores of 4 to 5 on this scale, which corresponds to ‘not satisfied’ to ‘satisfied,’ while the placebo-treated patients reported scores of 2 to 3, which corresponds to ‘dissatisfied’ or ‘very dissatisfied,’ ” Dr. Stambler reported.

The favorable patient experience is also reflected in the Treatment Satisfaction with Questionnaire for Medication (TSQM-9), which was another NODE-301 endpoint. Evaluated when patients were still blinded to their assigned therapy, the advantage of etripamil over placebo for both global satisfaction (P = .007) and treatment effectiveness (P = .002) were also highly statistically significant.

The subjective experience of patients appeared to be reflected in objective measures. When the two groups were compared for interventions in an emergency room, the need was reduced by about half (12.1% vs. 24.5%; P = .051) among those treated with etripamil. Although this just missed the conventional measure of statistical significance, it was close. Similarly, patients randomized to etripamil required numerically fewer rescue medications (14.0% vs. 26.5%; P = .059). 

Adenosine was the most common of the rescue medications, according to Dr. Stambler. He said there was no difference between the groups in use of rescue oral therapies.

When comparing etripamil and placebo in the subgroup that did visit an emergency room for PSVT, there was a delay in ER visits among those randomized to etripamil (116 vs. 79 minutes; P < 0.05), suggesting that this agent reduced the sense of urgency when PSVT symptoms develop, according to Dr. Stambler.

On average, the patients who enrolled in this trial had a PSVT history of about 1.5 years. In the year prior to enrollment, the mean number of ER visits was about nine. 

In the trial design, patients were required to take a test dose of etripamil under observation by a physician before being sent home with their assigned therapy, but Dr. Stambler does not believe that the requirement, if the drug is approved, will be in the label. 

Unexpectedly, many patients had symptom relief even without converting to sinus rhythm, Dr. Stambler acknowledged. He speculated that the reduction in heart rate associated with etripamil might have provided a relief of symptoms sufficient to relieve anxiety, producing the relative advantage for patient satisfaction.

Jodie L. Hurwitz, MD, director of the electrophysiology lab at Medical City Hospital, Dallas, indicated that there is a need for new options for PSVT. An expert panelist during the session where these data were presented, she was particularly interested in rapid symptom relief. 

“It would be great to have a therapy that could be self-administered at home. Patients would like it, too,” she said. 

Mary N. Walsh, MD, a heart failure specialist affiliated with Indiana University, Indianapolis, sees a potential role of a self-administered therapy like etripamil in conjunction with wearable devices. She noted that the proportion of patients using these devices to monitor arrhythmias is increasing, providing a role for an easily transportable therapy that could be used quickly when symptoms develop. 

However, after the negative phase 3 trial, more data must now be collected to satisfy the regulatory authorities that this agent is safe and effective. Dr. Stambler said that the developer is now committed to pursue these studies.

Dr. Stambler has a financial relationship with Milestone Pharmaceuticals, which is developing etripamil nasal spray and was the sponsor of this trial. Dr. Walsh and Dr. Hurwitz have no potential relevant conflicts of interest.
 

Significant improvement in the control of symptoms related to paroxysmal supraventricular tachycardia (PSVT) is resurrecting etripamil as a self-administered nasal spray a year after it failed to meet the primary endpoint in a phase 3 trial, according to a new analysis from this same study presented at the annual scientific sessions of the American College of Cardiology.

Thinkstock

In the phase 3 NODE-301 trial, presented at the 2020 Heart Rhythm Society annual meeting, etripamil did not show an advantage over placebo at 5 hours for achieving sinus rhythm. Nevertheless, a new presentation of the secondary outcomes suggests substantial clinical benefit.

These advantages include significant reductions in PSVT symptoms, a trend for fewer emergency room visits, and a degree of patient satisfaction that appears meaningful, according to Bruce S. Stambler, MD, an electrophysiologist affiliated with Piedmont Heart Institute, Atlanta.

The data, despite the phase 3 trial results, “support continued development of etripamil nasal spray acute treatment of PSVT,” Dr. Stambler said.
Etripamil is an L-type calcium channel blocker. When administered by nasal spray, it reaches peak effects within about 10 minutes. But the action is short, with a decline in antiarrhythmia effects beginning about 30 minutes after the peak effect. 

In the NODE-301 trial, which employed a 2:1 randomization ratio, 138 patients self-administered 70 mg of etripamil or placebo immediately upon experiencing a suspected episode of PSVT.

Up until 45 minutes, the proportion of episodes that converted to sinus rhythm was about 66% greater (hazard ratio, 1.66; P = .02) on etripamil than placebo, but the advantage was then lost. By predefined primary endpoint of 5 hours, when 100% of placebo patients but not all etripamil patients had converted, there was a slight but nonstatistical advantage for placebo (HR 1.08; P = .1212).

However, because of the rapid onset and then the rapid offset of this agent, the 5-hour time point for comparing effects might not have been the optimal duration to compare effects, according to Dr. Stambler.

On the basis of safety of etripamil, which was not associated with any significant adverse events in NODE-301, and the early clinical effect, the investigators have looked again at the data.

