Cardiology

CHICAGO – None of six commercial dietary supplements widely promoted and taken for lowering LDL cholesterol did the job any better than placebo in a randomized trial of adults without cardiovascular disease but at increased cardiovascular risk.

In contrast, those who took the low dose of a high-potency statin in the eight-arm comparative study showed a significant 38% drop in LDL cholesterol levels over 28 days, a performance that blew away the six supplements containing fish oil, cinnamon, garlic, turmeric, plant sterols, or red yeast rice.

The supplements showed little or no effect on any measured lipid biomarkers, which also included total cholesterol and triglycerides, or C-reactive protein (CRP), which reflects systemic inflammation.

The findings undercut the widespread heart-health marketing claims for such supplements and could potentially restore faith in statins for the many patients looking for alternatives, researchers say.

“We all see patients that have their medication lists littered with dietary supplements,” observed Luke J. Laffin, MD, of the Cleveland Clinic Foundation. And it’s more than just heart patients who use them.

Almost $50 billion is spent on dietary supplements annually in the United States, and recent data suggest that more than three-fourths of the population use them, 18% of those based on specious heart-health claims, Dr. Laffin said in a Nov. 6 presentation at the American Heart Association scientific sessions.

The findings of the Supplements, Placebo, or Rosuvastatin Study (SPORT) and how they are framed for the public “are important for public health,” he said.

“As cardiologists, primary care doctors, and others, we really should use these results to have evidence-based discussions with patients” regarding the value of even low-dose statins and the supplements’ “lack of benefit,” said Dr. Laffin, lead author on the SPORT publication, which was published the same day in the Journal of the American College of Cardiology.

Patients assigned to low-dose rosuvastatin showed a mean 24.4% drop in total cholesterol levels over 28 days, the study’s primary endpoint. That differed from the placebo group and those for each supplement at P < .001.

They also averaged a 19.2% decrease in serum triglycerides, P < .05 for all group comparisons. None of the six supplements was significantly different from placebo for change in levels of either total cholesterol or triglycerides.

Nor were there significant differences in adverse events across the groups; there were no adverse changes in liver or kidney function tests or glucose levels; and there were no signs of musculoskeletal symptoms, the published report notes.
 

How to message the results

The SPORT trial is valuable for “addressing the void of data on supplements and cardiovascular health,” Chiadi E. Ndumele, MD, PhD, Johns Hopkins University, Baltimore, said as the invited discussant following Dr. Laffin’s presentation.

But they also send a reassuring message about statins, he noted. In a recent study of statin-nonadherent patients, 80% “were worried about statin side effects as the primary reason for not taking their statin, and 72% preferred using natural supplements instead of taking their prescription therapy,” Dr. Ndumele said. “The reason for this is clearly mistrust, misinformation, and a lack of evidence.”

The next step, he proposed, should be to get the study’s positive message about statins to the public, and especially patients “who are hesitant about statin use.” The current study “underscores the fact that using a low dose of a high-potency statin is associated with a very, very low risk of side effects.”

At a media briefing on SPORT, Amit Khera, MD, agreed the randomized trial provides some needed evidence that can be discussed with patients. “If someone’s coming to see me for cholesterol, we can say definitively now, at least there is data that these [supplements] don’t help your cholesterol and statins do.” Dr. Khera directs the preventive cardiology program at University of Texas Southwestern Medical Center, Dallas.

“I think for those who are there very specifically to lower their cholesterol, hopefully this will resonate,” he said.

“I personally didn’t see a lot of harms in using these supplements. But I also didn’t see any benefits,” Dr. Khera told this news organization.

“Now, if you’re taking them for other reasons, so be it. But if you need to lower your cholesterol for cardiovascular health reasons,” he said, “you need to know that they are minimally to not effective at all.”

But such supplements still “are not without harm,” Dr. Laffin proposed at the press conference. For example, they have potential for drug-drug interactions, “not only with cardiovascular medicines, but those taken for other reasons,” he said. “There are 90,000 supplements on the market in the United States today, and there are all kinds of potential safety issues associated with them.”

In patient discussions, Dr. Laffin said, “I do not think it’s good enough to say, you can waste your money [on supplements] as long as you’re taking your statin. These can actually be harmful in certain situations.”

SPORT, described as a single-center study, randomly assigned 199 participants from “throughout the Cleveland Clinic Health System in northeast Ohio” to one of the eight treatment groups. The investigators were blinded to treatment assignments, Dr. Laffin reported.
 

High adherence

Entry criteria included age 40 to 75 years with no history of cardiovascular disease, LDL-cholesterol from 70 to 189 mg/dL, and a 5%-20% 10-year risk of atherosclerotic cardiovascular disease by the pooled cohort equations. The predominantly White cohort averaged 64.4 years in age and 59% were women.

They were assigned to receive rosuvastatin 5 mg daily, placebo, or daily doses of supplements, with 25 patients per group, except the fish-oil group, which comprised 24 patients.

The daily supplement dosages were 2,400 mg for fish oil (Nature Made); 2,400 mg for cinnamon (NutriFlair), 5,000 mcg allicin for the garlic (Garlique), 4,500 mg for turmeric curcumin (BioSchwartz), 1,600 mg plant sterols (CholestOff Plus, Nature Made), and 2,400 mg red yeast rice (Arazo Nutrition).

Adherence to the assigned regimens was high, Dr. Laffin said, given that only four participants took less than 70% of their assigned doses.

Levels of LDL cholesterol in the statin group fell by 37.9% in 28 days, and by 35.2% relative to the placebo group (P < .001 for both differences), whereas any changes in LDL cholesterol among patients taking the most supplements were not significantly different from the placebo group. Of note, LDL cholesterol levels rose 7.8% (P = .01) compared with placebo among the group assigned to the garlic supplement.

Rosuvastatin had no apparent effect on HDL cholesterol levels, nor did most of the supplements; but such levels in patients taking the plant sterol supplement decreased by 7.1% (P = .02) compared to placebo and by 4% (P = .01) compared to the statin group.

None of the noncontrol groups, including those assigned to rosuvastatin, showed significant changes in high-sensitivity CRP levels compared with the placebo group. The lack of rosuvastatin effect on the inflammatory biomarker, the researchers speculated, is probably explained by the statins’ low dose as well as the limited size of the trial population.

There were two serious adverse events, including one deep venous thrombosis in the placebo group and a liver adenocarcinoma in a patient assigned to fish oil who “had not yet taken any of the study drug at the time of the serious adverse event,” the published report notes.
It remains open whether any of the assigned regimens could show different results over the long term, Dr. Laffin said. The SPORT trial’s 28-day duration, he said, “may not have fully captured the impact of supplements on lipid and inflammatory biomarkers.”

Nor is it known whether the supplements can potentially affect clinical outcomes. But “you could make an argument that it would be unethical” to randomize similar patients to a placebo-controlled, cardiovascular outcomes trial comparing the same six supplements and a statin.

Dr. Laffin has disclosed consulting or serving on a steering committee for Medtronic, Lilly, Mineralys Therapeutics, AstraZeneca, and Crispr Therapeutics; receiving research funding from AstraZeneca; and having ownership interest in LucidAct Health and Gordy Health. Dr. Ndumele and Dr. Khera have reported no relevant financial relationships.

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

CHICAGO – None of six commercial dietary supplements widely promoted and taken for lowering LDL cholesterol did the job any better than placebo in a randomized trial of adults without cardiovascular disease but at increased cardiovascular risk.

In contrast, those who took the low dose of a high-potency statin in the eight-arm comparative study showed a significant 38% drop in LDL cholesterol levels over 28 days, a performance that blew away the six supplements containing fish oil, cinnamon, garlic, turmeric, plant sterols, or red yeast rice.

The supplements showed little or no effect on any measured lipid biomarkers, which also included total cholesterol and triglycerides, or C-reactive protein (CRP), which reflects systemic inflammation.

The findings undercut the widespread heart-health marketing claims for such supplements and could potentially restore faith in statins for the many patients looking for alternatives, researchers say.

“We all see patients that have their medication lists littered with dietary supplements,” observed Luke J. Laffin, MD, of the Cleveland Clinic Foundation. And it’s more than just heart patients who use them.

Almost $50 billion is spent on dietary supplements annually in the United States, and recent data suggest that more than three-fourths of the population use them, 18% of those based on specious heart-health claims, Dr. Laffin said in a Nov. 6 presentation at the American Heart Association scientific sessions.

The findings of the Supplements, Placebo, or Rosuvastatin Study (SPORT) and how they are framed for the public “are important for public health,” he said.

“As cardiologists, primary care doctors, and others, we really should use these results to have evidence-based discussions with patients” regarding the value of even low-dose statins and the supplements’ “lack of benefit,” said Dr. Laffin, lead author on the SPORT publication, which was published the same day in the Journal of the American College of Cardiology.

Patients assigned to low-dose rosuvastatin showed a mean 24.4% drop in total cholesterol levels over 28 days, the study’s primary endpoint. That differed from the placebo group and those for each supplement at P < .001.

They also averaged a 19.2% decrease in serum triglycerides, P < .05 for all group comparisons. None of the six supplements was significantly different from placebo for change in levels of either total cholesterol or triglycerides.

Nor were there significant differences in adverse events across the groups; there were no adverse changes in liver or kidney function tests or glucose levels; and there were no signs of musculoskeletal symptoms, the published report notes.
 

How to message the results

The SPORT trial is valuable for “addressing the void of data on supplements and cardiovascular health,” Chiadi E. Ndumele, MD, PhD, Johns Hopkins University, Baltimore, said as the invited discussant following Dr. Laffin’s presentation.

But they also send a reassuring message about statins, he noted. In a recent study of statin-nonadherent patients, 80% “were worried about statin side effects as the primary reason for not taking their statin, and 72% preferred using natural supplements instead of taking their prescription therapy,” Dr. Ndumele said. “The reason for this is clearly mistrust, misinformation, and a lack of evidence.”

The next step, he proposed, should be to get the study’s positive message about statins to the public, and especially patients “who are hesitant about statin use.” The current study “underscores the fact that using a low dose of a high-potency statin is associated with a very, very low risk of side effects.”

At a media briefing on SPORT, Amit Khera, MD, agreed the randomized trial provides some needed evidence that can be discussed with patients. “If someone’s coming to see me for cholesterol, we can say definitively now, at least there is data that these [supplements] don’t help your cholesterol and statins do.” Dr. Khera directs the preventive cardiology program at University of Texas Southwestern Medical Center, Dallas.

“I think for those who are there very specifically to lower their cholesterol, hopefully this will resonate,” he said.

“I personally didn’t see a lot of harms in using these supplements. But I also didn’t see any benefits,” Dr. Khera told this news organization.

“Now, if you’re taking them for other reasons, so be it. But if you need to lower your cholesterol for cardiovascular health reasons,” he said, “you need to know that they are minimally to not effective at all.”

But such supplements still “are not without harm,” Dr. Laffin proposed at the press conference. For example, they have potential for drug-drug interactions, “not only with cardiovascular medicines, but those taken for other reasons,” he said. “There are 90,000 supplements on the market in the United States today, and there are all kinds of potential safety issues associated with them.”

In patient discussions, Dr. Laffin said, “I do not think it’s good enough to say, you can waste your money [on supplements] as long as you’re taking your statin. These can actually be harmful in certain situations.”

SPORT, described as a single-center study, randomly assigned 199 participants from “throughout the Cleveland Clinic Health System in northeast Ohio” to one of the eight treatment groups. The investigators were blinded to treatment assignments, Dr. Laffin reported.
 

High adherence

Entry criteria included age 40 to 75 years with no history of cardiovascular disease, LDL-cholesterol from 70 to 189 mg/dL, and a 5%-20% 10-year risk of atherosclerotic cardiovascular disease by the pooled cohort equations. The predominantly White cohort averaged 64.4 years in age and 59% were women.

They were assigned to receive rosuvastatin 5 mg daily, placebo, or daily doses of supplements, with 25 patients per group, except the fish-oil group, which comprised 24 patients.

The daily supplement dosages were 2,400 mg for fish oil (Nature Made); 2,400 mg for cinnamon (NutriFlair), 5,000 mcg allicin for the garlic (Garlique), 4,500 mg for turmeric curcumin (BioSchwartz), 1,600 mg plant sterols (CholestOff Plus, Nature Made), and 2,400 mg red yeast rice (Arazo Nutrition).

Adherence to the assigned regimens was high, Dr. Laffin said, given that only four participants took less than 70% of their assigned doses.

Levels of LDL cholesterol in the statin group fell by 37.9% in 28 days, and by 35.2% relative to the placebo group (P < .001 for both differences), whereas any changes in LDL cholesterol among patients taking the most supplements were not significantly different from the placebo group. Of note, LDL cholesterol levels rose 7.8% (P = .01) compared with placebo among the group assigned to the garlic supplement.

Rosuvastatin had no apparent effect on HDL cholesterol levels, nor did most of the supplements; but such levels in patients taking the plant sterol supplement decreased by 7.1% (P = .02) compared to placebo and by 4% (P = .01) compared to the statin group.

None of the noncontrol groups, including those assigned to rosuvastatin, showed significant changes in high-sensitivity CRP levels compared with the placebo group. The lack of rosuvastatin effect on the inflammatory biomarker, the researchers speculated, is probably explained by the statins’ low dose as well as the limited size of the trial population.

There were two serious adverse events, including one deep venous thrombosis in the placebo group and a liver adenocarcinoma in a patient assigned to fish oil who “had not yet taken any of the study drug at the time of the serious adverse event,” the published report notes.
It remains open whether any of the assigned regimens could show different results over the long term, Dr. Laffin said. The SPORT trial’s 28-day duration, he said, “may not have fully captured the impact of supplements on lipid and inflammatory biomarkers.”

Nor is it known whether the supplements can potentially affect clinical outcomes. But “you could make an argument that it would be unethical” to randomize similar patients to a placebo-controlled, cardiovascular outcomes trial comparing the same six supplements and a statin.

Dr. Laffin has disclosed consulting or serving on a steering committee for Medtronic, Lilly, Mineralys Therapeutics, AstraZeneca, and Crispr Therapeutics; receiving research funding from AstraZeneca; and having ownership interest in LucidAct Health and Gordy Health. Dr. Ndumele and Dr. Khera have reported no relevant financial relationships.

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

CHICAGO – None of six commercial dietary supplements widely promoted and taken for lowering LDL cholesterol did the job any better than placebo in a randomized trial of adults without cardiovascular disease but at increased cardiovascular risk.

In contrast, those who took the low dose of a high-potency statin in the eight-arm comparative study showed a significant 38% drop in LDL cholesterol levels over 28 days, a performance that blew away the six supplements containing fish oil, cinnamon, garlic, turmeric, plant sterols, or red yeast rice.

The supplements showed little or no effect on any measured lipid biomarkers, which also included total cholesterol and triglycerides, or C-reactive protein (CRP), which reflects systemic inflammation.

The findings undercut the widespread heart-health marketing claims for such supplements and could potentially restore faith in statins for the many patients looking for alternatives, researchers say.

“We all see patients that have their medication lists littered with dietary supplements,” observed Luke J. Laffin, MD, of the Cleveland Clinic Foundation. And it’s more than just heart patients who use them.

Almost $50 billion is spent on dietary supplements annually in the United States, and recent data suggest that more than three-fourths of the population use them, 18% of those based on specious heart-health claims, Dr. Laffin said in a Nov. 6 presentation at the American Heart Association scientific sessions.

The findings of the Supplements, Placebo, or Rosuvastatin Study (SPORT) and how they are framed for the public “are important for public health,” he said.

“As cardiologists, primary care doctors, and others, we really should use these results to have evidence-based discussions with patients” regarding the value of even low-dose statins and the supplements’ “lack of benefit,” said Dr. Laffin, lead author on the SPORT publication, which was published the same day in the Journal of the American College of Cardiology.

Patients assigned to low-dose rosuvastatin showed a mean 24.4% drop in total cholesterol levels over 28 days, the study’s primary endpoint. That differed from the placebo group and those for each supplement at P < .001.

They also averaged a 19.2% decrease in serum triglycerides, P < .05 for all group comparisons. None of the six supplements was significantly different from placebo for change in levels of either total cholesterol or triglycerides.

Nor were there significant differences in adverse events across the groups; there were no adverse changes in liver or kidney function tests or glucose levels; and there were no signs of musculoskeletal symptoms, the published report notes.
 

How to message the results

The SPORT trial is valuable for “addressing the void of data on supplements and cardiovascular health,” Chiadi E. Ndumele, MD, PhD, Johns Hopkins University, Baltimore, said as the invited discussant following Dr. Laffin’s presentation.

But they also send a reassuring message about statins, he noted. In a recent study of statin-nonadherent patients, 80% “were worried about statin side effects as the primary reason for not taking their statin, and 72% preferred using natural supplements instead of taking their prescription therapy,” Dr. Ndumele said. “The reason for this is clearly mistrust, misinformation, and a lack of evidence.”

The next step, he proposed, should be to get the study’s positive message about statins to the public, and especially patients “who are hesitant about statin use.” The current study “underscores the fact that using a low dose of a high-potency statin is associated with a very, very low risk of side effects.”

At a media briefing on SPORT, Amit Khera, MD, agreed the randomized trial provides some needed evidence that can be discussed with patients. “If someone’s coming to see me for cholesterol, we can say definitively now, at least there is data that these [supplements] don’t help your cholesterol and statins do.” Dr. Khera directs the preventive cardiology program at University of Texas Southwestern Medical Center, Dallas.

“I think for those who are there very specifically to lower their cholesterol, hopefully this will resonate,” he said.

“I personally didn’t see a lot of harms in using these supplements. But I also didn’t see any benefits,” Dr. Khera told this news organization.

“Now, if you’re taking them for other reasons, so be it. But if you need to lower your cholesterol for cardiovascular health reasons,” he said, “you need to know that they are minimally to not effective at all.”

But such supplements still “are not without harm,” Dr. Laffin proposed at the press conference. For example, they have potential for drug-drug interactions, “not only with cardiovascular medicines, but those taken for other reasons,” he said. “There are 90,000 supplements on the market in the United States today, and there are all kinds of potential safety issues associated with them.”

In patient discussions, Dr. Laffin said, “I do not think it’s good enough to say, you can waste your money [on supplements] as long as you’re taking your statin. These can actually be harmful in certain situations.”

SPORT, described as a single-center study, randomly assigned 199 participants from “throughout the Cleveland Clinic Health System in northeast Ohio” to one of the eight treatment groups. The investigators were blinded to treatment assignments, Dr. Laffin reported.
 

High adherence

Entry criteria included age 40 to 75 years with no history of cardiovascular disease, LDL-cholesterol from 70 to 189 mg/dL, and a 5%-20% 10-year risk of atherosclerotic cardiovascular disease by the pooled cohort equations. The predominantly White cohort averaged 64.4 years in age and 59% were women.

They were assigned to receive rosuvastatin 5 mg daily, placebo, or daily doses of supplements, with 25 patients per group, except the fish-oil group, which comprised 24 patients.

The daily supplement dosages were 2,400 mg for fish oil (Nature Made); 2,400 mg for cinnamon (NutriFlair), 5,000 mcg allicin for the garlic (Garlique), 4,500 mg for turmeric curcumin (BioSchwartz), 1,600 mg plant sterols (CholestOff Plus, Nature Made), and 2,400 mg red yeast rice (Arazo Nutrition).

Adherence to the assigned regimens was high, Dr. Laffin said, given that only four participants took less than 70% of their assigned doses.

Levels of LDL cholesterol in the statin group fell by 37.9% in 28 days, and by 35.2% relative to the placebo group (P < .001 for both differences), whereas any changes in LDL cholesterol among patients taking the most supplements were not significantly different from the placebo group. Of note, LDL cholesterol levels rose 7.8% (P = .01) compared with placebo among the group assigned to the garlic supplement.

Rosuvastatin had no apparent effect on HDL cholesterol levels, nor did most of the supplements; but such levels in patients taking the plant sterol supplement decreased by 7.1% (P = .02) compared to placebo and by 4% (P = .01) compared to the statin group.

None of the noncontrol groups, including those assigned to rosuvastatin, showed significant changes in high-sensitivity CRP levels compared with the placebo group. The lack of rosuvastatin effect on the inflammatory biomarker, the researchers speculated, is probably explained by the statins’ low dose as well as the limited size of the trial population.

There were two serious adverse events, including one deep venous thrombosis in the placebo group and a liver adenocarcinoma in a patient assigned to fish oil who “had not yet taken any of the study drug at the time of the serious adverse event,” the published report notes.
It remains open whether any of the assigned regimens could show different results over the long term, Dr. Laffin said. The SPORT trial’s 28-day duration, he said, “may not have fully captured the impact of supplements on lipid and inflammatory biomarkers.”

Nor is it known whether the supplements can potentially affect clinical outcomes. But “you could make an argument that it would be unethical” to randomize similar patients to a placebo-controlled, cardiovascular outcomes trial comparing the same six supplements and a statin.

Dr. Laffin has disclosed consulting or serving on a steering committee for Medtronic, Lilly, Mineralys Therapeutics, AstraZeneca, and Crispr Therapeutics; receiving research funding from AstraZeneca; and having ownership interest in LucidAct Health and Gordy Health. Dr. Ndumele and Dr. Khera have reported no relevant financial relationships.

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

Brain wave recordings obtained during cardiopulmonary resuscitation (CPR) offer support to near-death experiences subjectively reported by some people who survive cardiac arrest, according to a novel new study.

“These recalled experiences and brain wave changes may be the first signs of the so-called ‘near-death’ experience, and we have captured them for the first time in a large study,” lead investigator Sam Parnia, MD, PhD, with NYU Langone Health, said in a news release.

Identifying measurable electrical signs of lucid and heightened brain activity during CPR, coupled with stories of recalled near-death experiences, suggests that the human sense of self and consciousness, much like other biological body functions, may not stop completely around the time of death, Dr. Parnia added.

He presented the findings Nov. 6 at a resuscitation science symposium at the American Heart Association scientific sessions.
 

The AWARE II study

“For years, some people in cardiac arrest have reported being lucid, often with a heightened sense of consciousness, while seemingly unconscious and on the brink of death,” Dr. Parnia noted in an interview.

“Yet, no one’s ever be able to prove it and a lot of people have dismissed these experiences, thinking it’s all just a trick on the brain,” Dr. Parnia said.

In a first-of-its-kind study, Dr. Parnia and colleagues examined consciousness and its underlying electrocortical biomarkers during CPR for in-hospital cardiac arrest (IHCA).

They incorporated independent audiovisual testing of awareness with continuous real-time EEG and cerebral oxygenation (rSO₂) monitoring into CPR.

Only 53 of the 567 IHCA patients survived (9.3%). Among the 28 (52.8%) IHCA survivors who completed interviews, 11 (39.3%) reported unique, lucid experiences during resuscitation.

These experiences included a perception of separation from one’s body, observing events without pain or distress, and an awareness and meaningful evaluation of life, including of their actions, intentions, and thoughts toward others.

“These lucid experiences of death are not hallucinations or delusions. They cannot be considered a trick of a disordered or dying brain, but rather a unique human experience that emerges on the brink of death,” Dr. Parnia said. 

And what’s “fascinating,” he added, is that despite marked cerebral ischemia (mean regional oxygen saturation [rSO₂]  43%), near-normal/physiologic EEG activity (gamma, delta, theta, alpha, and beta rhythms) consistent with consciousness and a possible resumption of a network-level of cognitive and neuronal activity emerged for as long as 35-60 minutes into CPR.

Some of these brain waves normally occur when people are conscious and performing higher mental functions, including thinking, memory retrieval, and conscious perception, he said.
 

‘Seismic shift’ in understanding of death

This is the first time such biomarkers of consciousness have been identified during cardiac arrest and CPR, Dr. Parnia said.

He said further study is needed to more precisely define biomarkers of what is considered to be clinical consciousness and the recalled experience of death, and to monitor the long-term psychological effects of resuscitation after cardiac arrest.

“Our understanding of death has gone through a seismic shift in the last few years,” he said.

“The biological discoveries around death and the postmortem period are completely different to the social conventions that we have about death. That is, we perceive of death as being the end, but actually what we’re finding is that brain cells don’t die immediately. They die very slowly over many hours of time,” Dr. Parnia noted.

Reached for comment, Ajmal Zemmar, MD, PhD, of University of Louisville (Ky.), noted that several studies, including this one, “challenge the traditional way that we think of death – that when the heart stops beating that’s when we die.”

The observation that during cardiac arrest and CPR, the brain waves are still normal for up to an hour is “fairly remarkable,” Dr. Zemmar told this news organization.

“However, whether there is conscious perception or not is very hard to answer,” he cautioned. 

“This type of research tries to bridge the objective EEG recordings with the subjective description you get from the patient, but it’s hard to know when conscious perception stops,” he said.

Funding and support for the study were provided by NYU Langone Health, The John Templeton Foundation, and the UK Resuscitation Council, and National Institutes for Health Research. Dr. Parnia and Dr. Zemmar reported no relevant financial relationships.

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

Brain wave recordings obtained during cardiopulmonary resuscitation (CPR) offer support to near-death experiences subjectively reported by some people who survive cardiac arrest, according to a novel new study.

“These recalled experiences and brain wave changes may be the first signs of the so-called ‘near-death’ experience, and we have captured them for the first time in a large study,” lead investigator Sam Parnia, MD, PhD, with NYU Langone Health, said in a news release.

Identifying measurable electrical signs of lucid and heightened brain activity during CPR, coupled with stories of recalled near-death experiences, suggests that the human sense of self and consciousness, much like other biological body functions, may not stop completely around the time of death, Dr. Parnia added.

He presented the findings Nov. 6 at a resuscitation science symposium at the American Heart Association scientific sessions.
 

The AWARE II study

“For years, some people in cardiac arrest have reported being lucid, often with a heightened sense of consciousness, while seemingly unconscious and on the brink of death,” Dr. Parnia noted in an interview.

“Yet, no one’s ever be able to prove it and a lot of people have dismissed these experiences, thinking it’s all just a trick on the brain,” Dr. Parnia said.

In a first-of-its-kind study, Dr. Parnia and colleagues examined consciousness and its underlying electrocortical biomarkers during CPR for in-hospital cardiac arrest (IHCA).

They incorporated independent audiovisual testing of awareness with continuous real-time EEG and cerebral oxygenation (rSO₂) monitoring into CPR.

Only 53 of the 567 IHCA patients survived (9.3%). Among the 28 (52.8%) IHCA survivors who completed interviews, 11 (39.3%) reported unique, lucid experiences during resuscitation.

These experiences included a perception of separation from one’s body, observing events without pain or distress, and an awareness and meaningful evaluation of life, including of their actions, intentions, and thoughts toward others.

“These lucid experiences of death are not hallucinations or delusions. They cannot be considered a trick of a disordered or dying brain, but rather a unique human experience that emerges on the brink of death,” Dr. Parnia said. 

And what’s “fascinating,” he added, is that despite marked cerebral ischemia (mean regional oxygen saturation [rSO₂]  43%), near-normal/physiologic EEG activity (gamma, delta, theta, alpha, and beta rhythms) consistent with consciousness and a possible resumption of a network-level of cognitive and neuronal activity emerged for as long as 35-60 minutes into CPR.

Some of these brain waves normally occur when people are conscious and performing higher mental functions, including thinking, memory retrieval, and conscious perception, he said.
 

‘Seismic shift’ in understanding of death

This is the first time such biomarkers of consciousness have been identified during cardiac arrest and CPR, Dr. Parnia said.

He said further study is needed to more precisely define biomarkers of what is considered to be clinical consciousness and the recalled experience of death, and to monitor the long-term psychological effects of resuscitation after cardiac arrest.

“Our understanding of death has gone through a seismic shift in the last few years,” he said.

“The biological discoveries around death and the postmortem period are completely different to the social conventions that we have about death. That is, we perceive of death as being the end, but actually what we’re finding is that brain cells don’t die immediately. They die very slowly over many hours of time,” Dr. Parnia noted.

Reached for comment, Ajmal Zemmar, MD, PhD, of University of Louisville (Ky.), noted that several studies, including this one, “challenge the traditional way that we think of death – that when the heart stops beating that’s when we die.”

The observation that during cardiac arrest and CPR, the brain waves are still normal for up to an hour is “fairly remarkable,” Dr. Zemmar told this news organization.

“However, whether there is conscious perception or not is very hard to answer,” he cautioned. 

“This type of research tries to bridge the objective EEG recordings with the subjective description you get from the patient, but it’s hard to know when conscious perception stops,” he said.

Funding and support for the study were provided by NYU Langone Health, The John Templeton Foundation, and the UK Resuscitation Council, and National Institutes for Health Research. Dr. Parnia and Dr. Zemmar reported no relevant financial relationships.

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

Brain wave recordings obtained during cardiopulmonary resuscitation (CPR) offer support to near-death experiences subjectively reported by some people who survive cardiac arrest, according to a novel new study.

“These recalled experiences and brain wave changes may be the first signs of the so-called ‘near-death’ experience, and we have captured them for the first time in a large study,” lead investigator Sam Parnia, MD, PhD, with NYU Langone Health, said in a news release.

Identifying measurable electrical signs of lucid and heightened brain activity during CPR, coupled with stories of recalled near-death experiences, suggests that the human sense of self and consciousness, much like other biological body functions, may not stop completely around the time of death, Dr. Parnia added.

He presented the findings Nov. 6 at a resuscitation science symposium at the American Heart Association scientific sessions.
 

The AWARE II study

“For years, some people in cardiac arrest have reported being lucid, often with a heightened sense of consciousness, while seemingly unconscious and on the brink of death,” Dr. Parnia noted in an interview.

“Yet, no one’s ever be able to prove it and a lot of people have dismissed these experiences, thinking it’s all just a trick on the brain,” Dr. Parnia said.

In a first-of-its-kind study, Dr. Parnia and colleagues examined consciousness and its underlying electrocortical biomarkers during CPR for in-hospital cardiac arrest (IHCA).

They incorporated independent audiovisual testing of awareness with continuous real-time EEG and cerebral oxygenation (rSO₂) monitoring into CPR.

Only 53 of the 567 IHCA patients survived (9.3%). Among the 28 (52.8%) IHCA survivors who completed interviews, 11 (39.3%) reported unique, lucid experiences during resuscitation.

These experiences included a perception of separation from one’s body, observing events without pain or distress, and an awareness and meaningful evaluation of life, including of their actions, intentions, and thoughts toward others.

“These lucid experiences of death are not hallucinations or delusions. They cannot be considered a trick of a disordered or dying brain, but rather a unique human experience that emerges on the brink of death,” Dr. Parnia said. 

And what’s “fascinating,” he added, is that despite marked cerebral ischemia (mean regional oxygen saturation [rSO₂]  43%), near-normal/physiologic EEG activity (gamma, delta, theta, alpha, and beta rhythms) consistent with consciousness and a possible resumption of a network-level of cognitive and neuronal activity emerged for as long as 35-60 minutes into CPR.

Some of these brain waves normally occur when people are conscious and performing higher mental functions, including thinking, memory retrieval, and conscious perception, he said.
 

‘Seismic shift’ in understanding of death

This is the first time such biomarkers of consciousness have been identified during cardiac arrest and CPR, Dr. Parnia said.

He said further study is needed to more precisely define biomarkers of what is considered to be clinical consciousness and the recalled experience of death, and to monitor the long-term psychological effects of resuscitation after cardiac arrest.

“Our understanding of death has gone through a seismic shift in the last few years,” he said.

“The biological discoveries around death and the postmortem period are completely different to the social conventions that we have about death. That is, we perceive of death as being the end, but actually what we’re finding is that brain cells don’t die immediately. They die very slowly over many hours of time,” Dr. Parnia noted.

Reached for comment, Ajmal Zemmar, MD, PhD, of University of Louisville (Ky.), noted that several studies, including this one, “challenge the traditional way that we think of death – that when the heart stops beating that’s when we die.”

The observation that during cardiac arrest and CPR, the brain waves are still normal for up to an hour is “fairly remarkable,” Dr. Zemmar told this news organization.

“However, whether there is conscious perception or not is very hard to answer,” he cautioned. 

“This type of research tries to bridge the objective EEG recordings with the subjective description you get from the patient, but it’s hard to know when conscious perception stops,” he said.

Funding and support for the study were provided by NYU Langone Health, The John Templeton Foundation, and the UK Resuscitation Council, and National Institutes for Health Research. Dr. Parnia and Dr. Zemmar reported no relevant financial relationships.

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

A new Japanese study of highly purified eicosapentaenoic acid (EPA; icosapent ethyl) has suggested a possible benefit in reducing adverse cardiovascular events in patients with chronic coronary artery disease taking statins.

The open-label randomized RESPECT-EPA study showed a reduction of borderline statistical significance in its primary endpoint of a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal ischemic stroke, unstable angina, and coronary revascularization in patients allocated to the EPA product at a dosage of 1,800 mg/day.

The results were presented at the American Heart Association scientific sessions by Hiroyuki Daida, MD, Juntendo University Graduate School of Medicine, Japan. 

However, the trial has several limitations, including a high number of patient withdrawals or protocol deviations, and as such, its conclusions are uncertain.  

Regardless, it has inevitably added to the debate on the cardiovascular benefits of EPA, which were shown in the REDUCE-IT trial. However, that trial has been dogged with controversy because of concerns that the mineral oil placebo used may have had an adverse effect.

Commenting on the new RESPECT-EPA trial for this article, lead investigator of the REDUCE-IT trial, Deepak Bhatt, MD, said the results were consistent with REDUCE-IT and another previous Japanese trial, the Japan EPA Lipid Intervention Study (JELIS), and added to the evidence supporting cardiovascular benefits of EPA.

“In isolation, this study may not be viewed as showing conclusive benefits, but looking at the totality of the data from this trial and from the field more widely, this together shows a convincing cardiovascular benefit with EPA,” Dr. Bhatt said. “We now have 3 randomized controlled trials all showing benefits of highly purified EPA in reducing cardiovascular events.”

However, long-time critic of the REDUCE-IT trial, Steve Nissen, MD, Cleveland Clinic, was not at all impressed with the RESPECT-EPA trial and does not believe it should be used to support the EPA data from REDUCE-IT. 

“The many limitations of the RESPECT-EPA trial make it uninterpretable. It just doesn’t meet contemporary standards for clinical trials,” Dr. Nissen said in an interview. “I don’t think it sheds any light at all on the debate over the efficacy of EPA in cardiovascular disease.”

Dr. Nissen was the lead investigator of another largescale trial, STRENGTH, which showed no benefit of a different high dose omega-3 fatty acid product including a combination of EPA and docosahexaenoic acid (DHA).  

In his AHA presentation on the RESPECT-EPA study, Dr. Daida explained as background that in 2005, JELIS first demonstrated a beneficial effect of highly purified EPA on cardiovascular outcomes in patients with and without coronary artery disease. 

Recently, optimal medical therapy, particularly with high-intensity statins, has become the gold standard of care for patients with coronary artery disease, but they are still at substantially high residual risk, he noted.

Despite of the evidence provided by JELIS, the conflicting results in recent omega-3 fatty acid trials (REDUCE-IT and STRENGTH) have led to an intense controversy regarding the relevance of EPA intervention on top of the latest optimal medical therapy, Dr. Daida said.

The current study – Randomized trial for Evaluating the Secondary Prevention Efficacy of Combination Therapy Statin and EPA (RESPECT-EPA) – was conducted to determine the effect of highly purified EPA on cardiovascular events in Japanese patients with chronic coronary artery disease and a low EPA/arachidonic acid (AA) ratio (< 0.4), who were already receiving statins.

They were randomly assigned to highly purified EPA (icosapent ethyl, 1,800 mg/day) plus statin therapy or to statin therapy alone.

The enrollment period started in 2013 and continued for 4 years. Patients were followed for a further 4 years from the end of the enrollment period.

The trial included 2,506 patients, 1,249 assigned to the EPA group and 1,257 to the control group. In both groups there were a high number of early withdrawals or protocol deviations (647 in the EPA group and 350 in the control group).

The analysis was conducted on 1,225 patients in the EPA group and 1,235 patients in the control group, although at 6 years’ follow-up there were fewer than 400 patients in each arm.  

Baseline characteristics showed median low-density lipoprotein (LDL) cholesterol levels of 80 mg/dL, EPA levels of 45 mcg/mL, and triglyceride levels of 120 mg/dL.

The primary endpoint, a composite of cardiovascular death, nonfatal MI, nonfatal ischemic stroke, unstable angina, and coronary revascularization showed a borderline significant reduction in the EPA group at 6 years since the start of randomization (10.9% vs. 14.9%; hazard ratio, 0.785; P = .0547).

The secondary endpoint, a composite of sudden cardiac death, MI, unstable angina, and coronary revascularization, showed a significant reduction in the EPA group (8.0% vs. 11.3%; HR, 0.734; P = .0306).

In terms of adverse events, there was an increase in gastrointestinal disorders (3.4% vs. 1.2%) and new-onset atrial fibrillation (3.1% vs. 1.6%) in the EPA group.

In a post hoc analysis, which excluded patients with an increase of more than 30 mcg/mL in the control group (182 patients) and those with an increase of less than 30 mcg/mL in the EPA group (259 patients), the primary endpoint showed a significant reduction the EPA group (HR, 0.725; P = .0202).

Dr. Daida noted that limitations of the study included a lower than expected event rate (suggesting that the study may be underpowered), an open-label design, and the fact that baseline levels of EPA in this Japanese population would be higher than those in Western countries.
 

‘Massive loss’ of patients

Critiquing the study, Dr. Nissen highlighted the large dropout and protocol violation rate.

“There was a massive loss of patients over the 6- to 8-year follow-up, and the Kaplan-Meier curves didn’t start to diverge until after 4 years, by which time many patients had dropped out. It would have been a very selective population that lasted 6 years in the study. Patients that drop out are different to those that stay in, so they are cherry-picking the patients that persist in the trial. There is enormous bias here,” he commented. 

“Another weakness is the open-label design. Everyone knew who is getting what. Blinding is important in a study. And there was no control treatment in this trial,” he noted.

The researchers also selected patients with low EPA levels at baseline, Dr. Nissen added. “That is completely different hypothesis to what was tested in the REDUCE-IT and STRENGTH trials. And even with all these problems, the results are still statistically insignificant.”  

On the post hoc subgroup analysis showing a significant benefit, Dr. Nissen said, “they compared a subgroup in the active treatment arm who had large increases in EPA to a subgroup of control patients who had the smallest increase in EPA. That would be like comparing patients who had the largest reductions in LDL in a statin trial to those in the control arm who had no reductions or increases in LDL. That’s scientifically totally inappropriate.”
 

Supportive data

But Dr. Bhatt argues that the RESPECT-EPA trial supports the two previous trials showing benefits of EPA.

“Some may quibble with the P value, but to me this study has shown clear results, with obvious separation of the Kaplan-Meier curves,” he said.  

“It is an investigator-initiated study, which is good in principle but has some of the usual caveats of such a study in that – probably as a consequence of budget constraints – it has an open-label design and is underpowered. But as they did not use a placebo and still showed a benefit of EPA, that helps resolve the issue of the placebo used in REDUCE-IT for those who were concerned about it,” Dr. Bhatt noted.  

He pointed out that the 1,800-mg dose of EPA is the same dose used in the JELIS trial and is the dose used in Japan. The REDUCE-IT trial used a higher dose (4 g), but in general, Japanese people have higher levels of EPA than Western populations, he explained.  

“While this trial included patients with lower levels of EPA, what is considered low in Japan is much higher than average American levels,” he added.
 

Magnitude of benefit uncertain?

Discussant of the study at the Late Breaking Clinical Trials session, Pam R. Taub, MD, professor of medicine at the University of California, San Diego School of Medicine, said, “Despite being underpowered with a sample size of 2,460, RESPECT-EPA shows benefit in decreasing composite coronary events.”

“There is benefit with EPA, but the magnitude of benefit is uncertain,” she stated.

Dr. Taub pointed out that there is a signal across studies for new-onset atrial fibrillation, but the absolute increase is “rather small.”

She noted that more mechanistic and clinical data are needed to hone in on which patients will derive the most benefit, such as those with elevated high-sensitivity C-reactive protein or highest change in EPA levels. But she concluded that in clinical practice, physicians could consider addition of EPA for reduction of residual risk in secondary prevention patients.

The RESPECT-EPA study was supported by the Japan Heart Foundation. Dr. Daida reports peakers’ bureau/honorarium fees from Novartis Pharma, Bayer Yakuhin, Sanofi, Kowa Company, Taisho Pharmaceutical, Abbott Medical Japan, Otsuka Pharmaceutical, Amgen, MSD, Daiichi Sankyo, Pfizer Japan, FUKUDA DENSHI, Tsumura, and TOA EIYO and research funding from Philips Japan, FUJIFILM Holdings, Asahi Kasei, Inter Reha, TOHO HOLDINGS, GLORY, BMS, Abbott Japan, and Boehringer Ingelheim Japan.

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

A new Japanese study of highly purified eicosapentaenoic acid (EPA; icosapent ethyl) has suggested a possible benefit in reducing adverse cardiovascular events in patients with chronic coronary artery disease taking statins.

The open-label randomized RESPECT-EPA study showed a reduction of borderline statistical significance in its primary endpoint of a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal ischemic stroke, unstable angina, and coronary revascularization in patients allocated to the EPA product at a dosage of 1,800 mg/day.

The results were presented at the American Heart Association scientific sessions by Hiroyuki Daida, MD, Juntendo University Graduate School of Medicine, Japan. 

However, the trial has several limitations, including a high number of patient withdrawals or protocol deviations, and as such, its conclusions are uncertain.  

Regardless, it has inevitably added to the debate on the cardiovascular benefits of EPA, which were shown in the REDUCE-IT trial. However, that trial has been dogged with controversy because of concerns that the mineral oil placebo used may have had an adverse effect.

Commenting on the new RESPECT-EPA trial for this article, lead investigator of the REDUCE-IT trial, Deepak Bhatt, MD, said the results were consistent with REDUCE-IT and another previous Japanese trial, the Japan EPA Lipid Intervention Study (JELIS), and added to the evidence supporting cardiovascular benefits of EPA.

“In isolation, this study may not be viewed as showing conclusive benefits, but looking at the totality of the data from this trial and from the field more widely, this together shows a convincing cardiovascular benefit with EPA,” Dr. Bhatt said. “We now have 3 randomized controlled trials all showing benefits of highly purified EPA in reducing cardiovascular events.”

However, long-time critic of the REDUCE-IT trial, Steve Nissen, MD, Cleveland Clinic, was not at all impressed with the RESPECT-EPA trial and does not believe it should be used to support the EPA data from REDUCE-IT. 

“The many limitations of the RESPECT-EPA trial make it uninterpretable. It just doesn’t meet contemporary standards for clinical trials,” Dr. Nissen said in an interview. “I don’t think it sheds any light at all on the debate over the efficacy of EPA in cardiovascular disease.”

Dr. Nissen was the lead investigator of another largescale trial, STRENGTH, which showed no benefit of a different high dose omega-3 fatty acid product including a combination of EPA and docosahexaenoic acid (DHA).  

In his AHA presentation on the RESPECT-EPA study, Dr. Daida explained as background that in 2005, JELIS first demonstrated a beneficial effect of highly purified EPA on cardiovascular outcomes in patients with and without coronary artery disease. 

Recently, optimal medical therapy, particularly with high-intensity statins, has become the gold standard of care for patients with coronary artery disease, but they are still at substantially high residual risk, he noted.

Despite of the evidence provided by JELIS, the conflicting results in recent omega-3 fatty acid trials (REDUCE-IT and STRENGTH) have led to an intense controversy regarding the relevance of EPA intervention on top of the latest optimal medical therapy, Dr. Daida said.

The current study – Randomized trial for Evaluating the Secondary Prevention Efficacy of Combination Therapy Statin and EPA (RESPECT-EPA) – was conducted to determine the effect of highly purified EPA on cardiovascular events in Japanese patients with chronic coronary artery disease and a low EPA/arachidonic acid (AA) ratio (< 0.4), who were already receiving statins.

They were randomly assigned to highly purified EPA (icosapent ethyl, 1,800 mg/day) plus statin therapy or to statin therapy alone.

The enrollment period started in 2013 and continued for 4 years. Patients were followed for a further 4 years from the end of the enrollment period.

The trial included 2,506 patients, 1,249 assigned to the EPA group and 1,257 to the control group. In both groups there were a high number of early withdrawals or protocol deviations (647 in the EPA group and 350 in the control group).

The analysis was conducted on 1,225 patients in the EPA group and 1,235 patients in the control group, although at 6 years’ follow-up there were fewer than 400 patients in each arm.  

Baseline characteristics showed median low-density lipoprotein (LDL) cholesterol levels of 80 mg/dL, EPA levels of 45 mcg/mL, and triglyceride levels of 120 mg/dL.

The primary endpoint, a composite of cardiovascular death, nonfatal MI, nonfatal ischemic stroke, unstable angina, and coronary revascularization showed a borderline significant reduction in the EPA group at 6 years since the start of randomization (10.9% vs. 14.9%; hazard ratio, 0.785; P = .0547).

The secondary endpoint, a composite of sudden cardiac death, MI, unstable angina, and coronary revascularization, showed a significant reduction in the EPA group (8.0% vs. 11.3%; HR, 0.734; P = .0306).

In terms of adverse events, there was an increase in gastrointestinal disorders (3.4% vs. 1.2%) and new-onset atrial fibrillation (3.1% vs. 1.6%) in the EPA group.

In a post hoc analysis, which excluded patients with an increase of more than 30 mcg/mL in the control group (182 patients) and those with an increase of less than 30 mcg/mL in the EPA group (259 patients), the primary endpoint showed a significant reduction the EPA group (HR, 0.725; P = .0202).

Dr. Daida noted that limitations of the study included a lower than expected event rate (suggesting that the study may be underpowered), an open-label design, and the fact that baseline levels of EPA in this Japanese population would be higher than those in Western countries.
 