For relief of patient-reported symptoms and patient-reported satisfaction, which were secondary endpoints of the study, the data support a clinical role, according to this new analysis. 

Specifically, there were large differences on a 7-point scale for all of the measured symptoms of PSVT in favor of etripamil, including rapid pulse (P = .002), palpitations (P = .0001), dizziness (P = 0.01), shortness of breath (P = 0.008), and anxiety (P = 0.006). A numerical advantage for chest pain did not reach significance.

“In general, patients reported scores of 4 to 5 on this scale, which corresponds to ‘not satisfied’ to ‘satisfied,’ while the placebo-treated patients reported scores of 2 to 3, which corresponds to ‘dissatisfied’ or ‘very dissatisfied,’ ” Dr. Stambler reported.

The favorable patient experience is also reflected in the Treatment Satisfaction with Questionnaire for Medication (TSQM-9), which was another NODE-301 endpoint. Evaluated when patients were still blinded to their assigned therapy, the advantage of etripamil over placebo for both global satisfaction (P = .007) and treatment effectiveness (P = .002) were also highly statistically significant.

The subjective experience of patients appeared to be reflected in objective measures. When the two groups were compared for interventions in an emergency room, the need was reduced by about half (12.1% vs. 24.5%; P = .051) among those treated with etripamil. Although this just missed the conventional measure of statistical significance, it was close. Similarly, patients randomized to etripamil required numerically fewer rescue medications (14.0% vs. 26.5%; P = .059). 

Adenosine was the most common of the rescue medications, according to Dr. Stambler. He said there was no difference between the groups in use of rescue oral therapies.

When comparing etripamil and placebo in the subgroup that did visit an emergency room for PSVT, there was a delay in ER visits among those randomized to etripamil (116 vs. 79 minutes; P < 0.05), suggesting that this agent reduced the sense of urgency when PSVT symptoms develop, according to Dr. Stambler.

On average, the patients who enrolled in this trial had a PSVT history of about 1.5 years. In the year prior to enrollment, the mean number of ER visits was about nine. 

In the trial design, patients were required to take a test dose of etripamil under observation by a physician before being sent home with their assigned therapy, but Dr. Stambler does not believe that the requirement, if the drug is approved, will be in the label. 

Unexpectedly, many patients had symptom relief even without converting to sinus rhythm, Dr. Stambler acknowledged. He speculated that the reduction in heart rate associated with etripamil might have provided a relief of symptoms sufficient to relieve anxiety, producing the relative advantage for patient satisfaction.

Jodie L. Hurwitz, MD, director of the electrophysiology lab at Medical City Hospital, Dallas, indicated that there is a need for new options for PSVT. An expert panelist during the session where these data were presented, she was particularly interested in rapid symptom relief. 

“It would be great to have a therapy that could be self-administered at home. Patients would like it, too,” she said. 

Mary N. Walsh, MD, a heart failure specialist affiliated with Indiana University, Indianapolis, sees a potential role of a self-administered therapy like etripamil in conjunction with wearable devices. She noted that the proportion of patients using these devices to monitor arrhythmias is increasing, providing a role for an easily transportable therapy that could be used quickly when symptoms develop. 

However, after the negative phase 3 trial, more data must now be collected to satisfy the regulatory authorities that this agent is safe and effective. Dr. Stambler said that the developer is now committed to pursue these studies.

Dr. Stambler has a financial relationship with Milestone Pharmaceuticals, which is developing etripamil nasal spray and was the sponsor of this trial. Dr. Walsh and Dr. Hurwitz have no potential relevant conflicts of interest.
 

Significant improvement in the control of symptoms related to paroxysmal supraventricular tachycardia (PSVT) is resurrecting etripamil as a self-administered nasal spray a year after it failed to meet the primary endpoint in a phase 3 trial, according to a new analysis from this same study presented at the annual scientific sessions of the American College of Cardiology.

Thinkstock

In the phase 3 NODE-301 trial, presented at the 2020 Heart Rhythm Society annual meeting, etripamil did not show an advantage over placebo at 5 hours for achieving sinus rhythm. Nevertheless, a new presentation of the secondary outcomes suggests substantial clinical benefit.

These advantages include significant reductions in PSVT symptoms, a trend for fewer emergency room visits, and a degree of patient satisfaction that appears meaningful, according to Bruce S. Stambler, MD, an electrophysiologist affiliated with Piedmont Heart Institute, Atlanta.

The data, despite the phase 3 trial results, “support continued development of etripamil nasal spray acute treatment of PSVT,” Dr. Stambler said.
Etripamil is an L-type calcium channel blocker. When administered by nasal spray, it reaches peak effects within about 10 minutes. But the action is short, with a decline in antiarrhythmia effects beginning about 30 minutes after the peak effect. 

In the NODE-301 trial, which employed a 2:1 randomization ratio, 138 patients self-administered 70 mg of etripamil or placebo immediately upon experiencing a suspected episode of PSVT.