‘Massive loss’ of patients

Critiquing the study, Dr. Nissen highlighted the large dropout and protocol violation rate.

“There was a massive loss of patients over the 6- to 8-year follow-up, and the Kaplan-Meier curves didn’t start to diverge until after 4 years, by which time many patients had dropped out. It would have been a very selective population that lasted 6 years in the study. Patients that drop out are different to those that stay in, so they are cherry-picking the patients that persist in the trial. There is enormous bias here,” he commented. 

“Another weakness is the open-label design. Everyone knew who is getting what. Blinding is important in a study. And there was no control treatment in this trial,” he noted.

The researchers also selected patients with low EPA levels at baseline, Dr. Nissen added. “That is completely different hypothesis to what was tested in the REDUCE-IT and STRENGTH trials. And even with all these problems, the results are still statistically insignificant.”  

On the post hoc subgroup analysis showing a significant benefit, Dr. Nissen said, “they compared a subgroup in the active treatment arm who had large increases in EPA to a subgroup of control patients who had the smallest increase in EPA. That would be like comparing patients who had the largest reductions in LDL in a statin trial to those in the control arm who had no reductions or increases in LDL. That’s scientifically totally inappropriate.”
 

Supportive data

But Dr. Bhatt argues that the RESPECT-EPA trial supports the two previous trials showing benefits of EPA.

“Some may quibble with the P value, but to me this study has shown clear results, with obvious separation of the Kaplan-Meier curves,” he said.  

“It is an investigator-initiated study, which is good in principle but has some of the usual caveats of such a study in that – probably as a consequence of budget constraints – it has an open-label design and is underpowered. But as they did not use a placebo and still showed a benefit of EPA, that helps resolve the issue of the placebo used in REDUCE-IT for those who were concerned about it,” Dr. Bhatt noted.  

He pointed out that the 1,800-mg dose of EPA is the same dose used in the JELIS trial and is the dose used in Japan. The REDUCE-IT trial used a higher dose (4 g), but in general, Japanese people have higher levels of EPA than Western populations, he explained.  

“While this trial included patients with lower levels of EPA, what is considered low in Japan is much higher than average American levels,” he added.
 

Magnitude of benefit uncertain?

Discussant of the study at the Late Breaking Clinical Trials session, Pam R. Taub, MD, professor of medicine at the University of California, San Diego School of Medicine, said, “Despite being underpowered with a sample size of 2,460, RESPECT-EPA shows benefit in decreasing composite coronary events.”

“There is benefit with EPA, but the magnitude of benefit is uncertain,” she stated.

Dr. Taub pointed out that there is a signal across studies for new-onset atrial fibrillation, but the absolute increase is “rather small.”

She noted that more mechanistic and clinical data are needed to hone in on which patients will derive the most benefit, such as those with elevated high-sensitivity C-reactive protein or highest change in EPA levels. But she concluded that in clinical practice, physicians could consider addition of EPA for reduction of residual risk in secondary prevention patients.

The RESPECT-EPA study was supported by the Japan Heart Foundation. Dr. Daida reports peakers’ bureau/honorarium fees from Novartis Pharma, Bayer Yakuhin, Sanofi, Kowa Company, Taisho Pharmaceutical, Abbott Medical Japan, Otsuka Pharmaceutical, Amgen, MSD, Daiichi Sankyo, Pfizer Japan, FUKUDA DENSHI, Tsumura, and TOA EIYO and research funding from Philips Japan, FUJIFILM Holdings, Asahi Kasei, Inter Reha, TOHO HOLDINGS, GLORY, BMS, Abbott Japan, and Boehringer Ingelheim Japan.

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

A new Japanese study of highly purified eicosapentaenoic acid (EPA; icosapent ethyl) has suggested a possible benefit in reducing adverse cardiovascular events in patients with chronic coronary artery disease taking statins.

The open-label randomized RESPECT-EPA study showed a reduction of borderline statistical significance in its primary endpoint of a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal ischemic stroke, unstable angina, and coronary revascularization in patients allocated to the EPA product at a dosage of 1,800 mg/day.

The results were presented at the American Heart Association scientific sessions by Hiroyuki Daida, MD, Juntendo University Graduate School of Medicine, Japan. 

However, the trial has several limitations, including a high number of patient withdrawals or protocol deviations, and as such, its conclusions are uncertain.  

Regardless, it has inevitably added to the debate on the cardiovascular benefits of EPA, which were shown in the REDUCE-IT trial. However, that trial has been dogged with controversy because of concerns that the mineral oil placebo used may have had an adverse effect.

Commenting on the new RESPECT-EPA trial for this article, lead investigator of the REDUCE-IT trial, Deepak Bhatt, MD, said the results were consistent with REDUCE-IT and another previous Japanese trial, the Japan EPA Lipid Intervention Study (JELIS), and added to the evidence supporting cardiovascular benefits of EPA.

“In isolation, this study may not be viewed as showing conclusive benefits, but looking at the totality of the data from this trial and from the field more widely, this together shows a convincing cardiovascular benefit with EPA,” Dr. Bhatt said. “We now have 3 randomized controlled trials all showing benefits of highly purified EPA in reducing cardiovascular events.”

However, long-time critic of the REDUCE-IT trial, Steve Nissen, MD, Cleveland Clinic, was not at all impressed with the RESPECT-EPA trial and does not believe it should be used to support the EPA data from REDUCE-IT. 

“The many limitations of the RESPECT-EPA trial make it uninterpretable. It just doesn’t meet contemporary standards for clinical trials,” Dr. Nissen said in an interview. “I don’t think it sheds any light at all on the debate over the efficacy of EPA in cardiovascular disease.”

Dr. Nissen was the lead investigator of another largescale trial, STRENGTH, which showed no benefit of a different high dose omega-3 fatty acid product including a combination of EPA and docosahexaenoic acid (DHA).  

In his AHA presentation on the RESPECT-EPA study, Dr. Daida explained as background that in 2005, JELIS first demonstrated a beneficial effect of highly purified EPA on cardiovascular outcomes in patients with and without coronary artery disease. 

Recently, optimal medical therapy, particularly with high-intensity statins, has become the gold standard of care for patients with coronary artery disease, but they are still at substantially high residual risk, he noted.

Despite of the evidence provided by JELIS, the conflicting results in recent omega-3 fatty acid trials (REDUCE-IT and STRENGTH) have led to an intense controversy regarding the relevance of EPA intervention on top of the latest optimal medical therapy, Dr. Daida said.

The current study – Randomized trial for Evaluating the Secondary Prevention Efficacy of Combination Therapy Statin and EPA (RESPECT-EPA) – was conducted to determine the effect of highly purified EPA on cardiovascular events in Japanese patients with chronic coronary artery disease and a low EPA/arachidonic acid (AA) ratio (< 0.4), who were already receiving statins.

They were randomly assigned to highly purified EPA (icosapent ethyl, 1,800 mg/day) plus statin therapy or to statin therapy alone.

The enrollment period started in 2013 and continued for 4 years. Patients were followed for a further 4 years from the end of the enrollment period.

The trial included 2,506 patients, 1,249 assigned to the EPA group and 1,257 to the control group. In both groups there were a high number of early withdrawals or protocol deviations (647 in the EPA group and 350 in the control group).

The analysis was conducted on 1,225 patients in the EPA group and 1,235 patients in the control group, although at 6 years’ follow-up there were fewer than 400 patients in each arm.  

Baseline characteristics showed median low-density lipoprotein (LDL) cholesterol levels of 80 mg/dL, EPA levels of 45 mcg/mL, and triglyceride levels of 120 mg/dL.

The primary endpoint, a composite of cardiovascular death, nonfatal MI, nonfatal ischemic stroke, unstable angina, and coronary revascularization showed a borderline significant reduction in the EPA group at 6 years since the start of randomization (10.9% vs. 14.9%; hazard ratio, 0.785; P = .0547).

The secondary endpoint, a composite of sudden cardiac death, MI, unstable angina, and coronary revascularization, showed a significant reduction in the EPA group (8.0% vs. 11.3%; HR, 0.734; P = .0306).

In terms of adverse events, there was an increase in gastrointestinal disorders (3.4% vs. 1.2%) and new-onset atrial fibrillation (3.1% vs. 1.6%) in the EPA group.

In a post hoc analysis, which excluded patients with an increase of more than 30 mcg/mL in the control group (182 patients) and those with an increase of less than 30 mcg/mL in the EPA group (259 patients), the primary endpoint showed a significant reduction the EPA group (HR, 0.725; P = .0202).

Dr. Daida noted that limitations of the study included a lower than expected event rate (suggesting that the study may be underpowered), an open-label design, and the fact that baseline levels of EPA in this Japanese population would be higher than those in Western countries.
 

‘Massive loss’ of patients

Critiquing the study, Dr. Nissen highlighted the large dropout and protocol violation rate.

“There was a massive loss of patients over the 6- to 8-year follow-up, and the Kaplan-Meier curves didn’t start to diverge until after 4 years, by which time many patients had dropped out. It would have been a very selective population that lasted 6 years in the study. Patients that drop out are different to those that stay in, so they are cherry-picking the patients that persist in the trial. There is enormous bias here,” he commented. 

“Another weakness is the open-label design. Everyone knew who is getting what. Blinding is important in a study. And there was no control treatment in this trial,” he noted.

The researchers also selected patients with low EPA levels at baseline, Dr. Nissen added. “That is completely different hypothesis to what was tested in the REDUCE-IT and STRENGTH trials. And even with all these problems, the results are still statistically insignificant.”  

On the post hoc subgroup analysis showing a significant benefit, Dr. Nissen said, “they compared a subgroup in the active treatment arm who had large increases in EPA to a subgroup of control patients who had the smallest increase in EPA. That would be like comparing patients who had the largest reductions in LDL in a statin trial to those in the control arm who had no reductions or increases in LDL. That’s scientifically totally inappropriate.”
 

Supportive data

But Dr. Bhatt argues that the RESPECT-EPA trial supports the two previous trials showing benefits of EPA.

“Some may quibble with the P value, but to me this study has shown clear results, with obvious separation of the Kaplan-Meier curves,” he said.  

“It is an investigator-initiated study, which is good in principle but has some of the usual caveats of such a study in that – probably as a consequence of budget constraints – it has an open-label design and is underpowered. But as they did not use a placebo and still showed a benefit of EPA, that helps resolve the issue of the placebo used in REDUCE-IT for those who were concerned about it,” Dr. Bhatt noted.  

He pointed out that the 1,800-mg dose of EPA is the same dose used in the JELIS trial and is the dose used in Japan. The REDUCE-IT trial used a higher dose (4 g), but in general, Japanese people have higher levels of EPA than Western populations, he explained.  

“While this trial included patients with lower levels of EPA, what is considered low in Japan is much higher than average American levels,” he added.
 

Magnitude of benefit uncertain?

Discussant of the study at the Late Breaking Clinical Trials session, Pam R. Taub, MD, professor of medicine at the University of California, San Diego School of Medicine, said, “Despite being underpowered with a sample size of 2,460, RESPECT-EPA shows benefit in decreasing composite coronary events.”

“There is benefit with EPA, but the magnitude of benefit is uncertain,” she stated.

Dr. Taub pointed out that there is a signal across studies for new-onset atrial fibrillation, but the absolute increase is “rather small.”

She noted that more mechanistic and clinical data are needed to hone in on which patients will derive the most benefit, such as those with elevated high-sensitivity C-reactive protein or highest change in EPA levels. But she concluded that in clinical practice, physicians could consider addition of EPA for reduction of residual risk in secondary prevention patients.

The RESPECT-EPA study was supported by the Japan Heart Foundation. Dr. Daida reports peakers’ bureau/honorarium fees from Novartis Pharma, Bayer Yakuhin, Sanofi, Kowa Company, Taisho Pharmaceutical, Abbott Medical Japan, Otsuka Pharmaceutical, Amgen, MSD, Daiichi Sankyo, Pfizer Japan, FUKUDA DENSHI, Tsumura, and TOA EIYO and research funding from Philips Japan, FUJIFILM Holdings, Asahi Kasei, Inter Reha, TOHO HOLDINGS, GLORY, BMS, Abbott Japan, and Boehringer Ingelheim Japan.

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

CHICAGO – The traditional Chinese herbal medicine tongxinluo added to guideline-directed therapy improves clinical outcomes in patients with ST-segment elevation myocardial infarction (STEMI), the CTS-AMI study suggests.

Compared with those assigned to placebo, Chinese patients assigned to tongxinluo had lower rates of 30-day and 1-year major adverse cardiovascular and cerebrovascular events (MACCE), driven by fewer cardiac deaths. Severe STEMI complications were also lower.

Tongxinluo, which contains 10 or more potential active herbs and insects, did not result in severe adverse effects, including major bleeding.

The results were presented at the American Heart Association scientific sessions by Yuejin Yang, MD, PhD, a professor of cardiology at Fuwai Hospital, National Center for CV Disease, Beijing.

He noted that despite reperfusion and optimal medical therapy, patients with STEMI still face high in-hospital mortality, myocardial no-flow, and reperfusion injury, which have no targeted drugs so far worldwide. In addition, “inadequate implementation of timely revascularization for STEMI in China (50-70%) and other developing countries leaves a substantial infarct size in many patients.”

Tongxinluo has been approved for angina and stroke since 1996 in China. Previous preclinical studies and the investigators’ proof-of-concept ENLEAT trial in STEMI suggested tongxinluo could reduce myocardial no-flow and infarction size and protect the cardiomyocytes, Dr. Yang said.

The CTS-AMI trial was conducted at 124 hospitals in mainland China and evenly randomly assigned 3,797 patients with STEMI or new left bundle-branch block within 24 hours of symptom onset to eight capsules of tongxinluo, 2.08 g, or to placebo plus dual antiplatelet therapy before percutaneous coronary intervention (PCI), thrombolysis, or medical management alone, followed by four capsules thrice daily plus guideline-directed therapy for 12 months.

In the modified intention-to-treat cohort of 1,889 tongxinluo- and 1,888 placebo-treated patients, primary PCI was performed in 94.2% and 92.3%, respectively.

The relative risk of 30-day MACCE was reduced 36% in the tongxinluo group, compared with the placebo group (3.39% vs. 5.24%; RR, 0.64; 95% confidence interval, 0.47-0.88).

Among the primary endpoint components, the relative risk of cardiac death was reduced 30% (2.97% vs. 4.24%; RR, 0.70; 95% CI, 0.50-0.99) and MI reinfarction 65% (0 vs. 9 events; RR, 0.35; 95% CI, 0.13-0.99).

Strokes were similar in the tongxinluo and control groups (4 vs. 9; RR, 0.44; 95% CI, 0.14-1.43) and no patient had emergent coronary revascularization at 30 days.

The benefit of the traditional Chinese compound on the primary endpoint was consistent across subgroups, Dr. Yang reported.

At 30 days, severe STEMI complications (11.79% vs. 14.80%; P = .008) and malignant arrhythmias (7.84% vs. 10.20%; P = .011) were lower in the tongxinluo group, whereas mechanical complications (10 vs. 13; P = .526) and cardiogenic shock (2.37% vs. 3.31%; P =.082) were similar.

At 1 year, hazard ratios favored tongxinluo for MACCE (0.64; 95% CI, 0.49-0.82), cardiac death (0.73; 95% CI, 0.55-0.97), MI reinfarction (0.26; 95% CI, 0.10-0.67), and stroke (0.44; 95% CI, 0.21-0.92).

In terms of safety issues, 41 patients receiving tongxinluo and 52 patients receiving placebo had a serious adverse event (2.17% vs. 2.75%; P = .25).

Except for fewer renal injuries with tongxinluo (3.81% vs. 5.30%; P = .029), there were no significant between-group differences in adverse effects including allergic rash, hepatic injury, prolonged activated partial thromboplastin time or prothrombin time, digestive tract hemorrhage, nausea, diarrhea, and headache or dizziness.

“These findings support the use of tongxinluo as an adjunctive therapy in treating STEMI, at least in China and other developing countries,” Dr. Yang concluded.

Invited discussant Kenneth Mahaffey, MD, associate dean, Stanford (Calif.) University, and director of the Stanford Center for Clinical Research, said the results “likely will support use of tongxinluo in China” but that “more studies are needed in other populations and treatment paradigms.”

Asked for further comment by this news organization, Dr. Mahaffey said, “The surprising thing is where are all the MIs? Where are all the revascularization procedures?”

Usually one would expect MIs in about 1% of patients, or about 40 MIs among the 4,000 patients but, he noted, there were zero MIs in the treatment group and 9 among controls.

“We haven’t seen a 30% reduction in cardiovascular death or overall mortality with a therapy in ages with good background therapy,” Dr. Mahaffey said. “We need to see how they ascertained all those events.”

He noted that the results were based on the modified intention-to-treat cohort, which did not include data on 20 patients allocated to treatment, and showed no difference in ST-segment resolution at 2 hours and only a slight difference at 24 hours.

“So even in this trial, for at least some of the data we’ve gotten already that supports the proposed mechanism, it doesn’t show the benefit on that mechanistic substudy. And that’s why we need to see these echoes, the biomarkers, and probably the angios to see: Did it have any effect on the proposed mechanism?” Dr. Mahaffey said.

Finally, information on background therapy is critical for putting the treatment effect into context for other health systems and populations, he said. “Unfortunately, we need to see some additional information to really understand how this will fit in, even in Chinese therapy for STEMI patients, but definitely not outside of China, particularly in the United States, because I don’t know what their background therapy was.”

The study was funded by the National Key Research and Development Program of China. Tongxinluo and placebo were provided by Yiling Pharmacological. The study was designed, conducted, and analyzed independent of the sponsors. Dr. Yang reports no relevant financial conflicts of interest. Dr. Mahaffey reports research funding from the AHA, Apple, Bayer, CIRM, Eidos, Ferring, Gilead, Idorsia, Johnson & Johnson, Luitpold, PAC-12, Precordior, Sanifit, and Verily; consultancy fees from Amgen, Applied Therapeutics, AstraZeneca, CLS Behring, Elsevier, Fibrogen, Inova, Johnson & Johnson, Lexicon, Myokardia, Novartis, Novo Nordisk, Otsuka, Phasebio, Portola, Quidel, Sanofi, and Theravance; and equity in Precordior.

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

CHICAGO – The traditional Chinese herbal medicine tongxinluo added to guideline-directed therapy improves clinical outcomes in patients with ST-segment elevation myocardial infarction (STEMI), the CTS-AMI study suggests.

Compared with those assigned to placebo, Chinese patients assigned to tongxinluo had lower rates of 30-day and 1-year major adverse cardiovascular and cerebrovascular events (MACCE), driven by fewer cardiac deaths. Severe STEMI complications were also lower.

Tongxinluo, which contains 10 or more potential active herbs and insects, did not result in severe adverse effects, including major bleeding.

The results were presented at the American Heart Association scientific sessions by Yuejin Yang, MD, PhD, a professor of cardiology at Fuwai Hospital, National Center for CV Disease, Beijing.

He noted that despite reperfusion and optimal medical therapy, patients with STEMI still face high in-hospital mortality, myocardial no-flow, and reperfusion injury, which have no targeted drugs so far worldwide. In addition, “inadequate implementation of timely revascularization for STEMI in China (50-70%) and other developing countries leaves a substantial infarct size in many patients.”

Tongxinluo has been approved for angina and stroke since 1996 in China. Previous preclinical studies and the investigators’ proof-of-concept ENLEAT trial in STEMI suggested tongxinluo could reduce myocardial no-flow and infarction size and protect the cardiomyocytes, Dr. Yang said.

The CTS-AMI trial was conducted at 124 hospitals in mainland China and evenly randomly assigned 3,797 patients with STEMI or new left bundle-branch block within 24 hours of symptom onset to eight capsules of tongxinluo, 2.08 g, or to placebo plus dual antiplatelet therapy before percutaneous coronary intervention (PCI), thrombolysis, or medical management alone, followed by four capsules thrice daily plus guideline-directed therapy for 12 months.

In the modified intention-to-treat cohort of 1,889 tongxinluo- and 1,888 placebo-treated patients, primary PCI was performed in 94.2% and 92.3%, respectively.

The relative risk of 30-day MACCE was reduced 36% in the tongxinluo group, compared with the placebo group (3.39% vs. 5.24%; RR, 0.64; 95% confidence interval, 0.47-0.88).

Among the primary endpoint components, the relative risk of cardiac death was reduced 30% (2.97% vs. 4.24%; RR, 0.70; 95% CI, 0.50-0.99) and MI reinfarction 65% (0 vs. 9 events; RR, 0.35; 95% CI, 0.13-0.99).

Strokes were similar in the tongxinluo and control groups (4 vs. 9; RR, 0.44; 95% CI, 0.14-1.43) and no patient had emergent coronary revascularization at 30 days.

The benefit of the traditional Chinese compound on the primary endpoint was consistent across subgroups, Dr. Yang reported.

At 30 days, severe STEMI complications (11.79% vs. 14.80%; P = .008) and malignant arrhythmias (7.84% vs. 10.20%; P = .011) were lower in the tongxinluo group, whereas mechanical complications (10 vs. 13; P = .526) and cardiogenic shock (2.37% vs. 3.31%; P =.082) were similar.

At 1 year, hazard ratios favored tongxinluo for MACCE (0.64; 95% CI, 0.49-0.82), cardiac death (0.73; 95% CI, 0.55-0.97), MI reinfarction (0.26; 95% CI, 0.10-0.67), and stroke (0.44; 95% CI, 0.21-0.92).

In terms of safety issues, 41 patients receiving tongxinluo and 52 patients receiving placebo had a serious adverse event (2.17% vs. 2.75%; P = .25).

Except for fewer renal injuries with tongxinluo (3.81% vs. 5.30%; P = .029), there were no significant between-group differences in adverse effects including allergic rash, hepatic injury, prolonged activated partial thromboplastin time or prothrombin time, digestive tract hemorrhage, nausea, diarrhea, and headache or dizziness.

“These findings support the use of tongxinluo as an adjunctive therapy in treating STEMI, at least in China and other developing countries,” Dr. Yang concluded.

Invited discussant Kenneth Mahaffey, MD, associate dean, Stanford (Calif.) University, and director of the Stanford Center for Clinical Research, said the results “likely will support use of tongxinluo in China” but that “more studies are needed in other populations and treatment paradigms.”

Asked for further comment by this news organization, Dr. Mahaffey said, “The surprising thing is where are all the MIs? Where are all the revascularization procedures?”

Usually one would expect MIs in about 1% of patients, or about 40 MIs among the 4,000 patients but, he noted, there were zero MIs in the treatment group and 9 among controls.

“We haven’t seen a 30% reduction in cardiovascular death or overall mortality with a therapy in ages with good background therapy,” Dr. Mahaffey said. “We need to see how they ascertained all those events.”

He noted that the results were based on the modified intention-to-treat cohort, which did not include data on 20 patients allocated to treatment, and showed no difference in ST-segment resolution at 2 hours and only a slight difference at 24 hours.

“So even in this trial, for at least some of the data we’ve gotten already that supports the proposed mechanism, it doesn’t show the benefit on that mechanistic substudy. And that’s why we need to see these echoes, the biomarkers, and probably the angios to see: Did it have any effect on the proposed mechanism?” Dr. Mahaffey said.

Finally, information on background therapy is critical for putting the treatment effect into context for other health systems and populations, he said. “Unfortunately, we need to see some additional information to really understand how this will fit in, even in Chinese therapy for STEMI patients, but definitely not outside of China, particularly in the United States, because I don’t know what their background therapy was.”

The study was funded by the National Key Research and Development Program of China. Tongxinluo and placebo were provided by Yiling Pharmacological. The study was designed, conducted, and analyzed independent of the sponsors. Dr. Yang reports no relevant financial conflicts of interest. Dr. Mahaffey reports research funding from the AHA, Apple, Bayer, CIRM, Eidos, Ferring, Gilead, Idorsia, Johnson & Johnson, Luitpold, PAC-12, Precordior, Sanifit, and Verily; consultancy fees from Amgen, Applied Therapeutics, AstraZeneca, CLS Behring, Elsevier, Fibrogen, Inova, Johnson & Johnson, Lexicon, Myokardia, Novartis, Novo Nordisk, Otsuka, Phasebio, Portola, Quidel, Sanofi, and Theravance; and equity in Precordior.

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

CHICAGO – The traditional Chinese herbal medicine tongxinluo added to guideline-directed therapy improves clinical outcomes in patients with ST-segment elevation myocardial infarction (STEMI), the CTS-AMI study suggests.

Compared with those assigned to placebo, Chinese patients assigned to tongxinluo had lower rates of 30-day and 1-year major adverse cardiovascular and cerebrovascular events (MACCE), driven by fewer cardiac deaths. Severe STEMI complications were also lower.

Tongxinluo, which contains 10 or more potential active herbs and insects, did not result in severe adverse effects, including major bleeding.

The results were presented at the American Heart Association scientific sessions by Yuejin Yang, MD, PhD, a professor of cardiology at Fuwai Hospital, National Center for CV Disease, Beijing.

He noted that despite reperfusion and optimal medical therapy, patients with STEMI still face high in-hospital mortality, myocardial no-flow, and reperfusion injury, which have no targeted drugs so far worldwide. In addition, “inadequate implementation of timely revascularization for STEMI in China (50-70%) and other developing countries leaves a substantial infarct size in many patients.”

Tongxinluo has been approved for angina and stroke since 1996 in China. Previous preclinical studies and the investigators’ proof-of-concept ENLEAT trial in STEMI suggested tongxinluo could reduce myocardial no-flow and infarction size and protect the cardiomyocytes, Dr. Yang said.

The CTS-AMI trial was conducted at 124 hospitals in mainland China and evenly randomly assigned 3,797 patients with STEMI or new left bundle-branch block within 24 hours of symptom onset to eight capsules of tongxinluo, 2.08 g, or to placebo plus dual antiplatelet therapy before percutaneous coronary intervention (PCI), thrombolysis, or medical management alone, followed by four capsules thrice daily plus guideline-directed therapy for 12 months.

In the modified intention-to-treat cohort of 1,889 tongxinluo- and 1,888 placebo-treated patients, primary PCI was performed in 94.2% and 92.3%, respectively.

The relative risk of 30-day MACCE was reduced 36% in the tongxinluo group, compared with the placebo group (3.39% vs. 5.24%; RR, 0.64; 95% confidence interval, 0.47-0.88).

Among the primary endpoint components, the relative risk of cardiac death was reduced 30% (2.97% vs. 4.24%; RR, 0.70; 95% CI, 0.50-0.99) and MI reinfarction 65% (0 vs. 9 events; RR, 0.35; 95% CI, 0.13-0.99).

Strokes were similar in the tongxinluo and control groups (4 vs. 9; RR, 0.44; 95% CI, 0.14-1.43) and no patient had emergent coronary revascularization at 30 days.

The benefit of the traditional Chinese compound on the primary endpoint was consistent across subgroups, Dr. Yang reported.

At 30 days, severe STEMI complications (11.79% vs. 14.80%; P = .008) and malignant arrhythmias (7.84% vs. 10.20%; P = .011) were lower in the tongxinluo group, whereas mechanical complications (10 vs. 13; P = .526) and cardiogenic shock (2.37% vs. 3.31%; P =.082) were similar.

At 1 year, hazard ratios favored tongxinluo for MACCE (0.64; 95% CI, 0.49-0.82), cardiac death (0.73; 95% CI, 0.55-0.97), MI reinfarction (0.26; 95% CI, 0.10-0.67), and stroke (0.44; 95% CI, 0.21-0.92).

In terms of safety issues, 41 patients receiving tongxinluo and 52 patients receiving placebo had a serious adverse event (2.17% vs. 2.75%; P = .25).

Except for fewer renal injuries with tongxinluo (3.81% vs. 5.30%; P = .029), there were no significant between-group differences in adverse effects including allergic rash, hepatic injury, prolonged activated partial thromboplastin time or prothrombin time, digestive tract hemorrhage, nausea, diarrhea, and headache or dizziness.

“These findings support the use of tongxinluo as an adjunctive therapy in treating STEMI, at least in China and other developing countries,” Dr. Yang concluded.

Invited discussant Kenneth Mahaffey, MD, associate dean, Stanford (Calif.) University, and director of the Stanford Center for Clinical Research, said the results “likely will support use of tongxinluo in China” but that “more studies are needed in other populations and treatment paradigms.”

Asked for further comment by this news organization, Dr. Mahaffey said, “The surprising thing is where are all the MIs? Where are all the revascularization procedures?”

Usually one would expect MIs in about 1% of patients, or about 40 MIs among the 4,000 patients but, he noted, there were zero MIs in the treatment group and 9 among controls.

“We haven’t seen a 30% reduction in cardiovascular death or overall mortality with a therapy in ages with good background therapy,” Dr. Mahaffey said. “We need to see how they ascertained all those events.”

He noted that the results were based on the modified intention-to-treat cohort, which did not include data on 20 patients allocated to treatment, and showed no difference in ST-segment resolution at 2 hours and only a slight difference at 24 hours.

“So even in this trial, for at least some of the data we’ve gotten already that supports the proposed mechanism, it doesn’t show the benefit on that mechanistic substudy. And that’s why we need to see these echoes, the biomarkers, and probably the angios to see: Did it have any effect on the proposed mechanism?” Dr. Mahaffey said.

Finally, information on background therapy is critical for putting the treatment effect into context for other health systems and populations, he said. “Unfortunately, we need to see some additional information to really understand how this will fit in, even in Chinese therapy for STEMI patients, but definitely not outside of China, particularly in the United States, because I don’t know what their background therapy was.”

The study was funded by the National Key Research and Development Program of China. Tongxinluo and placebo were provided by Yiling Pharmacological. The study was designed, conducted, and analyzed independent of the sponsors. Dr. Yang reports no relevant financial conflicts of interest. Dr. Mahaffey reports research funding from the AHA, Apple, Bayer, CIRM, Eidos, Ferring, Gilead, Idorsia, Johnson & Johnson, Luitpold, PAC-12, Precordior, Sanifit, and Verily; consultancy fees from Amgen, Applied Therapeutics, AstraZeneca, CLS Behring, Elsevier, Fibrogen, Inova, Johnson & Johnson, Lexicon, Myokardia, Novartis, Novo Nordisk, Otsuka, Phasebio, Portola, Quidel, Sanofi, and Theravance; and equity in Precordior.

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

CHICAGO – A stepwise care pathway was associated with a substantial reduction in the number of invasive tests performed and a major improvement in outcomes, relative to usual management, in patients suspected of coronary artery disease (CAD), according to 1-year results of the multinational, randomized PRECISE trial.

The care pathway is appropriate for patients with nonacute chest pain or equivalent complaints that have raised suspicion of CAD, and it is extremely simple, according to the description from the principal investigator, Pamela S. Douglas, MD, given in her presentation at the annual scientific sessions of the American Heart Association.

Ted Bosworth/MDedge News

Unlike the highly complex diagnostic algorithms shunting suspected CAD patients to the vast array of potential evaluations, the newly tested protocol, characterized as a “precision strategy,” divides patients into those who are immediate candidates for invasive testing and those who are not. The discriminator is the PROMISE minimal risk assessment score, a tool already validated.

Those deemed candidates for testing on the basis of an elevated score undergo computed coronary CT angiography (cCTA). In those who are not, testing is deferred.
 

Strategy is simple but effective

Although simple, this pathway is highly effective, judging by the results of the PRECISE trial, which tested the strategy in 2,103 patients at 65 sites in North America and Europe. The primary outcome was a composite of major adverse cardiovascular events (MACE) that included death, nonfatal MI, and catheterization without observed CAD.

After a median follow-up of 11.8 months, the primary MACE endpoint was reached in about 11.3% of those in the usual-care group, which was more than twofold higher than the 4.2% in the precision strategy group. The unadjusted risk reduction was 65% but rose to more than 70% (hazard ratio, 0.29; P < .001) after adjustment for gender and baseline characteristics.

In the arm randomized to the precision strategy, 16% were characterized as low risk and received no further testing. Almost all the others underwent cCTA alone (48%) or cCTA with fractional flow reserve (FFR) (31%). Stress echocardiography, treadmill electrocardiography, and other functional studies were performed in the small proportion of remaining patients.
 

cCTA performed in just 15% of usual care

In the usual-care arm, cCTA with or without FFR was only performed in 15%. More than 80% of patients underwent evaluations with one or more of an array of functional tests. For example, one-third were evaluated with single photon emission CT/PET and nearly as many underwent stress echocardiography testing. Only 7% in usual care underwent no testing after referral.

Within the MACE composite endpoint, almost all the relative benefit in the precision strategy arm was derived from the endpoint of angiography performed without evidence of obstructive CAD (2.6% vs. 10.2%). Rates of all-cause mortality and MI were not significantly different.

Important for the safety and utility of the precision strategy, there “were no deaths or MI events among those assigned deferred testing ” in that experimental arm, according to Dr. Douglas, professor of research in cardiovascular diseases at Duke University, Durham, N.C.

Instead, those in the precision strategy arm were far less likely to undergo catheterization without finding CAD (20% vs. 60%) and far less likely to undergo catheterization without revascularization (28% vs. 70%).

In addition, the group randomized to the precision strategy were more likely to be placed on risk reducing therapies following testing. Although the higher proportion of patients placed on antihypertensive therapy did not reach statistical significance (P = .1), the increased proportions placed on lipid therapy (P < .001) and antiplatelet therapy (P < .001) did.

Citing a study in JAMA Cardiology that found that more than 25% of patients presenting with stable chest pain have normal coronary arteries, Dr. Douglas said that the precision strategy as shown in the PRECISE trial addresses several agreed-upon goals in guidelines from the AHA, the European Society of Cardiology and the U.K.’s National Institute for Health and Care Excellence. These goals include reducing unnecessary testing by risk stratification, improving diagnostic yield of the testing that is performed, and avoiding the costs and complications of unneeded invasive testing.

New protocol called preferred approach

On the basis of these results, Dr. Douglas called the precision strategy “a preferred approach in evaluating patients with stable symptoms and suspected coronary disease.”

Julie Indik, MD, PhD, a professor of medicine at the University of Arizona, Tuscon, said that application of this approach in routine care could have “a major impact on care” by avoiding unnecessary tests with no apparent adverse effect on outcomes.

Although not demonstrated in this study, Dr. Indik suggested that the large number of patients tested for CAD each year – she estimated 4 million visits – means that less testing is likely to have a major impact on the costs of care, and she praised “the practical, efficient” approach of the precision strategy.

Ted Bosworth/MDedge News

Ron Blankstein, MD, director of cardiac computed tomography, Brigham and Women’s Hospital, Boston, also said these data “have both economic and safety implications.” As an AHA-invited discussant of this study, he emphasized that this is a strategy that should only be applied to lower risk patients with no prior history of CAD, but, in this group, he believes these data “will inform future guidelines.”

Dr. Douglas declined to speculate on whether the precision strategy will be incorporated into future guidelines, but she did say that the PRECISE data demonstrate that this approach improves quality of care.

In an interview, Dr. Douglas suggested that this care pathway could provide a basis on which to demonstrate improved outcomes with more efficient use of resources, a common definition of quality care delivery.

Dr. Douglas reported financial relationships with Caption Health, Kowa, and Heartflow, which provided funding for the PRECISE trial. Dr. Indik reported no potential conflicts of interest. Dr. Blankstein reported financial relationships with Amgen, Caristo Diagnostics, and Novartis.

CHICAGO – A stepwise care pathway was associated with a substantial reduction in the number of invasive tests performed and a major improvement in outcomes, relative to usual management, in patients suspected of coronary artery disease (CAD), according to 1-year results of the multinational, randomized PRECISE trial.

The care pathway is appropriate for patients with nonacute chest pain or equivalent complaints that have raised suspicion of CAD, and it is extremely simple, according to the description from the principal investigator, Pamela S. Douglas, MD, given in her presentation at the annual scientific sessions of the American Heart Association.

Ted Bosworth/MDedge News

Unlike the highly complex diagnostic algorithms shunting suspected CAD patients to the vast array of potential evaluations, the newly tested protocol, characterized as a “precision strategy,” divides patients into those who are immediate candidates for invasive testing and those who are not. The discriminator is the PROMISE minimal risk assessment score, a tool already validated.

Those deemed candidates for testing on the basis of an elevated score undergo computed coronary CT angiography (cCTA). In those who are not, testing is deferred.
 

Strategy is simple but effective

Although simple, this pathway is highly effective, judging by the results of the PRECISE trial, which tested the strategy in 2,103 patients at 65 sites in North America and Europe. The primary outcome was a composite of major adverse cardiovascular events (MACE) that included death, nonfatal MI, and catheterization without observed CAD.

After a median follow-up of 11.8 months, the primary MACE endpoint was reached in about 11.3% of those in the usual-care group, which was more than twofold higher than the 4.2% in the precision strategy group. The unadjusted risk reduction was 65% but rose to more than 70% (hazard ratio, 0.29; P < .001) after adjustment for gender and baseline characteristics.

In the arm randomized to the precision strategy, 16% were characterized as low risk and received no further testing. Almost all the others underwent cCTA alone (48%) or cCTA with fractional flow reserve (FFR) (31%). Stress echocardiography, treadmill electrocardiography, and other functional studies were performed in the small proportion of remaining patients.
 

cCTA performed in just 15% of usual care

In the usual-care arm, cCTA with or without FFR was only performed in 15%. More than 80% of patients underwent evaluations with one or more of an array of functional tests. For example, one-third were evaluated with single photon emission CT/PET and nearly as many underwent stress echocardiography testing. Only 7% in usual care underwent no testing after referral.

Within the MACE composite endpoint, almost all the relative benefit in the precision strategy arm was derived from the endpoint of angiography performed without evidence of obstructive CAD (2.6% vs. 10.2%). Rates of all-cause mortality and MI were not significantly different.

Important for the safety and utility of the precision strategy, there “were no deaths or MI events among those assigned deferred testing ” in that experimental arm, according to Dr. Douglas, professor of research in cardiovascular diseases at Duke University, Durham, N.C.

Instead, those in the precision strategy arm were far less likely to undergo catheterization without finding CAD (20% vs. 60%) and far less likely to undergo catheterization without revascularization (28% vs. 70%).

In addition, the group randomized to the precision strategy were more likely to be placed on risk reducing therapies following testing. Although the higher proportion of patients placed on antihypertensive therapy did not reach statistical significance (P = .1), the increased proportions placed on lipid therapy (P < .001) and antiplatelet therapy (P < .001) did.

Citing a study in JAMA Cardiology that found that more than 25% of patients presenting with stable chest pain have normal coronary arteries, Dr. Douglas said that the precision strategy as shown in the PRECISE trial addresses several agreed-upon goals in guidelines from the AHA, the European Society of Cardiology and the U.K.’s National Institute for Health and Care Excellence. These goals include reducing unnecessary testing by risk stratification, improving diagnostic yield of the testing that is performed, and avoiding the costs and complications of unneeded invasive testing.

New protocol called preferred approach

On the basis of these results, Dr. Douglas called the precision strategy “a preferred approach in evaluating patients with stable symptoms and suspected coronary disease.”

Julie Indik, MD, PhD, a professor of medicine at the University of Arizona, Tuscon, said that application of this approach in routine care could have “a major impact on care” by avoiding unnecessary tests with no apparent adverse effect on outcomes.

Although not demonstrated in this study, Dr. Indik suggested that the large number of patients tested for CAD each year – she estimated 4 million visits – means that less testing is likely to have a major impact on the costs of care, and she praised “the practical, efficient” approach of the precision strategy.

Ted Bosworth/MDedge News

Ron Blankstein, MD, director of cardiac computed tomography, Brigham and Women’s Hospital, Boston, also said these data “have both economic and safety implications.” As an AHA-invited discussant of this study, he emphasized that this is a strategy that should only be applied to lower risk patients with no prior history of CAD, but, in this group, he believes these data “will inform future guidelines.”

Dr. Douglas declined to speculate on whether the precision strategy will be incorporated into future guidelines, but she did say that the PRECISE data demonstrate that this approach improves quality of care.

In an interview, Dr. Douglas suggested that this care pathway could provide a basis on which to demonstrate improved outcomes with more efficient use of resources, a common definition of quality care delivery.

Dr. Douglas reported financial relationships with Caption Health, Kowa, and Heartflow, which provided funding for the PRECISE trial. Dr. Indik reported no potential conflicts of interest. Dr. Blankstein reported financial relationships with Amgen, Caristo Diagnostics, and Novartis.

CHICAGO – A stepwise care pathway was associated with a substantial reduction in the number of invasive tests performed and a major improvement in outcomes, relative to usual management, in patients suspected of coronary artery disease (CAD), according to 1-year results of the multinational, randomized PRECISE trial.

The care pathway is appropriate for patients with nonacute chest pain or equivalent complaints that have raised suspicion of CAD, and it is extremely simple, according to the description from the principal investigator, Pamela S. Douglas, MD, given in her presentation at the annual scientific sessions of the American Heart Association.

Ted Bosworth/MDedge News

Unlike the highly complex diagnostic algorithms shunting suspected CAD patients to the vast array of potential evaluations, the newly tested protocol, characterized as a “precision strategy,” divides patients into those who are immediate candidates for invasive testing and those who are not. The discriminator is the PROMISE minimal risk assessment score, a tool already validated.

Those deemed candidates for testing on the basis of an elevated score undergo computed coronary CT angiography (cCTA). In those who are not, testing is deferred.
 

Strategy is simple but effective

Although simple, this pathway is highly effective, judging by the results of the PRECISE trial, which tested the strategy in 2,103 patients at 65 sites in North America and Europe. The primary outcome was a composite of major adverse cardiovascular events (MACE) that included death, nonfatal MI, and catheterization without observed CAD.

After a median follow-up of 11.8 months, the primary MACE endpoint was reached in about 11.3% of those in the usual-care group, which was more than twofold higher than the 4.2% in the precision strategy group. The unadjusted risk reduction was 65% but rose to more than 70% (hazard ratio, 0.29; P < .001) after adjustment for gender and baseline characteristics.

In the arm randomized to the precision strategy, 16% were characterized as low risk and received no further testing. Almost all the others underwent cCTA alone (48%) or cCTA with fractional flow reserve (FFR) (31%). Stress echocardiography, treadmill electrocardiography, and other functional studies were performed in the small proportion of remaining patients.
 

cCTA performed in just 15% of usual care

In the usual-care arm, cCTA with or without FFR was only performed in 15%. More than 80% of patients underwent evaluations with one or more of an array of functional tests. For example, one-third were evaluated with single photon emission CT/PET and nearly as many underwent stress echocardiography testing. Only 7% in usual care underwent no testing after referral.

Within the MACE composite endpoint, almost all the relative benefit in the precision strategy arm was derived from the endpoint of angiography performed without evidence of obstructive CAD (2.6% vs. 10.2%). Rates of all-cause mortality and MI were not significantly different.

Important for the safety and utility of the precision strategy, there “were no deaths or MI events among those assigned deferred testing ” in that experimental arm, according to Dr. Douglas, professor of research in cardiovascular diseases at Duke University, Durham, N.C.

Instead, those in the precision strategy arm were far less likely to undergo catheterization without finding CAD (20% vs. 60%) and far less likely to undergo catheterization without revascularization (28% vs. 70%).

In addition, the group randomized to the precision strategy were more likely to be placed on risk reducing therapies following testing. Although the higher proportion of patients placed on antihypertensive therapy did not reach statistical significance (P = .1), the increased proportions placed on lipid therapy (P < .001) and antiplatelet therapy (P < .001) did.

Citing a study in JAMA Cardiology that found that more than 25% of patients presenting with stable chest pain have normal coronary arteries, Dr. Douglas said that the precision strategy as shown in the PRECISE trial addresses several agreed-upon goals in guidelines from the AHA, the European Society of Cardiology and the U.K.’s National Institute for Health and Care Excellence. These goals include reducing unnecessary testing by risk stratification, improving diagnostic yield of the testing that is performed, and avoiding the costs and complications of unneeded invasive testing.

New protocol called preferred approach

On the basis of these results, Dr. Douglas called the precision strategy “a preferred approach in evaluating patients with stable symptoms and suspected coronary disease.”

Julie Indik, MD, PhD, a professor of medicine at the University of Arizona, Tuscon, said that application of this approach in routine care could have “a major impact on care” by avoiding unnecessary tests with no apparent adverse effect on outcomes.

Although not demonstrated in this study, Dr. Indik suggested that the large number of patients tested for CAD each year – she estimated 4 million visits – means that less testing is likely to have a major impact on the costs of care, and she praised “the practical, efficient” approach of the precision strategy.

Ted Bosworth/MDedge News

Ron Blankstein, MD, director of cardiac computed tomography, Brigham and Women’s Hospital, Boston, also said these data “have both economic and safety implications.” As an AHA-invited discussant of this study, he emphasized that this is a strategy that should only be applied to lower risk patients with no prior history of CAD, but, in this group, he believes these data “will inform future guidelines.”

Dr. Douglas declined to speculate on whether the precision strategy will be incorporated into future guidelines, but she did say that the PRECISE data demonstrate that this approach improves quality of care.

In an interview, Dr. Douglas suggested that this care pathway could provide a basis on which to demonstrate improved outcomes with more efficient use of resources, a common definition of quality care delivery.

Dr. Douglas reported financial relationships with Caption Health, Kowa, and Heartflow, which provided funding for the PRECISE trial. Dr. Indik reported no potential conflicts of interest. Dr. Blankstein reported financial relationships with Amgen, Caristo Diagnostics, and Novartis.

CHICAGO – Routine early, expeditious use of extracorporeal membrane oxygenation (ECMO) is a common strategy in patients with severe cardiogenic shock, but a less aggressive initial approach may be just as effective, a randomized trial suggests.