Up until 45 minutes, the proportion of episodes that converted to sinus rhythm was about 66% greater (hazard ratio, 1.66; P = .02) on etripamil than placebo, but the advantage was then lost. By predefined primary endpoint of 5 hours, when 100% of placebo patients but not all etripamil patients had converted, there was a slight but nonstatistical advantage for placebo (HR 1.08; P = .1212).

However, because of the rapid onset and then the rapid offset of this agent, the 5-hour time point for comparing effects might not have been the optimal duration to compare effects, according to Dr. Stambler.

On the basis of safety of etripamil, which was not associated with any significant adverse events in NODE-301, and the early clinical effect, the investigators have looked again at the data.

For relief of patient-reported symptoms and patient-reported satisfaction, which were secondary endpoints of the study, the data support a clinical role, according to this new analysis. 

Specifically, there were large differences on a 7-point scale for all of the measured symptoms of PSVT in favor of etripamil, including rapid pulse (P = .002), palpitations (P = .0001), dizziness (P = 0.01), shortness of breath (P = 0.008), and anxiety (P = 0.006). A numerical advantage for chest pain did not reach significance.

“In general, patients reported scores of 4 to 5 on this scale, which corresponds to ‘not satisfied’ to ‘satisfied,’ while the placebo-treated patients reported scores of 2 to 3, which corresponds to ‘dissatisfied’ or ‘very dissatisfied,’ ” Dr. Stambler reported.

The favorable patient experience is also reflected in the Treatment Satisfaction with Questionnaire for Medication (TSQM-9), which was another NODE-301 endpoint. Evaluated when patients were still blinded to their assigned therapy, the advantage of etripamil over placebo for both global satisfaction (P = .007) and treatment effectiveness (P = .002) were also highly statistically significant.

The subjective experience of patients appeared to be reflected in objective measures. When the two groups were compared for interventions in an emergency room, the need was reduced by about half (12.1% vs. 24.5%; P = .051) among those treated with etripamil. Although this just missed the conventional measure of statistical significance, it was close. Similarly, patients randomized to etripamil required numerically fewer rescue medications (14.0% vs. 26.5%; P = .059). 

Adenosine was the most common of the rescue medications, according to Dr. Stambler. He said there was no difference between the groups in use of rescue oral therapies.

When comparing etripamil and placebo in the subgroup that did visit an emergency room for PSVT, there was a delay in ER visits among those randomized to etripamil (116 vs. 79 minutes; P < 0.05), suggesting that this agent reduced the sense of urgency when PSVT symptoms develop, according to Dr. Stambler.

On average, the patients who enrolled in this trial had a PSVT history of about 1.5 years. In the year prior to enrollment, the mean number of ER visits was about nine. 

In the trial design, patients were required to take a test dose of etripamil under observation by a physician before being sent home with their assigned therapy, but Dr. Stambler does not believe that the requirement, if the drug is approved, will be in the label. 

Unexpectedly, many patients had symptom relief even without converting to sinus rhythm, Dr. Stambler acknowledged. He speculated that the reduction in heart rate associated with etripamil might have provided a relief of symptoms sufficient to relieve anxiety, producing the relative advantage for patient satisfaction.

Jodie L. Hurwitz, MD, director of the electrophysiology lab at Medical City Hospital, Dallas, indicated that there is a need for new options for PSVT. An expert panelist during the session where these data were presented, she was particularly interested in rapid symptom relief. 

“It would be great to have a therapy that could be self-administered at home. Patients would like it, too,” she said. 

Mary N. Walsh, MD, a heart failure specialist affiliated with Indiana University, Indianapolis, sees a potential role of a self-administered therapy like etripamil in conjunction with wearable devices. She noted that the proportion of patients using these devices to monitor arrhythmias is increasing, providing a role for an easily transportable therapy that could be used quickly when symptoms develop. 

However, after the negative phase 3 trial, more data must now be collected to satisfy the regulatory authorities that this agent is safe and effective. Dr. Stambler said that the developer is now committed to pursue these studies.

Dr. Stambler has a financial relationship with Milestone Pharmaceuticals, which is developing etripamil nasal spray and was the sponsor of this trial. Dr. Walsh and Dr. Hurwitz have no potential relevant conflicts of interest.
 

Left atrial appendage occlusion performed at the time of other heart surgery reduces the risk for stroke by about one-third in high-risk patients with atrial fibrillation (AFib), according to results of the Left Atrial Appendage Occlusion Study III (LAAOS III).

At 3.8 years’ follow-up, the primary endpoint of ischemic stroke or systemic embolism occurred in 4.8% of patients randomly assigned to left atrial appendage occlusion (LAAO) and 7.0% of those with no occlusion. This translated into a 33% relative risk reduction (hazard ratio, 0.67; 95% confidence interval, 0.53-0.85; P = .001).

In a landmark analysis, the effect was present early on but was more pronounced after the first 30 days, reducing the relative risk by 42% (HR, 0.58; 95% CI, 0.42-0.80), the researchers report.

The reduction in ongoing stroke risk was on top of oral anticoagulation (OAC) and consistent across all subgroups, Richard Whitlock, MD, PhD, professor of surgery, McMaster University, Hamilton, Ont., reported in a late-breaking trial session at the annual scientific sessions of the American College of Cardiology.