In the study that assigned patients with “rapidly deteriorating or severe” cardiogenic shock to one or the other approach, clinical outcomes were no better for those who received immediate ECMO than for those initially managed with inotropes and vasopressors, researchers said.

The conservative strategy, importantly, allowed for downstream ECMO in the event of hemodynamic deterioration, which occurred in a substantial 39% of cases, observed Petr Ostadal, MD, PhD, when presenting the results at the American Heart Association scientific sessions.

Dr. Ostadal of Na Homolce Hospital, Prague, is also first author on the published report of the study, called Extracorporeal Membrane Oxygenation in the Therapy of Cardiogenic Shock (ECMO-CS), which was published the same day in Circulation.

The trial makes a firm case for preferring the conservative initial approach over routine early ECMO in the kind of patients it entered, Larry A. Allen, MD, MHS, University of Coloradoat Denver, Aurora, told this news organization.

More than 60% of the trial’s 117 patients had shock secondary to an acute coronary syndrome; another 23% were in heart failure decompensation.

A preference for the conservative initial approach would be welcome, he said. The early aggressive ECMO approach is resource intensive and carries some important risks, such as stroke or coagulopathy, said Dr. Allen, who is not connected with ECMO-CS. Yet it is increasingly the go-to approach in such patients, based primarily on observational data.

Although early ECMO apparently didn’t benefit patients in this study in their specific stage of cardiogenic shock, Dr. Allen observed, it would presumably help some, but identifying them in practice presents challenges. “Defining where people are in the spectrum of early versus middle versus late cardiogenic shock is actually very tricky.”

It will therefore be important, he said, to identify ways to predict which conservatively managed patients do well with the strategy, and which are most at risk for hemodynamic deterioration and for whom ECMO should be readily available.

“I think part of what ECMO-CS tells us is that, if a patient is stable on intravenous inotropic and vasopressor support, you can defer ECMO while you’re thinking about the patient – about their larger context and the right medical decision-making for them.”

The trial randomly assigned 122 patients with rapidly deteriorating or severe cardiogenic shock to the immediate-ECMO or the conservative strategy at four centers in the Czech Republic. The 117 patients for whom informed consent could be obtained were included in the analysis, 58 and 59 patients, respectively. Their mean age was about 65 years and three-fourths were male.

The primary endpoint, the only endpoint for which the study was powered, consisted of death from any cause, resuscitated circulatory arrest, or use of a different form of mechanical circulatory support (MCS) by 30 days.

It occurred in 63.8% of patients assigned to immediate ECMO and 71.2% of those in the conservative strategy group, for a hazard ratio of 0.72 (95% confidence interval, 0.46-1.12; P = .21).

As individual endpoints, rates of death from any cause and resuscitated arrest did not significantly differ between the groups, but conservatively managed patients more often used another form of MCS. The HRs were 1.11 (95% CI, 0.66-1.87) for death from any cause, 0.79 (95% CI, 0.27-2.28) for resuscitated cardiac arrest, and 0.38 (95% CI, 0.18-0.79) for use of another MCS device.

The rates for serious adverse events – including bleeding, ischemia, stroke, pneumonia, or sepsis – were similar at 60.3% in the early-ECMO group and 61% in group with conservative initial management, Dr. Ostadal reported.

Other than the 23 patients in the conservative initial strategy group who went on to receive ECMO (1.9 days after randomization, on average), 1 went on to undergo implantation with a HeartMate (Abbott) ventricular assist device and 3 received an Impella pump (Abiomed).

Six patients in the early-ECMO group were already receiving intra-aortic balloon pump (IABP) support at randomization, two underwent temporary implantation with a Centrimag device (Abbott), and three went on to receive a HeartMate device, the published report notes.

ECMO is the optimal first choice for MCS in such patients with cardiogenic shock who need a circulatory support device, especially because it also oxygenates the blood, Dr. Ostadal told this news organization.

But ECMO doesn’t help with ventricular unloading. Indeed, it can sometimes reduce ventricular preload, especially if right-heart pressures are low. So MCS devices that unload the ventricle, typically an IABP, can complement ECMO.

Dr. Ostadal speculates, however, that there may be a better pairing option. “Impella plus ECMO, I think, is the combination which has a future,” he said, for patients in cardiogenic shock who need a short-term percutaneous hemodynamic support device. Impella “supports the whole circulation” and unloads the left ventricle.

“A balloon pump in combination with ECMO is still not a bad choice. It’s very cheap in comparison with Impella.” But in his opinion, Dr. Ostadal said, “The combination of Impella plus ECMO is more efficient from a hemodynamic point of view.”

As the published report notes, ongoing randomized trials looking at ECMO plus other MCS devices in cardiogenic shock include ECLS-SHOCK, with a projected enrollment of 420 patients, and EURO-SHOCK, aiming for a similar number of patients; both compare routine ECMO to conservative management.

In addition, ANCHOR, in which ECMO is combined with IABP, and DanShock, which looks at early use of Impella rather than ECMO, are enrolling patients with shock secondary to acute coronary syndromes.

Dr. Ostadal disclosed consulting for Getinge, Edwards, Medtronic, Biomedica, and Xenios/Fresenius, and receiving research support from Xenios/Fresenius. Dr. Allen disclosed modest or significant relationships with ACI Clinical, Novartis, UpToDate, Boston Scientific, and Cytokinetics.

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

CHICAGO – Routine early, expeditious use of extracorporeal membrane oxygenation (ECMO) is a common strategy in patients with severe cardiogenic shock, but a less aggressive initial approach may be just as effective, a randomized trial suggests.

In the study that assigned patients with “rapidly deteriorating or severe” cardiogenic shock to one or the other approach, clinical outcomes were no better for those who received immediate ECMO than for those initially managed with inotropes and vasopressors, researchers said.

The conservative strategy, importantly, allowed for downstream ECMO in the event of hemodynamic deterioration, which occurred in a substantial 39% of cases, observed Petr Ostadal, MD, PhD, when presenting the results at the American Heart Association scientific sessions.

Dr. Ostadal of Na Homolce Hospital, Prague, is also first author on the published report of the study, called Extracorporeal Membrane Oxygenation in the Therapy of Cardiogenic Shock (ECMO-CS), which was published the same day in Circulation.

The trial makes a firm case for preferring the conservative initial approach over routine early ECMO in the kind of patients it entered, Larry A. Allen, MD, MHS, University of Coloradoat Denver, Aurora, told this news organization.

More than 60% of the trial’s 117 patients had shock secondary to an acute coronary syndrome; another 23% were in heart failure decompensation.

A preference for the conservative initial approach would be welcome, he said. The early aggressive ECMO approach is resource intensive and carries some important risks, such as stroke or coagulopathy, said Dr. Allen, who is not connected with ECMO-CS. Yet it is increasingly the go-to approach in such patients, based primarily on observational data.

Although early ECMO apparently didn’t benefit patients in this study in their specific stage of cardiogenic shock, Dr. Allen observed, it would presumably help some, but identifying them in practice presents challenges. “Defining where people are in the spectrum of early versus middle versus late cardiogenic shock is actually very tricky.”

It will therefore be important, he said, to identify ways to predict which conservatively managed patients do well with the strategy, and which are most at risk for hemodynamic deterioration and for whom ECMO should be readily available.

“I think part of what ECMO-CS tells us is that, if a patient is stable on intravenous inotropic and vasopressor support, you can defer ECMO while you’re thinking about the patient – about their larger context and the right medical decision-making for them.”

The trial randomly assigned 122 patients with rapidly deteriorating or severe cardiogenic shock to the immediate-ECMO or the conservative strategy at four centers in the Czech Republic. The 117 patients for whom informed consent could be obtained were included in the analysis, 58 and 59 patients, respectively. Their mean age was about 65 years and three-fourths were male.

The primary endpoint, the only endpoint for which the study was powered, consisted of death from any cause, resuscitated circulatory arrest, or use of a different form of mechanical circulatory support (MCS) by 30 days.

It occurred in 63.8% of patients assigned to immediate ECMO and 71.2% of those in the conservative strategy group, for a hazard ratio of 0.72 (95% confidence interval, 0.46-1.12; P = .21).

As individual endpoints, rates of death from any cause and resuscitated arrest did not significantly differ between the groups, but conservatively managed patients more often used another form of MCS. The HRs were 1.11 (95% CI, 0.66-1.87) for death from any cause, 0.79 (95% CI, 0.27-2.28) for resuscitated cardiac arrest, and 0.38 (95% CI, 0.18-0.79) for use of another MCS device.

The rates for serious adverse events – including bleeding, ischemia, stroke, pneumonia, or sepsis – were similar at 60.3% in the early-ECMO group and 61% in group with conservative initial management, Dr. Ostadal reported.

Other than the 23 patients in the conservative initial strategy group who went on to receive ECMO (1.9 days after randomization, on average), 1 went on to undergo implantation with a HeartMate (Abbott) ventricular assist device and 3 received an Impella pump (Abiomed).

Six patients in the early-ECMO group were already receiving intra-aortic balloon pump (IABP) support at randomization, two underwent temporary implantation with a Centrimag device (Abbott), and three went on to receive a HeartMate device, the published report notes.

ECMO is the optimal first choice for MCS in such patients with cardiogenic shock who need a circulatory support device, especially because it also oxygenates the blood, Dr. Ostadal told this news organization.

But ECMO doesn’t help with ventricular unloading. Indeed, it can sometimes reduce ventricular preload, especially if right-heart pressures are low. So MCS devices that unload the ventricle, typically an IABP, can complement ECMO.

Dr. Ostadal speculates, however, that there may be a better pairing option. “Impella plus ECMO, I think, is the combination which has a future,” he said, for patients in cardiogenic shock who need a short-term percutaneous hemodynamic support device. Impella “supports the whole circulation” and unloads the left ventricle.

“A balloon pump in combination with ECMO is still not a bad choice. It’s very cheap in comparison with Impella.” But in his opinion, Dr. Ostadal said, “The combination of Impella plus ECMO is more efficient from a hemodynamic point of view.”

As the published report notes, ongoing randomized trials looking at ECMO plus other MCS devices in cardiogenic shock include ECLS-SHOCK, with a projected enrollment of 420 patients, and EURO-SHOCK, aiming for a similar number of patients; both compare routine ECMO to conservative management.

In addition, ANCHOR, in which ECMO is combined with IABP, and DanShock, which looks at early use of Impella rather than ECMO, are enrolling patients with shock secondary to acute coronary syndromes.

Dr. Ostadal disclosed consulting for Getinge, Edwards, Medtronic, Biomedica, and Xenios/Fresenius, and receiving research support from Xenios/Fresenius. Dr. Allen disclosed modest or significant relationships with ACI Clinical, Novartis, UpToDate, Boston Scientific, and Cytokinetics.

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

CHICAGO – Routine early, expeditious use of extracorporeal membrane oxygenation (ECMO) is a common strategy in patients with severe cardiogenic shock, but a less aggressive initial approach may be just as effective, a randomized trial suggests.

In the study that assigned patients with “rapidly deteriorating or severe” cardiogenic shock to one or the other approach, clinical outcomes were no better for those who received immediate ECMO than for those initially managed with inotropes and vasopressors, researchers said.

The conservative strategy, importantly, allowed for downstream ECMO in the event of hemodynamic deterioration, which occurred in a substantial 39% of cases, observed Petr Ostadal, MD, PhD, when presenting the results at the American Heart Association scientific sessions.

Dr. Ostadal of Na Homolce Hospital, Prague, is also first author on the published report of the study, called Extracorporeal Membrane Oxygenation in the Therapy of Cardiogenic Shock (ECMO-CS), which was published the same day in Circulation.

The trial makes a firm case for preferring the conservative initial approach over routine early ECMO in the kind of patients it entered, Larry A. Allen, MD, MHS, University of Coloradoat Denver, Aurora, told this news organization.

More than 60% of the trial’s 117 patients had shock secondary to an acute coronary syndrome; another 23% were in heart failure decompensation.

A preference for the conservative initial approach would be welcome, he said. The early aggressive ECMO approach is resource intensive and carries some important risks, such as stroke or coagulopathy, said Dr. Allen, who is not connected with ECMO-CS. Yet it is increasingly the go-to approach in such patients, based primarily on observational data.

Although early ECMO apparently didn’t benefit patients in this study in their specific stage of cardiogenic shock, Dr. Allen observed, it would presumably help some, but identifying them in practice presents challenges. “Defining where people are in the spectrum of early versus middle versus late cardiogenic shock is actually very tricky.”

It will therefore be important, he said, to identify ways to predict which conservatively managed patients do well with the strategy, and which are most at risk for hemodynamic deterioration and for whom ECMO should be readily available.

“I think part of what ECMO-CS tells us is that, if a patient is stable on intravenous inotropic and vasopressor support, you can defer ECMO while you’re thinking about the patient – about their larger context and the right medical decision-making for them.”

The trial randomly assigned 122 patients with rapidly deteriorating or severe cardiogenic shock to the immediate-ECMO or the conservative strategy at four centers in the Czech Republic. The 117 patients for whom informed consent could be obtained were included in the analysis, 58 and 59 patients, respectively. Their mean age was about 65 years and three-fourths were male.

The primary endpoint, the only endpoint for which the study was powered, consisted of death from any cause, resuscitated circulatory arrest, or use of a different form of mechanical circulatory support (MCS) by 30 days.

It occurred in 63.8% of patients assigned to immediate ECMO and 71.2% of those in the conservative strategy group, for a hazard ratio of 0.72 (95% confidence interval, 0.46-1.12; P = .21).

As individual endpoints, rates of death from any cause and resuscitated arrest did not significantly differ between the groups, but conservatively managed patients more often used another form of MCS. The HRs were 1.11 (95% CI, 0.66-1.87) for death from any cause, 0.79 (95% CI, 0.27-2.28) for resuscitated cardiac arrest, and 0.38 (95% CI, 0.18-0.79) for use of another MCS device.

The rates for serious adverse events – including bleeding, ischemia, stroke, pneumonia, or sepsis – were similar at 60.3% in the early-ECMO group and 61% in group with conservative initial management, Dr. Ostadal reported.

Other than the 23 patients in the conservative initial strategy group who went on to receive ECMO (1.9 days after randomization, on average), 1 went on to undergo implantation with a HeartMate (Abbott) ventricular assist device and 3 received an Impella pump (Abiomed).

Six patients in the early-ECMO group were already receiving intra-aortic balloon pump (IABP) support at randomization, two underwent temporary implantation with a Centrimag device (Abbott), and three went on to receive a HeartMate device, the published report notes.

ECMO is the optimal first choice for MCS in such patients with cardiogenic shock who need a circulatory support device, especially because it also oxygenates the blood, Dr. Ostadal told this news organization.

But ECMO doesn’t help with ventricular unloading. Indeed, it can sometimes reduce ventricular preload, especially if right-heart pressures are low. So MCS devices that unload the ventricle, typically an IABP, can complement ECMO.

Dr. Ostadal speculates, however, that there may be a better pairing option. “Impella plus ECMO, I think, is the combination which has a future,” he said, for patients in cardiogenic shock who need a short-term percutaneous hemodynamic support device. Impella “supports the whole circulation” and unloads the left ventricle.

“A balloon pump in combination with ECMO is still not a bad choice. It’s very cheap in comparison with Impella.” But in his opinion, Dr. Ostadal said, “The combination of Impella plus ECMO is more efficient from a hemodynamic point of view.”

As the published report notes, ongoing randomized trials looking at ECMO plus other MCS devices in cardiogenic shock include ECLS-SHOCK, with a projected enrollment of 420 patients, and EURO-SHOCK, aiming for a similar number of patients; both compare routine ECMO to conservative management.

In addition, ANCHOR, in which ECMO is combined with IABP, and DanShock, which looks at early use of Impella rather than ECMO, are enrolling patients with shock secondary to acute coronary syndromes.

Dr. Ostadal disclosed consulting for Getinge, Edwards, Medtronic, Biomedica, and Xenios/Fresenius, and receiving research support from Xenios/Fresenius. Dr. Allen disclosed modest or significant relationships with ACI Clinical, Novartis, UpToDate, Boston Scientific, and Cytokinetics.

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

CHICAGO – The case for survival equipoise between an invasive or conservative strategy for managing patients with stable coronary disease and moderate or severe cardiac ischemia grew stronger with an additional 2.5 years of median follow-up of the landmark ISCHEMIA trial.

During a median follow-up of 5.7 years in ISCHEMIA-EXTEND – and as long as 7 years – patients randomized to an upfront invasive strategy regardless of their symptoms had an all-cause mortality rate of 12.7%, compared with a 13.4% rate in the patients randomized to the conservative, medication-based management strategy that employed revascularization only when the medical approach failed to resolve their angina. This survival difference fell far short of significance (adjusted hazard ratio, 1.00; 95% confidence interval, 0.85-1.18), solidifying a finding first seen in the main ISCHEMIA results when they came out 3 years before, in late 2019, Judith S. Hochman, MD, said at the American Heart Association scientific sessions.

Mitchel L. Zoler/MDedge News

The new results “provide evidence for patients with chronic coronary disease and their physicians as they decide whether to add invasive management to guideline-directed medical therapy,” concluded Dr. Hochman, professor and senior associate dean for clinical sciences at New York University Langone Health. Simultaneous with her report, the extended follow-up results also appeared in an article published online in Circulation.
 

Nil probability of a survival benefit

“The probability over 5.7 years that a patient’s risk of dying is lower with the invasive strategy is nil, which means: Go with the patient’s preference. Not undergoing revascularization is a reasonable strategy because there is no excess mortality,” Dr. Hochman said in an interview. The trial’s extended follow-up provides “much more robust evidence” for the neutral effect on survival. The investigators plan to further follow-up out to a maximum of 10 years to continue to monitor for a signal of a mortality difference.

Mitchel L. Zoler/MDedge News

“These findings might help physicians in shared decision-making as to whether to add invasive management to guideline-directed medical management in selected patients with chronic coronary artery disease and moderate or severe ischemia,” commented M. Cecilia Bahit, MD, designated discussant for the report and chief of cardiology for INECO Neurosciences in Rosario, Argentina.

The original ISCHEMIA results had also shown that invasive intervention can improve the quality of life in patients who have angina as a result of their coronary disease, but also showed “minimal benefits” from an invasive approach in asymptomatic patients, who comprised 35% of the study cohort of 5,179 patients.

While ISCHEMIA enrolled patients with moderate to severe coronary ischemia identified with noninvasive testing, it excluded certain patients for whom an invasive strategy is recommended, including those with unprotected left main coronary stenoses of at least 50%, a recent acute coronary syndrome event, a left ventricular ejection fraction of less than 35%, more advanced functional limitations from heart failure, or advanced chronic kidney disease.

Follow-up without adjudication

The extended follow-up included 4,825 patients from the initial cohort, with data collected from 4,540 patients. One limitation of the follow-up was that the cause of death was not adjudicated as it had been during the initial follow-up phase. It instead relied on unconfirmed information collected either from patients’ families or national databases. The demographics and clinical profiles of the study participants available for extended follow-up closely matched the entire original study cohort.

The additional follow-up also revealed a significant survival benefit from the invasive approach for cardiovascular deaths, with an incidence of 8.6% in the conservative arm and 6.4% in the invasive group, an adjusted 22% relative reduction in this outcome favoring the invasive strategy (95% CI, 0.63-0.96). This difference had appeared as a nonsignificant signal in the initial 3.2-year median follow-up.

However, this significant benefit from the invasive strategy was counterbalanced by a surprising and inexplicable increase in deaths from noncardiovascular causes in those managed with the invasive strategy. Noncardiovascular deaths occurred in 5.5% of those in the invasive arm and in 4.4% of those in the conservative arm, a significant adjusted 44% relative increase in this outcome associated with invasive management. Again, this difference was not as clearly apparent after the initial follow-up phase.

“The increase in noncardiovascular deaths with the invasive strategy surprisingly persisted over time and offset” the cardiovascular survival benefit from upfront invasive treatment, explained Dr. Hochman. A prior report from the investigators looked in depth at the noncardiovascular deaths during the initial follow-up phase and found that most of the excess was caused by malignancies, although why this happened in the invasively treated patients remains a mystery.

Staying alive is what patients care about

“I think that interventional cardiologists who favor an invasive strategy will be excited to see this significant reduction in cardiovascular deaths, but patients don’t care what they die from. What patients care about is whether they are dead or alive,” Dr. Hochman noted.

Mitchel L. Zoler/MDedge News

But B. Hadley Wilson, MD, an interventional cardiologist and vice president of the American College of Cardiology, had a somewhat different take on these findings.

“We need to consider the significant decrease in cardiovascular mortality, as we sort out the conundrum” of the increase in noncardiovascular deaths,” he said in an interview. “Hopefully, the 10-year outcomes will help answer this.”

But until more information is available, the ISCHEMIA and ISCHEMIA-EXTEND results have already helped advance the conversation that patients with stable coronary disease and their families have with clinicians about management decisions.

“I love that ISCHEMIA highlighted the importance of shared decision making and a heart team approach,” said Dr. Wilson, executive vice chair of the Sanger Heart & Vascular Institute of Atrium Health in Charlotte, N.C.
 

Anecdotally, ISCHEMIA reduced invasive management

After the initial ISCHEMIA results were published nearly 3 years ago, “I think use of invasive treatment for these patients has decreased, although I have seen no numbers” that document this, said Dr. Wilson. “I think most interventional cardiologists would say that ISCHEMIA has had an impact,” with fewer patients who match the trial’s enrollment criteria undergoing invasive management.

“Anecdotally, cardiologists are reviewing the ISCHEMIA data with their patients,” agreed Dr. Hochman, who added that no actual data have yet appeared to document this, nor do data yet document a change in the use of invasive management. “It takes time to measure the impact.”

To expedite the shared decision-making process for these patients, the ISCHEMIA researchers are planning to make available an app that will allow patients and physicians to enter clinical and demographic data and see a calculated estimate of their future cardiovascular disease risk and how amenable it may be to modification by invasive management, Dr. Hochman said. The app would be available on the ISCHEMIA study website in 2023.

ISCHEMIA and ISCHEMIA EXTEND received no commercial funding. Dr. Hochman and Dr. Wilson had no disclosures. Dr. Bahit has received honoraria from Behring, Boehringer Ingelheim, Bristol-Myers Squibb, Janssen, MSD, and Pfizer.






 

CHICAGO – The case for survival equipoise between an invasive or conservative strategy for managing patients with stable coronary disease and moderate or severe cardiac ischemia grew stronger with an additional 2.5 years of median follow-up of the landmark ISCHEMIA trial.

During a median follow-up of 5.7 years in ISCHEMIA-EXTEND – and as long as 7 years – patients randomized to an upfront invasive strategy regardless of their symptoms had an all-cause mortality rate of 12.7%, compared with a 13.4% rate in the patients randomized to the conservative, medication-based management strategy that employed revascularization only when the medical approach failed to resolve their angina. This survival difference fell far short of significance (adjusted hazard ratio, 1.00; 95% confidence interval, 0.85-1.18), solidifying a finding first seen in the main ISCHEMIA results when they came out 3 years before, in late 2019, Judith S. Hochman, MD, said at the American Heart Association scientific sessions.