The procedure was safe and added, on average, just 6 minutes to cardiopulmonary bypass time, according to the results, simultaneously published in the New England Journal of Medicine.

“Any patient who comes to the operating room who fits the profile of a LAAOS III patient – so has atrial fibrillation and an elevated stroke risk based on their CHA₂DS₂-VASc score – the appendage should come off,” he said in an interview.

Commenting during the formal discussion, panelist Michael J. Mack, MD, of Baylor Health Care System in Houston, said, “This is potentially a game-changing, practice-changing study” but asked if there are any patients who shouldn’t undergo LAAO, such as those with heart failure (HF).

Dr. Whitlock said about 10%-15% of patients coming for heart surgery have a history of AFib and “as surgeons, you do need to individualize therapy. If you have a very frail patient, have concerns about tissue quality, you really need to think about how you would occlude the left atrial appendage or if you would occlude.”

Reassuringly, he noted, the data show no increase in HF hospitalizations and a beneficial effect on stroke among patients with HF and those with low ejection fractions, below 50%.

Observational data on surgical occlusion have been inconsistent, and current guidelines offer a weak recommendation in patients with AFib who have a contraindication to long-term anticoagulation. This is the first study to definitively prove that ischemic stroke is reduced by managing the left atrial appendage, he said in an interview.

“The previous percutaneous trials failed to demonstrate that; they demonstrated noninferiority but it was driven primarily by the avoidance of hemorrhagic events or strokes through taking patients off oral anticoagulation,” he said.

The results should translate into a class I guideline recommendation, he added. “This opens up a new paradigm of treatment for atrial fibrillation and stroke prevention in that it is really the first study that has looked at the additive effects of managing the left atrial appendage in addition to oral anticoagulation, and it’s protective on top of oral anticoagulation. That is a paradigm shift.”

In an accompanying editorial, Richard L. Page, MD, University of Vermont in Burlington, said the trial provides no insight on the possible benefit of surgical occlusion in patients unable to receive anticoagulation or with a lower CHA2DS2-VASc score, but he agreed a class I recommendation is likely for the population studied.

“I hope and anticipate that the results of this paper will strengthen the guideline indications for surgical left atrial appendage occlusion and will increase the number of cardiac surgeons who routinely perform this add-on procedure,” he said. “While many already perform this procedure, cardiac surgeons should now feel more comfortable that surgical left atrial appendage occlusion is indicated and supported by high-quality randomized data.”

Unfortunately, LAAOS III does not answer the question of whether patients can come off anticoagulation, but it does show surgical occlusion provides added protection from strokes, which can be huge with atrial fibrillation, Dr. Whitlock said.

“I spoke with a patient today who is an active 66-year-old individual on a [direct oral anticoagulant], and his stroke risk has been further reduced by 30%-40%, so he was ecstatic to hear the results,” Dr. Whitlock said. “I think it’s peace of mind.”

Global, nonindustry effort

LAAOS III investigators at 105 centers in 27 countries enrolled 4,811 patients undergoing cardiac surgery (mean age, 71 years; 68% male) who had a CHA₂DS₂-VASc score of at least 2.

In all, 4,770 were randomly assigned to no LAAO or occlusion via the preferred technique of amputation with suture closure of the stump as well as stapler occlusion, or epicardial device closure with the AtriClip (AtriCure) or TigerPaw (Maquet Medical). The treating team, researchers, and patients were blinded to assignment.

Patients were followed every 6 months with a validated stroke questionnaire. The trial was stopped early by the data safety monitoring board after the second interim analysis.

The mean CHA₂DS₂-VASc score was 4.2, one-third of patients had permanent AFib, 9% had a history of stroke, and more than two-thirds underwent a valve procedure, which makes LAAOS III unique, as many previous trials excluded valvular AFib, Dr. Whitlock pointed out.

Operative outcomes in the LAAO and no-LAAO groups were as follows:

• Bypass time: mean, 119 minutes vs. 113 minutes.  
• Cross-clamp time: mean, 86 minutes vs. 82 minutes.
• Chest tube output: median, 520 mL vs. 500 mL.
• Reoperation for bleeding: both, 4.0%.
• Prolonged hospitalization due to HF: 5 vs. 14 events.
• 30-day mortality: 3.7% vs 4.0%.

The primary safety outcome of HF hospitalization at 3.8 years occurred in 7.7% of patients with LAAO and 6.8% without occlusion (HR, 1.13; 95% CI, 0.92-1.40), despite concerns that taking off the appendage could worsen HF risk by impairing renal clearance of salt and water.

“There’s observational data on either side of the fence, so it was an important endpoint that people were concerned about,” Dr. Whitlock told this news organization. “We had a data collection firm dedicated to admission for heart failure to really tease that out and, in the end, we saw no adverse effect.”

Although rates of ischemic stroke at 3.8 years were lower with LAAO than without (4.2% vs. 6.6%; HR, 0.62; 95% CI, 0.48-0.80), there was no difference in systemic embolism (0.3% for both) or death (22.6% vs. 22.5%).

In LAAOS III, fewer than 2% of the deaths were attributed to stroke, which is consistent with large stroke registries, Dr. Whitlock said. “Stroke is not what causes people with atrial fibrillation to die; it’s actually the progression on to heart failure.”

The positive effect on stroke was consistent across all subgroups, including sex, age, rheumatic heart disease, type of OAC at baseline, CHA₂DS₂-VASc score (≤4 vs. >4), type of surgery, history of heart failure or hypertension, and prior stroke/transient ischemic attack/systemic embolism.

Panelist Anne B. Curtis, MD, State University of New York at Buffalo, expressed surprise that about half of patients at baseline were not receiving anticoagulation and questioned whether event rates varied among those who did and didn’t stay on OAC.

Dr. Whitlock noted that OAC is often underused in AFib and that analyses showed the effects were consistent whether patients were on or off anticoagulants.

The study was sponsored by the Population Health Research Institute, McMaster University. Dr. Whitlock reported no relevant disclosures. Dr. Curtis reported consultant fees/honoraria from Abbott, Janssen, Medtronic, Milestone Pharmaceuticals, and Sanofi Aventis, and data safety monitoring board participation for Medtronic.
 

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

Left atrial appendage occlusion performed at the time of other heart surgery reduces the risk for stroke by about one-third in high-risk patients with atrial fibrillation (AFib), according to results of the Left Atrial Appendage Occlusion Study III (LAAOS III).

At 3.8 years’ follow-up, the primary endpoint of ischemic stroke or systemic embolism occurred in 4.8% of patients randomly assigned to left atrial appendage occlusion (LAAO) and 7.0% of those with no occlusion. This translated into a 33% relative risk reduction (hazard ratio, 0.67; 95% confidence interval, 0.53-0.85; P = .001).

In a landmark analysis, the effect was present early on but was more pronounced after the first 30 days, reducing the relative risk by 42% (HR, 0.58; 95% CI, 0.42-0.80), the researchers report.

The reduction in ongoing stroke risk was on top of oral anticoagulation (OAC) and consistent across all subgroups, Richard Whitlock, MD, PhD, professor of surgery, McMaster University, Hamilton, Ont., reported in a late-breaking trial session at the annual scientific sessions of the American College of Cardiology.

The procedure was safe and added, on average, just 6 minutes to cardiopulmonary bypass time, according to the results, simultaneously published in the New England Journal of Medicine.

“Any patient who comes to the operating room who fits the profile of a LAAOS III patient – so has atrial fibrillation and an elevated stroke risk based on their CHA₂DS₂-VASc score – the appendage should come off,” he said in an interview.

Commenting during the formal discussion, panelist Michael J. Mack, MD, of Baylor Health Care System in Houston, said, “This is potentially a game-changing, practice-changing study” but asked if there are any patients who shouldn’t undergo LAAO, such as those with heart failure (HF).

Dr. Whitlock said about 10%-15% of patients coming for heart surgery have a history of AFib and “as surgeons, you do need to individualize therapy. If you have a very frail patient, have concerns about tissue quality, you really need to think about how you would occlude the left atrial appendage or if you would occlude.”

Reassuringly, he noted, the data show no increase in HF hospitalizations and a beneficial effect on stroke among patients with HF and those with low ejection fractions, below 50%.

Observational data on surgical occlusion have been inconsistent, and current guidelines offer a weak recommendation in patients with AFib who have a contraindication to long-term anticoagulation. This is the first study to definitively prove that ischemic stroke is reduced by managing the left atrial appendage, he said in an interview.

“The previous percutaneous trials failed to demonstrate that; they demonstrated noninferiority but it was driven primarily by the avoidance of hemorrhagic events or strokes through taking patients off oral anticoagulation,” he said.

The results should translate into a class I guideline recommendation, he added. “This opens up a new paradigm of treatment for atrial fibrillation and stroke prevention in that it is really the first study that has looked at the additive effects of managing the left atrial appendage in addition to oral anticoagulation, and it’s protective on top of oral anticoagulation. That is a paradigm shift.”

In an accompanying editorial, Richard L. Page, MD, University of Vermont in Burlington, said the trial provides no insight on the possible benefit of surgical occlusion in patients unable to receive anticoagulation or with a lower CHA2DS2-VASc score, but he agreed a class I recommendation is likely for the population studied.

“I hope and anticipate that the results of this paper will strengthen the guideline indications for surgical left atrial appendage occlusion and will increase the number of cardiac surgeons who routinely perform this add-on procedure,” he said. “While many already perform this procedure, cardiac surgeons should now feel more comfortable that surgical left atrial appendage occlusion is indicated and supported by high-quality randomized data.”

Unfortunately, LAAOS III does not answer the question of whether patients can come off anticoagulation, but it does show surgical occlusion provides added protection from strokes, which can be huge with atrial fibrillation, Dr. Whitlock said.

“I spoke with a patient today who is an active 66-year-old individual on a [direct oral anticoagulant], and his stroke risk has been further reduced by 30%-40%, so he was ecstatic to hear the results,” Dr. Whitlock said. “I think it’s peace of mind.”