Mitchel L. Zoler/MDedge News

The new results “provide evidence for patients with chronic coronary disease and their physicians as they decide whether to add invasive management to guideline-directed medical therapy,” concluded Dr. Hochman, professor and senior associate dean for clinical sciences at New York University Langone Health. Simultaneous with her report, the extended follow-up results also appeared in an article published online in Circulation.
 

Nil probability of a survival benefit

“The probability over 5.7 years that a patient’s risk of dying is lower with the invasive strategy is nil, which means: Go with the patient’s preference. Not undergoing revascularization is a reasonable strategy because there is no excess mortality,” Dr. Hochman said in an interview. The trial’s extended follow-up provides “much more robust evidence” for the neutral effect on survival. The investigators plan to further follow-up out to a maximum of 10 years to continue to monitor for a signal of a mortality difference.

Mitchel L. Zoler/MDedge News

“These findings might help physicians in shared decision-making as to whether to add invasive management to guideline-directed medical management in selected patients with chronic coronary artery disease and moderate or severe ischemia,” commented M. Cecilia Bahit, MD, designated discussant for the report and chief of cardiology for INECO Neurosciences in Rosario, Argentina.

The original ISCHEMIA results had also shown that invasive intervention can improve the quality of life in patients who have angina as a result of their coronary disease, but also showed “minimal benefits” from an invasive approach in asymptomatic patients, who comprised 35% of the study cohort of 5,179 patients.

While ISCHEMIA enrolled patients with moderate to severe coronary ischemia identified with noninvasive testing, it excluded certain patients for whom an invasive strategy is recommended, including those with unprotected left main coronary stenoses of at least 50%, a recent acute coronary syndrome event, a left ventricular ejection fraction of less than 35%, more advanced functional limitations from heart failure, or advanced chronic kidney disease.

Follow-up without adjudication

The extended follow-up included 4,825 patients from the initial cohort, with data collected from 4,540 patients. One limitation of the follow-up was that the cause of death was not adjudicated as it had been during the initial follow-up phase. It instead relied on unconfirmed information collected either from patients’ families or national databases. The demographics and clinical profiles of the study participants available for extended follow-up closely matched the entire original study cohort.

The additional follow-up also revealed a significant survival benefit from the invasive approach for cardiovascular deaths, with an incidence of 8.6% in the conservative arm and 6.4% in the invasive group, an adjusted 22% relative reduction in this outcome favoring the invasive strategy (95% CI, 0.63-0.96). This difference had appeared as a nonsignificant signal in the initial 3.2-year median follow-up.

However, this significant benefit from the invasive strategy was counterbalanced by a surprising and inexplicable increase in deaths from noncardiovascular causes in those managed with the invasive strategy. Noncardiovascular deaths occurred in 5.5% of those in the invasive arm and in 4.4% of those in the conservative arm, a significant adjusted 44% relative increase in this outcome associated with invasive management. Again, this difference was not as clearly apparent after the initial follow-up phase.

“The increase in noncardiovascular deaths with the invasive strategy surprisingly persisted over time and offset” the cardiovascular survival benefit from upfront invasive treatment, explained Dr. Hochman. A prior report from the investigators looked in depth at the noncardiovascular deaths during the initial follow-up phase and found that most of the excess was caused by malignancies, although why this happened in the invasively treated patients remains a mystery.

Staying alive is what patients care about

“I think that interventional cardiologists who favor an invasive strategy will be excited to see this significant reduction in cardiovascular deaths, but patients don’t care what they die from. What patients care about is whether they are dead or alive,” Dr. Hochman noted.

Mitchel L. Zoler/MDedge News

But B. Hadley Wilson, MD, an interventional cardiologist and vice president of the American College of Cardiology, had a somewhat different take on these findings.

“We need to consider the significant decrease in cardiovascular mortality, as we sort out the conundrum” of the increase in noncardiovascular deaths,” he said in an interview. “Hopefully, the 10-year outcomes will help answer this.”

But until more information is available, the ISCHEMIA and ISCHEMIA-EXTEND results have already helped advance the conversation that patients with stable coronary disease and their families have with clinicians about management decisions.

“I love that ISCHEMIA highlighted the importance of shared decision making and a heart team approach,” said Dr. Wilson, executive vice chair of the Sanger Heart & Vascular Institute of Atrium Health in Charlotte, N.C.
 

Anecdotally, ISCHEMIA reduced invasive management

After the initial ISCHEMIA results were published nearly 3 years ago, “I think use of invasive treatment for these patients has decreased, although I have seen no numbers” that document this, said Dr. Wilson. “I think most interventional cardiologists would say that ISCHEMIA has had an impact,” with fewer patients who match the trial’s enrollment criteria undergoing invasive management.

“Anecdotally, cardiologists are reviewing the ISCHEMIA data with their patients,” agreed Dr. Hochman, who added that no actual data have yet appeared to document this, nor do data yet document a change in the use of invasive management. “It takes time to measure the impact.”

To expedite the shared decision-making process for these patients, the ISCHEMIA researchers are planning to make available an app that will allow patients and physicians to enter clinical and demographic data and see a calculated estimate of their future cardiovascular disease risk and how amenable it may be to modification by invasive management, Dr. Hochman said. The app would be available on the ISCHEMIA study website in 2023.

ISCHEMIA and ISCHEMIA EXTEND received no commercial funding. Dr. Hochman and Dr. Wilson had no disclosures. Dr. Bahit has received honoraria from Behring, Boehringer Ingelheim, Bristol-Myers Squibb, Janssen, MSD, and Pfizer.






 

CHICAGO – The case for survival equipoise between an invasive or conservative strategy for managing patients with stable coronary disease and moderate or severe cardiac ischemia grew stronger with an additional 2.5 years of median follow-up of the landmark ISCHEMIA trial.

During a median follow-up of 5.7 years in ISCHEMIA-EXTEND – and as long as 7 years – patients randomized to an upfront invasive strategy regardless of their symptoms had an all-cause mortality rate of 12.7%, compared with a 13.4% rate in the patients randomized to the conservative, medication-based management strategy that employed revascularization only when the medical approach failed to resolve their angina. This survival difference fell far short of significance (adjusted hazard ratio, 1.00; 95% confidence interval, 0.85-1.18), solidifying a finding first seen in the main ISCHEMIA results when they came out 3 years before, in late 2019, Judith S. Hochman, MD, said at the American Heart Association scientific sessions.

Mitchel L. Zoler/MDedge News

The new results “provide evidence for patients with chronic coronary disease and their physicians as they decide whether to add invasive management to guideline-directed medical therapy,” concluded Dr. Hochman, professor and senior associate dean for clinical sciences at New York University Langone Health. Simultaneous with her report, the extended follow-up results also appeared in an article published online in Circulation.
 

Nil probability of a survival benefit

“The probability over 5.7 years that a patient’s risk of dying is lower with the invasive strategy is nil, which means: Go with the patient’s preference. Not undergoing revascularization is a reasonable strategy because there is no excess mortality,” Dr. Hochman said in an interview. The trial’s extended follow-up provides “much more robust evidence” for the neutral effect on survival. The investigators plan to further follow-up out to a maximum of 10 years to continue to monitor for a signal of a mortality difference.

Mitchel L. Zoler/MDedge News

“These findings might help physicians in shared decision-making as to whether to add invasive management to guideline-directed medical management in selected patients with chronic coronary artery disease and moderate or severe ischemia,” commented M. Cecilia Bahit, MD, designated discussant for the report and chief of cardiology for INECO Neurosciences in Rosario, Argentina.

The original ISCHEMIA results had also shown that invasive intervention can improve the quality of life in patients who have angina as a result of their coronary disease, but also showed “minimal benefits” from an invasive approach in asymptomatic patients, who comprised 35% of the study cohort of 5,179 patients.

While ISCHEMIA enrolled patients with moderate to severe coronary ischemia identified with noninvasive testing, it excluded certain patients for whom an invasive strategy is recommended, including those with unprotected left main coronary stenoses of at least 50%, a recent acute coronary syndrome event, a left ventricular ejection fraction of less than 35%, more advanced functional limitations from heart failure, or advanced chronic kidney disease.

Follow-up without adjudication

The extended follow-up included 4,825 patients from the initial cohort, with data collected from 4,540 patients. One limitation of the follow-up was that the cause of death was not adjudicated as it had been during the initial follow-up phase. It instead relied on unconfirmed information collected either from patients’ families or national databases. The demographics and clinical profiles of the study participants available for extended follow-up closely matched the entire original study cohort.

The additional follow-up also revealed a significant survival benefit from the invasive approach for cardiovascular deaths, with an incidence of 8.6% in the conservative arm and 6.4% in the invasive group, an adjusted 22% relative reduction in this outcome favoring the invasive strategy (95% CI, 0.63-0.96). This difference had appeared as a nonsignificant signal in the initial 3.2-year median follow-up.

However, this significant benefit from the invasive strategy was counterbalanced by a surprising and inexplicable increase in deaths from noncardiovascular causes in those managed with the invasive strategy. Noncardiovascular deaths occurred in 5.5% of those in the invasive arm and in 4.4% of those in the conservative arm, a significant adjusted 44% relative increase in this outcome associated with invasive management. Again, this difference was not as clearly apparent after the initial follow-up phase.

“The increase in noncardiovascular deaths with the invasive strategy surprisingly persisted over time and offset” the cardiovascular survival benefit from upfront invasive treatment, explained Dr. Hochman. A prior report from the investigators looked in depth at the noncardiovascular deaths during the initial follow-up phase and found that most of the excess was caused by malignancies, although why this happened in the invasively treated patients remains a mystery.

Staying alive is what patients care about

“I think that interventional cardiologists who favor an invasive strategy will be excited to see this significant reduction in cardiovascular deaths, but patients don’t care what they die from. What patients care about is whether they are dead or alive,” Dr. Hochman noted.

Mitchel L. Zoler/MDedge News

But B. Hadley Wilson, MD, an interventional cardiologist and vice president of the American College of Cardiology, had a somewhat different take on these findings.

“We need to consider the significant decrease in cardiovascular mortality, as we sort out the conundrum” of the increase in noncardiovascular deaths,” he said in an interview. “Hopefully, the 10-year outcomes will help answer this.”

But until more information is available, the ISCHEMIA and ISCHEMIA-EXTEND results have already helped advance the conversation that patients with stable coronary disease and their families have with clinicians about management decisions.

“I love that ISCHEMIA highlighted the importance of shared decision making and a heart team approach,” said Dr. Wilson, executive vice chair of the Sanger Heart & Vascular Institute of Atrium Health in Charlotte, N.C.
 

Anecdotally, ISCHEMIA reduced invasive management

After the initial ISCHEMIA results were published nearly 3 years ago, “I think use of invasive treatment for these patients has decreased, although I have seen no numbers” that document this, said Dr. Wilson. “I think most interventional cardiologists would say that ISCHEMIA has had an impact,” with fewer patients who match the trial’s enrollment criteria undergoing invasive management.

“Anecdotally, cardiologists are reviewing the ISCHEMIA data with their patients,” agreed Dr. Hochman, who added that no actual data have yet appeared to document this, nor do data yet document a change in the use of invasive management. “It takes time to measure the impact.”

To expedite the shared decision-making process for these patients, the ISCHEMIA researchers are planning to make available an app that will allow patients and physicians to enter clinical and demographic data and see a calculated estimate of their future cardiovascular disease risk and how amenable it may be to modification by invasive management, Dr. Hochman said. The app would be available on the ISCHEMIA study website in 2023.

ISCHEMIA and ISCHEMIA EXTEND received no commercial funding. Dr. Hochman and Dr. Wilson had no disclosures. Dr. Bahit has received honoraria from Behring, Boehringer Ingelheim, Bristol-Myers Squibb, Janssen, MSD, and Pfizer.






 

ORLANDO – Treatment with a renin-angiotensin system (RAS) inhibitor is widely accepted as standard practice for slowing progression of chronic kidney disease (CKD), but data have been inconsistent as to whether there is benefit to continuing RAS inhibition when patients develop advanced CKD, defined as an estimated glomerular filtration rate (eGFR) of less than 30 mL/min per 1.73 m².

Now, in STOP ACEi, a new multicenter, randomized trial of 411 patients, maintaining treatment with a RAS inhibitor in adults with advanced and progressive CKD did not cause a clinically relevant change in kidney function, or in the long-term rate of decline in kidney function, compared with stopping treatment, for 3 years.

People who continued RAS inhibitor treatment did not develop a significant or clinically relevant decrease in eGFR, the study’s primary outcome, both overall as well as in several prespecified subgroups compared with those who discontinued treatment, said Sunil Bhandari, MBChB, PhD, and associates, who presented the research in a poster at the annual meeting of the American Society of Nephrology.

“I hope these results will reassure clinicians to continue ACE inhibitors or ARBs” in patients with advanced CKD, “with their known beneficial cardiovascular effects,” Dr. Bhandari said in an interview.

The results were simultaneously published in the New England Journal of Medicine.
 

Similar eGFR levels after 3 years

While it’s clear that in patients with mild or moderate CKD, treatment with a RAS inhibitor, which includes angiotensin-converting enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs), reduces blood pressure, slows decline in eGFR, reduces proteinuria, and delays progression to advanced CKD, there has been little evidence that the use of RAS inhibitors benefits patients with advanced CKD.

Data from previous trials have been inconsistent regarding whether the use of RAS inhibitors is nephroprotective in patients with advanced CKD, say Dr. Bhandari, a nephrologist and professor at Hull York Medical School, Hull, England, and colleagues.

“Current guidelines do not provide specific advice on whether to continue or stop ACE inhibitors or ARBs for advanced chronic kidney disease,” they also note.

And so they decided to assess whether discontinuation of ACE inhibitors/ARBs could slow progression of CKD in patients with advanced CKD.

Three years after 206 study participants stopped RAS inhibitor treatment, the least-squares mean eGFR was 12.6 mL/min per 1.73m² in the discontinuation group and 13.3 mL/min per 1.73 m² in the 205 patients in the continuation group, a difference that was not significant.

In addition to the primary outcome, 62% of patients who stopped RAS inhibitor treatment and 56% of those who continued developed end-stage kidney disease or required renal-replacement therapy, which translated into an adjusted hazard ratio of 1.28 for this outcome among those who discontinued compared with those who continued, which was just short of significance (95% CI, 0.99-1.65).

The two study groups also showed no significant differences in the 3-year incidence of hospitalization for any reason, cardiovascular events, or deaths. The two groups also showed no meaningful differences in various domains of quality of life and no differences in serious adverse effects.
 

Participants had an eGFR less than 30 mL/min per 1.73 m²

The study ran at 39 United Kingdom centers in 2014-2019. Investigators enrolled adults with an eGFR of less than 30 mL/min per 1.73 m² who were not on dialysis and had not received a kidney transplant. In addition, all enrolled patients had to have an annual drop in eGFR of more than 2 mL/min per 1.73 m² during the prior 2 years and had to have been on treatment with at least one RAS inhibitor for more than 6 months.

The randomization protocol insured balanced distribution of subjects between the two study arms by age, eGFR, presence of diabetes, and level of proteinuria, among other factors. The study design also mandated that participants maintain a blood pressure of no more than 140/85 mm Hg.

Those who discontinued RAS-inhibitor treatment could receive any guideline-recommended antihypertensive agent that was not a RAS inhibitor, although adding a RAS inhibitor was permitted as a last treatment resort.

People in the maintenance group could receive whichever additional antihypertensive agents their treating clinicians deemed necessary for maintaining the target blood pressure.

The enrolled population was a median age of 63 years old and 68% were men. Their average eGFR at baseline was 18 mL/min per 1.73 m², and 118 (29%) had an eGFR of less than 15 mL/min per 1.73 m². Their median level of proteinuria was 115 mg/mmol (about 1,018 mg/g). Diabetes was prevalent in 37%, and 58% of participants were taking at least three antihypertensive medications at entry.

Among the study’s limitations, the researchers cited the open-label design, which may have affected clinical care and the tally of subjective endpoints, including quality of life and exercise capacity. Also, because the study enrolled people who were on a RAS inhibitor at the time of randomization, it did not include anyone who had already discontinued these agents.
 

Continue RAS inhibitors in advanced CKD for best outcomes

Dr. Bhandari and colleagues note that in a large observational trial published in January 2021, Swedish researchers found an increase in the incidence of major cardiovascular events and death among patients with advanced CKD who had discontinued RAS inhibitors.

But they observe, “Our trial did not have sufficient power to investigate the effect of the discontinuation of RAS inhibitors on cardiovascular events or mortality. However, because our findings are consistent with a lack of advantage for such discontinuation with respect to kidney function, there is little rationale to conduct a larger randomized trial to investigate cardiovascular safety.”

“Our findings do not support the hypothesis that the discontinuation of RAS inhibitors in patients with advanced and progressive chronic kidney disease would improve kidney function, quality of life, or exercise capacity.”

“The results of this trial will inform future clinical practice worldwide and guideline recommendations,” they conclude.

STOP ACEi received no commercial funding. Dr. Bhandari has reported no relevant financial relationships.

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

ORLANDO – Treatment with a renin-angiotensin system (RAS) inhibitor is widely accepted as standard practice for slowing progression of chronic kidney disease (CKD), but data have been inconsistent as to whether there is benefit to continuing RAS inhibition when patients develop advanced CKD, defined as an estimated glomerular filtration rate (eGFR) of less than 30 mL/min per 1.73 m².

Now, in STOP ACEi, a new multicenter, randomized trial of 411 patients, maintaining treatment with a RAS inhibitor in adults with advanced and progressive CKD did not cause a clinically relevant change in kidney function, or in the long-term rate of decline in kidney function, compared with stopping treatment, for 3 years.

People who continued RAS inhibitor treatment did not develop a significant or clinically relevant decrease in eGFR, the study’s primary outcome, both overall as well as in several prespecified subgroups compared with those who discontinued treatment, said Sunil Bhandari, MBChB, PhD, and associates, who presented the research in a poster at the annual meeting of the American Society of Nephrology.

“I hope these results will reassure clinicians to continue ACE inhibitors or ARBs” in patients with advanced CKD, “with their known beneficial cardiovascular effects,” Dr. Bhandari said in an interview.

The results were simultaneously published in the New England Journal of Medicine.
 

Similar eGFR levels after 3 years

While it’s clear that in patients with mild or moderate CKD, treatment with a RAS inhibitor, which includes angiotensin-converting enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs), reduces blood pressure, slows decline in eGFR, reduces proteinuria, and delays progression to advanced CKD, there has been little evidence that the use of RAS inhibitors benefits patients with advanced CKD.

Data from previous trials have been inconsistent regarding whether the use of RAS inhibitors is nephroprotective in patients with advanced CKD, say Dr. Bhandari, a nephrologist and professor at Hull York Medical School, Hull, England, and colleagues.

“Current guidelines do not provide specific advice on whether to continue or stop ACE inhibitors or ARBs for advanced chronic kidney disease,” they also note.

And so they decided to assess whether discontinuation of ACE inhibitors/ARBs could slow progression of CKD in patients with advanced CKD.

Three years after 206 study participants stopped RAS inhibitor treatment, the least-squares mean eGFR was 12.6 mL/min per 1.73m² in the discontinuation group and 13.3 mL/min per 1.73 m² in the 205 patients in the continuation group, a difference that was not significant.

In addition to the primary outcome, 62% of patients who stopped RAS inhibitor treatment and 56% of those who continued developed end-stage kidney disease or required renal-replacement therapy, which translated into an adjusted hazard ratio of 1.28 for this outcome among those who discontinued compared with those who continued, which was just short of significance (95% CI, 0.99-1.65).

The two study groups also showed no significant differences in the 3-year incidence of hospitalization for any reason, cardiovascular events, or deaths. The two groups also showed no meaningful differences in various domains of quality of life and no differences in serious adverse effects.
 

Participants had an eGFR less than 30 mL/min per 1.73 m²

The study ran at 39 United Kingdom centers in 2014-2019. Investigators enrolled adults with an eGFR of less than 30 mL/min per 1.73 m² who were not on dialysis and had not received a kidney transplant. In addition, all enrolled patients had to have an annual drop in eGFR of more than 2 mL/min per 1.73 m² during the prior 2 years and had to have been on treatment with at least one RAS inhibitor for more than 6 months.

The randomization protocol insured balanced distribution of subjects between the two study arms by age, eGFR, presence of diabetes, and level of proteinuria, among other factors. The study design also mandated that participants maintain a blood pressure of no more than 140/85 mm Hg.

Those who discontinued RAS-inhibitor treatment could receive any guideline-recommended antihypertensive agent that was not a RAS inhibitor, although adding a RAS inhibitor was permitted as a last treatment resort.

People in the maintenance group could receive whichever additional antihypertensive agents their treating clinicians deemed necessary for maintaining the target blood pressure.

The enrolled population was a median age of 63 years old and 68% were men. Their average eGFR at baseline was 18 mL/min per 1.73 m², and 118 (29%) had an eGFR of less than 15 mL/min per 1.73 m². Their median level of proteinuria was 115 mg/mmol (about 1,018 mg/g). Diabetes was prevalent in 37%, and 58% of participants were taking at least three antihypertensive medications at entry.

Among the study’s limitations, the researchers cited the open-label design, which may have affected clinical care and the tally of subjective endpoints, including quality of life and exercise capacity. Also, because the study enrolled people who were on a RAS inhibitor at the time of randomization, it did not include anyone who had already discontinued these agents.
 

Continue RAS inhibitors in advanced CKD for best outcomes

Dr. Bhandari and colleagues note that in a large observational trial published in January 2021, Swedish researchers found an increase in the incidence of major cardiovascular events and death among patients with advanced CKD who had discontinued RAS inhibitors.

But they observe, “Our trial did not have sufficient power to investigate the effect of the discontinuation of RAS inhibitors on cardiovascular events or mortality. However, because our findings are consistent with a lack of advantage for such discontinuation with respect to kidney function, there is little rationale to conduct a larger randomized trial to investigate cardiovascular safety.”

“Our findings do not support the hypothesis that the discontinuation of RAS inhibitors in patients with advanced and progressive chronic kidney disease would improve kidney function, quality of life, or exercise capacity.”

“The results of this trial will inform future clinical practice worldwide and guideline recommendations,” they conclude.

STOP ACEi received no commercial funding. Dr. Bhandari has reported no relevant financial relationships.

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

ORLANDO – Treatment with a renin-angiotensin system (RAS) inhibitor is widely accepted as standard practice for slowing progression of chronic kidney disease (CKD), but data have been inconsistent as to whether there is benefit to continuing RAS inhibition when patients develop advanced CKD, defined as an estimated glomerular filtration rate (eGFR) of less than 30 mL/min per 1.73 m².

Now, in STOP ACEi, a new multicenter, randomized trial of 411 patients, maintaining treatment with a RAS inhibitor in adults with advanced and progressive CKD did not cause a clinically relevant change in kidney function, or in the long-term rate of decline in kidney function, compared with stopping treatment, for 3 years.