Global, nonindustry effort

LAAOS III investigators at 105 centers in 27 countries enrolled 4,811 patients undergoing cardiac surgery (mean age, 71 years; 68% male) who had a CHA₂DS₂-VASc score of at least 2.

In all, 4,770 were randomly assigned to no LAAO or occlusion via the preferred technique of amputation with suture closure of the stump as well as stapler occlusion, or epicardial device closure with the AtriClip (AtriCure) or TigerPaw (Maquet Medical). The treating team, researchers, and patients were blinded to assignment.

Patients were followed every 6 months with a validated stroke questionnaire. The trial was stopped early by the data safety monitoring board after the second interim analysis.

The mean CHA₂DS₂-VASc score was 4.2, one-third of patients had permanent AFib, 9% had a history of stroke, and more than two-thirds underwent a valve procedure, which makes LAAOS III unique, as many previous trials excluded valvular AFib, Dr. Whitlock pointed out.

Operative outcomes in the LAAO and no-LAAO groups were as follows:

• Bypass time: mean, 119 minutes vs. 113 minutes.  
• Cross-clamp time: mean, 86 minutes vs. 82 minutes.
• Chest tube output: median, 520 mL vs. 500 mL.
• Reoperation for bleeding: both, 4.0%.
• Prolonged hospitalization due to HF: 5 vs. 14 events.
• 30-day mortality: 3.7% vs 4.0%.

The primary safety outcome of HF hospitalization at 3.8 years occurred in 7.7% of patients with LAAO and 6.8% without occlusion (HR, 1.13; 95% CI, 0.92-1.40), despite concerns that taking off the appendage could worsen HF risk by impairing renal clearance of salt and water.

“There’s observational data on either side of the fence, so it was an important endpoint that people were concerned about,” Dr. Whitlock told this news organization. “We had a data collection firm dedicated to admission for heart failure to really tease that out and, in the end, we saw no adverse effect.”

Although rates of ischemic stroke at 3.8 years were lower with LAAO than without (4.2% vs. 6.6%; HR, 0.62; 95% CI, 0.48-0.80), there was no difference in systemic embolism (0.3% for both) or death (22.6% vs. 22.5%).

In LAAOS III, fewer than 2% of the deaths were attributed to stroke, which is consistent with large stroke registries, Dr. Whitlock said. “Stroke is not what causes people with atrial fibrillation to die; it’s actually the progression on to heart failure.”

The positive effect on stroke was consistent across all subgroups, including sex, age, rheumatic heart disease, type of OAC at baseline, CHA₂DS₂-VASc score (≤4 vs. >4), type of surgery, history of heart failure or hypertension, and prior stroke/transient ischemic attack/systemic embolism.

Panelist Anne B. Curtis, MD, State University of New York at Buffalo, expressed surprise that about half of patients at baseline were not receiving anticoagulation and questioned whether event rates varied among those who did and didn’t stay on OAC.

Dr. Whitlock noted that OAC is often underused in AFib and that analyses showed the effects were consistent whether patients were on or off anticoagulants.

The study was sponsored by the Population Health Research Institute, McMaster University. Dr. Whitlock reported no relevant disclosures. Dr. Curtis reported consultant fees/honoraria from Abbott, Janssen, Medtronic, Milestone Pharmaceuticals, and Sanofi Aventis, and data safety monitoring board participation for Medtronic.
 

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

Left atrial appendage occlusion performed at the time of other heart surgery reduces the risk for stroke by about one-third in high-risk patients with atrial fibrillation (AFib), according to results of the Left Atrial Appendage Occlusion Study III (LAAOS III).

At 3.8 years’ follow-up, the primary endpoint of ischemic stroke or systemic embolism occurred in 4.8% of patients randomly assigned to left atrial appendage occlusion (LAAO) and 7.0% of those with no occlusion. This translated into a 33% relative risk reduction (hazard ratio, 0.67; 95% confidence interval, 0.53-0.85; P = .001).

In a landmark analysis, the effect was present early on but was more pronounced after the first 30 days, reducing the relative risk by 42% (HR, 0.58; 95% CI, 0.42-0.80), the researchers report.

The reduction in ongoing stroke risk was on top of oral anticoagulation (OAC) and consistent across all subgroups, Richard Whitlock, MD, PhD, professor of surgery, McMaster University, Hamilton, Ont., reported in a late-breaking trial session at the annual scientific sessions of the American College of Cardiology.

The procedure was safe and added, on average, just 6 minutes to cardiopulmonary bypass time, according to the results, simultaneously published in the New England Journal of Medicine.

“Any patient who comes to the operating room who fits the profile of a LAAOS III patient – so has atrial fibrillation and an elevated stroke risk based on their CHA₂DS₂-VASc score – the appendage should come off,” he said in an interview.

Commenting during the formal discussion, panelist Michael J. Mack, MD, of Baylor Health Care System in Houston, said, “This is potentially a game-changing, practice-changing study” but asked if there are any patients who shouldn’t undergo LAAO, such as those with heart failure (HF).

Dr. Whitlock said about 10%-15% of patients coming for heart surgery have a history of AFib and “as surgeons, you do need to individualize therapy. If you have a very frail patient, have concerns about tissue quality, you really need to think about how you would occlude the left atrial appendage or if you would occlude.”

Reassuringly, he noted, the data show no increase in HF hospitalizations and a beneficial effect on stroke among patients with HF and those with low ejection fractions, below 50%.

Observational data on surgical occlusion have been inconsistent, and current guidelines offer a weak recommendation in patients with AFib who have a contraindication to long-term anticoagulation. This is the first study to definitively prove that ischemic stroke is reduced by managing the left atrial appendage, he said in an interview.

“The previous percutaneous trials failed to demonstrate that; they demonstrated noninferiority but it was driven primarily by the avoidance of hemorrhagic events or strokes through taking patients off oral anticoagulation,” he said.

The results should translate into a class I guideline recommendation, he added. “This opens up a new paradigm of treatment for atrial fibrillation and stroke prevention in that it is really the first study that has looked at the additive effects of managing the left atrial appendage in addition to oral anticoagulation, and it’s protective on top of oral anticoagulation. That is a paradigm shift.”

In an accompanying editorial, Richard L. Page, MD, University of Vermont in Burlington, said the trial provides no insight on the possible benefit of surgical occlusion in patients unable to receive anticoagulation or with a lower CHA2DS2-VASc score, but he agreed a class I recommendation is likely for the population studied.

“I hope and anticipate that the results of this paper will strengthen the guideline indications for surgical left atrial appendage occlusion and will increase the number of cardiac surgeons who routinely perform this add-on procedure,” he said. “While many already perform this procedure, cardiac surgeons should now feel more comfortable that surgical left atrial appendage occlusion is indicated and supported by high-quality randomized data.”

Unfortunately, LAAOS III does not answer the question of whether patients can come off anticoagulation, but it does show surgical occlusion provides added protection from strokes, which can be huge with atrial fibrillation, Dr. Whitlock said.

“I spoke with a patient today who is an active 66-year-old individual on a [direct oral anticoagulant], and his stroke risk has been further reduced by 30%-40%, so he was ecstatic to hear the results,” Dr. Whitlock said. “I think it’s peace of mind.”

Global, nonindustry effort

LAAOS III investigators at 105 centers in 27 countries enrolled 4,811 patients undergoing cardiac surgery (mean age, 71 years; 68% male) who had a CHA₂DS₂-VASc score of at least 2.

In all, 4,770 were randomly assigned to no LAAO or occlusion via the preferred technique of amputation with suture closure of the stump as well as stapler occlusion, or epicardial device closure with the AtriClip (AtriCure) or TigerPaw (Maquet Medical). The treating team, researchers, and patients were blinded to assignment.

Patients were followed every 6 months with a validated stroke questionnaire. The trial was stopped early by the data safety monitoring board after the second interim analysis.

The mean CHA₂DS₂-VASc score was 4.2, one-third of patients had permanent AFib, 9% had a history of stroke, and more than two-thirds underwent a valve procedure, which makes LAAOS III unique, as many previous trials excluded valvular AFib, Dr. Whitlock pointed out.

Operative outcomes in the LAAO and no-LAAO groups were as follows:

• Bypass time: mean, 119 minutes vs. 113 minutes.  
• Cross-clamp time: mean, 86 minutes vs. 82 minutes.
• Chest tube output: median, 520 mL vs. 500 mL.
• Reoperation for bleeding: both, 4.0%.
• Prolonged hospitalization due to HF: 5 vs. 14 events.
• 30-day mortality: 3.7% vs 4.0%.

The primary safety outcome of HF hospitalization at 3.8 years occurred in 7.7% of patients with LAAO and 6.8% without occlusion (HR, 1.13; 95% CI, 0.92-1.40), despite concerns that taking off the appendage could worsen HF risk by impairing renal clearance of salt and water.

“There’s observational data on either side of the fence, so it was an important endpoint that people were concerned about,” Dr. Whitlock told this news organization. “We had a data collection firm dedicated to admission for heart failure to really tease that out and, in the end, we saw no adverse effect.”

Although rates of ischemic stroke at 3.8 years were lower with LAAO than without (4.2% vs. 6.6%; HR, 0.62; 95% CI, 0.48-0.80), there was no difference in systemic embolism (0.3% for both) or death (22.6% vs. 22.5%).

In LAAOS III, fewer than 2% of the deaths were attributed to stroke, which is consistent with large stroke registries, Dr. Whitlock said. “Stroke is not what causes people with atrial fibrillation to die; it’s actually the progression on to heart failure.”

The positive effect on stroke was consistent across all subgroups, including sex, age, rheumatic heart disease, type of OAC at baseline, CHA₂DS₂-VASc score (≤4 vs. >4), type of surgery, history of heart failure or hypertension, and prior stroke/transient ischemic attack/systemic embolism.

Panelist Anne B. Curtis, MD, State University of New York at Buffalo, expressed surprise that about half of patients at baseline were not receiving anticoagulation and questioned whether event rates varied among those who did and didn’t stay on OAC.