People who continued RAS inhibitor treatment did not develop a significant or clinically relevant decrease in eGFR, the study’s primary outcome, both overall as well as in several prespecified subgroups compared with those who discontinued treatment, said Sunil Bhandari, MBChB, PhD, and associates, who presented the research in a poster at the annual meeting of the American Society of Nephrology.

“I hope these results will reassure clinicians to continue ACE inhibitors or ARBs” in patients with advanced CKD, “with their known beneficial cardiovascular effects,” Dr. Bhandari said in an interview.

The results were simultaneously published in the New England Journal of Medicine.
 

Similar eGFR levels after 3 years

While it’s clear that in patients with mild or moderate CKD, treatment with a RAS inhibitor, which includes angiotensin-converting enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs), reduces blood pressure, slows decline in eGFR, reduces proteinuria, and delays progression to advanced CKD, there has been little evidence that the use of RAS inhibitors benefits patients with advanced CKD.

Data from previous trials have been inconsistent regarding whether the use of RAS inhibitors is nephroprotective in patients with advanced CKD, say Dr. Bhandari, a nephrologist and professor at Hull York Medical School, Hull, England, and colleagues.

“Current guidelines do not provide specific advice on whether to continue or stop ACE inhibitors or ARBs for advanced chronic kidney disease,” they also note.

And so they decided to assess whether discontinuation of ACE inhibitors/ARBs could slow progression of CKD in patients with advanced CKD.

Three years after 206 study participants stopped RAS inhibitor treatment, the least-squares mean eGFR was 12.6 mL/min per 1.73m² in the discontinuation group and 13.3 mL/min per 1.73 m² in the 205 patients in the continuation group, a difference that was not significant.

In addition to the primary outcome, 62% of patients who stopped RAS inhibitor treatment and 56% of those who continued developed end-stage kidney disease or required renal-replacement therapy, which translated into an adjusted hazard ratio of 1.28 for this outcome among those who discontinued compared with those who continued, which was just short of significance (95% CI, 0.99-1.65).

The two study groups also showed no significant differences in the 3-year incidence of hospitalization for any reason, cardiovascular events, or deaths. The two groups also showed no meaningful differences in various domains of quality of life and no differences in serious adverse effects.
 

Participants had an eGFR less than 30 mL/min per 1.73 m²

The study ran at 39 United Kingdom centers in 2014-2019. Investigators enrolled adults with an eGFR of less than 30 mL/min per 1.73 m² who were not on dialysis and had not received a kidney transplant. In addition, all enrolled patients had to have an annual drop in eGFR of more than 2 mL/min per 1.73 m² during the prior 2 years and had to have been on treatment with at least one RAS inhibitor for more than 6 months.

The randomization protocol insured balanced distribution of subjects between the two study arms by age, eGFR, presence of diabetes, and level of proteinuria, among other factors. The study design also mandated that participants maintain a blood pressure of no more than 140/85 mm Hg.

Those who discontinued RAS-inhibitor treatment could receive any guideline-recommended antihypertensive agent that was not a RAS inhibitor, although adding a RAS inhibitor was permitted as a last treatment resort.

People in the maintenance group could receive whichever additional antihypertensive agents their treating clinicians deemed necessary for maintaining the target blood pressure.

The enrolled population was a median age of 63 years old and 68% were men. Their average eGFR at baseline was 18 mL/min per 1.73 m², and 118 (29%) had an eGFR of less than 15 mL/min per 1.73 m². Their median level of proteinuria was 115 mg/mmol (about 1,018 mg/g). Diabetes was prevalent in 37%, and 58% of participants were taking at least three antihypertensive medications at entry.

Among the study’s limitations, the researchers cited the open-label design, which may have affected clinical care and the tally of subjective endpoints, including quality of life and exercise capacity. Also, because the study enrolled people who were on a RAS inhibitor at the time of randomization, it did not include anyone who had already discontinued these agents.
 

Continue RAS inhibitors in advanced CKD for best outcomes

Dr. Bhandari and colleagues note that in a large observational trial published in January 2021, Swedish researchers found an increase in the incidence of major cardiovascular events and death among patients with advanced CKD who had discontinued RAS inhibitors.

But they observe, “Our trial did not have sufficient power to investigate the effect of the discontinuation of RAS inhibitors on cardiovascular events or mortality. However, because our findings are consistent with a lack of advantage for such discontinuation with respect to kidney function, there is little rationale to conduct a larger randomized trial to investigate cardiovascular safety.”

“Our findings do not support the hypothesis that the discontinuation of RAS inhibitors in patients with advanced and progressive chronic kidney disease would improve kidney function, quality of life, or exercise capacity.”

“The results of this trial will inform future clinical practice worldwide and guideline recommendations,” they conclude.

STOP ACEi received no commercial funding. Dr. Bhandari has reported no relevant financial relationships.

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

CHICAGO – Treatment with the investigational CRISPR-Cas9 gene-editing therapy, NTLA-2001, led to rapid responses in patients with transthyretin (TTR) amyloidosis with cardiomyopathy (ATTR-CM), interim phase 1 results show.

Serum levels of the disease-causing TTR protein were reduced by at least 90% at day 28 with a single infusion of NTLA-2001 at two different doses, with reductions sustained across 4-6 months’ follow-up.

NTLA-2001 was generally well-tolerated, and the results were similar in patients with New York Heart Association (NYHA) class I-III heart failure.

“These data further support and extend the early findings demonstrating the promise of CRISPR-based in vivo genome editing in humans,” said Julian Gillmore, MD, PhD, MBBS, who is leading the study at University College London.

“More specifically, the deep TTR reductions observed in patients with ATTR amyloidosis in this study provide a real possibility of genuine clinical improvement in a condition that has hitherto been ultimately progressive and invariably fatal,” he said.

The results were reported in a late-breaking session at the American Heart Association scientific sessions.

Mutations in the TTR gene and age-related changes in the stability of the TTR protein can cause misfolding of the TTR protein, resulting in amyloid deposits in skin and myocardial tissues.

An estimated 50,000 people worldwide are thought to have hereditary ATTR and up to 500,000 to have wild-type ATTR amyloidosis. Amyloid cardiomyopathy is underdiagnosed and fatal in 3-10 years without treatment. Current treatment options only slow progression and require lifelong administration, he said.

Results reported last year from the polyneuropathy arm of the study were hailed as a breakthrough and further proof-of-concept that CRISPR could be used to treat other diseases

CRISPR gene editing has shown success, for example, in beta-thalassemia and sickle cell disease but involved stem cells extracted from patients’ bone marrow, edited in the lab, and then replaced.

NTLA-2001 (Intellia Therapeutics/Regeneron) is an in vivo treatment that uses lipid nanoparticles containing messenger RNA for Cas9 and a single-guide RNA targeting TTR in the liver, where it’s almost exclusively produced.

The new analysis included 12 patients with heart failure: 3 in NYHA  class I-II and 6 in NYHA class III who received a single dose of NTLA-2001 at 0.7 mg/kg, while the remaining 3 patients in NYHA class I-II received a single dose of 1.0 mg/kg.

During follow-up out to 6 months, TTR reductions averaged:

• 93% in the 0.7 mg/kg NYHA I-II group at 6 months.
• 94% in the 0.7 mg/kg NYHA III group at 4 months.
• 92% in the 1.0 mg/kg NYHA I-II group at 4 months.

Eight patients reported mild or moderate adverse events, and two patients experienced transient infusion reactions, including one grade 3 reaction in the 0.7 mg/kg NYHA class III group that resolved without clinical consequence. This group was expanded to six patients per study protocol. No additional treatment-related adverse events higher than grade 1 were reported, and no further dose escalation was undertaken, Dr. Gillmore reported.

There were no clinically relevant laboratory findings; one patient had a transient grade 1 liver enzyme elevation.

One disadvantage of CRISPR is the potential for off-target effects, but Dr. Gillmore said in an interview that the drug developers went through a “very rigorous process when selecting the guide RNA, which is what really targets the specificity of the TTR gene.”

“That’s a really, really important point,” he said. “When they did various studies using, for example, primary human hepatocytes, they found no evidence of off-target editing at concentrations of NTLA-2001 threefold greater than the EC90, the concentration at which one knocks down the protein by 90%. So, what we can say at the moment, is the specificity of NTLA-2001 for the TTR gene seems to be absolute.”

In terms of other challenges going forward, Dr. Gillmore added, “I think that it’s really to see whether the knockdown that is being achieved is going to translate into greater clinical benefit.”

Invited discussant Kevin M. Alexander, MD, of Stanford (Calif.) University, said therapies that stabilize or reduce TTR have recently emerged that have improved ATTR amyloidosis outcomes, including tafamidis and patisiran.

Nevertheless, there has been an unmet need to develop therapies that can halt or reverse disease, are effective in advanced ATTR, and have an improved route or frequency of administration, given that this is a chronic disease, he said.

Dr. Alexander noted that the reductions of greater than 90% were achieved with higher doses than used in the polyneuropathy arm reported last year but were well tolerated in patients that for the most part had wild-type ATTR (83%) and reflect the wild-type ATTR population in practice. “The data support consideration for subsequent efficacy trials for this compound.”

Unanswered questions in ongoing ATTR trials are whether TTR reductions translate into improved clinical outcomes, the long-term safety of TTR lowering, and the efficacy of NTLA-2001, particularly in higher-risk patients, such as those in NYHA class III and those with hereditary ATTR, Dr. Alexander said.

During a media briefing earlier in the day, invited discussant Kiran Musunuru, MD, University of Pennsylvania, Philadelphia, pointed out that, in the recent APOLLO-B trial of patisiran, patients with ATTR amyloidosis with cardiomyopathy had an average 87% TTR reduction but need intravenous infusions every 3 weeks for the rest of their lives.

“In contrast, gene editing is a one-and-done proposition,” he said. “You receive a single treatment that turns off the TTR gene permanently and the effects are durable and likely last a lifetime.”

Dr. Musunuru noted that patients who received patisiran also had significantly and substantially better functional capacity and quality of life, compared with those who received placebo. “Based on today’s results, we can expect future clinical trials for gene editing to have the same beneficial effects and possibly a mortality benefit as well.”

Today’s study is also important because it is part of the first wave of putting CRISPR into the body for an array of diseases, he commented.

“TTR gene editing stands out because it’s the very first CRISPR trial to show unequivocal success – you see that with a greater than 90% reduction in TTR,” Dr. Musunuru said. “So, in my view that makes it a milestone for modern medicine.”

Dosing at 55 mg, corresponding to a fixed 0.7 mg/kg dose, is ongoing in the dose-expansion portion of the trial, with enrollment across both arms expected to be completed by the end of 2022, Intellia Therapeutics reported.

The study was funded by Intellia Therapeutics and Regeneron Pharmaceuticals. Dr. Gillmore reports receiving consultancy fees from Alnylam, Ionis, AstraZeneca, Pfizer, Intellia, ATTRalus, and Novo Nordisk and has received grant support from Alnylam Pharmaceuticals. Dr. Alexander reports serving on advisory boards for Almylam and Arbor Biotechnologies; has consulted  for Eidos, Ionis, Novo Nordisk, and Pfizer; and has received grants from AHA, Alnylam, Eidos, and the National Institutes of Health.

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

CHICAGO – Treatment with the investigational CRISPR-Cas9 gene-editing therapy, NTLA-2001, led to rapid responses in patients with transthyretin (TTR) amyloidosis with cardiomyopathy (ATTR-CM), interim phase 1 results show.

Serum levels of the disease-causing TTR protein were reduced by at least 90% at day 28 with a single infusion of NTLA-2001 at two different doses, with reductions sustained across 4-6 months’ follow-up.

NTLA-2001 was generally well-tolerated, and the results were similar in patients with New York Heart Association (NYHA) class I-III heart failure.

“These data further support and extend the early findings demonstrating the promise of CRISPR-based in vivo genome editing in humans,” said Julian Gillmore, MD, PhD, MBBS, who is leading the study at University College London.

“More specifically, the deep TTR reductions observed in patients with ATTR amyloidosis in this study provide a real possibility of genuine clinical improvement in a condition that has hitherto been ultimately progressive and invariably fatal,” he said.

The results were reported in a late-breaking session at the American Heart Association scientific sessions.

Mutations in the TTR gene and age-related changes in the stability of the TTR protein can cause misfolding of the TTR protein, resulting in amyloid deposits in skin and myocardial tissues.

An estimated 50,000 people worldwide are thought to have hereditary ATTR and up to 500,000 to have wild-type ATTR amyloidosis. Amyloid cardiomyopathy is underdiagnosed and fatal in 3-10 years without treatment. Current treatment options only slow progression and require lifelong administration, he said.

Results reported last year from the polyneuropathy arm of the study were hailed as a breakthrough and further proof-of-concept that CRISPR could be used to treat other diseases

CRISPR gene editing has shown success, for example, in beta-thalassemia and sickle cell disease but involved stem cells extracted from patients’ bone marrow, edited in the lab, and then replaced.

NTLA-2001 (Intellia Therapeutics/Regeneron) is an in vivo treatment that uses lipid nanoparticles containing messenger RNA for Cas9 and a single-guide RNA targeting TTR in the liver, where it’s almost exclusively produced.

The new analysis included 12 patients with heart failure: 3 in NYHA  class I-II and 6 in NYHA class III who received a single dose of NTLA-2001 at 0.7 mg/kg, while the remaining 3 patients in NYHA class I-II received a single dose of 1.0 mg/kg.

During follow-up out to 6 months, TTR reductions averaged:

• 93% in the 0.7 mg/kg NYHA I-II group at 6 months.
• 94% in the 0.7 mg/kg NYHA III group at 4 months.
• 92% in the 1.0 mg/kg NYHA I-II group at 4 months.

Eight patients reported mild or moderate adverse events, and two patients experienced transient infusion reactions, including one grade 3 reaction in the 0.7 mg/kg NYHA class III group that resolved without clinical consequence. This group was expanded to six patients per study protocol. No additional treatment-related adverse events higher than grade 1 were reported, and no further dose escalation was undertaken, Dr. Gillmore reported.

There were no clinically relevant laboratory findings; one patient had a transient grade 1 liver enzyme elevation.

One disadvantage of CRISPR is the potential for off-target effects, but Dr. Gillmore said in an interview that the drug developers went through a “very rigorous process when selecting the guide RNA, which is what really targets the specificity of the TTR gene.”

“That’s a really, really important point,” he said. “When they did various studies using, for example, primary human hepatocytes, they found no evidence of off-target editing at concentrations of NTLA-2001 threefold greater than the EC90, the concentration at which one knocks down the protein by 90%. So, what we can say at the moment, is the specificity of NTLA-2001 for the TTR gene seems to be absolute.”

In terms of other challenges going forward, Dr. Gillmore added, “I think that it’s really to see whether the knockdown that is being achieved is going to translate into greater clinical benefit.”

Invited discussant Kevin M. Alexander, MD, of Stanford (Calif.) University, said therapies that stabilize or reduce TTR have recently emerged that have improved ATTR amyloidosis outcomes, including tafamidis and patisiran.

Nevertheless, there has been an unmet need to develop therapies that can halt or reverse disease, are effective in advanced ATTR, and have an improved route or frequency of administration, given that this is a chronic disease, he said.

Dr. Alexander noted that the reductions of greater than 90% were achieved with higher doses than used in the polyneuropathy arm reported last year but were well tolerated in patients that for the most part had wild-type ATTR (83%) and reflect the wild-type ATTR population in practice. “The data support consideration for subsequent efficacy trials for this compound.”

Unanswered questions in ongoing ATTR trials are whether TTR reductions translate into improved clinical outcomes, the long-term safety of TTR lowering, and the efficacy of NTLA-2001, particularly in higher-risk patients, such as those in NYHA class III and those with hereditary ATTR, Dr. Alexander said.

During a media briefing earlier in the day, invited discussant Kiran Musunuru, MD, University of Pennsylvania, Philadelphia, pointed out that, in the recent APOLLO-B trial of patisiran, patients with ATTR amyloidosis with cardiomyopathy had an average 87% TTR reduction but need intravenous infusions every 3 weeks for the rest of their lives.

“In contrast, gene editing is a one-and-done proposition,” he said. “You receive a single treatment that turns off the TTR gene permanently and the effects are durable and likely last a lifetime.”

Dr. Musunuru noted that patients who received patisiran also had significantly and substantially better functional capacity and quality of life, compared with those who received placebo. “Based on today’s results, we can expect future clinical trials for gene editing to have the same beneficial effects and possibly a mortality benefit as well.”

Today’s study is also important because it is part of the first wave of putting CRISPR into the body for an array of diseases, he commented.

“TTR gene editing stands out because it’s the very first CRISPR trial to show unequivocal success – you see that with a greater than 90% reduction in TTR,” Dr. Musunuru said. “So, in my view that makes it a milestone for modern medicine.”

Dosing at 55 mg, corresponding to a fixed 0.7 mg/kg dose, is ongoing in the dose-expansion portion of the trial, with enrollment across both arms expected to be completed by the end of 2022, Intellia Therapeutics reported.

The study was funded by Intellia Therapeutics and Regeneron Pharmaceuticals. Dr. Gillmore reports receiving consultancy fees from Alnylam, Ionis, AstraZeneca, Pfizer, Intellia, ATTRalus, and Novo Nordisk and has received grant support from Alnylam Pharmaceuticals. Dr. Alexander reports serving on advisory boards for Almylam and Arbor Biotechnologies; has consulted  for Eidos, Ionis, Novo Nordisk, and Pfizer; and has received grants from AHA, Alnylam, Eidos, and the National Institutes of Health.

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

CHICAGO – Treatment with the investigational CRISPR-Cas9 gene-editing therapy, NTLA-2001, led to rapid responses in patients with transthyretin (TTR) amyloidosis with cardiomyopathy (ATTR-CM), interim phase 1 results show.

Serum levels of the disease-causing TTR protein were reduced by at least 90% at day 28 with a single infusion of NTLA-2001 at two different doses, with reductions sustained across 4-6 months’ follow-up.

NTLA-2001 was generally well-tolerated, and the results were similar in patients with New York Heart Association (NYHA) class I-III heart failure.

“These data further support and extend the early findings demonstrating the promise of CRISPR-based in vivo genome editing in humans,” said Julian Gillmore, MD, PhD, MBBS, who is leading the study at University College London.

“More specifically, the deep TTR reductions observed in patients with ATTR amyloidosis in this study provide a real possibility of genuine clinical improvement in a condition that has hitherto been ultimately progressive and invariably fatal,” he said.

The results were reported in a late-breaking session at the American Heart Association scientific sessions.

Mutations in the TTR gene and age-related changes in the stability of the TTR protein can cause misfolding of the TTR protein, resulting in amyloid deposits in skin and myocardial tissues.

An estimated 50,000 people worldwide are thought to have hereditary ATTR and up to 500,000 to have wild-type ATTR amyloidosis. Amyloid cardiomyopathy is underdiagnosed and fatal in 3-10 years without treatment. Current treatment options only slow progression and require lifelong administration, he said.

Results reported last year from the polyneuropathy arm of the study were hailed as a breakthrough and further proof-of-concept that CRISPR could be used to treat other diseases

CRISPR gene editing has shown success, for example, in beta-thalassemia and sickle cell disease but involved stem cells extracted from patients’ bone marrow, edited in the lab, and then replaced.

NTLA-2001 (Intellia Therapeutics/Regeneron) is an in vivo treatment that uses lipid nanoparticles containing messenger RNA for Cas9 and a single-guide RNA targeting TTR in the liver, where it’s almost exclusively produced.

The new analysis included 12 patients with heart failure: 3 in NYHA  class I-II and 6 in NYHA class III who received a single dose of NTLA-2001 at 0.7 mg/kg, while the remaining 3 patients in NYHA class I-II received a single dose of 1.0 mg/kg.

During follow-up out to 6 months, TTR reductions averaged:

• 93% in the 0.7 mg/kg NYHA I-II group at 6 months.
• 94% in the 0.7 mg/kg NYHA III group at 4 months.
• 92% in the 1.0 mg/kg NYHA I-II group at 4 months.

Eight patients reported mild or moderate adverse events, and two patients experienced transient infusion reactions, including one grade 3 reaction in the 0.7 mg/kg NYHA class III group that resolved without clinical consequence. This group was expanded to six patients per study protocol. No additional treatment-related adverse events higher than grade 1 were reported, and no further dose escalation was undertaken, Dr. Gillmore reported.

There were no clinically relevant laboratory findings; one patient had a transient grade 1 liver enzyme elevation.

One disadvantage of CRISPR is the potential for off-target effects, but Dr. Gillmore said in an interview that the drug developers went through a “very rigorous process when selecting the guide RNA, which is what really targets the specificity of the TTR gene.”

“That’s a really, really important point,” he said. “When they did various studies using, for example, primary human hepatocytes, they found no evidence of off-target editing at concentrations of NTLA-2001 threefold greater than the EC90, the concentration at which one knocks down the protein by 90%. So, what we can say at the moment, is the specificity of NTLA-2001 for the TTR gene seems to be absolute.”

In terms of other challenges going forward, Dr. Gillmore added, “I think that it’s really to see whether the knockdown that is being achieved is going to translate into greater clinical benefit.”

Invited discussant Kevin M. Alexander, MD, of Stanford (Calif.) University, said therapies that stabilize or reduce TTR have recently emerged that have improved ATTR amyloidosis outcomes, including tafamidis and patisiran.

Nevertheless, there has been an unmet need to develop therapies that can halt or reverse disease, are effective in advanced ATTR, and have an improved route or frequency of administration, given that this is a chronic disease, he said.

Dr. Alexander noted that the reductions of greater than 90% were achieved with higher doses than used in the polyneuropathy arm reported last year but were well tolerated in patients that for the most part had wild-type ATTR (83%) and reflect the wild-type ATTR population in practice. “The data support consideration for subsequent efficacy trials for this compound.”

Unanswered questions in ongoing ATTR trials are whether TTR reductions translate into improved clinical outcomes, the long-term safety of TTR lowering, and the efficacy of NTLA-2001, particularly in higher-risk patients, such as those in NYHA class III and those with hereditary ATTR, Dr. Alexander said.

During a media briefing earlier in the day, invited discussant Kiran Musunuru, MD, University of Pennsylvania, Philadelphia, pointed out that, in the recent APOLLO-B trial of patisiran, patients with ATTR amyloidosis with cardiomyopathy had an average 87% TTR reduction but need intravenous infusions every 3 weeks for the rest of their lives.

“In contrast, gene editing is a one-and-done proposition,” he said. “You receive a single treatment that turns off the TTR gene permanently and the effects are durable and likely last a lifetime.”

Dr. Musunuru noted that patients who received patisiran also had significantly and substantially better functional capacity and quality of life, compared with those who received placebo. “Based on today’s results, we can expect future clinical trials for gene editing to have the same beneficial effects and possibly a mortality benefit as well.”

Today’s study is also important because it is part of the first wave of putting CRISPR into the body for an array of diseases, he commented.

“TTR gene editing stands out because it’s the very first CRISPR trial to show unequivocal success – you see that with a greater than 90% reduction in TTR,” Dr. Musunuru said. “So, in my view that makes it a milestone for modern medicine.”