Dr. Whitlock noted that OAC is often underused in AFib and that analyses showed the effects were consistent whether patients were on or off anticoagulants.

The study was sponsored by the Population Health Research Institute, McMaster University. Dr. Whitlock reported no relevant disclosures. Dr. Curtis reported consultant fees/honoraria from Abbott, Janssen, Medtronic, Milestone Pharmaceuticals, and Sanofi Aventis, and data safety monitoring board participation for Medtronic.
 

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

The Food and Drug Administration is recommending patients and caregivers keep cell phones and smart watches at least 6 inches away from implanted medical devices, such as pacemakers and defibrillators.

Terry Rudd/MDedge News

The warning, published on May 13, comes on the heels of recent research reporting that high–field strength magnets in newer smartphones may cause some implanted medical devices to switch to “magnet mode” and suspend normal lifesaving operations until the magnet is moved away.

This, for example, may cause a cardiac defibrillator to be unable to detect tachycardia events, the agency noted. The magnets may also change the operational mode such as turning on asynchronous mode in a pacemaker.

“The FDA is aware of published articles which describe the effect that sufficiently strong magnetic fields can turn on the magnetic safe mode when in close contact,” it said. “The FDA also conducted its own testing on some products that use the high–field strength magnet feature and have confirmed the magnetic field is both consistent with the publications and strong enough to turn on the magnetic safety mode of the medical devices in question.”

The FDA said it believes the risk to patients is low and is not aware of any adverse events associated with this issue at this time.

The American Heart Association has also cautioned that magnetic fields can inhibit the pulse generators for implantable cardioverter defibrillators and pacemakers.

The FDA offered the following simple precautions for individuals with implanted medical devices:

• Keep the consumer electronics, such as certain cell phones and smart watches, 6 inches away from implanted medical devices.
• Do not carry consumer electronics in a pocket over the medical device.
• Check your device using your home monitoring system, if you have one.
• Talk to your health care provider if you are experiencing any symptoms or have questions regarding magnets in consumer electronics and implanted medical devices.

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

The Food and Drug Administration is recommending patients and caregivers keep cell phones and smart watches at least 6 inches away from implanted medical devices, such as pacemakers and defibrillators.

Terry Rudd/MDedge News

The warning, published on May 13, comes on the heels of recent research reporting that high–field strength magnets in newer smartphones may cause some implanted medical devices to switch to “magnet mode” and suspend normal lifesaving operations until the magnet is moved away.

This, for example, may cause a cardiac defibrillator to be unable to detect tachycardia events, the agency noted. The magnets may also change the operational mode such as turning on asynchronous mode in a pacemaker.

“The FDA is aware of published articles which describe the effect that sufficiently strong magnetic fields can turn on the magnetic safe mode when in close contact,” it said. “The FDA also conducted its own testing on some products that use the high–field strength magnet feature and have confirmed the magnetic field is both consistent with the publications and strong enough to turn on the magnetic safety mode of the medical devices in question.”

The FDA said it believes the risk to patients is low and is not aware of any adverse events associated with this issue at this time.

The American Heart Association has also cautioned that magnetic fields can inhibit the pulse generators for implantable cardioverter defibrillators and pacemakers.

The FDA offered the following simple precautions for individuals with implanted medical devices:

• Keep the consumer electronics, such as certain cell phones and smart watches, 6 inches away from implanted medical devices.
• Do not carry consumer electronics in a pocket over the medical device.
• Check your device using your home monitoring system, if you have one.
• Talk to your health care provider if you are experiencing any symptoms or have questions regarding magnets in consumer electronics and implanted medical devices.

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

The Food and Drug Administration is recommending patients and caregivers keep cell phones and smart watches at least 6 inches away from implanted medical devices, such as pacemakers and defibrillators.

Terry Rudd/MDedge News

The warning, published on May 13, comes on the heels of recent research reporting that high–field strength magnets in newer smartphones may cause some implanted medical devices to switch to “magnet mode” and suspend normal lifesaving operations until the magnet is moved away.

This, for example, may cause a cardiac defibrillator to be unable to detect tachycardia events, the agency noted. The magnets may also change the operational mode such as turning on asynchronous mode in a pacemaker.

“The FDA is aware of published articles which describe the effect that sufficiently strong magnetic fields can turn on the magnetic safe mode when in close contact,” it said. “The FDA also conducted its own testing on some products that use the high–field strength magnet feature and have confirmed the magnetic field is both consistent with the publications and strong enough to turn on the magnetic safety mode of the medical devices in question.”

The FDA said it believes the risk to patients is low and is not aware of any adverse events associated with this issue at this time.

The American Heart Association has also cautioned that magnetic fields can inhibit the pulse generators for implantable cardioverter defibrillators and pacemakers.

The FDA offered the following simple precautions for individuals with implanted medical devices:

• Keep the consumer electronics, such as certain cell phones and smart watches, 6 inches away from implanted medical devices.
• Do not carry consumer electronics in a pocket over the medical device.
• Check your device using your home monitoring system, if you have one.
• Talk to your health care provider if you are experiencing any symptoms or have questions regarding magnets in consumer electronics and implanted medical devices.

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