Dosing at 55 mg, corresponding to a fixed 0.7 mg/kg dose, is ongoing in the dose-expansion portion of the trial, with enrollment across both arms expected to be completed by the end of 2022, Intellia Therapeutics reported.

The study was funded by Intellia Therapeutics and Regeneron Pharmaceuticals. Dr. Gillmore reports receiving consultancy fees from Alnylam, Ionis, AstraZeneca, Pfizer, Intellia, ATTRalus, and Novo Nordisk and has received grant support from Alnylam Pharmaceuticals. Dr. Alexander reports serving on advisory boards for Almylam and Arbor Biotechnologies; has consulted  for Eidos, Ionis, Novo Nordisk, and Pfizer; and has received grants from AHA, Alnylam, Eidos, and the National Institutes of Health.

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

CHICAGO – The choice of loop diuretic for decongestion in patients hospitalized with heart failure (HF) may make little difference to survival or readmission risk over the next year, at least when deciding between furosemide or torsemide, a randomized trial suggests.

Both drugs are old and widely used, but differences between the two loop diuretics in bioavailability, effects on potassium levels, and other features have led some clinicians to sometimes prefer torsemide. Until now, however, no randomized HF trials have compared the two drugs.

The new findings suggest clinicians can continue starting such patients with HF on either agent, at their discretion, without concern that the choice may compromise outcomes, say researchers from the TRANSFORM-HF trial, which compared furosemide-first and torsemide-first diuretic strategies in a diverse population of patients with HF.

Given that the two strategies were similarly effective for survival and rehospitalization, clinicians caring for patients with HF can focus more on “getting patients on the right dose for their loop diuretic, and prioritizing those therapies proven to improve clinical outcomes,” said Robert J. Mentz, MD, of Duke University Clinical Research Institute, Durham, N.C.

Dr. Mentz, a TRANSFORM-HF principal investigator, presented the primary results November 5 at the American Heart Association scientific sessions.

The trial had randomly assigned 2,859 patients hospitalized with HF and with a plan for oral loop diuretic therapy to initiate treatment with furosemide or torsemide. Clinicians were encouraged to maintain patients on the assigned diuretic, but crossovers to the other drug or other diuretic changes were allowed.

Rates of death from any cause, the primary endpoint, were about 26% in both groups over a median 17-month follow-up, regardless of ejection fraction (EF).

The composite rates of all-cause death or hospitalization at 12 months were also not significantly different, about 49% for those started on furosemide and about 47% for patients initially prescribed torsemide.

As a pragmatic comparative effectiveness trial, TRANSFORM-HF entered diverse patients with HF, broadly representative of actual clinical practice, who were managed according to routine practice and a streamlined study protocol at more than 60 U.S. centers, Dr. Mentz observed.

One of the pragmatic design’s advantages, he told this news organization, was “how efficient it was” as a randomized comparison of treatment strategies for clinical outcomes. It was “relatively low cost” and recruited patients quickly, compared with conventional randomized trials, “and we answered the question clearly.” The trial’s results, Dr. Mentz said, reflect “what happens in the real world.”

When might torsemide have the edge?

Although furosemide is the most commonly used loop diuretic in HF, and there are others besides it and torsemide, the latter has both known and theoretical advantages that set it apart. Torsemide is more than twice as potent as furosemide and more bioavailable, and its treatment effect lasts longer, the TRANSFORM-HF investigators have noted.

In addition, preclinical and small clinical studies suggest torsemide may have pleiotropic effects that might be theoretical advantages for patients with HF. For example, it appears to downregulate the renin-angiotensin-aldosterone system (RAAS) and reduce myocardial fibrosis and promote reverse ventricular remodeling, the group writes.

In practice, therefore, torsemide may be preferred in patients with furosemide resistance or “challenges with bioavailability, especially those with very advanced heart failure with congestion who may have gut edema, where oral furosemide and other loop diuretics are not effectively absorbed,” Biykem Bozkurt, MD, PhD, Baylor College of Medicine, Houston, told this news organization.  

In such patients, she said, torsemide “is considered to be a better choice  for individuals who have diuretic resistance with advanced congestion.”

The drug’s apparent pleiotropic effects, such as RAAS inhibition, may have less relevance to the TRANSFORM-HF primary endpoint of all-cause mortality than to clinical outcomes more likely associated with successful decongestion, such as HF hospitalization, Dr. Bozkurt proposed.

The trial’s pragmatic design, however, made it more feasible to focus on all-cause mortality and less practical to use measures of successful decongestion, such as volume loss or reduction in natriuretic peptide levels, she observed. Those are endpoints of special interest when diuretics are compared, “especially for the subgroup of patients who are diuretic resistant.”

Over the last 20 years or so, “we’ve learned that hospitalized heart failure is a very different disease process with a different natural history,” observed Clyde W. Yancy, MD, MSc, Northwestern University, Chicago, who was not part of the current study.

“So, the idea that something as nuanced as choice of one loop diuretic over the other, in that setting, would be sufficient to change the natural history, may be still a high bar for us,” he said in an interview.

“Based on these data, one would have to argue that whichever loop diuretic you select for the hospitalized patient – and a lot of that is driven by market exigencies right now – it turns out that the response is indistinguishable,” Dr. Yancy said. “That means  if your hospital happens to have furosemide on the formulary, use it. If furosemide is not available but torsemide is available, use it.”

Dr. Yancy said he’d like to see a trial similar to TRANSFORM-HF but in outpatients receiving today’s guideline-directed medical therapy, which includes the sodium-glucose cotransporter 2 (SGLT2) inhibitors, drugs that increase the fractional excretion of sodium and have a “diureticlike” effect.

Such a trial, he said, would explore “the combination of not one, or two, but three agents with a diuretic effect – a loop diuretic, a mineralocorticoid antagonist, and an SGLT2 inhibitor – in ambulatory, optimized patients. It might make a difference.”

HF regardless of EF

The trial enrolled patients hospitalized with worsening or new-onset HF with a plan for long-term loop diuretic therapy who had either an EF of 40% or lower or, regardless of EF, elevated natriuretic peptide levels when hospitalized.

Of the 2,859 participants, whose mean age was about 65 years, about 36% were women and 34% African American. Overall, 1,428 were assigned to receive furosemide as their initial oral diuretic and 1,431 patients were assigned to the torsemide-first strategy.

The rate of death from any cause in both groups was 17 per 100 patient-years at a median of 17.4 months. The hazard ratio for torsemide vs. furosemide was 1.02 (95% confidence interval, 0.89-1.18; P = .77).

The corresponding HR at 12 months for all-cause death or hospitalization was 0.92 (95% CI, 0.83-1.02;  P = .11). The relative risk for any hospitalization was 0.94 (95% CI, 0.84-1.07).

Pragmatic design: Other implications

Dosing was left to clinician discretion in the open-label study, as was whether patients maintained their assigned drug or switched over to the other agent. Indeed, 5.4% of patients crossed over to the other loop diuretic, and 2.8% went off loop diuretics entirely between in-hospital randomization and discharge, Dr. Mentz reported. By day 30, 6.7% had crossed over, and 7% had stopped taking loop diuretics.

The diuretic crossovers and discontinuations, Dr. Mentz said, likely biased the trial’s outcomes, such that the two strategies performed about equally well. Efforts were made, however, to at least partially overcome that limitation.

“We put measures in place to support adherence – sending letters to their primary doctors, giving them a wallet card so they would know which therapy they were on, having conversations about the importance of trying to stay on the randomized therapy,” Dr. Mentz said in an interview. Still, some clinicians saw differences between the two agents that prompted them, at some point, to switch patients from one loop diuretic to the other.

But interestingly, Dr. Mentz reported, the two strategies did not significantly differ in all-cause mortality or the composite of all-cause mortality or hospitalization in analysis by intention to treat.

Dr. Mentz discloses receiving honoraria from AstraZeneca, Bayer/Merck, Boehringer Ingelheim/Lilly, Cytokinetics, Pharmacosmos, Respicardia, Windtree Therapeutics, and Zoll; and research grants from American Regent and Novartis. Dr. Bozkurt discloses receiving honoraria from AstraZeneca, Baxter Health Care, and Sanofi Aventis and having other relationships with Renovacor, Respicardia, Abbott Vascular, Liva Nova, Vifor, and Cardurion. Dr. Yancy discloses a modest relationship with Abbott.

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

CHICAGO – The choice of loop diuretic for decongestion in patients hospitalized with heart failure (HF) may make little difference to survival or readmission risk over the next year, at least when deciding between furosemide or torsemide, a randomized trial suggests.

Both drugs are old and widely used, but differences between the two loop diuretics in bioavailability, effects on potassium levels, and other features have led some clinicians to sometimes prefer torsemide. Until now, however, no randomized HF trials have compared the two drugs.

The new findings suggest clinicians can continue starting such patients with HF on either agent, at their discretion, without concern that the choice may compromise outcomes, say researchers from the TRANSFORM-HF trial, which compared furosemide-first and torsemide-first diuretic strategies in a diverse population of patients with HF.

Given that the two strategies were similarly effective for survival and rehospitalization, clinicians caring for patients with HF can focus more on “getting patients on the right dose for their loop diuretic, and prioritizing those therapies proven to improve clinical outcomes,” said Robert J. Mentz, MD, of Duke University Clinical Research Institute, Durham, N.C.

Dr. Mentz, a TRANSFORM-HF principal investigator, presented the primary results November 5 at the American Heart Association scientific sessions.

The trial had randomly assigned 2,859 patients hospitalized with HF and with a plan for oral loop diuretic therapy to initiate treatment with furosemide or torsemide. Clinicians were encouraged to maintain patients on the assigned diuretic, but crossovers to the other drug or other diuretic changes were allowed.

Rates of death from any cause, the primary endpoint, were about 26% in both groups over a median 17-month follow-up, regardless of ejection fraction (EF).

The composite rates of all-cause death or hospitalization at 12 months were also not significantly different, about 49% for those started on furosemide and about 47% for patients initially prescribed torsemide.

As a pragmatic comparative effectiveness trial, TRANSFORM-HF entered diverse patients with HF, broadly representative of actual clinical practice, who were managed according to routine practice and a streamlined study protocol at more than 60 U.S. centers, Dr. Mentz observed.

One of the pragmatic design’s advantages, he told this news organization, was “how efficient it was” as a randomized comparison of treatment strategies for clinical outcomes. It was “relatively low cost” and recruited patients quickly, compared with conventional randomized trials, “and we answered the question clearly.” The trial’s results, Dr. Mentz said, reflect “what happens in the real world.”

When might torsemide have the edge?

Although furosemide is the most commonly used loop diuretic in HF, and there are others besides it and torsemide, the latter has both known and theoretical advantages that set it apart. Torsemide is more than twice as potent as furosemide and more bioavailable, and its treatment effect lasts longer, the TRANSFORM-HF investigators have noted.

In addition, preclinical and small clinical studies suggest torsemide may have pleiotropic effects that might be theoretical advantages for patients with HF. For example, it appears to downregulate the renin-angiotensin-aldosterone system (RAAS) and reduce myocardial fibrosis and promote reverse ventricular remodeling, the group writes.

In practice, therefore, torsemide may be preferred in patients with furosemide resistance or “challenges with bioavailability, especially those with very advanced heart failure with congestion who may have gut edema, where oral furosemide and other loop diuretics are not effectively absorbed,” Biykem Bozkurt, MD, PhD, Baylor College of Medicine, Houston, told this news organization.  

In such patients, she said, torsemide “is considered to be a better choice  for individuals who have diuretic resistance with advanced congestion.”

The drug’s apparent pleiotropic effects, such as RAAS inhibition, may have less relevance to the TRANSFORM-HF primary endpoint of all-cause mortality than to clinical outcomes more likely associated with successful decongestion, such as HF hospitalization, Dr. Bozkurt proposed.

The trial’s pragmatic design, however, made it more feasible to focus on all-cause mortality and less practical to use measures of successful decongestion, such as volume loss or reduction in natriuretic peptide levels, she observed. Those are endpoints of special interest when diuretics are compared, “especially for the subgroup of patients who are diuretic resistant.”

Over the last 20 years or so, “we’ve learned that hospitalized heart failure is a very different disease process with a different natural history,” observed Clyde W. Yancy, MD, MSc, Northwestern University, Chicago, who was not part of the current study.

“So, the idea that something as nuanced as choice of one loop diuretic over the other, in that setting, would be sufficient to change the natural history, may be still a high bar for us,” he said in an interview.

“Based on these data, one would have to argue that whichever loop diuretic you select for the hospitalized patient – and a lot of that is driven by market exigencies right now – it turns out that the response is indistinguishable,” Dr. Yancy said. “That means  if your hospital happens to have furosemide on the formulary, use it. If furosemide is not available but torsemide is available, use it.”

Dr. Yancy said he’d like to see a trial similar to TRANSFORM-HF but in outpatients receiving today’s guideline-directed medical therapy, which includes the sodium-glucose cotransporter 2 (SGLT2) inhibitors, drugs that increase the fractional excretion of sodium and have a “diureticlike” effect.

Such a trial, he said, would explore “the combination of not one, or two, but three agents with a diuretic effect – a loop diuretic, a mineralocorticoid antagonist, and an SGLT2 inhibitor – in ambulatory, optimized patients. It might make a difference.”

HF regardless of EF

The trial enrolled patients hospitalized with worsening or new-onset HF with a plan for long-term loop diuretic therapy who had either an EF of 40% or lower or, regardless of EF, elevated natriuretic peptide levels when hospitalized.

Of the 2,859 participants, whose mean age was about 65 years, about 36% were women and 34% African American. Overall, 1,428 were assigned to receive furosemide as their initial oral diuretic and 1,431 patients were assigned to the torsemide-first strategy.

The rate of death from any cause in both groups was 17 per 100 patient-years at a median of 17.4 months. The hazard ratio for torsemide vs. furosemide was 1.02 (95% confidence interval, 0.89-1.18; P = .77).

The corresponding HR at 12 months for all-cause death or hospitalization was 0.92 (95% CI, 0.83-1.02;  P = .11). The relative risk for any hospitalization was 0.94 (95% CI, 0.84-1.07).

Pragmatic design: Other implications

Dosing was left to clinician discretion in the open-label study, as was whether patients maintained their assigned drug or switched over to the other agent. Indeed, 5.4% of patients crossed over to the other loop diuretic, and 2.8% went off loop diuretics entirely between in-hospital randomization and discharge, Dr. Mentz reported. By day 30, 6.7% had crossed over, and 7% had stopped taking loop diuretics.

The diuretic crossovers and discontinuations, Dr. Mentz said, likely biased the trial’s outcomes, such that the two strategies performed about equally well. Efforts were made, however, to at least partially overcome that limitation.

“We put measures in place to support adherence – sending letters to their primary doctors, giving them a wallet card so they would know which therapy they were on, having conversations about the importance of trying to stay on the randomized therapy,” Dr. Mentz said in an interview. Still, some clinicians saw differences between the two agents that prompted them, at some point, to switch patients from one loop diuretic to the other.

But interestingly, Dr. Mentz reported, the two strategies did not significantly differ in all-cause mortality or the composite of all-cause mortality or hospitalization in analysis by intention to treat.

Dr. Mentz discloses receiving honoraria from AstraZeneca, Bayer/Merck, Boehringer Ingelheim/Lilly, Cytokinetics, Pharmacosmos, Respicardia, Windtree Therapeutics, and Zoll; and research grants from American Regent and Novartis. Dr. Bozkurt discloses receiving honoraria from AstraZeneca, Baxter Health Care, and Sanofi Aventis and having other relationships with Renovacor, Respicardia, Abbott Vascular, Liva Nova, Vifor, and Cardurion. Dr. Yancy discloses a modest relationship with Abbott.

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

CHICAGO – The choice of loop diuretic for decongestion in patients hospitalized with heart failure (HF) may make little difference to survival or readmission risk over the next year, at least when deciding between furosemide or torsemide, a randomized trial suggests.

Both drugs are old and widely used, but differences between the two loop diuretics in bioavailability, effects on potassium levels, and other features have led some clinicians to sometimes prefer torsemide. Until now, however, no randomized HF trials have compared the two drugs.

The new findings suggest clinicians can continue starting such patients with HF on either agent, at their discretion, without concern that the choice may compromise outcomes, say researchers from the TRANSFORM-HF trial, which compared furosemide-first and torsemide-first diuretic strategies in a diverse population of patients with HF.

Given that the two strategies were similarly effective for survival and rehospitalization, clinicians caring for patients with HF can focus more on “getting patients on the right dose for their loop diuretic, and prioritizing those therapies proven to improve clinical outcomes,” said Robert J. Mentz, MD, of Duke University Clinical Research Institute, Durham, N.C.

Dr. Mentz, a TRANSFORM-HF principal investigator, presented the primary results November 5 at the American Heart Association scientific sessions.

The trial had randomly assigned 2,859 patients hospitalized with HF and with a plan for oral loop diuretic therapy to initiate treatment with furosemide or torsemide. Clinicians were encouraged to maintain patients on the assigned diuretic, but crossovers to the other drug or other diuretic changes were allowed.

Rates of death from any cause, the primary endpoint, were about 26% in both groups over a median 17-month follow-up, regardless of ejection fraction (EF).

The composite rates of all-cause death or hospitalization at 12 months were also not significantly different, about 49% for those started on furosemide and about 47% for patients initially prescribed torsemide.

As a pragmatic comparative effectiveness trial, TRANSFORM-HF entered diverse patients with HF, broadly representative of actual clinical practice, who were managed according to routine practice and a streamlined study protocol at more than 60 U.S. centers, Dr. Mentz observed.

One of the pragmatic design’s advantages, he told this news organization, was “how efficient it was” as a randomized comparison of treatment strategies for clinical outcomes. It was “relatively low cost” and recruited patients quickly, compared with conventional randomized trials, “and we answered the question clearly.” The trial’s results, Dr. Mentz said, reflect “what happens in the real world.”

When might torsemide have the edge?

Although furosemide is the most commonly used loop diuretic in HF, and there are others besides it and torsemide, the latter has both known and theoretical advantages that set it apart. Torsemide is more than twice as potent as furosemide and more bioavailable, and its treatment effect lasts longer, the TRANSFORM-HF investigators have noted.

In addition, preclinical and small clinical studies suggest torsemide may have pleiotropic effects that might be theoretical advantages for patients with HF. For example, it appears to downregulate the renin-angiotensin-aldosterone system (RAAS) and reduce myocardial fibrosis and promote reverse ventricular remodeling, the group writes.

In practice, therefore, torsemide may be preferred in patients with furosemide resistance or “challenges with bioavailability, especially those with very advanced heart failure with congestion who may have gut edema, where oral furosemide and other loop diuretics are not effectively absorbed,” Biykem Bozkurt, MD, PhD, Baylor College of Medicine, Houston, told this news organization.  

In such patients, she said, torsemide “is considered to be a better choice  for individuals who have diuretic resistance with advanced congestion.”

The drug’s apparent pleiotropic effects, such as RAAS inhibition, may have less relevance to the TRANSFORM-HF primary endpoint of all-cause mortality than to clinical outcomes more likely associated with successful decongestion, such as HF hospitalization, Dr. Bozkurt proposed.

The trial’s pragmatic design, however, made it more feasible to focus on all-cause mortality and less practical to use measures of successful decongestion, such as volume loss or reduction in natriuretic peptide levels, she observed. Those are endpoints of special interest when diuretics are compared, “especially for the subgroup of patients who are diuretic resistant.”

Over the last 20 years or so, “we’ve learned that hospitalized heart failure is a very different disease process with a different natural history,” observed Clyde W. Yancy, MD, MSc, Northwestern University, Chicago, who was not part of the current study.

“So, the idea that something as nuanced as choice of one loop diuretic over the other, in that setting, would be sufficient to change the natural history, may be still a high bar for us,” he said in an interview.

“Based on these data, one would have to argue that whichever loop diuretic you select for the hospitalized patient – and a lot of that is driven by market exigencies right now – it turns out that the response is indistinguishable,” Dr. Yancy said. “That means  if your hospital happens to have furosemide on the formulary, use it. If furosemide is not available but torsemide is available, use it.”

Dr. Yancy said he’d like to see a trial similar to TRANSFORM-HF but in outpatients receiving today’s guideline-directed medical therapy, which includes the sodium-glucose cotransporter 2 (SGLT2) inhibitors, drugs that increase the fractional excretion of sodium and have a “diureticlike” effect.

Such a trial, he said, would explore “the combination of not one, or two, but three agents with a diuretic effect – a loop diuretic, a mineralocorticoid antagonist, and an SGLT2 inhibitor – in ambulatory, optimized patients. It might make a difference.”

HF regardless of EF

The trial enrolled patients hospitalized with worsening or new-onset HF with a plan for long-term loop diuretic therapy who had either an EF of 40% or lower or, regardless of EF, elevated natriuretic peptide levels when hospitalized.

Of the 2,859 participants, whose mean age was about 65 years, about 36% were women and 34% African American. Overall, 1,428 were assigned to receive furosemide as their initial oral diuretic and 1,431 patients were assigned to the torsemide-first strategy.

The rate of death from any cause in both groups was 17 per 100 patient-years at a median of 17.4 months. The hazard ratio for torsemide vs. furosemide was 1.02 (95% confidence interval, 0.89-1.18; P = .77).

The corresponding HR at 12 months for all-cause death or hospitalization was 0.92 (95% CI, 0.83-1.02;  P = .11). The relative risk for any hospitalization was 0.94 (95% CI, 0.84-1.07).

Pragmatic design: Other implications

Dosing was left to clinician discretion in the open-label study, as was whether patients maintained their assigned drug or switched over to the other agent. Indeed, 5.4% of patients crossed over to the other loop diuretic, and 2.8% went off loop diuretics entirely between in-hospital randomization and discharge, Dr. Mentz reported. By day 30, 6.7% had crossed over, and 7% had stopped taking loop diuretics.

The diuretic crossovers and discontinuations, Dr. Mentz said, likely biased the trial’s outcomes, such that the two strategies performed about equally well. Efforts were made, however, to at least partially overcome that limitation.

“We put measures in place to support adherence – sending letters to their primary doctors, giving them a wallet card so they would know which therapy they were on, having conversations about the importance of trying to stay on the randomized therapy,” Dr. Mentz said in an interview. Still, some clinicians saw differences between the two agents that prompted them, at some point, to switch patients from one loop diuretic to the other.

But interestingly, Dr. Mentz reported, the two strategies did not significantly differ in all-cause mortality or the composite of all-cause mortality or hospitalization in analysis by intention to treat.

Dr. Mentz discloses receiving honoraria from AstraZeneca, Bayer/Merck, Boehringer Ingelheim/Lilly, Cytokinetics, Pharmacosmos, Respicardia, Windtree Therapeutics, and Zoll; and research grants from American Regent and Novartis. Dr. Bozkurt discloses receiving honoraria from AstraZeneca, Baxter Health Care, and Sanofi Aventis and having other relationships with Renovacor, Respicardia, Abbott Vascular, Liva Nova, Vifor, and Cardurion. Dr. Yancy discloses a modest relationship with Abbott.

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